Supplement Ii to the Japanese Pharmacopoeia Fifteenth Edition

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SUPPLEMENT II TO THE JAPANESE PHARMACOPOEIA FIFTEENTH EDITION

Official From October 1, 2009

English Version

THE MINISTRY OF HEALTH, LABOUR AND WELFARE

Notice: This English Version of the Japanese Pharmacopoeia is published for the conven- ience of users unfamiliar with the Japanese language. When and if any discrepancy arises between the Japanese original and its English translation, the former is authentic.

The Ministry of Health, Labour and Welfare Ministerial Notification No. 425

Pursuant to Paragraph 1, Article 41 of the Pharmaceutical Affairs Law (Law No. 145, 1960), we hereby revise a part of the Japanese Pharmacopoeia (Ministerial Notification No. 285, 2006) as follows*, and the revised Japanese Pharmacopoeia shall come into effect on October 1, 2009. However, in the case of drugs which are listed in the Japanese Pharmacopoeia (hereinafter referred to as “previous Pharmacopoeia”) [limited to those listed in the Japanese Pharmacopoeia whose standards are changed in accordance with this notification (hereinafter referred to as “new Pharmacopoeia”)] and drugs which have been approved as of October 1, 2009 as prescribed under Paragraph 1, Article 14 of the same law [including drugs the Minister of Health, Labour and Welfare specifies (the Ministry of Health and Welfare Ministerial Notification No. 104, 1994) as those exempted from marketing approval pursuant to Paragraph 1, Article 14 of the Pharmaceu- tical Affairs Law (hereinafter referred to as “drugs exempted from approval”)], the Name and Standards established in the previous Pharmacopoeia (limited to part of the Name and Standards for the drugs concerned) may be accepted to conform to the Name and Standards established in the new Pharmacopoeia before and on March 31, 2011. In the case of drugs which are listed in the new Pharmacopoeia (excluding those listed in the previous Pharmacopoeia) and drugs which have been approved as of October 1, 2009 as prescribed under Paragraph 1, Article 14 of the same law (including those exempted from approval), they may be accepted as those being not listed in the new Pharmacopoeia before and on March 31, 2011.

Akira Nagatsuma The Minister of Health, Labour and Welfare

September 30, 2009

(The text referred to by the term “as follows” are omitted here. All of them are made available for public exhibition at the Evaluation and Licensing Division, Pharmaceuti- cal and Food Safety Bureau, Ministry of Health, Labour and Welfare, at each Regional Bureau of Health and Welfare, and at each Prefectural Office in Japan).

*The term “as follows” here indicates the contents of Supplement II to the Japanese Pharmacopoeia Fifteenth Edition from General Notice to Ultraviolet-visible Reference Spectra (pp. 2041‐2276).

CONTENTS

Preface ...... i Official Monographs ...... 2073 Supplement II to The Japanese Pharmacopoeia, Crude Drugs ...... 2219 Fifteenth Edition...... 2041-2276 General Rules for Crude Drugs ...... 2041 Infrared Reference Spectra ...... 2241-2260 General Tests, Process and Apparatus ...... 2043 1.07 Heavy Metals Limit Test...... 2043 Ultraviolet-visible Reference Spectra ...... 2261-2276 1.08 Nitrogen Determination (Semimicro- Kjeldahl Method)...... 2043 General Information ...... 2277 1.09 Qualitative Tests ...... 2044 8. International Harmonization Implemented in the 2.01 Liquid Chromatography...... 2045 Japanese Pharmacopoeia Fifteenth 2.04 Amino Acid Analysis of Proteins...... 2046 Edition...... 2279 3.01 Determination of Bulk and Tapped 14. Mycoplasma Testing for Cell Substrates used for Densities ...... 2047 the Production of Biotechnological/ 3.02 Specific Surface Area by Gas Adsorp- Biological Products...... 2281 tion...... 2049 32. Near Infrared Spectrometry ...... 2284 3.03 Powder Particle Density Determination.. 2052 34. System Suitability...... 2290 3.04 Particle Size Determination ...... 2053 35. Powder Fineness...... 2291 7.02 Test Methods for Plastic Containers ...... 2057 9.01 Reference Standards ...... 2057 Index ...... 2293 9.41 Reagents, Test Solutions...... 2058 Index in Latin Name...... 2309 9.42 Solid Supports/Column Packings for Index in Japanese ...... 2311 Chromatography ...... 2072

PREFACE

The 15th Edition of the Japanese Pharmacopoeia and medical treatment, clinical results and frequency (JP) was promulgated by Ministerial Notification No. of use, as soon as possible after they reach the market. 285 of the Ministry of Health, Labour and Welfare The target date for the publication of JP 16th Edition (MHLW) on March 31, 2006. (the Japanese edition) was set as April 2011. In July 2006, the Committee on JP established the JP Expert Committees are organized with the fol- basic principles for the preparation of the JP 16th Edi- lowing panels: Panel on the Principles of Revisions; tion, setting out the roles and characteristics of the JP, Sub-committee on the Principles of Revisions; Panel the definite measures for the revision, and the date of on Medicinal Chemicals; Panel on Antibiotics; Panel the revision. on Biologicals; Panel on Crude Drugs; Panel on Phar- At the above Committee, the five basic principles of maceutical Excipients; Panel on Physico-Chemical JP, which we refer to as the “five pillars” were estab- Methods; Panel on Preparations; Panel on Physical lished as follows: 1) Including all drugs which are im- Methods; Panel on Biological Tests; Panel on Nomen- portant from the viewpoint of health care and medical clature; Panel on International Harmonization; Panel treatment; 2) Making qualitative improvement by in- on Pharmaceutical Water; and Panel on Reference troducing the latest science and technology; 3) Pro- Standards. Furthermore, working groups are estab- moting internationalization; 4) Making prompt partial lished under the Panel on Physico-Chemical Methods, revision as necessary and facilitating smooth adminis- Panel on Preparations and Panel on Biological Tests to trative operation; and 5) Ensuring transparency re- expedite discussion of revision drafts of Monographs. garding the revision, and disseminating the JP to the In the Committee on JP, Takao Hayakawa took the public. It was agreed that the Committee on JP should role of chairman from July 2003 to September 2009. make efforts, on the basis of these principles, to ensure In addition to the regular revision every five years in that the JP is used more effectively in the fields of line with the basic principles for the preparation of the health care and medical treatment by taking appropri- JP it was agreed that partial revision should be done as ate measurements, including getting the understanding necessary to take account of recent progress of science and cooperation of other parties concerned. and in the interests of international harmonization. It was agreed that the JP should provide an official In accordance with the above principles, the panels standard, being required to assure the quality of medi- initiated deliberations on selection of articles, and on cines in Japan in response to the progress of science revisions for General Notices, General Rules for Crude and technology and medical demands at the time. It Drugs, General Rules for Preparations, General Tests, should define the standards for specifications, as well Monographs and so on. as the methods of testing to assure overall quality of all Draft revisions covering subjects in General Rules drugs in principle, and it should have a role in clarify- for Crude Drugs, General Tests and Monographs, for ing the criteria for quality assurance of drugs that are which discussions were finished between April 2007 recognized to be essential for public health and medi- and March 2009, were prepared for a supplement to cal treatment. the JP 15. They were examined by the Committee on The JP has been prepared with the aid of the knowl- JP in April 2009, followed by the Pharmaceutical Af- edge and experience of many professionals in the fairs and Food Sanitation Council (PAFSC) in June pharmaceutical field. Therefore, the JP should have the 2009, and then submitted to the Minister of MHLW. characteristics of an official standard, which might be Numbers of discussions in the panels to prepare the widely used by all parties concerned. It should provide supplement drafts were as follows: Panel on Principles information and understanding about the quality of of Revisions (3); Panel on Medicinal Chemicals (23); drugs to the public, and it should be conducive to Panel on Antibiotics (8); Panel on Biologicals (8); smooth and effective regulatory control of the quality Panel on Crude Drugs (21); Panel on Pharmaceutical of drugs, as well as promoting and maintaining inter- Excipients (10): Panel on Physico-Chemical Methods national consistency and harmonization of technical (11, including the working groups); Panel on Prepara- requirements. tions (19, including the working groups); Panel on It was also agreed that JP articles should cover drugs, Physico-Chemical Methods (9): Panel on Biological which are important from the viewpoint of health care Tests (9); Panel on Nomenclature (6); Panel on Inter- i ii Preface Supplement II, JP XV national Harmonization (3); and Panel on Pharmaceu- (16) Loss on drying or ignition, or water tical Water (8). (17) Residue on ignition, total ash or acid-insoluble It should be noted that in the preparation of the ash drafts for the supplement, generous cooperation was (18) Tests being required for pharmaceutical prepa- given by the Technical Committee of the Pharmaceu- rations and other special tests tical Manufacturer’s Association of Osaka and of To- (19) Isomer ratio kyo, the Tokyo Crude Drugs Association, the Japan (20) Assay or the content of the ingredient(s) Pharmaceutical Excipients Council, the Home Medi- (21) Containers and storage cine Association of Japan, the Japan Kampo Medicine (22) Expiration date Manufacturers’ Association, the Japan Flavor and Fra- (23) Others grance Materials Association, the Japan Medical Plants Federation, the Japan Parental Drug Association, the 4. In each monograph, the following physical and Japan Reagent Association, the Japan Oilseeds Proc- chemical values representing the properties and quality essors Association, and the Association of Membrane of the drug are given in the order indicated below, ex- Separation Technology of Japan. cept that unnecessary items are omitted depending on In consequence of this revision, the JP 15th Edition the nature of the drug: carries 1673 articles, owing to the addition of 106 arti- (1) Alcohol number cles and the deletion of 1 article. (2) Absorbance (3) Congealing point The principles of description and the salient points (4) Refractive index of the revision in this Supplement are as follows: (5) Osmolarity 1. The Supplement II to JP 15th Edition comprises (6) Optical rotation the following items, in order: Notification of MHLW; (7) Viscosity Contents; Preface; General Rules for Crude Drugs; (8) pH General Tests, Official Monographs; Infrared Refer- (9) Specific gravity ence Spectra; and Ultraviolet-visible Reference Spec- (10) Boiling point tra; then followed by General Information; and as an (11) Melting point appendix a Cumulative Index containing references to (12) Acid value the main volume and the Supplements I and II. (13) Saponification value (14) Ester value 2. The articles in General Rules for Preparations, (15) Hydroxyl value Official Monographs, Infrared Reference Spectra and (16) Iodine value Ultraviolet-visible Reference Spectra are respectively placed in alphabetical order. 5. Identification tests comprise the following items, which are generally put in the order given below: 3. The following items in each monograph are put (1) Coloration reactions in the order shown below, except that unnecessary (2) Precipitation reactions items are omitted depending on the nature of the drug: (3) Decomposition reactions (1) English title (4) Derivatives (2) Commonly used name(s) (5) Infrared and/or ultraviolet-visible absorption (3) Latin title (only for crude drugs) spectrometry (4) Title in Japanese (6) Special reactions (5) Structural formula or empirical formula (7) Cations (6) Molecular formula and molecular mass (8) Anions (7) Chemical name (8) Origin 6. Purity tests comprise the following items, which (9) Limits of the content of the ingredient(s) and/or are generally put in the order given below, except that the unit of potency unnecessary items are omitted depending on the nature (10) Labeling requirements of the drug: (11) Method of preparation (1) Color (12) Description/Description of crude drugs (2) Odor (13) Identification tests (3) Clarity and/or color of solution (14) Specific physical and/or chemical values (4) Acidity or alkalinity (15) Purity tests (5) Acidity

Supplement II, JP XV Preface iii

(6) Alkalinity (2) 1.08 Nitrogen Determination (7) Chloride (Semimicro-Kjeldahl Method) (8) Sulfate (3) 1.09 Qualitative Tests (9) Sulfite (4) 2.01 Liquid Chromatography (10) Nitrate (5) 3.01 Determination of Bulk and Tapped (11) Nitrite Densities (12) Carbonate (6) 3.02 Specific Surface Area by Gas Adsorption (13) Bromide (7) 3.03 Powder Particle Density Determination (14) Iodide (8) 3.04 Particle Size Determination (15) Soluble halide (9) 7.02 Test Methods for Plastic Containers (16) Thiocyanide (17) Selenium 11. The following Reference Standards were (18) Cationic salts newly added: (19) Ammonium Aciclovir (20) Heavy metals Calcitonin (Salmon) (21) Iron Danazol (22) Manganese Diflucortolone Valerate (23) Chromium Doxazosin Mesilate (24) Bismuth Fludrocortisone Acetate (25) Tin Flutamide (26) Aluminum Gefarnate (27) Zinc D-Glucuronolactone (28) Cadmium Indapamide (29) Mercury Ipriflavone (30) Copper Losartan Potassium (31) Lead Pioglitazone Hydrochloride (32) Silver Prazosin Hydrochloride (33) Alkaline earth metals Probucol (34) Arsenic Sevoflurane (35) Foreign matter Simvastatin (36) Related substances Tacrolimus Hydrate (37) Residual solvent Tazobactam (38) Other impurities Teprenone (39) Readily carbonizable substances Tosulfloxacin Tosilate Hydrate Troxipide 7. The following articles were newly added to the General Rules for Crude Drugs: 12. The following Reference Standards were (1) Pogostemon Herb revised: (2) Nutmeg Amlodipine Besilate (3) Quercus Bark Amoxicillin (4) Longan Aril Azathioprine (5) Royal Jelly Cefalexin Cefatrizine Propylene Glycolate 8. The following article was deleted from the Cefixime General Rules for Crude Drugs: Cefroxadine Hydrate (1) Rice Starch Cefteram Pivoxil Mesitylenesulfonate Clomifene Citrate 9. The following item was newly added to the Diethylcarbamazine Citrate General Tests, Processes and Apparatus: Ethenzamide (1) 2.04 Amino Acid Analysis of Proteins Faropenem Sodium 10. The following items of the General Tests, Griseofulvin Processes and Apparatus were revised: Minocycline Hydrochloride (1) 1.07 Heavy Metals Limit Test Pivmecillinam Hydrochloride iv Preface Supplement II, JP XV

Probenecid Doxazosin Mesilate Prochlorperazine Maleate Droxidopa Warfarin Potassium Droxidopa Capsules Doroxidopa Fine Granules 13. English and Latin titles of drugs were based, in Ecabet Sodium Granules principle, on the International Nonproprietary Names Ecabet Sodium Hydrate for Pharmaceutical Substances, and the chemical Emorfazone Tablets names were based on the Rules of the International Fludrocortisone Acetate Union of Pure and Applied Chemistry (IUPAC). Flutamide 14. Molecular formulas of organic compounds Flutoprazepam begin with C and then H, followed by other involved Flutoprazepam Tablets elements in the alphabetical order of the symbols of the Furosemide Injection elements. Gefarnate Gentamicin Sulfate Ophthalmic Solution 15. Structural formula of drug represents, as far as Gliclazide possible, the steric configuration. Heparin Calcium Imidapril Hydrochloride 16. The test procedures in monographs were Imidapril Hydrochloride Tablets written in full, except within the same monograph and Indapamide in the monographs for preparation having a Indapamide Tablets corresponding monograph of their principal material Ipriflavone substances. Ipriflavone Tablets Irsogladine Maleate 17. The following monographs were added: Irsogladine Maleate Fine Granules Acemetacin Capsules Irsogladine Maleate Tablets Acemetacin Tablets Isepamicin Sulfate Injection Aciclovir Ketoconazole L-Alanine Ketoconazole Cream Allopurinol Tablets Ketoconazole Lotion Amiodarone Hydrochloride Ketoconazole Solution Amiodarone Hydrochloride Tablets Levofloxacin Hydrate Amlodipine Besilate Tablets Lincomycin Hydrochloride Injection Amoxicillin Capsules Losartan Potassium Aprindine Hydrochloride L-Lysine Acetate Aprindine Hydrochloride Capsules Meropenem for Injection Argatroban Hydrate Minocycline Hydrochloride Tablets Azelastine Hydrochloride Granules Mosapride Citrate Hydrate Betaxolol Hydrochloride Mosapride Citrate Tablets Cadralazine Pimozide Cadralazine Tablets Pioglitazone Hydrochloride Calcitonin (Salmon) Pivmecillinam Hydrochloride Tablets Cefalexin Capsules Prazosin Hydrochloride Cefalexin for Syrup Prednisolone Sodium Phosphate Cefatrizine Propylene Glycolate for Syrup Probucol Cefixime Capsules Propafenone Hydrochloride Cefroxadine for Syrup Propafenone Hydrochloride Tablets Cefteram Pivoxil Tablets Rebamipide Cinoxacin Rebamipide Tablets Cinoxacin Capsules Sevoflurane Clebopride Malate Simvastatin Danazol Purified Sodium Hyaluronate Dibekacin Sulfate Ophthalmic Solution Sodium Valproate Syrup Diflucortolone Valerate Sodium Valproate Tablets

Supplement II, JP XV Preface v

Streptomycin Sulfate for Injection Erythromycin Enteric-Coated Tablets Sulindac Estradiol Benzoate Injection (Aqueous Suspension) Tacrolimus Hydrate Estriol Injection (Aqueous Suspension) Tazobactam Ethenzamide Teprenone Ethinylestradiol Tiapride Hydrochloride Famotidine Powder Tiapride Hydrochloride Tablets Faropenem Sodium for Syrup Tosufloxacin Tosilate Hydrate Faropenem Sodium Tablets Tosufloxacin Tosilate Tablets Flopropione Troxipide Fosfomycin Sodium for Injection Troxipide Fine Granules Griseofulvin Tablets Troxipide Tablets Heparin Sodium Ubenimex Capsules Human Menopausal Gonadotrophin Ursodeoxycholic Acid Granules Hydralazine Hydrochloride for Injection Ursodeoxycholic Acid Tablets Hydrocortisone Sodium Phosphate Zolpidem Tartrate Hydroxypropylcellulose Goshajinkigan Extract Low Substituted Hydroxypropylcellulose Hachimijiogan Extract Hypromellose Longan Aril Hypromellose Phthalate Nutmeg Indigocarmine Injection Pogostemon Herb Indometacin Suppositories Quercus Bark Isoniazid Injection Royal Jelly Isoniazid Tablets Shimbuto Extract Isosorbide Dinitrate Tables Josamycin Tablets 18. The following monographs were revised: Anhydrous Lactose Dried Aluminum Hydroxide Gel Fine Granules Lactose Hydrate Aminophylline Injection Lidocaine Injection Amoxicillin Hydrate Meglumine Iotalamate Injection Azathioprine Tablets Meglumine Sodium Amidotrizoate Injection Betamethasone Tablets Mepivacaine Hydrochloride Injection Carmellose Methylcellulose Carmellose Calcium Minocycline Hydrochloride for Injection Carmellose Sodium Morphine Hydrochloride Injection Cefaclor Compound Granules Morphine Hydrochloride Tablets Cellacefate Nicomol Tablets Microcrystalline Cellulose Norethisterone Powdered Cellulose Phenobarbital Clindamycin Hydrochloride 10% Phenobarbital Powder Clindamycin Hydrochloride Capsules Phenolsulfonphthalein Injection Clomifene Citrate Tablets Phenytoin Powder Codeine Phosphate Tablets Phenytoin Tablets Corn Starch Pipemidic Acid Hydrate Wood Creosote Potato Starch Croscarmellose Sodium Probenecid Tablets Diethylcarbamazine Citrate Tablets Procainamide Hydrochloride Digoxin Procainamide Hydrochloride Injection Digoxin Injection Procainamide Hydrochloride Tablets Digoxin Tablets Prochlorperazine Maleate Tablets Dimenhydrinate Tablets Progesterone Distigmine Bromide Tablets Progesterone Injection Ephedrine Hydrochloride Tablets Propylthiouracil Tablets Ergometrine Maleate Injection Protamine Sulfate Injection vi Preface Supplement II, JP XV

Rice Starch Those who were engaged in the preparation of Sup- Rokitamycin Tablets plement II to JP 15 are as follows: Sodium Iotalamate Injection Sodium Valproate Mitsuo Aoki Junko Kizu Teicoplanin Nobuo Aoyagi Fumiyo Kusu Testosterone Enanthate Injection Fumiaki Akahori Takao Kunisada Testosterone Propionate Injection Toshiki Asano Hiroyuki Kurita Tolbutamide Tablets Hiroshi Asama Masaaki Kurihara Ursodeoxycholic Acid Kazuhide Ashizawa Haruo Kuriyama Vasopressin Injection Yukio Aso Yukihiro Goda Warfarin Potassium Tablets Teruo Amagasa Hiroyasu Kokubo Wheat Starch Hiroyuki Arai Shigeo Kojima Zinc Sulfate Hydrate Keiko Arimoto Takashi Goto Apricot Kernel Nobukazu Igoshi Masayoshi Kohase Astragalus Root Masao Izaki Katsuko Komatsu Bear Bile Akiko Ishii Toshifumi Konda Bupleurum Root Kenichi Izutsu Kenji Kondo Calumba Shigeru Itai Seizo Kondo Powdered Calumba Takashi Itoh Kenji Saiki Cardamon Yuji Ito Eiji Sakai Cornus Fruit Koichi Inubushi Yoshikazu Sakagami Daiokanzoto Extract Atsuhiro Uetake Tomoaki Sakamoto Eleutherococcus Senticosus Rhizome Yoshimasa Uehara Tsuguo Sasaki Hochuekkito Extract Eriko Uchida Tomoko Sasaki Japanese Valerian Kazuichi Umemoto Hiroshi Sasaki Powdered Japanese Valerian Ryozo Oishi Motoyoshi Satake Kakkonto Extract Tadashi Ouchi Kyoko Sato Lithospermum Root Tsuneo Okubo Yasuo Shimada Longgu Yuko Osumi Kesamitsu Shimizu Nuphar Rhizome Masami Otuka Kyoko Shimura Peach Kernel Atsuyuki Ohtsuki Osamu Shirota Powdered Peach Kernel Sumiaki Oba Mikio Suzuki Perilla Herb Kimiya Okazaki Keiichi Sudo Polygonatum Rhizome Satoshi Okada Hisakazu Sunada Saposhnikovia Root Minoru Okada Michiko Sekiguchi Scopolia Rhizome Haruhiro Okuda Setsuko Sekita Senega Shukichi Ochiai Takashi Sonobe Powdered Senega Kazuhiro Owada Kunihiro Takai Turmeric Kazuaki Kakehi Toshio Takachi Powdered Turmeric Hirohito Katayama Kikuo Takatera Zanthoxylum Fruit Yoshiaki Kato Yoshikazu Takahashi Powdered Zanthoxylum Fruit Noriko Katori Tadahiro Takeda 19. The following monograph was deleted: Takemine Kanai Yoshikazu Tashiro Meglumine Amidotrizoate Injection Urao Kawakami Shinichi Tadaki Nana Kawasaki Toshihiro Tanaka Yoshiaki Kawashima Toyoshige Tanabe Toru Kawanishi Kenichi Tanamoto** Nobuo Kawahara Tsuyoshi Tanimoto Yoshihiko Kawarasaki Hideya Tuge Fumiyuki Kiuchi Masafumi Teshigawara Yuuichi Kikuchi Reiko Teraoka

Keiji Kijima Keijiro Terashita Mitikazu Kitada Susumu Terabayashi

Supplement II, JP XV Preface vii

Yuji Tokunaga Mitsuru Hashida** Midori Makita Masato Yasuhara Kiyoshi Tomioka Rika Hatano Yoshihisa Matsuda Teruhide Yamaguchi Motowo Tomita Ruri Hanajiri Masahiko Marumoto Takeshi Yamazaki

Hiroyuki Tomitsuka Kentaro Hanada Tsuyoshi Miura Toshiyasu Yamada

Masaaki Naotsuka Takao Hayakawa* Eiichi Mikami Keiichi Yamamoto Sinsaku Nakagawa Masahiro Hayashi Takao Mitsuhashi Keiji Yamamoto Hiroaki Nagashige Yoshinori Hayashi Tamaki Miyazaki Tosuke Yamamoto Emi Nakajima Takashi Bamba Naoki Miyata Sumie Yoshioka Tatsumi Nakashima Kenji Higuchi Hiroto Miyamoto Hikaru Yoden Tatsuya Nakano Yukio Hiyama Toshimi Murai Etsuo Yonemochi Hiroshi Nakamura Masashi Hyuga Masashi Muroi Chikako Yomota Masao Nasu Fusayoshi Hirayama Takashi Morita Masaaki Wada Mitsuo Nanaura Kiyoshi Fukuhara Seiki Morimoto Eiji Watanabe Singo Niimi Hiroyuki Fuchino Takehiko Yajima Haruo Watanabe Yutaka Nishihara Kenji Hosoya *: Chairman, the Committee on JP Hiroshi Nishimura Masako Maeda **: Acting Chairman, the Committee on JP

Supplement II to The Japanese Pharmacopoeia Fifteenth Edition

GENERAL RULES FOR CRUDE DRUGS

Change the paragraph 1 to read: Seed, Phellodendron Bark, Picrasma Wood, Pinellia Tuber, Plantago Herb, Plantago Seed, Platycodon Root, Pogostemon 1. Crude drugs in the monographs include medicinal parts Herb, Polygala Root, Polygonatum Rhizome, Polygonum Root, obtained from plants or animals, cell inclusions and secretes Polyporus Sclerotium, Poria Sclerotium, Powdered Acacia, separated from the origins, their extracts, and minerals. General Powdered Agar, Powdered Alisma Rhizome, Powdered Aloe, Rules for Crude Drugs and Crude Drugs Test are applicable to Powdered Amomum Seed, Powdered Atractylodes Lancea Rhi- the following: zome, Powdered Atractylodes Rhizome, Powdered Calumba, Powdered Capsicum, Powdered Cinnamon Bark, Powdered Acacia, Achyranthes Root, Agar, Akebia Stem, Alisma Rhi- Clove, Powdered Cnidium Rhizome, Powdered Coix Seed, zome, Aloe, Alpinia Officinarum Rhizome, Amomum Seed, Powdered Coptis Rhizome, Powdered Corydalis Tuber, Pow- Anemarrhena Rhizome, Angelica Dahurica Root, Apricot Ker- dered Cyperus Rhizome, Powdered Dioscorea Rhizome, Pow- nel, Aralia Rhizome, Areca, Artemisia Capillaris Flower, Asi- dered Fennel, Powdered Gambir, Powdered Gardenia Fruit, asarum Root, Asparagus Tuber, Astragalus Root, Atractylodes Powdered Gentian, Powdered Geranium Herb, Powdered Ginger, Lancea Rhizome, Atractylodes Rhizome, Bear Bile, Bearberry Powdered Ginseng, Powdered Glycyrrhiza, Powdered Ipecac, Leaf, Belladonna Root, Benincasa Seed, Benzoin, Bitter Car- Powdered Japanese Angelica Root, Powdered Japanese Gentian, damon, Bitter Orange Peel, Bupleurum Root, Burdock Fruit, Powdered Japanese Valerian, Powdered Longgu, Powdered Calumba, Capsicum, Cardamon, Cassia Seed, Catalpa Fruit, Magnolia Bark, Powdered Moutan Bark, Powdered Oyster Shell, Chrysanthemum Flower, Cimicifuga Rhizome, Cinnamon Bark, Powdered Panax Japonicus Rhizome, Powdered Peach Kernel, Citrus Unshiu Peel, Clematis Root, Clove, Cnidium Monnieri Powdered Peony Root, Powdered Phellodendron Bark, Pow- Fruit, Cnidium Rhizome, Coix Seed, Condurango, Coptis Rhi- dered Picrasma Wood, Powdered Platycodon Root, Powdered zome, Cornus Fruit, Corydalis Tuber, Crataegus Fruit, Cyperus Polygala Root, Powdered Polypourus Sclerotium, Powderd Po- Rhizome, Digenea, Dioscorea Rhizome, Dolichos Seed, ria Sclerotium, Powdered Processed Aconite Root, Powdered Eleutherococcus Senticosus Rhizome, Ephedra Herb, Epime- Rhubarb, Powdered Rose Fruit, Powdered Scutellaria Root, dium Herb, Eucommia Bark, Evodia Fruit, Fennel, Forsythia Powdered Senega, Powdered Senna Leaf, Powdered Smilax Fruit, Fritillaria Bulb, Gambir, Gardenia Fruit, Gastrodia Tuber, Rhizome, Powdered Sophora Root, Powdered Sweet Hydrangea Gentian, Geranium Herb, Ginger, Ginseng, Glehnia Root, Gly- Leaf, Powdered Swertia Herb, Powdered Tragacanth, Powdered cyrrhiza, Gypsum, Hemp Fruit, Honey, Houttuynia Herb, Im- Turmeric, Powdered Zanthoxylum Fruit, Processed Aconite mature Orange, Imperata Rhizome, Ipecac, Japanese Angelica Root, Processed Ginger, Prunella Spike, Pueraria Root, Quercus Root, Japanese Gentian, Japanese Valerian, Jujube, Jujube Seed, Bark, Red Ginseng, Rehmannia Root, Rhubarb, Rose Fruit, Leonurus Herb, Lilium Bulb, Lindera Root, Lithospermum Root, Rosin, Royal Jelly, Safflower, Saffron, Saposhnikovia Root, Longan Aril, Longgu, Lonicera Leaf and Stem, Loquat Leaf, Sappan Wood, Saussurea Root, Schisandra Fruit, Schizonepeta Lycium Bark, Lycium Fruit, Magnolia Bark, Magnolia Flower, Spike, Scopolia Rhizome, Scutellaria Root, Senega, Senna Leaf, Mallotus Bark, Mentha Herb, Moutan Bark, Mulberry Bark, Sinomenium Stem, Smilax Rhizome, Sophora Root, Sweet Hy- Nelumbo Seed, Notopterygium Rhizome, Nuphar Rhizome, drangea Leaf, Swertia Herb, Turmeric, Toad Venom, Tragacanth, Nutmeg, Nux Vomica, Ophiopogon Tuber, Oriental Bezoar, Tribulus Fruit, Trichosanthes Root, Uncaria Hook, Zanthoxylum Oyster Shell, Panax Japonicus Rhizome, Peach Fruit, Zedoary. Kernel, Peony Root, Perilla Herb, Peucedanum Root, Pharbitis

2041

GENERAL TESTS, PROCESS AND APPARATUS

Change the introduction to read: items under Crude Drugs Test. The number of each test method is a category number given General Tests, Processes and Apparatus includes common individually. The number in blackets (< >) appeared in methods for tests, useful test methods for quality recognition of monograph indicates the number corresponding to the general drugs and other articles related to them. Unless otherwise speci- test method. fied, acid-neutralizing capacity determination of gastrointestinal medicines, alcohol number determination, amino acid analysis of proteins, ammonium determination, arsenic determination, 1.07 Heavy Metals Limit Test atomic absorption spectrophotometry, boiling point determination, chloride determination, conductivity measurement, con- Change (3) Method 3 under the Preparation of gealing point determination, determination of bulk and tapped test solutions and control solutions to read: densities, digestion test, disintegration test, dissolution test, distilling range determination, endpoint determination in titrimetry, (3) Method 3 flame coloration, fluorometry, foreign insoluble matter test for Place an amount of the sample, directed in the monograph, in injetcions, foreign insoluble matter test for ophthalmic solutions, a quartz or porcelain crucible, heat cautiously, gently at first, gas chromatography, heavy metal determination, infrared spec- and then incinerate by ignition between 500ºC and 600ºC. After trophotometry, insoluble particulate matter test for injections, cooling, add 1 mL of aqua regia, evaporate to dryness on a water insoluble particulate matter test for ophthalmic solutions, iron bath, moisten the residue with 3 drops of hydrochloric acid, add determination, liquid chromatography, loss on drying determi- 10 mL of hot water, and warm for 2 minutes. Add 1 drop of nation, loss on ignition determination, microbial assay for anti- phenolphthalein TS, add ammonia TS dropwise until the biotics, melting point determination, methanol determination, solution develops a pale red color, add 2 mL of dilute acetic acid, mineral oil determination, nitrogen determination, nuclear filter if necessary, wash with 10 mL of water, transfer the filtrate magnetic resonance spectroscopy, optical rotation determination, and washings to a Nessler tube, and add water to make 50 mL. osmolarity determination, oxygen flask combustion method, Designate it as the test solution. particle size determination, particle size distribution test for The control solution is prepared as follows: Evaporate 1 mL preparations, pH determination, powder particle density deter- of aqua regia to dryness on a water bath. Hereinafter, proceed as mination, qualitative test, refractive index determination, resid- directed for the test solution, and add the volume of Standard ual solvents test, residue on ignition determination, specific Lead Solution directed in the monograph and water to make 50 gravity and density determination, specific surface area deter- mL. mination, sulfate determination, test for bacterial endotoxins, test for glass containers for injections, test for metal particles in ophthalmic ointments, test for microbial limit, test for microbial 1.08 Nitrogen Determination limit for crude drugs, test for plastic containers, test for pyrogen, (Semimicro-Kjeldahl Method) test for readily carbonizable substances, test for rubber closure for aqueous infusions, test for sterility, test for total organic Change the following to read: carbon, test of extractable volume for injection , thermal analysis, thin-layer chromatography, ultraviolet-visible spectropho- Nitrogen Determination is a method to determine nitrogen in tometry, uniformity of dosage units (test for content uniformity, an organic substance in which the nitrogen is converted into mass variation test), viscosity determination, vitamin A assay, ammonia nitrogen by thermal decomposition of the organic water determination, and X-ray powder diffraction are per- substance with sulfuric acid, and the ammonia liberated by formed as directed in the corresponding articles under the Gen- alkali and trapped by distillation with steam is determined by eral Tests, Processes and Apparatus. The tests for melting point titration. of fats, congealing point of fatty acids, specific gravity, acid value, saponification value, ester value, hydroxyl value, 1. Apparatus unsaponifiable matter and iodine value of fats and fatty oils are Use the apparatus illustrated in Fig. 1.08-1. It is thoroughly performed as directed in the corresponding items under Fats and constructed of hard glass, and ground glass surfaces may be Fatty Oils Test, and sampling, preparation of sample for analysis, used for joints. All rubber parts used in the apparatus should be microscopic examination, purity test, loss on drying, total ash, boiled for 10 to 30 minutes in sodium hydroxide TS and for 30 acid-insoluble ash, extract content, and essential oil content of to 60 minutes in water, and finally washed thoroughly with crude drugs are performed as directed in the corresponding water before use. 2043 2044 General Tests, Process and Apparatus Supplement II, JP XV

Alternatively, apparatus can be used in which some of the Decomposition Accelerators Unless otherwise specified, procedures, such as digestion of organic substances, distillation use 1 g of a powdered mixture of 10 g of potassium sulfate and of the liberated ammonia, and endpoint detection methods in 1 g of cupper (II) sulfate pentahydrate. The composition and titrimetry (e.g., potentiometric titration or titration by amount of the digestion accelerator may be modified if it is colorimeter) are automated. confirmed that the modified one give almost the same results using the sample as those obtained from the conventional catalyst.

4. Procedure Usually, proceed by the following method. Weigh accurately or pipet a quantity of the sample corresponding to 2 to 3 mg of nitrogen (N:14.01), and place in the Kjeldahl flaks A. Add the decomposition accelerator and wash down any adhering sample from the neck of the flask with a small quantity of water. Add 7 mL of sulfuric acid, allowing it to flow down the inside wall of the flask. Then, while shaking the flask, add cautiously 1 mL of hydrogen peroxide (30) drop by drop along the inside wall of the flask. Heat the flask gradually, then heat so strong that the vapor of sulfuric acid is condensed at the neck of the flask, until the solution changes through a blue and clear to a vivid green and clear, and the inside wall of the flask is free from a carbonaceous material. If necessary, add a small quantity of hydrogen peroxide (30) after cooling, and heat again. After cooling, add cautiously 20 mL of water, cool the solution, and connect the flask to the distillation apparatus (Fig 1.08-1) washed beforehand by passing stream through it. To the absorption flask K add 15 mL of boric acid solution (1 in 25), 3 The figures are in mm. drops of bromocresol green-methyl red TS and sufficient water to immerse the lower end of the condenser tube J. Add 30 mL of A: Kjeldahl flask sodium hydroxide solution (2 in 5) through the funnel F, rinse B: Steam generator, containing water, to which 2 to 3 drops of cautiously the funnel with 10 mL of water, lose the clamp sulfuric acid and fragments of boiling tips for preventing attached to the rubber tubing G, then begin the distillation with bumping have been added stream, and continue until the distillate measures 80 to 100 mL. C: Spray trap Remove the absorption flask from the lower end of the D: Water supply funnel condenser tube J, rinsing the end part with a small quantity of E: Steam tube water, and titrate <2.50> the distillate with 0.005 mol/L sulfuric F: Funnel for addition of alkali solution to flask A acid VS until the color of the solution changes from green G: Rubber tubing with a clamp through pale grayish blue to pale grayish red-purple. Perform a H: A small hole having a diameter approximately equal to that blank determination in the same manner, and make any of the delivery tube necessary correction. J: Condenser, the lower end of which is beveled K: Absorption flask Each mL of 0.005 mol/L sulfuric acid VS = 0.1401 mg of N Fig. 1.08-1 If an automated apparatus is used, proceed as directed in the 2. System suitability instrumental procedure. If an automated apparatus is used, it is necessary to confirm periodically the suitability of the apparatus according to the following method: 1.09 Qualitative Tests Weigh accurately about 1.7 g of amidosulfuric acid (standard Change (2) under the Phosphate reagent), previously dried in a desiccator (in vacuum, silica gel) (Orthophosphate) to read: for about 48 hours, dissolve in water to make exactly 200 mL. Pipet 2 mL of this solution, and transfer to an digestion flask. Phosphate (Orthophosphate) When the test is, perform as directed in the instrumental (2) Acidic solutions in dilute nitric acid of phosphates yield manual.: the nitrogen content (%) in amidosulfuric acid should a yellow precipitate with hexaammonium heptamolybdate TS on be determined between 14.2% and 14.6%. warming. The precipitate dissolves upon subsequent addition of sodium hydroxide TS or ammonia TS. 3. Reagents, Test Solutions

Supplement II, JP XV General Tests, Process and Apparatus 2045 2.01 Liquid Chromatography For quantitative purity tests, “Test for required detectability” is usually required, and in order to confirm, in some degree, the Change the Apparatus to read: linearity of response near its specification limit, the range of expected response to the injection of a certain volume of target Apparatus impurity solution at the concentration of its specification limit Basically, the apparatus required for the liquid should be prescribed. For limit test, “Test for required chromatographic procedure consists of a pumping system for detectability” is not required, if the test is performed by the mobile phase, a sample injection port, a column, a detector comparing the response from sample solution with that from and a recorder. A mobile phase component regulator, a standard solution at the concentration of its specification limit. thermostat for the column, a pumping system for reaction “Test for required detectability” is also not required, if it is reagents and a chemical reaction chamber are also used, if confirmed that the impurity can be detected at its specification necessary. The pumping system serves to deliver the mobile limit by the evaluation of “System repeatability” or some other phase and the reagents into the column and connecting tube at a procedure. constant flow rate. The sample injection port is used to deliver a (2) System performance quantity of the sample to the apparatus with high reproducibility. When it is confirmed that the specificity for determining the The column is a tube with a smooth interior, made of inert metal, test ingredient is ensured, it is considered verified that the etc., in which a packing material for liquid chromatography is system used has adequate performance to achieve its intended uniformly packed. A column with a stationary phase chemically use. bound on the inside wall instead of the column packed with the In assay, “System performance” should be defined by the packing material may be used. The detector is used to detect a resolution between the test ingredient and a target substance to property of the samples which is different from that of the be separated (a closely eluting compound is preferable), and mobile phase, and may be an ultraviolet or visible when appropriate, by their order of elution. In purity tests, both spectrophotometer, fluorometric detector, differential the resolution and the order of elution between the test refractometer, electrochemical detector, chemiluminescence ingredient and a target substance to be separated (a closely detector, electric conductivity detector, mass spectrophotometer, eluting compound is preferable) should be prescribed. In etc. The output signal is usually proportional to the addition, if necessary, the symmetry factor of the test ingredient concentration of samples at amounts of less than a few µg. The should be prescribed together with them. However, if there is no recorder is used to record the output signals of the detector. As suitable target substance to be separated, it is acceptable to required, a data processor may be used as the recorder to record define “System performance” using the number of theoretical or output the chromatogram, retention times or amounts of the plates and the symmetry factor of the test ingredient. components. The mobile phase component regulator is used to (3) System repeatability vary the ratio of the mobile phase components in a stepwise or When it is confirmed that the degree of variation (precision) gradient fashion. of the response of the test ingredient is at a level that meets the requirement of “System repeatability”, it is considered verified Change the System Suitability to read: that the system used has adequate performance to achieve its intended use. System Suitability The allowable limit of “System repeatability” is normally System suitability testing is an integral part of test methods defined as the relative standard deviation (RSD) of the response using chromatography, and is used to ensure that the of the test ingredient in replicate injections of standard solution. performance of the chromatographic systems used is as suitable It is acceptable to confirm the repeatability of the system not for the analysis of the drug as was at the time when the only by replicate injections of standard solution before sample verification of the test method was performed using the system. injections, but also by divided injections of standard solution System suitability testing should be carried out at every series of before and after sample injections, or by interspersed injections drug analysis. The test procedures and acceptance criteria of of standard solution among sample injections. system suitability testing must be prescribed in the test method In principle, total number of replicate injections should be 6. of drugs. The results of drug analyses are not acceptable unless However, in the case that a long time is necessary for one the requirements of system suitability have been met. analysis, such as the analysis using the gradient method, or the In system suitability testing of the chromatographic systems, analysis of samples containing late eluting components, it may the evaluation of “System performance” and “System be acceptable to decrease the number of replicate injections by repeatability” is usually required. For quantitative purity tests, adopting new allowable limit of “System repeatability” which the evaluation of “Test for required detectability” may also be can guarantee a level of “System repeatability” equivalent to required. that at 6 replicate injections. The allowable limit of “System repeatability” should be set at (1) Test for required detectability an appropriate level based on the data when suitability of the For purity tests, when it is confirmed that the target impurity method for the evaluation of quality of the drug was verified, is distinctly detected at the concentration of its specification and the precision necessary for the quality test. limit, it is considered verified that the system used has adequate performance to achieve its intended use.

2046 General Tests, Process and Apparatus Supplement II, JP XV

(vi) Method 6: Hydrolysis using hydrochloric acid 2.04 Amino Acid Analysis containing dimethylsulfoxide (vapor phase hydrolysis) of Proteins Cysteine-cystine reduction and alkylation (vii) Method 7: Hydrochloric acid hydrolysis after a vapor Amino acid analysis of proteins refers to the methodology phase pyridylethylation reaction used to determine the amino acid composition or content of (viii) Method 8: Hydrochloric acid hydrolysis after a liquid proteins, peptides, and other pharmaceutical preparations. phase pyridylethylation reaction Amino acid analysis can be used to quantify protein and (ix) Method 9: Hydrochloric acid hydrolysis after a liquid peptides, to determine the identity of proteins or peptides based phase carboxymethylation reaction on their amino acid composition, to support protein and peptide structure analysis, to evaluate fragmentation strategies for Conversion of cysteine-cystine to mixed disulfide peptide mapping, and to detect atypical amino acids that might (x) Method 10: Hydrochloric acid hydrolysis after a be present in a protein or peptide. It is necessary to hydrolyze a reaction with dithiodiglycolic acid or dithiodipropionic acid protein/peptide to its individual amino acid constituents before amino acid analysis. Following protein/peptide hydrolysis, the Conversion of asparagine and glutamine amino acid analysis procedure can be the same as that practiced (xi) Method 11: Hydrochloric acid hydrolysis after reaction for free amino acids in other pharmaceutical preparations. The with bis(1,1-trifuoroacetoxy) iodobenzene amino acid constituents of the test sample are typically A time-course study is often employed to analyze the starting derivatized for analysis. concentration of amino acids that are partially destroyed or slow 1. Hydrolysis of Protein and Peptide to cleave. An acceptable alternative to the time-course study is Acid hydrolysis at 110°C for 24 hours using 6 mol/L to subject an amino acid calibration standard to the same hydrochloric acid containing phenol (Method 1) is the most hydrolysis conditions as the test sample. This technique will common method for hydrolyzing protein and samples. The allow the analyst to account for some residue destruction. result should be analyzed carefully because several amino acids Microwave acid hydrolysis has been used and is rapid but are chemically modified during the acid hydrolysis and thus not requires special equipment as well as special precautions. recovered quantitatively. Tryptophan is destroyed; serine and Complete proteolysis, using a mixture of proteases, has been threonine are partially destroyed; methionine might undergo used but can be complicated, requires the proper controls, and is oxidation; and cysteine is typically recovered as cystine (but typically more applicable to peptides than proteins. cystine recovery is usually poor because of partial destruction or 2. Methodologies of Amino Acid Analysis reduction to cysteine). Peptide bonds involving isoleucine and The amino acid analysis techniques include the postcolumn valine are partially cleaved; and asparagine and glutamine are derivatization for detection (Methods 1 to 2) after the deamidated, resulting in aspartic acid and glutamic acid, separation of the free amino acids by ion-exchange respectively. chromatography and the precolumn derivatization of the free The hydrolysis techniques, Methods 2 to 11, are used to amino acids (Methods 2 to 7) followed by reversed-phase address these concerns. Some of the hydrolysis techniques, HPLC. Methods 4 to 11, may cause modifications of cysteine, methionine, asparagines and glutamine to other amino acids. (i) Method l: Ninhydrin Therefore, the benefits of using a given hydrolysis technique are (ii) Method 2: o-Phthalaldehyde (OPA) weighed against the concerns with the technique and are tested (iii) Method 3: Phenylisothiocyanate (PITC) adequately before employing a method other than acid (iv) Method 4: 6-Aminoquinolyl-N-hydroxysuccinimidyl hydrolysis by Method 1. carbamate (AQC) (v) Method 5: (Dimethylamino)azobenzenesulfonyl (i) Method 1: Hydrolysis using hydrochloric acid chloride (DABS-Cl) containing phenol (liquid phase hydrolysis, vapor phase (vi) Method 6: 9-Fluorenylmethyl chloroformate hydrolysis) (FMOC-Cl) Prevention of tryptophan oxidation (vii) Method 7: 7-Fluoro-4-nitrobenzo-2-oxa-1,3-diazole (ii) Method 2: Mercaptoethanesulfonic acid hydrolysis (NBD-F) (vapor phase hydrolysis) (iii) Method 3: Hydrolysis using hydrochloric acid Among these methods, ion-exchange chromatography with containing thioglycolic acid (vapor phase hydrolysis) postcolumn ninhydrin derivertization is one of the most com- Cysteine-cystine and methionine oxidation mon methods employed for quantitative amino acid analysis. (iv) Method 4: Hydrolysis by Method 1 or Method 2 after The choice of any one technique often depends on the sensitiv- oxidation with performic acid ity required from the assay. Instruments and reagents for these Cysteine-cystine oxidation procedures are available commercially. Furthermore, many (v) Method 5: Hydrolysis using hydrochloric acid modifications of these methodologies exist with different re- containing sodium azide (liquid phase hydrolysis) agent preparations, reaction procedures, chromatographic sys-

Supplement II, JP XV General Tests, Process and Apparatus 2047 tems, etc. Specific parameters may vary according to the exact cent accuracy. Carefully level the powder without compacting, equipment and procedure used. if necessary, and read the unsettled apparent volume (V0) to the nearest graduated unit. Calculate the bulk density in g per mL by

the formula m/V0. Generally, replicate determinations are desirable for the determination of this property. 3.01 Determination of Bulk If the powder density is too low or too high, such that the test and Tapped Densities sample has an untapped apparent volume of either more than 250 mL or less than 150 mL, it is not possible to use 100 g of Change to read: powder sample. Therefore, a different amount of powder has to be selected as test sample, such that its untapped apparent This determination is harmonized with the European volume is 150 mL to 250 mL (apparent volume greater than or Pharmacopoeia and the U.S. Pharmacopeia. The parts of the text equal to 60 per cent of the total volume of the cylinder); the ◆ that are not harmonized are marked with symbols ( ◆). mass of the test sample is specified in the expression of results. ◆Determination of Bulk and Tapped Densities is a method to For test samples having an apparent volume between 50 mL determine the bulk densities of powdered drugs under loose and and 100 mL a 100 mL cylinder readable to 1 mL can be used; tapped packing conditions respectively. Loose packing is the volume of the cylinder is specified in the expression of defined as the state obtained by pouring a powder sample into a results. vessel without any consolidation, and tapped packing is defined as the state obtained when the vessel containing the powder Method 2: Measurement in a Volumeter sample is to be repeatedly dropped a specified distance at a Apparatus (1) constant drop rate until the apparent volume of sample in the The apparatus (Fig. 3.01-1) consists of a top funnel fitted with a 1.0 mm sieve. The funnel is mounted over a baffle box vessel becomes almost constant.◆ containing four glass baffle plates over which the powder slides Bulk density and bounces as it passes. At the bottom of the baffle box is a The bulk density of a powder is the ratio of the mass of an funnel that collects the powder and allows it to pour into a cup untapped powder sample and its volume including the mounted directly below it. The cup may be cylindrical (25.00 ± contribution of the interparticulate void volume. Hence, the bulk 0.05 mL volume with an inside diameter of 30.00 ± 2.00 mm) or density depends on both the density of powder particles and the a square (16.39 ± 2.00 mL volume with inside dimensions of spatial arrangement of particles in the powder bed. The bulk 25.4 ± 0.076 mm). density is expressed in grams per milliliter (g/mL) although the international unit is kilogram per cubic meter (1 g/mL = 1000 1.0 mm sieve kg/m3) because the measurements are made using cylinders. It Powder funnel may also be expressed in grams per cubic centimeter (g/cm3). The bulking properties of a powder are dependent upon the Loading funnel preparation, treatment and storage of the sample, i.e. how it was handled. The particles can be packed to have a range of bulk densities and, moreover, the slightest disturbance of the powder Baffle assembly bed may result in a changed bulk density. Thus, the bulk density of a powder is often very difficult to measure with good Glass baffles Stand reproducibility and, in reporting the results, it is essential to specify how the determination was made. The bulk density of a powder is determined by measuring the Sample receiving cup volume of a known mass of powder sample, that may have been passed through a screen, into a graduated cylinder (Method 1), or by measuring the mass of a known volume of powder that has been passed through a volumeter into a cup (Method 2) or a Fig. 3.01-1 Volumeter measuring vessel (Method 3). Method 1 and Method 3 are favoured. Procedure Allow an excess of powder to flow through the apparatus into Method 1: Measurement in a Graduated Cylinder the sample receiving cup until it overflows, using a minimum of Procedure 25 cm3 of powder with the square cup and 35 cm3 of powder Pass a quantity of powder sufficient to complete the test with the cylindrical cup. Carefully, scrape excess powder from through a sieve with apertures greater than or equal to 1.0 mm, the top of the cup by smoothly moving the edge of the blade of if necessary, to break up agglomerates that may have formed spatula perpendicular to and in contact with the top surface of during storage; this must be done gently to avoid changing the the cup, taking care to keep the spatula perpendicular to prevent nature of the material. Into a dry graduated cylinder of 250 mL packing or removal of powder from the cup. Remove any mate- (readable to 2 mL), gently introduce, without compacting, ap- rial from the side of the cup and determine the mass (m) of the proximately 100 g of the test sample (m) weighed with 0.1 per powder to the nearest 0.1 per cent. Calculate the bulk density in

2048 General Tests, Process and Apparatus Supplement II, JP XV g per mL by the formula m/V0 in which V0 is the volume of the nally 300 ± 15 taps from a height of 14 ± 2 mm. The support for cup and record the average of 3 determinations using 3 different the graduated cylinder, with its holder, has a mass of 450 ± 10 g. powder samples. (1) The apparatus (the Scott Volumeter) conforms to the dimensions in ASTM 329 90.

Method 3: Measurement in a Vessel

Apparatus The apparatus consists of a 100 mL cylindrical vessel of stainless steel with dimensions as specified in Fig. 3.01-2. Graduated cylinder

not less than 200 mm Graduated part 250 mL Cylinder height Total than 335 mm not more support

Anvil This dimension is such that the drop ① meets specifica- Fig. 3.01-2. Measuring vessel (left) and cap (right) tions and that, at the lowest point of the Dimensions in mm cam, the cylinder support is sitting Procedure Cam freely on the upper part of the anvil. Pass a quantity of powder sufficient to complete the test through a 1.0 mm sieve, if necessary, to break up agglomerates that may have formed during storage and allow the obtained Fig. 3.01-3. sample to flow freely into the measuring vessel until it overflows. Carefully scrape the excess powder from the top of Procedure the vessel as described for Method 2. Determine the mass (m0) Proceed as described above for the determination of the bulk of the powder to the nearest 0.1 per cent by subtraction of the volume (V0). previously determined mass of the empty measuring vessel. Secure the cylinder in the holder. Carry out 10, 500 and 1250 Calculate the bulk density (g/mL) by the formula m0/100 and taps on the same powder sample and read the corresponding record the average of 3 determinations using 3 different powder volumes V10, V500 and V1250 to the nearest graduated unit. If the samples. difference between V500 and V1250 is less than 2 mL, V1250 is the tapped volume. If the difference between V and V exceeds Tapped Density 500 1250 2 mL, repeat in increments such as 1250 taps, until the The tapped density is an increased bulk density attained after difference between succeeding measurements is less than 2 mL. mechanically tapping a container containing the powder sample. Fewer taps may be appropriate for some powders, when The tapped density is obtained by mechanically tapping a validated. Calculate the tapped density (g/mL) using the formula graduated measuring cylinder or vessel containing the powder m/V in which V is the final tapped volume. Generally, replicate sample. After observing the initial powder volume or mass, the f f determinations are desirable for the determination of this measuring cylinder or vessel is mechanically tapped, and property. Specify the drop height with the results. volume or mass readings are taken until little further volume or If it is not possible to use a 100 g test sample, use a reduced mass change is observed. The mechanical tapping is achieved amount and a suitable 100 mL graduated cylinder (readable to 1 by raising the cylinder or vessel and allowing it to drop, under mL) weighing 130 ± 16 g and mounted on a holder weighing its own mass, a specified distance by either of 3 methods as 240 ± 12 g. The modified test conditions are specified in the described below. Devices that rotate the cylinder or vessel expression of the results. during tapping may be preferred to minimize any possible separation of the mass during tapping down. Method 2 Procedure Method 1 Proceed as directed under Method 1 except that the Apparatus mechanical tester provides a fixed drop of 3 ± 0.2 mm at a The apparatus (Fig. 3.01-3) consists of the following: nominal rate of 250 taps per minute. – a 250 mL graduated cylinder (readable to 2 mL) with a mass of 220 ± 44 g. Method 3 – a settling apparatus capable of producing, in 1 min, either Procedure nominally 250 ± 15 taps from a height of 3 ± 0.2 mm, or nomi- Proceed as described in the method for measuring the bulk

Supplement II, JP XV General Tests, Process and Apparatus 2049 density using the measuring vessel equipped with the cap shown powder per unit mass) of a pharmaceutical powder sample by in Fig. 3.01-2. The measuring vessel with the cap is lifted 50-60 using gas adsorption method.◆ The specific surface area of a times per minute by the use of a suitable tapped density tester. powder is determined by physical adsorption of a gas on the Carry out 200 taps, remove the cap and carefully scrape excess surface of the solid and by calculating the amount of adsorbate powder from the top of the measuring vessel as described in gas corresponding to a monomolecular layer on the surface. Method 3 for measuring the bulk density. Repeat the procedure Physical adsorption results from relatively weak forces (van der using 400 taps. If the difference between the 2 masses obtained Waals forces) between the adsorbate gas molecules and the ad- after 200 and 400 taps exceeds 2 per cent, carry out a test using sorbent surface of the test powder. The determination is usually 200 additional taps until the difference between succeeding carried out at the temperature of liquid nitrogen The amount of measurements is less than 2 per cent. Calculate the tapped den- gas adsorbed can be measured by a volumetric or continuous sity (g/mL) using the formula mf/100 where mf is the mass of flow procedure. powder in the measuring vessel. Record the average of 3 determinations using 3 different powder samples. 1.1 MULTI-POINT MEASUREMENT When the gas is physically adsorbed by the powder sample, Measures of Powder Compressibility the following relationship (Brunauer, Emmett and Teller (BET)

Because the interparticulate interactions influencing the adsorption isotherm) holds when the relative pressure (P/P0) is bulking properties of a powder are also the interactions that in the range of 0.05 to 0.30 for pressure P of the adsorbate gas interfere with powder flow, a comparison of the bulk and tapped in equilibrium for the volume of gas adsorbed, Va. densities can give a measure of the relative importance of these interactions in a given powder. Such a comparison is often used 1/[Va{(P0/P) – 1}] = {(C – 1)/(VmC)} × (P/P0) + 1/(VmC) (1) as an index of the ability of the powder to flow, for example the P: Partial vapour pressure of adsorbate gas in equilibrium Compressibility Index or the Hausner Ratio. with the surface at -195.8ºC (b.p. of liquid nitrogen), in pascals, The Compressibility Index and Hausner Ratio are measures P : Saturated pressure of adsorbate gas, in pascals, of the propensity of a powder to be compressed as described 0 V : Volume of gas adsorbed at standard temperature and above. As such, they are measures of the powder ability to settle a pressure (STP) [0ºC and atmospheric pressure (1.013 × 105 Pa), and they permit an assessment of the relative importance of in milliliters, interparticulate interactions. In a free-flowing powder, such V : Volume of gas adsorbed at STP to produce an apparent interactions are less significant, and the bulk and tapped m monolayer on the sample surface, in milliliters, densities will be closer in value. For poorer flowing materials, C: Dimensionless constant that is related to the enthalpy of there are frequently greater interparticulate interactions, and a adsorption of the adsorbate gas on the powder sample. greater difference between the bulk and tapped densities will be observed. These differences are reflected in the Compressibility A value of Va is measured at each of not less than 3 values of Index and the Hausner Ratio. P/P0. Then the BET value, 1/[Va{(P0/P) – 1}], is plotted against P/P according to equation (1). This plot should yield a straight Compressibility Index: 0 line usually in the approximate relative pressure range 0.05 to 0.3. The data are considered acceptable if the correlation 100 (V0 – Vf)/V0 coefficient, r, of the linear regression is not less than 0.9975; 2 V0: unsettled apparent volume that is, r is not less than 0.995. From the resulting linear plot, Vf: final tapped volume the slope, which is equal to (C – 1)/(VmC), and the intercept,

which is equal to 1/(VmC), are evaluated by linear regression Hauser Ratio: analysis. From these values, Vm is calculated as 1/(slope + intercept), while C is calculated as (slope/intercept) + 1. From V0/Vf the value of Vm so determined, the specific surface area, S, in 2 -1 Depending on the material, the compressibility index can be m g , is calculated by the equation: determined using V10 instead of V0. S = (VmNa) / (m × 22400) (2)

N: Avogadro constant (6.022 × 1023 mol-1), 3.02 Specific Surface Area a: Effective cross-sectional area of one adsorbate molecule, in by Gas Adsorption square metres (0.162 × 10-18 m2 for nitrogen and 0.195 × 10-18 m2 for krypton), Change to read: m: Mass of test powder, in grams, 22400: Volume, in milliliters, occupied by one mole of the This test is harmonized with the European Pharmacopoeia adsorbate gas at STP allowing for minor departures from the and the U.S. Pharmacopoeia. The parts of the text that are not ideal. ◆ harmonized are marked with symbols ( ◆). ◆The specific surface area determination method is a method A minimum of 3 data points is required. Additional measure- to determine specific surface area (the total surface area of ments may be carried out, especially when non-linearity is ob-

2050 General Tests, Process and Apparatus Supplement II, JP XV tained at a P/P0 value close to 0.3. Because non-linearity is of- non-reactive, dry gas, or by applying a desorption-adsorption ten obtained at a P/P0 value below 0.05, values in this region are cycling method. In either case, elevated temperatures are some- not recommended. The test for linearity, the treatment of the times applied to increase the rate at which the contaminants data, and the calculation of the specific surface area of the sam- leave the surface. Caution should be exercised when outgassing ple are described above. powder samples using elevated temperatures to avoid affecting the nature of the surface and the integrity of the sample. 1.2 SINGLE-POINT MEASUREMENT If heating is employed, the recommended temperature and Normally, at least 3 measurements of Va each at different time of outgassing are as low as possible to achieve reproduci- values of P/P0 are required for the determination of specific ble measurement of specific surface area in an acceptable time. surface area by the dynamic flow gas adsorption technique For outgassing sensitive samples, other outgassing methods (Method I) or by volumetric gas adsorption (Method II). How- such as the desorption-adsorption cycling method may be em- ever, under certain circumstances described below, it may be ployed. acceptable to determine the specific surface area of a powder The standard technique is the adsorption of nitrogen at liquid from a single value of Va measured at a single value of P/P0 nitrogen temperature. such as 0.300 (corresponding to 0.300 mole of nitrogen or For powders of low specific surface area (<0.2 m2g-1) the 0.001038 mole fraction of krypton), using the following equa- proportion adsorbed is low. In such cases the use of krypton at tion for calculating Vm: liquid nitrogen temperature is preferred because the low vapor pressure exerted by this gas greatly reduces error. All gases used V = V {1－(P/P )} (3) m a 0 must be free from moisture. The single-point method may be employed directly for a se- Accurately weigh a quantity of the test powder such that the 2 ries of powder samples of a given material for which the mate- total surface of the sample is at least 1 m when the adsorbate is 2 rial constant C is much greater than unity. These circumstances nitrogen and 0.5 m when the adsorbate is krypton. Lower quan- may be verified by comparing values of specific surface area tities of sample may be used after appropriate validation. determined by the single-point method with that determined by Because the amount of gas adsorbed under a given pressure the multiple-point method for the series of powder samples. tends to increase on decreasing the temperature, adsorption Close similarity between the single-point values and multi- measurements are usually made at a low temperature. Meas- ple-point values suggests that 1/C approaches zero. The sin- urement is performed at -195.8ºC, the boiling point of liquid ni- gle-point method may be employed indirectly for a series of trogen. very similar powder samples of a given material for which the Adsorption of gas should be measured either by Method I or material constant C is not infinite but may be assumed to be in- Method II. variant. Under these circumstances, the error associated with the 3.1 Method I: the dynamic flow method single-point method can be reduced or eliminated by using the In the dynamic flow method (see Fig. 3.02-1), the recom- multiple-point method to evaluate C for one of the samples of mended adsorbate gas is dry nitrogen or krypton, while helium the series from the BET plot, from which C is calculated as (1 + is employed as a diluent gas, which is not adsorbed under the slope/intercept). Then V is calculated from the single value of m recommended conditions. A minimum of 3 mixtures of the ap- Va measured at a single value of P/P0 by the equation: propriate adsorbate gas with helium are required within the P/P0 range 0.05 to 0.30. Vm = Va{(P0/P) – 1}[(1/C) + {(C – 1)/C} × (P/P0)] (4) The gas detector-integrator should provide a signal that is ap- 2. SAMPLE PREPARATION proximately proportional to the volume of the gas passing Before the specific surface area of the sample can be deter- through it under defined conditions of temperature and pressure. mined, it is necessary to remove gases and vapors that may have For this purpose, a thermal conductivity detector with an elec- become physically adsorbed onto the surface during storage and tronic integrator is one among various suitable types. A mini- handling. If outgassing is not achieved, the specific surface area mum of 3 data points within the recommended range of 0.05 to may be reduced or may be variable because some parts of sur- 0.30 for P/P0 is to be determined. face area are covered with molecules of the previously adsorbed A known mixture of the gases, usually nitrogen and helium, is gases or vapors. The outgassing conditions are critical for ob- passed through a thermal conductivity cell, through the sample taining the required precision and accuracy of specific surface again through the thermal conductivity cell and then to a re- area measurements on pharmaceuticals because of the sensitiv- cording potentiometer. Immerse the sample cell in liquid nitro- ity of the surface of the materials. The outgassing conditions gen, then the sample adsorbs nitrogen from the mobile phase. must be demonstrated to yield reproducible BET plots, a con- This unbalances the thermal conductivity cell, and a pulse is stant weight of test powder, and no detectable physical or generated on a recorder chart. chemical changes in the test powder. Remove from the coolant; this gives a desorption peak equal The outgassing conditions defined by the temperature, pres- in area and in the opposite direction to the adsorption peak. sure and time should be so chosen that the original surface of Since this is better defined than the adsorption peak, it is the the solid is reproduced as closely as possible. one used for the determination. Outgassing of many substances is often achieved by applying To effect the calibration, inject a known quantity of adsorbate a vacuum, by purging the sample in a flowing stream of a into the system, sufficient to give a peak of similar magnitude to

Supplement II, JP XV General Tests, Process and Apparatus 2051 the desorption peak and obtain the proportion of gas volume per tube, insert the stopper, and weigh it. Calculate the weight of the unit peak area. sample. Attach the sample tube to the volumetric apparatus. Use a nitrogen/helium mixture for a single-point determina- Cautiously evacuate the sample down to the specified pressure tion and several such mixtures or premixing 2 streams of gas for (e.g. between 2 Pa and 10 Pa). Alternately, some instruments a multiple-point determination. Calculation is essentially the operate by evacuating to a defined rate of pressure change (e.g. same as for the volumetric method. less than 13 Pa/30 s) and holding for a defined period of time before commencing the next step. If the principle of operation of the instrument requires the determination of the dead volume in the sample tube, for example, by the admission of a non-adsorbed gas, such as helium, this procedure is carried out at this point, followed by evacuation of the sample. The determination of dead volume may be avoided using difference measurements, that is, by means of reference and sample tubes connected by a differential transducer. Raise a Dewar vessel containing liquid nitrogen at -195.8ºC up to a defined point on the sample cell. Admit a sufficient volume of adsorbate gas to give the lowest desired relative

pressure. Measure the volume adsorbed, Va. For multipoint measurements, repeat the measurement of Va at successively

higher P/P0 values. When nitrogen is used as the adsorbate gas, P/P0 values of 0.10, 0.20, and 0.30 are often suitable. A: Flow control valve B: Differential flow controller C: On-off valve D: Gas inlet E: O ring seals F: Cold trap G: Thermal equilibration tube H: Detector I: Digital display J: Calibrating septum K: Sample cell L: Self seals quick connection M: Short path ballast N: Detector

O: Path selection valve P: Long path ballast A: Vacuum gauge Q: Flow meter B: Nitrogen reservoir R: Outgassing station C: Helium reservoir S: Diffusion baffle D: Vapour pressure manometer T: Vent E: Vacuum air F : To cold traps and vacuum pumps Fig. 3.02-1 Schematic diagram of the dynamic flow method apparatus Fig. 3.02-2 Schematic diagram of the volumetric method apparatus 3.2 Method II: the volumetric method In the volumetric method (see Fig. 3.02-2), the recommended adsorbate gas is nitrogen which is admitted into the evacuated 4. REFERENCE MATERIALS space above the previously outgassed powder sample to give a Periodically verify the functioning of the apparatus using ap- defined equilibrium pressure, P, of the gas. The use of a diluent propriate reference materials of known surface area, such as gas, such as helium, is therefore unnecessary, although helium α-alumina for specific surface area determination, which should may be employed for other purposes, such as to measure the have a specific surface area similar to that of the sample to be dead volume. examined. Since only pure adsorbate gas, instead of a gas mixture, is employed, interfering effects of thermal diffusion are avoided in this method. Admit a small amount of dry nitrogen into the sample tube to prevent contamination of the clean surface, remove the sample

2052 General Tests, Process and Apparatus Supplement II, JP XV

3.03 Powder Particle Density Determination

Change to read:

This test is harmonized with the European Pharmacopoeia A: Valve, 3 and the U.S. Pharmacopoeia. The parts of the test that are not Vr: Expansion volume(cm ) ◆ 3 harmonized are marked with symbols ( ◆). Vc: Cell volume (cm ) ◆ 3 Powder Particle Density Determination is a method to de- Vs: Sample volume (cm ) termine particle density of powdered pharmaceutical drugs or M: Manometer raw materials of drugs◆, and the gas displacement pycnometer is generally used. The gas pycnometric density is determined by measuring the volume occupied by a known mass of powder which is equivalent to the volume of gas displaced by the powder using a gas displacement pycnometer. In gas pycnometric Fig. 3.03-1 Schematic diagram of a gas displacement density measurements, the volume determined excludes the pycnometer volume occupied by open pores; however, it includes the volume occupied by sealed pores or pores inaccessible to the gas. 2. Procedure Usually, helium is used as a test gas due to its high diffusivity The gas pycnometric density measurement is performed at a into small open pores. If gases other than helium are used, dif- temperature between 15ºC and 30ºC and must not vary by more ferent values would be obtained, since the penetration of the gas than 2ºC during the course of measurement. is dependent on the size of the pore as well as the Volatile contaminants in the powder are removed by de- cross-sectional area of the gas. gassing the powder under a constant purge of helium prior to the The measured density is a volume weighted average of the measurement. Occasionally, powders may have to be degassed densities of individual powder particles. It is called the particle under vacuum. Because volatiles may be evolved during the density, distinct from the true density of solid or the bulk density measurement, weighing of the sample is done after the of powder. The density of solids are expressed in grams per cu- pycnometric measurement of volume. 3 bic centimeter (g/cm ), although the international unit is the Weigh the mass of the test cell and record it. After weighing 3 3 kilogram per cubic meter (1 g/cm = 1000 kg/m ). out the amount of the sample as described in the individual monograph and placing it in the test cell, seal the cell in the 1. Apparatus pycnometer. The schematic diagram of particle density apparatus for gas Open the valve (A) which connects the expansion cell with displacement pycnometric measurement is shown in Fig. 3.03-1. the test cell, confirm with the manometer (M) that the pressure The apparatus consists of a test cell in which the sample is inside the system is stable, and then read the system reference placed, an expansion cell and a manometer (M). The test cell, pressure (P ). Secondly, close the valve that connects to the two with an empty cell volume (V ), is connected through a valve r c cells, and introduce the measurement gas into the test cell to (A) to an expansion cell, with a volume (V ). r achieve positive pressure. Confirm with the manometer that the Generally, helium is used as the measurement gas. The appa- pressure inside the system is stable, and then read the initial ratus has to be equipped with a system capable of pressuring the pressure (P ). Open the valve to connect the test cell with the test cell to the defined pressure (P) through the manometer. i expansion cell. After confirming that the indicator of the manometer is stable, read the final pressure (P ), and calculate the Calibration of apparatus The volumes of the test cell (Vc) f sample volume (V ) with the following equation. and the expansion cell (Vr) must be accurately determined to the s nearest 0.001 cm3, and to assure accuracy of the results of vol- V ume obtained, calibration of the apparatus is carried out as fol- V = V – r s c P – P lows using a calibration ball of known volume for particle den- i r – 1 Pf – Pr sity measurement. The final pressures (Pf) are determined for the initial empty test cell followed by the test cell placed with 3 Vr : Expansion volume (cm ) the calibration ball for particle density measurement in accor- 3 Vc : Cell volume (cm ) dance with the procedures, and Vc and Vr are calculated using 3 Vs : Sample volume (cm ) the equation described in the section of Procedure. Calculation Pi : Initial pressure (kPa) can be made taking into account that the sample volume (Vs) is Pf : Final pressure (kPa) zero in the first run. Pr : System reference pressure (kPa)

Repeat the measurement sequence for the same powder sample until consecutive measurements of the sample volume agree

Supplement II, JP XV General Tests, Process and Apparatus 2053 to within 0.2%, and calculate the mean of sample volumes (Vs). size distribution of a single material. It is not intended for de- Finally, unload the test cell, weigh the mass of the test cell, and termination of the proportion of particles passing or retained on calculate the final sample mass (m) by deducting the empty cell one or two sieves. mass from the test cell mass. The powder particle density ρ is Estimate the particle size distribution as described under Dry calculated by the following equation: Sieving Method, unless otherwise specified in the individual monograph. Where difficulty is experienced in reaching the ρ = m/Vs endpoint (i.e., material does not readily pass through the sieves) or when it is necessary to use the finer end of the sieving range ρ: Powder particle density in g/cm3, (below 75 µm), serious consideration should be given to the use m: Final sample mass in g, of an alternative particle-sizing method. V : Sample volume in cm3 s Sieving should be carried out under conditions that do not If the pycnometer differs in operation or construction from cause the test sample to gain or lose moisture. The relative hu- the one shown in Fig. 3.03-1, follow the instructions of the midity of the environment in which the sieving is carried out manufacturer of the pycnometer. The sample conditioning is in- should be controlled to prevent moisture uptake or loss by the dicated with the results. For example, indicate whether the sam- sample. In the absence of evidence to the contrary, analytical ple was tested as is or dried under specific conditions such as test sieving is normally carried at ambient humidity. Any special those described for loss on drying. conditions that apply to a particular material should be detailed in the individual monograph. 3.04 Particle Size Determination Principles of Analytical Sieving—Analytical test sieves are constructed from a woven-wire mesh, which is of simple weave Change the Method 2 to read: that is assumed to give nearly square apertures and is sealed into the base of an open cylindrical container. The basic analytical Method 2. Analytical Sieving Method method involves stacking the sieves on top of one another in ◆The analytical sieving method is a method to estimate the ascending degrees of coarseness, and then placing the test pow- particle size distribution of powdered pharmaceutical drugs by der on the top sieve. sieving. The particle size determined by this method is shown as The nest of sieves is subjected to a standardized period of the size of a minimum sieve opening through which the particle agitation, and then the weight of material retained on each sieve passes. “Powder” here means a gathering of numerous solid is accurately determined. The test gives the weight percentage particles.◆ of powder in each sieve size range. Sieving is one of the oldest methods of classifying powders This sieving process for estimating the particle size distribu- and granules by particle size distribution. When using a woven tion of a single pharmaceutical powder is generally intended for sieve cloth, the sieving will essentially sort the particles by their use where at least 80% of the particles are larger than 75 µm. intermediate size dimension (i.e., breadth or width). Mechanical The size parameter involved in determining particle size distri- sieving is most suitable where the majority of the particles are bution by analytical sieving is the length of the size of the larger than about 75 µm. For smaller particles, the light weight minimum square aperture through which the particle will pass. provides insufficient force during sieving to overcome the surface forces of cohesion and adhesion that cause the particles to TEST SIEVES stick to each other and to the sieve, and thus cause particles that Test sieves suitable for pharmacopoeial tests conform to the would be expected to pass through the sieve to be retained. For most current edition of International Organisation for Stan- such materials other means of agitation such as air-jet sieving or dardization (ISO) Specification ISO 3310-1; Test sonic sifting may be more appropriate. Nevertheless, sieving can sieves—Technical requirements and testing (see Table 3.04-1). sometimes be used for some powders or granules having median Unless otherwise specified in the monograph, use those ISO particle sizes smaller than 75 µm where the method can be vali- sieves listed in the Table 3.04-1 as recommended in the particu- dated. In pharmaceutical terms, sieving is usually the method of lar region. choice for classification of the coarser grades of single powders Sieves are selected to cover the entire range of particle sizes or granules. It is a particularly attractive method in that powders present in the test specimen. A nest of sieves having a 2 pro- and granules are classified only on the basis of particle size, and gression of the area of the sieve openings is recommended. The in most cases the analysis can be carried out in the dry state. nest of sieves is assembled with the coarsest screen at the top Among the limitations of sieving method are the need for an and the finest at the bottom. Use micrometers or millimeters in appreciable amount of sample (normally at least 25 g, depend- denoting test sieve openings. [Note—Mesh numbers are pro- ing on the density of the powder or granule, and the diameter of vided in the table for conversion purposes only.] Test sieves are test sieves) and difficulty in sieving oily or other cohesive pow- made from stainless steel or, less preferably, from brass or other ders or granules that tend to clog the sieve openings. The suitable non-reactive wire. method is essentially a two-dimensional estimate of size be- Calibration and recalibration of test sieves is in accordance 2) cause passage through the sieve aperture is frequently more de- with the most current edition of ISO 3310-1 . Sieves should be pendent on maximum width and thickness than on length. carefully examined for gross distortions and fractures, especially This method is intended for estimation of the total particle at their screen frame joints, before use. Sieves may be calibrated

2054 General Tests, Process and Apparatus Supplement II, JP XV optically to estimate the average opening size, and opening agitation conditions will give different results for the sieve variability, of the sieve mesh. Alternatively, for the evaluation of analysis and endpoint determinations, and may be sufficiently the effective opening of test sieves in the size range of 212 to different to give a failing result under some circumstances. 850 µm, Standard Glass Spheres are available. Unless otherwise Endpoint Determination—The test sieving analysis is com- specified in the individual monograph, perform the sieve analy- plete when the weight on any of the test sieves does not change sis at controlled room temperature and at ambient relative hu- by more than 5% or 0.1 g (10% in the case of 76 mm sieves) of midity. the previous weight on that sieve. If less than 5% of the total Cleaning Test Sieves—Ideally, test sieves should be cleaned specimen weight is present on a given sieve, the endpoint for using only an air jet or a liquid stream. If some apertures remain that sieve is increased to a weight change of not more than 20% blocked by test particles, careful gentle brushing may be used as of the previous weight on that sieve. a last resort. If more than 50% of the total specimen weight is found on Test Specimen—If the test specimen weight is not given in the any one sieve, unless this is indicated in the monograph, the test monograph for a particular material, use a test specimen having should be repeated, but with the addition to the sieve nest of a a weight between 25 and 100 g, depending on the bulk density more coarse sieve intermediate between that carrying the exces- of the material, and test sieves having a 200 mm diameter. For sive weight and the next coarsest sieve in the original nest, i.e., 76 mm sieves the amount of material that can be accommodated addition of the ISO series sieve omitted from the nest of sieves. is approximately 1/7th that which can be accommodated on a 200 mm sieve. Determine the most appropriate weight for a SIEVING METHODS given material by test sieving accurately weighed specimens of Mechanical agitation different weights, such as 25, 50, and 100 g, for the same time Dry Sieving Method—Tare each test sieve to the nearest 0.1 period on a mechanical shaker. [Note—If the test results are g. Place an accurately weighed quantity of test specimen on the similar for the 25-g and 50-g specimens, but the 100-g specimen top (coarsest) sieve, and place the lid. Agitate the nest of sieves shows a lower percentage through the finest sieve, the 100-g for 5 minutes. Then carefully remove each from the nest without specimen size is too large.] Where only a specimen of 10 to 25 g loss of material. Reweigh each sieve, and determine the weight is available, smaller diameter test sieves conforming to the same of material on each sieve. Determine the weight of material in mesh specifications may be substituted, but the endpoint must the collecting pan in a similar manner. Reassemble the nest of be re-determined. The use of test samples having a smaller mass sieves, and agitate for 5 minutes. Remove and weigh each sieve (e.g. down to 5 g) may be needed. For materials with low ap- as previously described. Repeat these steps until the endpoint parent particle density, or for materials mainly comprising parti- criteria are met (see Endpoint Determination under Test Sieves). cles with a highly iso-diametrical shape, specimen weights be- Upon completion of the analysis, reconcile the weights of mate- low 5 g for a 200 mm screen may be necessary to avoid exces- rial. Total losses must not exceed 5% of the weight of the origi- sive blocking of the sieve. During validation of a particular nal test specimen. sieve analysis method, it is expected that the problem of sieve Repeat the analysis with a fresh specimen, but using a single blocking will have been addressed. sieving time equal to that of the combined times used above. If the test material is prone to picking up or losing significant Confirm that this sieving time conforms to the requirements for amounts of water with varying humidity, the test must be carried endpoint determination. When this endpoint had been validated out in an appropriately controlled environment. Similarly, if the for a specific material, then a single fixed time of sieving may test material is known to develop an electrostatic charge, careful be used for future analyses, providing the particle size distribu- observation must be made to ensure that such charging is not in- tion falls within normal variation. fluencing the analysis. An antistatic agent, such as colloidal If there is evidence that the particles retained on any sieve are silicon dioxide and/or aluminum oxide, may be added at a 0.5 aggregates rather than single particles, the use of mechanical dry percent (m/m) level to minimize this effect. If both of the above sieving is unlikely to give good reproducibility, a different par- effects cannot be eliminated, an alternative particle-sizing tech- ticle size analysis method should be used. nique must be selected. Air Entrainment Methods Agitation Methods—Several different sieve and powder agi- Air Jet and Sonic Sifter Sieving—Different types of commer- tation devices are commercially available, all of which may be cial equipment that use a moving air current are available for used to perform sieve analyses. However, the different methods sieving. A system that uses a single sieve at a time is referred to of agitation may give different results for sieve analyses and as air jet sieving. It uses the same general sieving methodology endpoint determinations because of the different types and mag- as that described under the Dry Sieving Method, but with a nitude of the forces acting on the individual particles under test. standardized air jet replacing the normal agitation mechanism. It Methods using mechanical agitation or electromagnetic agita- requires sequential analyses on individual sieves starting with tion, and that can induce either a vertical oscillation or a hori- the finest sieve to obtain a particle size distribution. Air jet zontal circular motion, or tapping or a combination of both tap- sieving often includes the use of finer test sieves than used in ping and horizontal circular motion are available. Entrainment ordinary dry sieving. This technique is more suitable where only of the particles in an air stream may also be used. The results oversize or undersize fractions are needed. must indicate which agitation method was used and the agitation In the sonic sifting method, a nest of sieves is used, and the parameters used (if they can be varied), since changes in the test specimen is carried in a vertically oscillating column of air

Supplement II, JP XV General Tests, Process and Apparatus 2055 that lifts the specimen and then carries it back against the mesh openings at a given number of pulses per minute. It may be necessary to lower the sample amount to 5 g, when sonic sifting is employed. The air jet sieving and sonic sieving methods may be useful for powders or granules when mechanical sieving techniques are incapable of giving a meaningful analysis. These methods are highly dependent upon proper dispersion of the powder in the air current. This requirement may be hard to achieve if the method is used at the lower end of the sieving range (i.e., below 75 µm), when the particles tend to be more cohesive, and especially if there is any tendency for the material to develop an electrostatic charge. For the above reasons endpoint determination is particularly critical, and it is very important to confirm that the oversize material comprises single particles and is not composed of aggregates.

INTERPRETATION The raw data must include the weight of test specimen, the total sieving time, and the precise sieving methodology and the set values for any variable parameters, in addition to the weights retained on the individual sieves and in the pan. It may be con- venient to convert the raw data into a cumulative weight distribution, and if it is desired to express the distribution in terms of a cumulative weight undersize, the range of sieves used should include a sieve through which all the material passes. If there is evidence on any of the test sieves that the material remaining on it is composed of aggregates formed during the sieving process, the analysis is invalid. 1) Additional information on particle size measurement, sample size, and data analysis is available, for example, in ISO 9276. 2) International Organization for Standardization (ISO) Speci- fication ISO 3310-1; Test sieves-Technical requirements and testing

2056 General Tests, Process and Apparatus Supplement II, JP XV

Table 3.04-1. Sizes of Standard Sieve Series in Range of Interest

ISO Nominal Aperture Supplementary US Sieve Recommended European Sieve Japan Principal sizes sizes No. USP Sieves (mi- No. Sieve No. R 20/3 R 20 R 40/3 crons) 11.20 mm 11.20 mm 11.20 mm 11200 10.00 mm 9.50 mm 9.00 mm 8.00 mm 8.00 mm 8.00 mm 7.10 mm 6.70 mm 6.30 mm 5.60 mm 5.60 mm 5.60 mm 5600 3.5 5.00 mm 4.75 mm 4 4.50 mm 4.00 mm 4.00 mm 4.00 mm 5 4000 4000 4.7 3.55 mm 3.35 mm 6 5.5 3.15 mm 2.80 mm 2.80 mm 2.80 mm 7 2800 2800 6.5 2.50 mm 2.36 mm 8 7.5 2.24 mm 2.00 mm 2.00 mm 2.00 mm 10 2000 2000 8.6 1.80 mm 1.70 mm 12 10 1.60 mm 1.40 mm 1.40 mm 1.40 mm 14 1400 1400 12 1.25 mm 1.18 mm 16 14 1.12 mm 1.00 mm 1.00 mm 1.00 mm 18 1000 1000 16 900 µm 850 µm 20 18 800 µm 710 µm 710 µm 710 µm 25 710 710 22 630 µm 600 µm 30 26 560 µm 500 µm 500 µm 500 µm 35 500 500 30 450 µm 425 µm 40 36 400 µm 355 µm 355 µm 355 µm 45 355 355 42 315 µm 300 µm 50 50 280 µm 250 µm 250 µm 250 µm 60 250 250 60 224 µm 212 µm 70 70 200 µm 180 µm 180 µm 180 µm 80 180 180 83 160 µm 150 µm 100 100 140 µm 125 µm 125 µm 125 µm 120 125 125 119 112 µm 106 µm 140 140 100 µm 90 µm 90 µm 90 µm 170 90 90 166 80 µm 75 µm 200 200 71 µm 63 µm 63 µm 63 µm 230 63 63 235 56 µm 53 µm 270 282 50 µm 45 µm 45 µm 45 µm 325 45 45 330 40 µm 38 µm 38 391

Supplement II, JP XV General Tests, Process and Apparatus 2057 7.02 Test Methods for lution is 5 to 7 mm. Plastic Containers 9.01 Reference Standards Change (11) under 2. Polyvinyl chloride containers for aqueous injections to read: Change the following in (1) to read:

2. Polyvinyl chloride containers for aqueous injections *A: Assay (11) Vinyl chloride—Wash a cut piece of a container with D: Dissolution water, wipe thoroughly with a filter paper, subdivide into pieces I: Identification smaller than 5-mm square, and place 1.0 g of them in a 20-mL P: Purity volumetric flask. Add about 10 mL of tetrahydrofuran for gas U: Uniformity of dosage units chromatography, dissolve by occasional shaking in a cold place, add tetrahydrofuran for gas chromatography, previously cooled (1) The reference standards which are prepared by those who in a methanol-dry ice bath, to make 20 mL while cooling in a have been registered to prepare them by the Minister of Health, methanol-dry ice bath, and use this solution as the sample solu- Labour and Welfare, according to the Ministerial ordinance es- tion. Perform the tests as directed under Gas Chromatography tablished by the Minister separately. <2.02> according to the operating conditions 1 and 2, using 10 Reference Standard Intended Use* µL each of the sample solution and Standard Vinyl Chloride So- Amlodipine Besilate I, U, A lution. The peak height of vinyl chloride from the sample solu- Azathioprine I, U, A tion is not more than that from the Standard Vinyl Chloride So- Clomifene Citrate I, U, A lution under at least one of the conditions. Diethylcarbamazine Citrate U, A Operating conditions 1— Ethenzamide I, A Detector: A hydrogen flame-ionization detector. Probenecid I, U, D, A Column: A column about 3 mm in inside diameter and 2 to 3 Prochlorperazine Maleate I, U, D, A m in length, packed with 150 to 180 µm siliceous earth for gas Warfarin Potassium I, U, D, A chromatography coated with 15% to 20% polyalkylene glycol monoether for gas chromatography. Column temperature: A constant temperature of between 60ºC Change the following in (2) to read: and 70ºC. (2) The reference standards which are prepared by National In- Carrier gas: Nitrogen stitute of Infectious Diseases. Flow rate: Adjust the flow rate so that the retention time of vinyl chloride is about 1.5 minutes. Reference Standard Intended Use* Selection of column: Proceed with 10 µL of Standard Vinyl Amoxicillin I, D, A Chloride Solution under the above operating conditions. Use a Cefalexin U, D, A column from which vinyl chloride and ethanol are eluted in that Cefatrizine Propylene Glycolate I, D, A order, with a good resolution between their peaks. Cefixime I, P, U, D, A Detection sensitivity: Adjust the detection sensitivity so that Cefroxadine I, U, D, A the peak height from 10 µL of the Standard Vinyl Chloride So- Cefteram Pivoxil Mesitylene U, D, A lution is 5 to 7 mm. Sulfonate Faropenem Sodium I, P, U, D, A Operating conditions 2— Griseofulvin I, P, U, D, A Detector: A hydrogen flame-ionization detector. Minocycline Hydrochloride I, P, U, D, A Column: A column about 3 mm in inside diameter and about Pivmecillinam Hydrochloride I, P, U, A 1.5 m in length, packed with 150 to 180 µm porous acryloni- trile-divinylbenzene copolymer for gas chromatography (pore size: 0.06-0.08 µm; 100-200 m2/g). Column temperature: A constant temperature of about 120ºC. Carrier gas: Nitrogen Flow rate: Adjust the flow rate so that the retention time of vinyl chloride is about 3 minutes. Selection of column: Proceed with 10 µL of Standard Vinyl Chloride Solution under the above operating conditions. Use a column from which vinyl chloride and ethanol are eluted in that order, with a good resolution between their peaks. Detection sensitivity: Adjust the detection sensitivity so that the peak height from 10 µL of the Standard Vinyl Chloride So-

2058 General Tests, Process and Apparatus Supplement II, JP XV

Add the following to (1): and 245 nm. Purity Related substances—Dissolve 1.0 mg of bergenin for Reference Standard Intended Use* thin-layer chromatography in 1 mL of methanol. Perform the Aciclovir I, A test with 20 µL of this solution as directed in the Identification Calcitonin (Salmon) A under Mallotus Bark: no spot other than the principal spot at the

Danazol I, A Rf value of about 0.5 appears. Diflucortolone Valerate I, A Doxazosin Mesilate I, A (E)-Capsaicin for thin-layer chromatography C18H27NO3 Fludrocortisone Acetate I, A White crystals, having a strong irritative odor. Very soluble in Flutamide I, A methanol, freely soluble in ethanol (95) and in diethyl ether, and Gefarnate I, A practically insoluble in water. D-glucuronolactone A Melting point <2.60>: 65-70ºC. Indapamide I, U, D, A Purity Related substances—Dissolve 20 mg of Ipriflavone I, A (E)-capsaicin for thin-layer chromatography in 2 mL of metha- Losartan Potassium I, A nol, and use this solution as the sample solution. Pipet 1 mL of Pioglitazone Hydrochloride I, A this solution, add methanol to make exactly 100 mL, and use Prazosin Hydrochloride I, A this solution as the standard solution. Perform the test with 10 Probucol I, A µL each of the sample solution and standard solution as directed Sevoflurane I, A in the Identification under Capsicum: any spot other than the Simvastatin I, A principal spot at the Rf value of about 0.5 from the sample solu- Tacrolimus I, A tion is not more intense than the spot from the standard solution. Teprenone I, A Tosufloxacin Tosilate I, U, D, A Add the following: Troxipide I, U, D, A

Acemetacin C21H18ClNO6 [Same as the namesake monograph] Add the following to (2):

Acemetacin for assay C21H18ClNO6 [Same as the mono- Reference Standard Intended Use* graph Acemetacin. When died, it contains no less than 99.5% of Tazobactam I, A acemetacin (C21H18ClNO6) meeting the following additional specifications.] Purity Dissolve 40 mg of acemetacin for assay in 10 mL of 9.41 Reagents, Test Solutions methanol, and use this solution as the sample solution. Pipet 1 mL of this solution, and add methanol to make exactly 10 mL. Change the following to read: Pipet 1 mL of this solution, add methanol to make exactly 20 Benzoylmesaconine hydrochloride for thin-layer chroma- mL, and use this solution as the standard solution. Perform the test with exactly 10 µL each of the sample solution and standard tography C31H43NO10·HCl·xH2O White crystals or crystalline powder. Soluble in water and in ethanol (99.5) and spar- solution as directed under Liquid Chromatography <2.01> ac- ingly soluble in methanol. Melting point: about 250ºC (with cording to the following conditions. Determine each peak area decomposition). of both solutions by the automatic integration method: the area 1% of each peak other than acemetacin is not larger than 1/2 times Absorbance <2.24> E1cm (230 nm): 217 - 231 (5 mg calculated on the anhydrous basis, methanol, 200 mL) the peak area of acemetacin obtained from the standard solution, Purity Related substances—Dissolve 1.0 mg of benzoyl- and the total area of the peaks other than the peak of acemetacin mesaconine hydrochloride for thin-layer chromatography in ex- is not larger than the peak area of acemetacin from the standard actly 1 mL of ethanol (99.5). Perform the test with 5 µL of this solution. solution as directed in the Identification under Processed Aco- Operating conditions Detector, column, column temperature, mobile phase, and nite Root: no spot other than the principal spot at around Rf 0.4 appears. flow rate: Proceed as directed in the operating conditions in the Assay under Acemetacin Tablets.

Bergenin for thin-layer chromatography C14H16O9·xH2O Time span of measurement: About 4 times as long as the re- White crystals or crystalline powder. Slightly soluble in ethanol tention time of Acemetacin. (99.5), very slightly soluble in water, and practically insoluble in System Suitability diethyl ether. Test for required detectability: Pipet 1 mL of the standard so- Identification Determine the absorption spectrum of a solu- lution, and add methanol to make exactly 20 mL. Confirm that tion of bergenin for thin-layer chromatography in methanol (1 in the peak area of acemetacin obtained from 10 µL of this solution 50000) as directed under Ultraviolet-visible Spectrophotometry is equivalent to 3 to 7% of that of acemetacin from the standard <2.24>: it exhibits maxima between 217 nm and 221 nm, and solution. between 273 nm, and 277 nm, and a minimum between 241nm System performance: Dissolve 75 mg of acemetacin and 75

Supplement II, JP XV General Tests, Process and Apparatus 2059 mg of indometacin in 50 mL of methanol. To 4 mL of this solution shows a deep purplish red spot at around Rf 0.45, and the tion add 1 mL of a solution of hexyl parahydroxybenzoate in sample solution shows spots equivalent to those described be- methanol (1 in 250), and add methanol to make 50 mL. When low: the procedure is run with 10 µL of this solution under the above operating conditions, acemetacin, indometacin and hexyl para- Rf value Color and shape of the spot hydroxybenzoate are eluted in this order with the resolutions Around 0.25 A weak spot, strongly purplish red between the peaks of acemetacin and indometacin and between Around 0.25 A leading spot or two strong spots, strongly the peaks of indometacin and hexyl parahydroxybenzoate being - 0.3 purplish red not less than 3, respectively. Around 0.35 A deep purplish red spot Around 0.4 A weak spot, dull red System repeatability: When the test is repeated 6 times with Around 0.42 A dark red spot 10 µL of the standard solution under the above operating condi- Around 0.45 A weak spot, grayish red tions, the relative standard deviation of the peak area of Around 0.65 A weak spot, dull greenish yellow acemetacin is not more than 1.5%. Around 0.7 A weak spot, grayish red Around 0.85 A weak spot, grayish red Acetic acid buffer solution containing 0.1% bovine serum Around 0.95 A weak spot, dull yellow-red albumin Dissolve 0.1 g of bovine serum albumin in sodium acetate trihydrate solution (1 in 100) to make exactly 100 mL, Aconitum monoester alkaloids standard TS for compo- and adjust the pH to 4.0 with 1 mol/L hydrochloric acid TS. nent determination Weigh accurately about 20 mg of benzoylmesaconine hydrochloride for component determination Acetic acid-sodium acetate TS, pH 7.0 Dissolve 4.53 g of (separately, determine the water content), about 10 mg of ben- sodium acetate trihydrate in water to make 100 mL, and adjust zoylhypaconine hydrochloride for component determination the pH to 7.0 with diluted acetic acid (100) (1 in 50). (separately, determine the water content) and about 20 mg of Achyranthes root for thin-layer chromatography A 14-anisoylaconine hydrochloride for component determination (separately, determine the water content), dissolve in a mixture heat-dried, pulverized root of Achyranthes fauriei Leveillé et of phosphate buffer solution for processed aconite root and tet- Vaniot (Amaranthaceae) meeting the following additional rahydrofuran (183:17) to make exactly 1000 mL. Perform the specifications. test with 20 Identification (1) To 2 g of pulverized achyranthes root for µL of this solution as directed in the Purity under thin-layer chromatography add 10 mL of water, shake for 10 benzoylmesaconine hydrochloride for component determina- minutes, add 5 mL of 1-butanol, shake for 10 minutes, centri- tion: the peaks of benzoylmesaconine, benzoylhypaconine and fuge, and use the supernatant liquid as the sample solution. 14-anisoylaconine appear with a peak area ratio of about 2:1:2. Separately, dissolve 1 mg of chikusetsusaponin IV for thin-layer Alcian blue 8 GX C56H68Cl14CuN16S4 Dark blue-purple chromatography in 1 mL of methanol, and use this solution as powder. the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography <2.03>. Spot 10 µL Alcian blue staining solution Dissolve 0.5 g of alcian blue each of the sample solution and standard solution on a plate of 8 GX in 100 mL of diluted acetic acid (100) (3 in 100). silica gel for thin-layer chromatography. Develop the plate with a mixture of ethyl acetate, water and formic acid (5:1:1) to a Allopurinol C5H4N4O [Same as the namesake mono- distance of about 10 cm, and air-dry the plate. Spray evenly di- graph.] lute sulfuric acid on the plate, and heat the plate at 105ºC for 10 minutes: the standard solution shows a deep purplish red spot at Allopurinol for assay C5H4N4O [Same as the monograph Allopurinol. When dried, it contains not less than 99.0% of al- around Rf 0.35, and the sample solution shows spots equivalent lopurinol (C to those described below: 5H4N4O).] Alkaline copper (II) TS Dissolve 20 g of anhydrous so- Rf value Color and shape of the spot dium carbonate in dilute sodium hydroxide TS to make 1000 Around 0 A weak spot, black mL, and use this solution as solution A. Dissolve 0.5 g of copper Around 0.1 A weak spot, strong purplish red (II) sulfate pentahydrate in potassium sodium tartarate tetrahy- Around 0.2 A weak, tailing spot, strong purplish red drate solution (1 in 100) to make 100 mL, and use this solution Around 0.25 A strong spot, deep purplish red as solution B. To 50 mL of solution A add 1 mL of solution B. Around 0.35 A leading spot, deep purplish red Prepare before use. Around 0.45 A weak spot, dull yellow Around 0.5 A weak spot, grayish purplish red Alkaline phosphatase Obtained from bovine small intes- Around 0.75 A weak spot, grayish red tine, a white to grayish white or yellow-brown, freeze-dried Around 0.9 A weak spot, dull red powder having no odor. Alkaline phosphatase contains not less than 1 unit per mg and (2) Perform the test as directed in the operating conditions no salts. One unit of alkaline phosphatase indicates an amount under (1), except using a mixture of 1-propanol, ethyl acetate of the enzyme which produces 1 µmol of 4-nitrophenol in 1 and water (4:4:3) as the developing solvent: the standard solu-

2060 General Tests, Process and Apparatus Supplement II, JP XV minute at 37ºC and pH 9.8, from 4-nitrophenylphosphate ester System performance: When the procedure is run with 20 µL used as the substrate. of aconitum monoester alkaloids standard solution for component determination under the above operating conditions, ben- Alkaline phosphatase TS Dissolve 0.1 g of alkaline phos- zoylmesaconine, benzoylhypaconine and 14-anisoylaconine are phatase in 10 mL of boric acid-magnesium chloride buffer solu- eluted in this order with the resolution between these peaks be- tion, pH 9.0. Prepare before use. ing not less than 4. System repeatability: When the test is repeated 6 times with 6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate 20 µL of aconitum monoester alkaloids standard solution for C H N O Prepared for amino acid analysis or biochemistry. 14 11 3 4 component determination under the above operating conditions, the relative standard deviations of the peak areas of benzoylme- 2-Aminobenzimidazole C7H7N3 White to light yellow crystals or crystalline powder. Melting point: about 231ºC (with saconine, benzoylhypaconine and 14-anisoylaconine are not decomposition). more than 1.5%, respectively.

Aprindine hydrochloride for assay CH N ·HCl Amiodarone hydrochloride for assay C25H29I2NO3·HCl 22 30 2 [Same as the monograph Amiodarone Hydrochloride. When [Same as the monograph Aprindine Hydrochloride. When dried, dried, it contains not less than 99.5% of amiodarone hydrochlo- it contains not less than 99.5% of aprindine hydrochloride (C H N ·HCl).] ride (C25H29I2NO3·HCl).] 22 30 2

14-Anisoylaconine hydrochloride for component deter- Anode solution A for water determination Dissolve 100 g of diethanolamine in 900 mL of a mixture of methanol for water mination C33H47NO11·HCl·xH2O White crystalline powder or powder. Freely soluble in methanol, sparingly soluble in wa- determination and chloroform for water determination (1:1), ter and in ethanol (99.5). Melting point: about 210ºC (with de- pass dried sulfur dioxide gas through this solution while cooling composition). until the mass increase of the solution reaches 64 g. Then add 20 1% g of iodine, and add water until the color of the solution changes Absorbance <2.24> E1cm (258 nm): 276 - 294 (5 mg calculated on the anhydrous basis, methanol, 200 mL). from brown to yellow. To 600 mL of this solution add 400 mL Purity (1) Related substances—To 1.0 mg of of chloroform for water determination. 14-anisoylaconine hydrochloride for component determination (E)-Asarone C H O White powder. Freely soluble in add exactly 1 mL of ethanol (99.5). Perform the test with 5 µL 12 16 3 methanol and in ethanol (99.5) and practically insoluble in water. of this solution as directed in the Identification under Processed Melting point: about 60ºC Aconite Root: no spot other than the principle spot at around R f Identification Determine the infrared absorption spectrum 0.5 appears. of (E)-asarone as directed in the potassium bromide disk method (2) Related substances—Dissolve 5.0 mg of under Infrared Spectrophotometry <2.25>, it exhibits absorption 14-anisoylaconine hydrochloride for component determination at the wave numbers of about 2990 cm-1, 2940 cm-1, 2830 cm-1, in 5 mL of the mobile phase, and use this solution as the sample 1609 cm-1, 1519 cm-1, 1469 cm-1, 1203 cm-1, 1030 cm-1, 970 solution. Pipet 1 mL of this solution, add the mobile phase to cm-1 and 860 cm-1. make exactly 50 mL, and use this solution as the standard solu- Purity Related substances—Dissolve 2 mg of (E)-asarone in tion. Perform the test with exactly 20 µL each of the sample so- 10 mL of methanol, and use this solution as the sample solution. lution and standard solution as directed under Liquid Chroma- Pipet 1 mL of this solution, add methanol to make exactly 10 tography <2.01> according to the following conditions. Deter- mL, and use this solution as the standard solution. Perform the mine each peak area of both solutions by the automatic integra- test with 10 µL each of the sample solution and standard solution method: the total area of the peaks other than the peak of tion as directed under Liquid Chromatography <2.01> according 14-anisoylaconine obtained from the sample solution is not lar- to the following conditions. Determine each peak area of both ger than the peak area of 14-anisoylaconine from the standard solutions by the automatic integration method: the total area of solution. the peaks other than the peak of (E)-asarone obtained from the Operating conditions sample solution is not larger than the peak area of (E)-asarone Column, column temperature, mobile phase and flow rate: from the standard solution. Proceed as directed in the operating conditions in the Assay (3) Operating conditions under Goshajinkigan Extract. Detector, column, column temperature, mobile phase and Detector: An ultraviolet absorption photometer (wavelength: flow rate: Proceed as directed in the operating conditions in the 245 nm). Component determination under Perilla Herb. Time span of measurement: About 4 times as long as the re- Time span of measurement: About 3 times as long as the retention time of 14-anisoylaconine. tention time of (E)-asarone beginning after the solvent peak. System suitability System suitability Test for required detectability: Pipet 1 mL of the standard so- System performance: Proceed as directed in the system suit- lution, and add the mobile phase to make exactly 20 mL. Con- ability in the Component determination under Perilla Herb. firm that the peak area of 14-anisoylaconine obtained from 20 µL of this solution is equivalent to 3.5 to 6.5% of that of Azelastine hydrochloride for assay C22H24ClN3O·HCl 14-anisoylaconine from 20 µL of the standard solution.

Supplement II, JP XV General Tests, Process and Apparatus 2061

[Same as the monograph Azelastine Hydrochloride.] peaks other than benzo[a]pyrene is not more than 3.0%. Operating conditions Benz[a]anthracene C18H12 White to yellow crystalline Detector: A mass spectrophotometer (EI) powder or powder. Practically insoluble in water, in methanol Mass scan range: 15.00 - 300.00 and in ethanol (99.5). Melting point: 158 - 163ºC. Time of measurement: 12 - 30 minutes Identification Perform the test with benz[a]anthracene as Column: A fused silica column 0.25 mm in inside diameter directed in the Purity: the mass spectrum of the main peak and 30 m in length, coated inside with 5% diphenyl-95% di- shows a molecular ion peak (m/z 228) and a fragment ion peak methylpolysiloxane for gas chromatography in thickness of 0.25 (m/z 114). - 0.5 µm. Purity Related substances—Dissolve 3.0 mg of Column temperature: Inject at a constant temperature of about benz[a]anthracene in methanol to make 100 mL, and use this 45ºC, raise the temperature to 240ºC at a rate of 40ºC per minute, solution as the sample solution. Perform the test with 1 µL of maintain at 240ºC for 5 minutes, raise to 300ºC at a rate of 4ºC this solution as directed under Gas Chromatography <2.02>, and per minute, raise to 320ºC at a rate of 10ºC per minute, and determine each peak area by the automatic integration method. maintain at 320ºC for 3 minutes. Calculate the amounts of these peaks by the area percentage Injection port temperature: A constant temperature of about method: the total amount of the peaks other than 250ºC. benz[a]anthracene is not more than 2.0%. Interface temperature: A constant temperature of about 300ºC. Operating conditions Carrier gas: Helium. Detector: A mass spectrophotometer (EI) Flow rate: Adjust the flow rate so that the retention time of Mass scan range:15.00 - 300.00 benzo[a]pyrene is about 22 minutes. Time of measurement: 12 - 30 minutes Split ratio: Splitless. Column: A fused silica column 0.25 mm in inside diameter System suitability and 30 m in length, coated inside with 5% diphenyl-95% di- Test for required detectability: Pipet 1 mL of the sample solu- methylpolysiloxane for gas chromatography in thickness of 0.25 tion, add methanol to make exactly 10 mL. Confirm that the - 0.5 µm. peak area of benzo[a]pyrene obtained from 1 µL of this solution Column temperature: Inject at a constant temperature of about is equivalent to 5 to 15% of that of benzo[a]pyrene from the 45ºC, raise the temperature to 240ºC at a rate of 40ºC per minute, sample solution. maintain at 240ºC for 5 minutes, raise to 300ºC at a rate of 4ºC per minute, raise to 320ºC at a rate of 10ºC pr minute, and Benzoylhypaconine hydrochloride for component deter- maintain at 320ºC for 3 minutes. mination C31H43NO9·HCl·xH2O White crystals or crystal- Injection port temperature: At a constant temperature of about line powder. Freely soluble in methanol, soluble in water, and 250ºC. sparingly soluble in ethanol (99.5). Melting point: about 230ºC Interface temperature: At a constant temperature of 300ºC. (with decomposition). 1% Carrier gas: Helium Absorbance <2.24> E1cm (230 nm): 225 - 240 (5 mg calcu- Flow rate: Adjust the flow rate so that the retention time of lated on the anhydrous basis, methanol, 200 mL). benz[a]anthracene is about 15 minutes. Purity (1) Related substances—To 1.0 mg of benzoylhy- Split ratio: Splitless paconine hydrochloride for component determination add ex- System suitability actly 1 mL of ethanol (99.5). Perform the test with 5 µL of this Test for required detectability: Pipet 1 mL of the sample solu- solution as directed in the Identification under Processed Aco- tion, and add methanol to make exactly 10 mL. Confirm that the nite Root: no spot other than the principal spot at around Rf 0.5 peak area of benz[a]anthracene obtained from 1 µL of this solu- appears. tion is equivalent to 5 to 15% of that of benz[a]anthracene from (2) Related substance—Dissolve 5.0 mg of benzoylhypacon- the standard solution. ine hydrochloride for component determination in 5 mL of the mobile phase, and use this solution as the sample solution. Pipet Benzo[a]pyrene C20H12 Light yellow to green-yellow 1 mL of this solution, add the mobile phase to make exactly 50 crystalline powder or powder. Practically insoluble in water, in mL, and use this solution as the standard solution. Perform the methanol and in ethanol (99.5). Melting point: 176 - 181ºC. test with exactly 20 µL each of the sample solution and standard Identification Perform the test with benzo[a]pyrene as di- solution as directed under Liquid Chromatography <2.01> ac- rected in the Purity: the mass spectrum of the main peak shows cording to the following conditions. Determine each peak area a molecular ion peak (m/z 252) and a fragment ion peak (m/z of both solutions by the automatic integration method: the total 125). area of the peaks other than the peak of benzoylhypaconine ob- Purity Related substances―Dissolve 3.0 mg of tained from the sample solution is not larger than the peak area benzo[a]pyrene in methanol to make 100 mL, and use this solu- of benzoylhypaconine from the standard solution. tion as the sample solution. Perform the test with 1 µL of this Operating conditions solution as directed under Gas Chromatography <2.02> under Column, column temperature, mobile phase and flow rate: the following conditions, and determine each peak area by the Proceed as directed in the operating conditions in the Assay (3) automatic integration method. Calculate the amounts of these under Goshajinkigan Extract. peaks by the area percentage method: the total amount of the Detector: An ultraviolet absorption photometer (wavelength:

2062 General Tests, Process and Apparatus Supplement II, JP XV

245 nm). 20 µL of aconitum ester alkaloids standard solution for compo- Time span of measurement: About 5 times as long as the re- nent determination under the above operating conditions, the tention time of benzoylhypaconine. relative standard deviations of the peak areas of benzoylmesa- System suitability conine, benzoylhypaconine and 14-anisoylaconine are not more Test for required detectability: Pipet 1 mL of the standard so- than 1.5%, respectively. lution, and add the mobile phase to make exactly 20 mL. Con- firm that the peak area of benzoylhypaconine obtained from 20 Bifonazole C22H18N2 [Same as the namesake mono- µL of this solution is equivalent to 3.5 to 6.5% of that of ben- graph.] zoylhypaconine from the standard solution. Bis(cis-3,3,5-trimethylcyclohexyl) phthalate System performance: When the procedure is run with 20 µL C H [COOC H (CH ) ] White crystalline powder. of aconitum monoester alkaloids standard solution for compo- 4 4 6 8 3 3 2 Melting point <2.60>: 91 - 94ºC nent determination under the above operating conditions, benzoylmesaconine, benzoylhypaconine and 14-anisoylaconine are Bisdemethoxycurcumin C19H16O4 Yellow to orange eluted in this order with the resolution between these peaks be- crystalline powder. Sparingly soluble in methanol, slightly solu- ing not less than 4, respectively. ble in ethanol (99.5), and practically insoluble in water. Melting System repeatability: When the test is repeated 6 times with point: 213 - 217ºC. 20 µL of aconitum monoester alkaloids standard solution for Identification Determine the absorption spectrum of a solu- component determination under the above operating conditions, tion of bisdemethoxycurcumin in methanol (1 in 400000) as di- the relative standard deviations of the peak areas of benzoylme- rected under Ultraviolet-visible Spectrophotometry <2.24>: it saconine, benzoylhypaconine and 14-anisoylaconine are not exhibits a maximum between 413 nm and 417 nm. more than 1.5%, respectively. Purity Related substances (1) Dissolve 4 mg of bisdemethoxycurcumin in 2 mL of methanol, and use this solution as the Benzoylmesaconine hydrochloride for component deter- sample solution. Pipet 1 mL of this solution, add methanol to mination Benzoylmesaconine hydrochloride for thin-layer make 20 mL, and use this solution as the standard solution. chromatography meeting the following additional specifications. Perform the test with these solutions as directed under Purity Related substances—Dissolve 5.0 mg of benzoyl- Thin-layer Chromatography <2.03>. Spot 5 µL each of the sam- mesaconine hydrochloride for component determination in 5 mL ple solution and standard solution on a plate of silica gel for of the mobile phase, and use this solution as the sample solution. thin-layer chromatography. Develop the plate with a mixture of Pipet 1 mL of this solution, add the mobile phase to make ex- dichloromethane and methanol (19:1) to a distance of about 10 actly 50 mL, and use this solution as the standard solution. Per- cm, and air-dry the plate. Examine under ultraviolet light (main form the test with exactly 20 µL each of the sample solution and wavelength: 365 nm): the spots other than the principal spot at standard solution as directed under Liquid Chromatography R value of about 0.3 obtained from the sample solution are not <2.01> according to the following conditions. Determine each f more intense than the spot from the standard solution. peak area of both solutions by the automatic integration method: (2) Dissolve 1.0 mg of bisdemethoxycurcumin in 5 mL of the total area of the peaks other than the peak of benzoylmesa- methanol, and use this solution as the sample solution. Pipet 1 conine obtained from the sample solution is not larger than the mL of this solution, add methanol to make exactly 20 mL, and peak area of benzoylmesaconine from the standard solution. use this solution as the standard solution. Perform the test with Operating conditions exactly 10 µL each of the sample solution and standard solution Column, column temperature, mobile phase and flow rate: as directed under Liquid Chromatography <2.01> under the fol- Proceed as directed in the operating conditions in the Assay (3) lowing conditions. Determine each peak from both solutions by under Goshajinkigan Extract. the automatic integration method: the total area of the peaks Detector: An ultraviolet absorption photometer (wavelength: other than the peak of bisdemethoxycurcumin obtained from the 245 nm). sample solution is not larger than the peak area of bisdemeth- Time span of measurement: About 6 times as long as the re- oxycurcumin from the standard solution. tention time of benzoylmesaconine. Operating conditions System suitability Column, column temperature, mobile phase and flow rate: Test for required detectability: Pipet 1 mL of the standard so- Proceed as directed in the operating conditions in the Compo- lution, and add the mobile phase to make exactly 20 mL. Con- nent determination under Turmeric. firm that the peak area of benzoylmesaconine obtained from 20 Detector: A visible absorption photometer (wavelength: 422 µL of this solution is equivalent to 3.5 to 6.5% of that of ben- nm). zoylmesaconine from the standard solution. Time span of measurement: About 4 times as long as the re- System performance: When the procedure is run with 20 µL tention time of bisdemethoxycurcumin beginning after the sol- of aconitum monoester alkaloids standard solution for compo- vent peak. nent determination under the above operating conditions, ben- System suitability zoylmesaconine, benzoylhypaconine and 14-anisoylaconine are System performance and system repeatability: Proceed as di- eluted in this order with the resolution between these peaks be- rected in the operating conditions in the Component determina- ing not less than 4, respectively. tion under Turmeric. System repeatability: When the test is repeated 6 times with

Supplement II, JP XV General Tests, Process and Apparatus 2063

Test for required detectability: Pipet 1 mL of the standard so- Cinoxacin for assay C12H10N2O5 [Same as the mono- lution, and add methanol to make exactly 20 mL. Confirm that graph Cinoxacin. When dried, it contains not less than 99.0% of the peak area of bisdemethoxycurcumin obtained from 10 µL of cinoxacin (C12H10N2O5)] this solution is equivalent to 3.5 to 6.5% of that of bisdemethoxycurcumin from the standard solution. p-Cresol C7H8O [K 8306, Special class]

Curcumin for component determination CH O Bis(1,1-trifluoroacetoxy)iodobenzene C10H5F6IO4 Pre- 21 20 6 pared for amino acid analysis or biochemistry. Yellow to orange crystalline powder. Slightly soluble in methanol, very slightly soluble in ethanol (99.5), and practically in- Blood agar medium Sterilize 950 mL of heart infusion soluble in water. agar medium under increased pressure. Allow the media to cool 1% to about 50ºC, add 50 mL of horse or sheep defibrinated blood, Absorbance <2.24> E1cm (422 nm): 1460 - 1700 (dried for dispense in sterilized Petri dishes, and make them as plate me- 24 hours in a desiccator (in vacuum, silica gel), 2.5 mg, metha- dia. nol, 1000 mL). Melting point <2.60>: 180 - 184ºC. 1% blood suspension Wash a defibrinated animal blood in Purity Related substances—(1) Dissolve 4 mg of curcu- isotonic solution, and make it into suspension to contain 1 vol%. min for component determination in 2 mL of methanol, and use Prepare before use. this solution as the sample solution. Pipet 1 mL of this solution, add methanol to make exactly 50 mL, and use this solution as Boric acid-magnesium chloride buffer solution, pH 9.0 the standard solution. Perform the test with these solutions as Dissolve 3.1 g of boric acid in 210 mL of dilute sodium hy- directed under Thin-layer chromatography <2.03>. Spot 5 µL droxide, and add 10 mL of magnesium chloride hexahydrate (1 each of the sample solution and standard solution on a plate of in 50) and water to make 1000 mL. Adjust the pH to 9.0, if nec- silica gel for thin-layer chromatography. Develop the plate with essary. a mixture of dichloromethane and methanol (19:1) to a distance of about 10 cm, and air-dry the plate. Examine under ultraviolet Cadralazine for assay C H N O [Same as the mono- 12 21 5 3 light (main wavelength: 365 nm): the spots other than the prin- graph Cadralazine. When dried, it contains not less than 99.0% cipal spot at the R value of about 0.5 obtained from the sample of cadralazine (C H N O ).] f 12 21 5 3 solution are not more intense than the spot from the standard solution. Carbazole C12H9N White to nearly white foliaceous or plate-like crystals or crystalline powder. Freely soluble in pyri- (2) Dissolve 1.0 mg of curcumin for component determina- dine and in acetone, slightly soluble in ethanol (99.5), and prac- tion in 5 mL of methanol, and use this solution as the sample tically insoluble in water. It readily sublimes when heated. solution. Pipet 1 mL of this solution, add methanol to make ex- Melting point <2.60>: 243 - 245ºC actly 50 mL, and use this solution as the standard solution. Per- Purity Clarity and color of solution—To 0.5 g of carbazole form the test with 10 µL each of the sample solution and stan- add 20 mL of ethanol (99.5), and dissolve by warming: the solu- dard solution as directed under Liquid Chromatography <2.01>. tion is clear. Determine each peak from both solutions by the automatic inte- Residue on ignition: Not more than 0.1% (1 g). gration method: the total area of the peaks other than the peak of curcumin obtained from the sample solution is not larger than Carbazole TS Dissolve 0.125 g of carbazole in ethanol the peak area of curcumin from the standard solution. (99.5) to make 100 mL. Operating conditions Column, column temperature, mobile phase and flow rate: Chlorhexidine hydrochloride C22H30Cl2N10·2HCl [Same Proceed as directed in the operating conditions in the Compo- as the monograph Chlorhexidine Hydrochloride.] nent determination under Turmeric. Detector: A visible absorption photometer (wavelength: 422 (2-Chloroethyl) diethylamine hydrochloride nm). C H ClN·HCl White powder. 6 14 Time span of measurement: About 4 times as long as the re- Content: not less than 95.0%. Assay—Weigh accurately tention time of curcumin beginning after the solvent peak. about 0.2 g of (2-chloroethyl)diethylamine hydrochloride, pre- System suitability viously dried at 45ºC for 3 hours under reduced pressure, and System performance and system repeatability: Proceed as di- dissolve in 15 mL of acetic acid (100). To this solution add 10 rected in the system suitability in the Component determination mL of a mixture of acetic acid (100) and mercury (II) acetate TS under Turmeric. for nonaqueous titration (5:3), and titrate <2.50> with 0.1 mol/L Test for required detectability: Pipet 1 mL of the standard so- perchloric acid VS (potentiometric titration). Perform a blank lution, add methanol to make exactly 20 mL. Confirm that the determination in the same manner, and make any necessary cor- peak area of curcumin obtained from 10 µL of this solution is rection. equivalent to 3.5 to 6.5% of that of curcumin from 10 µL of the Each mL of 0.1 mol/L perchloric acid VS standard solution. = 17.21 mg of C H ClN·HCl 6 14 Cyanopropylmethylphenylsilicone for gas chromatogra-

2064 General Tests, Process and Apparatus Supplement II, JP XV phy Prepared for gas chromatography. Identification Perform the test with dibenz[a,h]anthracene as directed in the Purity: the mass spectrum of the main peak Demethoxycurcumin C20H18O5 Yellow to orange crystal- shows a molecular ion peak (m/z 278) and a fragment ion peak line powder or powder. Sparingly soluble in methanol and in (m/z 139). ethanol (99.5), and practically insoluble in water. Melting point: Purity Related substances—Dissolve 3.0 mg of 166 - 170ºC. dibenz[a,h]anthracene in methanol to make 100 mL, and use Identification Determine the absorption spectrum of a solu- this solution as the sample solution. Perform the test with 1 µL tion of demethoxycurcumin in methanol (1 in 400000) as di- of this solution as directed under Gas Chromatography <2.02> rected under Ultraviolet-visible Spectrophotometry <2.24>: it according to the following conditions, and determine each peak exhibits a maximum between 416 nm and 420 nm. area by the automatic integration method. Calculate the amounts of these peaks by the area percentage method: the total amount Purity Related substances—(1) Dissolve 4 mg of de- of the peaks other than dibenz[a,h]anthracene is not more than methoxycurcumin in 2 mL of methanol, and use this solution as 7.0%. the sample solution. Pipet 1 mL of this solution, add methanol to Operating conditions make exactly 20 mL, and use this solution as the standard solu- Detector: A mass spectrophotometer (EI) tion. Perform the test as directed under Thin-layer Chromatog- Mass scan range: 15.00 - 300.00 raphy <2.03>. Spot 5 µL each of the sample solution and stan- Time of measurement: 12 - 30 minutes dard solution on a plate of silica gel for thin-layer chromatog- Column: A fused silica column 0.25 mm in inside diameter raphy. Develop the plate with a mixture of dichloromethane and and 30 m in length, coated inside with 5% diphenyl-95% di- methanol (19:1) to a distance of about 10 cm, and air-dry the methylpolysiloxane for gas chromatography in thickness of 0.25 plate. Examine under ultraviolet light (main wavelength: 365 - 0.5 µm. nm): the spots other than the principal spot at the R value of f Column temperature: Inject at a constant temperature of about about 0.3 obtained from the sample solution are not more in- 45ºC, raise the temperature to 240ºC at a rate of 40ºC per minute, tense than the spot from the standard solution. maintain at 240ºC for 5 minutes, raise to 300ºC at a rate of 4ºC (2) Dissolve 1.0 mg of demethoxycurcumin in 5 mL of per minute, raise to 320ºC at a rate of 10ºC per minute, and methanol, and use this solution as the sample solution. Pipet 1 maintain at 320ºC for 3 minutes. mL of this solution, add methanol to make exactly 20 mL, and Injection port temperature: A constant temperature of about use this solution as the standard solution. Perform the test with 250ºC. exactly 10 µL each of the sample solution and standard solution Interface temperature: A constant temperature of about 300ºC. as directed under Liquid Chromatography <2.01> according to Carrier gas: Helium the following conditions. Determine each peak from both solu- Flow rate: Adjust the flow rate so that the reaction time of the tions by the automatic integration method: the total area of the peak of dibenz[a,h]anthracene is about 27 minutes. peaks other than the peak of demethoxycurcumin obtained from Split ratio: Splitless the sample solution is not larger than the peak area of demeth- System suitability oxycurcumin from the standard solution. Test for required detectability: Pipet 1 mL of the sample solu- Operating conditions tion, and add methanol to make exactly 10 mL. Confirm that the Column, column temperature, mobile phase and flow rate: peak area of dibenz[a,h]anthracene obtained from 1 µL of this Proceed as directed in the operating conditions in the Compo- solution is equivalent to 5 to 15% of that of nent determination under Turmeric dibenz[a,h]anthracene from the standard solution. Detector: A visible absorption photometer (wavelength: 422 nm) Dibutylamine C8H19N Colorless, clear liquid. Time span of measurement: About 4 times as long as the re- 20 Refractive index <2.45> n D : 1.415 - 1.419 tention time of demethoxycurcumin beginning after the solvent Density <2.56> (20ºC): 0.756 - 0.761 g/mL peak. System suitability 2,6-Dichloroindophenol sodium-sodium acetate TS Mix System performance and system repeatability: Proceed as di- equal volumes of 2,6-dichloroindophenol sodium dihydrate so- rected in the system suitability in the Component determination lution (1 in 20) and acetic acid-sodium acetate TS, pH 7.0. Pre- under Turmeric. pare before use. Test for required detectability: Pipet 1 mL of the standard solution, and add methanol to make exactly 20 mL. Confirm that Diisopropylamine [(CH3)2CH]2NH Colorless, clear liq- the peak area of demethoxycurcumin obtained from 10 µL of uid, having an amine-like odor. Miscible with water and with this solution is equivalent to 3.5 to 6.5% of that of demethoxy- ethanol (95). The solution in water is alkaline. 20 curcumin from the standard solution. Refractive index <2.45> n D : 1.391 - 1.394 20 Specific gravity <2.56> d 20 : 0.715 - 0.722 Dibenz[a,h]anthracene C22H14 Very pale yellow to green-yellow crystalline powder or powder. Practically insolu- Dimenhydrinate for assay C17H21NO·C7H7ClN4O2 ble in water, in methanol and in ethanol (99.5). Melting point: [Same as the monograph Dimenhydrinate. When dried, it con- 265 - 270ºC. tains not less than 53.8% and not more than 54.9% of diphen-

Supplement II, JP XV General Tests, Process and Apparatus 2065 hydramine (C17H21NO) and not less than 45.2% and not more than 2.0% than 46.1% of 8-chlorotheophylline (C7H7ClN4O2).] Operating conditions Detector: A hydrogen flame-ionization detector. Dimethoxymethane C3H8O2 Colorless, clear and volatile Column: A fused silica column 0.25 mm in inside diameter liquid. Miscible with methanol, with ethanol (95) and with di- and 60 m in length, coated inside with polymethylsiloxane for ethyl ether. gas chromatography in 0.25 to 0.5 µm in thickness. Column temperature: Raise the temperature from 100ºC to (Dimethylamino)azobenzenesulfonyl chloride 130ºC at a rate of 5ºC per minute, raise to 140ºC at a rate of 2ºC C H ClN O S Prepared for amino acid analysis or biochem- 14 14 3 2 per minute, raise to 200ºC at a rate of 15ºC per minute, and istry. maintain at 200ºC for 2 minutes. Disodium hydrogen phosphate-citric acid buffer solution, Injection port temperature: 200ºC. pH 7.5 Dissolve 5.25 g of citric acid monohydrate in water to Detector temperature: 250ºC. make 1000 mL. Add this solution to 1000 mL of 0.05 mol/L Carrier gas: Helium disodium hydrogen phosphate TS to adjust the pH to 7.5. Flow rate: Adjust the flow rate so that the retention time of guaiacol is about 8 minutes.

Dithiodiglycolic acid C4H6O4S2 Prepared for amino acid Split ratio: 1:50 analysis or biochemistry. System suitability Test for required detectability: Weigh accurately about 70 mg Dithiodipropionic acid C6H10O4S2 Prepared for amino of guaiacol for assay, add methanol to make exactly 100 mL, acid analysis or biochemistry. and use this solution for the solution for system suitability test. Confirm that the peak area of guaiacol obtained from 1 µL of the Droxidopa for assay CH NO [Same as the monograph 9 11 5 solution for system suitability test is equivalent to 0.08 to 0.16% Droxidopa. When dried, it contains not less than 99.5% of of that of guaiacol obtained when 0.5 µL of guaiacol for assay is droxidopa (C H NO ).] 9 11 5 injected. System performance: When the procedure is run with 1 µL of Ecabet sodium hydrate for assay C20H27NaO5S·5H2O [Same as the monograph Ecabet Sodium Hydrate. When dried, the solution for system suitability test under the above operating it contains not less than 99.5% of ecabet sodium conditions, the number of theoretical plates and the symmetry factor of the peak of guaiacol are not less than 200000 and not (C20H27NaO5S).] more than 1.5, respectively.

Emorfazone for assay C11H17N3O3 [Same as the mono- System repeatability: When the test is repeated 6 times with 1 graph Emorfazone. When dried, it contains not less than 99.0% µL of the solution for system suitability test under the above op- of emorfazone (C11H17N3O3).] erating conditions, the relative standard deviation of the peak area of guaiacol is not more than 2.0%. 9-Fluorenylmethyl chloroformate C15H11ClO2 Prepared for amino acid analysis or biochemistry. 4´-O-Glucosyl-5-O-methylvisamminol for thin-layer

chromatography C22H28O10 White crystals or crystalline 7-Fluoro-4-nitrobenzo-2-oxa-1,3-diazole C6H2FN3O3 powder. Freely soluble in methanol and in ethanol (99.5), and Prepared for amino acid analysis or biochemistry. sparingly soluble in water. Identification Determine the absorption spectrum of a solu- Flutoprazepam for assay C H ClFN O [Same as the 19 16 2 tion of 4´-O-glucosyl-5-O-methylvisamminol for thin-layer monograph Flutoprazepam. When dried, it contains not less than chromatography in ethanol (1 in 50000) as directed under Ultra- 99.5% of flutoprazepam (C H ClFN O).] 19 16 2 violet-visible Spectrophotometry <2.24>: it exhibits a maximum between 286 nm and 290 nm. Guaiacol for assay C7H8O2 Colorless to yellow clear liquid or colorless crystals with a characteristic, aromatic odor. Purity Related substances—Dissolve 1 mg of Miscible with methanol and with ethanol (99.5), and sparingly 4´-O-glucosyl-5-O-methylvisamminol for thin-layer chroma- soluble in water. Congealing point: 25 - 30ºC. tography in 1 mL of methanol. Perform the test with 5 µL of this Identification Determine the infrared absorption spectrum solution directed in the Identification under Saposhnikovia of guaiacol for assay as directed in the ATR method under In- Root: no spots other than the principal spot at around Rf 0.3 ap- frared Spectrophotometry <2.25>: it exhibits absorption at the pears. wave numbers of about 1595 cm-1, 1497 cm-1, 1443 cm-1, 1358 Guanine CH N O White to pale yellowish white pow- cm-1, 1255 cm-1, 1205 cm-1, 1108 cm-1, 1037 cm-1, 1020 cm-1, 5 5 5 der. 916 cm-1, 833 cm-1, and 738 cm-1. Absorbance <2.24> Weigh accurately about 10 mg of gua- Purity Related substances—Perform the test with 0.5 µL of nine, dissolve in 20 mL of dilute sodium hydroxide TS, and add guaiacol for assay as directed under Gas Chromatography 2 mL of 1 mol/L hydrochloric acid TS and 0.1 mol/L hydrochlo- <2.02> according to the following conditions. Determine each ric acid TS to make exactly 1000 mL. Determine the absorb- peak area by the automatic integration method: the total area of ances, E1% , of this solution at 248 nm and 273 nm: they are the peaks other than the peak of guaiacol for assay is not more 1% between 710 and 770, and between 460 and 500, respectively.

2066 General Tests, Process and Apparatus Supplement II, JP XV

Loss on drying <2.41>: Not more than 1.5% (0.5 g, 105ºC, 4 matography meeting the following additional specifications. hours). Purity Related substances—Dissolve 10 mg of 10-hydroxy-2-(E)-decenoic acid for component determination in Heart infusion agar medium Prepared for biochemical 100 mL of methanol, and use this solution as the sample solu- tests. tion. Pipet 1 mL of this solution, add methanol to make exactly 100 mL, and use this solution as the standard solution. Perform Heptyl parahydroxybenzoate C H O White crystals 14 20 3 the test with exactly 10 µL each of the sample solution and or crystalline powder. standard solution as directed under Liquid Chromatography Melting point <2.60>: 45 - 50ºC. <2.01> according to the following conditions. Determine each Content: Not less than 98.0% Assay—Weigh accurately peak from both solutions by the automatic integration method: about 3.5 g of heptyl parahydroxybenzoate, dissolve in 50 mL of the total area of the peaks other than the peak of diluted N,N-dimethylformamide (4 in 5), and titrate <2.50> with 10-hydroxy-2-(E)-decenoic acid is not larger than the peak area 1 mol/L sodium hydroxide VS (potentiometric titration). Per- of 10-hydroxy-2-(E)-decenoic acid from the standard solution. form a blank determination in the same manner, and make any necessary correction. Operating conditions Detector, column, column temperature, mobile phase and Each mL of 1 mol/L sodium hydroxide VS flow rate: Proceed as directed in the operating conditions in the = 236.3 mg of C H O 14 20 3 Component determination under Royal Jelly. Time span of measurement: About 4 times as long as the re- Hexyl parahydroxybenzoate C13H18O3 White crystals or crystalline powder. tention time of 10-hydroxy-2-(E)-decenoic acid beginning after Melting point <2.60>: 49 - 53ºC the solvent peak. Content: Not less than 98.0%. Assay—Proceed as directed System suitability in the Assay under Ethyl Parahydroxybenzoate. System performance and system repeatability: Proceed as directed in the system suitability in the Component determination Each mL of 1 mol/L sodium hydroxide VS under Royal Jelly.

= 222.3 mg of C13H18O3 Test for required detectability: Pipet 1 mL of the standard solution, and add methanol to make exactly 20 mL. Confirm that Hyodeoxycholic acid for thin-layer chromatography the peak area of 10-hydroxy-2-(E)-decenoic acid obtained from C24H40O4 White to pale brown crystalline powder or powder. 10 µL of this solution is equivalent to 3.5 to 6.5% of that of Freely soluble in methanol an in ethanol (99.5), and practically 10-hydroxy-2-(E)-decenoic acid from the standard solution. insoluble in water. Identification Determine the infrared absorption spectrum 10-Hydroxy-2-(E)-decenoic acid for thin-layer chroma- of hyodeoxycholic acid for thin-layer chromatography as di- tography C10H18O3 White crystalline powder. Very soluble rected in the potassium bromide disk method under Infrared in methanol, freely soluble in ethanol (99.5), soluble in diethyl Spectrophotometry <2.25>: it exhibits absorption at the wave ether, and slightly soluble in water. numbers of about 2940 cm-1, 2840 cm-1, 2360 cm-1, 1740 cm-1, Identification Determine the absorption spectrum of a solu- 1460 cm-1, 1340 cm-1, 1200 cm-1, 1160 cm-1, 1040 cm-1 and 600 tion of 10-hydroxy-2-(E)-decenoic acid for thin-layer chroma- cm-1. tography in ethanol (99.5) (1 in 125000) as directed under Ul- 20 Optical rotation <2.49> [α] D : +7 - +10º (0.4 g, ethanol traviolet-visible Spectrophotometry <2.24>: it exhibits a maxi- (99.5), 20 mL, 100 mm). mum between 206 nm and 210 nm. Melting point <2.60>: 198 - 205ºC Melting point <2.60>: 63 - 66ºC. Purity Related substances—Dissolve 20 mg of hyodeoxy- Purity Related substances—Dissolve 5.0 mg of cholic acid for thin-layer chromatography in 1 mL of methanol, 10-hydroxy-2-(E)-decenoic acid for thin-layer chromatography and use this solution as the sample solution. Pipet 0.2 mL of this in 1 mL of diethyl ether. Perform the test with 20 µL of this so- solution, add methanol to make exactly 10 mL, and use this solution as directed in the Identification under Royal Jelly: no spot lution as the standard solution. Perform the test as directed un- other than the principal spot at around Rf 0.5 appears. der Thin-layer Chromatography <2.03>. Spot 5 µL each of the sample solution and standard solution on a plate of silica gel for Imidapril hydrochloride C20H27N3O6·HCl [Same as the thin-layer chromatography. Develop the plate with a mixture of monograph Imidapril Hydrochloride.] chloroform, acetone and acetic acid (100) (7:2:1) to a distance Imidapril hydrochloride for assay CH N O ·HCl of about 10 cm, and air-dry the plate. Splay evenly dilute sulfu- 20 27 3 6 [Same as the monograph Imidapril Hydrochloride. When dried, ric acid on the plate, and heat at 105ºC for 10 minutes: the spots it contains not less than 99.0% of imidapril hydrochloride other than the principal spot at the R value of about 0.3 ob- f (C H N O ·HCl).] tained from the sample solution are not more intense than the 20 27 3 6 spot from the standard solution. Irsogladine maleate C9H7Cl2N5·C4H4O4 [Same as the monograph Irsogladine Maleate.] 10-Hydroxy-2-(E)-decenoic acid for component determination 10-hydroxy-2-(E)-decenoic acid for thin-layer chro- Irsogladine maleate for assay C9H7Cl2N5·C4H4O4 [Same

Supplement II, JP XV General Tests, Process and Apparatus 2067 as the monograph Irsogladine Maleate. When dried, it contains specifications. 1% not less than 99.5% of irsogladine maleate Absorbance <2.24> E1cm (235 nm): 275 - 303 (dried in a (C9H7Cl2N5·C4H4O4).] desiccator (silica gel) for 24 hours, 5 mg, methanol, 500 mL). Purity Related substances—Dissolve 2 mg of loganin for Isosorbide dinitrate for assay C6H8N2O8 [Same as the component determination in 5 mL of the mobile phase, and use monograph Isosorbide Dinitrate. It contains not less than 99.0% this solution as the sample solution. Pipet 1 mL of this solution, of isosorbide dinitrate (C6H8N2O8) meeting the following addi- add the mobile phase to make exactly 100 mL, and use this so- tional specifications.] lution as the standard solution. Perform the test with exactly 10 µL each of the sample solution and standard solution as directed Purity Related substances—Dissolve 50 mg of isosorbide under Liquid Chromatography <2.01> according to the follow- dinitrate for assay in 50 mL of a mixture of water and methanol ing conditions. Determine each peak area of both solutions by (1:1), and use this solution as the sample solution. Pipet 1 mL of the automatic integration method: the total area of the peaks this solution, add a mixture of water and methanol (1:1) to make other than the peak of loganin is not larger than the peak area of exactly 200 mL, and use this solution as the standard solution. loganin from the standard solution. Perform the test with exactly 10 µL each of the sample solution Operating conditions and standard solution as directed under Liquid Chromatography Detector, column, column temperature, mobile phase and <2.01>, and determine each peak area of both solutions by the flow rate: Proceed as directed in the operating conditions in the automatic integration method: the total area of the peaks other Assay (1) under Goshajinkigan Extract. than the peak of isosorbide dinitrate obtained from the sample Time span of measurement: About 3 times as long as the resolution is not larger than the peak area of isosorbide dinitrate tention time of loganin. from the standard solution. System suitability Operating conditions System performance and system repeatability: Proceed as di- Detector, column, column temperature, mobile phase and rected in the system suitability in the Assay (1) under Gosha- flow rate: Proceed as directed in the operating procedures in the jinkigan Extract. Assay under Isosorbide Dinitrate Tablets. Test for required detectability: Pipet 1 mL of the standard so- Time span of measurement: About 2 times as long as the re- lution, and add the mobile phase to make exactly 20 mL. Con- tention time of isosorbide dinitrate beginning after the solvent firm that the peak area of loganin obtained from 10 µL of this peak. solution is equivalent to 3.5 to 6.5% of that of loganin from the System suitability standard solution. Test for required detectability: Pipet 5 mL of the standard solution, and add a mixture of water and methanol (1:1) to make Lovastatin C24H36O5 White crystals or crystalline powder. exactly 50 mL. Confirm that the peak area of isosorbide dini- Soluble in acetonitrile and in methanol, sparingly soluble in trate obtained from 10 µL of this solution is equivalent to 7 to ethanol (99.5), and practically insoluble in water. 13% of that of isosorbide dinitrate from the standard solution. 20 Optical rotation <2.49> [α] D : +325 - +340º (50 mg calcu- System performance: When the procedure is run with 10 µL lated on the anhydrous basis, acetonitrile, 10 mL, 100 mm). of the standard solution under the above operating conditions, Loss on drying <2.41>: Not more than 1.0% (1 g, under re- the number of theoretical plates and the symmetry factor of the duced pressure not exceeding 0.67 kPa, 60ºC, 3 hours). peak of isosorbide dinitrate are not less than 3000 and not more than 1.5, respectively. Mebendazole C16H13N3O3 White powder. Practically in- System repeatability: When the test is repeated 6 times with soluble in water and in ethanol (95). 10 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of isosor- Mercaptoethanesulfonic acid C2H6O3S2 Prepared for bide dinitrate is not more than 2.0%. amino acid analysis or biochemistry.

2-Methoxy-4-methylphenol CH O Colorless to pale Ketoconazole C26H28Cl2N4O4 [Same as the namesake 8 10 2 monograph.] yellow liquid. Miscible with methanol and with ethanol (99.5), and slightly soluble in water. Congealing point: 3 - 8ºC.

Ketoconazole for assay C26H28Cl2N4O4 [Same as the Identification Determine the infrared absorption spectrum monograph Ketoconazole. When dried, it contains not less than of 2-methoxy-4-methylphenol as directed in the ATR method

99.5% of ketoconazole (C26H28Cl2N4O4).] under Infrared Spectrophotometry <2.25>: it exhibits absorption at the wave numbers of about 1511 cm-1, 1423 cm-1, 1361 cm-1, 4-methoxybenzaldehyde-sulfuric acid-acetic acid-ethanol 1268 cm-1, 1231 cm-1, 1202 cm-1, 1148 cm-1, 1120 cm-1, 1031 TS for spray To 9 mL of ethanol (95) add 0.5 mL of cm-1, 919 cm-1, 807 cm-1 and 788 cm-1. 4-methoxybenzaldehyde, mix gently, add gently 0.5 mL of sul- Purity Related substances—Perform the test with 0.2 µL of furic acid and 0.1 mL of acetic acid (100) in this order, and mix 2-methoxy-4-methylphenol as directed under Gas Chromatog- well. raphy <2.02> according to the following conditions. Determine each peak by the automatic integration method: the total area of Loganin for component determination Loganin for the peaks other than the peak of 2-methoxy-4-methylphenol is thin-layer chromatography meeting the following additional

2068 General Tests, Process and Apparatus Supplement II, JP XV not more than 3.0%. Perillaldehyde for component determination Perillalde- Operating conditions hyde for thin-layer chromatography meeting the following Detector: A hydrogen flame-ionization detector. specifications. 1% Column: A fused silica column 0.25 mm in inside diameter Absorbance <2.24> E1cm (230 nm): 850 - 950 (10 mg, and 60 m in length, coated inside with polymethylsiloxane for methanol, 2000 mL). gas chromatography in 0.25 to 0.5 µm in thickness. Purity Related substances—Dissolve 10 mg of perillalde- Column temperature: Inject at a constant temperature of about hyde in 250 mL of methanol, and use this solution as the sample 100ºC, raise the temperature to 130ºC at a rate of 5ºC per minute, solution. Pipet 1 mL of this solution, add methanol to make ex- raise to 140ºC at a rate of 2ºC per minute, raise to 200ºC at a actly 50 mL, and use this solution as the standard solution. Per- rate of 15ºC per minute, and maintain at 200ºC for 2 minutes. form the test with exactly 10 µL each of the sample solution and Injection port temperature: 200ºC. standard solution as directed under Liquid Chromatography Detector temperature: 250ºC. <2.01> according to the following conditions. Determine each Carrier gas: Helium peak from both solutions by the automatic integration method: Flow rate: Adjust the flow rate so that the retention time of the total area of the peaks other than the peak of perillaldehyde 2-methoxy-4-methylphenol is about 10 minutes. is not larger than the peak of perillaldehyde from the standard Split ratio: 1:50 solution. System suitability Operating conditions System performance: Dissolve 60 mg of Detector, column, column temperature, mobile phase and 2-methoxy-4-methylphenol in methanol to make 100 mL, and flow rate: proceed as directed in the operating conditions in the use this solution as the solution for system suitability test. Pro- Component determination under Perilla Herb. ceed with 1 µL of the solution for system suitability test under Time span of measurement: About 3 times as long as the re- the above operating conditions: the symmetry factor of the peak tention time of perillaldehyde beginning after the solvent peak. of 2-methoxy-4-methylphenol is not more than 1.5. System suitability System repeatability: When the test is repeated 6 times with 1 System performance and system repeatability: Proceed as di- µL of the standard solution under the above operating conditions, rected in the system suitability in the Component determination the relative standard deviation of the peak area of under Perilla Herb. 2-methoxy-4-methylphenol is not more than 2.0%. Test for required detectability: Pipet 1 mL of the standard solution, and add methanol to make exactly 20 mL. Confirm that Methyl acetate CH3COOCH3 [K 8382, Special class] the peak area of perillaldehyde obtained from 10 µL of this solution is equivalent to 3.5 to 6.5% of that of perillaldehyde from Mosapride citrate for assay C H ClFN O ·C H O ·2H O 21 25 3 3 6 8 7 2 the standard solution. [Same as the monograph Mosapride Citrate Hydrate. It contains not less than 99.0% of mosapride citrate Perillaldehyde for thin-layer chromatography C10H14O (C21H25ClFN3O3·C6H8O7) calculated on the anhydrous basis.] Colorless to light brown transparent liquid, having a characteristic odor. Miscible with methanol and with ethanol (99.5), and Myristicin for thin-layer chromatography CH O 11 12 3 very slightly soluble in water. Colorless, clear liquid, having a characteristic odor. Miscible Identification Determine the infrared absorption spectrum with ethanol (95), and practically insoluble in water. of perillaldehyde for thin-layer chromatography as directed in Identification Determine the infrared absorption spectrum the liquid film method under Infrared Spectrophotometry of myristicin for thin-layer chromatography as directed in the <2.25>: it exhibits absorption at the wave numbers of about liquid film method under Infrared Spectrophotometry <2.25>: it 3080 cm-1, 2930 cm-1, 1685 cm-1, 1644 cm-1, 1435 cm-1 and 890 exhibits absorption at the wave numbers of about 3080 cm-1, cm-1. 2890 cm-1, 1633 cm-1, 1508 cm-1, 1357 cm-1, 1318 cm-1, 1239 Purity Related substances—Dissolve 1.0 mg of perillalde- cm-1, 1194 cm-1, 1044 cm-1, 994 cm-1, 918 cm-1, 828 cm-1 and hyde for thin-layer chromatography in 10 mL of methanol, and 806 cm-1. perform the test with 10 µL of this solution as directed in the Purity Related substances—Dissolve 20 mg of myristicin Identification under Perilla Herb: no spot other than the princi- for thin-layer chromatography in 1 mL of ethanol (95), and use pal spot at around R 0.5 appears. this solution as the sample solution. Pipet 0.5 mL of this solu- f tion, add ethanol (95) to make exactly 25 mL, and use this solu- Phenyl isothiocyanate C7H5NS Prepared for amino acid tion as the standard solution. Perform the test with 5 µL each of analysis or biochemistry. the sample solution and standard solution as directed in the

Identification under Nutmeg: the spots other than the principle Phenobarbital for assay C12H12N2O3 [Same as the spot at the Rf value of about 0.4 obtained from the sample solu- monograph Phenobarbital.] tion are not more intense than the spot from the standard solution. Phenytoin for assay C15H12N2O2 [Same as the monograph Phenytoin meeting the following additional specifica-

Ofloxacin C18H20FN3O4 [Same as the namesake mono- tions.] graph.] Purity Related substances—Dissolve 25 mg of phenytoin

Supplement II, JP XV General Tests, Process and Apparatus 2069 for assay in 50 mL of the mobile phase, and use this solution as Rf value Color and shape of the spot the sample solution. Pipet 1 mL of this solution, add the mobile Around 0 A strong spot, very dark blue phase to make exactly 200 mL, and use this solution as the Around 0.08 A very dark blue spot standard solution. Perform the test with exactly 10 µL each of Around 0.1 - 0.2 A leading spot, very dark blue the sample solution and standard solution as directed under Liq- Around 0.25 A strong spot, deep blue (correspond- uid Chromatography <2.01>. Determine each peak from both ing to plantagoguanidinic acid) solutions by the automatic integration method: the total area of Around 0.35 A strong spot, dark grayish blue (cor- the peaks other than the peak of phenytoin obtained from the responding to geniposidic acid) sample solution is not larger than the peak area of phenytoin Around 0.45 A weak spot, grayish yellowish green from the standard solution. Around 0.50 A strong spot, deep yellow-green Operating conditions (corresponding to acteoside) Column, column temperature and flow rate: Proceed as di- Around 0.6 A weak spot, light blue rected in the operating conditions in the Assay under Phenytoin Around 0.85 A deep blue spot Tablets. Around 0.9 - 0.95 A tailing spot, grayish blue Detector: An ultraviolet absorption photometer (wavelength: 220 nm) (2) Proceed as directed in the operating conditions under (1), Mobile phase: A mixture of 0.02 mol/L phosphate buffer so- except using a mixture of ethyl acetate, water and formic acid lution, pH 3.5, and acetonitrile for liquid chromatography (6:1:1) as developing solvent: spots equivalent to those de- (11:9). scribed below appear. Time span of measurement: About 5 times as long as the retention time of phenytoin beginning after the solvent peak. Rf value Color and shape of the spot System suitability Around 0 A yellow-greenish dark gray spot Test for required detectability: Pipet 2 mL of the standard so- Around 0.05 A weak spot, dark grayish yel- lution, and add the mobile phase to make exactly 20 mL. Con- low-green firm that the peak area of phenytoin obtained from 10 µL of this Around 0.2 A weak spot, dark green solution is equivalent to 8 to 12% of that of phenytoin from the Around 0.25 A strong spot, dark reddish purple standard solution. (corresponding to geniposidic acid) System performance: When the procedure is run with 10 µL Around 0.35 A weak spot, bright blue of the standard solution under the above operating conditions, Around 0.4 - 0.45 A weak tailing spot, dull greenish blue the number of theoretical plates and the symmetry factor of the Around 0.45 A strong spot, deep yellow-green peak of phenytoin are not less than 6000 and not more than 2.0, (corresponding to acteoside) respectively. Around 0.5 A strong spot, deep blue (correspond- System repeatability: When the test is repeated 6 times with ing to plantagoguanidinic acid) 10 µL of the standard solution under the above operating condi- Around 0.95 A strong spot, dark grayish blue-green tions, the relative standard deviation of the peak area of pheny- Around 0.97 A dark grayish blue-green spot toin is not more than 2.0%. Polyethylene glycol 2-nitroterephthalate for gas chroma- Plantago seed for thin-layer chromatography [Same as tography Prepared for gas chromatography. the monograph Plantago Seed meeting the following additional Polymethylsiloxane for gas chromatography Prepared for specifications.] gas chromatography. Identification (1) To 1 g of pulverized plantago seed for thin-layer chromatography add 3 mL of methanol, and warm on (E)-2-methoxycinnamaldehyde for thin-layer chromatog- a water bath for 3 minutes. After cooling, centrifuge, and use the raphy C10H10O2 White to yellow crystalline powder or supernatant liquid as the sample solution. Perform the test with powder. Freely soluble in methanol and in ethanol (99.5), and this solution as directed under Thin-layer Chromatography practically insoluble in water. Melting point: 44 - 50ºC. <2.03>. Spot 10 µL of the sample solution on a plate of silica Identification (1) Determine the absorption spectrum of gel for thin-layer chromatography. Develop the plate with a (E)-2-methoxycinnamaldehyde for thin-layer chromatography mixture of acetone, ethyl acetate, water and acetic acid (100) as directed under Ultraviolet-visible Spectrophotometry <2.24>: (10:10:3:1) to a distance of about 10 cm, and air-dry the plate. it exhibits maxima between 282 nm and 286 nm, and between Splay evenly 4-methoxybenzaldehyde-sulfuric acid TS on the 331 nm and 335 nm. plate, heat at 105ºC for 10 minutes: spots equivalent to those (2) Determine the infrared absorption spectrum of described below appear. (E)-2-methoxycinnamaldehyde for thin-layer chromatography as directed in the potassium bromide disk method under Infrared

Spectrophotometry <2.25>: it exhibits absorption at the wave -1 -1 -1 -1 numbers of about 1675 cm , 1620 cm , 1490 cm , 1470 cm , 1295 cm-1, 1165 cm-1, 1130 cm-1, 1025 cm-1 and 600 cm-1. Purity Related substances—Dissolve 10 mg of

2070 General Tests, Process and Apparatus Supplement II, JP XV

(E)-2-methoxycinnamaldehyde for thin-layer chromatography in Sodium glycocholate for thin-layer chromatography

5 mL of methanol, and use this solution as the sample solution. C26H42NNaO6·xH2O White to pale brown crystalline powder Pipet 1 mL of this solution, add methanol to make exactly 50 or powder. Freely soluble in water and in methanol, and slightly mL, and use this solution as the standard solution. Perform the soluble in ethanol (99.5). Melting point: about 260ºC (with de- test with 5 µL each of the sample solution and standard solution composition). as directed in the Identification (5) (ii) under Goshajinkigan Ex- Identification Determine the infrared absorption spectrum tract: the spots other than the principal spot at the Rf value of of sodium glycocholate for thin-layer chromatography as di- about 0.4 obtained from the sample solution are not more in- rected in the potassium bromide disk method under Infrared tense than the spot from the standard solution. Spectrophotometry <2.25>, it exhibits absorption at the wave numbers of about 2940 cm-1, 1640 cm-1, 1545 cm-1, 1450 cm-1, 0.01 mol/L Potassium dihydrogen phosphate TS, pH 4.0 1210 cm-1, 1050 cm-1, and 600 cm-1. Dissolve 1.4 g of potassium dihydrogen phosphate in 1000 mL 20 Optical rotation <2.49> [α] D : +25 - +35º (60 mg, methanol, of water, and adjust the pH to 4.0 with phosphoric acid. 20 mL, 100 mm). Purity Related substances—Dissolve 5 mg of sodium gly- Pig bile powder for thin-layer chromatography A yel- cocholate for thin-layer chromatography in 1 mL of methanol, low-gray to yellow-brown powder, having a characteristic odor and use this solution as the sample solution. Pipet 0.2 mL of this and a bitter taste. It is practically insoluble in water, in methanol solution, add methanol to make exactly 10 mL, and use this so- and in ethanol (99.5) lution as the standard solution. Perform the test with these solu- Identification To 0.1 g of pig bile powder for thin-layer tions as directed under Thin-layer Chromatography <2.03>. chromatography in a screw-capped test tube, add 1 mL of so- Proceed with 5 µL each of the sample solution and standard sodium hydroxide solution (3 in 25), and shake. Heat the tube in lution as directed in the Identification under Bear Bile: the spots an oil bath at 120ºC for 4 hours, allow to cool to a lukewarm other than the principal spot at the R value of about 0.2 ob- temperature, add 2 mL of 3 mol/L hydrochloric acid TS and 2 f tained from the sample solution are not more intense than the mL of ethyl acetate, shake at 50ºC for 30 minutes, and separate spot from the standard solution. ethyl acetate layer as the sample solution. Separately, dissolve 10 mg of hyodeoxycholic acid for thin-layer chromatography in Sodium 1-nonanesulfonate CH3(CH2)8SO3Na White 5 mL of methanol, and use this solution as the standard solution. crystalline powder. Freely soluble in water. Perform the test with these solutions as directed under Loss on drying <2.41>: Not more than 1.0% (1 g, 105ºC, 3 Thin-layer Chromatography <2.03>. Spot 2 µL each of the sam- hours). ple solution and standard solution on a plate of silica gel for Residue on ignition <2.44>: 30 - 32% (0.5 g). thin-layer chromatography. Develop the plate with a mixture of chloroform, acetone and acetic acid (100) (7:2:1) to a distance Sodium tauroursodeoxycholate for thin-layer chromatog- of about 10 cm, and air-dry the plate. Spray evenly dilute sulfu- raphy C26H44NNaO6S·xH2O White to pale brown crystalline ric acid on the plate, and heat the plate at 105ºC for 10 minutes: powder or powder. Freely soluble in methanol, soluble in water, one of the several spots obtained from the sample solution and sparingly soluble in ethanol (99.5). shows the same color tone and the same Rf value as the spot Identification Determine the infrared absorption spectrum from the standard solution. of sodium tauroursodeoxycholate for thin-layer chromatography as directed in the potassium bromide disk method under Infrared Propafenone hydrochloride for assay C21H27NO3·HCl Spectrophotometry <2.25>: it exhibits the absorption at the [Same as the monograph Propafenone Hydrochloride. When wave numbers of about 2940 cm-1, 1600 cm-1, 1410 cm-1, 1305 dried, it contains not less than 99.0% of propafenone hydrochlo- cm-1, 1195 cm-1, 1080 cm-1, 1045 cm-1, 980 cm-1, 950 cm-1, 910 ride (C21H27NO3·HCl). When proceed as directed in the Purity cm-1 and 860 cm-1. (2), the total area of the peaks other than the peak of 20 Optical rotation <2.49> [α] D : +40 - +50º (40 mg, methanol, propafenone is not larger than 3 times the peak area of 20 mL, 100 mm) propafenone from the standard solution.] Purity Related substances—Dissolve 10 mg of sodium 0.2 mol/L Pyridine-formic acid buffer solution, pH 3.0 tauroursodeoxycholate for thin-layer chromatography in 1 mL To 15.82 g of pyridine add 900 mL of water, shake well, adjust of methanol, and use this solution as the sample solution. Pipet the pH to 3.0 with diluted formic acid (1 in 2), and add water to 0.2 mL of this solution, add methanol to make exactly 10 mL, make 1000 mL. and use this solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatogra- Rebamipide for assay C H ClN O [Same as the 19 15 2 4 phy <2.03>. Perform the test as directed in the Identification monograph Rebamipide. When dried, it contains not less than under Bear Bile: the spots other than the principal spot at the R 99.5% of rebamipide (C H ClN O ).] f 19 15 2 4 value of about 0.2 obtained from the sample solution are not more intense than the spot from the standard solution. Sodium Azide NaN3 [K 9501, Special class]

0.2 mol/L Sodium chloride TS Dissolve 11.7 g of sodium Sodium tetraborate-sulfuric acid TS To 9.5 g of sodium chloride in water to make 1000 mL. tetraborate decahydrate add 1000 mL of purified sulfuric acid,

Supplement II, JP XV General Tests, Process and Apparatus 2071 and dissolve by shaking for a night. tions, the relative standard deviation of the peak area of theophylline is not more than 3.0%. Sodium valproate for assay C8H15NaO2 [Same as the monograph Sodium Valproate. When dried, it contains not less Tiapride hydrochloride for assay C15H24N2O4S·HCl than 99.0% of sodium valproate (C8H15NaO2).] [Same as the monograph Tiapride Hydrochloride.]

Strontium TS Dissolve 76.5 g of strontium chloride in wa- 1% Triethylamine-phosphate buffer solution, pH 3.0 ter to make exactly 500 mL. Pipet 20 mL of this solution, and Dissolve 10 g of triethylamine in 950 mL of water, adjust the pH add water to make exactly 1000 mL (1000 ppm). to 3.0 with phosphoric acid, and make exactly 1000 mL.

Testosterone C19H28O2 White crystals or crystalline Tris(4-t-butylphenyl)phosphate [(CH3)3CC6H4O]3PO powder. White crystals or crystalline powder. Identification Determine the infrared absorption spectrum Melting point <2.60>: 100 - 104ºC of testosterone as directed in the potassium bromide disk method under Infrared Spectrophotometry <2.25>: it exhibits Ubenimex for assay C16H24N2O4 [Same as the mono- the absorption at the wave numbers of about 3530 cm-1, 3380 graph Ubenimex. When dried, it contains not less than 99.0% of cm-1, 1612 cm-1, 1233 cm-1, 1067 cm-1 and 1056 cm-1. ubenimex (C16H24N2O4).] Ursodeoxycholic acid for assay C H O [Same as the Theophylline for assay C7H8N4O2 [Same as the mono- 24 40 4 graph Theophylline meeting the following additional specifica- monograph Ursodeoxycholic Acid. However, when dried, it tions.] contains not less than 99.0% of ursodeoxycholic acid Purity Related substances—Dissolve 50 mg of theophylline (C24H40O4) meeting the following additional specifications.] for assay in water to make 100 mL, and use this solution as the Purity Related substances—Dissolve 0.15 g of ursodeoxy- sample solution. Pipet 1 mL of this solution, add water to make cholic acid in 5 mL of methanol for liquid chromatography, and exactly 200 mL, and use this solution as the standard solution. use this solution as the sample solution. Pipet 2 mL of this solu- Perform the test with exactly 20 µL of the sample solution and tion and add methanol for liquid chromatography to make ex- standard solution as directed under Liquid Chromatography actly 50 mL. Pipet 2.5 mL of this solution, add methanol for liq- <2.01>. Determine each peak from both solutions by the auto- uid chromatography to make exactly 20 mL, and use this solu- matic integration method: the total area of peaks other than the tion as the standard solution. Perform the test with exactly 5 µL peak of theophylline obtained from the sample solution is not each of the sample solution and standard solution as directed larger than the peak area of theophylline from the standard solu- under Liquid Chromatography <2.01> according to the follow- tion. ing conditions. Determine each peak area of both solutions by Operating conditions the automatic integration method: the area of the peak, having Detector: An ultraviolet absorption photometer (wavelength: the relative retention time of about 2.5 with respect to ursode- 270 nm) oxycholic acid, obtained from the sample solution is not larger Column: A stainless steel column 6 mm in inside diameter than the peak area of ursodeoxycholic acid from the standard and 15 cm in length, packed with octadecylsilanized silica gel solution, and the area of the peak, having the relative retention for liquid chromatography (5 µm in particle diameter). time of about 5.5, obtained from the sample solution is not lar- Column temperature: A constant temperature of about 40ºC. ger than 1/5 times the peak area of ursodeoxycholic acid from Mobile phase: A mixture of diluted acetic acid (100) (1 in the standard solution. Furthermore, the total area of the peaks 100) and methanol (4:1). other than the peak of ursodeoxycholic acid and other than the Flow rate: Adjust the flow rate so that the retention time of peaks mentioned above is not larger than 1/5 times the peak area theophylline is about 10 minutes. of ursodeoxycholic acid from the standard solution. Time span of measurement: About 3 times as long as the re- Operating conditions tention time of theophylline. Detector: An ultraviolet absorption photometer (wavelength: System suitability 210 nm). Test for required detectability: Pipet 5 mL of the standard so- Column: A stainless steel column 3 mm in inside diameter lution, and add water to make exactly 25 mL. Confirm that the and 7.5 cm in length, packed with octylsilanized silica gel for peak area of theophylline obtained from 20 µL of this solution is liquid chromatography (5 µm in particle diameter). equivalent to 15 to 25% of that of theophylline from the stan- Column temperature: A constant temperature of about 40ºC. dard solution. Mobile phase: A mixture of methanol for liquid chromatog- System performance: When the procedure is run with 20 µL raphy, diluted phosphoric acid (1 in 1000) and acetonitrile for of the standard solution under the above operating conditions, liquid chromatography (96:69:35). the number of theoretical plates and the symmetry factor of the Flow rate: Adjust the flow rate so that the retention time of peak of theophylline are not less than 3000 and not more than ursodeoxycholic acid is about 2.3 minutes. 1.5, respectively. Time span of measurement: About 7 times as long as the re- System repeatability: When the test is repeated 6 times with tention time of ursodeoxycholic acid. 20 µL of the standard solution under the above operating condi- System suitability— Test for required detectability: Pipet 2 mL of the standard so-

2072 General Tests, Process and Apparatus Supplement II, JP XV lution, and add methanol for liquid chromatography to make exactly 20 mL. Confirm that the peak area of ursodeoxycholic acid obtained from 5 µL of this solution is equivalent to 8 to 12% of that of ursodeoxycholic acid from the standard solution. System performance: To 30 mg of chenodeoxycholic acid for thin-layer chromatography and 30 mg of lithocholic acid for thin-layer chromatography, add 1 mL of the sample solution, dissolve in methanol for liquid chromatography to make 50 mL. When the procedure is run with 5 µL of this solution under the above operating conditions, ursodeoxycholic acid, chenodeoxycholic acid, and lithocholic acid are eluted in this order with the resolution between these peaks being not less than 7, respectively. System repeatability: When the test is repeated 6 times with 5 µL of the standard solution under the above conditions, the relative standard deviation of the peak area of ursodeoxycholic acid is not more than 2.0%.

9.42 Solid Supports/Column Packings for Chromatography

Add the following:

Sulfonamide group bound to hexadecylsilanized silica gel for liquid chromatography Prepared for column chromatography.

Official Monographs

Add the following: Acemetacin Capsules is not less than 70%. Start the test with 1 capsule of Acemetacin Capsules, with- Acemetacin Capsules draw not less than 20 mL of the medium at the specified minute アセメタシンカプセル after starting the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the Acemetacin Capsules contain not less than 93.0% filtrate, pipet V mL of the subsequent filtrate, add 2nd fluid for and not more than 107.0% of the labeled amount of dissolution test to make exactly V´ mL so that each mL contains about 33 µg of acemetacin (C H ClNO ) according to the la- acemetacin (C21H18ClNO6: 415.82). 21 18 6 beled amount, and use this solution as the sample solution. Method of preparation Prepare as directed under Capsules, Separately, weigh accurately about 17 mg of acemetacin for as- with Acemetacin. say, previously dried at 105ºC for 2 hours, dissolve in the dissolution medium to make exactly 100 mL. Pipet 4 mL of this solu- Identification To an amount of powdered contents of tion, add the dissolution medium to make exactly 20 mL, and Acemetacin Capsules, equivalent to 0.1 g of Acemetacin ac- use this solution as the standard solution. Determine the ab- cording to the labeled amount, add 100 mL of methanol, shake sorbances, AT and AS, of the sample solution and standard solu- well, and filter. Take 10 mL of the filtrate, and distil the metha- tion at 319 nm as directed under Ultraviolet-visible Spectro- nol under reduced pressure. To the residue add 1 mL of metha- photometry <2.24>. nol, shake well, centrifuge, and use the supernatant liquid as the sample solution. Separately, dissolve 10 mg of acemetacin in 1 Dissolution rate (%) with respect to the labeled amount of mL of methanol, and use this solution as the standard solution. acemetacin (C21H18ClNO6) Perform the test with these solutions as directed under = WS × (AT / AS) × (V´/V) × (1/C) × 180 Thin-layer Chromatography <2.03>. Spot 2 µL each of the sample solution and standard solution on a plate of silica gel with WS: Amount (mg) of acemetacin for assay fluorescent indicator for thin-layer chromatography. Develop the C: Labeled amount (mg) of acemetacin (C21H18ClNO6) in 1 plate with a mixture of hexane, 4-methyl-2-pentanone and acetic capsule acid (100) (3:2:1) to a distance of about 10 cm, and air-dry the Assay Take out the contents of not less than 20 Acemetacin plate. Examine under ultraviolet light (main wavelength: 254 Capsules, weigh accurately the mass of the contents, and pow- nm): the spots obtained from the sample solution and standard der. Weigh accurately a portion of the powder, equivalent to solution show the same Rf value. about 30 mg of acemetacin (C21H18ClNO6), add 40 mL of Uniformity of dosage units <6.02> Perform the test accord- methanol, shake well, and add methanol to make exactly 50 mL. ing to the following method: it meets the requirement of the Filter this solution, discard the first 10 mL of the filtrate, pipet 5 Content uniformity test. mL of the subsequent filtrate, add exactly 2 mL of the internal Take out the contents of 1 capsule of Acemetacin Capsules, standard solution, add methanol to make 50 mL, and use this add 40 mL of methanol, shake well, and add methanol to make solution as the sample solution. Separately, weigh accurately exactly V mL so that each mL contains about 0.6 mg of about 30 mg of acemetacin for assay, previously dried at 105ºC for 2 hours, and dissolve in methanol to make exactly 50 mL. acemetacin (C21H18ClNO6). Filter this solution, discard the first 10 mL of the filtrate, pipet 5 mL of the subsequent filtrate, add Pipet 5 mL of this solution, add exactly 2 mL of the internal exactly 2 mL of the internal standard solution, add methanol to standard solution, add methanol to make 50 mL, and use this make 50 mL, and use this solution as the sample solution. Pro- solution as the standard solution. Perform the test with 20 µL ceed as directed in the Assay. each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the follow-

Amount (mg) of acemetacin (C21H18ClNO6) ing conditions, and calculate the ratios, QT and QS, of the peak = WS× (QT/QS) × (V/50) area of acemetacin to that of the internal standard.

WS: Amount (mg) of acemetacin for assay Amount (mg) of acemetacin (C21H18ClNO6) = WS × (QT/QS) Internal standard solution—A solution of hexyl parahydroxybenzoate in methanol (1 in 1000) WS: Amount (mg) of acemetacin for assay

Dissolution <6.10> When the test is performed at 50 revolu- Internal standard solution—A solution of hexyl parahydroxy- tions per minute according to the Paddle method using the benzoate in methanol (1 in 1000) sinker, using 900 mL of 2nd fluid for dissolution test as the dissolution medium, the dissolution rate in 30 minutes of Operating Conditions—

2073 2074 Official Monographs Supplement II, JP XV

Detector: An ultraviolet absorption photometer (wavelength sample solution and standard solution show the same Rf value. 254 nm) Column: A stainless steel column 4.6 mm in inside diameter Uniformity of dosage units <6.02> Perform the test accord- and 25 cm in length, packed with octadecylsilanized silica gel ing to the following method: it meets the requirement of the for liquid chromatography (5 µm in particle diameter). Content uniformity test. Column temperature: A constant temperature of about 40ºC. To 1 tablet of Acemetacin Tablets add 3 mL of water, and Mobile phase: To 6 g of acetic acid (100) add water to make shake until the tablet is disintegrated. Add 15 mL of methanol, 1000 mL, and adjust the pH to 3.2 with a solution of 1.36 g of shake for 20 minutes, and add methanol to make exactly V mL sodium acetate trihydrate in 100 mL of water. To 200 mL of this so that each mL contains about 1.2 mg of acemetacin solution add 300 mL of acetonitrile. (C21H18ClNO6). Centrifuge this solution, filter the supernatant Flow rate: Adjust the flow rate so that the retention time of liquid, discard the first 10 mL of the filtrate, pipet 5 mL of the acemetacin is about 7 minutes. subsequent filtrate, add exactly 1 mL of the internal standard System suitability— solution, add methanol to make 50 mL, and use this solution as System performance: Dissolve 75 mg of acemetacin and 75 the sample solution. Proceed as directed in the Assay. mg of indometacin in 50 mL of methanol. To 2 mL of this solu- Amount (mg) of acemetacin (C H ClNO ) tion add 2 mL of the internal standard solution, and add metha- 21 18 6 = W × (Q /Q ) × (V/25) nol to make 50 mL. When the procedure is run with 20 µL of S T S this solution under the above operating conditions, acemetacin, WS: Amount (mg) of acemetacin for assay indometacin and the internal standard are eluted in this order with the resolutions between the peaks of acemetacin and indo- Internal standard solution—A solution of hexyl parahydroxy- metacin and between the peaks of indometacin and the internal benzoate in methanol (1 in 250) standard being not less than 3, respectively. System repeatability: When the test is repeated 6 times with Dissolution <6.10> When the test is performed at 50 revolu- 20 µL of the standard solution under the above operating conditions per minute according to the Paddle method, using 900 mL tions, the relative standard deviation of the ratio of the peak area of 2nd fluid for dissolution test as the dissolution medium, the of acemetacin to that of the internal standard is not more than dissolution rate in 45 minutes of Acemetacin Tablets is not less 1.0%. than 80%. Start the test with 1 tablet of Acemetacin Tablets, withdraw Containers and storage Containers—Tight containers. not less than 20 mL of the medium at the specified minute after starting the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the fil- Add the following: trate, pipet V mL of the subsequent filtrate, add the dissolution medium to make exactly V´ mL so that each mL contains about

Acemetacin Tablets 33 µg of acemetacin (C21H18ClNO6) according to the labeled amount, and use this solution as the sample solution. Separately, アセメタシン錠 weigh accurately about 17 mg of acemetacin for assay, previously dried at 105ºC for 2 hours, dissolve in the dissolution me- Acemetacin Tablets contain not less than 93.0% and dium to make exactly 100 mL. Pipet 4 mL of this solution, add not more than 107.0% of the labeled amount of the dissolution medium to make exactly 20 mL, and use this so- acemetacin (C21H18ClNO6: 415.82). lution as the standard solution. Determine the absorbances, AT Method of preparation Prepare as directed under Tablets, and AS, of the sample solution and standard solution at 319 nm with Acemetacin. as directed under Ultraviolet-visible Spectrophotometry <2.24>.

Identification To a quantity of powdered Acemetacin Tablets, Dissolution rate (%) with respect to the labeled amount of equivalent to 0.1 g of Acemetacin according to the labeled acemetacin (C21H18ClNO6) amount, add 100 mL of methanol, shake well, and filter. Take 10 = WS × (AT / AS) × (V´/V) × (1/C) × 180 mL of the filtrate, and distil the methanol under reduced pres- W : Amount (mg) of acemetacin for assay sure. Dissolve the residue in 1 mL of methanol, centrifuge, and S C: Labeled amount (mg) of acemetacin (C H ClNO ) in 1 use the supernatant liquid as the sample solution. Separately, 21 18 6 tablet dissolve 10 mg of acemetacin in 1 mL of methanol, and use this solution as the standard solution. Perform the test with these so- Assay Weigh accurately the mass of not less than 20 lutions as directed under Thin-layer Chromatography <2.03>. Acemetacin Tablets, and powder. Weigh accurately a portion of Spot 2 µL each of the sample solution and standard solution on a the powder, equivalent to about 0.6 g of acemetacin plate of silica gel with fluorescent indicator for thin-layer chro- (C21H18ClNO6), add 120 mL of methanol, shake for 20 minutes, matography. Develop the plate with a mixture of hexane, and add methanol to make exactly 200 mL. Centrifuge this solu- 4-methyl-2-pentanone and acetic acid (100) (3:2:1) to a distance tion, filter the supernatant liquid, discard the first 10 mL of the of about 10 cm, and air-dry the plate. Examine under ultraviolet filtrate, pipet 2 mL of the subsequent filtrate, add exactly 1 mL light (main wavelength: 254 nm): the spots obtained from the

Supplement II, JP XV Official Monographs 2075 of the internal standard solution, add methanol to make 50 mL, Add the following: and use this solution as the sample solution. Separately, weigh accurately about 30 mg of acemetacin for assay, previously dried at 105ºC for 2 hours, and dissolve in methanol to make Aciclovir exactly 25 mL. Pipet 5 mL of this solution, add exactly 1 mL of アシクロビル the internal standard solution, add methanol to make 50 mL, and use this solution as the standard solution. Perform the test with 10 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and calculate the ratios, QT and QS, of the peak area of acemetacin to that of the internal standard.

C H N O : 225.20 Amount (mg) of acemetacin (C21H18ClNO6) 8 11 5 3 2-Amino-9-[(2-hydroxyethoxy)methyl]-1,9-dihydro- = WS × (QT/QS) × 20 6H-purin-6-one [59277-89-3]

WS: Amount (mg) of acemetacin for assay Aciclovir contains not less than 98.5 and not more Internal standard solution—A solution of hexyl parahydroxy- than 101.0% of C8H11N5O3, calculated on the anhy- benzoate in methanol (1 in 250) drous basis. Operating Conditions— Detector: An ultraviolet absorption photometer (wavelength Description Aciclovir occurs as a white to pale yellowish 254 nm) white crystalline powder. Column: A stainless steel column 4.6 mm in inside diameter It is slightly soluble in water and very slightly soluble in and 25 cm in length, packed with octadecylsilanized silica gel ethanol (99.5). for liquid chromatography (5 µm in particle diameter). It dissolves in 0.1 mol/L hydrochloric acid TS and in dilute Column temperature: A constant temperature of about 40ºC. sodium hydroxide TS. Mobile phase: To 6 g of acetic acid (100) add water to make Identification (1) Determine the absorption spectrum of a 1000 mL, and adjust the pH to 3.2 with a solution of 1.36 g of solution of Aciclovir in 0.1 mol/L hydrochloric acid TS (1 in sodium acetate trihydrate in 100 mL of water. To 200 mL of this 100000) as directed under Ultraviolet-visible Spectrophotome- solution add 300 mL of acetonitrile. try <2.24>, and compare the spectrum with the Reference Spec- Flow rate: Adjust the flow rate so that the retention time of trum or the spectrum of Aciclovir Reference Standard: both acemetacin is about 7 minutes. spectra exhibit similar intensities of absorption at the same System suitability— wavelengths. System performance: Dissolve 75 mg of acemetacin and 75 (2) Determine the infrared absorption spectrum of Aciclovir mg of indometacin in 50 mL of methanol. To 4 mL of this solu- as directed in the potassium bromide disk method under Infrared tion add 1 mL of the internal standard solution, and add metha- Spectrophotometry <2.25>, and compare the spectrum with the nol to make 50 mL. When the procedure is run with 10 µL of Reference Spectrum or the spectrum of Aciclovir Reference this solution under the above operating conditions, acemetacin, Standard: both spectra exhibit similar intensities of absorption at indometacin and the internal standard are eluted in this order the same wave numbers. with the resolutions between the peaks of acemetacin and indometacin and between the peaks of indometacin and the internal Purity (1) Clarity and color of solution—Dissolve 0.5 g of standard being not less than 3, respectively. Aciclovir in 20 mL of dilute sodium hydroxide TS: the solution System repeatability: When the test is repeated 6 times with is clear and is not more colored than the following control solu- 10 µL of the standard solution under the above operating condition. tions, the relative standard deviation of the ratio of the peak area Control solution: To 2.5 mL of Matching Fluid for Color F of acemetacin to that of the internal standard is not more than add diluted dilute hydrochloric acid (1 in 10) to make 100 mL. 1.0%. (2) Heavy metals <1.07>—Proceed with 1.0 g of Aciclovir according to Method 2, and perform the test. Prepare the control Containers and storage Containers—Tight containers. solution with 1.0 mL of Standard Lead Solution (not more than 10 ppm). (3) Related substances—Use the sample solution obtained in the Assay as the sample solution. Separately, weigh accurately about 25 mg of guanine, dissolve in 50 mL of dilute sodium hydroxide TS, and add the mobile phase to make exactly 100 mL. Pipet 2 mL of this solution, add the mobile phase to make exactly 100 mL, and use this solution as the standard solution. Perform the test with exactly 10 µL each of the sample solution and standard solution as directed under Liquid Chro-

2076 Official Monographs Supplement II, JP XV matography <2.01> according to the following conditions. De- Detector: An ultraviolet absorption photometer (wavelength: termine the peak areas of guanine, AT and AS, and calculate the 254 nm) amount of guanine by the following equation: it is not more than Column: A stainless steel column 4.6 mm in inside diameter 0.7%. Determine each peak area from the sample solution by the and 10 cm in length, packed with octadecylsilanized silica gel automatic integration method, and calculate the amount of each for liquid chromatography (3 µm in particle diameter). related substance other than aciclovir and guanine by the area Column temperature: A constant temperature of about 20ºC. percentage method: it is not more than 0.2%. Furthermore, the Mobile phase: Dissolve 1.0 g of sodium 1-decanesulfonate sum of the amount of guanine calculated above and the amounts and 6.0 g of sodium dihydrogen phosphate dihydrate in 1000 of related substances determined by the area percentage method mL of water, and adjust the pH to 3.0 with phosphoric acid. To is not more than 1.5%. this solution add 40 mL of acetonitrile. Flow rate: Adjust the flow rate so that the retention time of Amount (%) of guanine = (WS/WT) × (AT/AS) × (2/5) aciclovir is about 3 minutes. System suitability— W : Amount (mg) of guanine S System performance: Dissolve 0.1 g of Aciclovir in 5 mL of W : Amount (mg) of Aciclovir T dilute sodium hydroxide TS, add 2 mL of a solution of guanine Operating Conditions— in dilute sodium hydroxide TS (1 in 4000), and add the mobile Detector, column, column temperature, mobile phase, and phase to make 100 mL. When the procedure is run with 10 µL of flow rate: Proceed as directed in the operating conditions in the this solution under the above operating conditions, aciclovir and Assay. guanine are eluted in this order with the resolution between Time span of measurement: About 8 times as long as the re- these peaks being not less than 17. tention time of aciclovir beginning after the solvent peak. System repeatability: When the test is repeated 6 times with System suitability— 10 µL of the standard solution under the above operating condi- System performance: Proceed as directed in the system suit- tions, the relative standard deviation of the peak area of aci- ability in the Assay. clovir is not more than 1.0%. Test for required detectability: Pipet 1 mL of the sample solu- Containers and storage Containers—Well-closed containers. tion, add the mobile phase to make exactly 100 mL, and use this solution as the solution for system suitability test. Pipet 1 mL of Add the following: the solution for system suitability test, and add the mobile phase to make exactly 10 mL. Confirm that the peak area of aciclovir obtained from 10 µL of this solution is equivalent to 7 to 13% of L-Alanine that from the solution for system suitability test. L‐アラニン System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of guanine is not more than 2.0%. C H NO : 89.09 (4) Residual solvent—Being specified separately. 3 7 2 (2S)-2-Aminopropanoic acid [56-41-7] Water <2.48> Not more than 6.0% (50 mg, potentiometric ti- L-Alanine, when dried, contains not less than 98.5% tration). and not more than 101.0% of C3H7NO2. Residue on ignition <2.44> Not more than 0.1% (1 g). Description L-Alanine occurs as white crystals or crystalline Assay Weigh accurately about 20 mg each of Aciclovir and powder. It has a slightly sweet taste. Aciclovir Reference Standard (separately determine the water It is freely soluble in water and in formic acid, and practically <2.48> in the same manner as Aciclovir), dissolve each in 1 mL insoluble in ethanol (99.5). of dilute sodium hydroxide TS, add the mobile phase to make It dissolves in 6 mol/L hydrochloric acid TS. exactly 20 mL each, and use these solutions as the sample solu- Identification Determine the infrared absorption spectrum of tion and standard solutions, respectively. Perform the test with L-Alanine as directed in the potassium bromide disk method 10 µL each of the sample solution and standard solution as di- under Infrared Spectrophotometry <2.25>, and compare the rected under Liquid Chromatography <2.01> according to the spectrum with the Reference Spectrum: both spectra exhibit following conditions, and determine the peak areas, A and A , T S similar intensities of absorption at the same wave numbers. of aciclovir in each solution. Optical rotation <2.49> [α] 20 : +13.5 - +15.5º (after drying, Amount (mg) of C H N O = W × (A /A ) D 8 11 5 3 S T S 2.5 g, 6 mol/L hydrochloric acid TS, 25 mL, 100 mm). Ws: Amount (mg) of Aciclovir Reference Standard, calculated pH <2.54> Dissolve 1.0 g of L-Alanine in 20 mL of water: the on the anhydrous basis pH of the solution is between 5.7 and 6.7. Operating conditions—

Supplement II, JP XV Official Monographs 2077

Purity (1) Clarity and color of solution—Dissolve 1.0 g of L-histidine hydrochloride monohydrate, and L-arginine, dissolve L-Alanine in 10 mL of water: the solution is clear and colorless. in 0.1 mol/L hydrochloric acid TS to make exactly 1000 mL, (2) Chloride <1.03>—Perform the test with 0.5 g of and use this solution as the standard stock solution. Pipet 5 mL L-Alanine. Prepare the control solution with 0.30 mL of 0.01 of this solution, add 0.02 mol/L hydrochloric acid TS to make mol/L hydrochloric acid VS (not more than 0.021%). exactly 100 mL. Pipet 2 mL of this solution, add 0.02 mol/L hy- (3) Sulfate <1.14>—Perform the test with 0.6 g of drochloric acid TS to make exactly 50 mL, and use this solution L-Alanine. Prepare the control solution with 0.35 mL of 0.005 as the standard solution. Perform the test with 20 µL each of the mol/L sulfuric acid VS (not more than 0.028%). sample solution and standard solution as directed under Liquid (4) Ammonium <1.02>—Perform the test with 0.25 g of Chromatography <2.01> according to the following conditions. L-Alanine. Prepare the control solution with 5.0 mL of Standard Based on the peak heights obtained from the sample solution Ammonium Solution (not more than 0.02%). and standard solution, determine the mass of the amino acids (5) Heavy metals <1.07>—Proceed with 1.0 g of L-Alanine other than alanine contained in 1 mL of the sample solution, and according to Method 1, and perform the test. Prepare the control calculate the mass percent: the amount of each amino acid other solution with 1.0 mL of Standard Lead Solution (not more than than alanine is not more than 0.1%. 10 ppm). Operating conditions— (6) Iron <1.10>—Prepare the test solution with 1.0 g of Detector: A visible spectrophotometer (wavelength: 570 nm) L-Alanine according to Method 1, and perform the test accord- Column: A stainless steel column 4.6 mm in inside diameter ing to Method A. Prepare the control solution with 1.0 mL of and 8 cm in length, packed with strongly acidic ion-exchange Standard Iron Solution (not more than 10 ppm). resin for liquid chromatography (sodium type) composed with a (7) Related substances—Weigh accurately about 0.5 g of sulfonated polystyrene copolymer (3 µm in particle diameter). L-Alanine, dissolve in 0.5 mL of hydrochloric acid and water to Column temperature: A constant temperature of about 57ºC. make exactly 100 mL. Pipet 5 mL of this solution, add 0.02 Chemical reaction bath temperature: A constant temperature mol/L hydrochloric acid TS to make exactly 50 mL, and use this of about 130ºC. solution as the sample solution. Separately, accurately measure Reaction time: About 1 minute. 2.5 mmol amounts of L-aspartic acid, L-threonine, L-serine, Mobile phase: Prepare mobile phases A, B, C, D and E ac- L-glutamic acid, glycine, L-alanine, L-valine, L-cystine, cording to the following table, and add 0.1 mL of capric acid to L-methionine, L-isoleucine, L-leucine, L-tyrosine, each mobile phase. L-phenylalanine, L-lysine hydrochloride, ammonium chloride,

Mobile phase A Mobile phase B Mobile phase C Mobile phase D Mobile phase E

Citric acid monohydrate 19.80 g 22.00 g 12.80 g 6.10 g - Trisodium citrate dihydrate 6.19 g 7.74 g 13.31 g 26.67 g - Sodium chloride 5.66 g 7.07 g 3.74 g 54.35 g - Sodium hydroxide - - - - 8.00 g Ethanol (99.5) 260 mL 20 mL 4 mL - 100 mL Thiodiglycol 5 mL 5 mL 5 mL - - Benzyl alcohol - - - 5 mL - Lauromacrogol solution (1 in 4) 4 mL 4 mL 4 mL 4 mL 4 mL Appropriate Appropriate Appropriate Appropriate Appropriate Water amount amount amount amount amount

Total volume 2000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Changing mobile phases: When the procedure is run with 20 drate in water, add 245 mL of acetic acid (100) and 801 mL of µL of the standard solution under the above operating conditions, 1-methoxy-2-propanol, and water to make 2000 mL, introduce switchover to mobile phase A, mobile phase B, mobile phase C, nitrogen for 10 minutes, and use this solution as solution (I). mobile phase D and mobile phase E, in sequence so that aspartic Separately, add 77 g of ninhydrin to 1957 mL of acid, threonine, serine, glutamic acid, glycine, alanine, valine, 1-methoxy-2-propanol, introduce nitrogen for 5 minutes, add cystine, methionine, isoleucine, leucine, tyrosine, phenylalanine, 0.134 g of sodium borohydride, and introduce nitrogen for 30 lysine, ammonia, histidine, and arginine are eluted in this order minutes. To 12 volumes of this solution add 13 volumes of solu- with the resolution between the peaks of isoleucine and leucine tion (I). Prepare before use. being not less than 1.2. Flow rate of mobile phase: 0.32 mL per minute. Reaction reagents: Dissolve 407 g of lithium acetate dehy- Flow rate of reaction reagent: 0.30 mL per minute.

2078 Official Monographs Supplement II, JP XV

System suitability— length: 254 nm): the principal spots obtained from the sample

System performance: When the procedure is run with 20 µL solution and standard solution show the same Rf value. of the standard solution under the above operating conditions, the resolution between the peaks of glycine and alanine is not Uniformity of dosage units <6.02> Perform the test accord- less than 1.5. ing to the following method: it meets the requirement of the System repeatability: When the test is repeated 6 times with Content uniformity test. 20 µL of the standard solution under the above operating condi- To 1 tablet of Allopurinol Tablets add V/10 mL of 0.05 mol/L tions, the relative standard deviations of the peak height and re- sodium hydroxide TS, shake well, and treat with ultrasonic tention time of each amino acid obtained from the standard so- waves for 10 minutes. After cooling, add 0.1 mol/L hydrochloric lution are not more than 5.0% and not more than 1.0%, respec- acid TS to make exactly V mL so that each mL contains about tively. 0.5 mg of allopurinol (C5H4N4O), and filter through a membrane filter with a pore size not exceeding 0.8 µm. Discard the Loss on drying <2.41> Not more than 0.3% (1 g, 105ºC, 3 first 10 mL of the filtrate, pipet 2 mL of the subsequent filtrate, hours). add 0.1 mol/L of hydrochloric acid TS to make exactly 100 mL, Residue on ignition <2.44> Not more than 0.1% (1 g). and use this solution as the sample solution. Separately, weigh accurately about 50 mg of allopurinol for assay, previously dried Assay Weigh accurately about 90 mg of L-Alanine, previously at 105ºC for 4 hours, dissolve in 10 mL of 0.05 mol/L sodium dried, dissolve in 3 mL of formic acid, add 50 mL of acetic acid hydroxide TS, and add 0.1 mol/L hydrochloric acid TS to make (100), and titrate <2.50> with 0.1 mol/L perchloric acid VS (po- exactly 100 mL. Pipet 2 mL of this solution, add 0.1 mol/L hy- tentiometric titration). Perform a blank determination in the drochloric acid TS to make exactly 100 mL, and use this solu- same manner, and make any necessary correction. tion as the standard solution. Determine the absorbances, AT and AS, of the sample solution and standard solution at 250 nm as Each mL of 0.1 mol/L perchloric acid VS directed under Ultraviolet-visible Spectrophotometry <2.24>. = 8.909 mg of C3H7NO2 Amount (mg) of allopurinol (C5H4N4O) Containers and storage Containers—Tight containers. = WS × (AT/AS) × (V/100)

WS: Amount (mg) of allopurinol for assay Add the following: Dissolution <6.10> When the test is performed at 50 revolu- Allopurinol Tablets tions per minute according to the Paddle method, using 900 mL of water as the dissolution medium, the dissolution rate in 30 アロプリノール錠 minutes of Allopurinol Tablets is not less than 80%. Start the test with 1 tablet of Allopurinol Tablets, withdraw Allopurinol Tablets contain not less than 93.0% and not less than 20 mL of the medium at the specified minute after not more than 107.0% of the labeled amount of al- starting the test, and filter through a membrane filter with a pore lopurinol (C5H4N4O: 136.11). size not exceeding 0.8 µm. Discard the first 10 mL of the filtrate, pipet V mL of the subsequent filtrate, add water to make exactly Method of preparation Prepare as directed under Tablets, V´ mL so that each mL contains about 11 µg of allopurinol with Allopurinol. (C5H4N4O) according to the labeled amount, and use this solu- Identification (1) Determine the absorption spectrum of the tion as the sample solution. Separately, weigh accurately about sample solution obtained in the Assay as directed under Ultra- 11 mg of allopurinol for assay, previously dried at 105ºC for 4 violet-visible Spectrophotometry <2.24>: it exhibits a maximum hours, and dissolve in water to make exactly 100 mL. Pipet 5 between 248 nm and 252 nm. mL of this solution, add water to make exactly 50 mL, and use (2) To a quantity of powdered Allopurinol Tablets, equiva- this solution as the standard solution. Determine the absorb- lent to 0.1 g of Allopurinol according to the labeled amount, add ances, AT and AS, of the sample solution and standard solution at 5 mL of a solution of diethylamine (1 in 10), shake well, add 5 250 nm as directed under Ultraviolet-visible Spectrophotometry mL of methanol, centrifuge, and use the supernatant liquid as <2.24>. the sample solution. Separately, dissolve 0.1 g of allopurinol in Dissolution rate (%) with respect to the labeled amount of 5 mL of a solution of diethylamine (1 in 10), add 5 mL of allopurinol (C5H4N4O) methanol, and use this solution as the standard solution. Perform = WS × (AT/AS) × (V´/V) × (1/C) × 90 the test with these solutions as directed under Thin-layer Chro- matography <2.03>. Spot 2.5 µL each of the sample solution WS: Amount (mg) of allopurinol for assay and standard solution on a plate of silica gel with fluorescent in- C: Labeled amount (mg) of allopurinol (C5H4N4O) in 1 tablet dicator for thin-layer chromatography. Develop the plate with a mixture of 2-butanone, ammonia solution (28) and Assay Weigh accurately the mass of not less than 20 Al- 2-methoxyethanol (3:1:1) to a distance of about 10 cm, and lopurinol Tablets, and powder. Weigh accurately a portion of the air-dry the plate. Examine under ultraviolet light (main wave- powder, equivalent to about 0.1 g of allopurinol (C5H4N4O), add

Supplement II, JP XV Official Monographs 2079

20 mL of 0.05 mol/L sodium hydroxide TS, shake well, and = WS × (AT/AS) treat with ultrasonic waves for 10 minutes. After cooling, add 0.1 mol/L hydrochloric acid TS to make exactly 200 mL, and WS: Amount (mg) of theophylline for assay filter through a membrane filter with a pore size not exceeding Operating conditions— 0.8 µm. Discard the first 10 mL of the filtrate, pipet 2 mL of the Detector: An ultraviolet absorption photometer (wavelength: subsequent filtrate, add 0.1 mol/L hydrochloric acid TS to make 270 nm). exactly 100 mL, and use this solution as the sample solution. Column: A stainless steel column 6 mm in inside diameter Separately, weigh accurately about 0.1 g of allopurinol for assay, and 15 cm in length, packed with octadecylsilanized silica gel previously dried at 105ºC for 4 hours, dissolve in 20 mL of 0.05 for liquid chromatography (5 µm in particle diameter). mol/L sodium hydroxide TS, and add 0.1 mol/L hydrochloric Column temperature: A constant temperature of about 40ºC. acid TS to make exactly 200 mL. Pipet 2 mL of this solution, Mobile phase: A mixture of diluted acetic acid (100) (1 in add 0.1 mol/L hydrochloric acid TS to make exactly 100 mL, 100) and methanol (4:1). and use this solution as the standard solution. Determine the Flow rate: Adjust the flow rate so that the retention time of absorbances, A and A , of the sample solution and standard so- T S theophylline is about 5 minutes. lution at 250 nm as directed under Ultraviolet-visible Spectro- System suitability— photometry <2.24>. System performance: When the procedure is run with 5 µL of the standard solution under the above operating conditions, the Amount (mg) of allopurinol (C5H4N4O) = WS × (AT/AS) number of theoretical plates and the symmetry factor of the peak

WS: Amount (mg) of allopurinol for assay of theophylline are not less than 3000 and not more than 1.5, respectively. Containers and storage Containers—Well-closed containers. System repeatability: When the test is repeated 6 times with 5 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of theophylline Dried Aluminum Hydroxide Gel is not more than 1.0%. Fine Granules Add the following: 乾燥水酸化アルミニウムゲル細粒

Change the Method of preparation to read: Amiodarone Hydrochloride

Method of preparation Prepare to finely granulated form as アミオダロン塩酸塩 directed under Powders, with Dried Aluminum Hydroxide Gel.

Add the following next to the Identification:

Particle size <6.03> It meets the requirement.

C25H29I2NO3·HCl: 681.77 Aminophylline Injection (2-Butylbenzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3,5- diiodophenyl}methanone monohydrochloride [19774-82-4] アミノフィリン注射液 Amiodarone Hydrochloride, when dried, contains Change the Assay (1) to read: not less than 98.5% and not more than 101.0% of Assay (1) Theophylline—Pipet a volume of Aminophylline C25H29I2NO3·HCl. Injection, equivalent to about 39.4 mg of theophylline Description Amiodarone Hydrochloride occurs as a (C H N O ) (about 50 mg of Aminophylline Hydrate), add wa- 7 8 4 2 white to pale yellowish white crystalline powder. ter to make exactly 50 mL, and use this solution as the sample It is very soluble in water at 80ºC, freely soluble in di- solution. Separately, weigh accurately about 40 mg of theophyl- chloromethane, soluble in methanol, sparingly soluble in line for assay, previously dried at 105ºC for 4 hours, dissolve in ethanol (95), and very slightly soluble in water. water to make exactly 50 mL, and use this solution as the stan- Melting point: about 161ºC (with decomposition). dard solution. Perform the test with exactly 5 µL each of the sample solution and standard solution as directed under Liquid Identification (1) Determine the absorption spectrum of a Chromatography <2.01> according to the following conditions, solution of Amiodarone Hydrochloride in ethanol (95) (1 in and determine the peak areas, AT and AS, of theophylline in each 100000) as directed under Ultraviolet-visible Spectrophotome- solution. try <2.24>, and compare the spectrum with the Reference Spec- trum: both spectra exhibit similar intensities of absorption at the Amount (mg) of theophylline (C H N O ) 7 8 4 2 same wavelengths.

2080 Official Monographs Supplement II, JP XV

(2) Determine the infrared absorption spectrum of Amio- Perform the test with these solutions as directed under darone Hydrochloride as directed in the potassium bromide disk Thin-layer Chromatography <2.03>. Spot 5 µL each of the sam- method under Infrared Spectrophotometry <2.25>, and compare ple solution and standard solution on a plate of silica gel with the spectrum with the Reference Spectrum: both spectra exhibit fluorescent indicator for thin-layer chromatography. Develop the similar intensities of absorption at the same wave numbers. plate with a mixture of dichloromethane, methanol and formic (3) To 0.1 g of Amiodarone Hydrochloride add 10 mL of acid (17:2:1) to a distance of about 15 cm, and air-dry the plate. water, dissolve by warming at 80ºC, and cool: the solution re- Splay evenly bismuth subnitrate TS and then hydrogen peroxide sponds to the Qualitative Tests <1.09> (2) for chloride. TS: the spot obtained from the sample solution corresponding to the spot from the standard solution is not more intense than the pH <2.54> To 1.0 g of Amiodarone Hydrochloride add 20 mL spot from the standard solution. of freshly boiled and cooled water, dissolve by warming at 80ºC, (5) Related substance 2—Dissolve 0.125 g of Amiodarone and cool: the pH of this solution is between 3.2 and 3.8. Hydrochloride in 25 mL of a mixture of water and acetonitrile for liquid chromatography (1:1), and use this solution as the Purity (1) Clarity and color of solution—Dissolve 0.5 g of sample solution. Pipet 2 mL of this solution, and add a mixture Amiodarone Hydrochloride in 10 mL of methanol: the solution of water and acetonitrile for liquid chromatography (1:1) to is clear, and is not more colored than the following control solu- make exactly 50 mL. Pipet 1 mL of this solution, add a mixture tions (1) and (2). of water and acetonitrile for liquid chromatography (1:1) to Control solution (1): To a mixture of 1.0 mL of Cobalt (II) make exactly 20 mL, and use this solution as the standard solu- Chloride Colorimetric Stock Solution, 2.4 mL of Iron (III) tion. Perform the test with exactly 10 µL each of the sample so- Chloride Colorimetric Stock Solution and 0.4 mL of Copper (II) lution and standard solution as directed under Liquid Chroma- Sulfate Colorimetric Stock Solution, add diluted hydrochloric tography <2.01> according to the following conditions. Deter- acid (1 in 40) to make 10.0 mL. To 2.5 mL of this solution add mine each peak area by the automatic integration method: the diluted hydrochloric acid (1 in 40) to make 20 mL. area of any peak other than amiodarone obtained from the sam- Control solution (2): To 3.0 mL of a mixture of 0.2 mL of ple solution is not larger than the peak area of amiodarone from Cobalt (II) Chloride Colorimetric Stock Solution, 9.6 mL of Iron the standard solution, and the total area of the peaks other than (III) Chloride Colorimetric Stock Solution and 0.2 mL of Cop- the peak of amiodarone from the sample solution is not larger per (II) Sulfate Colorimetric Stock Solution, add diluted hydro- than 2.5 times the peak area of amiodarone from the standard chloric acid (1 in 40) to make 100 mL. solution. (2) Iodine—To 1.50 g of Amiodarone Hydrochloride add 40 Operating conditions— mL of water, dissolve by warming at 80ºC, cool, add water to Detector: An ultraviolet absorption photometer (wavelength: make exactly 50 mL, and use this solution as the sample stock 240 nm) solution. Pipet 15 mL of this solution, add exactly 1 mL of 0.1 Column: A stainless steel column 4.6 mm in inside diameter mol/L hydrochloric acid TS and exactly 1 mL of a solution of and 15 cm in length, packed with octadecylsilanized silica gel potassium iodate (107 in 10000), add water to make exactly 20 for liquid chromatography (5 µm in particle diameter). mL, and use this solution as the sample solution. Separately, pi- Column temperature: A constant temperature of about 30ºC. pet 15 mL of the sample stock solution, add exactly 1 mL of 0.1 Mobile phase: To 800 mL of water add 3.0 mL of acetic acid mol/L hydrochloric acid TS, exactly 1 mL of a solution of po- (100), adjust the pH to 4.95 with ammonia solution (28), and tassium iodide (441 in 5000000) and exactly 1 mL of a solution add water to make 1000 mL. To 300 mL of this solution add 400 of potassium iodate (107 in 10000), add water to make exactly mL of acetonitrile for liquid chromatography and 300 mL of 20 mL, and use this solution as the standard solution. Separately, methanol for liquid chromatography. pipet 15 mL of the sample stock solution, add exactly 1 mL of Flow rate: Adjust the flow rate so that the retention time of 0.1 mol/L hydrochloric acid TS, add water to make exactly 20 amiodarone is about 24 minutes. mL, and use this solution as the control solution. Allow the Time span of measurement: About 2 times as long as the re- sample solution, standard solution and control solution to stand tention time of amiodarone. in a dark place for 4 hours. Perform the test with the sample so- System suitability— lution and standard solution as directed under Ultraviolet-visible Test for required detectability: Pipet 5 mL of the standard so- Spectrophotometry <2.24>, using the control solution as the lution, and add a mixture of water and acetonitrile for liquid blank: the absorbance of the sample solution at 420 nm is not chromatography (1:1) to make exactly 25 mL. Confirm that the larger than 1/2 times the absorbance of the standard solution. peak area of amiodarone obtained from 10 µL of this solution is (3) Heavy metals <1.07>—Proceed with 1.0 g of Amiodar- equivalent to 14 to 26% of that of amiodarone from the standard one Hydrochloride according to Method 4, and perform the test. solution. Prepare the control solution with 2.0 mL of Standard Lead Solu- System performance: When the procedure is run with 10 µL tion (not more than 20 ppm). of the standard solution under the above operating conditions, (4) Related substance 1—Dissolve 0.5 g of Amiodarone the number of theoretical plates and the symmetry factor of the Hydrochloride in 5 mL of dichloromethane, and use this solu- peak of amiodarone are not less than 5000 and not more than tion as the sample solution. Separately, dissolve 10 mg of 1.5, respectively. 2-chloroethyl diethylamine hydrochloride in 50 mL of di- System repeatability: When the test is repeated 6 times with chloromethane, and use this solution as the standard solution.

Supplement II, JP XV Official Monographs 2081

10 µL of the standard solution under the above operating condi- lution as directed under Liquid Chromatography <2.01> ac- tions, the relative standard deviation of the peak area of amio- cording to the following conditions, and determine the peak ar- darone is not more than 1.0%. eas, AT and AS, of amiodarone in each solution. (6) Residual solvent—Being specified separately. Amount (mg) of amiodarone hydrochloride

Loss on drying <2.41> Not more than 0.5% (1 g, reduced (C25H29I2NO3·HCl) pressure not exceeding 0.3 kPa, 50ºC, 4 hours). = WS × (AT/AS) × (8/V)

Residue on ignition <2.44> Not more than 0.1% (1 g). WS: Amount (mg) of amiodarone for assay

Assay Weigh accurately about 0.6 g of Amiodarone Hydro- Operating conditions— chloride, previously dried, dissolve in 40 mL of a mixture of Proceed as directed in the operating conditions in the Assay. acetic anhydride and acetic acid (100) (3:1), and titrate <2.50> System suitability— with 0.1 mol/L perchloric acid VS (potentiometric titration). System performance: When the procedure is run with 10 µL Perform a blank determination in the same manner, and make of the standard solution under the above operating conditions, any necessary correction. the number of theoretical plates and the symmetry factor of the peak of amiodarone are not less than 5000 and not more than Each mL of 0.1 mol/L perchloric acid VS 1.5, respectively. = 68.18 mg of C25H29I2NO3·HCl System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- Containers and storage Containers—Tight containers. tions, the relative standard deviation of the peak area of amio- Storage—Light-resistant. darone is not more than 1.0%.

Dissolution <6.10> When the test is performed at 50 revolu- Add the following: tions per minute according to the Paddle method, using 900 mL of acetic acid-sodium acetate buffer solution, pH 4.0, as the Amiodarone Hydrochloride Tablets dissolution medium, the dissolution rate in 30 minutes of アミオダロン塩酸塩錠 Amiodarone Hydrochloride Tablets is not less than 80%. Start the test with 1 tablet of Amiodarone Hydrochloride Tab- Amiodarone Hydrochloride Tablets contain not less lets, withdraw not less than 20 mL of the medium at the speci- than 93.0% and not more than 107.0% of the labeled fied minute after starting the test, and filter through a membrane amount of amiodarone hydrochloride filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the filtrate, pipet V mL of the subsequent filtrate, add (C25H29I2NO3·HCl: 681.77). methanol to make exactly V´ mL so that each mL contains about

Method of preparation Prepare as directed under Tablets, 11 µg of amiodarone hydrochloride (C25H29I2NO3·HCl) accord- with Amiodarone Hydrochloride. ing to the labeled amount, and use this solution as the sample solution. Separately, weigh accurately about 28 mg of amiodar- Identification To 1 mL of the sample stock solution obtained one hydrochloride for assay, previously dried at 50ºC for 4 in the Assay add the mobile phase to make 50 mL. Determine hours under reduced pressure not exceeding 0.3 kPa, and dis- the absorption spectrum of this solution as directed under Ultra- solve in methanol to make exactly 50 mL. Pipet 2 mL of this violet-visible Spectrophotometry <2.24>: it exhibits a maximum solution, add exactly 10 mL of the dissolution medium, add between 239 nm and 243 nm. methanol to make exactly 100 mL, and use this solution as the standard solution. Determine the absorbances, A and A , of the Uniformity of dosage units <6.02> Perform the test accord- T S sample solution and standard solution at 241 nm as directed un- ing to the following method: it meets the requirement of the der Ultraviolet-visible Spectrophotometry <2.24>, using a solu- Content uniformity test. tion, prepared by adding methanol to 2 mL of the dissolution To 1 tablet of Amiodarone Hydrochloride Tablets add 160 mL medium to make 20 mL, as the blank. of the mobile phase, treat with ultrasonic waves for 10 minutes, add the mobile phase to make exactly 200 mL, and centrifuge. Dissolution rate (%) with respect to the labeled amount of Pipet V mL of the supernatant liquid, equivalent to about 1 mg amiodarone hydrochloride (C25H29I2NO3·HCl) of amiodarone hydrochloride (C H I NO ·HCl), add the mo- 25 29 2 3 = WS × (AT/AS) × (V´/V) × (1/C) × 36 bile phase to make exactly 50 mL, and use this solution as the sample solution. Separately, weigh accurately about 25 mg of WS: Amount (mg) of amiodarone for assay amiodarone hydrochloride for assay, previously dried at 50ºC C: Labeled amount (mg) of amiodarone hydrochloride for 4 hours under reduced pressure not exceeding 0.3 kPa, and (C25H29I2NO3·HCl) in 1 tablet dissolve in the mobile phase to make exactly 50 mL. Pipet 2 mL of this solution, add the mobile phase to make exactly 50 mL, Assay Weigh accurately the mass of not less than 20 Amio- and use this solution as the standard solution. Perform the test darone Hydrochloride Tablets, and powder. Weigh accurately a with exactly 10 µL each of the sample solution and standard so- portion of the powder, equivalent to about 50 mg of amiodarone

2082 Official Monographs Supplement II, JP XV hydrochloride (C25H29I2NO3·HCl), add 80 mL of the mobile Add the following: phase, treat with ultrasonic waves for 10 minutes, and add the mobile phase to make exactly 100 mL. Centrifuge this solution, Amlodipine Besilate Tablets and use the supernatant liquid as the sample stock solution. Pi- pet 2 mL of this solution, add 2 mL of the internal standard so- アムロジピンベシル酸塩錠 lution, add the mobile phase to make 50 mL, and use this solution as the sample solution. Separately, weigh accurately 25 mg Amlodipine Besilate Tablets contain not less than of amiodarone hydrochloride for assay, previously dried at 50ºC 95.0% and not more than 105.0% of the labeled for 4 hours under reduced pressure not exceeding 0.3 kPa, and amount of amlodipine besilate dissolve in the mobile phase to make exactly 50 mL. Pipet 2 mL (C20H25ClN2O5·C6H6O3S: 567.05). of this solution, add exactly 2 mL of the internal standard solu- Method of preparation Prepare as directed under Tablets, tion, add the mobile phase to make 50 mL, and use this solution with Amlodipine Besilate. as the standard solution. Perform the test with 10 µL each of the sample solution and standard solution as directed under Liquid Identification To a quantity of powdered Amlodipine Besilate Chromatography <2.01> according to the following conditions, Tablets, equivalent to 2.5 mg of Amlodipine Besilate according and calculate the ratios, QT and QS, of the peak area of amio- to the labeled amount, add 100 mL of 0.01 mol/L hydrochloric darone to that of the internal standard. acid-methanol TS, shake vigorously, and filter. Determine the absorption spectrum of the filtrate as directed under Ultravio- Amount (mg) of amiodarone hydrochloride let-visible Spectrophotometry <2.24>: it exhibits maxima be- (C H I NO ·HCl) 25 29 2 3 tween 235 nm and 239 nm, and between 358 nm and 362 nm. = WS × (QT/QS) × 2 Uniformity of dosage units <6.02> Perform the test accord- W : Amount (mg) of amiodarone hydrochloride for assay S ing to the following method: it meets the requirement of the Internal standard solution—A solution of chlorhexidine hydro- Content uniformity test. chloride in the mobile phase (1 in 2500) To 1 tablet of Amlodipine Besilate Tablets add 10 mL of wa- Operating conditions— ter to disintegrate, disperse with the aid of ultrasonic waves with Detector: An ultraviolet absorption photometer (wavelength: occasional shaking, add the mobile phase to make exactly V mL 242 nm) so that each mL contains about 69 µg of amlodipine besilate Column: A stainless steel column 4 mm in inside diameter (C H ClN O ·C H O S), and shake for 60 minutes. Centrifuge and 15 cm in length, packed with octadecylsilanized silica gel 20 25 2 5 6 6 3 this solution, pipet 10 mL of the supernatant liquid, add exactly for liquid chromatography (5 µm in particle diameter). 5 mL of the internal standard solution, add the mobile phase to Column temperature: A constant temperature of about 50ºC. make 25 mL, and use this solution as the sample solution. Pro- Mobile phase: A mixture of acetonitrile for liquid chromatog- ceed as directed in the Assay. raphy, a solution of sodium laurylsulfate (1 in 50) and phosphoric acid (750:250:1). Amount (mg) of amlodipine besilate Flow rate: Adjust the flow rate so that the retention time of (C20H25ClN2O5·C6H6O3S) amiodarone is about 7 minutes. = WS × (QT/QS) × (V/500) System suitability—

System performance: When the procedure is run with 10 µL WS: Amount (mg) of Amlodipine Besilate Reference Standard, of the standard solution under the above operating conditions, calculated on the anhydrous basis the internal standard and amiodarone are eluted in this order with the resolution between these peaks being not less than 5. Internal standard solution—A solution of isobutyl parahy- System repeatability: When the test is repeated 6 times with droxybenzoate in the mobile phase (3 in 20000) 10 µL of the standard solution under the above operating condi- Dissolution Being specified separately. tions, the relative standard deviation of the ratio of the peak area of amiodarone to that of the internal standard is not more than Assay To 20 Amlodipine Besilate Tablets add 100 mL of wa- 1.0%. ter to disintegrate, disperse with the aid of ultrasonic waves with occasional shaking, add the mobile phase to make exactly 1000 Containers and storage Containers—Tight containers. mL, and shake for 60 minutes. Centrifuge this solution, pipet a Storage—Light-resistant. volume of the supernatant liquid, equivalent to about 0.7 mg of

amlodipine besilate (C20H25ClN2O5·C6H6O3S), add exactly 5 mL of the internal standard solution, add the mobile phase to make 25 mL, and use this solution as the sample solution. Separately, weigh accurately about 35 mg of Amlodipine Besilate Reference Standard (separately, determine the water <2.48> in the same manner as Amlodipine Besilate), and dissolve in the mobile phase to make exactly 250 mL. Pipet 5 mL of this solution, add

Supplement II, JP XV Official Monographs 2083 exactly 5 mL of the internal standard solution, add the mobile and use the filtrate as the sample solution. Separately, dissolve phase to make 25 mL, and use this solution as the standard solu- an amount equivalent to 8 mg (potency) of Amoxicillin Refer- tion. Perform the test with 20 µL each of the sample solution ence Standard in 2 mL of 0.01 mol/L hydrochloric acid TS, and and standard solution as directed under Liquid Chromatography use this solution as the standard solution. Perform the test with <2.01> according to the following conditions, and calculate the these solutions as directed under Thin-layer Chromatography ratios, QT and QS, of the peak area of amlodipine to that of the <2.03>. Spot 5 µL each of the sample solution and standard so- internal standard. lution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of tetrahydrofuran, water and Amount (mg) of amlodipine besilate formic acid (50:5:2) to a distance of about 10 cm, and air-dry (C20H25ClN2O5·C6H6O3S) the plate. Spray evenly a solution of ninhydrin in ethanol (95) (1 = WS × (QT/QS) × (1/50) in 20) on the plate, and heat the plate at 110ºC for 15 minutes: the principal spot obtained from the sample solution and the W : Amount (mg) of Amlodipine Besilate Reference Standard, S standard solution show a red-purple color and the same R value. calculated on the anhydrous basis f Purity Related substances— Take out the contents of Amox- Internal standard solution—A solution of isobutyl parahy- icillin Capsules, to a quantity of the contents, equivalent to 0.1 g droxybenzoate in the mobile phase (3 in 20000) (potency) of Amoxicillin Hydrate according to the labeled Operating conditions— amount, add 30 mL of a solution of boric acid (1 in 200), shake Detector: An ultraviolet absorption photometer (wavelength: for 15 minutes, and add a solution of boric acid (1 in 200) to 237 nm) make 50 mL. Centrifuge this solution, and use the supernatant Column: A stainless steel column 4.6 mm in inside diameter liquid as the sample solution. Pipet 1 mL of this solution, add a and 15 cm in length, packed with octadecylsilanized silica gel solution of boric acid (1 in 200) to make exactly 100 mL, and for liquid chromatography (5 µm in particle diameter). use this solution as the standard solution. Perform the test with Column temperature: A constant temperature of about 25ºC. exactly 10 µL each of the sample solution and standard solution Mobile phase: A mixture of methanol and potassium dihy- as directed under Liquid Chromatography <2.01> according to drogen phosphate (41 in 10000) (13:7) the following conditions. Determine each peak area of both so- Flow rate: Adjust the flow rate so that the retention time of lutions by the automatic integration method: the area of each amlodipine is about 8 minutes. peak other than amoxicillin obtained from the sample solution is System suitability— not larger than the peak area of amoxicillin from the standard System performance: When the procedure is run with 20 µL solution. of the standard solution under the above operating conditions, Operating conditions— amlodipine and the internal standard are eluted in this order with Proceed as directed in the operating conditions in the Purity the resolution between these peaks being not less than 5. (3) under Amoxicillin Hydrate. System repeatability: When the test is repeated 6 times with System suitability— 20 µL of the standard solution under the above operating condi- Test for required detectability and system repeatability: Pro- tions, the relative standard deviation of the ratios of the peak ceed as directed in the system suitability in the Purity (3) under area of amlodipine to that of the internal standard is not more Amoxicillin Hydrate. than 1.0%. System performance: When the procedure is run with 10 µL Containers and storage Containers—Well-closed containers. of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry factor of the peak of amoxicillin is not less than 2500 and not more than 1.5, Add the following: respectively. Amoxicillin Capsules Water <2.48> Not more than 15.0% (0.1 g, volumetric titration, direct titration). アモキシシリンカプセル Uniformity of dosage units <6.02> It meets the requirement Amoxicillin Capsules contain not less than 92.0% of the Mass variation test. and not more than 105.0% of the labeled potency of Dissolution <6.10> When the test is performed at 100 revolu- Amoxicillin (C H N O S: 365.40). 16 19 3 5 tions per minute according to the Paddle method using the Method of preparation Prepare as directed under Capsules, sinker, using 900 mL of water as the dissolution medium, the with Amoxicillin Hydrate. dissolution rate in 60 minutes of Amoxicillin Capsules is not less than 75%. Identification Take out the contents of Amoxicillin Capsules, Start the test with 1 capsule of Amoxicillin Capsules, with- to a quantity of the contents, equivalent to 8 mg (potency) of draw not less than 20 mL of the medium at the specified minute Amoxicillin Hydrate according to the labeled amount, add 2 mL after starting the test, and filter through a membrane filter with a of 0.01 mol/L hydrochloric acid TS, shake for 30 minutes, filter, pore size not exceeding 0.45 µm. Discard the first 10 mL of the

2084 Official Monographs Supplement II, JP XV filtrate, pipet V mL of the subsequent filtrate, add water to make Column temperature, mobile phase, and flow rate: Proceed as exactly V´ mL so that each mL contains about 56 µg (potency) directed in the operating conditions in the Assay under Amox- of Amoxicillin Hydrate according to the labeled amount, and icillin Hydrate. use this solution as the sample solution. Separately, weigh accu- Detector: An ultraviolet absorption photometer (wavelength: rately an amount equivalent to about 28 mg (potency) of Amox- 254 nm). icillin Reference Standard, dissolve in water to make exactly Column: A stainless steel column 4 mm in inside diameter 100 mL. Pipet 5 mL of this solution, add water to make exactly and 30 cm in length, packed with octadecylsilanized silica gel 25 mL, and use this solution as the standard solution. Perform for liquid chromatography (10 µm in particle diameter). the test with exactly 50 µL each of the sample solution and System suitability— standard solution as directed under Liquid Chromatography System performance: When the procedure is run with 10 µL <2.01> according to the following conditions, and determine the of the standard solution under the above operating conditions, peak areas, AT and AS, of amoxicillin in each solution. the number of theoretical plates and the symmetry factor of the peak of amoxicillin are not less than 2500 and not more than 1.5, Dissolution rate (%) with respect to the labeled amount of respectively. amoxicillin (C16H19N3O5S) System repeatability: When the test is repeated 6 times with = WS × (AT/AS) × (V´/V) × (1/C) × 180 10 µL of the standard solution under the above operating conditions, the relative standard deviation of peak areas of amoxicil- W : Amount [mg (potency)] of Amoxicillin Reference Stan- S lin is not more than 1.0%. dard C: Labeled amount [mg (potency)] of amoxicillin Containers and storage Containers—Tight containers. (C16H19N3O5S) in 1 capsule Operating conditions— Amoxicillin Hydrate Proceed as directed in the operating conditions in the Assay under Amoxicillin Hydrate. アモキシシリン水和物 System suitability— Change the Purity (3) to read: System performance: When the procedure is run with 50 µL of the standard solution under the above operating conditions, Purity (3) Related substances—Dissolve 0.10 g of Amox- the number of theoretical plates and the symmetry factor of the icillin Hydrate in 50 mL of a solution of boric acid (1 in 200), peak of amoxicillin are not less than 2500 and not more than 2.0, and use this solution as the sample solution. Pipet 1 mL of the respectively. sample solution, add a solution of boric acid (1 in 200) to make System repeatability: When the test is repeated 6 times with exactly 100 mL, and use this solution as the standard solution. 50 µL of the standard solution under the above operating condi- Perform the test with exactly 10 µL each of the sample solution tions, the relative standard deviation of the peak area of amox- and standard solution as directed under Liquid Chromatography icillin is not more than 1.5%. <2.01> according to the following conditions. Determine each peak area of both solutions by the automatic integration method: Assay Weigh accurately the mass of not less than 10 Amox- the area of each peak other than amoxicillin obtained from the icillin Capsules, take out the contents, and weigh accurately the sample solution is not larger than the peak area of amoxicillin mass of the emptied shells. Weigh accurately an amount from the standard solution. equivalent to about 0.1 g (potency) of Amoxicillin Hydrate ac- Operating conditions— cording to the labeled amount, add 70 mL of water, shake for 15 Detector: An ultraviolet absorption photometer (wavelength: minutes, and add water to make exactly 100 mL. Centrifuge this 254 nm). solution, and use the supernatant liquid as the sample solution. Column: A stainless steel column 4 mm in inside diameter Separately, weigh accurately an amount equivalent to about 20 and 30 cm in length, packed with octadecylsilanized silica gel mg (potency) of Amoxicillin Reference Standard, dissolve in for liquid chromatography (10 µm in particle diameter). water to make exactly 20 mL, and use this solution as the stan- Column temperature: A constant temperature of about 25ºC. dard solution. Perform the test with exactly 10 µL each of the Mobile phase: Dissolve 1.36 g of sodium acetate trihydrate in sample solution and standard solution as directed under Liquid 750 mL of water, adjust the pH to 4.5 with acetic acid (31), and Chromatography <2.01> according to the following conditions, add water to make 1000 mL. To 950 mL of this solution add 50 and determine the peak areas, A and A , of amoxicillin in each T S mL of methanol. solution. Flow rate: Adjust the flow rate so that the retention time of amoxicillin is about 8 minutes. Amount [mg (potency)] of amoxicillin (C16H19N3O5S) Time span of measurement: About 4 times as long as the re- = WS × (AT/AS) × 5 tention time of amoxicillin.

WS: Amount [mg (potency)] of Amoxicillin Reference Stan- System suitability— dard Test for required detectability: To exactly 1 mL of the standard solution add a solution of boric acid (1 in 200) to make Operating conditions— exactly 10 mL. Confirm that the peak area of amoxicillin ob-

Supplement II, JP XV Official Monographs 2085 tained from 10 µL of this solution is equivalent to 7 to 13% of 50 mL of water: the pH of the solution is between 6.4 and 7.0. that of amoxicillin from the standard solution. System performance: When the procedure is run with 10 µL Melting point <2.60> 127-131ºC of the standard solution under the above operating conditions, Purity (1) Clarity and color of solution—Dissolve 1.0 g of the number of theoretical plates and the symmetry factor of the Aprindine Hydrochloride in 10 mL of methanol: the solution is peak of amoxicillin are not less than 2500 and not more than 1.5, clear, and its absorbance at 420 nm determined as directed under respectively. Ultraviolet-visible Spectrophotometry <2.24> is not more than System repeatability: When the test is repeated 6 times with 0.10. 10 µL of the standard solution under the above operating condi- (2) Heavy metals <1.07>—Proceed with 1.0 g of Aprindine tions, the relative standard deviation of the peak area of amox- Hydrochloride according to Method 2, and perform the test. icillin is not more than 1.0%. Prepare the control solution with 1.0 mL of Standard Lead Solu-

tion (not more than 10 ppm). Add the following: (3) Related substances—Dissolve 25 mg of Aprindine Hy- drochloride in 10 mL of the mobile phase, and use this solution Aprindine Hydrochloride as the sample solution. Pipet 1 mL of this solution, add the mobile phase to make exactly 100 mL, and use this solution as the アプリンジン塩酸塩 standard solution. Perform the test with exactly 10 µL each of the sample solution and standard solution as directed under Liq- uid Chromatography <2.01> according to the following conditions. Determine each peak area of both solutions by the automatic integration method: the area of the peak other than aprindine obtained from the sample solution is not larger than 1/10 times the peak area of aprindine from the standard solution. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: C22H30N2·HCl: 358.95 254 nm). N-(2,3-Dihydro-1H-inden-2-yl)-N´,N´-diethyl- Column: A stainless steel column 4.6 mm in inside diameter N-phenylpropane-1,3-diamine monohydrochloride and 15 cm in length, packed with octadecylsilanized silica gel [33237-74-0] for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 40ºC. Aprindine Hydrochloride, when dried, contains not Mobile phase: Dissolve 3.40 g of potassium dihydrogen less than 98.5% and not more than 101.0% of phosphate in 500 mL of water, and adjust the pH to 3.0 with hy- C H N ·HCl. 22 30 2 drochloric acid. To 500 mL of this solution add 500 mL of ace- Description Aprindine Hydrochloride occurs as a white to tonitrile. pale yellowish white crystalline powder. It has a bitter taste, Flow rate: Adjust the flow rate so that the retention time of numbing the tongue. aprindine is about 6 minutes. It is very soluble in water, methanol and in acetic acid (100), Time span of measurement: About 4 times as long as the re- and freely soluble in ethanol (99.5). tention time of aprindine. It gradually turns brown on exposure to light. System suitability— Test for required detectability: Pipet 1 mL of the standard so- Identification (1) Dissolve 10 mg of Aprindine Hydrochlo- lution, and add the mobile phase to make exactly 10 mL. Con- ride in a solution of hydrochloric acid in diluted ethanol (1 in 2) firm that the peak area of aprindine obtained from 10 µL of this (1 in 125) to make 50 mL. Determine the absorption spectrum solution is equivalent to 7 to 13% of that of aprindine from the of this solution as directed under Ultraviolet-visible Spectro- standard solution. photometry <2.24>, and compare the spectrum with the Refer- System performance: When the procedure is run with 10 µL ence Spectrum: both spectra exhibit similar intensities of ab- of the standard solution under the above operating conditions, sorption at the same wavelengths. the number of theoretical plates and the symmetry factor of the (2) Determine the infrared absorption spectrum of peak of aprindine are not less than 3000 and not more than 2.0, Aprindine Hydrochloride as directed in the potassium chloride respectively. disk method under Infrared Spectrophotometry <2.25>, and System repeatability: When the test is repeated 6 times with compare the spectrum with the Reference Spectrum: both spec- 10 µL of the standard solution under the above operating condi- tra exhibit similar intensities of absorption at the same wave tions, the relative standard deviation of the peak area of numbers. aprindine is not more than 1.5%. (3) To 5 mL of a solution of Aprindine Hydrochloride (1 in (4) Residual solvent—Being specified separately. 50) add 1 mL of dilute nitric acid: this solution responds to the Qualitative Tests <1.09> for chloride. Loss on drying <2.41> Not more than 0.5% (1 g, in vacuum, pH <2.54> Dissolve 1.0 g of Aprindine Hydrochloride in 60ºC, 4 hours).

2086 Official Monographs Supplement II, JP XV

Residue on ignition <2.44> Not more than 0.1% (1 g). specified minute after starting the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Dis- Assay Weigh accurately about 0.5 g of Aprindine Hydrochlo- card the first 10 mL of the filtrate, pipet V mL of the subsequent ride, previously dried, dissolve in 80 mL of acetic acid (100), filtrate, add water to make exactly V´ mL so that each mL con- and titrate <2.50> with 0.1 mol/L perchloric acid VS (potenti- tains about 11 µg of aprindine hydrochloride (C22H30N2·HCl) ometric titration). Perform a blank determination in the same according to the labeled amount, and use this solution as the manner, and make any necessary correction. sample solution. Separately, weigh accurately about 28 mg of aprindine hydrochloride for assay, previously dried in vacuum at Each mL of 0.1 mol/L perchloric acid VS 60ºC for 4 hours, and dissolve in water to make exactly 100 mL. = 35.90 mg of C H N ·HCl 22 30 2 Pipet 2 mL of this solution, add water to make exactly 50 mL, Containers and storage Containers—Well-closed containers and use this solution as the standard solution. Perform the test Storage—Light-resistant. with exactly 20 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and determine the peak ar-

Add the following: eas, AT and AS, of aprindine in each solution. Aprindine Hydrochloride Capsules Dissolution rate (%) with respect to the labeled amount of aprindine hydrochloride (C22H30N2·HCl) アプリンジン塩酸塩カプセル = WS × (AT/AS) × (V´/V) × (1/C) × 36

Aprindine Hydrochloride Capsules contain not less WS: Amount (mg) of aprindine hydrochloride for assay than 95.0% and not more than 105.0% of the labeled C: Labeled amount (mg) of aprindine hydrochloride amount of aprindine hydrochloride (C H N ·HCl: 22 30 2 (C H N ·HCl) in 1 capsule 358.95). 22 30 2 Operating conditions— Method of preparation Prepare as directed under Capsules, Detector: An ultraviolet absorption photometer (wavelength: with Aprindine Hydrochloride. 254 nm) Identification Determine the absorption spectrum of the sam- Column: A stainless steel column 4.6 mm in inside diameter ple solution obtained in the Assay as directed under Ultravio- and 15 cm in length, packed with octadecylsilanized silica gel let-visible Spectrophotometry <2.24>, it exhibits maxima be- for liquid chromatography (5 µm in particle diameter). tween 264 nm and 268 nm, and between 271 nm and 275 nm. Column temperature: A constant temperature of about 40ºC. Mobile phase: Dissolve 3.40 g of potassium dihydrogen Uniformity of dosage units <6.02> Perform the test ac- phosphate in 500 mL of water, and adjust the pH to 3.0 with hy- cording to the following method: it meets the requirement of the drochloric acid. To 500 mL of this solution add 500 mL of ace- Content uniformity test. tonitrile. Flow rate: Adjust the flow rate so that the retention time of Take out the contents of 1 capsule of Aprindine Hydrochlo- aprindine is about 6 minutes. ride Capsules, add 30 mL of a solution of hydrochloric acid in System suitability— diluted ethanol (1 in 2) (1 in 125), shake vigorously for 20 min- System performance: When the procedure is run with 20 µL utes, add a solution of hydrochloric acid in diluted ethanol (1 in of the standard solution under the above operating conditions, 2) (1 in 125) to make exactly V mL so that each mL contains the number of theoretical plates and the symmetry factor of the about 0.2 mg of aprindine hydrochloride (C22H30N2·HCl), and peak of aprindine are not less than 3000 and not more than 2.0, filter. Discard the first 5 mL of the filtrate, and use the subse- respectively. quent filtrate as the sample solution. Proceed as directed in the System repeatability: When the test is repeated 6 times with Assay. 20 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of Amount (mg) of aprindine hydrochloride (C H N ·HCl) 22 30 2 aprindine is not more than 1.5%. = WS × (AT/AS) × (V/250) Assay Take out the contents of not less than 20 Aprindine Hy- W : Amount (mg) of aprindine hydrochloride for assay S drochloride Capsules, weigh accurately the mass of the contents, Dissolution <6.10> When the test is performed at 50 revolu- and powder. Weigh accurately a portion of the powder, equiva- tions per minute according to the Paddle method using the lent to about 0.1 g of aprindine hydrochloride (C22H30N2·HCl), sinker, using 900 mL of water as the dissolution medium, the add 60 mL of a solution of hydrochloric acid in diluted ethanol dissolution rate in 15 minutes of Aprindine Hydrochloride Cap- (1 in 2) (1 in 125), shake vigorously for 20 minutes, and add a sules is not less than 80%. solution of hydrochloric acid in diluted ethanol (1 in 2) (1 in Start the test with 1 capsule of Aprindine Hydrochloride 125) to make exactly 100 mL. Pipet 10 mL of this solution, add Capsules, withdraw not less than 20 mL of the medium at the a solution of hydrochloric acid in diluted ethanol (1 in 2) (1 in 125) to make exactly 50 mL, and filter, Discard the first 5 mL of

Supplement II, JP XV Official Monographs 2087 the filtrate, and use the subsequent filtrate as the sample solution. (2) Determine the infrared absorption spectrum of Argatro- Separately, weigh accurately about 50 mg of aprindine hydro- ban Hydrate as directed in the potassium bromide disk method chloride for assay, previously dried in vacuum at 60ºC for 4 under Infrared Spectrophotometry <2.25>, and compare the hours, and dissolve in a solution of hydrochloric acid in diluted spectrum with the Reference Spectrum: both spectra exhibit ethanol (1 in 2) (1 in 125) to make exactly 50 mL. Pipet 10 mL similar intensities of absorption at the same wave numbers. of this solution, add a solution of hydrochloric acid in diluted 20 ethanol (1 in 2) (1 in 125) to make exactly 50 mL, and use this Optical rotation <2.49> [α] D : +175 - +185º (0.2 g calculated on the anhydrous basis, methanol, 25 mL, 100 mm). solution as the standard solution. Determine the absorbances, AT and A , of the sample solution and standard solution at 265 nm S Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of as directed under Ultraviolet-visible Spectrophotometry <2.24>. Argatroban Hydrate according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solu- Amount (mg) of aprindine hydrochloride (C22H30N2·HCl) tion (not more than 10 ppm). = WS × (AT/AS) × 2 (2) Arsenic <1.11>—Incinerate 2.0 g of Argatroban Hydrate

WS: Amount (mg) of aprindine hydrochloride for assay according to Method 4. After cooling, add 10 mL of dilute hydrochloric acid to the residue, dissolve by warming on a water Containers and storage Containers—Tight containers. bath, and perform the test using this solution as the test solution. Storage—Light-resistant. Add 10 mL of a solution of magnesium nitrate hexahydrate in ethanol (95) (1 in 10), then add 1.5 mL of hydrogen peroxide (30), and fire to burn (not more than 1 ppm). Add the following: (3) Related substance 1—Dissolve 50 mg of Argatroban Hydrate in 40 mL of methanol, add water to make 100 mL, and Argatroban Hydrate use this solution as the sample solution. Perform the test with 10 アルガトロバン水和物 µL of the sample solution as directed under Liquid Chromatog- raphy <2.01> according to the following conditions. Determine each peak area from the sample solution by the automatic integration method, and calculate the amount of them by the area percentage method: the amount of each peak other than argatroban is not more than 0.1%. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: 254 nm).

Column: A stainless steel column 4.6 mm in inside diameter and epimer at C* and 25 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). C H N O S·H O: 526.65 23 36 6 5 2 Column temperature: A constant temperature of about 45ºC. (2R,4R)-4-Methyl-1-((2S)-2-{[(3RS)-3-methyl- Mobile phase A: To 2.5 mL of acetic acid (100) add water to 1,2,3,4-tetrahydroquinolin-8-yl]sulfonyl}amino- make 1000 mL, and adjust the pH to 5.0 with ammonia TS. To 5-guanidinopentanoyl)piperidine-2-carboxylic acid 500 mL of this solution add 500 mL of methanol. monohydrate [141396-28-3] Mobile phase B: To 2.5 mL of acetic acid (100) add water to Argatroban Hydrate contains not less than 98.5% make 1000 mL, and adjust the pH to 5.0 with ammonia TS. To and not more than 101.0% of argatroban 200 mL of this solution add 800 mL of methanol. Flowing of the mobile phase: Control the gradient by mixing (C23H36N6O5S: 508.63), calculated on the anhydrous basis. the mobile phases A and B as directed in the following table.

Time after in- Description Argatroban Hydrate occurs as white crystals or Mobile phase A Mobile phase B jection of sample crystalline powder. It has a bitter taste. (vol%) (vol%) It is freely soluble in acetic acid (100), sparingly soluble in (min) methanol, slightly soluble in ethanol (99.5), and very slightly 0-5 100 0 soluble in water. 5-35 100→5 0→95 It is gradually decomposed on exposure to light. Flow rate: About 1.0 mL per minute. Time span of measurement: About 1.5 times as long as the Identification (1) Determine the absorption spectrum of a retention time of argatroban beginning after the solvent peak. solution of Argatroban Hydrate in ethanol (99.5) (1 in 20000) as System suitability— directed under Ultraviolet-visible Spectrophotometry <2.24>, Test for required detectability: To 1 mL of the sample solution and compare the spectrum with the Reference Spectrum: both add the mobile phase A to make 100 mL, and use this solution spectra exhibit similar intensities of absorption at the same as the solution for system suitability test. Pipet 1 mL of the solu- wavelengths. tion for system suitability test, and add the mobile phase A to

2088 Official Monographs Supplement II, JP XV make exactly 10 mL. Confirm that the peak area of argatroban argatroban is about 40 minutes. obtained from 10 µL of this solution is equivalent to 7 to 13% of System suitability— that of argatroban from the solution for system suitability test. System performance: When the procedure is run with 10 µL System performance: Dissolve 5 mg of Argatroban Hydrate of the sample solution under the above operating conditions, the and 5 µL of methyl benzoate in 40 mL of methanol, and add resolution between the two peaks is not less than 1.2. water to make 100 mL. To 5 mL of this solution add 40 mL of System repeatability: When the test is repeated 6 times with methanol and water to make 100 mL. When the procedure is run 10 µL of the sample solution under the above operating condi- with 10 µL of this solution under the above operating conditions, tions, the relative standard deviation of the total area of the two methyl benzoate and argatroban are eluted in this order with the separate peaks of argatroban is not more than 2.0%. resolution between these peaks being not less than 3. System repeatability: When the test is repeated 6 times with Assay Weigh accurately about 0.5 g of Argatroban Hydrate, 10 µL of the solution for system suitability test under the above dissolve in 20 mL of acetic acid for nonaqueous titration, add 40 operating conditions, the relative standard deviation of the peak mL of acetone for nonaqueous titration, and titrate <2.50> with area of argatroban is not more than 2.0%. 0.1 mol/L perchloric acid VS (potentiometric titration). Perform (4) Related substance 2— Dissolve 0.10 g of Argatroban a blank determination in the same manner, and make any neces- Hydrate in 10 mL of methanol, and use this solution as the sam- sary correction. ple solution. Pipet 3 mL of this solution, and add methanol to Each mL of 0.1 mol/L perchloric acid VS make exactly 100 mL. Pipet 5 mL of this solution, add methanol = 50.86 mg of C H N O S to make exactly 50 mL, and use this solution as the standard so- 23 36 6 5 lution. Perform the test with these solutions as directed under Containers and storage Containers—Tight containers. Thin-layer Chromatography <2.03>. Spot 10 µL each of the Storage—Light-resistant. sample solution and standard solution on a plate of silica gel with fluorescent indicator for thin-layer chromatography. De- velop the plate with a mixture of methanol, ethyl acetate and Azathioprine Tablets water (10:10:1) to a distance of about 10 cm, and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 アザチオプリン錠 nm): the number of spots other than the principal spot obtained from the sample solution is not more than 2, and they are not Add the following next to the Identification: more intense than the spot from the standard solution. (5) Residual solvent—Being specified separately. Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the Water <2.48> 2.5 - 4.5% (0.2 g, volumetric titration, direct ti- Content uniformity test. tration). To 1 tablet of Azathioprine Tablets add 1 mL of dimethylsulfoxide for ultraviolet-visible spectrophotometry per 5 mg of Residue on ignition <2.44> Not more than 0.1% (1 g). Azathioprine (C9H7N7O2S), shake well, add 0.1 mol/L hydrochloric acid TS to make exactly V mL so that each mL contains Isomer ratio Dissolve 50 mg of Argatroban Hydrate in 50 mL about 0.2 mg of azathioprine (C H N O S), and filter. Discard of methanol, add water to make 100 mL, and use this solution as 9 7 7 2 the first 20 mL of the filtrate, pipet 3 mL of the subsequent fil- the sample solution. Perform the test with 10 µL of the sample trate, add 0.1 mol/L hydrochloric acid TS to make exactly 100 solution as directed under Liquid Chromatography <2.01> ac- mL, and use this solution as the sample solution. Proceed as di- cording to the following conditions. Determine the areas of two rected in the Assay. adjacent peaks, Aa and Ab, having the retention times of about 40 minutes, where A is the peak area of shorter retention time and a Amount (mg) of azathioprine (C9H7N7O2S) A is the peak area of longer retention time: A /(A + A ) is be- b b a b = WS × (AT/AS) × (V/500) tween 0.30 and 0.40.

Operating conditions— WS: Amount (mg) of Azathioprine Reference Standard Detector: An ultraviolet absorption photometer (wavelength: 254 nm). Column: A stainless steel column 6.0 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 40ºC. Mobile phase: To 500 mL of water add 500 mL of methanol, 13 mL of diluted 40% tetrabutylammonium hydroxide TS (1 in 4) and 0.68 mL of phosphoric acid, and adjust the pH to 6.8 with ammonia TS and diluted ammonia solution (28) (1 in 20). Flow rate: Adjust the flow rate so that the retention time of the peak having the shorter retention time of the two peaks of

Supplement II, JP XV Official Monographs 2089

Add the following: System performance: When the procedure is run with 50 µL of the standard solution under the above operating conditions, Azelastine Hydrochloride Granules the number of theoretical plates and the symmetry factor of the peak of azelastine are not less than 2000 and not more than 1.5, アゼラスチン塩酸塩顆粒 respectively. System repeatability: When the test is repeated 6 times with Azelastine Hydrochloride Granules contain not less 50 µL of the standard solution under the above operating condi- than 93.0% and not more than 107.0% of the labeled tions, the relative standard deviation of the peak area of aze- amount of azelastine hydrochloride lastine is not more than 2.0%. (C22H24ClN3O·HCl: 418.36). Particle size <6.03> It meets the requirement. Method of preparation Prepare as directed under Granules, with Azelastine Hydrochloride. Assay Weigh accurately an amount of Azelastine Hydrochlo- ride Granules, equivalent to about 2 mg of azelastine hydrochlo- Identification To a quantity of Azelastine Hydrochloride ride (C22H24ClN3O·HCl), add 50 mL of 0.1 mol/L hydrochloric Granules, equivalent to 2 mg of Azelastine Hydrochloride ac- acid TS, treat with ultrasonic waves for 20 minutes, add 40 mL cording to the labeled amount, add 30 mL of 0.1 mol/L hydro- of ethanol (99.5), add exactly 5 mL of the internal standard so- chloric acid TS, and treat with ultrasonic waves for 30 minutes. lution, and add ethanol (99.5) to make 100 mL. Centrifuge this After cooling, add 0.1 mol/L hydrochloric acid TS to make 50 solution, and use the supernatant liquid as the sample solution. mL, and centrifuge. Determine the absorption spectrum of the Separately, weigh accurately about 50 mg of azelastine hydro- supernatant liquid as directed under Ultraviolet-visible Spec- chloride for assay, previously dried at 105ºC for 2 hours, and trophotometry <2.24>: it exhibits a maximum between 283 nm dissolve in water to make exactly 50 mL. Pipet 10 mL of this and 287 nm. solution, and add 0.1 mol/L hydrochloric acid TS to make exactly 50 mL. Pipet 10 mL of this solution, add 40 mL of 0.1 Dissolution <6.10> When the test is performed at 50 revolu- mol/L hydrochloric acid TS and 40 mL of ethanol (99.5), add tions per minute according to the Paddle method, using 900 mL exactly 5 mL of the internal standard solution, add ethanol of 0.05 mol/L acetic acid-sodium acetate buffer solution, pH 4.0, (99.5) to make 100 mL, and use this solution as the standard as the dissolution medium, the dissolution rate in 45 minutes of solution. Perform the test with 20 µL each of the sample solution Azelastine Hydrochloride Granules is not less than 80%. and standard solution as directed under Liquid Chromatography Start the test with accurately weighed amount of Azelastine <2.01> according to the following conditions, and calculate the Hydrochloride Granules, equivalent to about 1 mg of azelastine ratios, Q and Q , of the peak area of azelastine to that of the hydrochloride (C H ClN O·HCl) according to the labeled T S 22 24 3 internal standard. amount, withdraw not less than 20 mL of the medium at the specified minute after starting the test, and filter through a Amount (mg) of azelastine hydrochloride membrane filter with a pore size not exceeding 0.5 µm. Discard (C22H24ClN3O·HCl) the first 10 mL of the filtrate, and use the subsequent filtrate as = WS × (QT/QS) × (1/25) the sample solution. Separately, weigh accurately about 50 mg of azelastine hydrochloride for assay, previously dried at 105ºC WS: Amount (mg) of azelastine hydrochloride for assay for 2 hours, and dissolve in the dissolution medium to make exactly 250 mL. Pipet 1 mL of this solution, add the dissolution Internal standard solution—Dissolve 0.2 g of 2-ethylhexyl medium to make exactly 200 mL, and use this solution as the parahydroxybenzoate in ethanol (99.5) to make 100 mL. standard solution. Perform the test with exactly 50 µL each of Operating conditions— the sample solution and standard solution as directed under Liq- Detector: An ultraviolet absorption photometer (wavelength: uid Chromatography <2.01> according to the following condi- 285 nm). Column: A stainless steel column 4.6 mm in inside diameter tions, and determine the peak areas, AT and AS, of azelastine in each solution. and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Dissolution rate (%) with respect to the labeled amount of Column temperature: A constant temperature of about 40ºC.

azelastine hydrochloride (C22H24ClN3O·HCl) Mobile phase: A mixture of acetonitrile and a solution of so- = (WS/WT) × (AT/AS) × (1/C) × (9/5) dium lauryl sulfate in diluted acetic acid (100) (1 in 250) (1 in 500) (11:9). WS: Amount (mg) of azelastine hydrochloride for assay Flow rate: Adjust the flow rate so that the retention time of WT: Amount (g) of Azelastine Hydrochloride Granules azelastine is about 6 minutes. C: Labeled amount (mg) of azelastine hydrochloride System suitability— (C22H24ClN3O·HCl) in 1 g System performance: When the procedure is run with 20 µL of the standard solution under the above operating conditions, Operating conditions— azelastine and the internal standard are eluted in this order with Proceed as directed in the Assay. the resolution between these peaks being not less than 2.0. System suitability— System repeatability: When the test is repeated 6 times with

2090 Official Monographs Supplement II, JP XV

20 µL of the standard solution under the above operating condi- Add the following: tions, the relative standard deviation of the ratio of the peak area of azelastine to that of the internal standard is not more than Betaxolol Hydrochloride 1.0%. ベタキソロール塩酸塩 Containers and storage Containers—Tight containers.

Betamethasone Tablets

ベタメタゾン錠 and enantiomer C H NO ·HCl: 343.89 Change the Uniformity of dosage units to read: 18 29 3 (2RS)-1-{4-[2-(Cyclopropylmethoxy)ethyl]phenoxy}- Uniformity of dosage units <6.02> Perform the test accord- 3-[(1-methylethyl)amino]propan-2-ol monohydrochloride ing to the following method: it meets the requirement of the [63659-19-8] Content uniformity test. Betaxolol Hydrochloride, when dried, contains not To 1 tablet of Betamethasone Tablets add V mL of water so less than 99.0% and not more than 101.0% of that each mL contains about 50 µg of betamethasone C18H29NO3·HCl. (C H FO ). Add exactly 2 V mL of the internal standard solu- 22 29 5 Description Betaxolol Hydrochloride occurs as white crystals tion, shake vigorously for 10 minutes, centrifuge, and use the or crystalline powder. supernatant liquid as the sample solution. Separately, weigh ac- It is very soluble in water, and freely soluble in methanol, curately about 20 mg of Betamethasone Reference Standard, ethanol (99.5) or acetic acid (100). previously dried for 4 hours in a desiccator (in vacuum, phos- Dissolve 1.0 g of Betaxolol Hydrochloride in 50 mL of water: phorus (V) oxide), dissolve in acetonitrile to make exactly 200 the pH of the solution is between 4.5 and 6.5. mL. Pipet 5 mL of this solution, add exactly 20 mL of the inter- A solution of Betaxolol Hydrochloride (1 in 100) shows no nal standard solution, add 5 mL of water, and use this solution optical rotation. as the standard solution. Perform the test with 20 µL each of the sample solution and standard solution as directed under Liquid Identification (1) Determine the absorption spectrum of a Chromatography <2.01>, and calculate the ratios, QT and QS, of solution of Betaxolol Hydrochloride in ethanol (99.5) (1 in the peak area of betamethasone to that of the internal standard. 10000) as directed under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spec- Amount (mg) of betamethasone (C H FO ) 22 29 5 trum: both spectra exhibit similar intensities of absorption at the = W × (Q /Q ) × (V/400) S T S same wavelengths. (2) Determine the infrared absorption spectrum of Betaxolol WS: Amount (mg) of Betamethasone Reference Standard Hydrochloride as directed in the potassium chloride disk method Internal standard solution—A solution of butyl parahydroxy- under Infrared Spectrophotometry <2.25>, and compare the benzoate in acetonitrile (1 in 40000) spectrum with the Reference Spectrum: both spectra exhibit Operating conditions— similar intensities of absorption at the same wave numbers. Proceed as directed in the operating conditions in the Assay. (3) A solution of Betaxolol Hydrochloride (1 in 10) re- System suitability— sponds to the Qualitative Tests <1.09> (2) for chloride. System performance: When the procedure is run with 20 µL of the standard solution under the above operating conditions, Melting point <2.60> 114-117ºC betamethasone and the internal standard are eluted in this order Purity (1) Clarity and color of solution—Dissolve 1.0 g of with the resolution between these peaks being not less than 10. Betaxolol Hydrochloride in 10 mL of water: the solution is clear System repeatability: When the test is repeated 6 times with and colorless. 20 µL of the standard solution under the above operating condi- (2) Heavy metals <1.07>—Proceed with 2.0 g of Betaxolol tions, the relative standard deviation of the ratio of the peak area Hydrochloride according to Method 4, and perform the test. of betamethasone to that of the internal standard is not more Prepare the control solution with 2.0 mL of Standard Lead Solu- than 1.0%. tion (not more than 10 ppm).

(3) Arsenic <1.11>—Prepare the test solution with 2.0 g of Betaxolol Hydrochloride according to Method 3, and perform the test (not more than 1 ppm). (4) Related substance I—Dissolve 0.10 g of Betaxolol Hy- drochloride in 10 mL of methanol, and use this solution as the sample solution. Pipet 3 mL of this solution, and add methanol to make exactly 50 mL. Pipet 1 mL of this solution, add metha-

Supplement II, JP XV Official Monographs 2091 nol to make exactly 20 mL, and use this solution as the standard Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 4 solution. Perform the test with these solutions as directed under hours). Thin-layer Chromatography <2.03>. Spot 10 µL each of the sample solution and standard solution on a plate of silica gel for Residue on ignition <2.44> Not more than 0.1% (1 g). thin-layer chromatography. Develop the plate with a mixture of Assay Weigh accurately about 0.3 g of Betaxolol Hydrochlo- ethyl acetate, water and acetic acid (100) (10:3:3) to a distance ride, previously dried, dissolve in 30 mL of acetic acid (100), of about 10 cm, and air-dry the plate. Allow the plate to stand in add 30 mL of acetic anhydride, and titrate <2.50> with 0.1 iodine vapor for 1 hour: the number of the spots other than the mol/L perchloric acid VS (potentiometric titration). Perform a principal spot obtained from the sample solution is not more blank determination in the same manner, and make any neces- than three, and they are not more intense than the spot from the sary correction. standard solution. (5) Related substance II—Dissolve 0.10 g of Betaxolol Hy- Each mL of 0.1 mol/L perchloric acid VS drochloride in 50 mL of the mobile phase, and use this solution = 34.39 mg of C18H29NO3·HCl as the sample solution. Pipet 1 mL of this solution, add the mobile phase to make exactly 200 mL, and use this solution as the Containers and storage Containers—Tight containers. standard solution. Perform the test with exactly 10 µL each of the sample solution and standard solution as directed under Liq- uid Chromatography <2.01> according to the following condi- Add the following: tions. Determine each peak area of both solutions by the automatic integration method: the area of the peak other than be- Cadralazine taxolol obtained from the sample solution is not larger than the peak area of betaxolol from the standard solution, and the total カドララジン area of the peaks other than the peak of betaxolol obtained from the sample solution is not larger than 2 times the peak area of betaxolol from the standard solution. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: 273 nm) and enantiomer Column: A stainless steel column 4.6 mm in inside diameter C12H21N5O3: 283.33 and 15 cm in length, packed with octadecylsilanized silica gel Ethyl 3-(6-{ethyl[(2RS)-2-hydroxypropyl]amino}pyridazin- for liquid chromatography (5 µm in particle diameter). 3-yl)carbazate [64241-34-5] Column temperature: A constant temperature of about 25ºC. Mobile phase: A mixture of diluted 0.05 mol/L potassium di- Cadralazine, when dried, contains not less than hydrogen phosphate TS (1 in 2) with the pH adjusted to 3.0 with 98.5% and not more than 101.0% of C12H21N5O3. 1 mol/L hydrochloric acid TS, acetonitrile and methanol (26:7:7). Description Cadralazine occurs as a pale yellow to light yel- Flow rate: Adjust the flow rate so that the retention time of low crystalline powder. betaxolol is about 9 minutes. It is freely soluble in acetic acid (100), soluble in methanol, Time span of measurement: About 2 times as long as the re- sparingly soluble in ethanol (99.5), and slightly soluble in water. tention time of betaxolol beginning after the solvent peak. It dissolves in 0.05 mol/L sulfuric acid TS. System suitability— A solution of Cadralazine in methanol (1 in 40) shows no op- Test for required detectability: Pipet 4 mL of the standard so- tical rotation. lution, and add the mobile phase to make exactly 20 mL. Con- Melting point: about 165ºC (with decomposition). firm that the peak area of betaxolol obtained from 10 µL of this Identification (1) Determine the absorption spectrum of a solution is equivalent to 14 to 26% of that of bataxolol from the solution of Cadralazine in 0.05 mol/L sulfuric acid TS (1 in standard solution. 125000) as directed under Ultraviolet-visible Spectrophotome- System performance: Dissolve 50 mg of Betaxolol Hydro- try <2.24>, and compare the spectrum with the Reference Spec- chloride and 5 mg of 2-naphthol in 200 mL of the mobile phase. trum: both spectra exhibit similar intensities of absorption at the When the procedure is run with 10 µL of this solution under the same wavelengths. above operating conditions, betaxolol and 2-naphthol are eluted (2) Determine the infrared absorption spectrum of Cadra- in this order with the resolution between these peaks being not lazine, previously dried, as directed in the potassium bromide less than 10. disk method under Infrared Spectrophotometry <2.25>, and System repeatability: When the test is repeated 6 times with compare the spectrum with the Reference Spectrum: both spec- 10 µL of the standard solution under the above operating condi- tra exhibit similar intensities of absorption at the same wave tions, the relative standard deviation of the peak area of be- numbers. taxolol is not more than 2.0%. (6) Residual solvent—Being specified separately. Purity (1) Chloride <1.03>—Dissolve 0.40 g of Cadralazine

2092 Official Monographs Supplement II, JP XV in 15 mL of methanol, add 6 mL of dilute nitric acid and water System repeatability: When the test is repeated 6 times with to make 50 mL. Perform the test using this solution as the test 10 µL of the standard solution under the above operating condi- solution. Prepare the control solution with 0.40 mL of 0.01 tions, the relative standard deviation of the peak area of cadra- mol/L hydrochloric acid VS by adding 15 mL of methanol, 6 lazine is not more than 4.0%. mL of dilute nitric acid, and water to make 50 mL (not more (4) Residual solvent—Being specified separately. than 0.036%). (2) Heavy metals <1.07>—Proceed with 1.0 g of Cadra- Loss on drying <2.41> Not more than 1.0% (1 g, 105ºC, 3 lazine according to Method 4, and perform the test. Prepare the hours). control solution with 2.0 mL of Standard Lead Solution (not Residue on ignition <2.44> Not more than 0.1% (1 g). more than 20 ppm). (3) Related substances—Dissolve 50 mg of Cadralazine in Assay Weigh accurately about 0.5 g of Cadralazine, previ- 20 mL of 0.05 mol/L sulfuric acid TS, add water to 100 mL, and ously dried, dissolve in 50 mL of acetic acid (100), and titrate use this solution as the sample solution. Pipet 1 mL of this solu- <2.50> with 0.1 mol/L perchloric acid VS (potentiometric titration, add water to make exactly 200 mL, and use this solution as tion). Perform a blank determination in the same manner, and the standard solution. Perform the test with exactly 10 µL each make any necessary correction. of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following con- Each mL of 0.1 mol/L perchloric acid VS ditions. Determine each peak area of both solutions by the = 28.33 mg of C12H21N5O3 automatic integration method: the area of the peak, having the relative retention time of about 2.1 with respect to cadralazine, Containers and storage Containers—Well-closed containers. obtained from the sample solution is not larger than the peak area of cadralazine from the standard solution, and the area of Add the following: the peak other than cadralazine and other than the peak mentioned above is not larger than 2/5 times the peak area of cadralazine from the standard solution. Furthermore, the total area of Cadralazine Tablets the peaks other than cadralazine obtained from the sample solu- カドララジン錠 tion is not larger than 2 times the peak area of cadralazine from the standard solution. For this calculation, use the areas of the Cadralazine Tablets contain not less than 95.0% and peaks, having the relative retention time of about 0.49 and about not more than 105.0% of the labeled amount of cadra- 2.1 with respect to cadralazine, after multiplying by their rela- lazine (C12H21N5O3: 283.33). tive response factors, 0.65 and 1.25, respectively. Operating conditions— Method of preparation Prepare as directed under Tablets, Detector: An ultraviolet absorption photometer (wavelength: with Cadralazine. 250 nm). Column: A stainless steel column 4.6 mm in inside diameter Identification To a quantity of powdered Cadralazine Tablets, and 15 cm in length, packed with octadecylsilanized silica gel equivalent to 20 mg of Cadralazine according to the labeled for liquid chromatography (5 µm in particle diameter). amount, add 50 mL of 0.05 mol/L sulfuric acid TS, shake well, Column temperature: A constant temperature of about 40ºC. and centrifuge. To 1 mL of the supernatant liquid add 0.05 Mobile phase: Dissolve 13.6 g of sodium acetate trihydrate in mol/L sulfuric acid TS to make 50 mL. Determine the absorp- 800 mL of water, adjust the pH to 5.8 with dilute acetic acid, tion spectrum of this solution as directed under Ultravio- and add water to make 1000 mL. To 860 mL add 140 mL of let-visible Spectrophotometry <2.24>: it exhibits a maximum acetonitrile. between 247 nm and 251 nm. Flow rate: Adjust the flow rate so that the retention time of Uniformity of dosage units <6.02> Perform the test accord- cadralazine is about 10 minutes. ing to the following method: it meets the requirement of the Time span of measurement: About 3 times as long as the re- Content uniformity test. tention time of cadralazine. To 1 tablet of Cadralazine Tablets add 30 mL of 0.05 mol/L System suitability— sulfuric acid TS, shake well to disintegrate, and add 0.05 mol/L Test for required detectability: Pipet 5 mL of the standard so- sulfuric acid TS to make exactly 50 mL. Centrifuge this solution, lution, and add water to make exactly 25 mL. Confirm that the pipet 3 mL of the supernatant liquid, add 0.05 mol/L sulfuric peak area of cadralazine obtained from 10 µL of this solution is acid TS to make exactly V mL so that each mL contains about 6 equivalent to 15 to 25% of that of cadralazine from the standard µg of cadralazine (C H N O ), and use this solution as the solution. 12 21 5 3 sample solution. Separately, weigh accurately about 20 mg of System performance: When the procedure is run with 10 µL cadralazine for assay, previously dried at 105ºC for 3 hours, and of the standard solution under the above operating conditions, dissolve in 0.05 mol/L sulfuric acid TS to make exactly 100 mL. the number of theoretical plates and the symmetry factor of the Pipet 3 mL of this solution, add 0.05 mol/L sulfuric acid TS to peak of cadralazine are not less than 4000 and not more than 1.5, make exactly 100 mL, and use this solution as the standard so- respectively. lution. Determine the absorbances, AT and AS, of the sample so-

Supplement II, JP XV Official Monographs 2093 lution and standard solution at 249 nm as directed under Ultra- Operating conditions— violet-visible Spectrophotometry <2.24>. Detector: An ultraviolet absorption photometer (wavelength: 250 nm). Amount (mg) of cadralazine (C12H21N5O3) Column: A stainless steel column 4.6 mm in inside diameter = WS × (AT/AS) × (V/200) and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). W : Amount (mg) of cadralazine for assay S Column temperature: A constant temperature of about 40ºC. Dissolution <6.10> When the test is performed at 50 revolu- Mobile phase: Dissolve 13.6 g of sodium acetate trihydrate in tions per minute according to the Paddle method using 900 mL 800 mL of water, adjust the pH to 5.8 with dilute acetic acid, of water as the dissolution medium, the dissolution rate in 30 and add water to make 1000 mL. To 860 mL of this solution add minutes of Cadralazine Tablets is not less than 80%. 140 mL of acetonitrile. Start the test with 1 tablet of Cadralazine Tablets, withdraw Flow rate: Adjust the flow rate so that the retention time of not less than 20 mL of the medium at the specified minute after cadralazine is about 10 minutes. starting the test, and filter through a membrane filter with a pore System suitability— size not exceeding 0.5 µm. Discard the first 10 mL of the filtrate, System performance: When the procedure is run with 5 µL of pipet V mL of the subsequent filtrate, add water to make exactly this solution under the above operating conditions, cadralazine V´ mL so that each mL contains about 5.6 µg of cadralazine and the internal standard are eluted in this order with the resolution between these peaks being not less than 3. (C12H21N5O3) according to the labeled amount, and use this solution as the sample solution. Separately, weigh accurately about System repeatability: When the test is repeated 6 times with 5 30 mg of cadralazine for assay, previously dried at 105ºC for 3 µL of the standard solution under the above operating conditions, hours, and dissolve in water to make exactly 200 mL. Pipet 4 the relative standard deviation of the ratio of the peak area of mL of this solution, add water to make exactly 100 mL, and use cadralazine to that of the internal standard is not more than this solution as the standard solution. Determine the absorb- 1.0%. ances, A and A , of the sample solution and standard solution at T S Containers and storage Containers—Well-closed containers. 254 nm as directed under Ultraviolet-visible Spectrophotometry <2.24>. Add the following: Dissolution rate (%) with respect to the labeled amount of cadralazine (C12H21N5O3) Calcitonin (Salmon) = WS × (AT/AS) × (V´/V) × (1/C) × 18 カルシトニン（サケ） WS: Amount (mg) of cadralazine for assay C: Labeled amount (mg) of cadralazine (C H N O ) in 1 12 21 5 3 ┌─────┐ tablet CSNLSTCVLG KLSQELHKLQ TYPRTNTGSG TP-NH2 Assay To 10 Cadralazine Tablets add 70 mL of 0.05 mol/L C H N O S : 3431.85 sulfuric acid TS, shake well to disintegrate, add 0.05 mol/L sul- 145 240 44 48 2 [47931-85-1] furic acid to make exactly 200 mL. Centrifuge this solution, pipet a volume of the supernatant liquid, equivalent to about 2.5 Calcitonin (Salmon) is a synthetic polypeptide con- mg of cadralazine (C12H21N5O3), add exactly 5 mL of the inter- sisting of 32 amino acid residues. It is a hormone with nal standard solution, add water to make 25 mL, and use this a blood calcium lowering effect. solution as the sample solution. Separately, weigh accurately It contains not less than 4000 Units of calcitonin about 25 mg of cadralazine for assay, previously dried at 105ºC (salmon) per 1 mg of peptide. for 3 hours, and dissolve in 0.05 mol/L of sulfuric acid TS to make exactly 50 mL. Pipet 5 mL of this solution, add exactly 5 Description Calcitonin (Salmon) occurs as a white powder. mL of the internal standard solution, add water to make 25 mL, It is freely soluble in water. and use this solution as the standard solution. Perform the test It dissolves in dilute acetic acid. with 5 µL each of the sample solution and standard solution as Dissolve 20 mg of Calcitonin (Salmon) in 2 mL of water: the directed under Liquid Chromatography <2.01> according to the pH of the solution is between 5.0 and 7.0. following conditions, and calculate the ratios, QT and QS, of the It is hygroscopic. peak area of cadralazine to that of the internal standard. Identification Dissolve 1 mg of Calcitonin (Salmon) in 1 mL

Amount (mg) of cadralazine (C12H21N5O3) of dilute acetic acid. Determine the absorption spectrum of this = WS × (QT/QS) × (1/10) solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spec- WS: Amount (mg) of cadralazine for assay trum: both spectra exhibit similar intensities of absorption at the same wavelengths. Internal standard solution—A solution of p-toluenesulfonamide in acetonitrile (1 in 50)

2094 Official Monographs Supplement II, JP XV

1% Absorbance <2.24> E1cm (275 nm): 3.3 - 4.0 (1 mg, dilute and use this solution as the standard solution. Perform the test acetic acid, 1 mL). with exactly 10 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> ac- 20 Optical rotation <2.49> [α] D : –24 - –32º (25 mg, diluted cording to the following conditions: 13 peaks of amino acids acetic acid (100) (1 in 2), 10 mL, 100 mm). appear on the chromatogram obtained from the sample solution, and their respective molar ratios with respect to leucine (=5) are Constituent amino acids Weigh accurately about 1 mg of 1.9 – 2.3 for lysine, 0.8 – 1.1 for histidine, 0.9 – 1.1 for arginine, Calcitonin (Salmon), put in a test tube for hydrolysis, dissolve in 1.9 – 2.1 for aspartic acid, 4.5 – 4.9 for threonine, 3.2 – 3.8 for 0.5 mL of diluted hydrochloric acid (1 in 2), freeze in a dry serine, 2.8 – 3.1 for glutamic acid, 1.9 – 2.4 for proline, 2.7 – ice-acetone bath, seal the tube under reduced pressure, and heat 3.3 for glycine, 1.5 – 2.5 for 1/2 cystine, 0.9 – 1.0 for valine, at 110 ± 2ºC for 24 hours. After cooling, open the tube, evapo- and 0.8 – 1.0 for tyrosine. rate the hydrolyzate to dryness under reduced pressure, dissolve Operating conditions— the residue in exactly 5 mL of 0.02 mol/L hydrochloric acid TS, Detector: A visible spectrophotometer (wavelength: 440 nm and use this solution as the sample solution. Separately, weigh and 570 nm) accurately about 27 mg of L-aspartic acid, about 24 mg of Column: A stainless steel column 4.6 mm in inside diameter L-threonine, about 21 mg of L-serine, about 29 mg of L-glutamic and 6 cm in length, packed with strongly acidic ion–exchange acid, about 23 mg of L-proline, about 15 mg of glycine, about 18 resin for liquid chromatography (sodium type) composed with a mg of L-alanine, about 23 mg of L-valine, about 48 mg of sulfonated polystyrene copolymer (3 µm in particle diameter). L-cystine, about 30 mg of methionine, about 26 mg of Column temperature: A constant temperature of about 57ºC. L-isoleucine, about 26 mg of L-leucine, about 36 mg of Chemical reaction bath temperature: A constant temperature L-tyrosine, about 33 mg of phenylalanine, about 37 mg of of about 130ºC. L-lysine hydrochloride, about 42 mg of L-histidine hydrochlo- Color developing time: About 1 minute. ride monohydrate and about 42 mg of L-arginine hydrochloride, dissolve them in 10 mL of 1 mol/L hydrochloric acid TS, and Mobile phase: Prepare mobile phases A, B, C, D and E ac- add water to make exactly 100 mL. Pipet 5 mL of this solution, cording to the following table. add 0.02 mol/L hydrochloric acid TS to make exactly 50 mL,

Mobile phase A Mobile phase B Mobile phase C Mobile phase D Mobile phase E

Citric acid monohydrate 19.80 g 22.00 g 12.80 g 6.10 g – Trisodium citrate dihydrate 6.19 g 7.74 g 13.31 g 26.67 g – Sodium hydroxide – – – – 8.00 g Sodium chloride 5.66 g 7.07 g 3.74 g 54.35 g – Ethanol (99.5) 130.0 mL 20.0 mL 4.0 mL – 100.0 mL Benzyl alcohol – – – 5.0 mL – Thiodiglycol 5.0 mL 5.0 mL 5.0 mL – – Lauromacrogol solution (1 in 4) 4.0 mL 4.0 mL 4.0 mL 4.0 mL 4.0 mL Caprylic acid 0.1 mL 0.1 mL 0.1 mL 0.1 mL 0.1 mL a sufficient a sufficient a sufficient a sufficient a sufficient Water amount amount amount amount amount

Total volume 1000 mL 1000 mL 1000 mL 1000 mL 1000 mL

Supplement II, JP XV Official Monographs 2095

Flowing of the mobile phase: Control the gradient by mixing the mobile phases A, B, C, D and E as directed in the following table.

Time after injection of Mobile phase A Mobile phase B Mobile phase C Mobile phase D Mobile phase E sample (min) (vol%) (vol%) (vol%) (vol%) (vol%)

0 – 1.5 100 0 0 0 0 1.5 – 4 0 100 0 0 0 4 – 12 0 0 100 0 0 12 – 26 0 0 0 100 0 26 – 30 0 0 0 0 100

Reaction reagent: Mix 407 g of lithium acetate dihydrate, 245 ple solution and standard solution as directed under Liquid mL of acetic acid (100) and 801 mL of 1–methoxy–2–propanol, Chromatography <2.01> according to the following conditions. add water to make 2000 mL, stir for 10 minutes while passing Determine the peak areas, AT and AS, of acetic acid in each solu- nitrogen, and use this solution as solution A. Separately, to 1957 tion, and calculate the amount of acetic acid by the following mL of 1–methoxy–2–propanol add 77 g of ninhydrin and 0.134 equation: the amount of acetic acid is not more than 7.0%. g of sodium borohydride, stir for 30 minutes while passing nitrogen, and use this solution as solution B. Mix solution A and Amount (%) of acetic acid (CH3COOH) solution B before use. = (WS/WT) × (AT/AS) × (1/10) Flow rate of mobile phase: About 0.4 mL per minute. W : Amount (mg) of acetic acid (100) Flow rate of reaction reagent: About 0.35 mL per minute. S W : Amount (mg) of Calcitonin (Salmon) System suitability— T System performance: When the procedure is run with 10 µL Operating conditions— of the standard solution under the above operating conditions, Detector: An ultraviolet absorption photometer (wavelength: aspartic acid, threonine, serine, glutamic acid, proline, glycine, 210 nm) alanine, cystine, valine, methionine, isoleucine, leucine, tyrosine, Column: A stainless steel column 4.6 mm in inside diameter phenylalanine, lysine, histidine and arginine are eluted in this and 25 cm in length, packed with octadecylsilanized silica gel order with the resolutions between the peaks of threonine and for liquid chromatography (5 µm in particle diameter). serine, glycine and alanine, and isoleucine and leucine being not Column temperature: A constant temperature of about 40ºC. less than 1.2, 1.0 and 1.2, respectively. Mobile phase A: To 0.7 mL of phosphoric acid add 900 mL of System repeatability: When the test is repeated 3 times with water, adjust the pH to 3.0 with 8 mol/L sodium hydroxide TS, 10 µL of the standard solution under the above operating condi- and add water to make 1000 mL. tions, the relative standard deviations of the peak areas of aspar- Mobile phase B: Methanol tic acid, proline, valine and arginine are not more than 2.0%, Flowing of the mobile phase: Control the gradient by mixing respectively. the mobile phases A and B as directed in the following table.

Peptide content Calculate the peptide content in Calcitonin Time after injec- Mobile phase A Mobile phase B (Salmon) by the following equation using amino acid analysis tion of sample (vol%) (vol%) values (µmol/mL) obtained in the Constituent amino acids: it is (min) not less than 80.0%. 0 – 5 95 5 5 – 10 95→50 5→50 Peptide content (%) = 3431.85 × (5/W) × (A/11) × 100 10 – 20 50 50 A: Total (µmol/mL) of the amino acid analysis values of 20 – 22 50→95 50→5 valine, leucine, glycine and proline 22 – 30 95 5 W: Amount (µg) of sample 11: Total of the theoretical residue numbers of valine, leucine, Flow rate: Adjust the flow rate so that the retention time of glycine and proline per one mole of calcitonin (salmon) acetic acid is about 4 minutes. System suitability— Purity (1) Acetic acid—Weigh accurately about 10 mg of System performance: When the procedure is run with 100 µL Calcitonin (Salmon), dissolve in water to make exactly 10 mL, of the standard solution under the above operating conditions, and use this solution as the sample solution. Separately, weigh the number of theoretical plates and the symmetry factor of the accurately about 1 g of acetic acid (100), and dissolve in water peak of acetic acid are not less than 3000 and not more than 2.0, to make exactly 100 mL. Pipet 2 mL of this solution, add water respectively. to make exactly 200 mL, and use this solution as the standard System repeatability: When the test is repeated 6 times with solution. Perform the test with exactly 100 µL each of the sam- 100 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak areas of ace-

2096 Official Monographs Supplement II, JP XV tic acid is not more than 2.0%. solve in acetic acid buffer solution containing 0.1% bovine se-

(2) Related substances—Dissolve 2 mg of Calcitonin rum albumin, and prepare a high–dose sample solution TH and (Salmon) in 2 mL of dilute acetic acid, and use this solution as the low–dose sample solution TL having Units equal to the the sample solution. Perform the test with 20 µL of this solution standard solutions in equal volumes, respectively. as directed under Liquid Chromatography <2.01> according to (iv) Dose for injection: Inject 0.3 mL per animal. the following conditions. Determine each peak area from the (v) Procedure: Divide the test animals at random into 4 sample solution by the automatic integration method, and cal- groups, A, B, C and D, with not less than 8 animals and equal culate the amount of them by the area percentage method: the numbers in each group. Inject SH, SL, TH and TL into the tail total amount of the peaks other than calcitonin (salmon) is not vein or subcutaneously into the neck of each animal of the re- more than 3%. spective groups. At 1 hour after the injection, collect blood from Operating conditions— the abdominal aorta in a way that minimizes the suffering of the Detector: An ultraviolet absorption photometer (wavelength: animals, allow the blood samples to stand at room temperature 210 nm) for about 30 minutes, and centrifuge at 3000 revolutions per Column: A stainless steel column 3.9 mm in inside diameter minute for 10 minutes to separate serum. and 30 cm in length, packed with octadecylsilanized silica gel (vi) Serum calcium determination: Pipet 0.1 mL of the se- for liquid chromatography (10 µm in particle diameter). rum, add exactly 6.9 mL of strontium TS, mix well, and use this Column temperature: A constant temperature of about 25ºC. solution as the sample solution for calcium determination. Mobile phase: A mixture of 1% trimethylamine–phosphate Separately, pipet a suitable volume of Standard Calcium Solu- buffer solution, pH 3.0, and acetonitrile (27:13). tion for Atomic Absorption Spectrophotometry, dissolve in Flow rate: Adjust the flow rate so that the retention time of strontium TS to make a solution so that each mL contains 0.2 to calcitonin (salmon) is about 9 minutes. 3 µg of calcium (Ca: 40.08), and use this solution as the stan- Time span of measurement: About 2 times as long as the re- dard solution for calcium determination. Perform the test as di- tention time of calcitonin (salmon) beginning after the solvent rected under Atomic Absorption Spectrometry <2.23> according peak. to the following conditions, and calculate the calcium content of System suitability— the sample solution for calcium determination from the calibra- Test for required detectability: Pipet 1 mL of the sample solution curve obtained from the absorbance of the standard solution tion, add the mobile phase to make exactly 100 mL, and use this for calcium determination. solution as the solution for system suitability test. Pipet 1 mL of the solution for system suitability test, and add the mobile phase Amount (mg) of Calcium (Ca) in 100 mL of the serum to make exactly 10 mL. Confirm that the peak area of calcitonin = Calcium content (ppm) in the sample solution for cal- (salmon) obtained from 20 µL of this solution is equivalent to 5 cium determination × 7 to 15% of that of calcitonin (salmon) from the solution for sys- Gas: Combustible gas—Acetylene tem suitability test. Supporting gas—Air System performance: Dissolve 5 mg of methyl parahydroxy- Lamp: Calcium hollow–cathode lamp benzoate and 7 mg of ethyl parahydroxybenzoate in 100 mL of Wavelength: 422.7 nm acetonitrile. When the procedure is run with 20 µL of this solution under the above operating conditions methyl parahydroxy- (vii) Calculation: Amounts of calcium in the serum obtained benzoate and ethyl parahydroxybenzoate are eluted in this order with SH, SL, TH and TL are symbolized as y1, y2, y3 and y4, re- with the resolution between these peaks being not less than 5. spectively. Sum up y1, y2, y3 and y4 on each set to obtain Y1, Y2, System repeatability: When the test is repeated 6 times with Y3 and Y4, respectively. 20 µL of the solution for system suitability test under the above operating conditions, the relative standard deviation of the peak Units per mg of peptide = antilog M × (b/a) × (1/c) × 5 areas of calcitonin (salmon) is not more than 2.0%. M = 0.3010 × (Ya/Yb) (3) Residual solvent—Being specified separately. Ya = – Y1 – Y2 + Y3 + Y4 Yb = Y1 – Y2 + Y3 – Y4 Water <2.48> Not more than 10.0% (5 mg, coulometric titration). a: Amount (mg) of Calcitonin (Salmon) b: Total volume (mL) of the high–dose sample solution pre- Assay (i) Test animals: Select healthy albino rats weighing pared by dissolving Calcitonin (Salmon) in acetic acid between 55 and 180 g, fasted for 24 hours before the test but al- buffer solution containing 0.1% bovine serum albumin. lowed to drink water ad libitum.. c: Peptide content (%) (ii) Standard solutions: Dissolve a quantity of Calcitonin (Salmon) Reference Standard in acetic acid buffer solution con- F´ computed by the following equation should be smaller 2 taining 0.1% bovine serum albumin, and prepare a high–dose than F1 shown in the table against n with which s is calculated. standard solution SH and a low–dose standard solution SL con- Calculate L (P=0.95) by use of the following equation: L should taining exactly 0.050 and 0.025 Units per mL, respectively. be not more than 0.20. If F´ exceeds F1, or if L exceeds 0.20, (iii) Sample solutions: According to the labeled units, weigh repeat the test, increasing the number of animals or arranging accurately a suitable amount of Calcitonin (Salmon), and dis- the assay conditions so that F´ is not more than F1 and L is not

Supplement II, JP XV Official Monographs 2097 more than 0.20. Cefaclor Compound Granules 2 2 F´ = (– Y1 + Y2 + Y3 – Y4) /4fs セファクロル複合顆粒 f: Number of the test animals of each group. 2 2 s = {Σy – (Y/f)}/n Change the Purity to read: 2 Σy : The sum of squares of y1, y2, y3 and y4 in each group. 2 2 2 2 Y = Y1 + Y2 + Y3 + Y4 Purity Related substances—Take out the total contents of not n = 4(f – 1) less than 5 packs of Cefaclor Compound Granules, add a small L = 2 (C – 1)(CM2 + 0.09062) amount of 0.1 mol/L phosphate buffer solution, pH 4.5, grind, 2 2 2 2 C = Yb /(Yb – 4fs t ) add 0.1 mol/L phosphate buffer solution, pH 4.5, shake vigor- t2: Value shown in the following table against n used to cal- ously for 10 minutes, and add 0.1 mol/L phosphate buffer solu- culate s2. tion, pH 4.5, to make exactly V mL so that each mL contains about 5 mg (potency) of Cefaclor according to the labeled total 2 2 2 n t = F1 n t = F1 n t = F1 potency. Pipet 10 mL of this solution, add 0.1 mol/L phosphate 1 161.45 13 4.667 25 4.242 buffer solution, pH 4.5, to make exactly 25 mL, and filter 2 18.51 14 4.600 26 4.225 through a membrane filter with a pore size not exceeding 0.45 3 10.129 15 4.543 27 4.210 µm. Discard the first 1 mL of the filtrate, and use the subsequent 4 7.709 16 4.494 28 4.196 filtrate as the sample solution. Separately, weigh accurately an 5 6.608 17 4.451 29 4.183 amount of Cefaclor Reference Standard, equivalent to about 20 6 5.987 18 4.414 30 4.171 mg (potency), and dissolve in 0.1 mol/L phosphate buffer solu- 7 5.591 19 4.381 40 4.085 tions, pH 4.5, to make exactly 20 mL. Pipet 2 mL of this solu- 8 5.318 20 4.351 60 4.001 tion, add 0.1 mol/L phosphate buffer solutions, pH 4.5, to make 9 5.117 21 4.325 120 3.920 exactly 100 mL, and use this solution as the standard solution. 10 4.965 22 4.301 ∞ 3.841 Perform the test with exactly 50 µL each of the sample solution 11 4.844 23 4.279 and standard solution as directed under Liquid Chromatography 12 4.747 24 4.260 <2.01> according to the following conditions, and determine each peak area of both solutions by the automatic integration Containers and storage Containers—Hermetic containers. method. Calculate the amount of each related substance by the – Storage—Light resistant, not exceeding 10ºC. following equation: the amount of each related substance is not more than 0.6%, and the total amount of the related substances

is not more than 2.8%. If necessary, correct the fluctuation of Carmellose the base line by performing the test in the same way with 50 µL of 0.1 mol/L phosphate buffer solution, pH 4.5. カルメロース Amount (%) of each related substance Add the following next to the Japanese title: = WS × (AT/AS) × (V/4) × {1/(C × T)}

[9000-11-7] Total amount (%) of the related substances = WS × (ΣAT/AS) × (V/4) × {1/(C × T)}

Carmellose Calcium WS: Amount [mg (potency)] of Cefaclor Reference Standard AT: Area of each peak other than cefaclor, solvent and ex- カルメロースカルシウム cipient from the sample solution

ΣAT: Total area of the peaks other than cefaclor, solvent and Add the following next to the Japanese title: excipient from the sample solution [9050-04-8] AS: Peak area of cefaclor from the standard solution C: Labeled total potency [mg (potency)] of Cefaclor in 1 pack T: Number (pack) of sample

Carmellose Sodium Operating conditions— Proceed as directed in the operating conditions in the Purity カルメロースナトリウム (3) under Cefaclor. Add the following next to the Japanese title: System suitability— Test for required detectability: Pipet 1 mL of the standard so- [9004-32-4] lution, and add 0.1 mol/L phosphate buffer solution, pH 4.5, to make exactly 20 mL. Confirm that the peak area of cefaclor obtained from 50 µL of this solution is equivalent to 3.5 to 6.5% of that of cefaclor from the standard solution. System performance: When the procedure is run with 50 µL

2098 Official Monographs Supplement II, JP XV of the standard solution under the above operating conditions, = WS × (QT/QS) × (V/20) the number of theoretical plates and the symmetry factor of the peak of cefaclor are not less than 40000, and between 0.8 and WS: Amount [mg (potency)] of Cefalexin Reference Standard 1.3, respectively. Internal standard solution—A solution of System repeatability: When the test is repeated 3 times with m-hydroxyacetophenone in 0.1 mol/L phosphate buffer solution, 50 µL of the standard solution under the above operating condi- pH 4.5 (1 in 15000) tions, the relative standard deviation of the peak area of cefaclor Operating conditions— is not more than 2.0%. Proceed as directed in the operating conditions in the Assay. System suitability— Add the following: System performance: When the procedure is run with 10 µL of the standard solution under the above operating conditions, Cefalexin Capsules cefalexin and the internal standard substance are eluted in this order with the resolution between these peaks being not less セファレキシンカプセル than 8. System repeatability: When the test is repeated 6 times with Cefalexin Capsules contain not less than 93.0% and 10 µL of the standard solution under the above operating condi- not more than 107.0% of the labeled potency of ce- tions, the relative standard deviation of the ratio of the peak area falexin (C16H17N3O4S: 347.39). of cefalexin to that of the internal standard substance is not more than 1.0%. Method of preparation Prepare as directed under Capsules, with Cefalexin. Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method using 900 mL Identification Take out the contents of Cefalexin Capsules, to of water as the dissolution medium, the dissolution rates in 30 a quantity of the contents, equivalent to 70 mg (potency) of Ce- minutes of 125-mg (potency) capsules and in 60 minutes of falexin according to the labeled amount, add 25 mL of water, 250-mg (potency) capsules are not less than 75% and 80%, re- shake vigorously for 5 minutes, and filter. To 1 mL of the filtrate spectively. add water to make 100 mL. Determine the absorption spectrum Start the test with 1 capsule of Cefalexin Capsules, withdraw of this solution as directed under Ultraviolet-visible Spectro- not less than 20 mL of the medium at the specified minute after photometry <2.24>: it exhibits a maximum between 260 nm and starting the test, and filter through a membrane filter with a pore 264 nm. size not exceeding 0.5 µm. Discard the first 10 mL of the filtrate, pipet V mL of the subsequent filtrate, add water to make exactly Water <2.48> Not more than 10.0% (0.2 g, volumetric titra- V´ mL so that each mL contains about 22 µg (potency) of Ce- tion, back titration) falexin according to the labeled amount, and use this solution as Uniformity of dosage units <6.02> Perform the test accord- the sample solution. Separately, weigh accurately an amount of ing to the following method: it meets the requirement of the Cefalexin Reference Standard, equivalent to about 22 mg (po- Content uniformity test. tency), and dissolve in water to make exactly 50 mL. Pipet 5 mL Open 1 capsule of Cefalexin Capsules, add 3V/5 mL of 0.1 of this solution, add water to make exactly 100 mL, and use this mol/L phosphate buffer solution, pH 4.5, shake vigorously for solution as the standard solution. Perform the test with the sam- 10 minutes, add 0.1 mol/L phosphate buffer solution, pH 4.5, to ple solution and standard solution as directed under Ultravio- make exactly V mL so that each mL contains about 1.25 mg let-visible Spectrophotometry <2.24>, and determine the ab- (potency) of Cefalexin. Centrifuge this solution, pipet 2 mL of sorbances, AT and AS, at 262 nm. the supernatant liquid, add exactly 10 mL of the internal stan- Dissolution rate (%) with respect to the labeled amount of dard solution, add 0.1 mol/L phosphate buffer solution, pH 4.5, cefalexin (C H N O S) to make 100 mL, and use this solution as the sample solution. 16 17 3 4 = W × (A /A ) × (V´/V) × (1/C) × 90 Separately, weigh accurately an amount of Cefalexin Reference S T S Standard, equivalent to about 25 mg (potency), dissolve in 0.1 WS: Amount [mg (potency)] of Cefalexin Reference Standard mol/L phosphate buffer solution, pH 4.5, to make exactly 100 C: Labeled amount [mg (potency)] of cefalexin mL. Pipet 10 mL of this solution, add exactly 10 mL of the in- (C16H17N3O4S) in 1 capsule ternal standard solution, add 0.1 mol/L phosphate buffer solution, pH 4.5, to make 100 mL, and use this solution as the stan- Assay Take out the contents of not less than 20 capsules of dard solution. Perform the test with 10 µL each of the sample Cefalexin Capsules, weigh accurately the mass of the contents, solution and standard solution as directed under Liquid Chro- and powder. Weigh accurately a portion of the powder, equiva- matography <2.01> according to the following conditions, and lent to about 0.1 g (potency) of Cefalexin, add 60 mL of 0.1 calculate the ratios, QT and QS, of the peak area of cefalexin to mol/L phosphate buffer solution, pH 4.5, shake vigorously for that of the internal standard in each solution. 10 minutes, add 0.1 mol/L phosphate buffer solution, pH 4.5, to make exactly 100 mL, and centrifuge. Pipet 2 mL of the super- Amount [mg (potency)] of cefalexin (C16H17N3O4S) natant liquid, add exactly 10 mL of the internal standard solu-

Supplement II, JP XV Official Monographs 2099 tion, add 0.1 mol/L phosphate buffer solution, pH 4.5, to make Add the following: 100 mL, and use this solution as the sample solution. Separately, weigh accurately an amount of Cefalexin Reference Standard, Cefalexin for Syrup equivalent to about 20 mg (potency), dissolve in 0.1 mol/L phosphate buffer solution, pH 4.5, to make exactly 100 mL. Pi- シロップ用セファレキシン pet 10 mL of this solution, add exactly 10 mL of the internal standard solution, add 0.1 mol/L phosphate buffer solution, pH Cefalexin for Syrup is a preparation for syrup, which 4.5, to make 100 mL, and use this solution as the standard solu- is dissolved or suspended before use. tion. Perform the test with 10 µL each of the sample solution It contains not less than 90.0% and not more than and standard solution as directed under Liquid Chromatography 110.0% of the labeled potency of cefalexin <2.01> according to the following conditions, and calculate the (C16H17N3O4S: 347.39). ratios, Q and Q , of the peak area of cefalexin to that of the in- T S Method of preparation Prepare as directed under Syrup, with ternal standard in each solution. Cefalexin. Amount [mg (potency)] of cefalexin (C H N O S) 16 17 3 4 Identification Dissolve a quantity of Cefalexin for Syrup, = W × (Q /Q ) × 5 S T S equivalent to 3 mg (potency) of Cefalexin according to the labeled amount, in water to make 100 mL. Determine the absorp- WS: Amount [mg (potency)] of Cefalexin Reference Standard tion spectrum of this solution as directed under Ultravio- Internal standard solution—A solution of let-visible Spectrophotometry <2.24>: it exhibits a maximum m-hydroxyacetophenone in 0.1 mol/L phosphate buffer solution, between 260 nm and 264 nm. pH 4.5 (1 in 15000) Operating conditions— Water <2.48> Not more than 5.0% (0.4 g, volumetric titration, Detector: An ultraviolet absorption photometer (wavelength: back titration) 254 nm). Uniformity of dosage units <6.02> Perform the test accord- Column: A stainless steel column 3.0 mm in inside diameter ing to the following method: Cefalexin for Syrup in single-unit and 7.5 cm in length, packed with octadecylsilanized silica gel containers meets the requirement of the Content uniformity test. for liquid chromatography (3 µm in particle diameter). Take out the total contents of 1 pack of Cefalexin for Syrup, Column temperature: A constant temperature of about 25ºC. add 3V/5 mL of 0.1 mol/L phosphate buffer solution, pH 4.5, Mobile phase: Dissolve 2.72 g of potassium dihydrogen shake vigorously for 10 minutes, add 0.1 mol/L phosphate phosphate in 1000 mL of water, and adjust the pH to 3.0 with buffer solution, pH 4.5, to make exactly V mL so that each mL diluted phosphoric acid (3 in 500). To 800 mL of this solution contains about 1 mg (potency) of Cefalexin, and centrifuge. Pi- add 200 mL of methanol. pet 2 mL of the supernatant liquid, add exactly 10 mL of the in- Flow rate: Adjust the flow rate so that the retention time of ternal standard solution, add 0.1 mol/L phosphate buffer solu- cefalexin is about 6 minutes. tion, pH 4.5, to make 100 mL, and use this solution as the sam- System suitability— ple solution. Then, proceed as directed in the Assay. System performance: When the procedure is run with 10 µL of the standard solution under the above operating conditions, Amount [mg (potency)] of cefalexin (C16H17N3O4S) cefalexin and the internal standard are eluted in this order with = WS × (QT/QS) × (V/20) the resolution between these peaks being not less than 8.

System repeatability: When the test is repeated 6 times with WS: Amount [mg (potency)] of Cefalexin Reference Standard 10 µL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of the peak area Internal standard solution—A solution of of cefalexin to that of the internal standard is not more than m-hydroxyacetophenone in 0.1 mol/L phosphate buffer solution, 1.0%. pH 4.5 (1 in 15000)

2100 Official Monographs Supplement II, JP XV about 22 mg (potency), and dissolve in water to make exactly 50 System performance: When the procedure is run with 10 µL mL. Pipet 5 mL of this solution, add water to make exactly 100 of the standard solution under the above operating conditions, mL, and use this solution as the standard solution. Perform the cefalexin and the internal standard are eluted in this order with test with the sample solution and standard solution as directed the resolution between these peaks being not less than 8. under Ultraviolet-visible Spectrophotometry <2.24>, and deter- System repeatability: When the test is repeated 6 times with mine the absorbances, AT and AS, at 262 nm. 10 µL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of the peak area Dissolution rate (%) with respect to the labeled amount of of cefalexin to that of the internal standard is not more than cefalexin (C16H17N3O4S) 1.0%. = (WS/WT) × (AT/AS) × (1/C) × 1125 Containers and storage Containers—Tight containers. WS: Amount [mg (potency)] of Cefalexin Reference Standard Storage—Light-resistant. WT: Amount (g) of Cefalexin for Syrup C: Labeled amount [mg (potency)] of cefalexin

(C16H17N3O4S) in 1 g Add the following: Assay Powder Cefalexin for Syrup, if necessary, and weigh Cefatrizine Propylene Glycolate accurately a portion of the powder, equivalent to about 0.1 g (potency) of Cefalexin, add 60 mL of 0.1 mol/L phosphate for Syrup buffer solution, pH 4.5, shake vigorously for 10 minutes, add 0.1 mol/L phosphate buffer solution, pH 4.5, to make exactly シロップ用セファトリジンプロピレングリコール 100 mL, and centrifuge. Pipet 2 mL of the supernatant liquid, Cefatrizine Propylene Glycolate for Syrup is a add exactly 10 mL of the internal standard solution, add 0.1 preparation for syrup, which is dissolved before use. mol/L phosphate buffer solution, pH 4.5, to make 100 mL, and It contains not less than 90.0% and not more than use this solution as the sample solution. Separately, weigh accu- 105.0% of the labeled potency of Cefatrizine rately an amount of Cefalexin Reference Standard, equivalent to (C H N O S : 462.50). about 20 mg (potency), dissolve in 0.1 mol/L phosphate buffer 18 18 6 5 2 solution, pH 4.5, to make exactly 100 mL. Pipet 10 mL of this Method of preparation Prepare as directed under Syrup, with solution, add exactly 10 mL of the internal standard solution, Cefatrizine Propylene Glycolate. add 0.1 mol/L phosphate buffer solution, pH 4.5, to make 100 mL, and use this solution as the standard solution. Perform the Identification Powder Cefatrizine Propylene Glycolate for test with 10 µL each of the sample solution and standard solu- Syrup, weigh a portion of the powder, equivalent to 10 mg (po- tion as directed under Liquid Chromatography <2.01> according tency) of Cefatrizine Propylene Glycolate according to the la- to the following conditions, and calculate the ratios, QT and QS, beled amount, and dissolve in 10 mL of water. To 2 mL of this of the peak area of cefalexin to that of the internal standard in solution add water to make 100 mL. Determine the absorption each solution. spectrum of this solution as directed under Ultraviolet-visible Spectrophotometry <2.24>: it exhibits maxima between 225 nm Amount [mg (potency)] of cefalexin (C16H17N3O4S) and 229 nm, and between 266 nm and 271 nm. = WS × (QT/QS) × 5 pH <2.54> Take an amount of Cefatrizine Propylene Glyco- WS: Amount [mg (potency)] of Cefalexin Reference Standard late for Syrup, equivalent to 0.4 g (potency) of Cefatrizine Pro- pylene Glycolate according to the labeled amount, and suspend Internal standard solution—A solution of in 10 mL of water: the pH of this suspension is between 4.0 and m-hydroxyacetophenone in 0.1 mol/L phosphate buffer solution, 6.0. pH 4.5 (1 in 15000) Operating conditions— Purity Related substances—Use the sample solution obtained Detector: An ultraviolet absorption photometer (wavelength: in the Assay as the sample solution. Pipet 1 mL of the sample 254 nm). solution, add water to make exactly 100 mL, and use this solu- Column: A stainless steel column 3.0 mm in inside diameter tion as the standard solution. Perform the test with exactly 10 µL and 7.5 cm in length, packed with octadecylsilanized silica gel each of the sample solution and standard solution as directed for liquid chromatography (3 µm in particle diameter). under Liquid Chromatography <2.01> according to the follow- Column temperature: A constant temperature of about 25ºC. ing conditions. Determine each peak area of both solutions by Mobile phase: Dissolve 2.72 g of potassium dihydrogen the automatic integration method: the area of each peak other phosphate in 1000 mL of water, and adjust the pH to 3.0 with than cefatrizine obtained from the sample solution is not larger diluted phosphoric acid (3 in 500). To 800 mL of this solution than the peak area of cefatrizine from the standard solution, and add 200 mL of methanol. the total area of the peaks other than the peak of cefatrizine ob- Flow rate: Adjust the flow rate so that the retention time of tained from the sample solution is not larger than 2 times the cefalexin is about 6 minutes. peak area of cefatrizine from the standard solution. System suitability— Operating conditions—

Supplement II, JP XV Official Monographs 2101

Detector, column, column temperature, mobile phase and gen phosphate (17 in 12500) and methanol (4:1). flow rate: Proceed as directed in the operating conditions in the Flow rate: Adjust the flow rate so that the retention time of Assay under Cefatrizine Propylene Glycolate. cefatrizine is about 8 minutes. Time span of measurement: About 2.5 times as long as the System suitability— retention time of cefatrizine, beginning after the solvent peak. System performance: When the procedure is run with 10 µL System suitability— of the standard solution under the above operating conditions, System performance: Proceed as directed in the system suit- the number of theoretical plates and the symmetry factor of the ability in the Assay under Cefatrizine Propylene Glycolate. peak of cefatrizine are not less than 3000 and not more than 2.0, Test for required detectability: Pipet 2 mL of the standard so- respectively. lution, and add water to make exactly 10 mL. Confirm that the System repeatability: When the test is repeated 6 times with peak area of cefatrizine obtained from 10 µL of this solution is 10 µL of the standard solution under the above operating condi- equivalent to 15 to 25% of that of cefatrizine from the standard tions, the relative standard deviation of the peak area of ce- solution. fatrizine is not more than 1.0%. System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- Assay Powder Cefatrizine Propylene Glycolate for Syrup, tions, the relative standard deviation of the peak area of ce- weigh accurately a portion of the powder, equivalent to about fatrizine is not more than 2.0%. 0.1 g (potency) of Cefatrizine Propylene Glycolate, dissolve in water to make exactly 500 mL, and use this solution as the sam- Uniformity of dosage units <6.02> Cefatrizine Propylene ple solution. Separately, weigh accurately an amount of Ce- Glycolate for Syrup in single-unit containers meets the require- fatrizine Propylene Glycolate Reference Standard, equivalent to ment of the Mass variation test. about 20 mg (potency), dissolve in water to make exactly 100 mL, and use this solution as the standard solution. Then, pro- Dissolution <6.10> When the test is performed at 50 revolu- ceed as directed in the Assay under Cefatrizine Propylene Gly- tions per minute according to the Paddle method using 900 mL colate. of water as the dissolution medium, the dissolution rate in 15 minutes of Cefatrizine Propylene Glycolate for Syrup is not less Amount [mg (potency)] of cefatrizine (C18H18N6O5S2) than 85%. = WS × (AT/AS) × 5 Start the test with an accurately weighed amount of Cefatriz- ine Propylene Glycolate for Syrup, equivalent to about 0.1 g WS: Amount [mg (potency)] of Cefatrizine Propylene Glyco- (potency) of Cefatrizine Propylene Glycolate, withdraw not less late Reference Standard than 20 mL of the medium at the specified minute after starting Containers and storage Containers—Tight containers. the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the filtrate, and use the subsequent filtrate as the sample solution. Separately, Add the following: weigh accurately an amount of Cefatrizine Propylene Glycolate Reference Standard, equivalent to about 28 mg (potency), and Cefixime Capsules dissolve in water to make exactly 50 mL. Pipet 5 mL of this solution, add water to make exactly 25 mL, and use this solution セフィキシムカプセル as the standard solution. Perform the test with exactly 10 µL each of the sample solution and standard solution as directed Cefixime Capsules contain not less than 90.0% and under Liquid Chromatography <2.01> according to the follow- not more than 105.0% of the labeled potency of ce- ing conditions, and determine the peak areas of cefatrizine, AT fixime (C16H15N5O7S2: 453.45). and AS, of both solution. Method of preparation Prepare as directed under Capsules, Dissolution rate (%) with respect to the labeled amount of with Cefixime.

cefatrizine (C18H18N6O5S2) Identification Take out the contents of Cefixime Capsules, to = (WS/WT)× (AT/AS) × (1/C) × 360 a quantity of the contents of Cefixime Capsules, equivalent to

WS: Amount [mg (potency)] of Cefatrizine Propylene Glyco- 70 mg (potency) of Cefixime according to the labeled amount, late Reference Standard add 100 mL of 0.1 mol/L phosphate buffer solution, pH 7.0,

WT: Amount (g) of Cefatrizine Propylene Glycolate for Syrup shake for 30 minutes, and filter. Pipet 1 mL of the filtrate, and C: Labeled amount [mg (potency)] of cefatrizine propylene add 0.1 mol/L phosphate buffer solution, pH 7.0, to make 50 mL.

glycolate (C18H18N6O5S2·C3H8O2) in 1 g Determine the absorption spectrum of this solution as directed under Ultraviolet-visible Spectrophotometry <2.24>: it exhibits Operating conditions— a maximum between 286 nm and 290 nm. Detector, column and column temperature: Proceed as directed in the operating conditions in the Assay under Cefatrizine Purity Related substances—Take out the contents of Cefixime Propylene Glycolate. Capsules, to a quantity of the contents of Cefixime Capsules, Mobile phase: A mixture of a solution of potassium dihydro- equivalent to 0.1 g (potency) of Cefixime according to the la-

2102 Official Monographs Supplement II, JP XV beled amount, add 100 mL of 0.1 mol/L phosphate buffer solu- WS: Amount [mg (potency)] of Cefixime Reference Standard tion, pH 7.0, shake for 30 minutes, filter, and use the filtrate as the sample solution. Perform the test with 10 µL of the sample Dissolution <6.10> When the test is performed at 50 revolu- solution as directed under Liquid Chromatography <2.01> ac- tions per minute according to the Paddle method using the cording to the following conditions. Determine each peak area sinker, using 900 mL of disodium hydrogen phosphate-citric from the sample solution by the automatic integration method, acid buffer solution, pH 7.5, as the dissolution medium, the dis- and calculate the amount of them by the area percentage solution rates in 60 minutes of 50-mg (potency) capsules and in method: the amount of each peak other than cefixime is not 90 minutes of 100-mg (potency) capsules are not less than 80%, more than 1.0%, and the total amount of the peaks other than respectively. cefixime is not more than 2.5%. Start the test with 1 capsule of Cefixime Capsules, withdraw Operating conditions— not less than 20 mL of the medium at the specified minute after Detector, column, column temperature, mobile phase and starting the test, and filter through a membrane filter with a pore flow rate: Proceed as directed in the operating conditions in the size not exceeding 0.5 µm. Discard the first 10 mL of the filtrate, Assay under Cefixime. pipet V mL of the subsequent filtrate, add the dissolution me- Time span for measurement: Proceed as directed in the oper- dium to make exactly V´ mL so that each mL contains about 56 ating conditions in the Purity under Cefixime. µg (potency) of Cefixime according to the labeled amount, and System suitability— use this solution as the sample solution. Separately, weigh accu- Test for required detectability: Pipet 1 mL of the sample solu- rately an amount of Cefixime Reference Standard, equivalent to tion, and add 0.1 mol/L phosphate buffer solution, pH 7.0, to about 28 mg (potency), and dissolve in the dissolution medium make exactly 100 mL, and use this solution as the solution for to make exactly 100 mL. Pipet 4 mL of this solution, add the system suitability test. Pipet 1 mL of the solution for system dissolution medium to make exactly 20 mL, and use this solu- suitability test, and add 0.1 mol/L phosphate buffer solution, pH tion as the standard solution. Perform the test with exactly 20 µL 7.0, to make exactly 10 mL. Confirm that the peak area of ce- each of the sample solution and standard solution as directed fixime obtained from 10 µL of this solution is equivalent to 7 to under Liquid Chromatography <2.01> according to the follow- 13% of that of cefixime from the solution for system suitability ing conditions, and determine the peak areas, AT and AS, of ce- test. fixime in each solution. System performance: When the procedure is run with 10 µL Dissolution rate (%) with respect to the labeled amount of of the solution for system suitability test under the above oper- cefixime (C H N O S ) ating conditions, the number of theoretical plates and the sym- 16 15 5 7 2 = W × (A /A ) × (V´/V) × (1/C) × 180 metry factor of the peak of cefixime are not less than 4000 and S T S not more than 2.0, respectively. WS: Amount [mg (potency)] of Cefixime Reference Standard System repeatability: When the test is repeated 6 times with C: Labeled amount [mg (potency)] of Cefixime in 1 capsule 10 µL of the solution for system suitability test under the above operating conditions, the relative standard deviation of the peak Operating conditions— area of cefixime is not more than 2.0%. Proceed as directed in the operating conditions in the Assay under Cefixime. Water <2.48> Not more than 12.0% (0.1 g of the contents, System suitability— volumetric titration, direct titration) System performance: When the procedure is run with 20 µL of the standard solution under the above operating conditions, Uniformity of dosage units <6.02> Perform the test accord- the number of theoretical plates and the symmetry factor of the ing to the following method: it meets the requirement of the peak of cefixime are not less than 4000 and not more than 2.0, Content uniformity test. respectively. Take out the contents of 1 capsule of Cefixime Capsules, and to System repeatability: When the test is repeated 6 times with the contents and the capsule shells add 7V/10 mL of 0.1 mol/L 20 µL of the standard solution under the above operating condi- phosphate buffer solution, pH 7.0, shake for 30 minutes, and tions, the relative standard deviation of the peak area of ce- add 0.1 mol/L phosphate buffer solution, pH 7.0, to make ex- fixime is not more than 2.0%. actly V mL so that each mL contains about 1 mg (potency) of Cefixime. Centrifuge this solution, pipet 10 mL of the super- Assay Take out the contents of not less than 20 Cefixime natant liquid, add 0.1 mol/L phosphate buffer solution, pH 7.0, Capsules, weigh accurately the mass of the contents, and pow- to make exactly 50 mL, and use this solution as the sample solu- der. Weigh accurately a portion of the powder, equivalent to tion. Separately, weigh accurately an amount of Cefixime Ref- about 0.1 g (potency) of Cefixime, add 70 mL of 0.1 mol/L erence Standard, equivalent to about 20 mg (potency), dissolve phosphate buffer solution, pH 7.0, and shake for 30 minutes, in 0.1 mol/L phosphate buffer solution, pH 7.0, to make exactly add 0.1 mol/L phosphate buffer solution, pH 7.0, to make ex- 100 mL, and use this solution as the standard solution. Then, actly 100 mL. Centrifuge this solution, pipet 10 mL of the su- proceed as directed in the Assay under Cefixime. pernatant liquid, add 0.1 mol/L phosphate buffer solution, pH 7.0, to make exactly 50 mL, and use this solution as the sample Amount [mg (potency)] of cefixime (C H N O S ) 16 15 5 7 2 solution. Separately, weigh accurately an amount of Cefixime = W × (A /A ) × (V/20) S T S Reference Standard, equivalent to about 20 mg (potency), dis-

Supplement II, JP XV Official Monographs 2103 solve in 0.1 mol/L phosphate buffer solution, pH 7.0, to make = WS × (QT/QS) × (V/200) exactly 100 mL, and use this solution as the standard solution. Then, proceed as directed in the Assay under Cefixime. WS: Amount [mg (potency)] of Cefroxadine Reference Stan- dard

Amount [mg (potency)] of cefixime (C16H15N5O7S2) Internal standard solution—Dissolve 1.6 g of vanillin in 5 mL = WS × (AT/AS) × 5 of methanol, and add a mixture of dilute acetic acid and phos-

WS: Amount [mg (potency)] of Cefixime Reference Standard phoric acid (500:1) to make 100 mL.

Containers and storage Containers—Tight containers. Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method using 900 mL of water as the dissolution medium, the dissolution rate in 15 Add the following: minutes of Cefroxadine for Syrup is not less than 85%. Start the test with an accurately weighed amount of Ce- Cefroxadine for Syrup froxadine for Syrup, equivalent to about 0.1 g (potency) of Ce- froxadine Hydrate according to the labeled amount, withdraw シロップ用セフロキサジン not less than 10 mL of the medium at the specified minute after starting the test, and filter through a membrane filter with a pore Cefroxadine for Syrup is a preparation for syrup, size not exceeding 0.8 µm. Discard the first 5 mL of the filtrate, which is suspended before use. pipet 4 mL of the subsequent filtrate, add 0.1 mol/L hydrochlo- It contains not less than 93.0% and not more than ric acid TS to make exactly 20 mL, and use this solution as the 107.0% of the labeled potency of cefroxadine sample solution. Separately, weigh accurately an amount of Ce- (C H N O S: 365.40). 16 19 3 5 froxadine Reference Standard, equivalent to about 22 mg (po- Method of preparation Prepare as directed under Syrup, with tency), and dissolve in 0.1 mol/L hydrochloric acid TS to make Cefroxadine Hydrate. exactly 100 mL. Pipet 5 mL of this solution, add 10 mL of water, add 0.1 mol/L hydrochloric acid TS to make exactly 50 mL, and Identification Powder Cefroxadine for Syrup, if necessary. To use this solution as the standard solution. Perform the test with a portion of the powder, equivalent to 2 mg (potency) of Ce- the sample solution and standard solution as directed under Ul- froxadine Hydrate according to the labeled amount, add 100 mL traviolet-visible Spectrophotometry <2.24>, and determine the of 0.001 mol/L hydrochloric acid TS, shake well, and filter. De- absorbances, AT and AS, at 267 nm. termine the absorption spectrum of this filtrate as directed under Ultraviolet-visible Spectrophotometry <2.24>: it exhibits a Dissolution rate (%) with respect to the labeled amount of maximum between 267 nm and 271 nm. cefroxadine (C16H19N3O5S) = (WS /WT) × (AT/AS) × (1/C) × 450 Water <2.48> Not more than 4.5% (0.1 g, volumetric titration, direct titration). WS: Amount [mg (potency)] of Cefroxadine Reference Stan- dard

Uniformity of dosage units <6.02> Perform the test accord- WT: Amount (g) of Cefroxadine for Syrup ing to the following method: Cefroxadine for Syrup in sin- C: Labeled amount [mg (potency)] of cefroxadine gle-unit containers meets the requirement of the Content uni- (C16H19N3O5S) in 1 g formity test. Take out the total contents of 1 pack of Cefroxadine for Syrup, Assay Powder Cefroxadine for Syrup, if necessary, weigh ac- add 4V/5 mL of a mixture of dilute acetic acid and phosphoric curately a portion of the powder, equivalent to about 50 mg acid (500:1), shake well for 15 minutes, add exactly 5 mL of the (potency) of Cefroxadine Hydrate, add 160 mL of a mixture of internal standard solution per 50 mg (potency) of Cefroxadine dilute acetic acid and phosphoric acid (500:1), shake well for 15 Hydrate, and add a mixture of dilute acetic acid and phosphoric minutes, add exactly 5 mL of the internal standard solution, and acid (500:1) to make V mL so that each mL contains 0.25 mg add a mixture of dilute acetic acid and phosphoric acid (500:1) (potency) of Cefroxadine Hydrate. Filter this solution through a to make 200 mL. Filter this solution through a membrane filter membrane filter with pore size of not exceeding 0.45 µm, and with a pore size not exceeding 0.45 µm, and use the filtrate as use the filtrate as the sample solution. Separately, weigh accu- the sample solution. Separately, weigh accurately an amount of rately an amount of Cefroxadine Reference Standard, equivalent Cefroxadine Reference Standard, equivalent to about 50 mg to about 50 mg (potency), dissolve in a mixture of dilute acetic (potency), dissolve in a mixture of dilute acetic acid and phos- acid and phosphoric acid (500:1), add exactly 5 mL of the in- phoric acid (500:1), add exactly 5 mL of the internal standard ternal standard solution, add a mixture of dilute acetic acid and solution, add a mixture of dilute acetic acid and phosphoric acid phosphoric acid (500:1) to make 200 mL, and use this solution (500:1) to make 200 mL, and use this solution as the standard as the standard solution. Then, proceed as directed in the Assay solution. Proceed as directed in the Assay under Cefroxadine under Cefroxadine Hydrate. Hydrate.

Amount [mg (potency)] of cefroxadine (C H N O S) Amount [mg (potency)] of cefroxadine (C16H19N3O5S) 16 19 3 5

2104 Official Monographs Supplement II, JP XV

= WS × (QT/QS) Operating conditions— Proceed as directed in the operating conditions in the Purity WS: Amount [mg (potency)] of Cefroxadine Reference Stan- (3) under Cefteram Pivoxil. dard System suitability— Proceed as directed in the system suitability in the Purity (3) Internal standard solution—Dissolve 1.6 g of vanillin in 5 mL under Cefteram Pivoxil. of methanol, and add a mixture of dilute acetic acid and phosphoric acid (500:1) to make 100 mL. Water <2.48> Not more than 4.0% (a quantity equivalent to 0.2 g (potency) of powdered Cefteram Pivoxil Tablets, volumet- Containers and storage Containers—Tight containers. ric titration, direct titration).

Uniformity of dosage units <6.02> Perform the test accord- Add the following: ing to the following method: it meets the requirement of the Content uniformity test. Cefteram Pivoxil Tablets To 1 tablet of Cefteram Pivoxil Tablets add exactly 5 mL of セフテラムピボキシル錠 the internal standard solution per 50 mg (potency) of Cefteram Pivoxil, and add diluted acetonitrile (1 in 2) to make V mL so Cefteram Pivoxil Tablets contain not less than 90.0% and not that each mL contains about 1 mg (potency) of Cefteram Pivoxil. more than 110.0% of the labeled amount of cefteram Disperse this solution with ultrasonic waves, filter through a membrane filter with pore size of not exceeding 0.45 µm, dis- (C16H17N9O5S2: 479.49). card the first 10 mL of the filtrate, and use the subsequent fil- Method of preparation Prepare as directed under Tablets, trate as the sample solution. Separately, weigh accurately an with Cefteram Pivoxil. amount of Cefteram Pivoxil Mesitylene Sulfonate Reference Standard, equivalent to about 50 mg (potency), dissolve in 20 Identification To a quantity of powdered Cefteram Pivoxil mL of diluted acetonitrile (1 in 2), add exactly 5 mL of the in- Tablets, equivalent to 0.1 g (potency) of Cefteram Pivoxil ac- ternal standard solution, add diluted acetonitrile (1 in 2) to make cording to the labeled amount, add 20 mL of methanol, shake 50 mL, and use this solution as the standard solution. Then, well, and filter. To 1 mL of the filtrate add 0.05 mol/L hydro- proceed as directed in the Assay under Cefteram Pivoxil. chloric acid-methanol TS to make 500 mL. Determine the absorption spectrum of this solution as directed under Ultravio- Amount [mg (potency)] of cefteram (C16H17N9O5S2) let-visible Spectrophotometry <2.24>: it exhibits a maximum = WS × (QT/QS) × (V/50) between 262 nm and 266 nm. WS: Amount [mg (potency)] of Cefteram Pivoxil Mesitylene Purity Related substances—To a quantity of powdered Sulfonate Reference Standard Cefteram Pivoxil Tablets, equivalent to 0.1 g (potency) of Cefteram Pivoxil according to the labeled amount, add diluted Internal standard solution—A solution of methyl parahydroxy- acetonitrile (1 in 2) to make 100 mL. Disperse this solution with benzoate in diluted acetonitrile (1 in 2) (1 in 1000) ultrasonic waves, filter, and use the filtrate as the sample solu- Dissolution <6.10> When the test is performed at 75 revolu- tion. Pipet 1 mL of this solution, add the mobile phase to make tions per minute according to the Paddle method using 900 mL exactly 50 mL and use this solution as the standard solution. of water as the dissolution medium, the dissolution rate in 30 Perform the test with exactly 10 µL each of the sample solution minutes of Cefteram Pivoxil Tablets is not less than 75%. and standard solution as directed under Liquid Chromatography Start the test with 1 tablet of Cefteram Pivoxil Tablets, with- <2.01> according to the following conditions. Determine each draw not less than 20 mL of the medium at the specified minute peak area of both solutions by the automatic integration method: after starting the test, and filter through a membrane filter with a the area of the peak, having the relative retention time of about pore size not exceeding 0.45 µm. Discard the first 10 mL of the 0.9 with respect to cefteram pivoxil, obtained from the sample filtrate, pipet V mL of the subsequent filtrate, add water to make solution is not larger than 1.75 times the peak area of cefteram exactly V´ mL so that each mL contains about 22 µg (potency) pivoxil from the standard solution, and the area of the peak, of Cefteram Pivoxil according to the labeled amount, and use having the relative retention time of about 0.1 with respect to this solution as the sample solution. Separately, weigh accu- cefteram pivoxil, obtained from the sample solution is not larger rately an amount of Cefteram Pivoxil Mesitylene Sulfonate than 17/25 times the peak area of cefteram pivoxil from the Reference Standard, equivalent to about 22 mg (potency), and standard solution. Furthermore, the total area of the peaks other dissolve in 20 mL of methanol, and add water to make exactly than cefteram pivoxil from the sample solution is not larger than 50 mL. Pipet 5 mL of this solution, add water to make exactly 3.7 times the peak area of cefteram pivoxil from the standard 100 mL, and use this solution as the standard solution. Perform solution. For this calculation, use the area of the peak, having the test with the sample solution and standard solution as di- the relative retention time of about 0.1 with respect to cefteram rected under Ultraviolet-visible Spectrophotometry <2.24>, us- pivoxil, after multiplying by the relative response factor, ing water as the blank, and determine the absorbances, A and 0.74.relative response T AS, at 300 nm.

Supplement II, JP XV Official Monographs 2105 Dissolution rate (%) with respect to the labeled amount of Powdered Cellulose cefteram (C16H17N9O5S2) = WS × (AT/AS) × (V´/V) × (1/C) × 90 粉末セルロース

WS: Amount [mg (potency)] of Cefteram Pivoxil Mesitylene Add the following next to the Japanese title: Sulfonate Reference Standard C: Labeled amount [mg (potency)] of cefteram [9004-34-6, Cellulose]

(C16H17N9O5S2) in 1 tablet

Assay To a number of tablet of Cefteram Pivoxil Tablets, Add the following: equivalent to about 1.0 g (potency) of Cefteram Pivoxil, add 120 mL of diluted acetonitrile (1 in 2), disperse with ultrasonic Cinoxacin waves, and add diluted acetonitrile (1 in 2) to make exactly 200 mL. Centrifuge this solution, pipet 10 mL of the supernatant シノキサシン liquid, add exactly 5 mL of the internal standard solution, add diluted acetonitrile (1 in 2) to make 50 mL, filter through a membrane filter with pore size not exceeding 0.45 µm, discard the first 3 mL of the filtrate, and use the subsequent filtrate as the sample solution. Separately, weigh accurately an amount of Cefteram Pivoxil Mesitylene Sulfonate Reference Standard, equivalent to about 50 mg (potency), dissolve in 20 mL of di- C12H10N2O5: 262.22 luted acetonitrile (1 in 2), add exactly 5 mL of the internal stan- 5-Ethyl-8-oxo-5,8-dihydro[1,3]dioxolo[4,5-g]cinnoline- dard solution, add diluted acetonitrile (1 in 2) to make 50 mL, 7-carboxylic acid [28657-80-9] and use this solution as the standard solution. Then, proceed as directed in the Assay under Cefteram Pivoxil. Cinoxacin, when dried, contains not less than 98.0% and not more than 101.0% of C12H10N2O5. Amount [mg (potency)] of cefteram (C16H17N9O5S2) Description Cinoxacin occurs as a white to pale yellow crys- = WS × (QT/QS) × 20 talline powder. It is odorless or has a slight, characteristic odor.

WS: Amount [mg (potency)] of Cefteram Pivoxil Mesitylene It has a bitter taste. Sulfonate Reference Standard It is slightly soluble in N,N-dimethylformamide or acetone, very slightly soluble in ethanol (99.5), and practically insoluble Internal standard solution—A solution of methyl parahydroxy- in water. benzoate in diluted acetonitrile (1 in 2) (1 in 1000) It dissolves in sodium hydroxide TS. Melting point: about 265ºC (with decomposition). Containers and storage Containers—Tight containers. Storage—Light-resistant. Identification (1) Dissolve 30 mg of Cinoxacin in 10 mL of dilute sodium hydroxide TS, and add water to make 100 mL. To

1 mL of this solution add 0.1 mol/L hydrochloric acid TS to Cellacefate make 50 mL. Determine the absorption spectrum of this solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, セラセフェート and compare the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same Change the Chemical name to read: wavelengths. [9004-38-0] (2) Determine the infrared absorption spectrum of Cinox- acin as directed in the potassium bromide disk method under In- frared Spectrophotometry <2.25>, and compare the spectrum Microcrystalline Cellulose with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave numbers. 結晶セルロース Purity (1) Sulfate <1.14>—Dissolve 0.20 g of Cinoxacin in Add the following next to the Japanese title: 10 mL of dilute sodium hydroxide TS, add 20 mL of 0.1 mol/L hydrochloric acid TS, shake, filter, and add water to the filtrate [9004-34-6, Cellulose] to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution with 0.20 mL of 0.005 mol/L sulfuric acid by adding 10 mL of dilute sodium hydroxide TS, 20 mL of 0.1 mol/L hydrochloric acid TS, and water to make 50 mL (not more than 0.048%). (2) Heavy metals <1.07>—Proceed with 1.0 g of Cinoxacin

2106 Official Monographs Supplement II, JP XV according to Method 2, and perform the test. Prepare the control phy. Develop the plate with a mixture of acetonitrile, water and solution with 2.0 mL of Standard Lead Solution (not more than ammonia solution (28) (14:4:1) to a distance of about 10 cm, 20 ppm). and air-dry the plate. Examine under ultraviolet light (main (3) Related substances—Dissolve 10 mg of Cinoxacin in 10 wavelength: 254 nm): the principal spot obtained from the sam- mL of acetone, and use this solution as the sample solution. Pi- ple solution and the spot from the standard solution show a pet 1 mL of this solution, add acetone to make exactly 200 mL, blue-purple color and the same Rf value. and use this solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatogra- Uniformity of dosage units <6.02> Perform the test accord- phy <2.03>. Spot 10 µL each of the sample solution and stan- ing to the following method: it meets the requirement of the dard solution on a plate of silica gel with fluorescent indicator Content uniformity test. for thin-layer chromatography. Develop the plate with a mixture To 1 capsule of Cinoxacin Capsules add 40 mL of dilute so- of acetonitrile, water and ammonia solution (28) (14:4:1) to a dium hydroxide TS, and dissolve the capsule in lukewarm water distance of about 10 cm, and air-dry the plate. Examine under with occasional shaking. After cooling, add water and shake ultraviolet light (main wavelength: 254 nm): the spots other than well, add water to make exactly V mL so that each mL contains the principal spot obtained from the sample solution are not about 1 mg of cinoxacin (C12H10N2O5), and filter. Discard the more intense than the spot from the standard solution. first 20 mL of the filtrate, pipet 1 mL of the subsequent filtrate, (4) Residual solvent—Being specified separately. add 0.1 mol/L hydrochloric acid TS to make exactly 100 mL, and use this solution as the sample solution. Separately, weigh Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 1 accurately about 0.2 g of cinoxacin for assay, previously dried at hour). 105ºC for 1 hour, dissolve in 40 mL of dilute sodium hydroxide TS, and add water to make exactly 200 mL. Pipet 1 mL of this Residue on ignition <2.44> Not more than 0.2% (1 g). solution, add 0.1 mol/L of hydrochloric acid TS to make exactly 100 mL, and use this solution as the standard solution. Perform Assay Weigh accurately about 0.4 g of Cinoxacin, previously the test with the sample solution and standard solution as di- dried, add 60 mL of a mixture of acetic anhydride and acetic rected under Ultraviolet-visible Spectrophotometry <2.24>, and acid (100) (7:3), and dissolve by warming. After cooling, titrate determine the absorbances, A and A , at 354 nm. <2.50> with 0.1 mol/L perchloric acid VS (potentiometric titra- T S tion). Perform a blank determination in the same manner, and Amount (mg) of cinoxacin (C12H10N2O5) make any necessary correction. = WS × (AT/AS) × (V/200) Each mL of 0.1 mol/L perchloric acid VS WS: Amount (mg) of cinoxacin for assay = 26.22 mg of C12H10N2O5 Dissolution <6.10> When the test is performed at 50 revolu- Containers and storage Containers—Tight containers. tions per minute according to the Paddle method using the sinker, using 900 mL of 2nd solution for dissolution test as the

dissolution medium, the dissolution rate in 90 minutes of Ci- Add the following: noxacin Capsules is not less than 70%. Start the test with 1 capsule of Cinoxacin Capsules, withdraw Cinoxacin Capsules not less than 20 mL of the medium at the specified minute after シノキサシンカプセル starting the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the fil- Cinoxacin Capsules contain not less than 95.0% and trate, pipet V mL of the subsequent filtrate, add the dissolution not more than 105.0% of the labeled amount of cinox- medium to make exactly V´ mL so that each mL contains about 11 µg of cinoxacin (C H N O ) according to the labeled acin (C12H10N2O5: 262.22). 12 10 2 5 amount, and use this solution as the sample solution. Separately, Method of preparation Prepare as directed under Capsules, weigh accurately about 22 mg of cinoxacin for assay, previously with Cinoxacin. dried at 105ºC for 1 hour, and dissolve in the dissolution medium to make exactly 100 mL. Pipet 5 mL of this solution, add Identification To a quantity of the contents of Cinoxacin the dissolution medium to make exactly 100 mL, and use this Capsules, equivalent to 10 mg of Cinoxacin according to the la- solution as the standard solution. Perform the test with the sam- beled amount, add 20 mL of acetone, shake well, and centrifuge. ple solution and standard solution as directed under Ultravio- To 3 mL of the supernatant liquid add acetone to make 10 mL, let-visible Spectrophotometry <2.24>, and determine the ab- and use this solution as the sample solution. Separately, dissolve sorbances, AT and AS, at 351 nm. 10 mg of cinoxacin for assay in 20 mL of acetone. To 3 mL of this solution add acetone to make 10 mL, and use this solution Dissolution rate (%) with respect to the labeled amount of as the standard solution. Perform the test with these solutions as cinoxacin (C12H10N2O5) directed under Thin-layer Chromatography <2.03>. Spot 10 µL = WS × (AT/AS) × (V´/V) × (1/C) × 45 each of the sample solution and standard solution on a plate of silica gel with fluorescent indicator for thin-layer chromatogra- WS: Amount (mg) of cinoxacin for assay

Supplement II, JP XV Official Monographs 2107

C: Labeled amount (mg) of cinoxacin (C12H10N2O5) in 1 Identification (1) Determine the absorption spectrum of a capsule solution of Clebopride Malate in methanol (1 in 80000) as directed under Ultraviolet-visible Spectrophotometry <2.24>, and Assay Weigh accurately the mass of not less than 20 Cinox- compare the spectrum with the Reference Spectrum: both spec- acin Capsules, take out the contents, and powder. Wash the cap- tra exhibit similar intensities of absorption at the same wave- sule shells with a small amount of diethyl ether, allow to stand lengths. at room temperature to vaporize the diethyl ether, weigh accu- (2) Determine the infrared absorption spectrum of Clebo- rately the mass of the capsule shells, and calculate the mass of pride Malate, previously dried, as directed in the potassium the contents. Weigh accurately a portion of the powder, equiva- bromide disk method under Infrared Spectrophotometry <2.25>, lent to about 50 mg of cinoxacin (C12H10N2O5), add 10 mL of and compare the spectrum with the Reference Spectrum: both dilute sodium hydroxide TS, shake, add water to make exactly spectra exhibit similar intensities of absorption at the same wave 100 mL, and filter. Discard the first 20 mL of the filtrate, pipet 1 numbers. mL of the subsequent filtrate, add 0.1 mol/L hydrochloric acid (3) Perform the test with Clebopride Malate under Flame TS to make exactly 50 mL, and use this solution as the sample Coloration Test <1.04> (2): a green color appears. solution. Separately, weigh accurately about 50 mg of cinoxacin for assay, previously dried at 105ºC for 1 hour, dissolve in 10 Purity (1) Chloride <1.03>—Dissolve 1.0 g of Clebopride mL of dilute sodium hydroxide TS, and add water to make ex- Malate in 20 mL of acetic acid (100), add 6 mL of dilute nitric actly 100 mL. Pipet 1 mL of this solution, add 0.1 mol/L hydro- acid and water to make 50 mL. Perform the test using this solu- chloric acid TS to make exactly 50 mL, and use this solution as tion as the test solution. Prepare the control solution with 0.25 the standard solution. Perform the test with the sample solution mL of 0.01 mol/L hydrochloric acid VS by adding 20 mL of and standard solution as directed under Ultraviolet-visible Spec- acetic acid (100), 6 mL of dilute nitric acid and water to make trophotometry <2.24>, and determine the absorbances, AT and 50 mL (not more than 0.009%). AS, at 354 nm. (2) Heavy metals <1.07>—Proceed with 2.0 g of Clebo- pride Malate according to Method 2, and perform the test. Pre- Amount (mg) of cinoxacin (C12H10N2O5) pare the control solution with 2.0 mL of Standard Lead Solution = WS × (AT/AS) (not more than 10 ppm). (3) Related substances—Dissolve 0.10 g of Clebopride W : Amount (mg) of cinoxacin for assay S Malate in 10 mL of the mobile phase, and use this solution as Containers and storage Containers—Well-closed containers. the sample solution. Pipet 0.2 mL of this solution, add the mobile phase to make 100 mL, and use this solution as the standard solution. Perform the test with exactly 10 µL each of the sample Add the following: solution and standard solution as directed under Liquid Chro- matography <2.01> according to the following conditions. De- termine each peak area of both solutions by the automatic inte- Clebopride Malate gration method: the total area of the peaks other than the peak of クレボプリドリンゴ酸塩 clebopride obtained from the sample solution is not larger than the peak area of clebopride from the standard solution. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: 240 nm). Column: A stainless steel column 4.6 mm in inside diameter and 25 cm in length, packed with octadecylsilanized silica gel and enantiomer for liquid chromatography (7 µm in particle diameter).

C20H24ClN3O2·C4H6O5: 507.96 Column temperature: A constant temperature of about 25ºC. 4-Amino-N-(1-benzylpiperidin-4-yl)-5-chloro- Mobile phase: Dissolve 3.85 g of ammonium acetate in water 2-methoxybenzamide mono-(2RS)-malate to make 500 mL, and filter through a membrane filter with a [57645-91-7] pore size not exceeding 0.5 µm. To 400 mL of the filtrate add 600 mL of methanol. Clebopride Malate, when dried, contains not less Flow rate: Adjust the flow rate so that the retention time of than 98.5% and not more than 101.0% of clebopride is about 15 minutes. C20H24ClN3O2·C4H6O5. Time span of measurement: About 2 times as long as the retention time of clebopride. Description Clebopride Malate occurs as a white crystalline System suitability— powder. Test for required detectability: Pipet 10 mL of the standard It is freely soluble in acetic acid (100), soluble in methanol, solution, and add water to make exactly 100 mL. Confirm that sparingly soluble in water, and slightly soluble in ethanol (99.5). the peak area of clebopride obtained from 10 µL of this solution A solution of Clebopride Malate in methanol (1 in 25) shows is equivalent to 7 to 13% of that of clebopride from the standard no optical rotation. solution.

2108 Official Monographs Supplement II, JP XV

System performance: Dissolve 30 mg Clebopride Malate and Operating conditions— 5 mg of propyl parahydroxybenzoate in the mobile phase to Detector: An ultraviolet absorption photometer (wavelength: make 100 mL. When the procedure is run with 10 µL of this so- 210 nm) lution under the above operating conditions, propyl parahy- Column: A stainless steel column 4.6 mm in inside diameter droxybenzoate and clebopride are eluted in this order with the and 25 cm in length, packed with octadecylsilanized silica gel resolution between these peaks being not less than 3. for liquid chromatography (5 µm in particle diameter). System repeatability: When the test is repeated 6 times with Column temperature: A constant temperature of about 25ºC. 10 µL of the standard solution under the above operating condi- Mobile phase: To 0.05 mol/L potassium dihydrogen phos- tions, the relative standard deviation of the peak area of clebo- phate TS add 8 mol/L potassium hydroxide TS to adjust the pH pride is not more than 2.5%. to 7.5. To 550 mL of this solution add 450 mL of acetonitrile for (4) Residual solvent—Being specified separately. liquid chromatography. Flow rate: Adjust the flow rate so that the retention time of Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 4 clindamycin is about 10 minutes. hours). System suitability— System performance: When the procedure is run with 20 µL Residue on ignition <2.44> Not more than 0.1% (1 g). of the standard solution under the above operating conditions, Assay Weigh accurately about 0.5 g of Clebopride Malate, the number of theoretical plates and the symmetry factor of the previously dried, dissolve in 30 mL of acetic acid (100), and ti- peak of clindamycin are not less than 6000 and not more than trate <2.50> with 0.1 mol/L perchloric acid VS (potentiometric 1.5, respectively. titration). Perform a blank determination in the same manner, System repeatability: When the test is repeated 6 times with and make any necessary correction. 20 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of clinda- Each mL of 0.1 mol/L perchloric acid VS mycin is not more than 1.0%.

= 50.80 mg of C20H24ClN3O2·C4H6O5

Containers and storage Containers—Tight containers. Clindamycin Hydrochloride Capsules Clindamycin Hydrochloride クリンダマイシン塩酸塩カプセルクリンダマイシン塩酸塩 Change the Origin/limits of content, Uniformity of Change the Origin/limits of content and Assay to dosage units and Assay to read: read: Clindamycin Hydrochloride Capsules contains not Clindamycin Hydrochloride is the hydrochloride of a deriva- less than 93.0% and not more than 107.0% of the la- tive of lincomycin. beled potency of clindamycin (C18H33ClN2O5S: It contains not less than 838 µg (potency) and not more than 424.98). 940 µg (potency) per mg, calculated on the anhydrous basis. The Uniformity of dosage units <6.02> Perform the test accord- potency of Clindamycin Hydrochloride is expressed as mass ing to the following method: it meets the requirement of the (potency) of clindamycin (C18H33ClN2O5S: 424.98). Content uniformity test. Assay Weigh accurately an amount of Clindamycin Hydro- To 1 capsule of Clindamycin Hydrochloride Capsules add a chloride and an amount of Clindamycin Hydrochloride Refer- suitable amount of the mobile phase, shake for 30 minutes, and ence Standard, equivalent to about 20 mg (potency), dissolve add the mobile phase to make exactly V mL so that each mL each in the mobile phase to make exactly 20 mL, and use these contains about 0.75 mg (potency) of Clindamycin Hydrochlo- solutions as the sample solution and standard solution, respec- ride. Centrifuge this solution, and use the supernatant liquid as tively. Perform the test with exactly 20 µL each of the sample the sample solution. Then, proceed as directed in the Assay. solution and standard solution as directed under Liquid Chro- Amount [mg (potency)] of clindamycin (C H ClN O S) matography <2.01> according to the following conditions, and 18 33 2 5 = WS × (AT/AS) × (V/100) determine the peak areas, AT and AS, of clindamycin in each solution. WS: Amount [mg (potency)] of Clindamycin Hydrochloride Reference Standard Amount [µg (potency)] of clindamycin (C18H33ClN2O5S) = WS × (AT/AS) × 1000 Assay Take out the contents of not less than 20 Clindamycin Hydrochloride Capsules, weigh accurately the mass of the con- WS: Amount [mg (potency)] of Clindamycin Hydrochloride tents, and powder. Weigh accurately a portion of the powder, Reference Standard equivalent to about 75 mg (potency) of Clindamycin Hydro-

Supplement II, JP XV Official Monographs 2109 chloride, add the mobile phase, shake for 30 minutes, and add tion. Proceed as directed in the Assay. the mobile phase to make exactly 100 mL. Centrifuge this solution, and use the supernatant liquid as the sample solution. Amount (mg) of clomifene citrate (C26H28ClNO·C6H8O7) Separately, weigh accurately about 75 mg (potency) of Clinda- = WS × (AT/AS) × (V/100) mycin Hydrochloride Reference Standard, dissolve in the mo- W : Amount (mg) of Clomifene Citrate Reference Standard bile phase to make exactly 100 mL, and use this solution as the S standard solution. Perform the test with exactly 20 µL each of the sample solution and standard solution as directed under Liq- uid Chromatography <2.01> according to the following condi- Codeine Phosphate Tablets tions, and calculate the peak areas, AT and AS, of clindamycin in コデインリン酸塩錠 each solution. Add the following next to the Identification: Amount [mg (potency)] of clindamycin (C18H33ClN2O5S) = WS × (AT/AS) Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the W : Amount [mg (potency)] of Clindamycin Hydrochloride S Content uniformity test. Reference Standard To 1 tablet of Codeine Phosphate Tablets add 3V/25 mL of Operating conditions— water to disintegrate, add 2V/25 mL of diluted dilute sulfuric Detector: An ultraviolet absorption photometer (wavelength: acid (1 in 20), and treat with ultrasonic waves for 10 minutes. To 210 nm) this solution add exactly 2V/25 mL of the internal standard solu- Column: A stainless steel column 4.6 mm in inside diameter tion, add water to make V mL so that each mL contains about and 15 cm in length, packed with octadecylsilanized silica gel 0.2 mg of codeine phosphate hydrate (C18H21NO3·H3PO4·½H2O), for liquid chromatography (5 µm in particle diameter). filter, and use the filtrate as the sample solution. Separately, Column temperature: A constant temperature of about 40ºC. weigh accurately about 50 mg of codeine phosphate for assay Mobile phase: To 0.05 mol/L of potassium dihydrogen phos- (separately, determine the water content <2.48> in the same phate TS add 8 mol/L potassium hydroxide TS to adjust the pH manner as Codeine Phosphate Hydrate), and dissolve in water to to 7.5. To 550 mL of this solution add 450 mL of acetonitrile for make exactly 100 mL. Pipet 10 mL of this solution, add exactly liquid chromatography. 2 mL of the internal standard solution, add water to make 25 mL, Flow rate: Adjust the flow rate so that the retention time of and use this solution as the standard solution. Proceed as di- clindamycin is about 7 minutes. rected in the Assay. System suitability— Amount (mg) of codeine phosphate hydrate System performance: When the procedure is run with 20 µL (C H NO ·H PO ·½H O) of the standard solution under the above operating conditions, 18 21 3 3 4 2 = W × (Q /Q ) × (V/250) × 1.023 the number of theoretical plates and the symmetry factor of the S T S peak of clindamycin are not less than 3000 and not more than WS: Amount (mg) of codeine phosphate for assay, calculated 2.0, respectively. on the anhydrous basis System repeatability: When the test is repeated 6 times with 20 µL of the standard solution under the above operating condi- Internal standard solution—A solution of ethylefurin hydro- tions, the relative standard deviation of the peak area of clinda- chloride (3 in 2000) mycin is not more than 1.0%. Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method, using 900 mL Clomifene Citrate Tablets of water as the dissolution medium, the dissolution rate in 30 minutes of Codeine Phosphate Tablets is not less than 80%. クロミフェンクエン酸塩錠 Start the test with 1 tablet of Codeine Phosphate Tablets, withdraw not less than 20 mL of the medium at the specified Add the following next to the Identification: minute after starting the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 Uniformity of dosage units <6.02> Perform the test accord- mL of the filtrate, pipet V mL of the subsequent filtrate, add wa- ing to the following method: it meets the requirement of the ter to make exactly V´ mL so that each mL contains about 5.6 µg Content uniformity test. of codeine phosphate hydrate (C18H21NO3·H3PO4·½H2O) ac- To 1 tablet of Clomifene Citrate Tablets add 10 mL of water, cording to the labeled amount, and use this solution as the sam- and shake until the tablets are disintegrated. To this solution add ple solution. Separately, weigh accurately about 28 mg of co- 50 mL of methanol, shake for 10 minutes, and add methanol to deine phosphate for assay (separately, determine the water con- make exactly 100 mL. Centrifuge this solution, pipet 4 mL of tent <2.48> in the same manner as Codeine Phosphate Hydrate), the supernatant liquid, add methanol to make exactly V mL so dissolve in water to make exactly 100 mL. Pipet 2 mL of this that each mL contains about 20 µg of clomifene citrate solution, add water to make exactly 100 mL, and use this solu- (C26H28ClNO·C6H8O7), and use this solution as the sample solu-

2110 Official Monographs Supplement II, JP XV tion as the standard solution. Perform the test with exactly 100 Change to read: µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the follow- Wood Creosote ing conditions, and determine the peak areas, AT and AS, of codeine in each solution. 木クレオソート

Dissolution rate (%) with respect to the labeled amount of Wood Creosote is a mixture of phenols obtained

codeine phosphate hydrate (C18H21NO3·H3PO4·½H2O) from by using wood tar derived from dry distillation of = WS × (AT/AS) × (V´/V) × (1/C) × 18 × 1.023 stems and branches of various plants of genus Pinus (Pinaceae), genus Cryptomeria (Taxodiaceae), genus WS: Amount (mg) of codeine phosphate for assay, calculated Fagus (Fagaceae), genus Afzelia (genus Intsia); on the anhydrous basis (Leguminosae), genus Shorea (Dipterocarpaceae) or C: Labeled amount (mg) of codeine phosphate hydrate genus Tectona (Verbenaceae), followed by distillation (C18H21NO3·H3PO4·½H2O) in 1 tablet and collection at 180 to 230°C, then further purifica- tion and then re-distillation. Operating procedures— Wood Creosote contains not less than 23.0% and not Proceed as directed in the Assay. more than 35 % of guaiacol (C H O :124.14). System suitability— 7 8 2 System performance: When the procedure is run with 100 µL Description Wood Creosote is a colorless or pale yellow, of the standard solution under the above operating conditions, clear liquid. It has a characteristic odor. the number of theoretical plates and the symmetry factor of the It is slightly soluble in water. peak of codeine are not less than 5000 and not more than 1.5, It is miscible with methanol or ethanol (99.5). respectively. Its saturated solution is acidic. System repeatability: When the test is repeated 6 times with It is highly refractive. 100 µL of the standard solution under the above operating con- It gradually changes in color by light or by air. ditions, the relative standard deviation of the peak area of codeine is not more than 2.0%. Identification The sample solution for assay is used as the sample solution. Separately dissolve 0.1 g of phenol, p-cresol, guaiacol and 2-methoxy-4-methylphenol in methanol respec- Corn Starch tively, to prepare 100 mL of solutions. Take 10 mL of each solution and add methanol to prepare 50 mL of solutions, which トウモロコシデンプン are used as Standard Solution (1), Standard Solution (2), Stan- dard Solution (3) and Standard Solution (4). The perform test Change the Identification (1) to read: with 10 µL each of the sample solution, Standard Solution (1), Standard Solution (2), Standard Solution (3) and Standard Solu- Identification (1) Under a microscope <5.01>, using a tion (4) as directed under liquid chromatography <2.01> ac- mixture of water and glycerin (1:1), Corn Starch appears as ei- cording to the following conditions: the main peaks show the ther angular polyhedral granules of irregular sizes with diame- same retention times with those obtained with the Standard So- ters ranging from about 2 µm to about 23 µm or as rounded or lution (1-4). spheroidal granules of irregular sizes with diameters ranging Operating conditions— from about 25 µm to about 35 µm. The central hilum consists of It meets test requirements directed in the assay. a distinct cavity or two- to five-rayed cleft, and there are no concentric striations. Between orthogonally oriented polarizing 20 Specific gravity <2.56> d 20 : Not less than 1.076. plates or prisms, the starch granules show a distinct black cross intersecting at the hilum. Purity (1) Coal Creosote Accurately measure 10 mL of this Coal Creosote, add methanol to prepare exactly 20 mL of Add the following next to the Purity (3): the solution, which is used as the standard solution. Separately prepare exactly 1 mg each of benzo[a]pyrene, Purity ◆(4) Foreign matter—Under a microscope <5.01>, benz[a]anthracene and dibenz[a, h]anthracene, dissolve ethyl Corn Starch does not contain starch granules of any other origin. acetate as needed and add methanol to prepare a 100 mL solu- It may contain a minute quantity, if any, of fragments of the tis- tion. Take 1 mL of this solution and add methanol to prepare sue of the original plant. ◆ 100 mL of the standard solution. Perform the test with exactly 1 µL each of sample solution and standard solution as directed

under gas chromatography <2.02> according to the following conditions: No peaks are detected for retention times that correspond to benzo[a]pyrene, benz[a]anthracene and dibenz[a, h]anthracene. Change these conditions if any peak is detected for retention times that correspond to benzo[a]pyrene, benz[a]anthracene or dibenz[a, h]anthracene, to verify that such

Supplement II, JP XV Official Monographs 2111 a peak does not belong to benzo[a]pyrene, benz[a]anthracene or tion. Change these conditions if any peak is detected for the re- dibenz[a, h]anthracene. tention time corresponding to acenaphthene, to verify that such Operating conditions— a peak does not belong to athenaphthene. Detector: Mass spectrometer (EI). Operating conditions— Monitored ions: Detector: A hydrogen flame-ionization detector.

Column: A fused silica tube 0.25 mm inside diameter and 60 Benz[a]anthracene: Molecular ion m/z About 14 to 20 m in length, with internal coating 0.25 – 0.5 µm in thickness 228, Fragment ion m/z 114 minutes made of polymethylsiloxane for gas chromatography. Benzo[a]pyrene: Molecular ion m/z 252, About 20 to 25 Column temperature: Perform injection at a constant tem- Fragment ion m/z 125 minutes perature in vicinity of 45°C, then raise the temperature by Dibenz[a, h]anthracene: Molecular ion About 25 to 30 11.5°C per minute until reaching 160°C, then raise the tempera- m/z 278, Fragment ion m/z 139 minutes ture by 4°C per minute until reaching 180°C, then raise the Column: A quartz tube 0.25 mm in inside diameter and 30 m temperature by 8°C until reaching 270°C, then maintain tem- in length, with internal coating 0.25 – 0.5 µm in thickness made perature at 270°C for 3 minutes. of 5% diphenyl and 95% dimethyl polysiloxane for gas chro- Injection port temperature: 250°C. matography. Detector temperature: 250°C. Column temperature: Perform injection at constant tempera- Carrier gas: Helium. ture in vicinity of 45°C, then raise temperature by 40°C each Flow rate: Adjust the flow rate so that the retention time of time to 240°C, maintain the temperature at 240°C for 5 minutes, acenaphthene is about 18 minutes. then raise temperature by 4°C per minute until it reaches 300°C, Split ratio: Splitless. then raise the temperature by 10°C each minute until it reaches System suitability— 320°C, then maintain temperature at 320°C for 3 minutes. Test for required detectability: Accurately measure 1 mL of Injection port temperature: Constant temperature in vicinity this solution, add methanol to prepare exactly 10 mL of the so- of 250°C. lution for system suitability test. When the procedure is run with Interface temperature: Constant temperature in vicinity of conditions described above for 1 µL of solution for system suit- 300°C. ability test, the S/N ratio of acenaphthene is not less than 3. Carrier gas: Helium. System repeatability: When the test is repeated 6 times with 1 Flow rate: Adjust the flow rate so that the retention time of µL of the solution for system suitability test under the above benzo [a]pyrene is about 22 minutes. operating conditions, the relative standard deviation of the peak Split ratio: Splitless. area of acenaphthene is not more than 6.0 %. System suitability— (3) Other impurities Test for required deectability: Accurately measure 1 mL of Add 2 mL of petroleum benzin to 1.0 mL of Wood Creosote, standard solution and add methanol to prepare exactly 10 mL of then add 2 mL of barium hydroxide test solution, agitate to mix the solution for system suitability test. When the test is per- and allow to stand. No blue or muddy brown color develops in formed with conditions described above for 1 µL of the solution the upper layer of the mixture. Furthermore, no red color de- for system suitability test, the S/N ratio of each substance is not velops in the lower layer. less than 3. Distilling range <2.57> 200 – 220°C, not less than 85 vol%. System performance: When the procedure is run with conditions described above for 1 µL of the solution for system suit- Assay Add methanol to exactly 0.1 g of Wood Creosote to ability test, the elution takes place in order of benz[a]anthracene, prepare exactly 50 mL of the solution. Add methanol to exactly benzo[a]pyrene and then dibenz[a, h]anthracene. 10 mL of this solution to prepare 50 mL of sample solution. System repeatability: When the test is repeated 6 times with 1 Separately add methanol to about 30 mg of accurately measured µL of the solution for system suitability test under the above guaiacol for assay to prepare exactly 50 mL of the solution. conditions, the relative standard deviation of the peak area of Accurately measure 10 mL of this solution, add methanol to benzo[a]pyrene, benz[a]anthracene and dibenz[a, h]anthracene prepare exactly 50 mL of the standard solution. Perform the test is respectively not more than 10 %. with 10 µL each of sample solution and standard solution as di- (2) Acenaphthene rected under liquid chromatography <2.01> according to the Add methanol to 0.12 g of Wood Creosote to prepare 50 mL following conditions, and calculate the peak areas, AT and AS, of of the sample solution. Separately dissolve 25 mg of ace- the guaiacol for each solution. naphthene in methanol to prepare a 50 mL of solution. Take 5 mL of this solution and add methanol to prepare 20 mL of solu- The amount of guaiacol (C7H8O2) (mg) tion. Take 2 mL of this solution and add methanol to prepare = WS × (AT / AS) 100 mL of standard solution. Perform the test with exactly 1 µL each of sample solution and standard solution as directed under WS: Amount of guaiacol for assay (mg) gas chromatography <2.02> according to the following condi- Operating conditions— tions: No peaks are detected with sample solution for the reten- Detector: Ultraviolet absorption detector (detected wave- tion time corresponding to acenaphthene of the standard solu- length: 275 nm).

2112 Official Monographs Supplement II, JP XV

Column: Fill a stainless steel tube with internal diameter of the spectrum with the Reference Spectrum or the spectrum of a 4.6 mm and length of 15 cm with 5 µm of octadecylsilanized solution of Danazol Reference Standard prepared in the same silica gel for gas chromatography. manner as the sample solution: both spectra exhibit similar in- Column temperature: Constant temperature in vicinity of tensities of absorption at the same wavelengths. 40°C. (2) Determine the infrared absorption spectrum of Danazol Mobile phase: Mixture of water and acetonitrile (4:1). as directed in the potassium bromide disk method under Infrared Flow rate: Adjust the flow rate so that the retention time of Spectrophotometry <2.25>, and compare the spectrum with the guaiacol is about 9 minutes. Reference Spectrum or the spectrum of a solution of Danazol System suitability— Reference Standard prepared in the same manner as the sample System performance: Dissolve 2 mg each of guaiacol and solution: both spectra exhibit similar intensities of absorption at phenol to obtain 10 mL of solution. The procedure is run with the same wave numbers. conditions described above for 10 µL of this solution, the elu- 20 tion takes place in order of phenol then guaiacol, with the de- Optical rotation <2.49> [α] D : +8 - +11º (after drying, 0.25 g, gree in separation of not less than 2.5. ethanol (99.5), 50 mL, 100 mm). System repeatability: When the test is repeated 6 times with Purity (1) Chloride <1.03>—To 2.0 g of Danazol add 80 10 µL of the standard solution under the above operating condi- mL of water, shake well, and boil for 5 minutes. After cooling, tions, the relative standard deviation of the peak area of guaiacol add water to make 100 mL, and filter through a glass filter (G4). is not more than 1.5 %. Discard the first 30 mL of the filtrate, take 40 mL of the subse- Containers and storage Containers— Tight containers. quent filtrate, and add 6 mL of dilute nitric acid and water to Storage—Light-resistant. make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution with 0.25 mL of 0.01 mol/L

hydrochloric acid VS (not more than 0.011%). Croscarmellose Sodium (2) Heavy metals <1.07>—Proceed with 2.0 g of Danazol according to Method 2, and perform the test. Prepare the control クロスカルメロースナトリウム solution with 2.0 mL of Standard Lead Solution (not more than 10 ppm). Add the following next to the Japanese title: (3) Related substances—Dissolve 0.20 g of Danazol in 4 mL of acetone, and use this solution as the sample solution. Pi- [74811-65-7] pet 2 mL of this solution, add acetone to make exactly 200 mL. Pipet 4 mL of this solution, add acetone to make exactly 20 mL,

and use this solution as the standard solution. Perform the test Add the following: with these solutions as directed under Thin-layer Chromatogra- phy <2.03>. Spot 5 µL each of the sample solution and standard Danazol solution on a plate of silica gel with fluorescent indicator for ダナゾール thin-layer chromatography. Develop the plate with a mixture of cyclohexane and ethyl acetate (3:2) to a distance of about 15 cm, and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 nm): the spots other than the principal spot and other than the spot at the starting point obtained from the sample solution are not more intense than the spot from the standard solution. (4) Residual solvent—Being specified separately. C22H27NO2: 337.46 17α-Pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol Loss on drying <2.41> Not more than 0.2% (1 g, in vacuum, [17230-88-5] phosphorous (V) oxide, 60ºC, 4 hours).

Danazol, when dried, contains not less than 98.5% Residue on ignition <2.44> Not more than 0.1% (1 g). and not more than 101.0% of C22H27NO2. Assay Weigh accurately about 25 mg each of Danazol and Description Danazol occurs as a white to pale yellow crystal- Danazol Reference Standard, previously dried, dissolve sepa- line powder. rately in ethanol (95) to make exactly 50 mL. Pipet 2 mL each It is soluble in acetone, sparingly soluble in ethanol (99.5), of these solutions, add ethanol (95) to make exactly 50 mL, and and practically insoluble in water. use these solutions as the sample solution and standard solution, Melting point: about 225ºC (with decomposition). respectively. Perform the test with the sample solution and standard solution as directed under Ultraviolet-visible Spectro- Identification (1) Determine the absorption spectrum of a photometry <2.24>, and determine the absorbances, A and A , solution of Danazol in ethanol (95) (1 in 50000) as directed un- T S at 285 nm. der Ultraviolet-visible Spectrophotometry <2.24>, and compare

Supplement II, JP XV Official Monographs 2113

Amount (mg) of danazol (C22H27NO2) to make solutions so that each mL contains 20 µg (potency) and = WS × (AT/AS) 5 µg (potency), and use these solutions as the high concentration sample solution and low concentration sample solution, respec- WS: Amount (mg) of Danazol Reference Standard tively.

Containers and storage Containers—Well-closed containers. Containers and storage Containers—Tight containers. Storage—Light-resistant.

Add the following: Diethylcarbamazine Citrate Tablets Dibekacin Sulfate Ophthalmic ジエチルカルバマジンクエン酸塩錠 Solution Change the Origin/limits of content and Identifi- cation to read: ジベカシン硫酸塩点眼液 Diethylcarbamazine Citrate Tablets contain not less Dibekacin Sulfate Ophthalmic Solution is an aque- than 95.0% and not more than 105.0% of the labeled ous ophthalmic solution. amount of diethylcarbamazine citrate It contains not less than 90.0% and not more than (C10H21N3O·C6H8O7: 391.42). 110.0% of the labeled potency of dibekacin Identification To a quantity of the powdered Diethylcar- (C H N O : 451.52). 18 37 5 8 bamazine Citrate Tablets, equivalent to 0.1 g of Diethylcar- Method of preparation Prepare as directed under Ophthalmic bamazine Citrate according to the labeled amount, add 10 mL of Solution, with Dibekacin Sulfate. water, shake well, and filter. To the filtrate add 1 mL of Reinecke salt TS: a light red precipitate is formed. Description Dibekacin Sulfate Ophthalmic Solution is a clear, colorless liquid. Add the following next to the Identification:

Identification To a volume of Dibekacin Sulfate Ophthalmic Uniformity of dosage units <6.02> Perform the test accord- Solution add water so that each mL contains about 2.5 mg (po- ing to the following method: it meets the requirement of the tency) of Dibekacin Sulfate according to the labeled amount, Content uniformity test. and use this solution as the sample solution. Separately, dissolve To 1 tablet of Diethylcarbamazine Citrate Tablets add 70 mL an amount of Dibekacin Sulfate Reference Standard, equivalent of the mobile phase, shake vigorously for 10 minutes, add the to 5 mg (potency), in 2 mL of water, and use this solution as the mobile phase to make exactly 100 mL, and filter through a standard solution. Perform the test with these solutions as di- membrane filter with a pore size not exceeding 0.45 µm. Dis- rected under Thin-layer Chromatography <2.03>. Spot 10 µL card the first 3 mL of the filtrate, pipet V mL of the subsequent each of the sample solution and standard solution on a plate of filtrate, equivalent to about 2.5 mg of diethylcarbamazine citrate silica gel for thin-layer chromatography. Proceed as directed in (C10H21N3O·C6H8O7), add exactly 5 mL of the internal standard the Identification (1) under Dibekacin Sulfate. solution, add the mobile phase to make 50 mL, and use this solution as the sample solution. Proceed as directed in the Assay. pH <2.54> 6.5 - 7.5 Amount (mg) of diethylcarbamazine citrate

Foreign insoluble matter <6.11> It meets the requirement. (C10H21N3O·C6H8O7) = WS × (QT/QS) × (10/V) Insoluble particulate matter <6.08> It meets the requirement. WS: Amount (mg) of Diethylcarbamazine Citrate Reference Standard Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement. Internal standard solution—A solution of 2-aminobenzimidazol in the mobile phase (1 in 12500) Assay Perform the test according to the Cylinder-plate method as directed under Microbial Assay for Antibiotics <4.02> ac- Change the Assay to read: cording to the following conditions. (i) Test organism, culture medium and standard solu- Assay Weigh accurately the mass of not less than 20 Diethyl- tions—Proceed as directed in the Assay under Dibekacin Sul- carbamazine Citrate Tablets, and powder. Weigh accurately a fate. portion of the powder, equivalent to about 50 mg of diethylcar- (ii) Sample solutions—Pipet a volume of Dibekacin Sulfate bamazine citrate (C10H21N3O·C6H8O7), add 70 mL of the mobile Ophthalmic Solution, equivalent to about 12 mg (potency), and phase, shake vigorously for 10 minutes, add the mobile phase to add water to make exactly 30 mL. Pipet a suitable volume of make exactly 100 mL, and filter through a membrane filter with this solution, add 0.1 mol/L phosphate buffer solution, pH 8.0, a pore size not exceeding 0.45 µm. Discard the first 3 mL of the

2114 Official Monographs Supplement II, JP XV filtrate, pipet 5 mL of the subsequent filtrate, add exactly 5 mL Add the following: of the internal standard solution, add the mobile phase to make 50 mL, and use this solution as the sample solution. Separately, Diflucortolone Valerate weigh accurately about 25 mg of Diethylcarbamazine Citrate Reference Standard, previously dried at 105ºC for 4 hours, dis- ジフルコルトロン吉草酸エステル solve in the mobile phase to make exactly 50 mL. Pipet 5 mL of this solution, add exactly 5 mL of the internal standard solution, add the mobile phase to make 50 mL, and use this solution as the standard solution. Perform the test with 20 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, and calculate the ratios, QT and QS, of the peak area of diethylcarbamazine to that of the internal standard.

Amount (mg) of diethylcarbamazine citrate C27H36F2O5: 478.57 (C10H21N3O·C6H8O7) 6α,9-Difluoro-11β,21-dihydroxy-16α-methylpregna- = WS × (QT/QS) × 2 1,4-diene-3,20-dione 21-pentanate [59198-70-8] WS: Amount (mg) of Diethylcarbamazine Citrate Reference Standard Diflucortolone Valerate contains not less than 98.0% and not more than 102.0% of C H F O , calculated Internal standard solution—A solution of 27 36 2 5 on the dried basis. 2-aminobenzimidazole in the mobile phase (1 in 12500) Operating conditions— Description Diflucortolone Valerate occurs as white crystals Detector: An ultraviolet absorption photometer (wavelength: or crystalline powder. 220 nm). It is sparingly soluble in methanol and in ethanol (99.5), and Column: A stainless steel column 4.6 mm in inside diameter practically insoluble in water. and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Identification (1) Prepare the test solution by proceeding Column temperature: A constant temperature of about 40ºC. with 10 mg of Diflucortolone Valerate according to the Oxygen Mobile phase: To 0.05 mol/L potassium dihydrogen phos- Flask Combustion Method <1.06>, using a mixture of 0.5 mL of phate TS add phosphoric acid to adjust the pH to 2.5. To 950 mL 0.01 mol/L sodium hydroxide TS and 20 mL of water as the ab- of this solution add 50 mL of methanol. sorbing liquid: the test solution responds to the Qualitative Tests Flow rate: Adjust the flow rate so that the retention time of <1.09> for fluoride. diethylcarbamazine is about 14 minutes. (2) Determine the absorption spectrum of a solution of System suitability— Diflucortolone Valerate in methanol (3 in 200000) as directed System performance: When the procedure is run with 20 µL under Ultraviolet-visible Spectrophotometry <2.24>, and com- of the standard solution under the above operating conditions, pare the spectrum with the Reference Spectrum or the spectrum diethylcarbamazine and the internal standard are eluted in this of a solution of Diflucortolone Valerate Reference Standard order with the resolution between these peaks being not less prepared in the same manner as the sample solution: both spec- than 2.5. tra exhibit similar intensities of absorption at the same wave- System repeatability: When the test is repeated 6 times with lengths. 20 µL of the standard solution under the above operating condi- (3) Determine the infrared absorption spectrum of Diflu- tions, the relative standard deviation of the ratio of the peak area cortolone Valerate as directed in the potassium bromide disk of diethylcarbamazine to that of the internal standard is not method under Infrared Spectrophotometry <2.25>, and compare more than 1.0%. the spectrum with the Reference Spectrum or the spectrum of Diflucortolone Valerate Reference Standard: both spectra exhibit similar intensities of absorption at the same wave numbers.

20 Optical rotation <2.49> [α] D : +110 - +115º (0.1 g calculated on the dried basis, ethanol (99.5), 10 mL, 100 mm).

Melting point <2.60> 200 - 204ºC

Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of Diflucortolone Valerate in a platinum crucible according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than 10 ppm). Carbonize and incinerate as directed under Residue on Ignition

Supplement II, JP XV Official Monographs 2115

<2.44>. WS: Amount (mg) of Diflucortolone Valerate Reference Stan- (2) Related substances—Perform the test with 10 µL of the dard, calculated on dried basis. sample solution obtained in the Assay as directed under Liquid Chromatography <2.01> according to the following conditions. Operating conditions— Determine each peak area of both solutions by the automatic in- Detector: An ultraviolet absorption photometer (wavelength: tegration method, and calculate the amounts of these peaks by 238 nm). the area percentage method: the amount of each peak of flucor- Column: A stainless steel column 4.6 mm in inside diameter tolone valerate, 12α diflucortolone valerate and ∆4 diflucor- and 25 cm in length, packed with sulfonamide group bound to tolone valerate, having the relative retention times of about 0.97, hexadecylsilanized silica gel for liquid chromatography (5 µm in 1.03 and 1.05 with respect to diflucortolone valerate, respec- particle diameter). tively, is not more than 0.6%, respectively; the amount of the Column temperature: A constant temperature of about 25ºC. peak of clocortolone valerate, having the relative retention time Mobile phase A: To 0.02 mol/L potassium dihydrogen phos- of about 1.09 with respect to diflucortolone valerate, is not more phate TS add phosphoric acid to adjust the pH to 3.0. Mix this than 0.3%; and the amount of each peak other than those men- solution with acetonitrile for liquid chromatography (11:9). tioned above is not more than 0.1%. Furthermore, the total Mobile phase B: Acetonitrile for liquid chromatography. amount of the peaks other than the peak of diflucortolone valer- Flowing of the mobile phase: Control the gradient by mixing ate is not more than 2.0%. the mobile phases A and B as directed in the following table. Operating conditions— Time after in- Detector, column, column temperature, mobile phase and Mobile phase A Mobile phase B jection of sample flow rate: Proceed as directed in the operating conditions in the (vol%) (vol%) Assay. (min) Time span of measurement: About 1.4 times as long as the 0 – 10 100 → 90 0 → 10 retention time of diflucortolone valerate, beginning after the solvent peak. 10 – 25 90 10 System suitability— 25 – 45 90 → 35 10 → 65 System performance and system repeatability: Proceed as directed in the system suitability in the Assay. 45 – 50 35 65 Test for required detectability: Pipet 0.1 mL of the sample solution, add a mixture of water and acetonitrile (1:1) to make Flow rate: 1.0 mL per minute. exactly 10 mL, and use this solution as the solution for system suitability test. Pipet 1 mL of the solution for system suitability System suitability— test, and add a mixture of water and acetonitrile (1:1) to make System performance: When the procedure is run with 10 µL exactly 20 mL. Confirm that the peak area of diflucortolone va- of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry factor of the lerate obtained from 10 µL of this solution is equivalent to 3.5 to peak of diflucortolone valerate are not less than 10000 and not 6.5% of that of diflucortolone valerate from the solution for more than 1.5, respectively. system suitability test. System repeatability: When the test is repeated 6 times with (3) Residual solvent—Being specified separately. 10 µL of the standard solution under the above operating condi- Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 3 tions, the relative standard deviation of the peak area of diflu- hours). cortolone valerate is not more than 1.0%.

Residue on ignition <2.44> Not more than 0.1% (1 g, plati- Containers and storage Containers—Tight containers. num crucible).

Assay Weigh accurately about 5 mg each of Diflucortolone Digoxin Valerate and Diflucortolone Valerate Reference Standard (separately, determine the loss on drying <2.41> in the same manner ジゴキシン as Diflucortolone Valerate), dissolve each in a mixture of water and acetonitrile (1:1) to make exactly 10 mL, and use these so- Change the System suitability in the Purity (2) lutions as the sample solution and standard solution, respectively. Related substances to read: Perform the test with exactly 10 µL each of the sample solution and standard solution as directed under Liquid Chromatography Purity (2) Related substances System suitability— <2.01> according to the following conditions, and determine the Test for required detectability: Dissolve 25 mg of Digoxin in peak areas, AT and AS, of diflucortolone valerate in each solu- 50 mL of warm ethanol (95), cool, and add ethanol (95) to make tion. 100 mL. To 10 mL of this solution add 10 mL of water and di-

Amount (mg) of diflucortolone valerate (C27H36F2O5) lute ethanol to make 50 mL, and use this solution as the solution = WS × (AT/AS) for system suitability test. Pipet 2 mL of the solution for system

2116 Official Monographs Supplement II, JP XV suitability test, and add dilute ethanol to make exactly 100 mL. warm ethanol (95), cool, and add ethanol (95) to make 100 mL. Pipet 5 mL of this solution, and add dilute ethanol to make ex- To 10 mL of this solution add 5 mL of a solution of propyl actly 100 mL. Confirm that the peak area of digoxin obtained parahydroxybenzoate in ethanol (95) (1 in 4000), 10 mL of wa- from 10 µL of this solution is equivalent to 0.07 to 0.13% of that ter and dilute ethanol to make 50 mL. When the procedure is run from the solution for system suitability test. with 10 µL of this solution under the above operating conditions, System performance: Dissolve 25 mg of Digoxin in 50 mL of digoxin and propyl parahydroxybenzoate are eluted in this order warm ethanol (95), cool, and add ethanol (95) to make 100 mL. with the resolution between these peaks being not less than 5. To 10 mL of this solution add 5 mL of a solution of propyl System repeatability: When the test is repeated 6 times with parahydroxybenzoate in ethanol (95) (1 in 4000), 10 mL of wa- 10 µL of the solution for system suitability test under the above ter and dilute ethanol to make 50 mL. When the procedure is run operating conditions, the relative standard deviation of the peak with 10 µL of this solution under the above operating conditions, area of digoxin is not more than 2.5%. digoxin and propyl parahydroxybenzoate are eluted in this order with the resolution between these peaks being not less than 5. System repeatability: When the test is repeated 6 times with Digoxin Tablets 10 µL of the solution for system suitability test under the above operating conditions, the relative standard deviation of the peak ジゴキシン錠 area of digoxin is not more than 2.5%. Add the following next to the Identification:

Purity Related substances—Powder not less than 20 Digoxin Digoxin Injection Tablets. Weigh a portion of the powder equivalent to 2.5 mg of ジゴキシン注射液 Digoxin according to the labeled amount, add 30 mL of dilute ethanol, treat with ultrasonic waves for 20 minutes, and shake Change the Method of preparation to read: for 5 minutes. After cooling, add dilute ethanol to make 50 mL, filter, and use the filtrate as the sample solution. Perform the test Method of preparation Prepare as directed under Injections, with 10 µL of the sample solution as directed under Liquid with a solution of Digoxin in 10 to 50 vol% ethanol. Chromatography <2.01> according to the following conditions. Determine each peak area of the sample solution by the auto- Add the following next to the Identification: matic integration method and calculate the amount of these peaks by the area percentage method: the total amount of the Alcohol number <1.01> 0.8 - 1.2 (Method 1). peaks other than digoxin is not more than 5%. Purity Related substances—To a volume of Digoxin Injection, Operating conditions— equivalent to 2.5 mg of Digoxin according to the labeled Detector, column, column temperature, mobile phase and amount, add dilute ethanol to make 50 mL, and use this solution flow rate: Proceed as directed in the operating conditions in the as the sample solution. Perform the test with 10 µL of the sam- Assay. ple solution as directed under Liquid Chromatography <2.01> Time span of measurement: About 4 times as long as the re- according to the following conditions. Determine each peak area tention time of digoxin, beginning after the solvent peak. of the sample solution by the automatic integration method and System suitability— calculate the amounts of these peaks: the total amount of the Test for required detectability: Dissolve 25 mg of digoxin in peaks other than digoxin is not more than 5%. 50 mL of warm ethanol (95), cool, add ethanol (95) to make 100 Operating conditions— mL. To 10 mL of this solution add 10 mL of water and dilute Detector, column, column temperature, mobile phase and ethanol to make 50 mL, and use this solution as the solution for flow rate: Proceed as directed in the operating conditions in the system suitability test. Pipet 2 mL of the solution for system Assay. suitability test, and add dilute ethanol to make exactly 100 mL. Time span of measurement: About 4 times as long as the re- Pipet 5 mL of this solution, and add dilute ethanol to make ex- tention time of digoxin, beginning after the solvent peak. actly 100 mL. Confirm that the peak area of digoxin obtained System suitability— from 10 µL of this solution is equivalent to 0.07 to 0.13% of that Test for required detectability: Dissolve 25 mg of digoxin in of digoxin from the solution for system suitability test. 50 mL of warm ethanol (95), cool, add ethanol (95) to make 100 System performance: Dissolve 25 mg of digoxin in 50 mL of mL. To 10 mL of this solution add 10 mL of water and dilute warm ethanol (95), cool, and add ethanol (95) to make 100 mL. ethanol to make 50 mL, and use this solution as the solution for To 10 mL of this solution add 5 mL of a solution of propyl system suitability test. Pipet 2 mL of the solution for system parahydroxybenzoate in ethanol (95) (1 in 4000), 10 mL of wa- suitability test, and add dilute ethanol to make exactly 100 mL. ter and dilute ethanol to make 50 mL. When the procedure is run Pipet 5 mL of this solution, and add dilute ethanol to make ex- with 10 µL of this solution under the above operating conditions, actly 100 mL. Confirm that the peak area of digoxin obtained digoxin and propyl parahydroxybenzoate are eluted in this order from 10 µL this solution is equivalent to 0.07 to 0.13% of that of with the resolution between these peaks being not less than 5. digoxin from the solution for system suitability test. System repeatability: When the test is repeated 6 times with System performance: Dissolve 25 mg of digoxin in 50 mL of 10 µL of the solution for system suitability test under the above

Supplement II, JP XV Official Monographs 2117 operating conditions, the relative standard deviation of the peak WS: Amount (mg) of distigmine bromide for assay, calculated area of digoxin is not more than 2.5%. on the anhydrous basis

Dissolution <6.10> When the test is performed at 75 revolu- Dimenhydrinate Tablets tions per minute according to the Paddle method using 500 mL of water as the dissolution medium, the dissolution rate in 30 ジメンヒドリナート錠 minutes of Distigmine Bromide Tablets is not less than 80%. Start the test with 1 tablet of Distigmine Bromide Tablets, Add the following next to the Identification: withdraw not less than 20 mL of the medium at the specified minute after starting the test, and filter through a membrane fil- Dissolution <6.10> When the test is performed at 50 revolu- ter with a pore size not exceeding 0.8 µm. Discard the first 10 tions per minute according to the Paddle method, using 900 mL mL of the filtrate, pipet V mL of the subsequent filtrate, add wa- of water as the dissolution medium, the dissolution rate in 15 ter to make exactly V´ mL so that each mL contains about 10 µg minutes of Dimenhydrinate Tablets is not less than 85%. of distigmine bromide (C22H32Br2N4O4) according to the labeled Start the test with 1 tablet of Dimenhydrinate Tablets, with- amount, and use this solution as the sample solution. Separately, draw not less than 20 mL of the medium at the specified minute weigh accurately about 50 mg of distigmine bromide for assay after starting the test, and filter through a membrane filter with a (separately, determine the water content <2.48> in the same pore size not exceeding 0.45 µm. Discard the first 10 mL of the manner as Distigmine Bromide), and dissolve in water to make filtrate, pipet V mL of the subsequent filtrate, add water to make exactly 100 mL. Pipet 10 mL of this solution, add water to make exactly V´ mL so that each mL contains about 28 µg of dimen- exactly 500 mL, and use this solution as the standard solution. hydrinate (C17H21NO·C7H7ClN4O2) according to the labeled Perform the test with the sample solution and standard solution amount, and use this solution as the sample solution. Separately, as directed under Ultraviolet-visible Spectrophotometry <2.24>, weigh accurately about 28 mg of dimenhydrinate for assay, pre- and determine the absorbances, AT1 and AS1, at 270 nm, and AT2 viously dried in vacuum over phosphorous (V) oxide for 24 and AS2, at 350 nm. hours, and dissolve in water to make exactly 50 mL. Pipet 5 mL of this solution, add water to make exactly 100 mL, and use this Dissolution rate (%) with respect to the labeled amount of solution as the standard solution. Determine the absorbances, AT distigmine bromide (C22H32Br2N4O4) and AS, of the sample solution and standard solution at 276 nm = WS × {(AT1 – AT2) / (AS1 – AS2)} × (V´/V) × (1/C) × 10 as directed under Ultraviolet-visible Spectrophotometry <2.24>. WS: Amount (mg) of distigmine bromide for assay, calculated Dissolution rate (%) with respect to the labeled amount of on the anhydrous basis

dimenhydrinate (C17H21NO·C7H7ClN4O2) C: Labeled amount (mg) of distigmine bromide = WS × (AT/AS) × (V´/V) × (1/C) × 90 (C22H32Br2N4O4) in 1 tablet

WS: Amount (mg) of dimenhydrinate for assay C: Labeled amount (mg) of dimenhydrinate Add the following:

(C17H21NO·C7H7ClN4O2) in 1 tablet Doxazosin Mesilate

Distigmine Bromide Tablets ドキサゾシンメシル酸塩

ジスチグミン臭化物錠

Add the following next to the Identification:

Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the Content uniformity test. and enantiomer To 1 tablet of Distigmine Bromide Tablets add 30 mL of 0.1 mol/L hydrochloric acid TS, shake for 1 hour, add 0.1 mol/L C H N O ·CH O S: 547.58 hydrochloric acid TS to make exactly 50 mL, and filter. Discard 23 25 5 5 4 3 1-(4-Amino-6,7-dimethoxyquinazolin-2-yl)-4-{[(2RS)- the first 20 mL of the filtrate, pipet V mL of the subsequent fil- 2,3-dihydro-1,4-benzodioxin-2-yl]carbonyl}piperazine trate, and add 0.1 mol/L hydrochloric acid TS to make exactly monomethansulfonate [77883-43-3] V´ mL so that each mL contains about 30 µg of distigmine bromide (C22H32Br2N4O4), and use this solution as the sample solu- Doxazosin Mesilate, when dried, contains not less tion. Proceed as directed in the Assay. than 98.0% and not more than 102.0% of C23H25N5O5·CH4O3S. Amount (mg) of distigmine bromide (C22H32Br2N4O4) = WS × {(AT2 – AT1) / (AS2 – AS1)} × (V´/V) × (1/20) Description Doxazosin Mesilate occurs as a white to yellow-

2118 Official Monographs Supplement II, JP XV ish white crystalline powder. Pipet 3 mL each of these solutions, add the mobile phase to It is freely soluble in dimethylsulfoxide, slightly soluble in make exactly 100 mL, and use these solutions as the sample so- water and in methanol, and very slightly soluble in ethanol lution and standard solution, respectively. Perform the test with (99.5). exactly 10 µL each of the sample solution and standard solution A solution of Doxazosin Mesilate in dimethylsulfoxide solu- as directed under Liquid Chromatography <2.01> according to tion (1 in 20) shows no optical rotation. the following conditions, and determine the peak areas, AT and Melting point: about 272ºC (with decomposition). AS, of doxazosin in each solution.

Identification (1) Determine the absorption spectrum of a Amount (mg) of doxazosin mesilate (C23H25N5O5·CH4O3S) solution of Doxazosin Mesilate in 0.01 mol/L hydrochloric = WS × (AT/AS) acid-methanol TS (1 in 200000) as directed under Ultravio- let-visible Spectrophotometry <2.24>, and compare the spec- WS: Amount (mg) of Doxazosin Mesilate Reference Standard trum with the Reference Spectrum or the spectrum of a solution Operating conditions— of Doxazosin Mesilate Reference Standard prepared in the same Detector: An ultraviolet absorption photometer (wavelength: manner as the sample solution: both spectra exhibit similar in- 246 nm) tensities of absorption at the same wavelengths. Column: A stainless steel column 3.9 mm in inside diameter (2) Determine the infrared absorption spectrum of Doxa- and 15 cm in length, packed with octadecylsilanized silica gel zosin Mesilate as directed in the potassium bromide disk for liquid chromatography (4 µm in particle diameter). method under Infrared Spectrophotometry <2.25>, and compare Column temperature: A constant temperature of about 25ºC. the spectrum with the Reference Spectrum or the spectrum of Mobile phase: A mixture of 0.05 mol/L potassium dihydrogen Doxazosin Mesilate Reference Standard: both spectra exhibit phosphate TS, pH 3.0, methanol and acetonitrile (12:8:3). similar intensities of absorption at the same wave numbers. Flow rate: Adjust the flow rate so that the retention time of (3) 30 mg of Doxazosin Mesilate responds to the Qualita- doxazosin is about 5 minutes. tive Tests <1.09> (2) for mesilate. System suitability— Purity (1) Heavy metals <1.07>—Proceed with 1.0 g of System performance: When the procedure is run with 10 µL Doxazosin Mesilate according to Method 2, and perform the test. of the standard solution under the above operating conditions, Prepare the control solution with 2.0 mL of Standard Lead Solu- the number of theoretical plates and the symmetry factor of the tion (not more than 20 ppm). peak of doxazosin are not less than 2000 and not more than 2.0, (2) Related substances—Dissolve 20 mg of Doxazosin Me- respectively. silate in 5 mL of a mixture of methanol and acetic acid (100) System repeatability: When the test is repeated 6 times with (1:1), and use this solution as the sample solution. Pipet 1 mL of 10 µL of the standard solution under the above operating condi- this solution, add a mixture of methanol and acetic acid (100) tions, the relative standard deviation of the peak area of doxa- (1:1) to make exactly 100 mL. Pipet 5 mL of this solution, add a zosin is not more than 1.0%. mixture of methanol and acetic acid (100) (1:1) to make exactly 10 mL, and use this solution as the standard solution. Perform Containers and storage Containers—Tight containers. the test with these solutions as directed under Thin-layer Chro- matography <2.03>. Spot 5 µL each of the sample solution and standard solution on a plate of silica gel with fluorescent indi- Add the following: cator for thin-layer chromatography. Develop the plate with an upper layer of a mixture, prepared by adding 1 volume of water Droxidopa and 1 volume of acetic acid (100) to 2 volumes of 4-methyl-2-pentanon and shaking, to a distance of about 10 cm, ドロキシドパ and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 nm): the spot at the Rf value of about 0.15 obtained from the sample solution is not more intense than the spot from the standard solution, and no spots other than the principal spot and other than the spots mentioned above appear from the sample solution. (3) Residual solvent—Being specified separately. C9H11NO5: 213.19 Loss on drying <2.41> Not more than 1.0% (1 g, 105ºC, 4 (2S,3R)-2-Amino-3-(3,4-dihydroxyphenyl)- hours). 3-hydroxypropanoic acid [23651-95-8]

Residue on ignition <2.44> Not more than 0.2% (1 g). Droxidopa, when dried, contains not less than 99.0% and not more than 101.0% of C9H11NO5. Assay Weigh accurately about 25 mg each of Doxazosin Me- silate and Doxazosin Mesilate Reference Standard, previously Description Droxidopa occurs as white to light brown crystals dried, dissolve separately in methanol to make exactly 50 mL. or crystalline powder.

Supplement II, JP XV Official Monographs 2119

It is slightly soluble in water and practically insoluble in Time span of measurement: About 12 times as long as the re- ethanol (99.5). tention time of droxidopa, beginning after the solvent peak. It dissolves in 0.1 mol/L hydrochloric acid TS. System suitability— System performance: When the procedure is run with 10 µL Identification (1) Determine the absorption spectrum of a of the standard solution under the above operating conditions, solution of Droxidopa in 0.1 mol/L hydrochloric acid TS (1 in the number of theoretical plates and the symmetry factor of the 25000) as directed under Ultraviolet-visible Spectrophotometry peak of droxidopa are not less than 10000 and not more than 1.5, <2.24>, and compare the spectrum with the Reference Spec- respectively. trum: both spectra exhibit similar intensities of absorption at the System repeatability: When the test is repeated 6 times with same wavelengths. 10 µL of the standard solution under the above operating condi- (2) Determine the infrared absorption spectrum of Droxi- tions, the relative standard deviation of the peak area of droxidopa as directed in the potassium bromide disk method under dopa is not more than 2.0%. Infrared Spectrophotometry <2.25>, and compare the spectrum (5) Residual solvent—Being specified separately. with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave numbers. Loss on drying <2.41> Not more than 0.1% (1 g, in vacuum, 60ºC, 3 hours). 20 Optical rotation <2.49> [α] D : –38 - –43º (after drying, 0.1 g, 0.1 mol/L hydrochloric acid TS, 20 mL, 100 mm). Residue on ignition <2.44> Not more than 0.2% (1 g).

Purity (1) Chloride <1.03>—Dissolve 0.40 g of Droxidopa Assay Weigh accurately about 0.3 g of Droxidopa, previously in 6 mL of dilute nitric acid, and add water to make 50 mL. dried, dissolve in exactly 20 mL of 0.1 mol/L perchloric acid VS, Perform the test using this solution as the test solution. Prepare add 50 mL of acetic acid (100), and titrate <2.50> the excess the control solution with 0.40 mL of 0.01 mol/L hydrochloric perchloric acid with 0.1 mol/L sodium acetate VS (potentiomet- acid VS (not more than 0.036%). ric titration). Perform a blank determination in the same manner, (2) Heavy metals <1.07>—Proceed with 2.0 g of Droxidopa and make any necessary correction. according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than Each mL of 0.1 mol/L perchloric acid VS 10 ppm). = 21.32 mg of C9H11NO5 (3) Arsenic <1.11>—Prepare the test solution with 1.0 g of Containers and storage Containers—Well-closed containers. Droxidopa according to Method 3, and perform the test (not more than 2 ppm). (4) Related substances—To 0.10 g of Droxidopa add 50 mL Add the following: of 0.1 mol/L hydrochloric acid TS, dissolve by shaking while cooling in an ice bath, and use this solution as the sample solu- Droxidopa Capsules tion. Pipet 1 mL of this solution, add 0.1 mol/L hydrochloric acid TS to make exactly 100 mL. Pipet 5 mL of this solution, ドロキシドパカプセル add 0.1 mol/L hydrochloric acid TS to make 50 mL, and use this solution as the standard solution. Perform the test with exactly Droxidopa Capsules contain not less than 93.0% and 10 µL each of the sample solution and standard solution as di- not more than 107.0% of the labeled amount of droxi- rected under Liquid Chromatography <2.01> according to the dopa (C9H11NO5: 213.19). following conditions. Determine each peak area of both solutions by the automatic integration method: the area of each peak Method of preparation Prepare as directed under Capsules, other than droxidopa obtained from the sample solution is not with Droxidopa. larger than the peak area of droxidopa from the standard solu- Identification (1) To an amount of the contents of Droxi- tion. dopa Capsules, equivalent to 50 mg of Droxidopa according to Operating conditions— the labeled amount, add 50 mL of water, shake for 10 minutes, Detector: An ultraviolet absorption photometer (wavelength: and filter. To 5 mL of the filtrate add 1 mL of ninhydrin TS, and 220 nm). heat in a water bath for 3 minutes: a blue-purple color develops. Column: A stainless steel column 4.6 mm in inside diameter (2) To an amount of the contents of Droxidopa Capsules, and 15 cm in length, packed with octadecylsilanized silica gel equivalent to 20 mg of Droxidopa according to the labeled for liquid chromatography (3 µm in particle diameter). amount, add 20 mL of diluted acetic acid (100) (1 in 500), shake Column temperature: A constant temperature of about 25ºC. for 10 minutes, and filter. To 1 mL of the filtrate add 4 mL of Mobile phase: Dissolve 1.0 g of sodium 1-heptanesulfonate water and 1 drop of iron (III) chloride TS: a deep green color is and 1.36 g of potassium dihydrogen phosphate in 1000 mL of produced, and it gradually changes to light brown. water, and adjust the pH to 2.0 with phosphoric acid. To 930 mL (3) To an amount of the contents of Droxidopa Capsules, of this solution add 70 mL of acetonitrile. equivalent to 50 mg of Droxidopa according to the labeled Flow rate: Adjust the flow rate so that the retention time of amount, add 50 mL of 0.1 mol/L hydrochloric acid TS, shake droxidopa is about 5 minutes. well, add 0.1 mol/L hydrochloric acid TS to make 100 mL, and

2120 Official Monographs Supplement II, JP XV filter. Discard the first 10 mL of the filtrate, and to 2 mL of the Assay Take out the contents of not less than 20 Droxidopa subsequent filtrate add 0.1 mol/L hydrochloric acid TS to make Capsules, weigh accurately the mass of the contents, and mix 25 mL. Determine the absorption spectrum of this solution as uniformly. Weigh accurately an amount equivalent to about 50 directed under Ultraviolet-visible Spectrophotometry <2.24>: it mg of droxidopa (C9H11NO5), add 50 mL of 0.1 mol/L hydro- exhibits a maximum between 278 nm and 282 nm. chloric acid TS, shake well, add 0.1 mol/L hydrochloric acid TS to make exactly 100 mL, and filter. Discard the first 10 mL of Uniformity of dosage units <6.02> Perform the test accord- the filtrate, pipet 2 mL of the subsequent filtrate, add 0.1 mol/L ing to the following method: it meets the requirement of the hydrochloric acid TS to make exactly 25 mL, and use this solu- Content uniformity test. tion as the sample solution. Separately, weigh accurately about To the contents of 1 capsule of Droxidopa Capsules, add 100 50 mg of droxidopa for assay, previously dried in vacuum at mL of 0.1 mol/L hydrochloric acid TS, shake well, and add 0.1 60ºC for 3 hours, dissolve in 0.1 mol/L hydrochloric acid TS to mol/L hydrochloric acid TS to make exactly V mL so that each make exactly 100 mL. Pipet 2 mL of this solution, add 0.1 mL contains about 0.5 mg of droxidopa (C9H11NO5). Filter this mol/L hydrochloric acid TS to make exactly 25 mL, and use this solution, discard the first 10 mL of the filtrate, pipet 2 mL of the solution as the standard solution. Perform the test with the sam- subsequent filtrate, add 0.1 mol/L hydrochloric acid TS to make ple solution and standard solution as directed under Ultravio- exactly 25 mL, and use this solution as the sample solution. let-visible Spectrophotometry <2.24>, and determine the ab- Separately, weigh accurately about 50 mg of droxidopa for assay, sorbances, AT and AS, at 280 nm. previously dried in vacuum at 60ºC for 3 hours, dissolve in 0.1 mol/L hydrochloric acid TS to make exactly 100 mL. Pipet 2 Amount (mg) of droxidopa (C9H11NO5) mL of this solution, add 0.1 mol/L hydrochloric acid TS to make = WS × (AT/AS) exactly 25 mL, and use this solution as the standard solution. Perform the test with the sample solution and standard solution WS: Amount (mg) of droxidopa for assay as directed under Ultraviolet-visible Spectrophotometry <2.24>, Containers and storage Containers—Tight containers. and determine the absorbances, AT and AS, at 280 nm.

Amount (mg) of droxidopa (C H NO ) 9 11 5 Add the following: = WS × (AT/AS) × (V/100)

WS: Amount (mg) of droxidopa for assay Droxidopa Fine Granules

Dissolution <6.10> When the test is performed at 75 revolu- ドロキシドパ細粒 tions per minute according to the Paddle method using the sinker, using 900 mL of water as the dissolution medium, the Droxidopa Fine Granules contain not less than dissolution rate in 90 minutes of Droxidopa Capsules is not less 93.0% and not more than 107.0% of droxidopa than 70%. (C9H11NO5: 213.19). Start the test with 1 capsule of Droxidopa Capsules, withdraw Method of preparation Prepare fine granules as directed un- not less than 20 mL of the medium at the specified minute after der Powders, with Droxidopa. starting the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the fil- Identification (1) To a quantity of powdered Droxidopa trate, pipet V mL of the subsequent filtrate, add water to make Fine Granules, equivalent to 50 mg of Droxidopa according to exactly V´ mL so that each mL contains about 56 µg of droxi- the labeled amount, add 50 mL of water, shake for 10 minutes, dopa (C9H11NO5) according to the labeled amount, and use this and filter. To 5 mL of the filtrate add 1 mL of ninhydrin TS, heat solution as the sample solution. Separately, weigh accurately in a water bath for 3 minutes: a blue-purple color develops. about 28 mg of droxidopa for assay, previously dried in vacuum (2) To a quantity of powdered Droxidopa Fine Granules, at 60ºC for 3 hours, dissolve in water to make exactly 100 mL. equivalent to 20 mg of Droxidopa according to the labeled Pipet 4 mL of this solution, add water to make exactly 20 mL, amount, add 20 mL of diluted acetic acid (100) (1 in 500), shake and use this solution as the standard solution. Perform the test for 10 minutes, and filter. To 1 mL of the filtrate add 4 mL of with the sample solution and standard solution as directed under water and 1 drop of iron (III) chloride TS: a deep green color is Ultraviolet-visible Spectrophotometry <2.24>, and determine produced, and it gradually changes to light brown. the absorbances, AT1 and AS1, at 280 nm, and AT2 and AS2, at 350 (3) To a quantity of powdered Droxidopa Fine Granules, nm. equivalent to 50 mg of Droxidopa according to the labeled amount, add 50 mL of 0.1 mol/L hydrochloric acid TS, shake Dissolution rate (%) with respect to the labeled amount of well, add 0.1 mol/L hydrochloric acid TS to make 100 mL, and droxidopa (C H NO ) 9 11 5 filter. Discard the first 10 mL of the filtrate, to 2 mL of the sub- = W × {(A – A ) / (A – A )} × (V´/V) × (1/C) × 180 S T1 T2 S1 S2 sequent filtrate add 0.1 mol/L hydrochloric acid TS to make 25 mL. Determine the absorption spectrum of this solution as di- WS: Amount (mg) of droxidopa for assay rected under Ultraviolet-visible Spectrophotometry <2.24>: it C: Labeled amount (mg) of droxidopa (C9H11NO5) in 1 capsule exhibits a maximum between 278 nm and 282 nm.

Supplement II, JP XV Official Monographs 2121 Dissolution <6.10> When the test is performed at 75 revolu- Ecabet Sodium Granules tions per minute according to the Paddle method using 900 mL of water as the dissolution medium, the dissolution rate in 45 エカベトナトリウム顆粒 minutes of Droxidopa Fine Granules is not less than 70%. Start the test with an accurately weighed amount of Droxi- Ecabet Sodium Granules contain not less than dopa Fine Granules, equivalent to about 0.1 g of droxidopa 95.0% and not more than 105.0% of the labeled

(C9H11NO5), according to the labeled amount, withdraw not less amount of ecabet sodium hydrate than 20 mL of the medium at the specified minute after starting (C20H27NaO5S·5H2O: 492.56). the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the filtrate, pipet Method of preparation Prepare as directed under Granules, 5 mL of the subsequent filtrate, add exactly 5 mL of water, and with Ecabet Sodium Hydrate. use this solution as the sample solution. Separately, weigh accu- Identification To a quantity of Ecabet Sodium Granules, rately about 28 mg of droxidopa for assay, previously dried in equivalent to 50 mg of Ecabet Sodium Hydrate according to the vacuum at 60ºC for 3 hours, dissolve in water to make exactly labeled amount, add 25 mL of dilute sodium hydroxide TS, 100 mL. Pipet 4 mL of this solution, add water to make exactly shake, and filter. Discard the first 10 mL of the filtrate, and to 3 20 mL, and use this solution as the standard solution. Perform mL of the subsequent filtrate add dilute sodium hydroxide TS to the test with the sample solution and standard solution as di- make 20 mL. Determine the absorption spectrum of this solution rected under Ultraviolet-visible Spectrophotometry <2.24>, and as directed under Ultraviolet-visible Spectrophotometry <2.24>: determine the absorbances, A and A , at 280 nm, and A and T1 S1 T2 it exhibits maxima between 269 nm and 273 nm, and between A , at 350 nm. S2 278 nm and 282 nm. Dissolution rate (%) with respect to the labeled amount of Uniformity of dosage units <6.02> Perform the test accord- droxidopa (C H NO ) 9 11 5 ing to the following method: Ecabet Sodium Granules in sin- = (W /W ) × {(A – A ) / (A – A )} × (1/C) × 360 S T T1 T2 S1 S2 gle-unit containers meets the requirement of the Content uniformity test. WS: Amount (mg) of droxidopa for assay Take out the total contents of 1 pack of Ecabet Sodium Gran- WT: Amount (g) of Droxidopa Fine Granules ules, add 70 mL of dilute sodium hydroxide TS, treat with ul- C: Labeled amount (mg) of droxidopa (C9H11NO5) in 1 g trasonic waves for 5 minutes with occasional shaking, add dilute Particle size <6.03> It meets the requirement. sodium hydroxide TS to make exactly V mL so that each mL contains about 10 mg of ecabet sodium hydrate Assay Powder not less than 20 g of Droxidopa Fine Granules. (C20H27NaO5S·5H2O), and filter. Discard the first 10 mL of the Weigh accurately a portion of the powder, equivalent to about filtrate, pipet 2 mL of the subsequent filtrate, add water to make 50 mg of droxidopa (C9H11NO5), add 50 mL of 0.1 mol/L hy- exactly 50 mL, and use this solution as the sample solution. drochloric acid TS, shake well, add 0.1 mol/L hydrochloric acid Separately, weigh accurately about 20 mg of ecabet sodium hy- TS to make exactly 100 mL, and filter. Discard the first 10 mL drate for assay (separately, determine the water content <2.48> of the filtrate, pipet 2 mL of the subsequent filtrate, add 0.1 in the same manner as Ecabet Sodium Hydrate), dissolve in 2 mol/L hydrochloric acid TS to make exactly 25 mL, and use this mL of dilute sodium hydroxide TS, add water to make exactly solution as the sample solution. Separately, weigh accurately 50 mL, and use this solution as the standard solution. Determine about 50 mg of droxidopa for assay, previously dried in vacuum the absorbances, AT and AS, of the sample solution and standard at 60ºC for 3 hours, dissolve in 0.1 mol/L hydrochloric acid TS solution at 271 nm as directed under Ultraviolet-visible Spec- to make exactly 100 mL. Pipet 2 mL of this solution, add 0.1 trophotometry <2.24>, using water as the blank mol/L hydrochloric acid TS to make exactly 25 mL, and use this solution as the standard solution. Perform the test with the sam- Amount (mg) of ecabet sodium hydrate (C20H27NaO5S·5H2O) ple solution and standard solution as directed under Ultravio- = WS × (AT/AS) × (V/2) × 1.224 let-visible Spectrophotometry <2.24>, and determine the ab- W : Amount (mg) of ecabet sodium hydrate for assay, calcu- sorbances, AT and AS, at 280 nm. S lated on the anhydrous basis.

Amount (mg) of droxidopa (C9H11NO5) Dissolution <6.10> When the test is performed at 50 revolu- = WS × (AT/AS) tions per minute according to the Paddle method using 900 mL

WS: Amount (mg) of droxidopa for assay of water as the dissolution medium, the dissolution rate in 30 minutes of Ecabet Sodium Granules is not less than 80%. Containers and storage Containers—Tight containers. Start the test with an accurately weighed amount of Ecabet Sodium Granules, equivalent to about 1 g (potency) of Ecabet Add the following: Sodium Hydrate according to the labeled amount, withdraw not less than 20 mL of the medium at the specified minute after starting the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the fil-

2122 Official Monographs Supplement II, JP XV trate, pipet 2 mL of the subsequent filtrate, add water to make TS add phosphoric acid to adjust the pH to 3.0. To 730 mL of exactly 10 mL, and use this solution as the sample solution. this solution add 270 mL of acetonitrile. Separately, weigh accurately about 22 mg of ecabet sodium hy- Flow rate: Adjust the flow rate so that the retention time of drate for assay (separately, determine the water content <2.48> ecabet is about 8 minutes. in the same manner as Ecabet Sodium Hydrate), dissolve in 1 System suitability— mL of methanol, add water to make exactly 100 mL, and use System performance: When the procedure is run with 20 µL this solution as the standard solution. Determine the absorb- of the standard solution under the above operating conditions, ances, AT and AS, at 271 nm of the sample solution and standard ecabet and the internal standard are eluted in this order with the solution as directed under Ultraviolet-visible Spectrophotometry resolution between these peaks being not less than 6. <2.24>, using water as the blank System repeatability: When the test is repeated 6 times with 20 µL of the standard solution under the above operating condi- Dissolution rate (%) with respect to the labeled amount of tions, the relative standard deviation of the ratio of the peak area ecabet sodium hydrate (C20H27NaO5S·5H2O) of ecabet to that of the internal standard is not more than 1.0%. = (WS /WT) × (AT/AS) × (1/C) × 4500 × 1.224 Containers and storage Containers—Well-closed containers. WS: Amount (mg) of ecabet sodium hydrate for assay, calculated on the anhydrous basis

WT: Amount (g) of Ecabet Sodium Granules Add the following: C: Labeled amount (mg) of ecabet sodium hydrate (C20H27NaO5S·5H2O) in 1 g Ecabet Sodium Hydrate

Particle size <6.03> It meets the requirement. エカベトナトリウム水和物

Assay Weigh accurately an amount of Ecabet Sodium Gran- ules, equivalent to about 30 mg of ecabet sodium hydrate

(C20H27NaO5S·5H2O), add exactly 5 mL of the internal standard solution, add 25 mL of diluted methanol (1 in 2), shake vigorously for 20 minutes, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 5 mL of the filtrate, to 3 mL of the subsequent filtrate add the mobile phase to make 50 mL, and use this solution as the sample solution. C20H27NaO5S·5H2O: 492.56 Separately, weigh accurately about 30 mg of ecabet sodium hy- (1R,4aS,10aS)-1,4a-Dimethyl-7-(1-methylethyl)- drate for assay (separately, determine the water content <2.48> 6-sodiosulfonato-1,2,3,4,4a,9,10,10a- in the same manner as Ecabet Sodium Hydrate), add exactly 5 octahydrophenanthrene-1-carboxylic acid pentahydrate mL of the internal standard solution, and dissolve in dilute [219773-47-4] methanol (1 in 2) to make 30 mL. To 3 mL of this solution add the mobile phase to make 50 mL, and use this solution as the Ecabet Sodium Hydrate contains not less than standard solution. Perform the test with 20 µL each of the sam- 98.5% and not more than 101.5% of ecabet sodium ple solution and standard solution as directed under Liquid (C20H27NaO5S: 402.48), calculated on the anhydrous Chromatography <2.01> according to the following conditions, basis. and calculate the ratios, Q and Q , of the peak area of ecabet to T S Description Ecabet Sodium Hydrate is white crystals. that of the internal standard. It is freely soluble in methanol, and slightly soluble in water and in ethanol (99.5). Amount (mg) of ecabet sodium hydrate (C20H27NaO5S·5H2O) It dissolves in sodium hydroxide TS. = WS × (QT/QS) × 1.224 Dissolve 1.0 g of Ecabet Sodium Hydrate in 200 mL of water:

WS: Amount (mg) of ecabet sodium hydrate for assay, calcu- the pH of the solution is about 3.5. lated on the anhydrous basis Identification (1) Determine the absorption spectrum of a Internal standard solution—A solution of ethyl parahydroxy- solution of Ecabet Sodium Hydrate in dilute sodium hydroxide benzoate in diluted methanol (1 in 2) (3 in 400) TS (3 in 10000) as directed under Ultraviolet-visible Spectro- Operating conditions— photometry <2.24>, and compare the spectrum with the Refer- Detector: An ultraviolet absorption photometer (wavelength: ence Spectrum: both spectra exhibit similar intensities of ab- 225 nm). sorption at the same wavelengths. Column: A stainless steel column 4.6 mm in inside diameter (2) Determine the infrared absorption spectrum of Ecabet and 15 cm in length, packed with octadecylsilanized silica gel Sodium Hydrate as directed in the potassium bromide disk for liquid chromatography (5 µm in particle diameter). method under Infrared Spectrophotometry <2.25>, and compare Column temperature: A constant temperature of about 40ºC. the spectrum with the Reference Spectrum: both spectra exhibit Mobile phase: To 0.1 mol/L potassium dihydrogen phosphate similar intensities of absorption at the same wave numbers.

Supplement II, JP XV Official Monographs 2123

(3) Place 1 g of Ecabet Sodium Hydrate in a porcelain cru- the same manner, and make any necessary correction. cible, and carbonize. After cooling, add 0.5 mL of nitric acid, heat gradually to incinerate, and dissolve the residue in 10 mL Each mL of 0.1 mol/L sodium hydroxide VS of water: the solution responds to the Qualitative Tests <1.09> = 40.25 mg of C20H27NaO5S for sodium salt. Containers and storage Containers—Well-closed containers. Optical rotation <2.49> [α] 20 : +69 - +76º (0.25 g calculated D on the anhydrous basis, methanol, 25 mL, 100 mm). Add the following: Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of Ecabet Sodium Hydrate according to Method 2, and perform the Emorfazone Tablets test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than 10 ppm). エモルファゾン錠 (2) Related substances—Dissolve 10 mg of Ecabet Sodium Emorfazone Tablets contain not less than 95.0% and Hydrate in 10 mL of the mobile phase, and use this solution as not more than 105.0% of the labeled amount of emor- the sample solution. Pipet 2 mL of this solution, add the mobile fazone (C H N O : 239.27). phase to make exactly 20 mL. Pipet 1 mL of this solution, add 11 17 3 3 the mobile phase to make exactly 100 mL, and use this solution Method of preparation Prepare as directed under Tablets, as the standard solution. Perform the test with exactly 20 µL with Emorfazone. each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the follow- Identification To a quantity of powdered Emorfazone Tablets, ing conditions. Determine each peak area of both solutions by equivalent to 0.1 g of Emorfazone according to the labeled the automatic integration method: the area of each peak other amount, add 100 mL of water, shake well, and centrifuge. Filter than ecabet obtained from the sample solution is not larger than the supernatant liquid, and to 1 mL of the filtrate add water to the peak area of ecabet from the standard solution. make 100 mL. Determine the absorption spectrum of this solu- Operating conditions— tion as directed under Ultraviolet-visible Spectrophotometry Detector: An ultraviolet absorption photometer (wavelength: <2.24>: it exhibits maxima between 237 nm and 241 nm, and 225 nm). between 310 nm and 314 nm, and a shoulder between 288 nm Column: A stainless steel column 4.6 mm in inside diameter and 298 nm. and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Uniformity of dosage units <6.02> Perform the test accord- Column temperature: A constant temperature of about 40ºC. ing to the following method: it meets the requirement of the Mobile phase: To 0.1 mol/L potassium dihydrogen phosphate Content uniformity test. TS add phosphoric acid to adjust the pH to 3.0. To 730 mL of To 1 tablet of Emorfazone Tablets add methanol to make ex- this solution add 270 mL of acetonitrile. actly V mL so that each mL contains about 4 mg of emorfazone Flow rate: Adjust the flow rate so that the retention time of (C11H17N3O3), and shake well to disintegrate. Centrifuge this ecabet is about 8 minutes. solution, pipet 2 mL of the supernatant liquid, add exactly 10 Time span of measurement: About 2 times as long as the re- mL of the internal standard solution, add methanol to make 50 tention time of ecabet, beginning after the solvent peak. mL, and use this solution as the sample solution. Proceed as di- System suitability— rected in the Assay. System performance: When the procedure is run with 20 µL Amount (mg) of emorfazone (C H N O ) of the standard solution under the above operating conditions, 11 17 3 3 = W × (Q /Q ) × (V/5) the number of theoretical plates and the symmetry factor of the S T S peak of ecabet are not less than 5000 and not more than 1.5, re- WS: Amount (mg) of emorfazone for assay spectively. System repeatability: When the test is repeated 6 times with Internal standard solution—A solution of 20 µL of the standard solution under the above operating condi- 2,4-dinitrophenylhidrazine in methanol (3 in 2000). Prepare be- tions, the relative standard deviation of the peak area of ecabet fore use. is not more than 2.0%. (3) Residual solvent—Being specified separately. Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method, using 900 mL Water <2.48> 17.3 - 19.2% (0.2 g, volumetric titration, direct of water as the dissolution medium, the dissolution rate in 45 titration). minutes of Emorfazone Tablets is not less than 80%. Start the test with 1 tablet of Emorfazone Tablets, withdraw Assay Weigh accurately about 1.2 g of Ecabet Sodium Hy- not less than 20 mL of the medium at the specified minute after drate, dissolve in 30 mL of methanol, add 30 mL of water, and starting the test, and filter through a membrane filter with a pore titrate <2.50> with 0.1 mol/L sodium hydroxide VS (indicator: 4 size not exceeding 0.45 µm. Discard the first 10 mL of the fil- drops of phenolphthalein TS). Perform a blank determination in trate, pipet V mL of the subsequent filtrate, add water to make

2124 Official Monographs Supplement II, JP XV exactly V´ mL so that each mL contains about 11 µg of emorfa- System repeatability: When the test is repeated 6 times with zone (C11H17N3O3) according to the labeled amount, and use 20 µL of the standard solution under the above operating condi- this solution as the sample solution. Separately, weigh accu- tions, the relative standard deviation of the ratio of the peak area rately about 28 mg of emorfazone for assay, previously dried in of emorfazone to that of the internal standard is not more than vacuum at 60ºC for 4 hours, and dissolve in water to make ex- 1.0%. actly 100 mL. Pipet 4 mL of this solution, add water to make exactly 100 mL, and use this solution as the standard solution. Containers and storage Containers—Tight containers. Storage—Light-resistant. Determine the absorbances, AT and AS, of the sample solution and standard solution at 239 nm as directed under Ultravio- let-visible Spectrophotometry <2.24> Ephedrine Hydrochloride Tablets Dissolution rate (%) with respect to the labeled amount of

emorfazone (C11H17N3O3) エフェドリン塩酸塩錠 = WS × (AT/AS) × (V´/V) × (1/C) × 36 Add the following next to the Uniformity of dos-

WS: Amount (mg) of emorfazone for assay age units: C: Labeled amount (mg) of emorfazone (C11H17N3O3) in 1 tablet Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method using 900 mL Assay To 10 tablets of Emorfazone Tablets add 200 mL of of water as the dissolution medium, the dissolution rate in 30 methanol, shake well to disintegrate, add methanol to make ex- minutes of Ephedrine Hydrochloride Tablets is not less than actly 250 mL, and centrifuge. Pipet a volume of the supernatant, 80%. equivalent to about 8 mg of emorfazone (C11H17N3O3), add ex- Start the test with 1 tablet of Ephedrine Hydrochloride Tablets, actly 10 mL of the internal standard solution, add methanol to withdraw not less than 20 mL of the medium at the specified make 50 mL, and use this solution as the sample solution. minute after starting the test, and filter through a membrane fil- Separately, weigh accurately about 20 mg of emorfazone for as- ter with a pore size not exceeding 0.45 µm. Discard the first 10 say, previously dried in vacuum at 60ºC for 4 hours, and dis- mL of the filtrate, and use the subsequent filtrate as the sample solve in methanol to make exactly 25 mL. Pipet 10 mL of this solution. Separately, weigh accurately about 28 mg of ephedrine solution, add exactly 10 mL of the internal standard solution, hydrochloride for assay, previously dried at 105ºC for 3 hours, add methanol to make 50 mL, and use this solution as the stan- and dissolve in water to make exactly 100 mL. Pipet 5 mL of dard solution. Perform the test with 20 µL each of the sample this solution, add water to make exactly 50 mL, and use this so- solution and standard solution as directed under Liquid Chro- lution as the standard solution. Perform the test with exactly 10 matography <2.01> according to the following conditions, and µL each of the sample solution and standard solution as directed calculate the ratios, QT and QS, of the peak area of emorfazone under Liquid Chromatography <2.01> according to the follow- to that of the internal standard. ing conditions, and determine the peak areas , AT and AS, of ephedrine in each solution. Amount (mg) of emorfazone (C11H17N3O3) = WS × (QT/QS) × (2/5) Dissolution rate (%) with respect to the labeled amount of ephedrine hydrochloride (C10H15NO·HCl) W : Amount (mg) of emorfazone for assay S = WS × (AT/AS) × (1/C) × 90 Internal standard solution—A solution of WS: Amount (mg) of ephedrine hydrochloride for assay 2,4-dinitrophenylhidrazine in methanol (3 in 2000). Prepare be- C: Labeled amount (mg) of ephedrine hydrochloride fore use. (C10H15NO·HCl) in 1 tablet Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: Operating conditions— 313 nm) Detector, column, column temperature, mobile phase and Column: A stainless steel column 4.6 mm in inside diameter flow rate: Proceed as directed in the operating conditions in the and 15 cm in length, packed with octadecylsilanized silica gel Purity (4) under Ephedrine Hydrochloride. for liquid chromatography (5 µm in particle diameter). System suitability— Column temperature: A constant temperature of about 25ºC. System performance: When the procedure is run with 10 µL Mobile phase: A mixture of water and methanol (11:10) of the standard solution under the above operating conditions, Flow rate: Adjust the flow rate so that the retention time of the number of theoretical plates and the symmetry factor of the emorfazone is about 5 minutes. peak of ephedrine are not less than 10000 and not more than 2.0, System suitability— respectively. System performance: When the procedure is run with 20 µL System repeatability: When the test is repeated 6 times with of the standard solution under the above operating conditions, 10 µL of the standard solution under the above operating condi- emorfazone and the internal standard are eluted in this order tions, the relative standard deviation of the peak area of ephed- with the resolution between these peaks being not less than 2.5. rine is not more than 2.0%.

Supplement II, JP XV Official Monographs 2125

Sterility <4.06> Perform the test according to the Direct Ergometrine Maleate Injection method: it meets the requirement.

エルゴメトリンマレイン酸塩注射液 Ethenzamide Add the following next to the Identification: エテンザミド Bacterial endotoxins <4.01> Less than 1500 EU/mg. Change the following to read:

Add the following next to the Extractable volume: Description Ethenzamide occurs as white crystals or crystalline powder. Foreign insoluble matter <6.06> Perform the test according It is soluble in methanol, in ethanol (95), and in acetone, and to Method 1: it meets the requirement. practically insoluble in water. Insoluble particulate matter <6.07> It meets the require- It begins to sublime slightly at about 105ºC. ment. Identification (1) Determine the absorption spectrum of a Sterility <4.06> Perform the test according to the Membrane solution of Ethenzamide in methanol (1 in 100000) as directed filtration method: it meets the requirement. under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spectrum or the spectrum of a solution of Ethenzamide Reference Standard prepared in the Erythromycin Enteric-Coated same manner as the sample solution: both spectra exhibit similar intensities of absorption at the same wavelengths. Tablets (2) Determine the infrared absorption spectrum of Ethen- zamide, previously dried, as directed in the potassium bromide エリスロマイシン腸溶錠 disk method under Infrared Spectrophotometry <2.25>, and compare the spectrum with the Reference Spectrum or the spec- Change the Disintegration to read: trum of Ethenzamide Reference Standard: both spectra exhibit Disintegration <6.09> It meets the requirement. For the test similar intensities of absorption at the same wave numbers. with 2nd fluid for disintegration test, use the disk.

Ethinylestradiol

Estradiol Benzoate Injection エチニルエストラジオール (Aqueous Suspension) Change the following to read: エストラジオール安息香酸エステル水性懸濁注射液 20 Optical rotation <2.49> [α] D : –26 - –31º (after drying, 0.1 g, Add the following next to the Extractable volume: pyridine, 25 mL, 100 mm).

Foreign insoluble matter <6.06> Perform the test according to Method 1: no readily detectable foreign insoluble matters are Famotidine Powder observed. ファモチジン散 Sterility <4.06> Perform the test according to the Direct method: it meets the requirement. Add the following next to the Identification:

Uniformity of dosage units <6.02> Perform the test accord- Estriol Injection ing to the following method: Famotidine Powder in single-unit containers meets the requirement of the Content uniformity test. (Aqueous Suspension) Take out the total contents of 1 pack of Famotidine Powder,

add 10 mL of water per 10 mg of famotidine (C8H15N7O2S3), エストリオール水性懸濁注射液 shake well, add 10 mL of methanol, shake well, add methanol to make exactly V mL so that each mL contains about 0.4 mg of Add the following next to the Extractable volume: famotidine (C8H15N7O2S3), and centrifuge. Pipet 5 mL of the Foreign insoluble matter <6.06> Perform the test according supernatant liquid, add exactly 2 mL of the internal standard so- to Method 1: no readily detectable foreign insoluble matters are lution, add the mobile phase to make 20 mL, and use this solu- observed. tion as the sample solution. Proceed as directed in the Assay.

2126 Official Monographs Supplement II, JP XV

Amount (mg) of famotidine (C8H15N7O2S3) Start the test with 1 tablet of Faropenem Sodium Tablets, = WS × (QT/QS) × (V/250) withdraw not less than 20 mL of the medium at the specified minute after starting the test, and filter through a membrane fil- WS: Amount (mg) of famotidine for assay ter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the filtrate, pipet V mL of the subsequent filtrate, add wa- Internal standard solution—To 5 mL of a solution of methyl ter to make exactly V´ mL so that each mL contains about 56 µg parahydroxybenzoate in methanol (1 in 500) add water to make (potency) of Faropenem Sodium Hydrate according to the la- 50 mL. beled amount, and use this solution as the sample solution. Separately, weigh accurately an amount of Faropenem Sodium Reference Standard, equivalent to about 18 mg (potency), and Faropenem Sodium for Syrup dissolve in water to make exactly 100 mL. Pipet 5 mL of this シロップ用ファロペネムナトリウム solution, add water to make exactly 20 mL, and use this solution as the standard solution. Perform the test with the sample solu- Add the following next to the Uniformity of dos- tion and standard solution as directed under Ultraviolet-visible age unit: Spectrophotometry <2.24>, and determine the absorbances, AT and AS, at 306 nm. Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method using 900 mL Dissolution rate (%) with respect to the labeled amount of of water as the dissolution medium, the dissolution rate in 15 faropenem (C12H15NO5S) minutes of Faropenem Sodium for Syrup is not less than 85%. = WS × (AT/AS) × (V´/V) × (1/C) × 225 Start the test with an accurately weighed amount of Faro- W : Amount [mg (potency)] of Faropenem Sodium Reference penem Sodium for Syrup, equivalent to about 50 mg (potency) S Standard of Faropenem Sodium Hydrate according to the labeled amount, C: Labeled amount [mg (potency)] of faropenem withdraw not less than 20 mL of the medium at the specified (C H NO S) in 1 tablet minute after starting the test, and filter through a membrane fil- 12 15 5 ter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the filtrate, and use the subsequent filtrate as the sample solution. Separately, weigh accurately an amount of Faropenem Flopropione Sodium Reference Standard, equivalent to about 18 mg (po- フロプロピオン tency), and dissolve in water to make exactly 100 mL. Pipet 5 mL of this solution, add water to make exactly 20 mL, and use Change the Origin/limits of content, Description, this solution as the standard solution. Perform the test with the Identification and Purity to read: sample solution and standard solution as directed under Ultra- violet-visible Spectrophotometry <2.24>, and determine the ab- Flopropione contains not less than 98.0% and not sorbances, AT and AS, at 306 nm. more than 101.0% of C9H10O4, calculated on the anhydrous basis. Dissolution rate (%) with respect to the labeled amount of

faropenem (C12H15NO5S) Description Flopropione occurs as a white to pale yel- = (WS/WT) × (AT/AS) × (1/C) × 225 low-brown crystalline powder. It is very soluble in N,N-dimethylformamide, freely soluble in WS: Amount [mg (potency)] of Faropenem Sodium Reference methanol and in ethanol (99.5), and practically insoluble in wa- Standard ter. WT: Amount (g) of Faropenem Sodium for Syrup C: Labeled amount [mg (potency)] of faropenem Identification (1) Determine the absorption spectrum of a

(C12H15NO5S) in 1 g solution of Flopropione in ethanol (99.5) (1 in 200000) as directed under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spectrum: both spec- Faropenem Sodium Tablets tra exhibit similar intensities of absorption at the same wavelengths. ファロペネムナトリウム錠 (2) Determine the infrared absorption spectrum of Flo- propione as directed in the potassium bromide disk method un- Delete the Disintegration and add the following der Infrared Spectrophotometry <2.25>, and compare the spec- next to the Uniformity of dosage unit: trum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave numbers. Dissolution <6.10> When the test is performed at 50 revolu- Purity (1) Heavy metals <1.07> —Proceed with 1.0 g of tions per minute according to the Paddle method using 900 mL Flopropione according to Method 4, and perform the test. Pre- of water as the dissolution medium, the dissolution rate in 30 pare the control solution with 2.0 mL of Standard Lead Solution minutes of Faropenem Sodium Tablets is not less than 85%. (not more than 20 ppm).

Supplement II, JP XV Official Monographs 2127

(2) Related substances—Dissolve 50 mg of Flopropione in Add the following: 50 mL of the mobile phase, and use this solution as the sample solution. Pipet 1 mL of this solution, add the mobile phase to Fludrocortisone Acetate make exactly 100 mL, and use this solution as the standard solution. Perform the test with exactly 20 µL each of the sample フルドロコルチゾン酢酸エステル solution and standard solution as directed under Liquid Chro- matography <2.01> according to the following conditions. De- termine each peak area of both solutions by the automatic integration method: the area of each peak other than the peak of flopropione obtained from the sample solution is not larger than 1/10 times the peak area of flopropione from the standard solution. Operating conditions— C H FO : 422.49 Detector: An ultraviolet absorption photometer (wavelength: 23 31 6 9-Fluoro-11β,17,21-trihydroxypregn-4-ene-3,20-dione 267 nm). 21-acetate [514-36-3] Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel Fludrocortisone Acetate, when dried, contains not for liquid chromatography (5 µm in particle diameter). less than 97.5% and not more than 102.5% of Column temperature: A constant temperature of about 35ºC. C23H31FO6. Mobile phase: A mixture of acetonitrile, water and phosphoric acid (114:86:1) Description Fludrocortisone Acetate occurs as a white to pale Flow rate: Adjust the flow rate so that the retention time of yellow crystals or crystalline powder. flopropione is about 3 minutes. It is soluble in acetone, sparingly soluble in ethanol (95), and Time span of measurement: About 7 times as long as the re- practically insoluble in water. tention time of flopropione. Melting point: about 220ºC (with decomposition). System suitability— Test for required detectability: Pipet 1 mL of the standard so- Identification (1) Prepare the test solution by proceeding lution, and add the mobile phase to make exactly 10 mL. Con- with 10 mg of Fludrocortisone Acetate according to the Oxygen firm that the peak area of flopropione obtained from 20 µL of Flask Combustion Method <1.06>, using 0.5 mL of 0.01 mol/L this solution is equivalent to 7 to 13% of that of flopropione sodium hydroxide VS as the absorbing liquid: the test solution from the standard solution. responds to the Qualitative Tests <1.09> for fluoride. System performance: Dissolve 25 mg of ethyl parahydroxy- (2) Determine the absorption spectrum of a solution of benzoate in 30 mL of acetonitrile, and add the mobile phase to Fludrocortisone Acetate in ethanol (95) (1 in 100000) as di- make 50 mL. To 2.5 mL of this solution add 2 mL of the sample rected under Ultraviolet-visible Spectrophotometry <2.24>, and solution and the mobile phase to make 50 mL. When the proce- compare the spectrum with the Reference Spectrum or the spec- dure is run with 20 µL of this solution under the above operating trum of a solution of Fludrocortisone Acetate Reference Stan- conditions, flopropione and ethyl parahydroxybenzoate are dard in the same manner as the sample solution: both spectra eluted in this order with the resolution between these peaks be- exhibit similar intensities of absorption at the same wave- ing not less than 2.0. lengths. System repeatability: When the test is repeated 6 times with 20 (3) Determine the infrared absorption spectrum of Fludro- µL of the standard solution under the above operating conditions, cortisone Acetate, previously dried, as directed in the potassium the relative standard deviation of the peak area of flopropione is bromide disk method under Infrared Spectrophotometry <2.25>, not more than 1.0%. and compare the spectrum with the Reference Spectrum or the spectrum of Fludrocortisone Acetate Reference Standard, previously dried: both spectra exhibit similar intensities of absorption at the same wave numbers.

20 Optical rotation <2.49> [α] D : +131 - +138º (after drying, 0.1 g, acetone, 20 mL, 100 mm).

Purity (1) Heavy metals <1.07>—Proceed with 0.5 g of Fludrocortisone Acetate according to Method 2, and perform the test. Prepare the control solution with 1.5 mL of Standard Lead Solution (not more than 30 ppm). (2) Related substances—Dissolve 20 mg of Fludrocortisone Acetate in 10 mL of the mobile phase, and use this solution as the sample solution. Pipet 1 mL of this solution, add the mobile phase to make exactly 50 mL, and use this solution as the stan-

2128 Official Monographs Supplement II, JP XV dard solution. Perform the test with exactly 20 µL each of the Amount (mg) of fludrocortisone acetate (C23H31FO6) sample solution and standard solution as directed under Liquid = WS × (AT/AS) Chromatography <2.01> according to the following conditions. W : Amount (mg) of Fludrocortisone Acetate Reference Determine each peak area of both solutions by the automatic in- S Standard tegration method: the area of each peak other than the peak of fludrocortisone acetate obtained from the sample solution is not Containers and storage Containers—Well-closed containers. larger than 1/4 times the peak area of fludrocortisone acetate Storage—Light-resistant. from the standard solution, and the total area of the peaks other than the peak of fludrocortisone acetate obtained from the sample solution is not larger than 1/2 times the peak area of fludro- Add the following: cortisone acetate from the standard solution. Operating conditions— Flutamide Detector: An ultraviolet absorption photometer (wavelength: 254 nm). フルタミド Column: A stainless steel column 4.6 mm in inside diameter and 20 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 25ºC. Mobile phase: A mixture of water and tetrahydrofuran (13:7) Flow rate: Adjust the flow rate so that the retention time of fludrocortisone acetate is about 10 minutes. Time span of measurement: About 2 times as long as the re- C11H11F3N2O3: 276.21 tention time of fludrocortisone acetate, beginning after the sol- 2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide vent peak. [13311-84-7] System suitability— Flutamide, when dried, contains not less than 98.5% Test for required detectability: Pipet 5 mL of the standard so- and not more than 101.5% of C H F N O . lution, and add the mobile phase to make exactly 100 mL. Con- 11 11 3 2 3 firm that the peak area of fludrocortisone acetate obtained from Description Flutamide occurs as a light yellow crystalline 20 µL of this solution is equivalent to 4.0 to 6.0% of that of powder. fludrocortisone acetate from the standard solution. It is freely soluble in methanol and in ethanol (95), and prac- System performance: Dissolve 2 mg each of Fludrocortisone tically insoluble in water. Acetate and hydrocortisone acetate in 50 mL of the mobile phase. When the procedure is run with 20 µL of this solution Identification (1) Determine the absorption spectrum of a under the above operating conditions, hydrocortisone acetate solution of Flutamide in ethanol (95) (1 in 50000) as directed and fludrocortisone acetate are eluted in this order with the under Ultraviolet-visible Spectrophotometry <2.24>, and com- resolution between these peaks being not less than 1.5. pare the spectrum with the Reference Spectrum or the spectrum System repeatability: When the test is repeated 6 times with of a solution of Flutamide Reference Standard prepared in the 20 µL of the standard solution under the above operating condi- same manner as the sample solution: both spectra exhibit similar tions, the relative standard deviation of the peak area of fludro- intensities of absorption at the same wavelengths. cortisone acetate is not more than 2.0%. (2) Determine the infrared absorption spectrum of Flu- (3) Residual solvent—Being specified separately. tamide as directed in the potassium bromide disk method under Infrared Spectrophotometry <2.25>, and compare the spectrum Loss on drying <2.41> Not more than 1.0% (1 g, in vacuum, with the Reference Spectrum or the spectrum of Flutamide Ref- 100ºC, 2 hours). erence Standard: both spectra exhibit similar intensities of absorption at the same wave numbers. Residue on ignition <2.44> Not more than 0.1% (1 g, platinum crucible). Melting point <2.60> 109 - 113ºC

Assay Weigh accurately about 25 mg each of Fludrocortisone Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of Acetate and Fludrocortisone Acetate Reference Standard, pre- Flutamide according to Method 2, and perform the test. Prepare viously dried, and dissolve separately in ethanol (95) to make the control solution with 2.0 mL of Standard Lead Solution (not exactly 100 mL. Pipet 4 mL each of these solutions, add ethanol more than 10 ppm). (95) to make exactly 100 mL, and use these solutions as the (2) Related substances—Dissolve 40 mg of Flutamide in 50 sample solution and standard solution, respectively. Perform the mL of methanol, and use this solution as the sample solution. test with the sample solution and standard solution as directed Perform the test with exactly 10 µL of the sample solution as under Ultraviolet-visible Spectrophotometry <2.24>, and deter- directed under Liquid Chromatography <2.01> according to the mine the absorbances, AT and AS, at 238 nm. following conditions. Determine each peak area of the sample solution by the automatic integration method and calculate the

Supplement II, JP XV Official Monographs 2129 amounts of them by the area percentage method: the amount of sium dihydrogen phosphate (7:4) each peak other than flutamide is not more than 0.3%, and the Flow rate: Adjust the flow rate so that the retention time of total amount of the peaks other than flutamide is not more than flutamide is about 12 minutes. 0.5%. System suitability— Operating conditions— System performance: When the procedure is run with 10 µL Column, column temperature, mobile phase and flow rate: of the standard solution under the above operating conditions, Proceed as directed in the operating conditions in the Assay. flutamide and the internal standard are eluted in this order with Detector: An ultraviolet absorption photometer (wavelength: the resolution between these peaks being not less than 2.0. 230 nm). System repeatability: When the test is repeated 6 times with Time span of measurement: About 2 times as long as the re- 10 µL of the standard solution under the above operating condi- tention time of flutamide, beginning after the solvent peak. tions, the relative standard deviation of the peak area of flu- System suitability— tamide is not more than 1.0%. System performance: Proceed as directed in the system suitability in the Assay. Containers and storage Containers—Tight containers. Test for required detectability: Pipet 1 mL of the standard solution, add methanol to make exactly 100 mL, and use this solu- Add the following: tion as the solution for system suitability test. Pipet 2 mL of the solution for system suitability test, and add methanol to make exactly 20 mL. Confirm that the peak area of flutamide obtained Flutoprazepam from 10 µL of this solution is equivalent to 7 to 13% of that of フルトプラゼパム flutamide from the solution for system suitability test. System repeatability: When the test is repeated 6 times with 10 µL of the solution for system suitability test under the above operating conditions, the relative standard deviation of the peak area of flutamide is not more than 2.0%. (3) Residual solvent—Being specified separately.

Loss on drying <2.41> Not more than 0.5% (0.5 g, in vacuum , phosphorus (V) oxide, 60ºC, 3 hours).

Residue on ignition <2.44> Not more than 0.1% (1 g, plati- C19H16ClFN2O: 342.79 num crucible). 7-Chloro-1-cyclopropylmethyl-5-(2-fluorophenyl)- 1,3-dihydro-2H-1,4-benzodiazepin-2-one [25967-29-7] Assay Weigh accurately about 40 mg each of Flutamide and Flutamide Reference Standard, and dissolve separately in Flutoprazepam, when dried, contains not less than methanol to make exactly 25 mL. Pipet 5 mL each of these solu- 99.0% and not more than 101.0% of C19H16ClFN2O. tions, add 5 mL of the internal standard solution, add methanol to make 50 mL, and use these solutions as the sample solution Description Flutoprazepam occurs as a white to light yellow and standard solution, respectively. Perform the test with 10 µL crystals or crystalline powder. each of the sample solution and standard solution as directed It is freely soluble in ethyl acetate, soluble in ethanol (99.5) under Liquid Chromatography <2.01> according to the follow- and in acetic anhydride, and practically insoluble in water. ing conditions, and calculate the ratios, Q and Q , of the peak T S Identification (1) Dissolve 2 mg of Flutoprazepam in 200 area of flutamide to that of the internal standard, respectively. mL of a solution of sulfuric acid in ethanol (99.5) (3 in 1000). Determine the absorption spectrum of this solution as directed Amount (mg) of flutamide (C11H11F3N2O3) under Ultraviolet-visible Spectrophotometry <2.24>, and com- = WS × (QT/QS) pare the spectrum with the Reference Spectrum: both spectra

WS: Amount (mg) of Flutamide Reference Standard exhibit similar intensities of absorption at the same wavelengths. Internal standard solution—A solution of testosterone in (2) Determine the infrared absorption spectrum of Fluto- methanol (9 in 10000) prazepam as directed in the potassium bromide disk method Operating conditions— under Infrared Spectrophotometry <2.25>, and compare the Detector: An ultraviolet absorption photometer (wavelength: spectrum with the Reference Spectrum: both spectra exhibit 254 nm). similar intensities of absorption at the same wave numbers. Column: A stainless steel column 3.9 mm in inside diameter (3) Perform the test with Flutoprazepam as directed under and 30 cm in length, packed with octadecylsilanized silica gel Flame Coloration Test <1.04> (2): a green color appears. for liquid chromatography (10 µm in particle diameter). Column temperature: A constant temperature of about 25ºC. Melting point <2.60> 118 - 122ºC Mobile phase: A mixture of methanol and 0.05 mol/L potas-

2130 Official Monographs Supplement II, JP XV

Purity (1) Chloride <1.03>—To 1.0 g of Flutoprazepam add beled amount, add 20 mL of a solution of sulfuric acid in etha- 50 mL of water, allow to stand for 1 hour with occasional shak- nol (99.5) (3 in 1000), shake well, and add a solution of sulfuric ing, and filter. Pipet 20 mL of the filtrate, add 6 mL of dilute ni- acid in ethanol (99.5) (3 in 1000) to make 100 mL. Centrifuge tric acid and water to make 50 mL. Perform the test using this this solution, pipet 10 mL of the supernatant liquid, and add a solution as the test solution. Prepare the control solution with solution of sulfuric acid in ethanol (99.5) (3 in 1000) to make 0.40 mL of 0.01 mol/L hydrochloric acid VS (not more than 100 mL. Determine the absorption spectrum of this solution as 0.036%). directed under Ultraviolet-visible Spectrophotometry <2.24>: it (2) Heavy metals <1.07>—Proceed with 1.0 g of Fluto- exhibits maxima between 240 nm and 244 nm, between 279 nm prazepam according to Method 2, and perform the test. Prepare and 285 nm, and between 369 nm and 375 nm. the control solution with 1.0 mL of Standard Lead Solution (not more than 10 ppm). Uniformity of dosage units <6.02> Perform the test accord- (3) Related substances—Dissolve 0.10 g of Flutoprazepam ing to the following method: it meets the requirement of the in 20 mL of ethyl acetate, and use this solution as the sample Content uniformity test. solution. Pipet 1 mL of this solution, and add ethyl acetate to To 1 tablet of Flutoprazepam Tablets add 60 mL of the mobile make exactly 50 mL. Pipet 1 mL of this solution, add ethyl ace- phase, shake for 15 minutes to disintegrate, disperse the particle tate to make exactly 20 mL, and use this solution as the standard with the aid of ultrasonic waves, and add the mobile phase to solution. Perform the test with these solutions as directed under make exactly V mL so that each mL contains about 20 µg of Thin-layer Chromatography <2.03>. Spot 10 µL each of the flutoprazepam (C19H16ClFN2O). Filter this solution through a sample solution and standard solution on a plate of silica gel membrane filter with a pore size not exceeding 0.45 µm, discard with fluorescent indicator for thin-layer chromatography. De- the first 5 mL of the filtrate, and use the subsequent filtrate as velop the plate with a mixture of ethyl acetate and hexane (3:2) the sample solution. Proceed as directed in the Assay. to a distance of about 12 cm, and air-dry the plate. Examine un- Amount (mg) of flutoprazepam (C H ClFN O) der ultraviolet light (main wavelength: 254 nm): the spots other 19 16 2 = W × (A /A ) × (V/1000) than the principal spot obtained from the sample solution are not S T S more intense than the spot from the standard solution. WS: Amount (mg) of flutoprazepam for assay (4) Residual solvent—Being specified separately. Dissolution <6.10> When the test is performed at 50 revolu- Loss on drying <2.41> Not more than 0.20% (1 g, 105ºC, 2 tions per minute according to the Paddle method, using 900 mL hours). of water as the dissolution medium, the dissolution rate in 90 minutes of Flutoprazepam Tablets is not less than 70%. Residue on ignition <2.44> Not more than 0.1% (1 g, plati- Start the test with 1 tablet of Flutoprazepam Tablets, with- num crucible). draw not less than 20 mL of the medium at the specified minute Assay Weigh accurately about 0.5 g of Flutoprazepam, previ- after starting the test, and filter through a membrane filter with a ously dried, dissolve in 70 mL of acetic anhydride, and titrate pore size not exceeding 0.45 µm. Discard the first 10 mL of the <2.50> with 0.1 mol/L perchloric acid VS (potentiometric titra- filtrate, pipet V mL of the subsequent filtrate, add water to make tion). Perform a blank determination in the same manner, and exactly V´ mL so that each mL contains about 2.2 µg of fluto- make any necessary correction. prazepam (C19H16ClFN2O) according to the labeled amount, and use this solution as the sample solution. Separately, weigh accu- Each mL of 0.1 mol/L perchloric acid VS rately about 22 mg of flutoprazepam for assay, previously dried

= 34.28 mg of C19H16ClFN2O at 105ºC for 2 hours, and dissolve in methanol to make exactly 100 mL. Pipet 1 mL of this solution, add water to make exactly Containers and storage Containers—Well-closed containers. 100 mL, and use this solution as the standard solution. Perform the test with exactly 20 µL each of the sample solution and

standard solution as directed under Liquid Chromatography Add the following: <2.01> according to the following conditions, and determine the Flutoprazepam Tablets peak areas of flutoprazepam, AT and AS, of both solution. Dissolution rate (%) with respect to the labeled amount of フルトプラゼパム錠 flutoprazepam (C19H16ClFN2O) = W × (A /A ) × (V´/V) × (1/C) × 9 Flutoprazepam Tablets contain not less than 93.0% S T S and not more than 107.0% of the labeled amount of WS: Amount (mg) of flutoprazepam for assay flutoprazepam (C H ClFN O: 342.79). 19 16 2 C: Labeled amount (mg) of flutoprazepam (C19H16ClFN2O) in 1 tablet Method of preparation Prepare as directed under Tablets, with Flutoprazepam. Operating conditions— Proceed as directed in the operating conditions in the Assay. Identification To a quantity of powdered Flutoprazepam Tab- System suitability— lets, equivalent to 10 mg of Flutoprazepam according to the la-

Supplement II, JP XV Official Monographs 2131 System performance: When the procedure is run with 20 µL Fosfomycin Sodium for Injection of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry factor of the 注射用ホスホマイシンナトリウム peak of flutoprazepam are not less than 4000 and not more than 1.5, respectively. Change the Identification (2) and Water to read: System repeatability: When the test is repeated 6 times with 20 µL of the standard solution under the above operating condi- Identification (2) To 2 mL of a solution of Fosfomycin So- tions, the relative standard deviation of the peak area of fluto- dium for Injection (1 in 250) add 1 mL of perchloric acid and 2 prazepam is not more than 1.0%. mL of 0.1 mol/L sodium periodate solution, and heat in a water bath for 10 minutes. After cooling, add 1 mL of hexaammonium Assay Weigh accurately not less than 20 Flutoprazepam Tab- heptamolybdate-sulfuric acid TS and 1 mL of lets, and powder. Weigh accurately a portion of the powder, 1-amino-2-naphtol-4-sulfonic acid TS, and allow to stand for 30 equivalent to about 2 mg of flutoprazepam (C19H16ClFN2O), minutes: a blue color develops. add 60 mL of the mobile phase, shake for 15 minutes, and add the mobile phase to make exactly 100 mL. Filter this solution Water <2.48> Not more than 4.0% (0.1 g, coulometric titra- through a membrane filter with a pore size not exceeding 0.45 tion). µm. Discard the first 5 mL of the filtrate, and use the subsequent filtrate as the sample solution. Separately, weigh accurately Add the following: about 20 mg of flutoprazepam for assay, previously dried at 105ºC for 2 hours, and dissolve in the mobile phase to make exactly 100 mL. Pipet 2 mL of this solution, add the mobile Furosemide Injection phase to make exactly 20 mL, and use this solution as the stan- フロセミド注射液 dard solution. Perform the test with exactly 20 µL each of the sample solution and standard solution as directed under Liquid Furosemide Injection is an aqueous solution for in- Chromatography <2.01> according to the following conditions, jection. and determine the peak areas , AT and AS, of flutoprazepam in It contains not less than 95.0% and not more than each solution. 105.0% of the labeled amount of furosemide (C12H11ClN2O5S: 330.74). Amount (mg) of flutoprazepam (C19H16ClFN2O) = WS × (AT/AS) × (1/10) Method of preparation Prepare as directed under Injection, with Furosemide. WS: Amount (mg) of flutoprazepam for assay Description Furosemide Injection is a colorless, clear liquid. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: Identification (1) To a volume of Furosemide Injection, 230 nm). equivalent to 2.5 mg of Furosemide according to the labeled Column: A stainless steel column 4.6 mm in inside diameter amount, add 10 mL of 2 mol/L hydrochloric acid TS, heat under and 15 cm in length, packed with octadecylsilanized silica gel a reflux condenser on a water bath for 15 minutes. After cooling, for liquid chromatography (5 µm in particle diameter). render the solution slightly acid with 18 mL of sodium hydrox- Column temperature: A constant temperature of about 40ºC. ide TS: the solution responds to the Qualitative Tests <1.09> for Mobile phase: A mixture of methanol and water (3:1) primary aromatic amines. The color of the solution is red to Flow rate: Adjust the flow rate so that the retention time of red-purple. flutoprazepam is about 5 minutes. (2) To a volume of Furosemide Injection, equivalent to 20 System suitability— mg of Furosemide according to the labeled amount, add water to System performance: When the procedure is run with 20 µL make 100 mL. Pipet 2 mL of this solution, add 0.01 mol/L so- of the standard solution under the above operating conditions, dium hydroxide TS to make 50 mL. Determine the absorption the number of theoretical plates and the symmetry factor of the spectrum of this solution as directed under Ultraviolet-visible peak of flutoprazepam are not less than 4000 and not more than Spectrophotometry <2.24>: it exhibits maxima between 227 nm 1.5, respectively. and 231 nm, between 269 nm and 273 nm, and between 330 nm System repeatability: When the test is repeated 6 times with and 336 nm. 20 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of fluto- Osmotic pressure ratio Being specified separately. prazepam is not more than 1.0%. pH Being specified separately. Containers and storage Containers—Well-closed containers. Purity Pipet a volume of Furosemide Injection, equivalent to 40 mg of Furosemide according to the labeled amount, add 30 mL of acetone, shake well, and add acetone to make exactly 50 mL. Centrifuge this solution, to 1.0 mL of the supernatant liquid

2132 Official Monographs Supplement II, JP XV add 3.0 mL of water, cool in a ice bath, add 3.0 mL of dilute hy- Add the following: drochloric acid and 0.15 mL of sodium nitrite TS, shake, and allow to stand for 1 minute. To this solution add 1.0 mL of am- Gefarnate monium amidosulfate TS, shake well, allow to stand for 3 minutes, add 1.0 mL of N,N-diethyl-N´-1-naphtylethylenediamine ゲファルナート oxalate TS, shake well, and allow to stand for 5 minutes. De- termine the absorbance of this solution at 530 nm as directed under Ultraviolet-visible Spectrophotometry <2.24> using a solution, prepared in the same manner with 1.0 mL of acetone, as the blank: the absorbance is not more than 0.10. C27H44O2: 400.64 Bacterial endotoxins <4.01> Less than 1.25 EU/mg. (2E)-3,7-Dimethylocta-2,6-dienyl(4E,8E)-5,9,13- trimethyltetradeca-4,8,12-trienoate Extractable volume <6.05> It meets the requirement. [51-77-4, 4E isomer]

Foreign insoluble matter <6.06> Perform the test according Gefarnate is a mixture of 4E geometrical isomer. to Method 1: it meets the requirement. It contains not less than 98.0% and not more than 101.0% of C27H44O2. Insoluble particulate matter <6.07> It meets the requirement. Description Gefarnate is a light yellow to yellow, clear oily liquid. Sterility <4.06> Perform the test according to the Membrane It is miscible with acetonitrile, with ethanol (99.5) and with filtration method: it meets the requirement. cyclohexane. It is practically insoluble in water. Assay To an exactly measured volume of Furosemide Injec- tion, equivalent to about 20 mg of Furosemide (C12H11ClN2O5S), Identification Determine the infrared absorption spectrum of add water to make exactly 100 mL. Pipet 3 mL of this solution, Gefarnate as directed in the liquid film method under Infrared add 0.01 mol/L sodium hydrochloride TS to make exactly 100 Spectrophotometry <2.25>, and compare the spectrum with the mL, and use this solution as the sample solution. Separately, Reference Spectrum or the spectrum of Gefarnate Reference weigh accurately about 20 mg of Furosemide Reference Stan- Standard: both spectra exhibit similar intensities of absorption at dard, previously dried at 105ºC for 4 hours, add 0.01 mol/L so- the same wave numbers. dium hydroxide TS to make exactly 100 mL. Pipet 3 mL of this 20 solution, add 0.01 mol/L sodium hydroxide TS to make exactly Specific gravity <2.56> d 20 : 0.906 - 0.914 100 mL, and use this solution as the standard solution. Perform the test with the sample solution and standard solution as di- Purity (1) Acidity—To 1.0 g of Gefarnate add 30 mL of rected under Ultraviolet-visible Spectrophotometry <2.24>, and neutralized ethanol. To this solution add 1 drop of phenolphthalein TS and 0.40 mL of 0.1 mol/L sodium hydroxide VS: a determine the absorbances, AT and AS, at 271 nm. red color develops.

Amount (mg) of furosemide (C12H11ClN2O5S) (2) Heavy metals <1.07>—Proceed with 2.0 g of Gefarnate = WS × (AT/AS) according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than WS: Amount (mg) of Furosemide Reference Standard 10 ppm). (3) Related substances—Use a solution of Gefarnate in Containers and storage Containers—Hermetic containers. acetonitrile (1 in 500) as the sample solution. Pipet 2 mL of this Storage—Light-resistant. solution, add acetonitrile to make exactly 100 mL, and use this solution as the standard solution. Perform the test with exactly 2 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions. Determine each peak area of both solutions by the automatic integration method: the area of each peak other than the peak of gefarnate obtained from the sample solution is not larger than 1/2 times the peak area of gefarnate from the standard solution, and the total area of the peaks other than the peak of gefarnate obtained from the sample solution is not larger than the peak area of gefarnate from the standard solution. Operating conditions— Detector, column, column temperature, mobile phase and flow rate: Proceed as directed in the operating conditions in the Assay.

Supplement II, JP XV Official Monographs 2133

Time span of measurement: About 2 times as long as the re- WS: Amount (mg) of Gefarnate Reference Standard tention time of gefarnate, beginning after the solvent peak. System suitability— Internal standard solution—A solution of tris (4-t-butylphenyl) Test for required detectability: Pipet 2 mL of the standard so- phosphate in acetonitrile (1 in 400) lution, add acetonitrile to make exactly 20 mL. Confirm that the Operating conditions— peak area of gefarnate obtained from 2 µL of this solution is Detector: An ultraviolet absorption photometer (wavelength: equivalent to 7 to 13% of that of gefarnate from the standard 220 nm) solution. Column: A stainless steel column 4 mm in inside diameter System performance: When the procedure is run with 2 µL of and 30 cm in length, packed with octadecylsilanized silica gel the standard solution under the above operating conditions, the for liquid chromatography (10 µm in particle diameter). number of theoretical plates and the symmetry factor of the peak Column temperature: A constant temperature of about 40ºC. of gefarnate are not less than 4000, and between 0.9 and 1.2, Mobile phase: A mixture of acetonitrile for liquid chromatog- respectively. raphy, water and phosphoric acid (700:300:1). System repeatability: When the test is repeated 6 times with 2 Flow rate: Adjust the flow rate so that the retention time of µL of the standard solution under the above operating conditions, gefarnate is about 19 minutes. the relative standard deviation of the peak area of gefarnate is System suitability— not more than 1.0%. System performance: When the procedure is run with 2 µL of the standard solution under the above operating conditions, the Isomer ratio To 1 mL of Gefarnate add 100 mL of ethanol internal standard and gefarnate are eluted in this order with the (99.5), and use this solution as the sample solution. Perform the resolution between these peaks being not less than 2.0. test with 4 µL of the sample solution as directed under Gas System repeatability: When the test is repeated 6 times with 2 Chromatography <2.02> according to the following conditions. µL of the standard solution under the above operating conditions,

Determine the areas of two adjacent peaks, Aa and Ab, having the relative standard deviation of the ratio of the peak area of the retention time of about 37 minutes, where Aa is the peak gefarnate to that of the internal standard is not more than 1.0%. area of shorter retention time and Ab is the peak area of longer Containers and storage Containers—Tight containers. retention time: Aa/(Aa + Ab) is between 0.2 and 0.3. Operating conditions— Storage—Light-resistant, and under nitrogen atmosphere. Detector: A hydrogen flame-ionization detector.

Column: A glass column 3 mm in inside diameter and 160 cm Add the following: in length, packed with polyethylene glycol 20M for gas chromatography coated at the ratio of 5% on acid-treated and silan- ized siliceous earth for gas chromatography (149 to 177 µm in Gentamicin Sulfate Ophthalmic particle diameter). Solution Column temperature: A constant temperature of about 210ºC. Carrier gas: Nitrogen. ゲンタマイシン硫酸塩点眼液 Flow rate: Adjust the flow rate so that the reaction time of the peak showing earlier elution of the two peaks of gefarnate is Gentamicin Sulfate Ophthalmic Solution is an aqueous oph- about 35 minutes. thalmic solution System suitability— It contains not less than 90.0% and not more than 110.0% of System performance: When the procedure is run with 4 µL of the labeled potency of expressed as mass of gentamicin C1 the sample solution under the above conditions: the resolution (C21H43N5O7: 477.60). between the two peaks of gefarnate is not less than 1.0. Method of preparation Prepare as directed under Ophthalmic System repeatability: When the test is repeated 6 times with 4 Solution, with Gentamicin Sulfate. µL of the sample solution under the above operating conditions: the relative standard deviation of the peak area of gefarnate with Description Gentamicin Sulfate Ophthalmic Solution is a the shorter retention time of the two peaks is not more than clear, colorless or pale yellow liquid. 2.0%. Identification To a volume of Gentamicin Sulfate Ophthalmic Assay Weigh accurately about 50 mg each of Gefarnate and Solution, equivalent to 10 mg (potency) of Gentamicin Sulfate Gefarnate Reference Standard, add exactly 5 mL of the internal according to the labeled amount, add water to make 5 mL, and standard solution and 20 mL of acetonitrile, and use these solu- use this solution as the sample solution. Separately, dissolve an tions as the sample solution and standard solution. Perform the amount of Gentamicin Sulfate Reference Standard, equivalent to test with 2 µL each of the sample solution and standard solution 10 mg (potency), in 5 mL of water, and use this solution as the as directed under Liquid Chromatography <2.01> according to standard solution. Perform the test with these solutions as di- the following conditions, and calculate the ratios, QT and QS, of rected under Thin-layer Chromatography <2.03>. Spot 5 µL the peak area of gefarnate to that of the internal standard. each of the sample solution and standard solution on a plate of silica gel for thin-layer chromatography. Develop the plate with Amount (mg) of gefarnate (C H O ) = W × (Q /Q ) 27 44 2 S T S the lower layer of a mixture of chloroform, ammonia solution

2134 Official Monographs Supplement II, JP XV

(28) and methanol (2:1:1) to a distance of about 15 cm, and Identification (1) Determine the absorption spectrum of a air-dry the plate. Spray evenly 0.2% ninhydrin-water saturated solution of Gliclazide in methanol (1 in 62500) as directed un- 1-butanol TS on the plate, and heat the plate at 100ºC for 5 min- der Ultraviolet-visible Spectrophotometry <2.24>, and compare utes: three principal spots obtained from the sample solution are the spectrum with the Reference Spectrum: both spectra exhibit the same with the corresponding spots from the standard solu- similar intensities of absorption at the same wavelengths. tion in color tone and the Rf value, respectively. (2) Determine the infrared absorption spectrum of Gli- clazide as directed in the potassium bromide disk method under pH <2.54> 5.5 - 7.5 Infrared Spectrophotometry <2.25>, and compare the spectrum with the Reference Spectrum: both spectra exhibit similar inten- Foreign insoluble matter <6.11> It meets the requirement. sities of absorption at the same wave numbers. Insoluble particulate matter <6.08> It meets the require- Melting point <2.60> 165 - 169ºC. ment. Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of Gli- Sterility <4.06> Perform the test according to the Membrane clazide according to Method 2, and perform the test. Prepare the filtration method: it meets the requirement. control solution with 2.0 mL of Standard Lead Solution (not Assay Perform the test according to the Cylinder-plate method more than 10 ppm). as directed under Microbial Assay for Antibiotics <4.02> ac- (2) Related substances—Conduct this procedure within 2 cording to the following conditions. hours after preparation of the sample solution. Dissolve 50 mg (i) Test organism, agar media for seed and base layer, agar of Gliclazide in 23 mL of acetonitrile, add water to make 50 mL, medium for transferring test organism, and standard solutions— and use this solution as the sample solution. Pipet 1 mL of this Proceed as directed in the Assay under Gentamicin Sulfate. solution, and add a mixture of water and acetonitrile (11:9) to (ii) Sample solutions—Pipet a volume of Gentamicin Sul- make exactly 100 mL. Pipet 10 mL of this solution, add a mix- fate Ophthalmic Solution, equivalent to about 12 mg (potency) ture of water and acetonitrile (11:9) to make exactly 100 mL, of Gentamicin Sulfate, add 0.1 mol/L phosphate buffer solution, and use this solution as the standard solution. Perform the test pH 8.0, to make a solution so that each mL contains about 1 mg with exactly 20 µL each of the sample solution and standard so- (potency). Pipet a suitable volume of this solution, add 0.1 lution as directed under Liquid Chromatography <2.01> ac- mol/L phosphate buffer solution, pH 8.0, to make solutions so cording to the following conditions. Determine each peak area that each mL contains 4 µg (potency) and 1 µg (potency), and of both solutions by the automatic integration method: the area use these solutions as the high concentration sample solution of each peak other than gliclazide obtained from the sample so- and low concentration sample solution, respectively. lution is not larger than the peak area of gliclazide from the standard solution, and the total area of the peaks other than the Containers and storage Containers—Tight containers. peak of gliclazide obtained from the sample solution is not larger than 3 times the peak area of gliclazide from the standard Expiration date 24 months after preparation. solution. For this calculation, use the area of the peak, having the relative retention time of about 0.9 with respect to gliclazide, after multiplying by their relative response factor, 5.65. Add the following: Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: Gliclazide 235 nm). グリクラジド Column: A stainless steel column 4.0 mm in inside diameter and 25 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (4 µm in particle diameter). Column temperature: A constant temperature of about 25ºC. Mobile phase: A mixture of water, acetonitrile, triethylamine and trifluoroacetic acid (550:450:1:1) Flow rate: Adjust the flow rate so that the retention time of gliclazide is about 14 minutes. Time span of measurement: About 2 times as long as the re- C15H21N3O3S: 323.41 1-(Hexahydrocyclopenta[c]pyrrol-2(1H)-yl)- tention time of gliclazide, beginning after the solvent peak. 3-[(4-methylphenyl)sulfonyl]urea [21187-98-4] System suitability— Test for required detectability: Pipet 4 mL of the standard so- Gliclazide, when dried, contains not less than 98.5% lution, and add a mixture of water and acetonitrile (11:9) to and not more than 101.0% of C15H21N3O3S. make exactly 20 mL. Confirm that the peak area of gliclazide obtained from 20 µL of this solution is equivalent to 10 to 30% Description Gliclazide is a white crystalline powder. of that of gliclazide from the standard solution. It is sparingly soluble in acetonitrile and in methanol, slightly System performance: When the procedure is run with 20 µL soluble in ethanol (99.5) and practically insoluble in water. of the standard solution under the above operating conditions,

Supplement II, JP XV Official Monographs 2135 the number of theoretical plates and the symmetry factor of the WS: Amount [mg (potency)] of Griseofulvin Reference Stan- peak of gliclazide are not less than 8000 and not more than 1.5, dard respectively. C: Labeled amount [mg (potency)] of griseofulvin

System repeatability: When the test is repeated 6 times with (C17H17ClO6) in 1 tablet 20 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of gliclazide is not more than 2.0%. Add the following: (3) Residual solvent—Being specified separately. Heparin Calcium Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 2 hours). ヘパリンカルシウム

Residue on ignition <2.44> Not more than 0.1% (1 g).

Assay Weigh accurately about 0.3 g of Gliclazide, previously dried, dissolve in 30 mL of a mixture of acetic anhydride and acetic acid (100) (7:3), and titrate <2.50> with 0.1 mol/L perchloric acid VS (potentiometric titration). Perform a blank determination in the same manner, and make any necessary correction.

Each mL of 0.1 mol/L perchloric acid VS

= 32.34 mg of C H N O S 1 3 4 - 15 21 3 3 R , R , R = SO3 or H 2 - R = SO3 or Containers and storage Containers—Well-closed containers. 5 - 6 R = CO2 , R = H or 5 6 - R = H, R = CO2 Griseofulvin Tablets [37270-89-6]

グリセオフルビン錠 Heparin Calcium is the calcium salt of sulfated glycosaminoglycans composed of disaccharide units of Delete the Disintegration and add the following D-glucosamine and uronic acid (L-iduronic acid or next to the Uniformity of dosage units: D-glucuronic acid) obtained from the intestinal mucosa Dissolution <6.10> When the test is performed at 100 revolu- of healthy edible swine. tions per minute according to the Paddle method using 900 mL Heparin Calcium prolongs the clotting time of blood. of a solution of sodium laurylsulfate (1 in 100) as the dissolu- It contains not less than 150 Heparin Units per mg. tion medium, the dissolution rate in 120 minutes of Griseofulvin Heparin Calcium, calculated on the dried basis, Tablets is not less than 70%. contains not less than 90% and not more than 110% of Start the test with 1 tablet of Griseofulvin Tablets, withdraw the labeled Units, and not less than 8.0% and not more not less than 20 mL of the medium at the specified minute after than 12.0% of calcium (Ca: 40.08). starting the test, and filter through a membrane filter with a pore Description Heparin Calcium occurs as a white to grayish size not exceeding 0.45 µm. Discard the first 10 mL of the fil- brown powder or grains. It is freely soluble in water, and prac- trate, pipet V mL of the subsequent filtrate, add water to make tically insoluble in ethanol (99.5). exactly V´ mL so that each mL contains about 6.9 µg (potency) It is hygroscopic. of Griseofulvin according to the labeled amount, and use this solution as the sample solution. Separately, weigh accurately an Identification (1) Dissolve 10 mg of Heparin Calcium in 5 amount of Griseofulvin Reference Standard, equivalent to about mL of water. To this solution add 0.1 mL of 1 mol/L hydrochlo- 28 mg (potency), and dissolve in ethanol (95) to make exactly ric acid TS and 5 mL of a solution of toluidine blue O (1 in 200 mL. Pipet 5 mL of this solution, add 5 mL of the dissolution 20000): a purple to red-purple color develops. medium and water to make exactly 100 mL, and use this solu- (2) Dissolve 50 mg of Heparin Calcium in 5 mL of water: tion as the standard solution. Determine the absorbances, AT and the solution responds to the Qualitative Tests <1.09> for cal- AS, at 295 nm of the sample solution and standard solution as cium salt. directed under Ultraviolet-visible Spectrophotometry <2.24>, using water as the blank pH <2.54> Dissolve 1.0 g of Heparin Calcium in 100 mL of water: the pH of the solution is between 6.0 and 8.0. Dissolution rate (%) with respect to the labeled amount of

griseofulvin (C17H17ClO6) Purity (1) Clarity and color of solution—Dissolve 0.5 g of = WS × (AT/AS) × (V´/V) × (1/C) × (45/2) Heparin Calcium in 20 mL of water: the solution is clear. De-

2136 Official Monographs Supplement II, JP XV termine the absorbance of this solution at 400 nm as directed Number of scans: Repeat until the S/N ratio of the signal of under Ultraviolet-visible Spectrophotometry <2.24>: the ab- N-acetyl proton of heparin is not less than 200. sorbance is not more than 0.05. Window function: Exponential function (Line broadening (2) Chloride <1.03>—Perform the test with 0.5 g of Hepa- factor = 0.2 Hz) rin Calcium. Prepare the control solution with 0.30 mL of 0.01 System suitability— mol/L hydrochloric acid VS (not more than 0.021%). Dissolve 0.10 mg of Oversulfated Chondroitin Sulfate Refer- (3) Heavy metals <1.07>—Proceed with 0.5 g of Heparin ence Standard in 0.60 mL of a solution of sodium

Calcium according to Method 2, and perform the test. Prepare 3-trimethylsilylpropionate-d4 for nuclear magnetic resonance the control solution with 1.5 mL of Standard Lead Solution (not spectroscopy in heavy water for nuclear magnetic resonance more than 30 ppm). spectroscopy (1 in 10000), and use this solution as the standard (4) Barium—Dissolve 30 mg of Heparin Calcium in 3.0 mL solution. Dissolve about 20 mg of heparin calcium in 0.60 mL of water, and use this solution as the sample solution. To 1.0 mL of the standard solution, and use this solution as the solution for of the sample solution add 3 drops of dilute sulfuric acid, and system suitability test. Proceed under the above operating con- allow to stand for 10 minutes: no turbidity is produced. ditions: Signals occur from the N-acetyl protons of heparin and (5) Residual solvent—Being specified separately. oversulfated chondroitin sulfate at δ 2.02 – 2.06 ppm and at δ (6) Total nitrogen—Weigh accurately about 0.1 g of Hepa- 2.13 – δ 2.23 ppm, respectively. rin Calcium, previously dried, and perform the test as directed under Nitrogen Determination <1.08>: the amount of nitrogen Loss on drying <2.41> Not more than 8% (50 mg, in vacuum, (N: 14.01) is not more than 3.0%. 60ºC, 3 hours). (7) Protein—To 1.0 mL of the sample solution obtained in Bacterial endotoxins <4.01> Less than 0.0030 EU/heparin (4) add 5 drops of a solution of trichloroacetic acid (1 in 5): Unit. neither a precipitate nor turbidity is produced. (8) Oversulfated chondroitin sulfate—Dissolve 20 mg of Assay (1) Heparin Heparin Calcium in 0.60 mL of a solution of sodium (i) Substrate solution: Dissolve 15 mg of 3-trimethylsilylpropionate-d4 for nuclear magnetic resonance N-benzoyl-L-isoleucyl-L-glutamyl(γ-OR)-glycyl-L-arginyl-p-nitr spectroscopy in heavy water for nuclear magnetic resonance oanilide hydrochloride in 20 mL of water. spectroscopy (1 in 10000), and use this solution as the sample (ii) Activated blood coagulation factor X solution: Dissolve solution. Determine the spectrum of the sample solution, using bovine activated blood coagulation factor X in water to make a sodium 3-trimethylsilylpropionate-d4 for nuclear magnetic solution containing 0.426 Unit per mL. resonance spectroscopy as an internal reference compound, as (iii) Buffer solution: Dissolve 6.06 g of directed under Nuclear Magnetic Resonance Spectroscopy 2-amino-2-hydroxymethyl-1,3-propanediol in 750 mL of water, 1 <2.21> ( H) in accordance with the following conditions, using adjust the pH to 8.4 with 1 mol/L hydrochloric acid TS, and add spectrometer (1) with a proton resonance frequency of not less water to make 1000 mL. than 400 MHz: no signal occurs from the N-acetyl proton of (iv) Reaction stop solution: To 20 mL of acetic acid (100) oversulfated chondroitin sulfate between δ 2.13 ppm and δ 2.23 add water to make 40 mL. ppm. (v) Heparin standard solutions: Dissolve Heparin Sodium Operating conditions— Reference Standard in isotonic sodium chloride solution to Temperature: 25ºC make a solution containing 10 Units per mL. To 100 µL of this Spinning: Off solution add buffer solution to make exactly 5 mL, and use this Number of data points: 32,768 solution as the standard stock solution. Prepare the heparin Spectral range: ±6.0 ppm with the DHO signal at the center standard solutions (1), (2), (3), (4) and (5) by addition of anti- Flip angle: 90º thrombin III TS, human normal plasma and the buffer solution Delay time: 20 seconds to the standard solution as directed in the following table. Number of dummy scans: 4

Heparin standard solution Antithrombin III TS Human normal Heparin concen- Buffer solution (µL) Standard solution (µL) No. (µL) plasma (µL) tration (Unit/mL) (1) 0 800 100 100 0 (2) 0.02 700 100 100 100 (3) 0.04 600 100 100 200 (4) 0.06 500 100 100 300 (5) 0.08 400 100 100 400

(vi) Sample solution: Weigh accurately an adequate amount labeled amount. To 100 µL of this solution add 100 µL of anti- of Heparin Calcium, dissolve in isotonic sodium chloride solu- thrombin III TS, 100 µL of human normal plasma and 700 µL of tion so that each mL contains about 0.5 Units according to the the buffer solution, and use this solution as the sample solution.

Supplement II, JP XV Official Monographs 2137 (vii) Procedure: Transfer 400 µL of the sample solution to a Heparin Sodium test tube, and warm at 37ºC for 4 minutes. To this solution add 200 µL of the activated blood coagulation factor X solution, mix ヘパリンナトリウム well, warm at 37ºC for exactly 30 seconds, add 400 µL of the substrate solution, previously warmed at 37ºC, and mix well. Add the following next to the Japanese title: Warm this solution at 37ºC for exactly 3 minutes, add 600 µL of the reaction stop solution, and mix immediately. Determine the absorbance at 405 nm as directed under Ultraviolet-visible Spectrophotometry <2.24>, using the blank solution prepared by addition of 600 µL of the reaction stop solution and 600 µL of water to 400 µL of the sample solution. Proceed the same way with the heparin standard solution (1), the heparin standard solution (2), the heparin standard solution (3), the heparin standard solution (4) and the heparin standard solution (5), and determine their absorbances. (viii) Calculation: Plot the absorbances of the standard solu- R1, R3, R4 = SO Na or H tions and their heparin concentrations to prepare a calibration 3 curve. Determine the heparin concentration, C, of the sample 2 R = SO3Na or solution, and calculate heparin Units per mg of Heparin Calcium 5 6 from the following formula. R = CO2Na, R = H or Units per mg of Heparin Calcium = C × 10 × (b/a) 5 6 R = H, R = CO2Na a: Amount of sample (mg) [9041-08-1] b: Total volume (mL) of isotonic sodium chloride solution used to dissolve the sample to make the solution contain- Change the Origin/limits of content to read: ing about 0.5 Units per mL Heparin Sodium is the sodium salt of sulfated glycosami- (2) Calcium Weigh accurately about 50 mg of Heparin noglycans composed of disaccharide units of D-glucosamine and Calcium, dissolve in 20 mL of water, add 2 mL of 8 mol/L so- uronic acid (L-iduronic acid or D-glucuronic acid) obtained from dium hydroxide TS, allow to stand for 3 to 5 minutes with occa- the livers, the lungs and the intestinal mucosa of healthy edible sional shaking, add 0.1 g of NN indicator, and immediately ti- animals. It prolongs the clotting time of blood. Heparin Sodium trate <2.50> with 0.1 mol/L disodium dihydrogen ethylenedia- obtained from the livers and the lungs contains not less than 110 mine tetraacetate VS until the color of the solution changes from Heparin Units per mg, and that obtained from the intestinal red-purple to blue. mucosa contains not less than 130 Heparin Units per mg. Heparin Sodium, calculated on the dried basis, contains not Each mL of 0.01 mol/L disodium dihydrogen ethylenedia- less than 90% and not more than 110% of the labeled Units. mine tetraacetate VS Label the name of the organ used as the starting material. = 0.4008 mg of Ca Containers and storage Containers—Tight containers. Human Menopausal Gonadotrophin

ヒト下垂体性性腺刺激ホルモン

Change the Purity to read:

Purity Interstitial cell-stimulating hormone—Perform the test according to the following method: the ratio of the unit of interstitial cell-stimulating hormone (luteinizing hormone) to that of follicle-stimulating hormone is not more than 1. The luteinizing activity of the hormone is determined by the seminal vesicle weight assay or ovarian ascorbic acid depletion assay. The seminal vesicle weight assay may be used when the ratio of the unit of interstitial cell-stimulating hormone to that of follicle-stimulating hormone is not more than 1 and not less than 0.10.

1. Seminal vesicle weight assay (i) Test animals—Select healthy male albino rats weighing about 45 to 65 g.

2138 Official Monographs Supplement II, JP XV

(ii) Standard solutions—Weigh accurately a suitable amount (iii) Sample solutions—According to the labeled units, of Human Menopausal Gonadotrophin Reference Standard, and weigh accurately a suitable amount of Human Menopausal Go- dissolve in bovine serum albumin-sodium chloride-phosphate nadotrophin, and dissolve in the bovine serum albumin-sodium buffer solution, pH 7.2, to prepare three kinds of solutions, con- chloride-phosphate buffer solution, pH 7.2, to prepare the taining 10, 20 and 40 interstitial cell-stimulating hormone (lu- high-dose sample solution and low-dose sample solution to teinizing hormone) units per 1.0 mL, respectively. Inject these contain units equal to those of the high-dose standard solution solutions into three groups consisting of five test animals each, and low-dose standard solution, and designate them as TH and and weigh their seminal vesicles as directed in (iv). According TL, respectively. to the result of the test, designate the concentration of the refer- (iv) Procedure—Inject subcutaneously to each animal 80 ence standard, which will make the mass of the seminal vesicle units of serum gonadotrophin dissolved in 0.5 mL of isotonic

20 to 35 mg, as the high-dose standard solution, SH. Dilute the sodium chloride solution. At 56 to 72 hours after the injection, SH to 1.5 to 2.0 times the initial volume with the bovine serum inject subcutaneously to each animal 40 units of human chori- albumin-sodium chloride-phosphate buffer solution, pH 7.2, and onic gonadotrophin dissolved in 0.5 mL of isotonic sodium designate this solution as the low-dose standard solution, SL. chloride solution. On 6 to 9 days after the last injection, divide Store these solutions at 2 - 8ºC. the test animals at random into 4 groups, A, B, C and D, with (iii) Sample solutions—According to the labeled units, not less than 10 animals and equal numbers in each group. Inject weigh accurately a suitable amount of Human Menopausal Go- 1 mL each of SH, SL, TH and TL into the tail vein of each animal nadotrophin, and dissolve in the bovine serum albumin-sodium in groups A, B, C and D, respectively. At 2 to 4 hours after the chloride-phosphate buffer solution, pH 7.2, to prepare the injection, excise the both ovaries, remove the fat and other un- high-dose sample solution, TH and the low-dose sample solution, wanted tissues attached to the ovaries, weigh, add a prescribed TL, so that their concentrations are similar to those of the corre- volume between 5 and 15 mL of metaphosphoric acid solution sponding standard solutions, respectively. Store these solutions (1 in 40), homogenize with a homogenizer on ice, and centri- at 2 - 8ºC. fuge. To 0.5 to 1 mL (1 mL in principle. 0.5 mL may be used (iv) Procedure—Divide the test animals at random into 4 when the absorbance is not more than 0.1) of the supernatant groups, A, B, C and D, with not less than 10 animals and equal liquid, add 1.5 mL of metaphosphoric acid solution (1 in 40) and numbers in each group. Inject subcutaneously once every day 2.5 mL of 2,6-dichloroindophenol sodium-sodium acetate TS,

0.2 mL each of SH, SL, TH and TL to each animal in the respec- mix the solution, and immediately determine the absorbance of tive groups for five days. On the sixth day, excise the seminal the solution at 520 nm as directed under Ultraviolet-visible vesicles, remove extraneous tissue, remove fluid adhering to the Spectrophotometry <2.24>. Separately, weigh accurately 10.0 vesicles and the contents of the vesicles by lightly pressing be- mg of Ascorbic Acid Reference Standard, and add water to tween filter papers, and weigh the vesicles. make exactly 100 mL. Pipet 5 mL of this solution, and add wa- (v) Calculation—Proceed as directed in (v) in the Assay by ter to make exactly 50 mL. Pipet a suitable volume of this solu- changing the mass of ovaries to the mass of seminal vesicles to tion, and add metaphosphoric acid solution (1 in 40) to make a read. solution so that each mL contains 2.0 to 10.0 µg of ascorbic acid

2. Ovarian ascorbic acid depletion assay (C6H8O6: 176.12). To 2.5 mL of this solution, add 2.5 mL of (i) Test animals—Select healthy female albino rats weigh- 2,6-dichloroindophenol sodium-sodium acetate TS, mix the so- ing about 45 to 65 g. lution, immediately determine the absorbance in the same man- (ii) Standard solutions—Dissolve Human Menopausal Go- ner as mentioned above, and prepare the calibration curve. From nadotrophin Reference Standard in bovine serum albu- the calibration curve of ascorbic acid, determine the amount min-sodium chloride-phosphate buffer solution, pH 7.2, to pre- (mg) of ascorbic acid in 100 g of ovary. pare four kinds of solutions, containing 2, 4, 8 and 16 interstitial (v) Calculation—Proceed as directed in (v) in the Assay by cell-stimulating hormone (luteinizing hormone) units per 1.0 changing the mass of ovaries to the amount of ascorbic acid to mL, respectively. Inject these solutions into four groups con- read. sisting of five test animals each, and determine the amount of ovarian ascorbic acid. Separately, inject bovine serum albumin-sodium chloride-phosphate buffer solution, pH 7.2, to a Hydralazine Hydrochloride for control group of animals. According to the result of the test, designate the concentration of the reference standard, which will Injection make the amount of ovarian ascorbic acid 0.80 to 0.85 times 注射用ヒドララジン塩酸塩 that in the control group, as the concentration for the low-dose standard solution, and 4 to 6 times that as the concentration for Add the following next to the pH: the high-dose standard solution. Dissolve Human Menopausal Gonadotrophin Reference Standard in bovine serum albu- Bacterial endotoxins <4.01> Less than 5.0 EU/mg. min-sodium chloride-phosphate buffer solution, pH 7.2, to prepare the high-dose standard solution and low-dose standard so- Uniformity of dosage units <6.02> It meets the requirement lution to contain the concentrations described above, and desig- of the Mass variation test. (T: 106.0%) nate them as S and S , respectively. H L Foreign insoluble matter <6.06> Perform the test according

Supplement II, JP XV Official Monographs 2139 to Method 2: it meets the requirement. and the standard solution, respectively. Perform the test with 20 µL each of the sample solution and standard solution as directed Insoluble particulate matter <6.07> It meets the require- under Liquid Chromatography <2.01> according to the follow- ment. ing conditions, and calculate the ratios, QT and QS, of the peak area of hydrocortisone phosphate to that of the internal standard, Sterility <4.06> Perform the test according to the Membrane respectively. filtration method: it meets the requirement. Amount (mg) of hydrocortisone sodium phosphate

(C H Na O P ) = W × (Q /Q ) Hydrocortisone Sodium Phosphate 21 29 2 8 S T S WS: Amount (mg) of Hydrocortisone Sodium Phosphate Ref- ヒドロコルチゾンリン酸エステルナトリウム erence Standard, calculated on the anhydrous basis

Delete the Loss on drying and change the Ori- Internal standard solution—A solution of isopropyl parahy- gin/limits of content, Optical rotation and Purity droxybenzoate in the mobile phase (3 in 5000). (5) to read: Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: Hydrocortisone Sodium Phosphate contains not less 254 nm). than 96.0% and not more than 102.0% of Column: A stainless steel column 4.6 mm in inside diameter C21H29Na2O8P, calculated on the anhydrous basis. and 25 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (7 µm in particle diameter). Optical rotation <2.49> [α] 20 : +123 - +131º (1 g, calculated D Column temperature: A constant temperature of about 25ºC. on the anhydrous basis, phosphate buffer solution, pH 7.0, 100 Mobile phase: A mixture of 0.05 mol/L sodium dihydrogen mL, 100 mm). phosphate TS, pH 2.6 and methanol (1:1). Purity (5) Free phosphoric acid—Weigh accurately about Flow rate: Adjust the flow rate so that the retention time of 0.25 g of Hydrocortisone Sodium Phosphate, dissolve in water hydrocortisone phosphate is about 10 minutes. to make exactly 100 mL, and use this solution as the sample so- System suitability— lution. Pipet 5 mL each of the sample solution and Standard System performance: When the procedure is run with 20 µL Phosphoric Acid Solution into separate 25-mL volumetric flasks, of the standard solution under the above operating conditions, add 2.5 mL of hexaammonium heptamolybdate-sulfuric acid TS hydrocortisone phosphate and the internal standard are eluted in and 1 mL of 1-amino-2-naphthol-4-sulfonic acid TS, shake, add this order with the resolution between these peaks being not less water to make exactly 25 mL, and allow to stand at 20 ± 1ºC for than 8. 30 minutes. Perform the test with these solutions as directed System repeatability: When the test is repeated 6 times with under Ultraviolet-visible Spectrophotometry <2.24>, using a 20 µL of the standard solution under the above operating condi- solution prepared with 5 mL of water in the same manner as the tions, the relative standard deviation of the ratios of the peak area of hydrocortisone phosphate to that of the internal standard blank. Determine the absorbances, AT and AS, at 740 nm of the sample solution and Standard Phosphoric Acid Solution: the is not more than 1.0%. amount of free phosphoric acid is not more than 1.0%.

Content (%) of free phosphoric acid (H3PO4) Hydroxypropylcellulose = (AT/AS) × (1/W) × 258.0 ヒドロキシプロピルセルロース W: Amount (mg) of Hydrocortisone Sodium Phosphate, calculated on the anhydrous basis. Add the following next to the Japanese title:

Add the following next to the Purity: [9004-64-2]

Water <2.48> Not more than 5.0% (30 mg. coulometric titration). Low Substitute Change the Assay to read: Hydroxypropylcellulose

Assay Weigh accurately about 20 mg each of Hydrocortisone 低置換度ヒドロキシプロピルセルロース Sodium Phosphate and Hydrocortisone Sodium Phosphate Ref- erence Standard (previously determine the water content <2.48> Add the following next to the Japanese title: in the same manner as Hydrocortisone Sodium Phosphate), dissolve each in 50 mL of the mobile phase, add exactly 10 mL of [9004-64-2, Hydroxypropylcellulose] the internal standard solution, then add the mobile phase to make 200 mL, and use these solutions as the sample solution

2140 Official Monographs Supplement II, JP XV

Optical rotation <2.49> [α] 20 : –65.0 - –69.0º (after drying, Hypromellose D 0.1 g, methanol, 10 mL, 100 mm). ヒプロメロース Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of Change the Chemical name to read: Imidapril Hydrochloride according to Method 4, and perform the test. Prepare the control solution with 2.0 mL of Standard [9004-65-3] Lead Solution (not more than 10 ppm). (2) Related substances—Dissolve 25 mg of Imidapril Hy- drochloride in 50 mL of the mobile phase, and use this solution Hypromellose Phthalate as the test solution. Pipet 1 mL of this solution, add the mobile phase to make exactly 100 mL, and use this solution as the ヒプロメロースフタル酸エステル standard solution. Perform the test with exactly 20 µL each of the sample solution and standard solution as directed under Liq- Change the Chemical name to read: uid Chromatography <2.01> according to the following conditions. Determine each peak area of both solutions by the auto- [9050-31-1] matic integration method: the area of the peak having the relative retention time of about 0.45 with respect to imidapril, ob- Add the following: tained from the sample solution, is not larger than 2/5 times the peak area of imidapril from the standard solution, and the area Imidapril Hydrochloride of each peak other than the peaks of imidapril and other than those mentioned above from the sample solution is not larger イミダプリル塩酸塩 than 1/5 times the peak area of imidapril from the standard solution. Furthermore, the total area of the peaks other than imidapril from the sample solution is not larger than 1/2 times the peak area of imidapril from the standard solution. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: 215 nm). Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). C H N O ·HCl: 441.91 20 27 3 6 Column temperature: A constant temperature of about 40ºC. (4S)-3-{(2S)-2-[(1S)-1-Ethoxycarbonyl- Mobile phase: Dissolve 1.36 g of potassium dihydrogen 3-phenylpropylamino]propanoyl}-1-methyl- phosphate in 1000 mL of water, and adjust the pH to 2.7 with 2-oxoimidazolidine-4-carboxylic acid monohydrochloride phosphoric acid. To 600 mL of this solution add 400 mL of [89396-94-1] methanol. Imidapril Hydrochloride, when dried, contains not Flow rate: Adjust the flow rate so that the retention time of less than 98.5% and not more than 101.0% of imidapril is about 8 minutes. Time span of measurement: About 2 times as long as the re- C20H27N3O6·HCl. tention time of imidapril, beginning after the solvent peak. Description Imidapril Hydrochloride occurs as a white crys- System suitability— tals. Test for required detectability: Pipet 2 mL of the standard so- It is freely soluble in methanol, soluble in water, and sparingly lution, and add the mobile phase to make exactly 20 mL. Con- soluble in ethanol (99.5). firm that the peak area of imidapril obtained from 20 µL of this Dissolve 1.0 g of Imidapril Hydrochloride in 100 mL of water: solution is equivalent to 7 to 13% of that of imidapril from the the pH of the solution is about 2. standard solution. Melting point: about 203ºC (with decomposition). System performance: When the procedure is run with 20 µL of the standard solution under the above operating conditions, Identification (1) To 3 mL of a solution of Imidapril Hy- the number of theoretical plates and the symmetry factor of the drochloride (1 in 50) add 5 drops of Reinecke salt TS: a light red peak of imidapril are not less than 5000 and not more than 1.5, precipitate is formed. respectively. (2) Determine the infrared absorption spectrum of Imidapril System repeatability: When the test is repeated 6 times with Hydrochloride as directed in the potassium chloride disk method 20 µL of the standard solution under the above operating condi- under Infrared Spectrophotometry <2.25>, and compare the tions, the relative standard deviation of the peak area of imi- spectrum with the Reference Spectrum: both spectra exhibit dapril is not more than 2.0%. similar intensities of absorption at the same wave numbers. (3) Residual solvent—Being specified separately. (3) A solution of Imidapril Hydrochloride (1 in 50) responds to the Qualitative Tests <1.09> for chloride. Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 3

Supplement II, JP XV Official Monographs 2141 hours). the relative retention time of about 0.45 with respect to imidapril, obtained from the sample solution, is not larger than the Residue on ignition <2.44> Not more than 0.1% (1 g). peak area of imidapril from the standard solution; the area of the peak having the relative retention time of about 0.8 with respect Assay Weigh accurately about 0.4 g of Imidapril Hydrochlo- to imidapril from the sample solution is not larger than 7/10 ride, previously dried, dissolve in 70 mL of water, and titrate times the peak area of imidapril from the standard solution; and <2.50> with 0.1 mol/L sodium hydroxide VS from the first the area of each peak other than the peak of imidapril and other equivalent point to the second equivalent point (potentiometric than those mentioned above from the sample solution is not lar- titration). ger than 3/10 times the peak area of imidapril from the standard Each mL of 0.1 mol/L sodium hydroxide VS solution. Furthermore, the total area of the peaks other than the peak of imidapril from the sample solution is not larger than 1.5 = 44.19 mg of C20H27N3O6·HCl times the peak area of imidapril from the standard solution. Containers and storage Containers—Well-closed containers. Operating conditions— Detector, column, column temperature, mobile phase and flow rate: Proceed as directed in the operating conditions in the Add the following: Assay. Time span of measurement: About 2 times as long as the re- Imidapril Hydrochloride Tablets tention time of imidapril, beginning after the solvent peak. System suitability— イミダプリル塩酸塩錠 Test for required detectability: Pipet 2 mL of the standard solution, and add diluted methanol (2 in 5) to make exactly 20 mL. Imidapril Hydrochloride Tablets contain not less Confirm that the peak area of imidapril obtained from 20 µL of than 95.0% and not more than 105.0% of the labeled this solution is equivalent to 7 to 13% of that of imidapril from amount of Imidapril Hydrochloride (C H N O ·HCl: 20 27 3 6 the standard solution. 441.91). System performance: When the procedure is run with 20 µL Method of preparation Prepare as directed under Tablets, of the standard solution under the above operating conditions, with Imidapril Hydrochloride. the number of theoretical plates and the symmetry factor of the peak of imidapril are not less than 5000 and not more than 1.5, Identification Weigh accurately an amount of powdered Imi- respectively. dapril Hydrochloride Tablets, equivalent to 25 mg of Imidapril System repeatability: When the test is repeated 6 times with Hydrochloride, add 5 mL of ethanol (99.5), shake well, filter, 20 µL of the standard solution under the above operating condi- and use the filtrate as the sample solution. Separately, dissolve tions, the relative standard deviation of the peak area of imi- 25 mg of imidapril hydrochloride in 5 mL of ethanol (99.5), and dapril is not more than 2.0%. use this solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography Uniformity of dosage units <6.02> Perform the test accord- <2.03>. Spot 10 µL each of the sample solution and standard ing to the following method: it meets the requirement of the solution on a plate of silica gel with fluorescent indicator for Content uniformity test. thin-layer chromatography. Develop the plate with a mixture of To 1 tablet of Imidapril Hydrochloride Tablets add 2V/5 mL 1-butanol, ethyl acetate, water, ethanol (99.5) and acetic acid of water, shake vigorously for 10 minutes, add diluted methanol (100) (16:16:7:2:2) to a distance of about 13 cm, and air-dry the (2 in 3) to make exactly V mL so that each mL contains about plate. Examine under ultraviolet light (main wavelength: 254 0.1 mg of imidapril hydrochloride (C20H27N3O6·HCl), filter nm): the principal spot obtained from the sample solution has through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 2 mL of the filtrate, and use the subsequent the same Rf value as the spot from the standard solution. filtrate as the sample solution. Separately, weigh accurately Purity Related substances— To a quantity of powdered Imi- about 10 mg of imidapril for assay, previously dried at 105ºC dapril Hydrochloride Tablets, equivalent to 25 mg of Imidapril for 3 hours, dissolve in diluted methanol (2 in 5) to make ex- Hydrochloride according to the labeled amount, add 40 mL of actly 100 mL, and use this solution as the standard solution. diluted methanol (2 in 5), shake vigorously for 10 minutes, add Perform the test with exactly 20 µL each of the sample solution diluted ethanol (2 in 5) to make 50 mL, and filter through a and standard solution as directed under Liquid Chromatography membrane filter with a pore size not exceeding 0.45 µm. Dis- <2.01> according to the following conditions, and determine the card the first 2 mL of the filtrate, and use the subsequent filtrate peak areas , AT and AS, of imidapril in each solution. as the sample solution. Pipet 1 mL of this solution, add diluted methanol (2 in 5) to make exactly 100 mL, and use this solution Amount (mg) of imidapril hydrochloride (C20H27N3O6·HCl) as the standard solution. Perform the test with exactly 20 µL = WS × (AT/AS) × (V/100) each of the sample solution and standard solution as directed W : Amount (mg) of imidapril hydrochloride for assay under Liquid Chromatography <2.01> according to the follow- S ing conditions. Determine each peak area of both solutions by Operating conditions— the automatic integration method: the area of the peak having

2142 Official Monographs Supplement II, JP XV

Proceed as directed in the operating conditions in the Assay (C20H27N3O6·HCl), add 30 mL of diluted methanol (2 in 5) and System suitability— exactly 5 mL of the internal standard solution, shake vigorously System performance: When the procedure is run with 20 µL for 10 minutes, add diluted methanol (2 in 5) to make 50 mL, of the standard solution under the above operating conditions, and filter through a membrane filter with a pore size not ex- the number of theoretical plates and the symmetry factor of the ceeding 0.45 µm. Discard the first 2 mL of the filtrate, pipet 5 peak of imidapril are not less than 5000 and not more than 1.5, mL of the subsequent filtrate, add diluted methanol (2 in 5) to respectively. make 20 mL, and use this solution as the sample solution. System repeatability: When the test is repeated 6 times with Separately, weigh accurately about 20 mg of imidapril hydro- 20 µL of the standard solution under the above operating condi- chloride for assay, previously dried at 105ºC for 3 hours, dis- tions, the relative standard deviation of the peak area of imi- solve in 5 mL of the internal standard solution, add diluted dapril is not more than 1.0%. methanol (2 in 5) to make 50 mL. Pipet 5 mL of this solution, add diluted methanol (2 in 5) to make 20 mL, and use this solu- Dissolution <6.10> When the test is performed at 50 revolu- tion as the standard solution. Perform the test with 20 µL each of tions per minute according to the Paddle method, using 900 mL the sample solution and standard solution as directed under Liq- of water as the dissolution medium, the dissolution rate in 45 uid Chromatography <2.01> according to the following condi- minutes of Imidapril Hydrochloride Tablets is not less than tions, and calculate the ratios, QT and QS, of the peak area of 85%. imidapril to that of the internal standard. Start the test with 1 tablet of Imidapril Hydrochloride Tablets, withdraw not less than 20 mL of the medium at the specified Amount (mg) of imidapril hydrochloride (C20H27N3O6·HCl) minute after starting the test, and filter through a membrane fil- = WS × (QT/QS) ter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the filtrate, pipet V mL of the subsequent filtrate, add wa- WS: Amount (mg) of imidapril hydrochloride for assay ter to make exactly V´ mL so that each mL contains about 2.8 µg Internal standard solution—A solution of ethyl parahydroxy- of imidapril hydrochloride (C H N O ·HCl) according to the 20 27 3 6 benzoate in diluted methanol (2 in 5) (1 in 500) labeled amount, and use this solution as the sample solution. Operating conditions— Separately, weigh accurately about 28 mg of imidapril hydro- Detector: An ultraviolet absorption photometer (wavelength: chloride for assay, previously dried at 105ºC for 3 hours, and 215 nm). dissolve in water to make exactly 100 mL. Pipet 2 mL of this Column: A stainless steel column 4.6 mm in inside diameter solution, add water to make exactly 200 mL, and use this solu- and 15 cm in length, packed with octadecylsilanized silica gel tion as the standard solution. Perform the test with exactly 50 µL for liquid chromatography (5 µm in particle diameter). each of the sample solution and standard solution as directed Column temperature: A constant temperature of about 40ºC. under Liquid Chromatography <2.01> according to the follow- Mobile phase: Dissolve 1.36 g of potassium dihydrogen ing conditions, and determine the peak areas, A and A , of imi- T S phosphate in 1000 mL of water, and adjust the pH to 2.7 with dapril in each solution. phosphoric acid. To 600 mL of this solution add 400 mL of Dissolution rate (%) with respect to the labeled amount of methanol. Flow rate: Adjust the flow rate so that the retention time of imidapril hydrochloride (C20H27N3O6·HCl) imidapril is about 8 minutes. = WS × (AT/AS) × (V´/V) × (1/C) × 9 System suitability—

WS: Amount (mg) of imidapril hydrochloride for assay System performance: When the procedure is run with 20 µL C: Labeled amount (mg) of imidapril hydrochloride of the standard solution under the above operating conditions,

(C20H27N3O6·HCl) in 1 tablet imidapril and the internal standard are eluted in this order with the resolution between these peaks being not less than 4. Operating conditions— System repeatability: When the test is repeated 6 times with Proceed as directed in the operating conditions in the Assay. 20 µL of the standard solution under the above operating condi- System suitability— tions, the relative standard deviation of the ratio of the peak area System performance: When the procedure is run with 50 µL of imidapril to that of the internal standard is not more than of the standard solution under the above operating conditions, 1.0%. the number of theoretical plates and the symmetry factor of the peak of imidapril are not less than 5000 and not more than 1.5, Containers and storage Containers—Tight containers. respectively. System repeatability: When the test is repeated 6 times with 50 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of imidapril is not more than 2.0%.

Assay Weigh accurately not less than 20 Imidapril Hydrochlo- ride Tablets, and powder. Weigh accurately a portion of the powder, equivalent to about 20 mg of imidapril hydrochloride

Supplement II, JP XV Official Monographs 2143

Add the following: ethanol (99.5), and use this solution as the sample solution. Pi- pet 1 mL of this solution, add ethanol (99.5) to make exactly Indapamide 200 mL, and use this solution as the standard solution (1). Pipet 5 mL of this solution, add ethanol (99.5) to make exactly 10 mL, インダパミド and use this solution as the standard solution (2). Perform the test with these solutions as directed under Thin-layer Chroma- tography <2.03>. Spot 10 µL each of the sample solution, standard solution (1) and standard solution (2) on a plate of silica gel with fluorescent indicator for thin-layer chromatography. Immediately develop the plate with a mixture of ethyl acetate, cyclohexane and acetic acid (100) (100:80:1) to a distance of about 10 cm, and air-dry the plate. Examine under ultraviolet and enantiomer light (main wavelength: 254 nm): the spots other than the principal spot obtained from the sample solution are not more in-

C16H16ClN3O3S: 365.83 tense than the spot from the standard solution (1), and the total 4-Chloro-N-[(2RS)-2-methyl-2,3-dihydro-1H-indol-1-yl]- amount of these related substances, calculated by comparison 3-sulfamoylbenzamide [26807-65-8] with the spots from the standard solutions (1) and (2), is not more than 2.0%. Indapamide contains not less than 98.5% and not (4) Residual solvent—Being specified separately. more than 101.5% of C16H16ClN3O3S, calculated on the dried basis. Loss on drying <2.41> Not more than 3.0% (0.5 g, reduced pressure not exceeding 0.67 kPa, phosphorus (V) oxide, 110ºC, Description Indapamide occurs as a white crystalline powder. 2 hours). It is freely soluble in ethanol (99.5), and practically insoluble in water. Residue on ignition <2.44> Not more than 0.1% (1 g). A solution of Indapamide in ethanol (99.5) (1 in 10) shows no optical rotation. Assay Weigh accurately about 20 mg each of Indapamide and Indapamide Reference Standard (separately, determine the loss Identification (1) Determine the absorption spectrum of a on drying <2.41> in the same manner as Indapamide), and dissolution of Indapamide in ethanol (99.5) (1 in 100000) as di- solve each in a mixture of water and ethanol (99.5) (1:1) to rected under Ultraviolet-visible Spectrophotometry <2.24>, and make exactly 100 mL. Pipet 10 mL each of these solutions, add compare the spectrum with the Reference Spectrum or the spec- exactly 2 mL of the internal standard solution and a mixture of trum of a solution of Indapamide Reference Standard prepared water and ethanol (99.5) (1:1) to make 20 mL, and use these in the same manner as the sample solution: both spectra exhibit solutions as the sample solution and standard solution, respec- similar intensities of absorption at the same wavelengths. tively. Perform the test with 10 µL each of the sample solution (2) Determine the infrared absorption spectrum of Indapa- and standard solution as directed under Liquid Chromatography mide as directed in the potassium bromide disk method under <2.01> according to the following conditions, and calculate the

Infrared Spectrophotometry <2.25>, and compare the spectrum ratios, QT and QS, of the peak area of indapamide to that of the with the Reference Spectrum or the spectrum of Indapamide internal standard. Reference Standard: both spectra exhibit similar intensities of absorption at the same wave numbers. Amount (mg) of indapamide (C16H16ClN3O3S) (3) Perform the test with Indapamide as directed under = WS × (QT/QS) Flame Coloration Test <1.04> (2): a green color appears. WS: Amount (mg) of Indapamide Reference Standard, calcu- Melting point <2.60> 167 - 171ºC. lated on the dried basis

Purity (1) Chloride <1.03>—To 1.5 g of Indapamide add 50 Internal standard solution—A solution of isopropyl parahy- mL of water, shake for 15 minutes, allow to stand in an ice bath droxybenzoate in a mixture of water and ethanol (99.5) (1:1) (3 for 30 minutes, and filter. To 30 mL of the filtrate add 6 mL of in 1000) dilute nitric acid and water to make 50 mL. Perform the test us- Operating conditions— ing this solution as the test solution. Prepare the control solution Detector: An ultraviolet absorption photometer (wavelength: with 0.25 mL of 0.01 mol/L hydrochloric acid VS (not more 287 nm). than 0.01%). Column: A stainless steel column 4.6 mm in inside diameter (2) Heavy metals <1.07>—Proceed with 2.0 g of Indapa- and 15 cm in length, packed with octadecylsilanized silica gel mide according to Method 2, and perform the test. Prepare the for liquid chromatography (5 µm in particle diameter). control solution with 2.0 mL of Standard Lead Solution (not Column temperature: A constant temperature of about 40ºC. more than 10 ppm). Mobile phase: A mixture of diluted phosphoric acid (1 in (3) Related substances— Conduct this procedure using 1000), acetonitrile and methanol (6:3:1). light-resistant vessels. Dissolve 0.10 g of Indapamide in 5 mL of Flow rate: Adjust the flow rate so that the retention time of

2144 Official Monographs Supplement II, JP XV indapamide is about 6 minutes. WS: Amount (mg) of Indapamide Reference Standard, calcu- System suitability— lated on the dried basis System performance: When the procedure is run with 10 µL of the standard solution under the above operating conditions, Internal standard solution—A solution of isopropyl parahy- indapamide and the internal standard are eluted in this order droxybenzoate in a mixture of water and ethanol (99.5) (1:1) (3 with the resolution between these peaks being not less than 4. in 1000) System repeatability: When the test is repeated 6 times with Dissolution <6.10> When the test is performed at 50 revolu- 10 µL of the standard solution under the above operating conditions per minute according to the Paddle method using 900 mL tions, the relative standard deviation of the peak area of inda- of water as the dissolution medium, the dissolution rates in 45 pamide is not more than 1.0%. minutes of 1-mg tablets and in 90 minutes of 2-mg tablets are Containers and storage Containers—Tight containers. not less than 70%, respectively. Storage—Light-resistant. Start the test with 1 tablet of Indapamide Tablets, withdraw not less than 20 mL of the medium at the specified minute after starting the test, and filter through a membrane filter with a pore Add the following: size not exceeding 0.45 µm. Discard the first 10 mL of the filtrate, pipet V mL of the subsequent filtrate, add water to make Indapamide Tablets exactly V´ mL so that each mL contains about 1.1 µg of indapamide (C16H16ClN3O3S) according to the labeled amount, and use インダパミド錠 this solution as the sample solution. Separately, weigh accurately about 20 mg of Indapamide Reference Standard (sepa- Indapamide Tablets contain not less than 93.0% and rately, determine the loss on drying <2.41> in the same manner not more than 103.0% of the labeled amount of inda- as Indapamide), and dissolve in ethanol (99.5) to make exactly pamide (C16H16ClN3O3S: 365.83). 50 mL. Pipet 5 mL of this solution, and add water to make exactly 100 mL. Pipet 5 mL of this solution, add water to make Method of preparation Prepare as directed under Tablets, exactly 100 mL, and use this solution as the standard solution. with Indapamide. Perform the test with exactly 50 µL each of the sample solution Identification To an amount of powdered Indapamide Tablets, and standard solution as directed under Liquid Chromatography equivalent to 10 mg of Indapamide according to the labeled <2.01> according to the following conditions, and determine the amount, add 5 mL of ethyl acetate, shake for 10 minutes, cen- peak areas , AT and AS, of indapamide in each solution. trifuge, and use the supernatant liquid as the sample solution. Dissolution rate (%) with respect to the labeled amount of Separately, dissolve 10 mg of Indapamide Reference Standard in indapamide (C H ClN O S) 5 mL of ethyl acetate, and use this solution as the standard solu- 16 16 3 3 = W × (A /A ) × (V´/V) × (1/C) × (9/2) tion. Perform the test with these solutions as directed under S T S Thin-layer Chromatography <2.03>. Spot 10 µL each of the WS: Amount (mg) of Indapamide Reference Standard, calcu- sample solution and standard solution on a plate of silica gel lated on the dried basis with fluorescent indicator for thin-layer chromatography. De- C: Labeled amount (mg) of indapamide (C16H16ClN3O3S) in 1 velop the plate with a mixture of ethyl acetate, cyclohexane and tablet acetic acid (100) (100:80:1) to a distance of about 10 cm, and air-dry the plate. Examine under ultraviolet light (main wave- Operating conditions— length: 254 nm): the spots from the sample solution and the Proceed as directed in the operating conditions in the Assay standard solution show a blue-purple color and have the same Rf under Indapamide. value. System suitability— System performance: When the procedure is run with 50 µL Uniformity of dosage units <6.02> Perform the test accord- of the standard solution under the above operating conditions, ing to the following method: it meets the requirement of the the number of theoretical plates and the symmetry factor of the Content uniformity test. peak of indapamide are not less than 3500 and not more than 1.5, To 1 tablet of Indapamide Tablets add exactly V/10 mL of the respectively. internal standard solution, and add a mixture of water and etha- System repeatability: When the test is repeated 6 times with nol (99.5) (1:1) to make V mL so that each mL contains about 50 µL of the standard solution under the above operating condi- 0.1 mg of indapamide (C16H16ClN3O3S), shake to disintegrate, tions, the relative standard deviation of the peak area of inda- treat with ultrasonic waves for 10 minutes, shake again for 10 pamide is not more than 1.5%. minutes, centrifuge, and use the supernatant liquid as the sample solution. Proceed as directed in the Assay. Assay To 20 Indapamide Tablets add 80 mL of a mixture of water and ethanol (99.5) (1:1), shake well to disintegrate, and Amount (mg) of indapamide (C16H16ClN3O3S) treat with ultrasonic waves for 10 minutes. Shake the solution = WS × (QT/QS) × (V/200) for 10 minutes, and add a mixture of water and ethanol (99.5) (1:1) to make exactly 100 mL. Pipet a volume of indapamide

Supplement II, JP XV Official Monographs 2145

(C16H16ClN3O3S), equivalent to about 2 mg, and add exactly 2 equivalent to about 2 mg of indometacin (C19H16ClNO4), add a mL of the internal standard solution and a mixture of water and mixture of methanol and acetic acid (100) (200:1) to make ex- ethanol (99.5) (1:1) to make exactly 20 mL. Centrifuge this so- actly 50 mL, and use this solution as the sample solution. Sepa- lution, and use the supernatant liquid as the sample solution. rately, weigh accurately about 0.1 g of Indometacin Reference Separately, weigh accurately about 20 mg of Indapamide Ref- Standard, previously dried at 105ºC for 4 hours, and dissolve in erence Standard (separately, determine the loss on drying a mixture of methanol and acetic acid (100) (200:1) to make <2.41> in the same manner as Indapamide), and dissolve in a exactly 100 mL. Pipet 4 mL of this solution, add a mixture of mixture of water and ethanol (99.5) (1:1) to make 100 mL. Pipet methanol and acetic acid (100) (200:1) to make exactly 100 mL, 10 mL of this solution, add exactly 2 mL of the internal standard and use this solution as the standard solution. Perform the test solution and a mixture of water and ethanol (99.5) (1:1) to make with the sample solution and standard solution as directed under 20 mL, and use this solution as the standard solution. Proceed as Ultraviolet-visible Spectrophotometry <2.24>, and determine directed in the Assay under Indapamide. the absorbances, AT and AS, at 320 nm.

Amount (mg) of indapamide (C16H16ClN3O3S) Amount (mg) of indometacin (C19H16ClNO4) = WS × (QT/QS) × (1/10) = WS × (AT/AS) × (2/V)

WS: Amount [mg (potency)] of Indapamide Reference Stan- WS: Amount (mg) of Indometacin Reference Standard dard, calculated on the dried basis

Internal standard solution—A solution of isopropyl parahy- Add the following: droxybenzoate in a mixture of water and ethanol (99.5) (1:1) (3 in 1000) Ipriflavone

Containers and storage Containers—Tight containers. イプリフラボン

Indigocarmine Injection

インジゴカルミン注射液

Add the following next to the Identification: C18H16O3: 280.32 7-(1-Methylethyl)oxy-3-phenyl-4H-chromen-4-one Bacterial endotoxins <4.01> Less than 7.5 EU/mg. [35212-22-7]

Ipriflavone, when dried, contains not less than Add the following next to the Extractable volume: 98.5% and not more than 101.0% of C18H16O3.

Foreign insoluble matter <6.06> Perform the test according Description Ipriflavone occurs as white to yellowish white to Method 1: it meets the requirement. crystals or crystalline powder. It is soluble in acetonitrile, sparingly soluble in methanol and Insoluble particulate matter <6.07> Perform the test acin ethanol (99.5), and practically insoluble in water. cording to Method 2: it meets the requirement. It gradually turns yellow on exposure to light. Sterility <4.06> Perform the test according to the Membrane Identification (1) Determine the absorption spectrum of a filtration method: it meets the requirement. solution of Ipriflavone in methanol (1 in 200000) as directed under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spectrum or the spectrum Indometacin Suppositories of a solution of Ipriflavone Reference Standard prepared in the same manner as the sample solution: both spectra exhibit similar インドメタシン坐剤 intensities of absorption at the same wavelengths. (2) Determine the infrared absorption spectrum of Iprifla- Add the following next to the Identification: vone as directed in the potassium bromide disk method under Infrared Spectrophotometry <2.25>, and compare the spectrum Uniformity of dosage units <6.02> Perform the test accord- with the Reference Spectrum or the spectrum of Ipriflavone ing to the following method: it meets the requirement of the Reference Standard: both spectra exhibit similar intensities of Content uniformity test. absorption at the same wave numbers. To 1 suppository of Indometacin Suppositories add 80 mL of a mixture of methanol and acetic acid (100) (200:1), dissolve by Melting point <2.60> 116 - 119ºC. warming, add a mixture of methanol and acetic acid (100) (200:1) to make exactly 100 mL. Pipet V mL of this solution, Purity (1) Heavy metals <1.07>—Proceed with 1.0 g of

2146 Official Monographs Supplement II, JP XV

Ipriflavone according to Method 2, and perform the test. Prepare Perform the test with 20 µL each of the sample solution and the control solution with 1.0 mL of Standard Lead Solution (not standard solution as directed under Liquid Chromatography more than 10 ppm). <2.01> according to the following conditions, and calculate the

(2) Arsenic <1.11>—Prepare the test solution with 1.0 g of ratios, QT and QS, of the peak area of ipriflavone to that of the Ipriflavone according to Method 4, and perform the test. Prepare internal standard. the test solution with 10 mL of dilute hydrochloric acid instead of using 3 mL of hydrochloric acid. Prepare the standard color Amount (mg) of ipriflavone (C18H16O3) with 1.0 mL of Standard Arsenic Solution (not more than 1 = WS × (QT/QS) ppm). W : Amount (mg) of Ipriflavone Reference Standard (3) Related substances—Dissolve 30 mg of Ipriflavone in S 50 mL of acetonitrile. To 5 mL of this solution add acetonitrile Internal standard solution—A solution of di-n-butyl phthalate in to make 50 mL, and use this solution as the sample solution. acetonitrile (1 in 100) Pipet 1 mL of this solution, add acetonitrile to make exactly 100 Operating conditions— mL, and use this solution as the standard solution. Perform the Detector: An ultraviolet absorption photometer (wavelength: test with exactly 20 µL each of the sample solution and standard 280 nm) solution as directed under Liquid Chromatography <2.01> ac- Column: A stainless steel column 4 mm in inside diameter cording to the following conditions. Determine each peak area and 15 cm in length, packed with octylsilanized silica gel for of both solutions by the automatic integration method: the area liquid chromatography (5 µm in particle diameter). of each peak other than the peak of ipriflavone obtained from Column temperature: A constant temperature of about 25ºC. the sample solution is not larger than 1/2 times the peak area of Mobile phase: A mixture of acetonitrile and water (3:2) ipriflavone from the standard solution, and the total area of the Flow rate: Adjust the flow rate so that the retention time of peaks other than the peak of ipriflavone obtained from the sam- ipriflavone is about 6 minutes. ple solution is not larger than the peak area of ipriflavone from System suitability— the standard solution. System performance: When the procedure is run with 20 µL Operating conditions— of the standard solution under the above operating conditions, Detector, column, column temperature and flow rate: Proceed ipriflavone and the internal standard are eluted in this order with as directed in the operating conditions in the Assay. the resolution between these peaks being not less than 3. Time span of measurement: About 2 times as long as the re- System repeatability: When the test is repeated 6 times with tention time of ipriflavone, beginning after the solvent peak. 20 µL of the standard solution under the above operating condi- System suitability— tions, the relative standard deviation of the ratio of the peak area Test for required detectability: Pipet 2 mL of the standard so- of ipriflavone to that of the internal standard is not more than lution, and add acetonitrile to make exactly 20 mL. Confirm that 1.0%. the peak area of ipriflavone obtained from 20 µL of this solution is equivalent to 7 to 13% of that of ipriflavone from the standard Containers and storage Containers—Tight containers. solution. Storage—Light-resistant. System performance: When the procedure is run with 20 µL of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry factor of the Add the following: peak of ipriflavone are not less than 2000 and not more than 1.5, respectively. Ipriflavone Tablets System repeatability: When the test is repeated 6 times with 20 µL of the standard solution under the above operating condi- イプリフラボン錠 tions, the relative standard deviation of the ratio of the peak area Ipriflavone Tablets contain not less than 95.0% and of ipriflavone to that of the internal standard is not more than not more than 105.0% of the labeled amount of ipri- 2.0%. flavone (C H O : 280.32). (4) Residual solvent—Being specified separately. 18 16 3 Method of preparation Prepare as directed under Tablets, Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 2 with Ipriflavone. hours). Identification To a quantity of powdered Ipriflavone Tablets, Residue on ignition <2.44> Not more than 0.1% (1 g). equivalent to 11 mg of Ipriflavone according to the labeled Assay Weigh accurately about 30 mg each of Ipriflavone and amount, add 100 mL of methanol, shake vigorously for 10 min- Ipriflavone Reference Standard, previously dried, dissolve utes, and centrifuge. To 5 mL of the supernatant liquid add separately in acetonitrile to make exactly 50 mL. Pipet 5 mL methanol to make 100 mL. Determine the absorption spectrum each of these solutions, add exactly 5 mL of the internal stan- of this solution as directed under Ultraviolet-visible Spectro- dard solution and acetonitrile to make 50 mL, and use these so- photometry <2.24>: it exhibits maxima between 247 nm and lutions as the sample solution and standard solution, respectively. 251 nm, and between 297 nm and 301 nm.

Supplement II, JP XV Official Monographs 2147

Uniformity of dosage units <6.02> It meets the requirement water to make 20 mL. To 2 mL of this solution add water to of the Mass variation test. make 50 mL. Determine the absorption spectrum of this solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, Dissolution Being specified separately. and compare the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same Assay Weigh accurately the mass of not less than 20 Iprifla- wavelengths. vone Tablets, and powder. Weigh accurately a portion of the (2) Determine the infrared absorption spectrum of Irso- powder, equivalent to about 30 mg of ipriflavone (C H O ), 18 16 3 gladine Maleate as directed in the potassium bromide disk add 30 mL of acetonitrile, shake vigorously for 15 minutes, add method under Infrared Spectrophotometry <2.25>, and compare acetonitrile to make exactly 50 mL, and centrifuge. Pipet 5 mL the spectrum with the Reference Spectrum: both spectra exhibit of the supernatant liquid, add exactly 5 mL of the internal stan- similar intensities of absorption at the same wave numbers. dard solution. add acetonitrile to make 50 mL, and use this solu- (3) Dissolve 10 mg of Irsogladine Maleate in 1 mL of dilute tion as the sample solution. Separately, weigh accurately about hydrochloric acid and 4 mL of water, and add 3 drops of potas- 30 mg of Ipriflavone Reference Standard, previously dried at sium permanganate TS: the color of the solution is discharged 105ºC for 2 hours, and dissolve in acetonitrile to make exactly immediately. 50 mL. Pipet 5 mL of this solution, add exactly 5 mL of the internal standard solution and acetonitrile to make 50 mL, and use Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of Ir- this solution as the standard solution. Proceed as directed in the sogladine Maleate according to Method 4, and perform the test. Assay under Ipriflavone. Prepare the control solution with 2.0 mL of Standard Lead Solu- tion (not more than 10 ppm). Amount (mg) of ipriflavone (C H O ) 18 16 3 (2) Related substances—Dissolve 50 mg of Irsogladine = W × (Q /Q ) S T S Maleate in 10 mL of ethyleneglycol, and use this solution as the sample solution. Pipet 1 mL of this solution, add ethyleneglycol WS: Amount (mg) of Ipriflavone Reference Standard Internal standard solution—A solution of di-n-butyl phthalate in to make exactly 100 mL, and use this solution as the standard acetonitrile (1 in 100) solution. Perform the test with exactly 5 µL each of the sample solution and standard solution as directed under Liquid Chro- Containers and storage Containers—Tight containers. matography <2.01> according to the following conditions. De- Storage—Light-resistant. termine each peak area of both solutions by the automatic integration method: the area of each peak other than the peaks of maleic acid and irsogladine obtained from the sample solution is Add the following: not larger than 1/10 times the peak area of irsogladine from the standard solution. Irsogladine Maleate Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: イルソグラジンマレイン酸塩 250 nm). Column: A stainless steel column 4.6 mm in inside diameter and 7.5 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (3 µm in particle diameter). Column temperature: A constant temperature of about 40ºC. Mobile phase: A mixture of methanesulfonic acid solution (1 in 1000) and methanol (4:1) Flow rate: Adjust the flow rate so that the retention time of irsogladine is about 8 minutes. C9H7Cl2N5·C4H4O4: 372.16 6-(2,5-Dichlorophenyl)-1,3,5-triazine-2,4-diamine Time span of measurement: About 3 times as long as the re- monomaleate [84504-69-8] tention time of irsogladine, beginning after the solvent peak. System suitability—Test for required detectability: Pipet 1 mL of Irsogladine Maleate, when dried, contains not less the standard solution, and add ethyleneglycol to make exactly than 99.0% and not more than 101.0% of 10 mL. Confirm that the peak area of irsogladine obtained from C9H7Cl2N5·C4H4O4. 5 µL of this solution is equivalent to 7 to 13% of that of irsogladine from the standard solution. Description Irsogladine Maleate occurs as white crystals or System performance: When the procedure is run with 5 µL of crystalline powder. It has a slightly bitter taste. the standard solution under the above operating conditions, the It is sparingly soluble in acetic acid (100) and in ethylene- number of theoretical plates and the symmetry factor of the peak glycol, slightly soluble in methanol and in ethanol (99.5), and of irsogladine are not less than 3000 and not more than 1.5, re- practically insoluble in water. spectively. System repeatability: When the test is repeated 6 times with 5 Identification (1) Dissolve 20 mg of Irsogladine Maleate in µL of the standard solution under the above operating conditions, methanol to make 20 mL. Take 2 mL of this solution, and add the relative standard deviation of the peak area of irsogladine is

2148 Official Monographs Supplement II, JP XV not more than 2.0%. pipet 1 mL of the supernatant liquid, and add water to make ex- (3) Residual solvent—Being specified separately. actly 20 mL. Filter this solution through a membrane filter with a pore size not exceeding 0.5 µm, discard the first 10 mL of the Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 4 filtrate, and use the subsequent filtrate as the sample solution. hours). Separately, weigh accurately about 20 mg of irsogladine maleate for assay, previously dried at 105ºC for 4 hours, dissolve in Residue on ignition <2.44> Not more than 0.1% (1 g). methanol to make exactly 20 mL. Pipet 2 mL of this solution, Assay Weigh accurately about 0.3 g of Irsogladine Maleate, add water to make exactly 20 mL. Pipet 2 mL of this solution, previously dried, dissolve in 25 mL of acetic acid (100), add 25 add water to make exactly 100 mL, and use this solution as the mL of acetic anhydride, and titrate <2.50> with 0.05 mol/L per- standard solution. Perform the test with the sample solution and chloric acid VS (potentiometric titration). Perform a blank de- standard solution as directed under Ultraviolet-visible Spectro- termination in the same manner, and make any necessary cor- photometry <2.24>, using water as the blank, and determine the rection. absorbances, AT and AS, at 210 nm.

Each mL of 0.05 mol/L perchloric acid VS Amount (mg) of irsogladine maleate (C9H7Cl2N5·C4H4O4) = W × (A /A ) × (V/500) = 18.61 mg of C9H7Cl2N5·C4H4O4 S T S

Containers and storage Containers—Well-closed containers. WS: Amount (mg) of irsogladine maleate for assay

Dissolution <6.10> When the test is performed at 50 revolu- Add the following: tions per minute according to the Paddle method using 900 mL of water as the dissolution medium, the dissolution rate in 30 Irsogladine Maleate Fine Granules minutes of Irsogladine Maleate Fine Granules is not less than 70%. イルソグラジンマレイン酸塩細粒 Start the test with an accurately weighed amount of Irsoglad- ine Maleate Fine Granules, equivalent to about 4 mg of irso-

Irsogladine Maleate Fine Granules contain not less gladine maleate (C9H7Cl2N5·C4H4O4), withdraw not less than 20 than 93.0% and not more than 107.0% of irsogladine mL of the medium at the specified minute after starting the test, maleate (C9H7Cl2N5·C4H4O4: 372.16). and filter through a membrane filter with a pore size not exceeding 0.5 µm. Discard the first 10 mL of the filtrate, and use Method of preparation Prepare fine granules as directed un- the subsequent filtrate as the sample solution. Separately, weigh der Powders, with Irsogladine Maleate. accurately about 40 mg of irsogladine maleate for assay, previously dried at 105ºC for 4 hours, and dissolve in methanol to Identification To a quantity of powdered Irsogladine Maleate make exactly 20 mL. Pipet 2 mL of this solution, and add water Fine Granules, equivalent to 2 mg of Irsogladine Maleate ac- to make exactly 20 mL. Pipet 2 mL of this solution, add water to cording to the labeled amount, add 5 mL of methanol, shake for make exactly 100 mL, and use this solution as the standard so- 10 minutes, centrifuge, and use the supernatant liquid as the lution. Perform the test with the sample solution and standard sample solution. Separately, dissolve 2 mg of irsogladine solution as directed under Ultraviolet-visible Spectrophotometry maleate in 5 mL of methanol, and use this solution as the stan- <2.24>, using water as the blank, and determine the absorbances, dard solution. Perform the test with these solutions as directed A and A , at 210 nm. under Thin-layer Chromatography <2.03>. Spot 10 µL each of T S the sample solution and standard solution on a plate of silica gel Dissolution rate (%) with respect to the labeled amount of with fluorescent indicator for thin-layer chromatography. De- irsogladine maleate (C9H7Cl2N5·C4H4O4) velop the plate with a mixture of petroleum ether, acetone and = (WS /WT) × (AT/AS) × (1/C) × 9 acetic acid (100) (12:4:1) to a distance of about 10 cm, and air-dry the plate. Examine under ultraviolet light (main wave- WS: Amount (mg) of irsogladine maleate for assay length: 254 nm): the spot from the sample solution has the same WT: Amount (g) of Irsogladine Maleate Fine Granules Rf value as the spot from the standard solution. C: Labeled amount (mg) of irsogladine maleate (C9H7Cl2N5·C4H4O4) in 1 g Uniformity of dosage units <6.02> Perform the test according to the following method: Irsogladine Maleate Fine Granules Particle size <6.03> It meets the requirement. in single-unit containers meet the requirement of the Content uniformity test. Assay Weigh accurately an amount of powdered Irsogladine Take out the total contents of 1 pack of Irsogladine Maleate Maleate Fine Granules, equivalent to about 5 mg of irsogladine Fine Granules, add 2 mL of water, add 2 mL methanol per mg of maleate (C9H7Cl2N5·C4H4O4), add exactly 5 mL of the internal standard solution, shake until it is dispersed, and add 5 mL of irsogladine maleate (C9H7Cl2N5·C4H4O4), treat with ultrasonic waves for 10 minutes with occasional shaking, and add water to water. To the solution add 25 mL of ethyleneglycol, treat with make exactly V mL so that each mL contains about 40 µg of ir- ultrasonic waves for 10 minutes with occasional shaking, and add ethyleneglycol to make 50 mL. Filter this solution through a sogladine maleate (C9H7Cl2N5·C4H4O4). Centrifuge this solution,

Supplement II, JP XV Official Monographs 2149 membrane filter with a pore size not exceeding 0.5 µm, discard Identification To a quantity of powdered Irsogladine Maleate the first 10 mL of the filtrate, and use the subsequent filtrate as Tablets, equivalent 2 mg of Irsogladine Maleate according to the the sample solution. Separately, weigh accurately about 25 mg labeled amount, add 5 mL of methanol, shake for 10 minutes, of irsogladine maleate for assay, previously dried at 105ºC for 4 centrifuge, and use the supernatant liquid as the sample solution. hours, and dissolve in ethyleneglycol to make exactly 25 mL. Separately, dissolve 2 mg of irsogladine maleate in 5 mL of Pipet 5 mL of this solution, add exactly 5 mL of the internal methanol, and use this solution as the standard solution. Perform standard solution, add 5 mL of water and ethyleneglycol to the test with these solutions as directed under Thin-layer Chro- make 50 mL, and use this solution as the standard solution. matography <2.03>. Spot 10 µL each of the sample solution and Perform the test with 5 µL each of the sample solution and standard solution on a plate of silica gel with fluorescent indi- standard solution as directed under Liquid Chromatography cator for thin-layer chromatography. Develop the plate with a <2.01> according to the following conditions, and calculate the mixture of petroleum ether, acetone and acetic acid (100) ratios, QT and QS, of the peak area of irsogladine to that of the (12:4:1) to a distance of about 10 cm, and air-dry the plate. internal standard. Examine under ultraviolet light (main wavelength: 254 nm): the

spot from the sample solution has the same Rf value as the spot Amount (mg) of irsogladine maleate (C9H7Cl2N5·C4H4O4) from the standard solution. = WS × (QT/QS) × (1/5) Uniformity of dosage units <6.02> Perform the test accord- WS: Amount (mg) of irsogladine maleate for assay ing to the following method: it meets the requirement of the Content uniformity test. Internal standard solution—A solution of ethyl parahydroxy- To 1 tablet of Irsogladine Maleate Tablets add 2 mL of water, benzoate in methanol (1 in 2500) add 2 mL of methanol per mg of irsogladine maleate Operating conditions— (C H Cl N ·C H O ), treat with ultrasonic waves for 10 minutes Detector: An ultraviolet absorption photometer (wavelength: 9 7 2 5 4 4 4 with occasional shaking, add water to make exactly V mL so 250 nm). that each mL contains about 40 µg of irsogladine maleate Column: A stainless steel column 4.6 mm in inside diameter (C H Cl N ·C H O ). Centrifuge this solution, pipet 1 mL of the and 15 cm in length, packed with octadecylsilanized silica gel 9 7 2 5 4 4 4 supernatant liquid, and add water to make exactly 20 mL. Filter for liquid chromatography (5 µm in particle diameter). this solution through a membrane filter with a pore size not ex- Column temperature: A constant temperature of about 25ºC. ceeding 0.5 µm, discard the first 10 mL of the filtrate, and use Mobile phase: A mixture of water, acetonitrile and acetic acid the subsequent filtrate as the sample solution. Separately, weigh (100) (750:250:3) accurately about 20 mg of irsogladine maleate for assay, previ- Flow rate: Adjust the flow rate so that the retention time of ously dried at 105ºC for 4 hours, and dissolve in methanol to irsogladine is about 9 minutes. make exactly 20 mL. Pipet 2 mL of this solution, and add water System suitability— to make exactly 20 mL. Pipet 2 mL of this solution, add water to System performance: When the procedure is run with 5 µL of make exactly 100 mL, and use this solution as the standard so- the standard solution under the above operating conditions, ir- lution. Perform the test with the sample solution and standard sogladine and the internal standard are eluted in this order with solution as directed under Ultraviolet-visible Spectrophotometry the resolution between these peaks being not less than 10. <2.24>, using water as the blank, and determine the absorbances, System repeatability: When the test is repeated 6 times with 5 A and A , at 210 nm. µL of the standard solution under the above operating conditions, T S the relative standard deviation of the ratio of the peak area of Amount (mg) of irsogladine maleate (C9H7Cl2N5·C4H4O4) irsogladine to that of the internal standard is not more than = WS × (AT/AS) × (V/500) 1.0%.

WS: Amount (mg) of irsogladine maleate for assay Containers and storage Containers—Tight containers. Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method using 900 mL Add the following: of water as the dissolution medium, the dissolution rate in 30 minutes of Irsogladine Maleate Tablets is not less than 80%. Irsogladine Maleate Tablets Start the test with 1 tablet of Irsogladine Maleate Tablets, withdraw not less than 20 mL of the medium at the specified イルソグラジンマレイン酸塩錠 minute after starting the test, and filter through a membrane filter with a pore size not exceeding 0.5 µm. Discard the first 10 Irsogladine Maleate Tablets contain not less than mL of the filtrate, pipet V mL of the subsequent filtrate, add wa- 93.0% and not more than 107.0% of the labeled ter to make exactly V´ mL so that each mL contains about 2.2 µg amount of irsogladine maleate (C H Cl N ·C H O : 9 7 2 5 4 4 4 of irsogladine maleate (C H Cl N ·C H O ) according to the 372.16). 9 7 2 5 4 4 4 labeled amount, and use this solution as the sample solution. Method of preparation Prepare as directed under Tablets, Separately, weigh accurately about 20 mg of irsogladine maleate with Irsogladine Maleate. for assay, previously dried at 105ºC for 4 hours, and dissolve in

2150 Official Monographs Supplement II, JP XV methanol to make exactly 20 mL. Pipet 2 mL of this solution, sogladine and the internal standard are eluted in this order with and add water to make exactly 20 mL. Pipet 2 mL of this solu- the resolution between these peaks being not less than 10. tion, add water to make exactly 100 mL, and use this solution as System repeatability: When the test is repeated 6 times with 5 the standard solution. Perform the test with the sample solution µL of the standard solution under the above operating conditions, and standard solution as directed under Ultraviolet-visible Spec- the relative standard deviation of the ratio of the peak area of trophotometry <2.24>, using water as the blank, and determine irsogladine to that of the internal standard is not more than the absorbances, AT and AS, at 210 nm. 1.0%.

Dissolution rate (%) with respect to the labeled amount of Containers and storage Containers—Tight containers.

irsogladine maleate (C9H7Cl2N5·C4H4O4)

= WS × (AT/AS) × (V´/V) × (1/C) × 9 Add the following:

WS: Amount (mg) of irsogladine maleate for assay C: Labeled amount (mg) of irsogladine maleate Isepamicin Sulfate Injection (C9H7Cl2N5·C4H4O4) in 1 tablet イセパマイシン硫酸塩注射液 Assay Weigh accurately the mass of not less than 20 Irso- gladine Maleate Tablets, and powder. Weigh accurately a por- Isepamicin Sulfate Injection is an aqueous injection. tion of the powder, equivalent to about 5 mg of irsogladine It contains not less than 90.0% and not more than maleate (C9H7Cl2N5·C4H4O4), add exactly 5 mL of the internal 110.0% of the labeled potency of isepamicin standard solution, shake until it is dispersed, and add 5 mL of (C22H43N5O12: 569.60). water. To this solution add 25 mL of ethyleneglycol, treat with ultrasonic waves for 10 minutes with occasional shaking, and Method of preparation Prepare as directed under Injections, add ethyleneglycol to make 50 mL. Filter this solution through a with Isepamicin Sulfate. membrane filter with a pore size not exceeding 0.5 µm, discard Description Isepamicin Sulfate Injection is a clear, colorless the first 10 mL of the filtrate, and use the subsequent filtrate as liquid. the sample solution. Separately, weigh accurately about 25 mg of irsogladine maleate for assay, previously dried at 105ºC for 4 Identification To a volume of Isepamicin Sulfate Injection, hours, and dissolve in ethyleneglycol to make exactly 25 mL. equivalent to 20 mg (potency) of Isepamicin Sulfate according Pipet 5 mL of this solution, add exactly 5 mL of the internal to the labeled amount, add water to make 10 mL, and use this standard solution, add 5 mL of water and ethyleneglycol to solution as the sample solution. Separately, dissolve an amount make 50 mL, and use this solution as the standard solution. of Isepamicin Sulfate Reference Standard, equivalent to 20 mg Perform the test with 5 µL each of the sample solution and (potency) in 10 mL of water, and use this solution as the stan- standard solution as directed under Liquid Chromatography dard solution. Proceed with these solutions as directed in the <2.01> according to the following conditions, and calculate the Identification (2) under Isepamicin Sulfate. ratios, QT and QS, of the peak area of irsogladine to that of the internal standard. Osmotic pressure ratio Being specified separately.

Amount (mg) of irsogladine maleate (C9H7Cl2N5·C4H4O4) pH <2.54> 5.5 - 7.5 = WS × (QT/QS) × (1/5) Purity Related substances—Perform the test with 5 µL of the

WS: Amount (mg) of irsogladine maleate for assay sample solution obtained in the Assay as directed under Liquid Chromatography <2.01> according to the following conditions. Internal standard solution—A solution of ethyl parahydroxy- Determine each peak area of the sample solution by the auto- benzoate in methanol (1 in 2500) matic integration method and calculate the amounts of these Operating conditions— peaks by the area percentage method: the amount of isoserine, Detector: An ultraviolet absorption photometer (wavelength: having the relative retention time of about 0.3 with respect to 250 nm) isepamicin, is not more than 2.0%, and the amount of gen- Column: A stainless steel column 4.6 mm in inside diameter tamicin B, having the relative retention time of about 1.3 with and 15 cm in length, packed with octadecylsilanized silica gel respect to isepamicin, is not more than 4.0%. For this calcula- for liquid chromatography (5 µm in particle diameter). tion, use the peak area of gentamicin B after multiplying by the Column temperature: A constant temperature of about 25ºC. relative response factor, 1.11. Mobile phase: A mixture of water, acetonitrile and acetic acid Operating conditions— (100) (750:250:3) Apparatus, detector, column, column temperature, reaction Flow rate: Adjust the flow rate so that the retention time of coil, mobile phase, reaction reagent, reaction temperature, flow irsogladine is about 9 minutes. rate of the mobile phase, and flow rate of the reaction reagent: System suitability— Proceed as directed in the operating conditions in the Assay un- System performance: When the procedure is run with 5 µL of der Isepamicin Sulfate. the standard solution under the above operating conditions, ir- Time span of measurement: About 2 times as long as the re-

Supplement II, JP XV Official Monographs 2151 tention time of isepamicin. Insoluble particulate matter <6.07> It meets the require- System suitability— ment. System performance and system repeatability: Proceed as directed in the Assay under Isepamicin Sulfate. Sterility <4.06> Perform the test according to the Membrane Test for required detectability: To 1 mL of the sample solution filtration method: it meets the requirement. add water to make 10 mL, and use this solution as the solution for system suitability test. Pipet 1 mL of the solution for system suitability test, and add water to make exactly 10 mL. Confirm Isoniazid Tablets that the peak area of isepamicin obtained from 5 µL of this solution is equivalent to 7 to 13% of that of isepamicin from the so- イソニアジド錠 lution for system suitability test. Add the following next to the Identification: Bacterial endotoxins <4.01> Less than 0.50 EU/mg (po- Uniformity of dosage units <6.02> Perform the test accord- tency). ing to the following method: it meets the requirement of the Extractable volume <6.05> It meets the requirement. Content uniformity test. To 1 tablet of Isoniazid Tablets add exactly V mL of water so

Foreign insoluble matter <6.06> Perform the test according that each mL, contains about 0.5 mg of isoniazid (C6H7N3O), to Method 1: it meets the requirement. and shake well to disintegrate. Filter this solution, discard the first 10 mL of the filtrate, pipet 5 mL of the subsequent filtrate, Insoluble particulate matter <6.07> It meets the require- add the mobile phase to make exactly 50 mL, and use this solu- ment. tion as the sample solution. Proceed as directed in the Assay. Sterility <4.06> Perform the test according to the Membrane Amount (mg) of isoniazid (C6H7N3O) filtration method: it meets the requirement. = WS × (AT/AS) × (V/100) Assay Pipet a volume of Isepamicin Sulfate Injection, equiva- WS: Amount (mg) of isoniazid for assay lent to about 0.2 g (potency) of Isepamicin Sulfate, add water to make exactly 100 mL. Pipet 10 mL of this solution, add water to make exactly 100 mL, and use this solution as the sample solu- Isosorbide Dinitrate Tablets tion. Separately, weigh accurately an amount of Isepamicin Sul- fate Reference Standard, equivalent to about 20 mg (potency), 硝酸イソソルビド錠 dissolve in water to make exactly 100 mL, and use this solution as the standard solution. Proceed as directed in the Assay under Change the Origin/limits of content to read: Isepamicin Sulfate. Isosorbide Dinitrate Tablets contain not less than

Amount [mg (potency)] of isepamicin (C22H43N5O12) 93.0% and not more than 107.0% of the labeled = WS × (AT/AS) × 10 amount of isosorbide dinitrate (C6H8N2O8: 236.14).

WS: Amount [mg (potency)] of Isepamicin Sulfate Reference Add the following next to the Purity: Standard Uniformity of dosage units <6.02> Perform the test accord- Containers and storage Containers—Hermetic containers. ing to the following method: it meets the requirement of the Content uniformity test. Expiration date 24 months after preparation. To 1 tablet of Isosorbide Dinitrate Tablets add 1 mL of water, and shake to disintegrate. To this solution add a mixture of wa-

ter and methanol (1:1) to make exactly V mL so that each mL

Isoniazid Injection contains about 0.1 mg of isosorbide dinitrate (C6H8N2O8), and shake for 10 minutes. Centrifuge this solution, and use the su- イソニアジド注射液 pernatant liquid as the sample solution. Proceed as directed in the Assay. Add the following next to the Identification: Amount (mg) of isosorbide dinitrate (C H N O ) Bacterial endotoxins <4.01> Less than 0.50 EU/mg. 6 8 2 8 = WS × (AT/AS) × V × (1/500)

Add the following next to the Extractable volume: WS: Amount (mg) of isosorbide dinitrate for assay, calculated on the anhydrous basis Foreign insoluble matter <6.06> Perform the test according to Method 1: it meets the requirement.

2152 Official Monographs Supplement II, JP XV

Change the Assay to read: Add the following: Assay Weigh accurately the mass of not less than 20 tablets of Ketoconazole Isosorbide Dinitrate Tablets, and powder. Weigh accurately a portion of the powder, equivalent to about 5 mg of isosorbide ケトコナゾール dinitrate tablets (C6H8N2O8), add a mixture of water and methanol (1:1) to make exactly 50 mL, and shake for 10 minutes. Centrifuge this solution, and use the supernatant liquid as the sample solution. Separately, weigh accurately about 50 mg of isosorbide dinitrate for assay (separately, determine the water content <2.48> in the same manner as Isosorbide Dinitrate), dissolve in a mixture of water and methanol (1:1) to make exactly 100 mL. Pipet 10 mL of this solution, add a mixture of and enantiomer water and methanol (1:1) to make exactly 50 mL, and use this solution as the standard solution. Perform the test with exactly

10 µL each of the sample solution and standard solution as di- C26H28Cl2N4O4:531.43 rected under Liquid Chromatography <2.01> according to the 1-Acetyl-4-(4-{[(2RS,4SR)-2-(2,4-dichlorophenyl)- following conditions, and determine the peak areas, AT and AS, 2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan- of isosorbide dinitrate in each solution. 4-yl]methoxy}phenyl)piperazine [65277-42-1]

Amount (mg) of isosorbide dinitrate (C6H8N2O8) Ketoconazole, when dried, contains not less than = WS × (AT/AS) × (1/10) 99.0% and not more than 101.0% of C26H28Cl2N4O4.

WS: Amount (mg) of isosorbide dinitrate for assay, calculated Description Ketoconazole occurs as a white to light yellowish on the anhydrous basis white powder. It is soluble in methanol, sparingly soluble in ethanol (99.5), Operating conditions— and practically insoluble in water. Detector: An ultraviolet absorption photometer (wavelength: A solution of Ketoconazole in methanol (1 in 20) shows no 220 nm) optical rotation. Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel Identification (1) Determine the absorption spectrum of a for liquid chromatography (5 µm in particle diameter). solution of Ketoconazole in methanol (3 in 100000) as directed Column temperature: A constant temperature of about 40ºC. under Ultraviolet-visible Spectrophotometry <2.24>, and com- Mobile phase: A mixture of water and methanol (11:9) pare the spectrum with the Reference Spectrum: both spectra Flow rate: Adjust the flow rate so that the retention time of exhibit similar intensities of absorption at the same wave- isosorbide dinitrate is about 6 minutes. lengths. System suitability— (2) Determine the infrared absorption spectrum of Keto- System performance: When the procedure is run with10 µL of conazole as directed in the potassium bromide disk method un- the standard solution under the above operating conditions, the der Infrared Spectrophotometry <2.25>, and compare the spec- number of theoretical plates and the symmetry factor of the peak trum with the Reference Spectrum: both spectra exhibit similar of isosorbide dinitrate are not less than 3000 and not more than intensities of absorption at the same wave numbers. 1.5, respectively. (3) Perform the test with Ketoconazole as directed under System repeatability: When the test is repeated 6 times with Flame Coloration Test <1.04> (2): a green color appears. 10 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of isosor- Melting point <2.60> 148 - 152ºC. bide dinitrate is not more than 1.0%. Purity (1) Heavy metals <1.07>—Proceed with 1.0 g of

Ketoconazole according to Method 2, and perform the test. Pre- pare the control solution with 1.0 mL of Standard Lead Solution Josamycin Tablets (not more than 10 ppm). ジョサマイシン錠 (2) Related Substances Dissolve 0.10 g of Ketoconazole in 10 mL of methanol, and use this solution as the sample solu- Change the Disintegration to read: tion. Pipet 5 mL of this solution, and add methanol to make exactly 100 mL. Pipet 1 mL of this solution, add methanol to make Disintegration <6.09> Perform the test using the disk, it exactly 10 mL, and use this solution as the standard solution. meets the requirement. Perform the test with exactly 10 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions. Determine each peak area of both solutions by the automatic integration method:

Supplement II, JP XV Official Monographs 2153 the area of each peak other than the peak of ketoconazole ob- Each mL of 0.1 mol/L perchloric acid VS tained from the sample solution is not larger than 2/5 times the = 26.57 mg of C26H28Cl2N4O4 peak area of ketoconazole from the standard solution, and the total area of the peaks other than the peak of ketoconazole ob- Containers and storage Containers—Tight containers. tained from the sample solution is not larger than the peak area Storage—Light-resistant. of ketoconazole from the standard solution.

Operating conditions— Add the following: Detector: An ultraviolet absorption photometer (wavelength: 220 nm). Column: A stainless steel column 4.6 mm in inside diameter Ketoconazole Cream and 10 cm in length, packed with octadecylsilanized silica gel ケトコナゾールクリーム for liquid chromatography (3 µm in particle diameter). Column temperature: A constant temperature of about 25ºC. Ketoconazole Cream contains not less than 95.0% Mobile phase A: Acetonitrile for liquid chromatography. and not more than 105.0% of the labeled amount of Mobile phase B: A solution of tetrabutylammonium hydro- ketoconazole (C26H28Cl2N4O4:531.43) gensulfate (17 in 5000). Flowing of the mobile phase: Control the gradient by mixing Method of preparation Prepare as directed under Ointments, the mobile phases A and B as directed in the following table. with Ketoconazole.

Time after in- Identification To a quantity of Ketoconazole Cream, equiva- Mobile phase A Mobile phase B jection of sample lent to 0.1 g of Ketoconazole according to the labeled amount, (vol%) (vol%) (min) add 20 mL of 2-propanol, shake for 20 minutes, centrifuge, and use the supernatant liquid as the sample solution. Separately, 0 – 10 5 → 50 95 → 50 dissolve 25 mg of ketoconazole in 5 mL of 2-propanol, and use 10 – 15 50 50 this solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography <2.03>. Spot 5 Flow rate: 2.0 mL per minute. µL each of the sample solution and standard solution on a Time span of measurement: Beginning after the solvent peak plate of silica gel with fluorescent indicator for thin-layer chro- to 15 minutes after injection. matography. Develop the plate with a mixture of ethyl acetate, hexane, methanol, water and ammonia solution (28) System suitability— (40:40:25:2:1) to a distance of about 12 cm, and air-dry the plate. Test for required detectability: Pipet 2 mL of the standard so- Examine under ultraviolet light (main wavelength: 254 nm): the lution, and add methanol to make exactly 20 mL. Confirm that principal spot obtained from the sample solution has the same Rf the peak area of ketoconazole obtained from 10 µL of this solu- value as the spot from the standard solution. tion is equivalent to 7 to 13% of that of ketoconazole from the standard solution. Assay Weigh accurately an amount of Ketoconazole Cream, equivalent to about 25 mg of ketoconazole (C System performance: When the procedure is run with 10 µL 26H28Cl2N4O4), of the standard solution under the above operating conditions, dissolve in methanol to make exactly 100 mL. Pipet 10 mL of the number of theoretical plates and the symmetry factor of the this solution, add exactly 4 mL of the internal standard solution, peak of ketoconazole are not less than 40000 and not more than add methanol to make 50 mL, and use this solution as the sam- 1.5, respectively. ple solution. Separately, weigh accurately about 25 mg of keto- System repeatability: When the test is repeated 6 times with conazole for assay, previously dried at 105ºC for 4 hours, and dissolve in methanol to make exactly 50 mL. Pipet 5 mL of this 10 µL of the standard solution under the above operating condi- solution, add exactly 4 mL of the internal standard solution, add tions, the relative standard deviation of the peak area of keto- methanol to make 50 mL, and use this solution as the standard conazole is not more than 2.5%. solution. Perform the test with 10 (3) Residual solvent—Being specified separately. µL each of the sample solution and standard solution as directed under Liquid Chromatography Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 4 <2.01> according to the following conditions, and calculate the hours). ratios, QT and QS, of the peak area of ketoconazole to that of the internal standard. Residue on ignition <2.44> Not more than 0.1% (1 g). Amount (mg) of ketoconazole (C26H28Cl2N4O4) Assay Weigh accurately about 0.2 g of Ketoconazole, previ- = WS × (QT/QS) ously dried, dissolve in 70 mL of a mixture of 2-butanone and acetic acid (100) (7:1), and titrate <2.50> with 0.1 mol/L per- WS: Amount (mg) of ketoconazole for assay chloric acid VS (potentiometric titration). Perform a blank determination in the same manner, and make any necessary cor- Internal standard solution—A solution of xanthone in methanol rection. (1 in 10000) Operating conditions—

2154 Official Monographs Supplement II, JP XV

Detector: An ultraviolet absorption photometer (wavelength: conazole Lotion, equivalent to about 25 mg of ketoconazole

230 nm). (C26H28Cl2N4O4), dissolve in methanol to make exactly 100 mL. Column: A stainless steel column 4.6 mm in inside diameter Pipet 10 mL of this solution, add exactly 4 mL of the internal and 15 cm in length, packed with octadecylsilanized silica gel standard solution, add methanol to make 50 mL, and use this for liquid chromatography (5 µm in particle diameter). solution as the sample solution. Separately, weigh accurately Column temperature: A constant temperature of about 40ºC. about 25 mg of ketoconazole for assay, previously dried at Mobile phase: To ammonium acetate solution (1 in 200) add 105ºC for 4 hours, dissolve in methanol to make exactly 50 mL. acetic acid (100) to adjust the pH to 5.0. To 250 mL of this solu- Pipet 5 mL of this solution, add exactly 4 mL of the internal tion add 750 mL of methanol. standard solution, add methanol to make 50 mL, and use this Flow rate: Adjust the flow rate so that the retention time of solution as the standard solution. Perform the test with 10 µL ketoconazole is about 8 minutes. each of the sample solution and standard solution as directed System suitability— under Liquid Chromatography <2.01> according to the follow-

System performance: When the procedure is run with 10 µL ing conditions, and calculate the ratios, QT and QS, of the peak of the standard solution under the above operating conditions, area of ketoconazole to that of the internal standard. the internal standard and ketoconazole are eluted in this order with the resolution between these peaks being not less than 5. Amount (mg) of ketoconazole (C26H28Cl2N4O4) System repeatability: When the test is repeated 6 times with = WS × (QT/QS) 10 µL of the standard solution under the above operating condi- W : Amount (mg) of ketoconazole for assay tions, the relative standard deviation of the ratio of the peak area S of ketoconazole to that of the internal standard is not more than Internal standard solution—A solution of xanthone in methanol 1.0%. (1 in 10000) Operating conditions— Containers and storage Containers—Tight containers. Detector: An ultraviolet absorption photometer (wavelength: 230 nm). Add the following: Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel Ketoconazole Lotion for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 40ºC. ケトコナゾールローション Mobile phase: To ammonium acetate solution (1 in 200) add acetic acid (100) to adjust the pH to 5.0. To 250 mL of this solu- Ketoconazole Lotion is an emulsion lotion. tion add 750 mL of methanol. It contains not less than 93.0% and not more than Flow rate: Adjust the flow rate so that the retention time of 107.0% of the labeled amount of ketoconazole ketoconazole is about 8 minutes. (C26H28Cl2N4O4:531.43). System suitability— System performance: When the procedure is run with 10 µL Method of preparation Prepare as directed under Lotions, of the standard solution under the above operating conditions, with Ketoconazole. the internal standard and ketoconazole are eluted in this order with the resolution between these peaks being not less than 5. Description Ketoconazole Lotion occurs as a white emulsion. System repeatability: When the test is repeated 6 times with Identification Shake well and take an amount of Ketocona- 10 µL of the standard solution under the above operating condi- zole Lotion, equivalent to 0.1 g of Ketoconazole according to tions, the relative standard deviation of the ratio of the peak area the labeled amount, add 20 mL of 2-propanol, shake for 20 min- of ketoconazole to that of the internal standard is not more than utes, centrifuge, and use the supernatant liquid as the sample 1.0%. solution. Separately, dissolve 25 mg of ketoconazole in 5 mL of Containers and storage Containers—Tight containers. 2-propanol, and use this solution as the standard solution. Per- form the test with these solutions as directed under Thin-layer Chromatography <2.03>. Spot 5 µL each of the sample solution and standard solution on a plate of silica gel with fluorescent indicator for thin-layer chromatography. Develop the plate with a mixture of ethyl acetate, hexane, methanol, water and ammonia solution (28) (40:40:25:2:1) to a distance of about 12 cm, and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 nm): the principal spot obtained from the sample solution has the same Rf value as the spot from the standard solution.

Assay Shake well and weigh accurately an amount of Keto-

Supplement II, JP XV Official Monographs 2155

Add the following: Column: A stainless steel column 4.6 mm in inside diameter and 25 cm in length, packed with octadecylsilanized silica gel Ketoconazole Solution for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 40ºC. ケトコナゾール液 Mobile phase: A mixture of a solution of diisopropylamine in methanol (1 in 500), ammonium acetate solution (1 in 200) and Ketoconazole Solution is a liquid for external use. acetic acid (100) (1800:600:1). Ketoconazole Solution contains not less than 95.0% Flow rate: Adjust the flow rate so that the retention time of and not more than 105.0% of the labeled amount of ketoconazole is about 11 minutes. ketoconazole (C26H28Cl2N4O4:531.43). System suitability— System performance: When the procedure is run with 20 µL Method of preparation Prepare as directed under Solutions of the standard solution under the above operating conditions, with Ketoconazole. ketoconazole and the internal standard are eluted in this order Description Ketoconazole Solution is a clear liquid. with the resolution between these peaks being not less than 3. System repeatability: When the test is repeated 6 times with Identification To a volume of Ketoconazole Solution, 20 µL of the standard solution under the above operating condi- equivalent to 10 mg of Ketoconazole according to the labeled tions, the relative standard deviation of the ratio of the peak area amount, add methanol to make 10 mL, and use this solution as of ketoconazole to that of the internal standard is not more than the sample solution. Separately, dissolve 10 mg of ketoconazole 1.0%. in 10 mL of methanol, and use this solution as the standard solution. Perform the test with these solutions as directed under Containers and storage Containers—Tight containers. Thin-layer Chromatography <2.03>. Spot 5 µL each of the sample solution and standard solution on a plate of silica gel with fluorescent indicator for thin-layer chromatography. Develop the Anhydrous Lactose plate with a mixture of ethyl acetate, hexane, methanol, water and ammonia solution (28) (40:40:30:2:1) to a distance of about 無水乳糖 10 cm, and air-dry the plate. Examine under ultraviolet light Change the Purity (2) and Isomer ratio to read: (main wavelength: 254 nm): the principal spot obtained from the sample solution has the same Rf value as the spot from the Purity (2) Acidity or alkalinity—Dissolve 6 g of Anhydrous standard solution. Lactose by heating in 25 mL of freshly boiled and cooled water, and after cooling, add 0.3 mL of phenolphthalein TS: the solu- pH Being specified separately. tion is colorless, and not more than 0.4 mL of 0.1 mol/L sodium Assay Weigh accurately an amount of Ketoconazole Solution, hydroxide VS is required to produce a pale red color or red color. equivalent to about 10 mg of ketoconazole (C26H28Cl2N4O4), add exactly 5 mL of the internal standard solution, and add 15 Isomer ratio Place 1 mg of Anhydrous Lactose in a 5-mL mL of methanol. To 1 mL of this solution add methanol to make screw capped reaction vial for gas chromatography, add 0.45 25 mL, and use this solution as the sample solution. Separately, mL of dimethylsulfoxide, stopper, and shake well. Add 1.8 mL weigh accurately about 50 mg of ketoconazole for assay, previ- of a mixture of pyridine and trimethylsilylimidazole (18:7), seal ously dried at 105ºC for 4 hours, and dissolve in methanol to the vial tightly with a screw cap, and mix gently. Allow to stand make exactly 50 mL. Pipet 10 mL of this solution, add exactly 5 for 20 minutes, and use this solution as the sample solution. mL of the internal standard solution, add methanol to make 20 Perform the test with 2 µL of the sample solution as directed mL. Take 1 mL of this solution, add methanol to make 25 mL, under Gas Chromatography <2.02> according to the following and use this solution as the standard solution. Perform the test conditions. Determine the peak areas of α-lactose derivateive with 20 µL each of the sample solution and standard solution as and β-lactose derivateive, A and A , and calculate the contents directed under Liquid Chromatography <2.01> according to the a b (%) of α-lactose derivateive and β-lactose derivateive in Anhy- following conditions, and calculate the ratios, Q and Q , of the T S drous Lactose by the following equations. peak area of ketoconazole to that of the internal standard.

Content (%) of α-lactose = [Aa / (Aa + Ab)] × 100 Amount (mg) of ketoconazole (C26H28Cl2N4O4) Content (%) of β-lactose = [Ab / (Aa + Ab)] × 100 = WS × (QT/QS) × (1/5) Operating conditions— W : Amount (mg) of ketoconazole for assay S Detector: A hydrogen flame-ionization detector. Internal standard solution—A solution of bifonazole in metha- Injection port temperature: A constant temperature of about 275ºC nol (3 in 2000) Detector temperature: A constant temperature of about 275ºC. Operating conditions— Column: A glass column 4 mm in inside diameter and 90 cm Detector: An ultraviolet absorption photometer (wavelength: in length, packed with siliceous earth for gas chromatography 240 nm). coated at the ratio of 3% with 25% phenyl-25% cyanopro-

2156 Official Monographs Supplement II, JP XV pyl-methylsilicone polymer for gas chromatography. Melting point: about 226ºC (with decomposition). Column temperature: A constant temperature of about 215ºC. Carrier gas: Helium Identification (1) Determine the absorption spectrum of a Flow rate: A constant flow rate of about 40 mL per minute. solution of Levofloxacin Hydrate in 0.1 mol/L hydrochloric acid System suitability— solution (1 in 150000) as directed under Ultraviolet-visible System performance: Prepare a solution with 1 mg of a mix- Spectrophotometry <2.24>, and compare the spectrum with the ture of α-lactose and β-lactose (1:1) in the same manner as for Reference Spectrum: both spectra exhibit similar intensities of preparing the sample solution, and proceed with 2 µL of this so- absorption at the same wavelengths. lution under the above operating conditions, and determine the (2) Determine the infrared absorption spectrum of retention times of the peaks of α-lactose derivative and β-lactose Levofloxacin Hydrate as directed in the potassium bromide disk derivative: the relative retention time of α-lactose derivative method under Infrared Spectrophotometry <2.25>, and compare with respect to that of β-lactose derivative is about 0.7 with the the spectrum with the Reference Spectrum: both spectra exhibit resolution between these peaks being not less than 3.0. similar intensities of absorption at the same wave numbers.

20 Optical rotation <2.49> [α] D : –92 - –99º (0.1 g calculated Lactose Hydrate on the anhydrous basis, methanol, 10 mL, 100 mm). Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of 乳糖水和物 Levofloxacin Hydrate according to Method 4, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Change the Purity (2) to read: Solution (not more than 10 ppm). Purity (2) Acidity or alkalinity—Dissolve 6 g of Lactose (2) Related substances—Conduct this procedure using Hydrate by heating in 25 mL of freshly boiled and cooled water, light-resistant vessels. Dissolve 50 mg of Levofloxacin Hydrate and after cooling, add 0.3 mL of phenolphthalein TS: the solu- in 10 mL of a mixture of water and methanol (1:1), and use this tion is colorless, and not more than 0.4 mL of 0.1 mol/L sodium solution as the sample solution. Pipet 1 mL of this solution, and hydroxide VS is required to produce a pale red color or red add a mixture of water and methanol (1:1) to make exactly 10 color. mL. Pipet 1 mL of this solution, add a mixture of water and methanol (1:1) to make exactly 10 mL, and use this solution as the standard solution. Perform the test with exactly 10 µL each Add the following: of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following con- Levofloxacin Hydrate ditions. Determine each peak area of both solutions by the automatic integration method: the area of the peak having the レボフロキサシン水和物 relative retention time of about 1.2 with respect to levofloxacin obtained from the sample solution is not larger than 2/5 times the peak area of levofloxacin from the standard solution, and the area of each peak other than the peak of levofloxacin and other than the peak having the relative retention time of about 1.2 with respect to levofloxacin from the sample solution is not larger than 1/5 times the peak area of levofloxacin from the stan-

dard solution. Furthermore, the total area of the peaks other than the peak of levofloxacin and other than the peak having the rela- C H FN O ·½H O: 370.38 18 20 3 4 2 tive retention time of about 1.2 with respect to levofloxacin (3S)-9-Fluoro-3-methyl-10-(4-methylpiperazin-1-yl)- from the sample solution is not larger than 3/10 times the peak 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine- area of levofloxacin from the standard solution. 6-carboxylic acid hemihydrate [138199-71-0] Operating conditions— Levofloxacin Hydrate contains not less than 99.0% Detector: An ultraviolet absorption photometer (wavelength: and not more than 101.0% of levofloxacin 340 nm). Column: A stainless steel column 4.6 mm in inside diameter (C18H20FN3O4: 361.37), caluculated on the anhydrous basis. and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Description Levofloxacin Hydrate occurs as light yellowish Column temperature: A constant temperature of about 45ºC. white to yellowish white crystals or crystalline powder. Mobile phase: Dissolve 1.76 g of L-valine, 7.71 g of ammo- It is freely soluble in acetic acid (100), sparingly soluble in nium acetate and 1.25 g of Copper (II) sulfate pentahydrate in water and in methanol, and slightly soluble in ethanol (99.5). water to make 1000 mL. To this solution add 250 mL of metha- It dissolves in 0.1 mol/L hydrochloric acid TS. nol. It gradually turns dark light yellowish white on exposure to Flow rate: Adjust the flow rate so that the retention time of light. levofloxacin is about 22 minutes.

Supplement II, JP XV Official Monographs 2157

Time span of measurement: About 2 times as long as the re- Add the following: tention time of levofloxacin, beginning after the solvent peak. System suitability— Lincomycin Hydrochloride Test for required detectability: Pipet 1 mL of the standard solution, and add a mixture of water and methanol (1:1) to make Injection exactly 20 mL. Confirm that the peak area of levofloxacin ob- リンコマイシン塩酸塩注射液 tained from 10 µL of this solution is equivalent to 4 to 6% of that of levofloxacin from the standard solution. Lincomycin Hydrochloride Injection is an aqueous System performance: Dissolve 10 mg of ofloxacin in 20 mL injection. of a mixture of water and methanol (1:1). To 1 mL of this solu- It contains not less than 93.0% and not more than tion add a mixture of water and methanol (1:1) to make 10 mL. 107.0% of the labeled potency of lincomycin When the procedure is run with 10 µL of th is solution under the (C18H34N2O6S: 406.54). above operating conditions, the resolution between the peak of levofloxacin and the peak having the relative retention time of Method of preparation Prepare as directed under Injections, about 1.2 with respect to levofloxacin is not less than 3. with Lincomycin Hydrochloride Hydrate. System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- Description: Lincomycin Hydrochloride Injection is a clear, tions, the relative standard deviation of the peak area of colorless liquid. levofloxacin is not more than 3.0%. Identification To a volume of Lincomycin Hydrochloride In- (3) Residual solvent—Being specified separately. jection, equivalent to 30 mg (potency) of Lincomycin Hydro- Water <2.48> 2.1 - 2.7% (0.5 g, volumetric titration, direct ti- chloride Hydrate, add 30 mL of water, and use this solution as tration). the sample solution. Separately, dissolve 10 mg (potency) of Lincomycin Hydrochloride Reference Standard in 10 mL of Residue on ignition <2.44> Not more than 0.1% (1 g). water, and use this solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chroma- Assay Weigh accurately about 0.3 g of Levofloxacin Hydrate, tography <2.03>. Spot 5 µL each of the sample solution and dissolve in 100 mL of acetic acid (100), and titrate <2.50> with standard solution on a plate of silica gel for thin-layer chroma- 0.1 mol/L perchloric acid VS (potentiometric titration). Perform tography. Dissolve 150 g of ammonium acetate in 800 mL of a blank determination in the same manner, and make any neces- water, adjust the pH to 9.6 with ammonia solution (28), and add sary correction. water to make 1000 mL. To 80 mL of this solution add 40 mL of 2-propanol and 90 mL of ethyl acetate, shake, develop the plate Each mL of 0.1 mol/L perchloric acid VS with the upper layer of this solution to a distance of about 15 cm, = 36.14 mg of C H FN O 18 20 3 4 and air-dry the plate. Spray evenly a solution of potassium per- Containers and storage Containers—Tight containers. manganate (1 in 1000) on the plate: the principal spots from the Storage—Light-resistant. sample solution and the standard solution show the same Rf value.

Lidocaine Injection pH <2.54> 3.5 - 5.5 リドカイン注射液 Bacterial endotoxins <4.01> Less than 0.50 EU/mg (potency). Delete the Pyrogen and add the following next to the Identification: Extractable volume <6.05> It meets the requirement.

Bacterial endotoxins <4.01> Less than 1.0 EU/mg. Foreign insoluble matter <6.06> Perform the test according to Method 1: it meets the requirement. Add the following next to the Extractable volume: Insoluble particulate matter <6.07> It meets the require- Foreign insoluble matter <6.06> Perform the test according ment. to Method 1: it meets the requirement. Sterility <4.06> Perform the test according to the Membrane Insoluble particulate matter <6.07> It meets the require- filtration method: it meets the requirement. ment. Assay Pipet a volume of Lincomycin Hydrochloride Injection, Sterility <4.06> Perform the test according to the Membrane equivalent to about 0.3 g (potency) of Lincomycin Hydrochlo- filtration method: it meets the requirement. ride Hydrate, add the mobile phase to make exactly 30 mL. Pi- pet 2 mL of this solution, add the mobile phase to make exactly 20 mL, and use this solution as the sample solution. Separately, weigh accurately an amount of Lincomycin Hydrochloride Ref-

2158 Official Monographs Supplement II, JP XV erence Standard, equivalent to 20 mg (potency), dissolve in the (4) Perform the test with Losartan Potassium as directed un- mobile phase to make exactly 20 mL, and use this solution as der Flame Coloration Test <1.04> (2): a green color appears. the standard solution. Then, proceed as directed in the Assay under Lincomycin Hydrochloride Hydrate. Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of Losartan Potassium according to Method 2, and perform the test.

Amount [mg (potency)] of lincomycin (C18H34N2O6S) Prepare the control solution with 2.0 mL of Standard Lead Solu- = WS × (AT/AS) × 15 tion (not more than 10 ppm). (2) Related substances—Dissolve 30 mg of Losartan Potas- WS: Amount [mg (potency)] of Lincomycin Hydrochloride sium in 100 mL of methanol, and use this solution as the sample Reference Standard solution. Pipet 1 mL of this solution, add methanol to make exactly 100 mL, and use this solution as the standard solution. Containers and storage Containers—Hermetic containers. Perform the test with exactly 10 µL each of the sample solution and standard solution as directed under Liquid Chromatography Add the following: <2.01> according to the following conditions. Determine each peak area of both solutions by the automatic integration method: Losartan Potassium the area of each peak other than the peaks of solvent and losartan obtained from the sample solution is not larger than 1/10 ロサルタンカリウム times the peak area of losartan from the standard solution, and the total area of the peaks other than the peak of losartan from the sample solution is not larger than 3/10 times the peak area of losartan from the standard solution. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: 220 nm). Column: A stainless steel column 4 mm in inside diameter and 25 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 25ºC. Mobile phase A: Diluted phosphoric acid (1 in 1000). C22H22ClKN6O: 461.00 Mobile phase B: Acetonitrile. Monopotassium 5-{[4´-(2-butyl-4-chloro-5-hydroxymethyl- Flowing of the mobile phase: Control the gradient by mixing 1H-imidazol-1-yl)methyl]biphenyl-2-yl}-1H-tetrazol-1-ide the mobile phases A and B as directed in the following table. [124750-99-8] Time after in- Mobile phase A Mobile phase B Losartan Potassium contains not less than 98.5% jection of sample (vol%) (vol%) and not more than 101.0% of C22H22ClKN6O, calcu- (min) lated on the anhydrous basis. 0 – 25 75 → 10 25 → 90 25 – 35 10 90 Description Losartan Potassium occurs as a white crystalline powder. Flow rate: 1.0 mL per minute. It is very soluble in water, and freely soluble in methanol and Time span of measurement: 35 minutes after injection of the in ethanol (99.5). sample.

Identification (1) Determine the absorption spectrum of a System suitability— solution of Losartan Potassium in methanol (1 in 100000) as di- Test for required detectability: Pipet 1 mL of the standard so- rected under Ultraviolet-visible Spectrophotometry < 2.24>, and lution, and add methanol to make exactly 10 mL. Confirm that compare the spectrum with the Reference Spectrum or the spec- the peak area of losartan obtained from 10 µL of this solution is trum of a solution of Losartan Potassium Reference Standard equivalent to 7 to 13% of that of losartan from the standard so- prepared in the same manner as the sample solution: both spec- lution. tra exhibit similar intensities of absorption at the same wave- System performance: When the procedure is run with 10 µL lengths. of the standard solution under the above operating conditions, (2) Determine the infrared absorption spectrum of Losartan the number of theoretical plates and the symmetry factor of the Potassium as directed in the potassium bromide disk method peak of losartan are not less than 10000 and not more than 1.3, under Infrared Spectrophotometry < 2.25>, and compare the respectively. spectrum with the Reference Spectrum or the spectrum of System repeatability: When the test is repeated 6 times with Losartan Potassium Reference Standard: both spectra exhibit 10 µL of the standard solution under the above operating condi- similar intensities of absorption at the same wave numbers. tions, the relative standard deviation of the peak area of losartan (3) Losartan Potassium responds to the Qualitative Tests is not more than 2.0%. <1.09> (1) for potassium salt.

Supplement II, JP XV Official Monographs 2159

(3) Residual solvent—Being specified separately. Add the following:

Water <2.48> Not more than 0.5% (0.25 g, volumetric titra- L-Lysine Acetate tion, direct titration) L‐リジン酢酸塩 Assay Weigh accurately about 25 mg each of Losartan Potas- sium and Losartan Potassium Reference Standard (separately, determine the water content <2.48> in the same manner as Losartan Potassium), dissolve separately in methanol to make exactly 100 mL, and use these solutions as the sample solution and standard solution, respectively. Perform the test with exactly C6H14N2O2·C2H4O2: 206.24 10 µL each of the sample solution and standard solution as di- (2S)-2,6-Diaminohexanoic acid monoacetate rected under Liquid Chromatography <2.01> according to the [57282-49-2] following conditions, and calculate the peak areas, AT and AS, of losartan in each solution. L-Lysine Acetate, when dried, contains not less than 98.5% and not more than 101.0% of

Amount (mg) of losartan potassium (C22H22ClKN6O) C6H14N2O2·C2H4O2. = WS × (AT/AS) Description L-Lysine Acetate occurs as white crystals or

WS: Amount (mg) of Losartan Potassium Reference Standard, crystalline powder. It has a characteristic odor and a slightly calculated on the anhydrous basis. acid taste. It is very soluble in water, freely soluble in formic acid, and Operating conditions— practically insoluble in ethanol (99.5). Detector: An ultraviolet absorption photometer (wavelength: It is deliquescent. 254 nm). Column: A stainless steel column 4 mm in inside diameter Identification (1) Determine the infrared absorption spec- and 25 cm in length, packed with octadecylsilanized silica gel trum of L-Lysine Acetate as directed in the potassium bromide for liquid chromatography (5 µm in particle diameter). disk method under Infrared Spectrophotometry <2.25>, and Column temperature: A constant temperature of about 35ºC. compare the spectrum with the Reference Spectrum: both spec- Mobile phase: A mixture of diluted phosphoric acid (1 in tra exhibit similar intensities of absorption at the same wave 1000) and acetonitrile (3:2) numbers. Flow rate: Adjust the flow rate so that the retention time of (2) A solution of L-Lysine Acetate (1 in 20) responds to the losartan is about 6 minutes. Qualitative Tests <1.09> (2) for acetate. System suitability— 20 System performance: When the procedure is run with 10 µL Optical rotation <2.49> [α] D : +8.5 - +10.0º (after drying, of the standard solution under the above operating conditions, 2.5 g, water, 25 mL, 100 mm). the number of theoretical plates and the symmetry factor of the pH <2.54> Dissolve 1.0 g of L-Lysine Acetate in 10 mL of peak of losartan are not less than 5500 and not more than 1.4, water: the pH of the solution is between 6.5 and 7.5. respectively. System repeatability: When the test is repeated 6 times with Purity (1) Clarity and color of solution—Dissolve 1.0 g of 10 µL of the standard solution under the above operating condi- L-Lysine Acetate in 10 mL of water: the solution is colorless and tions, the relative standard deviation of the peak area of losartan clear. is not more than 1.0%. (2) Chloride <1.03>—Perform the test with 0.5 g of L-Lysine Acetate. Prepare the control solution with 0.30 mL of Containers and storage Containers—Tight containers. 0.01 mol/L hydrochloric acid VS (not more than 0.021%).

(3) Sulfate <1.14>—Perform the test with 0.6 g of L-Lysine Acetate. Prepare the control solution with 0.35 mL of 0.005 mol/L sulfuric acid VS (not more than 0.028%). (4) Ammonium <1.02>—Perform the test with 0.25 g of L-Lysine Acetate. Prepare the control solution with 5.0 mL of Standard Ammonium Solution (not more than 0.02%). (5) Heavy metals <1.07>—Proceed with 1.0 g of L-Lysine Acetate according to Method 4, and perform the test. Prepare the control solution with 1.0 mL of Standard Lead Solution (not more than 10 ppm). (6) Iron <1.10>—Prepare the test solution with 1.0 g of L-Lysine Acetate according to Method 1, and perform the test according to Method A. Prepare the control solution with 1.0

2160 Official Monographs Supplement II, JP XV mL of Standard Iron Solution (not more than 10 ppm). tions. Based on the peak heights of the amino acids obtained (7) Related substances—Weigh accurately about 0.5 g of from the sample solution and standard solution, determine the L-Lysine Acetate, dissolve in 0.5 mL of hydrochloric acid and mass of the amino acids other than lysine contained in 1 mL of water to make exactly 100 mL. Pipet 5 mL of this solution, add the sample solution, and calculate the mass per cent: the amount 0.02 mol/L hydrochloric acid to make exactly 50 mL, and use of each amino acids other than lysine is not more than 0.1%. this solution as the sample solution. Separately, weigh accu- Operating conditions— rately 2.5 mmol amounts of L-aspartic acid, L-threonine, Detector: A visible spectrophotometer (wavelength: 570 nm) L-serine, L-glutamic acid, glycine, L-alanine, L-valine, L-cystine, Column: A stainless steel column 4.6 mm in inside diameter L-methionine, L-isoleucine, L-leucine, L-tyrosine, and 8 cm in length, packed with strongly acidic ion-exchange L-phenylalanine, L-lysine hydrochloride, ammonium chloride, resin for liquid chromatography (sodium type) composed with a L-histidine hydrochloride monohydrate and L-arginine, dissolve sulfonated polystyrene copolymer (3 µm in particle diameter). in 0.1 mol/L hydrochloric acid TS to make exactly 1000 mL, Column temperature: A constant temperature of about 57ºC. and use this solution as the standard stock solution. Pipet 5 mL Chemical reaction bath temperature: A constant temperature of this solution, add 0.02 mol/L hydrochloric acid to make ex- of about 130ºC. actly 100 mL, Pipet 2 mL of this solution, add 0.02 mol/L hy- Color developing time: About 1 minute. drochloric acid to make exactly 50 mL, and use this solution as Mobile phase: Prepare mobile phases A, B, C, D and E ac- the standard solution. Perform the test with exactly 20 µL each cording to the following table, and to each phase add 0.1 mL of of the test solution and standard solution as directed under Liq- capric acid. uid Chromatography <2.01> according to the following condi-

Mobile phase A Mobile phase B Mobile phase C Mobile phase D Mobile phase E

Total volume 2000 mL 1000 mL 1000 mL 1000 mL 1000 mL Changing mobile phases: Proceed with 20 µL of the standard of the standard solution under the above operating conditions, solution under the above operating conditions: aspartic acid, the resolution between the peaks of glycine and alanine is not threonine, serine, glutamic acid, glycine, alanine, valine, cystine, less than 1.5. methionine, isoleucine, leucine, tyrosine, phenylalanine, lysine, System repeatability: When the test is repeated 6 times with ammonia, histidine and arginine are eluted in this order. 20 µL of the standard solution under the above operating condi- Switchover the mobile phases A, B, C, D and E in sequence so tions, the relative standard deviation of the peak height of each that the resolution between the peaks of isoleucine and leucine amino acid in the standard solution is not more than 5.0%, and is not less than 1.2. the relative standard deviation of the retention time is not more Reaction reagents: Dissolve 407 g of lithium acetate di- than 1.0%. hydrate in water, and add 245 mL of acetic acid (100), 801 mL of 1-methoxy-2-propanol, and water to make 2000 mL, gas with Loss on drying <2.41> Not more than 0.3% (1 g, 80ºC, 3 nitrogen for 10 minutes, and use this solution as the solution (I). hours). Separately, to 1957 mL of 1-methoxy-2-propanol add 77 g of Residue on ignition <2.44> Not more than 0.1% (1 g). ninhydrin, gas with nitrogen for 5 minutes, add 0.134 g of sodium borohydride, and gas the solution with nitrogen for 30 Assay Weigh accurately about 0.1 g of L-Lysine Acetate, pre- minutes. To this solution add the solution (I) (12:13). viously dried, dissolve in 3 mL of formic acid, add 50 mL of Mobile phase flow rate: 0.32 mL per minute. acetic acid (100), and titrate <2.50> with 0.1 mol/L perchloric Reaction reagent flow rate: 0.30 mL per minute. acid VS (potentiometric titration). Perform a blank determina- System suitability— tion in the same manner, and make any necessary correction. System performance: When the procedure is run with 20 µL

Supplement II, JP XV Official Monographs 2161 Each mL of 0.1 mol/L perchloric acid VS Mepivacaine Hydrochloride = 10.31 mg of C H N O ·C H O 6 14 2 2 2 4 2 Injection Containers and storage Containers—Tight containers. メピバカイン塩酸塩注射液

Meglumine Iotalamate Injection Change the Origin/limits of content, Description and Identification to read: イオタラム酸メグルミン注射液 Mepivacaine Hydrochloride Injection is an aqueous Delete the Bacterial endotoxins and add the fol- solution for injection. lowing next to the Extractable volume: It contains not less than 95.0% and not more than 105.0% of the labeled amount of mepivacaine hydro- Foreign insoluble matter <6.06> Perform the test according chloride (C15H22N2O·HCl: 282.81). to Method 1: it meets the requirement. Description Mepivacaine Hydrochloride Injection is a clear, Insoluble particulate matter <6.07> It meets the require- colorless liquid. ment. Identification To a volume of Mepivacaine Hydrochloride Sterility <4.06> Perform the test according to the Membrane Injection, equivalent to 20 mg of Mepivacaine Hydrochloride filtration method: it meets the requirement. according to the labeled amount, add 1 mL of sodium hydroxide TS, and extract with 20 mL of hexane. To 8 mL of the hexane extract add 20 mL of 1 mol/L hydrochloric acid TS, shake vig- Meglumine Sodium Amidotorizoate orously, and determine the absorption spectrum of the water layer separated as directed under Ultraviolet-visible Spectrome- Injection try <2.24>: it exhibits maxima between 261 nm and 265 nm, アミドトリゾ酸ナトリウムメグルミン注射液 and between 270 nm and 273 nm. Add the following next to the Identification Delete the Pyrogen and change the Method of preparation to read: pH Being specified separately.

Method of preparation Bacterial endotoxins <4.01> Less than 0.6 EU/mg. (1) Amidotorizoic Acid (anhydrous) 471.78 g Add the following next to the Extractable volume: Sodium Hydroxide 5.03 g Meglumine 125.46 g Foreign insoluble matter <6.06> Perform the test according Water for Injection a sufficient quantity to Method 1: it meets the requirement. To make 1000 mL Insoluble particulate matter <6.07> It meets the require- (2) ment. Amidotorizoic Acid (anhydrous) 597.30 g Sodium Hydroxide 6.29 g Sterility <4.06> Perform the test according to the Membrane Meglumine 159.24 g filtration method: it meets the requirement. Water for Injection a sufficient quantity To make 1000 mL Change the Assay to read:

Prepare as directed under Injections, with the above ingredi- Assay Pipet a volume of Mepivacaine Hydrochloride Injection, ents (1) or (2). equivalent to about 40 mg of Mepivacaine Hydrochloride

(C15H22N2O·HCl) according to the labeled amount, add exactly Add the following next to the Extractable volume: 4 mL of the internal standard solution and 0.001 mol/L hydrochloric acid TS to make 20 mL, and use this solution as the Foreign insoluble matter <6.06> Perform the test according sample solution. Separately, weigh accurately about 40 mg of to Method 1: it meets the requirement. mepivacaine hydrochloride for assay, previously dried at 105ºC Insoluble particulate matter <6.07> It meets the require- for 3 hours, dissolve in 0.001 mol/L hydrochloric acid TS, add ment. exactly 4 mL of the internal standard solution and 0.001 mol/L hydrochloride TS to make 20 mL, and use this solution as the Sterility <4.06> Perform the test according to the Membrane standard solution. Perform the test with 5 µL each of the sample filtration method: it meets the requirement. solution and standard solution as directed under Liquid Chro- matography <2.01> according to the following conditions, and

calculate the ratios, QT and QS, of the peak area of mepivacaine

2162 Official Monographs Supplement II, JP XV to that of the internal standard. to the labeled amount, in 5 mL of water: the pH of the solution is between 7.3 and 8.3. Amount (mg) of mepivacaine hydrochloride

(C15H22N2O·HCl) Purity (1) Clarity and color of solution—Dissolve an = WS × (QT/QS) amount of Meropenem for Injection, equivalent to 1.0 g (potency) of Meropenem Hydrate according to the labeled amount, WS: Amount (mg) of mepivacaine hydrochloride for assay in 20 mL of water: the solution is clear and is not more intensely colored than the following matching fluid. Internal standard solution—A solution of benzophenone in Matching fluid: To a mixture of 0.3 mL of Cobalt (II) Chlo- methanol (1 in 4000). ride Colorimetric Stock Solution and 1.2 mL of Iron (III) Chlo- Operating conditions— ride Colorimetric Stock Solution add 18.5 mL of diluted hydro- Detector: An ultraviolet absorption photometer (wavelength: chloric acid (1 in 40). 254 nm). (2) Related substances—Being specified separately. Column: A stainless steel column 4 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel Loss on drying <2.41> 9.5 - 12.0% (0.1 g, reduced pressure for liquid chromatography (10 µm in particle diameter). not exceeding 0.67 kPa, 60ºC, 3 hours). Column temperature: A constant temperature of about 25ºC. Mobile phase: Dissolve 2.88 g of sodium lauryl sulfate in Bacterial endotoxins <4.01> Less than 0.12 EU/mg (po- 1000 mL of a mixture of 0.02 mol/L phosphate buffer solution, tency). pH 3.0, and acetonitrile (11:9). Flow rate: Adjust the flow rate so that the retention time of Uniformity of dosage units <6.02> It meets the requirement mepivacaine is about 6 minutes. of the Mass variation test. System suitability— Foreign insoluble matter <6.06> Perform the test according System performance: When the procedure is run with 5 µL of to Method 2: it meets the requirement. the standard solution under the above operating conditions, mepivacaine and the internal standard are eluted in this order with Insoluble particulate matter <6.07> It meets the require- the resolution between these peaks being not less than 6. ment. System repeatability: When the test is repeated 6 times with 5 µL of the standard solution under the above operating conditions, Sterility <4.06> Perform the test according to the Membrane the relative standard deviation of the ratio of the peak area of filtration method: it meets the requirement. mepivacaine to that of the internal standard is not more than 1.0%. Assay Weigh accurately the mass on the contents of not less than 10 containers of Meropenem for Injection. Weigh accurately an amount of the contents, equivalent to about 50 mg Add the following: (potency) of Meropenem Hydrate, dissolve in exactly 10 mL of the internal standard solution, add triethylamine-phosphate Meropenem for Injection buffer solution, pH 5.0, to make 100 mL, and use this solution as the sample solution. Separately, weigh accurately an amount 注射用メロペネム of Meropenem Reference Standard, equivalent to about 50 mg (potency), dissolve in exactly 10 mL of the internal standard so- Meropenem for Injection is a preparation for injec- lution, add triethylamine-phosphate buffer solution, pH 5.0, to tion, which is dissolved before use. make 100 mL, and use this solution as the standard solution. It contains not less than 93.0% and not more than Perform the test with 5 µL each of the sample solution and 107.0% of the labeled potency of meropenem standard solution as directed under Liquid Chromatography (C17H25N3O5S: 383.46). <2.01> according to the following conditions, and calculate the ratios, Q and Q , of the peak area of meropenem to that of the Method of preparation Prepare as directed under Injections, T S internal standard. with Meropenem Hydrate. Amount [mg (potency)] of meropenem (C H N O S) Description Meropenem for Injection occurs as a white to 17 25 3 5 = W × (Q /Q ) light yellow crystalline powder. S T S W : Amount [mg (potency)] of Meropenem Reference Stan- Identification Determine the infrared absorption spectrum of S dard Meropenem for Injection as directed in the potassium bromide disk method under Infrared Spectrophotometry <2.25>: it ex- Internal standard solution—A solution of benzyl alcohol in -1 hibits absorption at the wave numbers of about 3410 cm , 1750 triethylamine-phosphate buffer solution, pH 5.0 (1 in 300) -1 -1 -1 -1 cm , 1655 cm , 1583 cm and 1391 cm . Operating conditions— Proceed as directed in the operating conditions in the Assay pH <2.54> Dissolve an amount of Meropenem for Injection, under Meropenem Hydrate. equivalent to 0.25 g (potency) of Meropenem Hydrate according

Supplement II, JP XV Official Monographs 2163

System suitability— nium hydroxide TS. System performance: Proceed as directed in the system suit- System suitability— ability in the Assay under Meropenem Hydrate. System performance: Dissolve 50 mg of minocycline hydro- System repeatability: When the test is repeated 6 times with 5 chloride in water to make 25 mL. Heat 5 mL of this solution on µL of the standard solution under the above operating conditions, a water bath for 60 minutes, and add water to make 25 mL. the relative standard deviation of the ratio of the peak area of When the procedure is run with 20 µL of this solution under the meropenem to that of the internal standard is not more than above operating conditions, epiminocycline and minocycline are 1.0%. eluted in this order with the resolution between these peaks being not less than 2.0. Containers and storage Containers—Hermetic containers. System repeatability: When the test is repeated 6 times with Plastic containers for aqueous injections may be used. 20 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of mino-

cycline is not more than 1.0%. Methylcellulose

メチルセルロース Add the following: Change the Chemical name to read: Minocycline Hydrochloride Tablets

[9004-67-5] ミノサイクリン塩酸塩錠

Minocycline Hydrochloride Tablets contain not less Minocycline Hydrochloride than 90.0% and not more than 110.0% of the labeled for Injection potency of Minocycline (C23H27N3O7: 457.48).

注射用ミノサイクリン塩酸塩 Method of preparation Prepare as directed under Tablets, with Minocycline Hydrochloride. Change the Assay to read: Identification To a quantity of powdered Minocycline Hy- Assay Weigh accurately the mass of the contents of not less drochloride Tablets, equivalent to 10 mg (potency) of Mino- than 10 containers of Minocycline Hydrochloride for Injection. cycline Hydrochloride according to the labeled amount, add 625 Weigh accurately an amount of the contents, equivalent to about mL of a solution of hydrochloric acid in methanol (19 in 20000), 0.1 g (potency) of Minocycline Hydrochloride, dissolve in the shake well, and filter. Determine the absorption spectrum of the mobile phase to make exactly 100 mL. Pipet 25 mL of this solu- filtrate as directed under Ultraviolet-visible Spectrophotometry tion, add the mobile phase to make exactly 50 mL, and use this <2.24>: it exhibits maxima between 221 nm and 225 nm, be- solution as the sample solution. Separately, weigh accurately an tween 261 nm and 265 nm, and between 354 nm and 358 nm. amount of Minocycline Hydrochloride Reference Standard, Purity Related substances—Conduct this procedure rapidly equivalent to about 25 mg (potency), dissolve in the mobile after preparation of the sample solution. Powder not less than 5 phase to make exactly 50 mL, and use this solution as the stan- Minocycline Hydrochloride Tablets. Weigh accurately a portion dard solution. Perform the test with exactly 20 µL each of the of the powder, equivalent to 50 mg (potency) of Minocycline sample solution and standard solution as directed under Liquid Hydrochloride according to the labeled amount, add 60 mL of Chromatography <2.01> according to the following conditions, the mobile phase, shake vigorously, and add the mobile phase to and determine the peak area of minocycline, A and A , of each T S make 100 mL. Centrifuge this solution, and use the supernatant solution. liquid as the sample solution. Perform the test with 20 µL of the sample solution as directed under Liquid Chromatography Amount [mg (potency)] of minocycline (C23H27N3O7) <2.01> according to the following conditions. Determine each = WS × (AT/AS) × 4 peak area from both solutions by the automatic integration

WS: Amount [mg (potency)] of Minocycline Hydrochloride method. Calculate the amounts of these peaks by the area per- Reference Standard centage method: the amount of the peak of epiminocycline, having the relative retention time of 0.83 with respect to mino- Operating conditions— cycline, is not more than 2.0%. Detector, column, column temperature, and flow rate: Pro- ceed as directed in the operating conditions in the Assay under Operating conditions— Minocycline Hydrochloride. Detector, column, column temperature, mobile phase and Mobile phase: Adjust the pH to 6.5 of a mixture of ammo- flow rate: Proceed as directed in the operating conditions in the nium oxalate monohydrate solution (7 in 250), Assay. N,N-dimethylformamide and 0.1 mol/L disodium dihydrogen Time span of measurement: About 2.5 times as long as the ethylenediamine tetraacetate TS (11:5:4) with tetrabutylammo- retention time of minocycline, beginning after the solvent peak.

2164 Official Monographs Supplement II, JP XV

System suitability— minocycline (C23H27N3O7) System performance: Proceed as directed in the system suit- = WS × (AT/AS) × (V´/V) × (1/C) × 36 ability in the Assay. Test for required detectability: To 2 mL of the sample solution WS: Amount [mg (potency)] of Minocycline Hydrochloride add the mobile phase to make 100 mL, and use this solution as Reference Standard the solution for system suitability test. Pipet 5 mL of the solu- C: Labeled amount [mg (potency)] of minocycline tion for system suitability test, and add the mobile phase to (C23H27N3O7) in 1 tablet make exactly 100 mL. Confirm that the peak area of mino- Assay To a number of Minocycline Hydrochloride Tablets, cycline obtained from 20 µL of this solution is equivalent to 3.5 equivalent to about 1 g (potency) of Minocycline Hydrochloride, to 6.5% of that of minocycline from 20 µL of the solution for add 120 mL of the mobile phase, treat with ultrasonic waves for system suitability test. 15 minutes, and add the mobile phase to make exactly 200 mL. System repeatability: When the test is repeated 6 times with Centrifuge this solution, pipet 5 mL of the supernatant liquid, 20µL of the solution for system suitability test under the above add the mobile phase to make exactly 50 mL, and use this solu- operating conditions, the relative standard deviation of the peak tion as the sample solution. Separately, weigh accurately an area of minocycline is not more than 2.0%. amount of Minocycline Hydrochloride Reference Standard, Water <2.48> Not more than 12.0% (0.5 g of powdered Mi- equivalent to about 25 mg (potency), dissolve in the mobile nocycline Hydrochloride Tablets, volumetric titration, back ti- phase to make exactly 50 mL, and use this solution as the stan- tration) dard solution. Perform the test with exactly 20 µL each of the sample solution and standard solution as directed under Liquid Uniformity of dosage units <6.02> Perform the test accord- Chromatography <2.01> according to the following conditions, ing to the following method: it meets the requirement of the and determine the peak areas, AT and AS, of minocycline in each Content uniformity test. solution. To 1 tablet of Minocycline Hydrochloride Tablets add 60 mL of the mobile phase, treat with ultrasonic waves for 15 minutes, Amount [mg (potency)] of minocycline (C23H27N3O7) and add the mobile phase to make exactly V mL so that each mL = WS × (AT/AS) × 40 contains about 0.5 mg (potency) of Minocycline Hydrochloride. W : Amount [mg (potency)] of Minocycline Hydrochloride Centrifuge this solution, and use the supernatant liquid as the S Reference Standard sample solution. Then, proceed as directed in the Assay. Operating conditions— Amount [mg (potency)] of minocycline (C H N O ) 23 27 3 7 Detector, column, column temperature and flow rate: Proceed = W × (A /A ) × (V/50) S T S as directed in the operating conditions in the Assay under Mi- nocycline Hydrochloride. WS: Amount [mg (potency)] of Minocycline Hydrochloride Reference Standard Mobile phase: Adjust the pH to 6.5 of a mixture of ammonium oxalate monohydrate solution (7 in 250), Dissolution <6.10> When the test is performed at 50 revolu- N,N-dimethylformamide and 0.1 mol/L disodium dihydrogen tions per minute according to the Paddle method using 900 mL ethylenediamine tetraacetate TS (11:5:4) with tetrabutylammo- of water as the dissolution medium, the dissolution rate in 30 nium hydroxide TS. minutes of Minocycline Hydrochloride Tablets is not less than System suitability— 85%. System performance: Dissolve 50 mg of minocycline hydro- Start the test with 1 tablet of Minocycline Hydrochloride chloride in 25 mL of water. Heat 5 mL of this solution on a wa- Tablets, withdraw not less than 20 mL of the medium at the ter bath for 60 minutes, and add water to make 25 mL. When the specified minute after starting the test, and filter through a procedure is run with 20 µL of this solution under the above op- membrane filter with a pore size not exceeding 0.45 µm. Dis- erating conditions, epiminocycline and minocycline are eluted card the first 10 mL of the filtrate, pipet V mL of the subsequent in this order with the resolution between these peaks being not filtrate, add water to make exactly V´ mL so that each mL con- less than 2.0. tains about 9 µg (potency) of Minocycline Hydrochloride ac- System repeatability: When the test is repeated 6 times with cording to the labeled amount, and use this solution as the sam- 20 µL of the standard solution under the above operating condi- ple solution. Separately, weigh accurately an amount of Mino- tions, the relative standard deviation of the peak area of minocycline Hydrochloride Reference Standard, equivalent to about cycline is not more than 1.0%. 30 mg (potency), and dissolve in water to make exactly 100 mL. Pipet 4 mL of this solution, add water to make exactly 100 mL, Containers and storage Containers—Tight containers. and use this solution as the standard solution. Perform the test Storage—Light-resistant. with the sample solution and standard solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, and determine the absorbances, AT and AS, at 348 nm.

Dissolution rate (%) with respect to the labeled amount of

Supplement II, JP XV Official Monographs 2165 Morphine Hydrochloride Injection System performance: When the procedure is run with 25 µL of the standard solution under the above operating conditions, モルヒネ塩酸塩注射液 the number of theoretical plates and the symmetry factor of the peak of morphine are not less than 5000 and not more than 2.0, Add the following next to the Identification: respectively. System repeatability: When the test is repeated 6 times with Bacterial endotoxins <4.01> Less than 1.5 EU/mg. 25 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of mor- Add the following next to the Extractable volume: phine is not more than 2.0%.

Foreign insoluble matter <6.06> Perform the test according to Method 1: it meets the requirement. Add the following:

Insoluble particulate matter <6.07> It meets the require- Mosapride Citrate Hydrate ment. モサプリドクエン酸塩水和物 Sterility <4.06> Perform the test according to the Membrane filtration method: it meets the requirement.

Morphine Hydrochloride Tablets モルヒネ塩酸塩錠 and enantiomer C H ClFN O ·C H O ·2H O: 650.05 Add the following next to the Uniformity of dos- 21 25 3 3 6 8 7 2 4-Amino-5-chloro-2-ethoxy-N-{[(2RS)- age units: 4-(4-fluorobenzyl)morpholin-2-yl]methyl}benzamide Dissolution <6.10> When the test is performed at 50 revolu- monocitrate dihydrate [636582-62-2] tions per minute according to the Paddle method using 900 mL Mosapride Citrate Hydrate contains not less than of water as the dissolution medium, the dissolution rate in 15 98.5% and not more than 101.0% of mosapride citrate minutes of Morphine Hydrochloride Tablets is not less than (C H ClFN O ·C H O : 614.02), calculated on the 85%. 21 25 3 3 6 8 7 anhydrous basis. Start the test with 1 tablet of Morphine Hydrochloride Tablets, withdraw not less than 20 mL of the medium at the specified Description Mosapride Citrate Hydrate occurs as a white to minute after starting the test, and filter through a membrane fil- yellowish white crystalline powder. ter with a pore size not exceeding 0.45 µm. Discard the first 10 It is freely soluble in N,N-dimethylformamide and in acetic mL of the filtrate, and use the subsequent filtrate as the sample acid (100), sparingly soluble in methanol, slightly soluble in solution. Separately, weigh accurately about 28 mg of morphine ethanol (99.5), and practically insoluble in water. hydrochloride for assay (separately, determine the water content A solution of Mosapride Citrate Hydrate in <2.48> in the same manner as Morphine Hydrochloride Hy- N,N-dimethylformamide (1 in 20) shows no optical rotation. drate), and dissolve in water to make exactly 100 mL. Pipet 2 mL of this solution, add water to make exactly 50 mL, and use Identification (1) Determine the absorption spectrum of a this solution as the standard solution. Perform the test with ex- solution of Mosapride Citrate Hydrate in methanol (1 in 50000) actly 25 µL each of the sample solution and standard solution as as directed under Ultraviolet-visible Spectrophotometry <2.24>, directed under Liquid Chromatography <2.01> according to the and compare the spectrum with the Reference Spectrum: both following conditions, and determine the peak areas , AT and AS, spectra exhibit similar intensities of absorption at the same of morphine in each solution. wavelengths. (2) Determine the infrared absorption spectrum of Dissolution rate (%) with respect to the labeled amount of Mosapride Citrate Hydrate as directed in the potassium bromide morphine hydrochloride hydrate (C17H19NO3·HCl·3H2O) disk method under Infrared Spectrophotometry <2.25>, and = WS × (AT/AS) × (1/C) × 36 × 1.168 compare the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave W : Amount (mg) of morphine hydrochloride for assay, cal- S numbers. culated on the anhydrous basis (3) A solution of Mosapride Citrate Hydrate in C: Labeled amount (mg) of morphine hydrochloride hydrate N,N-dimethylformamide (1 in 10) responds to the Qualitative (C H NO ·HCl·3H O) in 1 tablet 17 19 3 2 Tests <1.09> (1) for citrate. Operating conditions— Purity (1) Heavy metals <1.07>—Proceed with 1.0 g of Proceed as directed in the operating conditions in the Assay. Mosapride Citrate Hydrate in a platinum crucible according to System suitability—

2166 Official Monographs Supplement II, JP XV

Method 4, and perform the test. Prepare the control solution (3) Residual solvent—Being specified separately. with 2.0 mL of Standard Lead Solution (not more than 20 ppm). (2) Related substances—Dissolve 0.10 g of Mosapride Cit- Water <2.48> 5.0 - 6.5% (0.5 g, volumetric titration, back ti- rate Hydrate in 50 mL of methanol, and use this solution as the tration). sample solution. Pipet 1 mL of this solution, and add methanol Residue on ignition <2.44> Not more than 0.1% (1 g, plati- to make exactly 50 mL. Pipet 1 mL of this solution, add metha- num crucible). nol to make exactly 20 mL, and use this solution as the standard solution. Perform the test with exactly 5 µL each of the sample Assay Weigh accurately 0.5 g of Mosapride Citrate Hydrate, solution and standard solution as directed under Liquid Chro- dissolve in 70 mL of acetic acid (100), and titrate <2.50> with matography <2.01> according to the following conditions. De- 0.1 mol/L perchloric acid VS (potentiometric titration). Perform termine each peak area of both solutions by the automatic inte- a blank determination in the same manner, and make any neces- gration method: the area of the peak having the relative reten- sary correction. tion time of about 0.47 with respect to mosapride from the sample solution is not larger than 3 times the peak area of mosapride Each mL of 0.1 mol/L perchloric acid VS from the standard solution, and the area of each peak other than = 61.40 mg of C21H25ClFN3O3·C6H8O7 the peak of mosapride and other than the peak mentioned above from the sample solution is not larger than the peak area of Containers and storage Containers—Well-closed containers. mosapride from the standard solution. Furthermore, the total area of the peaks other than the peak of mosapride from the Add the following: sample solution is not larger than 5 times the peak area of mosapride from the standard solution. Mosapride Citrate Tablets Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: モサプリドクエン酸塩錠 274 nm). Column: A stainless steel column 4.6 mm in inside diameter Mosapride Citrate Tablets contain not less than and 15 cm in length, packed with octadecylsilanized silica gel 95.0% and not more than 105.0% of the labeled for liquid chromatography (5 µm in particle diameter). amount of mosapride citrate (C21H25ClFN3O3·C6H8O7: Column temperature: A constant temperature of about 40ºC. 614.02). Mobile phase A: Dissolve 8.82 g of trisodium citrate di- Method of preparation Prepare as directed under Tablets, hydrate in 800 mL of water, adjust the pH to 4.0 with dilute hy- with Mosapride Citrate Hydrate. drochloric acid, and add water to make 1000 mL. Mobile phase B: Acetonitrile Identification (1) To an amount of powdered Mosapride Flowing of the mobile phase: Control the gradient by mixing Citrate Tablets, equivalent to 10 mg of mosapride citrate the mobile phases A and B as directed in the following table. (C21H25ClFN3O3·C6H8O7), add 10 mL of dilute acetic acid, shake for 10 minutes, and filter. To 5 mL of the filtrate add 0.3 Time after injec- Mobile phase A Mobile phase B mL of Dragendorff’s TS: an orange precipitate is formed. tion of sample (vol%) (vol%) (2) Determine the absorption spectrum of the sample solu- (min) tion obtained in the Assay as directed under Ultraviolet-visible 0 – 35 80 → 45 20 → 55 Spectrophotometry <2.24>: it exhibits maxima between 271 nm and 275 nm, and between 306 nm and 310 nm. Flow rate: 1.0 mL per minute Time span of measurement: Beginning after the solvent peak Purity Related substances—Powder not less than 20 tablets of to 35 minutes after injection. Mosapride Citrate Tablets. Moisten a portion of the powder, System suitability— equivalent to 10 mg of mosapride citrate Test for required detectability: Pipet 4 mL of the standard so- (C21H25ClFN3O3·C6H8O7) according to the labeled amount, with lution, and add methanol to make exactly 20 mL. Confirm that 1 mL of water. Add 9 mL of methanol, shake for 20 minutes, the peak area of mosapride obtained from 5 µL of this solution is centrifuge, and use the supernatant liquid as the sample solution. equivalent to 15 to 25% of that of mosapride from the standard Pipet 1 mL of this solution, add methanol to make exactly 20 solution. mL. Pipet 2 mL of this solution, add methanol to make exactly System performance: When the procedure is run with 5 µL of 20 mL, and use this solution as the standard solution. Perform the standard solution under the above operating conditions, the the test with exactly 10 µL each of the sample solution and number of theoretical plates and the symmetry factor of the peak standard solution as directed under Liquid Chromatography of mosapride are not less than 40000 and not more than 1.5, re- <2.01> according to the following conditions. Determine each spectively. peak area of both solutions by the automatic integration method: System repeatability: When the test is repeated 6 times with 5 the area of the peaks having the relative retention times of about µL of the standard solution under the above operating conditions, 0.60 and about 0.85 with respect to mosapride from the sample the relative standard deviation of the peak area of mosapride is solution is not larger than the peak area of mosapride from the not more than 5.0%.

Supplement II, JP XV Official Monographs 2167 standard solution, and the area of each peak other than the peak solution medium, the dissolution rate in 45 minutes of of mosapride and other than those mentioned above from the Mosapride Citrate Tablets is not less than 80%. sample solution is not larger than 2/5 times the peak area of Start the test with 1 tablet of Mosapride Citrate Tablets, with- mosapride from the standard solution. Furthermore, the total draw not less than 20 mL of the medium at the specified minute area of the peaks other than mosapride from the sample solution after starting the test, and filter through a membrane filter with a is not larger than 2 times the peak area of mosapride from the pore size not exceeding 0.45 µm. Discard the first 10 mL of the standard solution. filtrate, pipet V mL of the subsequent filtrate, add the dissolution Operating conditions— medium to make exactly V´ mL so that each mL contains about

Detector, column, column temperature, mobile phase A, mo- 2.8 µg of mosapride citrate (C21H25ClFN3O3·C6H8O7) according bile phase B, and flow rate: Proceed as directed in the operating to the labeled amount, and use this solution as the sample solu- conditions in the Purity (2) under Mosapride Citrate Hydrate. tion. Separately, weigh accurately about 30 mg of mosapride Flowing of the mobile phase: Control the gradient by mixing citrate for assay (separately, determine the water content <2.48> the mobile phases A and B as directed in the following table. in the same manner as Mosapride Citrate Hydrate), and dissolve in the mobile phase to make exactly 100 mL. Pipet 2 mL of this Time after injec- solution, add the mobile phase to make exactly 200 mL, and use Mobile phase A Mobile phase B tion of sample this solution as the standard solution. Perform the test with ex- (vol%) (vol%) (min) actly 50 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the 0 – 40 85 → 45 15 → 55 following conditions, and determine the peak areas , AT and AS, Time span of measurement: Beginning after the solvent peak of mosapride in each solution. to 40 minutes after injection. Dissolution rate (%) with respect to the labeled amount of System suitability— mosapride citrate (C H ClFN O ·C H O ) Test for required detectability: Pipet 1 mL of the standard so- 21 25 3 3 6 8 7 = W × (A /A ) × (V´/V) × (1/C) × 9 lution, and add methanol to make exactly 25 mL. Confirm that S T S the peak area of mosapride obtained from 10 µL of this solution WS: Amount (mg) of mosapride citrate for assay, calculated is equivalent to 3.0 to 5.0% of that of mosapride from the stan- on the anhydrous basis dard solution. C: Labeled amount (mg) of mosapride citrate System performance: When the procedure is run with 10 µL (C21H25ClFN3O3·C6H8O7) in 1 tablet of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry factor of the Operating conditions— peak of mosapride are not less than 40000 and not more than 1.5, Detector: An ultraviolet absorption photometer (wavelength: respectively. 274 nm) System repeatability: When the test is repeated 6 times with Column: A stainless steel column 4.6 mm in inside diameter 10 µL of the standard solution under the above operating condi- and 15 cm in length, packed with octadecylsilanized silica gel tions, the relative standard deviation of the peak area of for liquid chromatography (5 µm in particle diameter). mosapride is not more than 3.0%. Column temperature: A constant temperature of about 40ºC. Mobile phase: Dissolve 8.82 g of trisodium citrate dihydrate Uniformity of dosage units <6.02> Perform the test accord- in 800 mL of water, adjust the pH to 3.3 with dilute hydrochlo- ing to the following method: it meets the requirement of the ric acid, and add water to make 1000 mL. To 240 mL of this so- Content uniformity test. lution add 90 mL of methanol and 70 mL of acetonitrile To 1 tablet of Mosapride Citrate Tablets add 5 mL of water, Flow rate: Adjust the flow rate so that the retention time of and shake well to disintegrate. Add 20 mL of methanol, shake mosapride is about 9 minutes. for 20 minutes, and add methanol to make exactly 50 mL. Cen- System suitability— trifuge this solution, pipet V mL of the supernatant liquid, add System performance: When the procedure is run with 50 µL methanol to make exactly V´ mL so that each mL contains about of the standard solution under the above operating conditions, 20 µg of mosapride citrate (C21H25ClFN3O3·C6H8O7), and use the number of theoretical plates and the symmetry factor of the this solution as the sample solution. Proceed as directed in the peak of mosapride are not less than 4000 and not more than 2.0, Assay. respectively. System repeatability: When the test is repeated 6 times with Amount (mg) of mosapride citrate (C H ClFN O ·C H O ) 21 25 3 3 6 8 7 50 µL of the standard solution under the above operating condi- = W × (A /A ) × (V´/V) × (1/50) S T S tions, the relative standard deviation of the peak area of mosapride is not more than 2.0%. WS: Amount (mg) of mosapride citrate for assay, calculated on the anhydrous basis Assay Weigh accurately the mass of not less than 20 Dissolution <6.10> When the test is performed at 50 revolu- Mosapride Citrate Tablets, and powder. Weigh accurately a por- tions per minute according to the Paddle method using the tion of the powder, equivalent to about 10 mg of mosapride cit- sinker, using 900 mL of 2nd fluid for dissolution test as the dis- rate (C21H25ClFN3O3·C6H8O7), and moisten with 2 mL of water.

2168 Official Monographs Supplement II, JP XV Add 70 mL of methanol, shake for 20 minutes, add methanol to Phenobarbital make exactly 100 mL, and centrifuge. Pipet 10 mL of the supernatant liquid, add methanol to make exactly 50 mL, and use フェノバルビタール this solution as the sample solution. Separately, weigh accurately about 53 mg of mosapride citrate for assay (separately, determine the water content <2.48> in the same manner as Change the Origin/limits of content and Identifi- Mosapride Citrate Hydrate), and dissolve in methanol to make cation to read: exactly 100 mL. Pipet 2 mL of this solution, add methanol to make exactly 50 mL, and use this solution as the standard solu- Phenobarbital, when dried, contains not less than tion. Perform the test with the sample solution and standard so- 99.0% and not more than 101.0% of C12H12N2O3. lution as directed under Ultraviolet-visible Spectrophotometry

<2.24>, and determine the absorbances, AT and AS, at 273 nm. Identification (1) Determine the absorption spectrum of a solution of Phenobarbital in boric acid-potassium chlo- Amount (mg) of mosapride citrate (C21H25ClFN3O3·C6H8O7) ride-sodium hydrochloride buffer solution, pH 9.6 (1 in 100000) = WS × (AT/AS) × (1/5) as directed under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spectrum: both W : Amount (mg) of mosapride citrate for assay, calculated S spectra exhibit similar intensities of absorption at the same on the anhydrous basis. wavelengths. Containers and storage Containers—Tight containers. (2) Determine the infrared absorption spectrum of Pheno- barbital as directed in the potassium bromide disk method under Infrared Spectrophotometry <2.25>, and compare the spectrum Nicomol Tablets with the Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave numbers. ニコモール錠 Add the following next to the Identification: 10% Phenobarbital Powder Uniformity of dosage units <6.02> It meets the requirement of the Mass variation test. フェノバルビタール散 10％

Change the Identification to read: Norethisterone Identification (1) Determine the absorption spectrum of the ノルエチステロン sample solution obtained in the Assay as directed under Ultra- violet-visible Spectrophotometry <2.24>: it exhibits a maximum Change the following to read: between 238 nm and 242 nm. (2) To 6 g of 10% Phenobarbital Powder add 150 mL of Description Norethisterone occurs as a white to pale yellow- ethanol, shake well, and filter. Condense the filtrate in a water ish white crystalline powder. it has no odor. bath to about 5 mL, filter with about 50 mL of water to collect It is sparingly soluble in ethanol (95), in acetone, and in tet- the crystals, and dry them at 105ºC for 2 hours. Determine the rahydrofuran, slightly soluble in diethyl ether, and very slightly infrared absorption spectrum of the crystals as directed in the soluble in water. potassium bromide disk method under Infrared Spectropho- It is affected by light. tometry <2.25>, and compare the spectrum with the Reference Spectrum: both spectra exhibit similar intensities of absorption Optical rotation <2.49> [α] 20 : –32 - –37º (after drying, 0.25 D at the same wave numbers. g, acetone, 25 mL, 100 mm). Add the following next to the Identification:

Dissolution <6.10> When the test is performed at 50 revolutions per minute according to the Paddle method using 900 mL of water as the dissolution medium, the dissolution rate in 30 minutes of 10% Phenobarbital Powder is not less than 80%. Start the test with an accurately weighted about 0.3 g of 10% Phenobarbital Powder, withdraw not less than 20 mL of the medium at the specified minute after starting the test, and filter through a membrane filter with a pore size not exceeding 0.45 µm. Discard the first 10 mL of the filtrate, pipet 5 mL of the subsequent filtrate, add exactly 10 mL of boric acid-potassium chloride-sodium hydroxide buffer solution, pH 9.6, and use this

Supplement II, JP XV Official Monographs 2169 solution as the sample solution. Separately, weigh accurately Add the following next to the Extractable volume: about 17 mg of phenobarbital for assay, previously dried at 105ºC for 2 hours, and dissolve in water to make exactly 100 Foreign insoluble matter <6.06> Perform the test according mL. Pipet 5 mL of this solution, and add water to make exactly to Method 1: it meets the requirement. 25 mL. Pipet 5 mL of this solution, add exactly 10 mL of boric acid-potassium chloride-sodium hydroxide buffer solution, pH Insoluble particulate matter <6.07> Perform the test ac- 9.6, and use this solution as the standard solution. Perform the cording to Method 2: it meets the requirement. test with the sample solution and standard solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, using a Sterility <4.06> Perform the test according to the Membrane mixture of boric acid-potassium chloride-sodium hydroxide filtration method: it meets the requirement. buffer solution, pH 9.6, and water (2:1) as the blank, and determine the absorbances, A and A , at 240 nm. T S Phenytoin Powder Dissolution rate (%) with respect to the labeled amount of phenobarbital (C12H12N2O3) フェニトイン散 = (WS /WT) × (AT/AS) × (1/C) × 180 Change the Origin/limits of content and Assay to WS: Amount (mg) of phenobarbital for assay read: WT: Amount (g) of 10% Phenobarbital Powder C: Labeled amount (mg) of phenobarbital (C12H12N2O3) in 1 Phenytoin Powder contains not less than 95.0% and g not more than 105.0% of the labeled amount of Particle size <6.03> It meets the requirement. phenytoin (C15H12N2O2: 252.27).

Change the Assay to read: Assay Weigh accurately an amount of Phenytoin Powder, equivalent to about 50 mg of phenytoin (C15H12N2O2), add 30 Assay Weigh accurately about 0.2 g of 10% Phenobarbital mL of methanol, treat with ultrasonic waves for 15 minutes with Powder, dissolve in a boric acid-potassium chloride-sodium hy- occasional shaking, shake for another 10 minutes, and add droxide buffer solution, pH 9.6 to make exactly 100 mL. Pipet 5 methanol to make exactly 50 mL. Centrifuge this solution, pipet mL of this solution, add a boric acid-potassium chloride-sodium 5 mL of the supernatant liquid, add exactly 5 mL of the internal hydroxide buffer solution, pH 9.6 to make exactly 100 mL, and standard solution, and use this solution as the sample solution. use this solution as the sample solution. Separately, weigh accu- Separately, weigh accurately about 25 mg of phenytoin for assay, rately about 20 mg of phenobarbital for assay, previously dried previously dried at 105ºC for 2 hours, and dissolve in methanol at 105ºC for 2 hours, and add a boric acid-potassium chlo- to make exactly 25 mL. Pipet 5 mL of this solution, add exactly ride-sodium hydroxide buffer solution, pH 9.6 to make exactly 5 mL of the internal standard solution, and use this solution as 100 mL. Pipet 5 mL of this solution, add a boric acid-potassium the standard solution. Perform the test with 10 µL each of the chloride-sodium hydroxide buffer solution, pH 9.6 to make ex- sample solution and standard solution as directed under Liquid actly 100 mL, and use this solution as the standard solution. Chromatography <2.01> according to the following conditions, Perform the test with the sample solution and standard solution and calculate the ratios, QT and QS, of the peak area of pheny- as directed under Ultraviolet-visible Spectrophotometry <2.24>, toin to that of the internal standard. using a boric acid-potassium chloride-sodium hydroxide buffer Amount (mg) of phenytoin (C15H12N2O2) solution, pH 9.6 as the blank, and determine the absorbances, AT = WS × (QT/QS) × 2 and AS, at 240 nm.

WS: Amount (mg) of phenytoin for assay Amount (mg) of phenobarbital (C12H12N2O3) = W × (A /A ) S T S Internal standard solution—A solution of propyl parahydroxybenzoate in the mobile phase (1 in 25000) WS: Amount (mg) of phenobarbital for assay Operating conditions— Detector: An ultraviolet absorption photometer (wave- Phenolsulfonphthalein Injection length: 258 nm) Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica フェノールスルホンフタレイン注射液 gel for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about Add the following next to the pH: 40ºC. Mobile phase: A mixture of methanol and 0.02 mol/L Bacterial endotoxins <4.01> Less than 7.5 EU/mg. phosphate buffer solution, pH 3.5 (11:9) Flow rate: Adjust the flow rate so that the retention time of

2170 Official Monographs Supplement II, JP XV phenytoin is about 5 minutes. toin Tablets, and powder in an agate mortar. Weigh accurately a System suitability— portion of the powder, equivalent to about 50 mg of phenytoin

System performance: When the procedure is run with 10 (C15H12N2O2), add 30 mL of a mixture of water and acetonitrile µL of the standard solution under the above operating condi- (1:1), treat with ultrasound waves for 15 minutes with occa- tions, phenytoin and the internal standard are eluted in this sional shaking, shake for another 10 minutes, and add a mixture order with the resolution between these peaks being not less of water and acetonitrile (1:1) to make exactly 50 mL. Centri- than 8. fuge this solution, pipet 5 mL of the supernatant liquid, add ex- System repeatability: When the test is repeated 6 times actly 5 mL of the internal standard solution, and use this solu- with 10 µL of the standard solution under the above operating tion as the sample solution. Separately, weigh accurately about conditions, the relative standard deviation of the ratio of the 25 mg of phenytoin for assay, previously dried at 105ºC for 2 peak area of phenytoin to that of the internal standard is not hours, and dissolve in a mixture of water and acetonitrile (1:1) more than 1.0%. to make exactly 25 mL. Pipet 5 mL of this solution, add exactly 5 mL of the internal standard solution, and use this solution as the standard solution. Perform the test with 10 µL each of the Phenytoin Tablets sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions,

フェニトイン錠 and calculate the ratios, QT and QS, of the peak area of phenytoin to that of the internal standard. Change the Origin/limits of content and Identifi- cation to read: Amount (mg) of phenytoin (C15H12N2O2) = WS × (QT/QS) × 2

Phenytoin Tablets contain not less than 95.0% and WS: Amount (mg) of phenytoin for assay not more than 105.0% of the labeled amount of Internal standard solution—A solution of propyl parahydroxy- phenytoin (C15H12N2O2: 252.27). benzoate in the mobile phase (1 in 25000) Identification Weigh a portion of powdered Phenytoin Tablets, Operating conditions— equivalent to about 0.3 g of Phenytoin, transfer to a separator, Detector: An ultraviolet absorption photometer (wavelength: and add 1 mL of dilute hydrochloric acid and 10 mL of water. 258 nm). Extract with 100 mL of diethyl ether, then with four 25-mL po- Column: A stainless steel column 4.6 mm in inside diameter tions of diethyl ether. Combine the extracts, evaporate the di- and 15 cm in length, packed with octadecylsilanized silica gel ethyl ether in a water bath, and dry the residue at 105ºC for 2 for liquid chromatography (5 µm in particle diameter). hours. Proceed with the residue as directed in the Identification Column temperature: A constant temperature of about 40ºC. under Phenytoin. Mobile phase: A mixture of methanol and 0.02 mol/L phosphate buffer solution, pH 3.5 (11:9) Add the following next to the Identification: Flow rate: Adjust the flow rate so that the retention time of phenytoin is about 5 minutes. Uniformity of dosage units <6.02> Perform the test accord- System suitability— ing to the following method: it meets the requirement of the System performance: When the procedure is run with 10 µL Content uniformity test. of the standard solution under the above operating conditions, To 1 tablet of Phenytoin Tablets add 3V/5 mL of a mixture of phenytoin and the internal standard are eluted in this order with water and acetonitrile (1:1), treat with ultrasonic waves for 15 the resolution between these peaks being not less than 8. minutes with occasional shaking, shake for another 10 minutes, System repeatability: When the test is repeated 6 times with and add a mixture of water and acetonitrile (1:1) to make ex- 10 µL of the standard solution under the above operating condi- actly V mL so that each mL contains about 1 mg of phenytoin tions, the relative standard deviation of the ratio of the peak area (C H N O ). Centrifuge this solution, pipet 5 mL of the su- 15 12 2 2 of phenytoin to that of the internal standard is not more than pernatant liquid, add exactly 5 mL of the internal standard solu- 1.0%. tion, and use this solution as the sample solution. Proceed as directed in the Assay.

Amount (mg) of phenytoin (C15H12N2O2) = WS × (QT/QS) × (V/25)

WS: Amount (mg) of phenytoin for assay

Internal standard solution—A solution of propyl parahydroxybenzoate in the mobile phase (1 in 25000)

Change the Assay to read:

Assay Weigh accurately the mass of not less than 20 Pheny-

Supplement II, JP XV Official Monographs 2171

Add the following times of the peak area of pimozide from the standard solution. Operating conditions— Pimozide Detector: An ultraviolet absorption photometer (wavelength: 280 nm). ピモジド Column: A stainless steel column 4.6 mm in inside diameter and 10 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (3 µm in particle diameter). Column temperature: A constant temperature of about 25ºC. Mobile phase A: Dissolve 2.5 g of ammonium acetate and 8.5 g of tetrabutylammonium hydrogensulfate in water to make 1000 mL. Mobile phase B: Acetonitrile Flowing of the mobile phase: Control the gradient by mixing the mobile phases A and B as directed in the following table. C28H29F2N3O: 461.55 1-{1-[4,4-Bis(4-fluorophenyl)butyl]piperidin-4-yl}- Time after in- 1,3-dihydro-2H-benzoimidazol-2-one [2062-78-4] Mobile phase A Mobile phase B jection of sample (vol%) (vol%) Pimozide contains not less than 98.5% and not more (min) than 101.0% of C28H29F2N3O. 0 – 10 80 → 70 20 → 30 10 – 15 70 30 Description Pimozide occurs as a white to pale yellowish white powder. Flow rate: 2.0 mL per minute. It is freely soluble in acetic acid (100), slightly soluble in Time span of measurement: 1.5 times as long as the retention methanol and in ethanol (99.5), and practically insoluble in wa- time of pimozide. ter. System suitability— Test for required detectability: Pipet 1 mL of the standard so- Identification (1) Determine the absorption spectrum of a lution, and add methanol to make exactly 10 mL. Confirm that solution of Pimozide in methanol (1 in 25000) as directed under the peak area of pimozide obtained from 10 µL of this solution Ultraviolet-visible Spectrophotometry <2.24>, and compare the is equivalent to 8 to 12% of that of pimozide from the standard spectrum with the Reference Spectrum: both spectra exhibit solution. similar intensities of absorption at the same wavelengths. System performance: Dissolve 5 mg of Pimozide and 2 mg of (2) Determine the infrared absorption spectrum of Pimozide mebendazole in methanol to make 100 mL. When the procedure as directed in the potassium bromide disk method under Infrared is run with 10 µL of this solution under the above operating Spectrophotometry <2.25>, and compare the spectrum with the conditions, mebendazole and pimozide are eluted in this order Reference Spectrum: both spectra exhibit similar intensities of with the resolution between these peaks being not less than 5. absorption at the same wave numbers. System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- Melting point < 2.60> 216 - 220ºC. tions, the relative standard deviation of the peak area of pimozide is not more than 2.0%. Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of (4) Residual solvent—Being specified separately. Pimozide according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solution by Loss on drying <2.41> Not more than 0.5% (1 g, 105ºC, 3 using 5 mL of sulfuric acid (not more than 10 ppm). hours). (2) Arsenic <1.11>—Prepare the test solution with 1.0 g of Pimozide according to Method 3, and perform the test (not more Residue on ignition <2.44> Not more than 0.1% (1 g). than 2 ppm). (3) Related substances—Dissolve 0.10 g of Pimozide in 10 Assay Weigh accurately about 70 mg of dried Pimozide, dis- mL of methanol, and use this solution as the sample solution. solve in 25 mL of acetic acid for nonaqueous titration, and ti- Pipet 1 mL of this solution, add methanol to make exactly 200 trate <2.50> with 0.02 mol/L perchloric acid VS (indicator: 2 mL, and use this solution as the standard solution. Perform the drops of crystal violet TS). Perform a blank determination in the test with exactly 10 µL each of the sample solution and standard same manner, and make any necessary correction. solution as directed under Liquid Chromatography <2.01> ac- Each mL of 0.02 mol/L perchloric acid VS cording to the following conditions. Determine each peak area = 9.231 mg of C of both solutions by the automatic integration method: the area 28H29F2N3O of the peak other than the peak of pimozide from the sample Containers and storage Containers—Well-closed containers. solution is not lager than the peak area of pimozide from the standard solution, and the total area of the peaks other than the peak of pimozide from the sample solution is not larger than 1.5

2172 Official Monographs Supplement II, JP XV

Add the following: 200 mL, and use this solution as the standard solution. Perform the test with exactly 40 µL each of the sample solution and Pioglitazone Hydrochloride standard solution as directed under Liquid Chromatography <2.01> according to the following conditions. Determine each ピオグリタゾン塩酸塩 peak area of both solutions by the automatic integration method: the area of the peaks, having the relative retention times of about 0.7, about 1.4 and about 3.0 with respect to pioglitazone from the sample solution, is not larger than 2/5 times the peak area of pioglitazone from the standard solution, and the area of each peak other than the peak of pioglitazone and other than and enantiomer those mentioned above is smaller than 1/5 times the peak area of pioglitazone from the standard solution. Furthermore, the total

C19H20N2O3S·HCl: 392.90 area of the peaks other than the peak of pioglitazone is not lar- (5RS)-5-{4-[2-(5-Ethylpyridin- ger than the peak area of pioglitazone from the standard solu- 2-yl)ethoxy]benzyl}thiazolidine-2,4-dione tion. monohydrochloride [112529-15-4] Operating conditions— Detector, column, column temperature, mobile phase and Pioglitazone Hydrochloride contains not less than flow rate: Proceed as directed in the operating conditions in the 99.0% and not more than 101.0% of C19H20N2O3S·HCl, Assay. calculated on the anhydrous basis. Time span of measurement: About 4 times as long as the retention time of pioglitazone, beginning after the solvent peak. Description Pioglitazone Hydrochloride occurs as white System suitability— crystals or crystalline powder. Test for required detectability: Pipet 1 mL of the standard so- It is soluble in N,N-dimethylformamide and in methanol, lution, and add the mobile phase to make exactly 10 mL. Con- slightly soluble in ethanol (99.5), and practically insoluble in firm that the peak area of pioglitazone obtained from 40 µL of water. this solution is equivalent to 7 to 13% of that of pioglitazone It dissolves in 0.1 mol/L hydrochloric acid TS. from the standard solution. A solution of Pioglitazone Hydrochloride in System performance: Dissolve 50 mg of Pioglitazone Hy- N,N-dimethylformamide (1 in 20) shows no optical rotation. drochloride in 10 mL of a solution of benzophenone in methanol Identification (1) Determine the absorption spectrum of a (1 in 750), and add methanol to make 100 mL. To 1 mL of this solution of Pioglitazone Hydrochloride in 0.1 mol/L hydrochlo- solution add the mobile phase to make 20 mL. When the proce- ric acid TS (1 in 50000) as directed under Ultraviolet-visible dure is run with 40 µL of this solution under the above operating Spectrophotometry <2.24>, and compare the spectrum with the conditions, pioglitazone and benzophenone are eluted in this Reference Spectrum or the spectrum of a solution of Pioglita- order with the resolution between these peaks being not less zone Hydrochloride Reference Standard prepared in the same than 10. manner as the sample solution: both spectra exhibit similar in- System repeatability: When the test is repeated 6 times with tensities of absorption at the same wavelengths. 40 µL of the standard solution under the above operating condi- (2) Determine the infrared absorption spectrum of Pioglita- tions, the relative standard deviation of the peak area of piogli- zone Hydrochloride as directed in the potassium bromide disk tazone is not more than 2.0%. method under Infrared Spectrophotometry <2.25>, and compare (3) Residual solvent—Being specified separately. the spectrum with the Reference Spectrum or the spectrum of Water <2.48> Not more than 0.2% (0.5 g, coulometric titra- Pioglitazone Hydrochloride Reference Standard: both spectra tion). For anolyte solution, use anolyte solution for water deter- exhibit similar intensities of absorption at the same wave num- mination A. bers. (3) Dissolve 50 mg of Pioglitazone Hydrochloride in 1 mL Residue on ignition <2.44> Not more than 0.1% (1 g). of nitric acid, and add 4 mL of dilute nitric acid: the solution responds to the Qualitative Tests <1.09> (2) for chloride. Assay Weigh accurately about 50 mg each of Pioglitazone Hydrochloride and Pioglitazone Hydrochloride Reference Stan- Purity (1) Heavy metals <1.07>—Proceed with 1.0 g of dard (separately, determine the water content <2.48> in the Pioglitazone Hydrochloride according to Method 4, and perform same manner as Pioglitazone Hydrochloride), add exactly 10 the test. After incineration, use 3 mL of hydrobromic acid in- mL of the internal standard solution and methanol to make 100 stead of 3 mL of hydrochloric acid. Prepare the control solution mL. Pipet 2 mL each of these solutions, add the mobile phase to with 1.0 mL of Standard Lead Solution (not more than 10 ppm). make 20 mL, and use these solutions as the sample solution and (2) Related substances—Dissolve 20 mg of Pioglitazone standard solution, respectively. Perform the test with 20 µL each Hydrochloride in 20 mL of methanol, add the mobile phase to of the sample solution and standard solution as directed under make 100 mL, and use this solution as the sample solution. Pi- Liquid Chromatography <2.01> according to the following con- pet 1 mL of this solution, add the mobile phase to make exactly ditions, and calculate the ratios, QT and QS, of the peak area of

Supplement II, JP XV Official Monographs 2173 pioglitazone to that of the internal standard. dilute nitric acid and water to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution Amount (mg) of pioglitazone hydrochloride (C19H20N2O3S·HCl) as follows: to 0.30 mL of 0.01 mol/L hydrochloric acid VS add = WS × (QT/QS) 5 mL of sodium hydroxide TS, 13.5 mL of dilute nitric acid and water to make 50 mL (not more than 0.021%). W : Amount (mg) of Pioglitazone Hydrochloride Reference S (2) Sulfate <1.14>—Dissolve 1.0 g of Pipemidic Acid Hy- Standard, calculated on the anhydrous basis drate in 35 mL of water and 10 mL of sodium hydroxide TS, Internal standard solution—A solution of benzophenone in shake well with 15 mL of dilute hydrochloric acid, and filter methanol (1 in 750) through a glass filter (G3). To 30 mL of the filtrate add water to Operating conditions— make 50 mL. Perform the test using this solution as the test so- Detector: An ultraviolet absorption photometer (wavelength: lution. Prepare the control solution as follows: to 0.50 mL of 269 nm) 0.005 mol/L sulfuric acid VS add 5 mL of sodium hydroxide TS, Column: A stainless steel column 4.6 mm in inside diameter 7.5 mL of dilute hydrochloric acid and water to make 50 mL and 15 cm in length, packed with octadecylsilanized silica gel (not more than 0.048%). for liquid chromatography (5 µm in particle diameter). Add the following next to the Purity: Column temperature: A constant temperature of about 25ºC. Mobile phase: A mixture of ammonium acetate solution (77 Water <2.48> 14.5 - 16.0% (20 mg, coulometric titration) in 10000), acetonitrile and acetic acid (100) (25:25:1) Flow rate: Adjust the flow rate so that the retention time of Change the Assay to read: pioglitazone is about 7 minutes. System suitability— Assay Weigh accurately about 0.35 g of Pipemidic Acid Hy- System performance: When the procedure is run with 20 µL drate, dissolve in 40 mL of acetic acid (100), and titrate <2.50> of the standard solution under the above operating conditions, with 0.1 mol/L perchloric acid VS (potentiometric titration). pioglitazone and the internal standard are eluted in this order Perform a blank determination in the same manner, and make with the resolution between these peaks being not less than 10. any necessary correction. System repeatability: When the test is repeated 6 times with Each mL of 0.1 mol/L perchloric acid VS 20 µL of the standard solution under the above operating condi- = 30.33 mg of C H N O tions, the relative standard deviation of the peak area of piogli- 14 17 5 3 tazone is not more than 1.0%. Add the following: Containers and storage Containers—Well-closed containers.

Pivmecillinam Hydrochloride Pipemidic Acid Hydrate Tablets

ピペミド酸水和物ピブメシリナム塩酸塩錠

Delete the Loss on drying and change the Origin/limits Pivmecillinam Hydrochloride Tablets contains not of content and Purity (1) and (2) to read: less than 93.0% and not more than 107.0% of the labeled potency of mecillinam (C15H23N3O3S: 325.43). Pipemidic Acid Hydrate contains not less than 98.5% and not more than 101.0% of pipemidic acid Method of preparation Prepare as directed under Tablets, (C14H17N5O3: 303.32), calculated on the anhydrous ba- with Pivmecillinam Hydrochloride. sis. Identification Powder Pivmecillinam Hydrochloride Tablets, Description Pipemidic Acid Hydrate occurs as a pale yellow, dissolve a portion of the powder, equivalent to 35 mg (potency) crystalline powder. of Pivmecillinam Hydrochloride according to the labeled It is freely soluble in acetic acid (100), very slightly soluble in amount, in 4 mL of a mixture of acetonitrile and acetic acid water and in ethanol (99.5), and practically insoluble in metha- (100) (97:3), and filter through a membrane filter with a pore nol. size not exceeding 0.45 µm. Discard the first 2 mL of the filtrate, It dissolves in sodium hydroxide TS. and use the subsequent filtrate as the sample solution. Sepa- It is gradually colored on exposure to light. rately dissolve 25 mg of Pivmecillinam Hydrochloride Refer- Melting point: about 250ºC (with decomposition). ence Standard in 2 mL of a mixture of acetonitrile and acetic acid (100) (97:3), and use this solution as the standard solution. Purity (1) Chloride <1.03>—Dissolve 1.0 g of Pipemidic Perform the test with these solutions as directed under Acid Hydrate in 35 mL of water and 10 mL of sodium hydrox- Thin-layer Chromatography <2.03>. Spot 2 µL each of the sam- ide TS, shake well with 15 mL of dilute nitric acid, and filter ple solution and standard solution on a plate of silica gel for through a glass filter (G3). To 30 mL of the filtrate add 6 mL of thin-layer chromatography, and immediately develop the plate

2174 Official Monographs Supplement II, JP XV with a mixture of acetone, water and acetic acid (100) (10:1:1) = WS × (QT/QS) × 5 to a distance of about 12 cm, and air-dry the plate. Allow the plate to stand in iodine vapor for 10 minutes: the principal spot WS: Amount [mg (potency)] of Pivmecillinam Hydrochloride Reference Standard obtained from the sample solution has the same Rf value as the spot from the standard solution. Internal standard solution—A solution of diphenyl in the mo- Water <2.48> Not more than 3.0% (1g of powdered Pivme- bile phase (1 in 12500) cillinam Hydrochloride Tablets, volumetric titration, direct titra- Containers and storage Containers—Tight containers. tion).

Uniformity of dosage units <6.02> Perform the test according to the following method: it meets the requirement of the Potato Starch Content uniformity test. To 1 tablet of Pivmecillinam Hydrochloride Tablets add 40 バレイショデンプン mL of the mobile phase, shake vigorously for 10 minutes, and Change the Identification to read: add the mobile phase to make exactly 50 mL. Pipet V mL, equivalent to about 10 mg (potency) of Pivmecillinam Hydro- Identification (1) Examined under a microscope <5.01> chloride, add exactly 5 mL of the internal standard solution and using a mixture of water and glycerin (1:1), Potato Starch pre- the mobile phase to make 50 mL, filter through a membrane fil- sents granules, either irregularly shaped, ovoid or pear-shaped, ter with a pore size not exceeding 0.45 µm, discard the first 10 usually 30-100 µm in size but occasionally exceeding 100 µm, mL of the filtrate, and use the subsequent filtrate as the sample or rounded, 10-35 µm in size. There are occasional compound solution. Separately, weigh accurately an amount of Pivmecilli- granules having two to four components. The ovoid and nam Hydrochloride Reference Standard, equivalent to about 20 pear-shaped granules have an eccentric hilum and the rounded mg (potency), dissolve in the mobile phase, add exactly 10 mL granules acentric or slightly eccentric hilum. All granules show of the internal standard solution, add the mobile phase to make clearly visible concentric striations. Between orthogonally ori- 100 mL, and use this solution as the standard solution. Then, ented polarizing plates or prisms, the granules show a distinct proceed as directed in the Assay under Pivmecillinam Hydro- black cross intersecting at the hilum. chloride. Add the following next to Purity (3): Amount [mg (potency)] of mecillinam (C15H23N3O3S) ◆ = WS × (QT/QS) × (25/V) Purity (4) Foreign matter—Under a microscope <5.01>, Potato Starch does not contain starch granules of any other ori- WS: Amount [mg (potency)] of Pivmecillinam Hydrochloride gin. It may contain a minute quantity, if any, of fragments of the Reference Standard tissue of the original plant.◆

Internal standard solution—A solution of diphenyl in the mobile phase (1 in 12500) Add the following: Disintegration <6.09> Perform the test using the disk: it meets the requirement. Prazosin Hydrochloride

Assay Weigh accurately the mass of not less than 20 Pivme- プラゾシン塩酸塩 cillinam Hydrochloride Tablets, and powder. Weigh accurately a portion of the powder, equivalent to about 0.1 g (potency) of Pivmecillinam Hydrochloride, add 50 mL of the mobile phase, shake vigorously for 10 minutes, and add the mobile phase to make exactly 100 mL. Pipet 10 mL of this solution, add exactly 5 mL of the internal standard solution and the mobile phase to make 50 mL, filter through a membrane filter with a pore size not exceeding 0.45 µm, discard the first 10 mL of the filtrate, and use the subsequent filtrate as the sample solution. Separately, C19H21N5O4·HCl: 419.86 weigh accurately an amount of Pivmecillinam Hydrochloride 1-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)- Reference Standard, equivalent to about 20 mg (potency), dis- 4-(2-furoyl)piperazine monohydrochloride [19237-84-4] solve in the mobile phase, add exactly 10 mL of the internal standard solution, add the mobile phase to make 100 mL, and Prazosin Hydrochloride, when dried, contains not use this solution as the standard solution. Then, proceed as di- less than 97.0% and not more than 103.0% of rected in the Assay under Pivmecillinam Hydrochloride. C19H21N5O4·HCl.

Description Prazosin Hydrochloride occurs as a white crys- Amount [mg (potency)] of mecillinam (C15H23N3O3S) talline powder.

Supplement II, JP XV Official Monographs 2175

It is slightly soluble in methanol, very slightly soluble in System suitability— ethanol (99.5) and practically insoluble in water. Test for required detectability: Pipet 5 mL of the standard so- It gradually turns pale yellowish white on exposure to light. lution, and add the mobile phase to make exactly 10 mL. Con- Melting point: about 270ºC (with decomposition). firm that the peak area of prazosin obtained from 20 µL of this solution is equivalent to 35 to 65% of that of prazosin from the Identification (1) Determine the absorption spectrum of a standard solution. solution of Prazosin Hydrochloride in 0.01 mol/L hydrochloric System performance: When the procedure is run with 20 µL acid-methanol TS (1 in 200000) as directed under Ultravio- of the standard solution under the above operating conditions, let-visible Spectrophotometry <2.24>, and compare the spec- the number of theoretical plates and the symmetry factor of the trum with the Reference Spectrum or the spectrum of a solution peak of prazosin are not less than 4000 and not more than 2.0, of Prazosin Hydrochloride Reference Standard prepared in the respectively. same manner as the sample solution: both spectra exhibit similar System repeatability: When the test is repeated 6 times with intensities of absorption at the same wavelengths. 20 µL of the standard solution under the above operating condi- (2) Determine the infrared absorption spectrum of Prazosin tions, the relative standard deviation of the peak area of prazosin Hydrochloride as directed in the potassium chloride disk method is not more than 2.0%. under Infrared Spectrophotometry <2.25>, and compare the (3) Residual solvent—Being specified separately. spectrum with the Reference Spectrum or the spectrum of Pra- zosin Hydrochloride Reference Standard: both spectra exhibit Loss on drying <2.41> Not more than 1.0% (1 g, 105ºC, 2 similar intensities of absorption at the same wave numbers. hours). (3) To 0.1 g of Prazosin Hydrochloride add 5 mL of water and 1 mL of ammonia TS, shake, allow to stand for 5 minutes, Residue on ignition <2.44> Not more than 0.2% (1 g). and filter. Render the filtrate acid with acetic acid (100): the so- Assay Weigh accurately about 25 mg each of Prazosin Hy- lution responds to the Qualitative Tests <1.09> for chloride. drochloride and Prazosin Hydrochloride Reference Standard, Purity (1) Heavy metals <1.07>—Proceed with 1.0 g of previously dried, and dissolve each in methanol to make exactly Prazosin Hydrochloride according to Method 4, and perform the 50 mL. Pipet 3 mL each of these solutions, and add a mixture of test. Prepare the control solution with 1.0 mL of Standard Lead methanol and water (7:3) to make exactly 100 mL, and use these Solution (not more than 10 ppm). solutions as the sample solution and standard solution, respec- (2) Related substances—Dissolve 20 mg of Prazosin Hy- tively. Perform the test with exactly 10 µL each of the sample drochloride in 20 mL of the mobile phase, and use this solution solution and standard solution as directed under Liquid Chro- as the sample solution. Pipet 1 mL of this solution, and add the matography <2.01> according to the following conditions, and mobile phase to make exactly 100 mL. Pipet 1 mL of this solu- calculate the peak areas, AT and AS, of prazosin in each solution. tion, add the mobile phase to make exactly 10 mL, and use this Amount (mg) of prazosin hydrochloride (C H N O ·HCl) solution as the standard solution. Perform the test with exactly 19 21 5 4 = W × (A /A ) 20 µL each of the sample solution and standard solution as di- S T S rected under Liquid Chromatography <2.01> according to the WS: Amount (mg) of Prazosin Hydrochloride Reference following conditions. Determine each peak area of both solu- Standard tions by the automatic integration method: the area of each peak other than the peak of prazosin from the sample solution is not Operating conditions— larger than 2 times the peak area of prazosin from the standard Detector: An ultraviolet absorption photometer (wavelength: solution, and the total area of the peaks other than the peak of 254 nm) prazosin from the sample solution is not larger than 5 times the Column: A stainless steel column 4.6 mm in inside diameter peak area of prazosin from the standard solution. and 25 cm in length, packed with silica gel for liquid chroma- Detector: An ultraviolet absorption photometer (wavelength: tography (5 µm in particle diameter). 254 nm). Column temperature: A constant temperature of about 25ºC. Column: A stainless steel column 4.6 mm in inside diameter Mobile phase: A mixture of methanol, water, acetic acid (100) and 25 cm in length, packed with octadecylsilanized silica gel and diethylamine (3500: 1500: 50:1) for liquid chromatography (5 µm in particle diameter). Flow rate: Adjust the flow rate so that the retention time of Column temperature: A constant temperature of about 25ºC. prazosin is about 8 minutes. Mobile phase: Dissolve 3.484 g of sodium 1-pentane sul- System suitability— fonate and 18 mL of tetramethylammonium hydroxide in 900 System performance: When the procedure is run with 10 µL mL of water, adjust the pH to 5.0 with acetic acid (100), and add of the standard solution under the above operating conditions, water to make 1000 mL. To this solution add 1000 mL of the number of theoretical plates and the symmetry factor of the methanol peak of prazosin are not less than 5000 and not more than 2.0, Flow rate: Adjust the flow rate so that the retention time of respectively. prazosin is about 9 minutes. System repeatability: When the test is repeated 6 times with Time span of measurement: About 6 times as long as the re- 10 µL of the standard solution under the above operating condi- tention time of prazosin. tions, the relative standard deviation of the peak area of prazosin

2176 Official Monographs Supplement II, JP XV is not more than 1.0%. pH <2.54> Dissolve 1.0 g of Prednisolone Sodium Phosphate in 100 mL of water: the pH of the solution is between 7.5 and Containers and storage Containers—Well-closed containers. 9.0. Storage—Light-resistant. Purity (1) Clarity and color of solution—Dissolve 1.0 g of Prednisolone Sodium Phosphate in 10 mL of water: the solution Add the following: is clear and not more colored than the following control solution Prednisolone Sodium Phosphate Control solution: To a mixture of 3.0 mL of Cobalt (II) Chlo- ride Colorimetric Stock Solution, 3.0 mL of Iron (III) Chloride プレドニゾロンリン酸エステルナトリウム Colorimetric Stock Solution and 2.4 mL of Copper (II) Sulfate Colorimetric Stock Solution add diluted hydrochloric acid (1 in 40) to make 10 mL. To 2.5 mL of this solution add diluted hydrochloric acid (1 in 40) to make 100 mL. (2) Heavy metals <1.07>—Proceed with 0.5 g of Predniso- lone Sodium Phosphate according to Method 3, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than 40 ppm). (3) Free phosphoric acid—Weigh accurately about 0.25 g of C21H27Na2O8P: 484.39 Disodium 11β,17,21-trihydroxypregna-1,4-diene- Prednisolone Sodium Phosphate, dissolve in water to make ex- 3,20-dione 21-phosphate [125-02-0] actly 100 mL, and use this solution as the sample solution. Pipet 5 mL of the sample solution and Phosphoric Acid Standard So- Prednisolone Sodium Phosphate contains not less lution, add 2.5 mL of hexaammonium heptamolybdate-sulfuric than 97.0% and not more than 103.0% of acid TS and 1 mL of 1-amino-2-naphtol-4-sulfonic acid TS, C21H27Na2O8P, calculated on the anhydrous basis. shake, add water to make exactly 25 mL, and allow to stand at 20±1ºC for 30 minutes. Perform the test with these solutions as Description Prednisolone Sodium Phosphate occurs as a directed under Ultraviolet-visible Spectrophotometry <2.24>, white to pale yellow powder. using a solution prepared with 5 mL of water in the same man- It is freely soluble in water, soluble in methanol, and practi- ner as the blank. Determine the absorbances, AT and AS, of each cally insoluble in ethanol (99.5). solution from the sample solution and standard solution at 740 It is hygroscopic. nm: the content of free phosphoric acid is not more than 1.0% Identification (1) Moisten 1.0 g of Prednisolone Sodium Content (%) of free phosphoric acid (H3PO4) Phosphate with a small amount of sulfuric acid, and gradually = (1/W) × (AT/AS) × 257.8 heat to incinerate. After cooling, dissolve the residue in 10 mL of dilute nitric acid, and heat in a water bath for 30 minutes. Af- W: Amount (mg) of Prednisolone Sodium Phosphate, calcu- ter cooling, filter if necessary. This solution responds to the lated on the anhydrous basis. Qualitative Tests <1.09> for phosphate. (2) Dissolve 2 mg of Prednisolone Sodium Phosphate in 2 (4) Related substances—Dissolve 10 mg of Prednisolone mL of sulfuric acid, and allow to stand for 2 minutes: a deep red Sodium Phosphate in 100 mL of the mobile phase, and use this color, without fluorescence, develops. solution as the sample solution. Pipet 2 mL of this solution, add (3) Determine the absorption spectrum of a solution of the mobile phase to make exactly 100 mL, and use this solution Prednisolone Sodium Phosphate (1 in 50000) as directed under as the standard solution. Perform the test with exactly 20 µL Ultraviolet-visible Spectrophotometry <2.24>, and compare the each of the sample solution and standard solution as directed spectrum with the Reference Spectrum: both spectra exhibit under Liquid Chromatography <2.01> according to the follow- similar intensities of absorption at the same wavelengths. ing conditions. Determine each peak area of both solutions by (4) Determine the infrared absorption spectrum of Predni- the automatic integration method: the area of each peak other solone Sodium Phosphate as directed in the potassium bromide than the peak of prednisolone phosphate from the sample solu- disk method under Infrared Spectrophotometry <2.25>, and tion is not larger than 1.5 times the peak area of prednisolone compare the spectrum with the Reference Spectrum: both spec- phosphate from the standard solution, and the total area of the tra exhibit similar intensities of absorption at the same wave peaks other than the peak of prednisolone phosphate from the numbers. sample solution is not larger than 2.5 times the peak area of (5) The solution obtained in (1) responds to the Qualitative prednisolone phosphate from the standard solution. Tests <1.09> for sodium salt. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: 20 Optical rotation <2.49> [α] D : +96 - +103º (1 g, calculated 245 nm) on the anhydrous basis, phosphate buffer solution, pH 7.0, 100 Column: A stainless steel column 4.6 mm in inside diameter mL, 100 mm). and 10 cm in length, packed with octadecylsilanized silica gel

Supplement II, JP XV Official Monographs 2177 for liquid chromatography (3 µm in particle diameter). Probenecid Tablets Column temperature: A constant temperature of about 40ºC. Mobile phase: Dissolve 6.80 g of potassium dihydrogen プロベネシド錠 phosphate in water to make 1000 mL, and adjust the pH to 2.5 with phosphoric acid. To 1000 mL of this solution add 250 mL Add the following next to the Identification: of acetonitrile. Flow rate: Adjust the flow rate so that the retention time of Uniformity of dosage units <6.02> Perform the test accord- prednisolone phosphate is about 7 minutes. ing to the following method: it meets the requirement of the Time span of measurement: About 4 times as long as the re- Content uniformity test. tention time of prednisolone phosphate. To 1 tablet of Probenecid Tablets add 30 mL of water and 2 System suitability— mL of 1 mol/L hydrochloric acid TS, treat with ultrasonic waves Test for required detectability: Pipet 5 mL of the standard so- with occasional shaking to disintegrate the tablet completely, lution, and add the mobile phase to make exactly 50 mL. Con- and add ethanol (99.5) to make exactly 100 mL. Centrifuge this firm that the peak area of prednisolone phosphate obtained from solution, pipet 3 mL of the supernatant liquid, and add 1 mL of 1 20 µL of this solution is equivalent to 7 to 13% of that of pred- mol/L hydrochloric acid TS and ethanol (99.5) to make exactly nisolone phosphate from the standard solution. 50 mL. Pipet 5 mL of this solution, and add ethanol (99.5) to System performance: When the procedure is run with 20 µL make exactly V mL so that each mL contains about 15 µg of of the standard solution under the above operating conditions, probenecid (C13H19NO4S), and use this solution as the sample the number of theoretical plates and the symmetry factor of the solution. Separately, weigh accurately about 0.125 g of Pro- peak of prednisolone phosphate are not less than 3000 and not benecid Reference Standard, previously dried at 105ºC for 4 more than 2.0, respectively. hours, dissolve in 15 mL of water, 1 mL of 1 mol/L hydrochloric System repeatability: When the test is repeated 6 times with acid TS and ethanol (99.5) to make exactly 50 mL. Pipet 3 mL 20 µL of the standard solution under the above operating condi- of this solution, and add 1 mL of 1 mol/L hydrochloric acid TS tions, the relative standard deviation of the peak area of predni- and ethanol (99.5) to make exactly 50 mL. Pipet 5 mL of this solone phosphate is not more than 2.0%. solution, add ethanol (99.5) to make exactly 50 mL, and use this (5) Residual solvent—Being specified separately. solution as the standard solution. Perform the test with the sample solution and standard solution as directed under Ultravio- Water <2.48> Not more than 8.0% (0.1 g, volumetric titration, let-visible Spectrophotometry <2.24>, using a solution, prepared direct titration). by adding ethanol (99.5) to 1 mL of 0.1 mol/L hydrochloric acid TS to make exactly 50 mL, as the blank, and determine the ab- Assay Weigh accurately about 0.1 g of Prednisolone Sodium sorbances, AT and AS, at 248 nm. Phosphate, and dissolve in water to make exactly 100 mL. Pipet

2 mL of this solution, add 1 mL of alkaline phosphatase TS, and Amount (mg) of probenecid (C13H19NO4S) allow to stand for 2 hours with occasional shaking. To this solu- = WS × (AT/AS) × (V/25) tion add exactly 20 mL of 1-octanol, and shake vigorously. Cen- trifuge this solution, pipet 10 mL of the 1-octanol layer, add WS: Amount (mg) of Probenecid Reference Standard 1-octanol to make exactly 50 mL, and use this solution as the sample solution. Separately, weigh accurately about 25 mg of Add the following: Prednisolone Reference Standard, previously dried at 105ºC for 3 hours, and dissolve in 1-octanol to make exactly 100 mL. Pi- pet 6 mL of this solution, add a solution prepared by adding 1 Probucol mL of alkaline phosphatase TS to 2 mL water and being allowed プロブコール to stand for 2 hours with occasional gentle shaking, add exactly 14 mL of 1-octanol, and shake vigorously. Proceed in the same manner as the sample solution to make the standard solution. Perform the test with the sample solution and standard solution as directed under Ultraviolet-visible Spectrophotometry <2.24>, using 1-octanol as the blank, and determine the absorbances, AT and AS, at 245 nm.

Amount (mg) of prednisolone sodium phosphate C31H48O2S2: 516.84 (C21H27Na2O8P) 4,4´-[Propan-2,2-diylbis(sulfandiyl)]bis[2,6-bis(1,1- = WS × (AT/AS) × 3 × 1.3439 dimethylethyl)phenol] [23288-49-5]

WS: Amount (mg) of Prednisolone Reference Standard Probucol, when dried, contains not less than 98.5% and not more than 101.0% of C H O S . Containers and storage Containers—Tight containers. 31 48 2 2 Description Probucol occurs as a white crystalline powder.

2178 Official Monographs Supplement II, JP XV

It is very soluble in tetrahydrofuran, freely soluble in ethanol System suitability— (99.5), soluble in methanol, and practically insoluble in water. Test for required detectability: Pipet 2 mL of the standard so- It gradually turns light yellow on exposure to light. lution, and add the mobile phase to make exactly 10 mL. Con- firm that the peak area of probucol obtained from 5 µL of this Identification (1) Determine the absorption spectrum of a solution is equivalent to 14 to 26% of that of probucol from the solution of Probucol in methanol (1 in 100000) as directed un- standard solution. der Ultraviolet-visible Spectrophotometry <2.24>, and compare System performance: To 1 mL of the sample solution add the the spectrum with the Reference Spectrum or the spectrum of a mobile phase to make 50 mL. To 1 mL of this solution add 1 mL solution of Probucol Reference Standard prepared in the same of a solution of phthalic acid bis(cis-3,3,5-trimethylcyclohexyl) manner as the sample solution: both spectra exhibit similar in- in the mobile phase (1 in 1000), 5 mL of ethanol (99.5), and the tensities of absorption at the same wavelengths. mobile phase to make 20 mL. When the procedure is run with 5 (2) Determine the infrared absorption spectrum of Probucol µL of this solution under the above operating conditions, as directed in the potassium bromide disk method under Infrared phthalic acid bis(cis-3,3,5-trimethylcyclohexyl) and probucol Spectrophotometry <2.25>, and compare the spectrum with the are eluted in this order with the resolution between these peaks Reference Spectrum or the spectrum of Probucol Reference being not less than 6. Standard: both spectra exhibit similar intensities of absorption at System repeatability: When the test is repeated 6 times with 5 the same wave numbers. µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of probucol is Melting point <2.60> 125 - 128ºC. not more than 5%. Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of (3) Residual solvent—Being specified separately. Probucol according to Method 2, and perform the test. Prepare Loss on drying <2.41> Not more than 0.5% (1 g, in vacuum, the control solution with 2.0 mL of Standard Lead Solution (not 80ºC, 1 hour). more than 10 ppm). (2) Related substances—Conduct this procedure using Residue on ignition <2.44> Not more than 0.1% (1 g). light-resistant vessels. Dissolve 0.40 g of Probucol in 5 mL of ethanol (99.5), add the mobile phase to make 20 mL, and use Assay Weigh accurately about 60 mg each of Probucol and this solution as the sample solution. Pipet 1 mL of this solution, Probucol Reference Standard, previously dried, dissolve each in and add the mobile phase to make exactly 50 mL. Pipet 1 mL of 5 mL of tetrahydrofuran, and add the mobile phase to make ex- this solution, add the mobile phase to make exactly 100 mL, and actly 50 mL. Pipet 5 mL each of these solutions, add exactly 5 use this solution as the standard solution. Perform the test with mL of the internal standard solution and the mobile phase to exactly 5 µL each of the sample solution and standard solution make 100 mL, and use these solutions as the sample solution as directed under Liquid Chromatography <2.01> according to and standard solution. Perform the test with 10 µL each of the the following conditions. Determine each peak area of both so- sample solution and standard solution as directed under Liquid lutions by the automatic integration method: the area of the peak Chromatography <2.01> according to the following conditions, having the relative retention time of about 0.9 with respect to and calculate the ratios, QT and QS, of the peak area of probucol probucol from the sample solution is not larger than the peak to that of the internal standard. area of probucol from the standard solution; the area of peak having the relative retention time of about 1.9 with respect to Amount (mg) of probucol (C31H48O2S2) probucol from the sample solution is no larger than 25 times the = WS × (QT/QS) peak area of probucol from the standard solution; and the area W : Amount (mg) of Probucol Reference Standard of each peak other than the peak of probucol and other than the S peaks mentioned above is not larger than 5 times the peak area Internal standard solution—Dissolve 0.2 g of phthalic acid of probucol from the standard solution. Furthermore, the total bis(cis-3,3,5-trimethylcyclohexyl) in 1 mL of tetrahydrofuran, area of the peaks other than probucol from the sample solution and add the mobile phase to make 50 mL. is not larger than 50 times the peak area of probucol from the Operating conditions— standard solution. For this calculation, use the areas of the peaks, Detector: An ultraviolet absorption photometer (wavelength: having the relative retention times of about 0.9 and about 1.9 242 nm) with respect to probucol, after multiplying by their relative re- Column: A stainless steel column 4.6 mm in inside diameter sponse factors, 1.2 and 1.4, respectively. and 25 cm in length, packed with octadecylsilanized silica gel Operating conditions— for liquid chromatography (5 µm in particle diameter). Detector, column, column temperature, mobile phase and Column temperature: A constant temperature of about 40ºC. flow rate: Proceed as directed in the operating conditions in the Mobile phase: A mixture of acetonitrile and water (93:7) Assay. Flow rate: Adjust the flow rate so that the retention time of Time span of measurement: About 3 times as long as the re- probucol is about 13 minutes. tention time of probucol, beginning after the solvent peak, ex- System suitability— cluding the peak having the relative retention time of about 0.5 System performance: When the procedure is run with 10 µL with respect to probucol. of the standard solution under the above operating conditions,

Supplement II, JP XV Official Monographs 2179 the internal standard solution and probucol are eluted in this or- larger than the peak area of procainamide from the standard so- der with the resolution between these peaks being not less than lution. 6. Operating conditions— System repeatability: When the test is repeated 6 times with Detector: An ultraviolet absorption photometer (wavelength: 10 µL of the standard solution under the above operating condi- 270 nm). tions, the relative standard deviation of the ratio of the peak area Column: A stainless steel column 4.6 mm in inside diameter of probucol to that of the internal standard is not more than and 25 cm in length, packed with octadecylsilanized silica gel 1.0%. for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 40ºC. Containers and storage Containers—Tight containers. Mobile phase: A mixture of 0.02 mol/L phosphate buffer so- Storage—Light-resistant. lution, pH 3.0 and methanol (9:1) Flow rate: Adjust the flow rate so that the retention time of procainamide is about 9 minutes. Procainamide Hydrochloride Time span of measurement: About 2 times as long as the retention time of procainamide. プロカインアミド塩酸塩 System suitability— Test for required detectability: Pipet 10 mL of the standard Change the Origin/limits of contents, Description, solution, and add the mobile phase to make exactly 20 mL. Identification, Purity and Loss on drying to read: Confirm that the peak area of procainamide obtained from 10 µL Procainamide Hydrochloride, when dried, contains of this solution is equivalent to 40 to 60% of that of procaina- not less than 98.0% and not more than 101.0% of mide from the standard solution. System performance: When the procedure is run with 10 µL C13H21N3O·HCl. of the standard solution under the above operating conditions, Description Procainamide Hydrochloride occurs as a white to the number of theoretical plates and the symmetry factor of the light yellow crystalline powder. peak of procainamide are not less than 10000 and not more than It is very soluble in water and soluble in ethanol (99.5). 1.5, respectively. It is hygroscopic. System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- Identification (1) Determine the infrared absorption spec- tions, the relative standard deviation of the peak area of pro- trum of Procainamide Hydrochloride, previously dried, as di- cainamide is not more than 2.0%. rected in the potassium chloride disk method under Infrared Spectrophotometry <2.25>, and compare the spectrum with the Loss on drying <2.41> Not more than 0.3% (2 g, 105ºC, 4 Reference Spectrum: both spectra exhibit similar intensities of hours). absorption at the same wave numbers. (2) A solution of Procainamide Hydrochloride (1 in 20) responds to the Qualitative Tests <1.09> for chloride. Procainamide Hydrochloride

Purity (1) Clarity and color of solution—Dissolve 1.0 g of Injection Procainamide Hydrochloride in 10 mL of water: the solution is プロカインアミド塩酸塩注射液 clear and colorless. (2) Heavy metals <1.07>—Proceed with 2.0 g of Procaina- Change the Origin/limits of content and Identifi- mide Hydrochloride according to Method 2, and perform the cation to read: test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than 10 ppm). Procainamide Hydrochloride Injection is an aqueous (3) Arsenic <1.11>—Prepare the test solution with 1.0 g of solution for injection. Procainamide Hydrochloride according to Method 1, and per- It contains not less than 95.0% and not more than form the test (not more than 2 ppm). 105.0% of the labeled amount of procainamide hydro- (4) Related substances—Dissolve 50 mg of Procainamide chloride (C13H21N3O·HCl: 271.79). Hydrochloride in 100 mL of the mobile phase, and use this solution as the sample solution. Pipet 1 mL of this solution, and add Identification (1) To a volume of Procainamide Hydrochlo- the mobile phase to make exactly 50 mL. Pipet 2 mL of this so- ride Injection, equivalent to 10 mg of Procainamide Hydrochlo- lution, add the mobile phase to make exactly 20 mL, and use ride according to the labeled amount, add 1 mL of dilute hydro- this solution as the standard solution. Perform the test with ex- chloric acid and water to make 5 mL: the solution responds to actly 10 µL each of the sample solution and standard solution as the Qualitative Tests <1.09> (1) for primary aromatic amines. directed under Liquid Chromatography <2.01> according to the (2) To a volume of Procainamide Hydrochloride Injection, following conditions. Determine each peak area of both solu- equivalent to 0.1 g of Procainamide Hydrochloride according to tions by the automatic integration method: the total area of the the labeled amount, add water to make 100 mL. To 1 mL of this peaks other than procainamide from the sample solution is not solution add water to make 100 mL. Determine the absorption

2180 Official Monographs Supplement II, JP XV spectrum of this solution as directed under Ultraviolet-visible WS: Amount (mg) of procainamide hydrochloride for assay Spectrophotometry <2.24>: it exhibits a maximum between 277 nm and 281 nm. Change the Dissolution and Assay to read: (3) Procainamide Hydrochloride Injection responds to the Dissolution <6.10> When the test is performed at 50 revolu- Qualitative Tests <1.09> (2) for chloride. tions per minute according to the Paddle method using 900 mL Add the following next to the Identification: of water as the dissolution medium, the dissolution rate in 30 minutes of Procainamide Hydrochloride Tablets is not less than Bacterial endotoxins <4.01> Less than 0.30 EU/mg. 80%. Start the test with 1 tablet of Procainamide Hydrochloride Foreign insoluble matter <6.06> Perform the test according Tablets, withdraw not less than 30 mL of the medium at the to Method 1: it meets the requirement. specified minute after starting the test, and filter through a membrane filter with a pore size not exceeding 0.8 µm. Discard Insoluble particulate matter <6.07> It meets the require- the first 10 mL of the filtrate, pipet V mL of the subsequent fil- ment. trate, add 2nd fluid for dissolution test to make exactly V´ mL so Sterility <4.06> Perform the test according to the Membrane that each mL contains about 7 µg of procainamide hydrochloride filtration method: it meets the requirement. (C13H21N3O·HCl) according to the labeled amount, and use this solution as the sample solution. Separately, weigh accurately about 0.125 g of procainamide hydrochloride for assay, previ- Procainamide Hydrochloride ously dried at 105ºC for 4 hours, and dissolve in water to make exactly 1000 mL. Pipet 5 mL of this solution, add 2nd fluid for Tablets dissolution test to make exactly 100 mL, and use this solution as the standard solution. Perform the test with the sample solution プロカインアミド塩酸塩錠 and standard solution as directed under Ultraviolet-visible Spec- trophotometry <2.24>, and determine the absorbances, A and Change the Origin/limits of content and Identifi- T A , at 278 nm. cation to read: S Dissolution rate (%) with respect to the labeled amount of Procainamide Hydrochloride Tablets contain not less procainamide hydrochloride (C H N O·HCl) than 95.0% and not more than 105.0% of the labeled 13 21 3 = W × (A /A ) × (V´/V) × (1/C) × (9/2) amount of procainamide hydrochloride S T S (C H N O·HCl: 271.79). 13 21 3 WS: Amount (mg) of procainamide hydrochloride for assay C: Labeled amount (mg) of procainamide hydrochloride Identification To a quantity of powdered Procainamide Hy- (C H N O·HCl) in 1 tablet drochloride Tablets, equivalent to 1.5 g of Procainamide Hy- 13 21 3 drochloride according to the labeled amount, add 30 mL of wa- Assay To 10 Procainamide Hydrochloride Tablets add 300 mL ter, shake well, filter, and use the filtrate as the sample solution. of 0.02 mol/L phosphate buffer solution, pH 3.0, and treat with To 0.2 mL of the sample solution add 1 mL of dilute hydrochlo- ultrasonic waves to disintegrate the tablets completely. To this ric acid and 4 mL of water: the solution responds to the Qualita- solution add 0.02 mol/L phosphate buffer solution, pH 3.0, to tive Tests <1.09> for primary aromatic amines. make exactly 500 mL, and stir for 5 minutes. Centrifuge this solution, pipet V mL of the supernatant liquid, and add 0.02 Add the following next to the Identification: mol/L phosphate buffer solution, pH 3.0, to make V´ mL so that Uniformity of dosage units <6.02> Perform the test accord- each mL contains about 10 µg of procainamide hydrochloride ing to the following method: it meets the requirement of the (C13H21N3O·HCl). Filter this solution through a membrane filter Content uniformity test. with a pore size not exceeding 0.45 µm, discard the first 10 mL To 1 tablet of Procainamide Hydrochloride Tablets add 3V/5 of the filtrate, and use the subsequent filtrate as the sample solu- mL of 0.02 mol/L phosphate buffer solution, pH 3.0, treat with tion. Separately, weigh accurately about 50 mg of procainamide ultrasonic waves to disintegrate the tablet completely, add 0.02 hydrochloride for assay, previously dried at 105ºC for 4 hours, mol/L phosphate buffer solution, pH 3.0, to make exactly V mL dissolve in 0.02 mol/L phosphate buffer solution, pH 3.0, to so that each mL contains about 2.5 mg of procainamide hydro- make exactly 100 mL. Pipet 2 mL of this solution, add 0.02 mol/L phosphate buffer solution, pH 3.0, to make 100 mL, and chloride (C13H21N3O·HCl), and shake for 5 minutes. Centrifuge this solution, pipet 1 mL of the supernatant liquid, add 0.02 use this solution as the standard solution. Perform the test with mol/L phosphate buffer solution, pH 3.0, to make 250 mL, and exactly 10 µL each of the sample solution and standard solution use this solution as the sample solution. Proceed as directed in as directed under Liquid Chromatography <2.01> according to the Assay. the following conditions, and calculate the peak areas, AT and AS, of procainamide in each solution. Amount (mg) of procainamide hydrochloride Amount (mg) of procainamide hydrochloride (C13H21N3O·HCl) (C H N O·HCl) = WS × (AT/AS) × (V/20) 13 21 3

Supplement II, JP XV Official Monographs 2181

= WS × (AT/AS) × (V´/V) × (1/10) tions per minute according to the Paddle method using the sinker, using 900 mL of 2nd fluid for dissolution test as the dis- WS: Amount (mg) of procainamide hydrochloride for assay solution medium, the dissolution rate in 45 minutes of Pro- chlorperazine Maleate Tablets is not less than 75%. Operating conditions— Start the test with 1 tablet of Prochlorperazine Maleate Tab- Detector: An ultraviolet absorption photometer (wavelength: lets, withdraw not less than 20 mL of the medium at the speci- 270 nm) fied minute after starting the test, and filter through a membrane Column: A stainless steel column 4.6 mm in inside diameter filter with a pore size not exceeding 0.45 µm. Discard the first and 25 cm in length, packed with octadecylsilanized silica gel 10 mL of the filtrate, pipet V mL of the subsequent filtrate, add for liquid chromatography (5 µm in particle diameter). the dissolution medium to make exactly V´ mL so that each mL Column temperature: A constant temperature of about 40ºC. contains about 9 µg of prochlorperazine maleate Mobile phase: A mixture of 0.02 mol/L phosphate buffer so- (C H ClN S·2C H O ) according to the labeled amount, and lution, pH 3.0, and methanol (9:1) 20 24 3 4 4 4 use this solution as the sample solution. Separately, weigh accu- Flow rate: Adjust the flow rate so that the retention time of rately about 18 mg of prochlorperazine maleate for assay, pre- procainamide is about 9 minutes. viously dried at 105ºC for 3 hours, and dissolve in methanol to System suitability— make exactly 100 mL. Pipet 5 mL of this solution, add the dis- System performance: When the procedure is run with 10 µL solution medium to make exactly 100 mL, and use this solution of the standard solution under the above operating conditions, as the standard solution. Perform the test with the sample solu- the number of theoretical plates and the symmetry factor of the tion and standard solution as directed under Ultraviolet-visible peak of procainamide are not less than 10000 and not more than Spectrophotometry <2.24>, using the dissolution medium as the 1.5, respectively. blank, and determine the absorbances, A and A , at 255 nm. System repeatability: When the test is repeated 6 times with T S 10 µL of the standard solution under the above operating condi- Dissolution rate (%) with respect to the labeled amount of tions, the relative standard deviation of the peak area of pro- prochlorperazine maleate (C20H24ClN3S·2C4H4O4) cainamide is not more than 1.0%. = WS × (AT/AS) × (V´/V) × (1/C) × 45

WS: Amount (mg) of Prochlorperazine Maleate Reference Prochlorperazine Maleate Tablets Standard C: Labeled amount (mg) of prochlorperazine maleate

プロクロルペラジンマレイン酸塩錠 (C20H24ClN3S·2C4H4O4) in 1 tablet

Add the following next to the Identification: Change the Assay to read:

Uniformity of dosage units <6.02> Perform the test accord- Assay Conduct this procedure using light-resistant vessels. ing to the following method: it meets the requirement of the Weigh accurately the mass of not less than 20 Prochlorperazine Content uniformity test. Maleate Tablets, and powder in an agate mortar. Weigh accu- Conduct this procedure using light-resistant vessels. To 1 rately a portion of the powder, equivalent to about 8 mg of pro- tablet of Prochlorperazine Maleate Tablets add 3V/5 mL of a chlorperazine maleate (C20H24ClN3S·2C4H4O4), add 60 mL of a mixture of dilute phosphoric acid (1 in 500) and ethanol (99.5) mixture of diluted phosphoric acid (1 in 500) and ethanol (99.5) (1:1), treat with ultrasonic waves until the tablet is disintegrated, (1:1), and shake vigorously for 10 minutes. Add exactly 5 mL of and shake vigorously for 10 minutes. Add exactly V/20 mL of the internal standard solution, and add a mixture of diluted the internal standard solution, and a mixture of dilute phospho- phosphoric acid (1 in 500) and ethanol (99.5) (1:1) to make 100 ric acid (1 in 500) and ethanol (99.5) (1:1) to make V mL so that mL. Centrifuge this solution, and use the supernatant liquid as each mL contains about 80 µg of prochlorperazine maleate the sample solution. Separately, weigh accurately about 20 mg

(C20H24ClN3S·2C4H4O4), and use this solution as the sample of Prochlorperazine Maleate Reference Standard, previously solution. Centrifuge this solution, and use the supernatant liquid dried at 105ºC for 3 hours, and dissolve in a mixture of diluted as the sample solution. Proceed as directed in the Assay. phosphoric acid (1 in 500) and ethanol (99.5) (1:1) to make exactly 25 mL. Pipet 10 mL of this solution, add exactly 5 mL of Amount (mg) of prochlorperazine maleate the internal standard solution and a mixture of diluted phospho- (C20H24ClN3S·2C4H4O4) ric acid (1 in 500) and ethanol (99.5) (1:1) to make 100 mL, and = WS × (QT/QS) × (V/250) use this solution as the standard solution. Perform the test with 5 WS: Amount (mg) of Prochlorperazine Maleate Reference µL each of the sample solution and standard solution as directed Standard under Liquid Chromatography <2.01> according to the following conditions, and calculate the ratios, Q and Q , of the peak Internal standard solution—A solution of butyl parahydroxy- T S area of prochlorperazine to that of the internal standard. benzoate in a mixture of diluted phosphoric acid (1 in 500) and ethanol (99.5) (1:1) (1 in 1000). Amount (mg) of prochlorperazine maleate (C H ClN S·2C H O ) Dissolution <6.10> When the test is performed at 50 revolu- 20 24 3 4 4 4 = WS × (QT/QS) × (2/5)

2182 Official Monographs Supplement II, JP XV

20 WS: Amount (mg) of Prochlorperazine Maleate Reference Optical rotation <2.49> [α] D : +184 - +194º (after drying, Standard 0.2 g, ethanol (99.5), 10 mL, 100 mm).

Internal standard solution—A solution of butyl parahydroxy- Melting point <2.60> 128 - 133ºC or 120 - 122ºC. benzoate in a mixture of diluted phosphoric acid (1 in 500) and ethanol (99.5) (1:1) (1 in 1000) Purity Related substances—Dissolve 80 mg of Progesterone Operating conditions— in 2 mL of methanol, and use this solution as the sample solu- Detector: An ultraviolet absorption photometer (wavelength: tion. Pipet 1 mL of this solution, add methanol to make exactly 257 nm) 100 mL, and use this solution as the standard solution. Perform Column: A stainless steel column 4.6 mm in inside diameter the test with these solutions as directed under Thin-layer Chro- and 15 cm in length, packed with octadecylsilanized silica gel matography <2.03>. Spot 5 µL each of the sample solution and for liquid chromatography (5 µm in particle diameter). standard solution on a plate of silica gel with fluorescent indi- Column temperature: A constant temperature of about 25ºC. cator for thin-layer chromatography. Develop the plate with a Mobile phase: A mixture of diluted 0.05 mol/L sodium dihy- mixture of diethyl ether and diethylamine (19:1) to a distance of drogen phosphate TS (1 in 2) and acetonitrile (11:9) about 15 cm, and air-dry the plate. Examine under ultraviolet Flow rate: Adjust the flow rate so that the retention time of light (main wavelength: 254 nm): the spots other than the prin- prochlorperazine is about 5 minutes. cipal spot obtained from the sample solution is not more intense System suitability— than the spot from the standard solution. System performance: When the procedure is run with 5 µL of Assay Weigh accurately about 10 mg each of Progesterone the standard solution under the above operating conditions, and Progesterone Reference Standard, previously dried, and prochlorperazine and the internal standard are eluted in this or- dissolve each in ethanol (99.5) to make exactly 100 mL. Pipet 5 der with the resolution between these peaks being not less than mL each of these solutions, add ethanol (99.5) to make exactly 10. 50 mL, and use these solution as the sample solution and stan- System repeatability: When the test is repeated 6 times with 5 dard solution, respectively. Determine the absorbances, A and µL of the standard solution under the above operating conditions, T A , of the sample solution and standard solution at the wave- the relative standard deviation of the ratio of the peak area of S length of maximum absorption at about 241 nm as directed un- prochlorperazine to that of the internal standard is not more than der Ultraviolet-visible Spectrophotometry <2.24>. 1.0%.

Amount (mg) of progesterone (C21H30O2) = WS × (AT/AS) W : Amount (mg) of Progesterone Reference Standard Progesterone S

プロゲステロン Progesterone Injection

Change the Description, Identification, Optical プロゲステロン注射液 rotation, Melting point, Purity and Assay to read: Change the Origin/limits of content and Identifi- Description Progesterone occurs as white crystals or a white cation to read: crystalline powder. It is soluble in methanol and in ethanol (99.5), and practically Progesterone Injection is an oily solution for injec- insoluble in water. tion. It contains not less than 95.0% and not more than Identification (1) Determine the absorption spectrum of a 105.0% of the labeled amount of progesterone solution of Progesterone in ethanol (99.5) (1 in 100000) as di- (C21H30O2: 314.46). rected under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spectrum or the spec- Identification To 1 mL of Progesterone Injection add 1 mL of trum of a solution of Progesterone Reference Standard prepared diluted ethanol (9 in 10), shake well, take the ethanol layer, in the same manner as the sample solution: both spectra exhibit shake well with 1 mL of petroleum benzin, and use the ethanol similar intensities of absorption at the same wavelengths. layer as the sample solution. Separately, dissolve about 5 mg of (2) Determine the infrared absorption spectrum of Proges- Progesterone Reference Standard in 1 mL of ethanol (99.5), and terone as directed in the potassium bromide disk method under use this solution as the standard solution. Perform the test with Infrared Spectrophotometry <2.25>, and compare the spectrum these solutions as directed under Thin-layer Chromatography with the Reference Spectrum or the spectrum of Progesterone <2.03>. Spot 2 µL each of the sample solution and standard so- Reference Standard: both spectra exhibit similar intensities of lution on a plate of silica gel for thin-layer chromatography. absorption at the same wave numbers. If any difference appears Develop the plate with a mixture of diethyl ether and diethyl- between the spectra, dissolve Progesterone and Progesterone amine (19:1) to a distance of about 10 cm, and air-dry the plate. Reference Standard in ethanol (95), respectively, then evaporate Spray evenly sulfuric acid on the plate, and heat the plate at the ethanol to dryness, and repeat the test on the residues. 105ºC for 10 minutes: the principal spot obtained from the sam-

Supplement II, JP XV Official Monographs 2183 ple solution has the same Rf value as the spot from the standard progesterone to that of the internal standard is not more than solution. 1.0%.

Add the following next to the Extractable volume: Add the following: Foreign insoluble matter <6.06> Perform the test according to Method 1: it meets the requirement. Propafenone Hydrochloride

Insoluble particulate matter <6.07> It meets the require- プロパフェノン塩酸塩 ment.

Sterility <4.06> Perform the test according to the Direct method: it meets the requirement.

Change the Assay to read: and enantiomer C H NO ·HCl: 377.90 Assay Measure the specific gravity of Progesterone Injection. 21 27 3 1-{2-[(2RS)-2-Hydroxy-3-(propylamino)propyloxy]phenyl}- Weigh accurately the mass of Progesterone Injection, equivalent 3-phenylpropan-1-one monohydrochloride [34183-22-7] to about 1 mL, mix with 2 mL of tetrahydrofuran, and add ethanol (99.5) to make exactly V mL so that each mL contains Propafenone Hydrochloride, when dried, contains about 0.5 mg of progesterone (C21H30O2). Pipet 2 mL of this so- not less than 98.5% and not more than 101.0% of lution, add exactly 10 mL of the internal standard solution and C21H27NO3·HCl. ethanol (99.5) to make 20 mL, and use this solution as the sample solution. Separately, weigh accurately about 10 mg of Pro- Description Propafenone Hydrochloride occurs as white gesterone Reference Standard, previously dried in vacuum for 4 crystals or a white crystalline powder. hours using phosphorus (V) oxide as the desiccant, dissolve in 2 It is freely soluble in formic acid, sparingly soluble in metha- mL of tetrahydrofuran, and add ethanol (99.5) to make exactly nol, and slightly soluble in water and in ethanol (99.5). 20 mL. Pipet 2 mL of this solution, add exactly 10 mL of the in- A solution of Propafenone Hydrochloride in methanol (1 in ternal standard solution and ethanol (99.5) to make 20 mL, and 100) shows no optical rotation. use this solution as the standard solution. Perform the test with 5 µL each of the sample solution and standard solution as directed Identification (1) Dissolve 0.1 g of Propafenone Hydro- under Liquid Chromatography <2.01> according to the follow- chloride in 20 mL of water by warming. After cooling, to 3 mL of this solution add water to make 500 mL. Determine the ab- ing conditions, and calculate the ratios, QT and QS, of the peak area of progesterone to that of the internal standard. sorption spectrum of this solution as directed under Ultravio- let-visible Spectrophotometry <2.24>, and compare the spec-

Amount (mg) of progesterone (C21H30O2) trum with the Reference Spectrum: both spectra exhibit similar = WS × (QT/QS) × (V/20) intensities of absorption at the same wavelengths. (2) Determine the infrared absorption spectrum of WS: Amount (mg) of Progesterone Reference Standard Propafenone Hydrochloride as directed in the potassium chloride disk method under Infrared Spectrophotometry <2.25>, and Internal standard solution—A solution of testosterone propi- compare the spectrum with the Reference Spectrum: both spec- onate in ethanol (99.5) (1 in 4000) tra exhibit similar intensities of absorption at the same wave Operating conditions— numbers. Detector: An ultraviolet absorption photometer (wavelength: (3) Dissolve 0.1 g of Propafenone Hydrochloride in 20 mL 241 nm) of water by warming. After cooling, to 10 mL of this solution Column: A stainless steel column 4.6 mm in inside diameter add 1 mL of dilute nitric acid, and filter to separate formed pre- and 15 cm in length, packed with octadecylsilanized silica gel cipitate : the filtrate responds to the Qualitative Tests <1.09> (2) for liquid chromatography (5 µm in particle diameter). for chloride. Column temperature: A constant temperature of about 35ºC. Mobile phase: A mixture of acetonitrile and water (7:3) Melting point <2.60> 172 - 175ºC. Flow rate: Adjust the flow rate so that the retention time of progesterone is about 6 minutes. Purity (1) Heavy metals <1.07>—Proceed with 1.0 g of System suitability— Propafenone Hydrochloride according to Method 4, and perform System performance: When the procedure is run with 5 µL of the test. Prepare the control solution with 2.0 mL of Standard the standard solution under the above operating conditions, Lead Solution (not more than 20 ppm). progesterone and the internal standard are eluted in this order (2) Related substances—Dissolve 0.10 g of Propafenone with the resolution between these peaks being not less than 9. Hydrochloride in 20 mL of the mobile phase in the operating System repeatability: When the test is repeated 6 times with 5 conditions 1, and use this solution as the sample solution. Pipet µL of the standard solution under the above operating conditions, 2 mL of this solution, and add the mobile phase in the operating the relative standard deviation of the ratio of the peak area of conditions 1 to make exactly 50 mL. Pipet 2.5 mL of this solu-

2184 Official Monographs Supplement II, JP XV tion, add 2.5 mL of a solution of diphenyl phthalate in methanol propafenone is not more than 2.0%. (1 in 2000), add the mobile phase in the operating conditions 1 (3) Residual solvent—Being specified separately. to make exactly 100 mL, and use this solution as the standard solution. Perform the test with exactly 10 µL each of the sample Loss on drying <2.41> Not more than 0.5% (1 g,105ºC, 2 solution and standard solution as directed under Liquid Chro- hours). matography <2.01> according to the following conditions 1 and Residue on ignition <2.44> Not more than 0.1% (1 g). 2. Determine each peak area of both solutions by the automatic integration method: the area of each peak other than the peak of Assay Weigh accurately about 0.3 g of Propafenone Hydro- propafenone from the sample solution is not larger than the peak chloride, previously dried, dissolve in 2 mL of formic acid, add area of propafenone from the standard solution. 50 mL of acetic anhydride, and titrate <2.50> with 0.05 mol/L Operating conditions 1— perchloric acid VS (potentiometric titration). Perform a blank Detector: An ultraviolet absorption photometer (wavelength: determination in the same manner, and make any necessary cor- 254 nm). rection. Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel Each mL of 0.05 mol/L perchloric acid VS = 18.90 mg of for liquid chromatography (5 µm in particle diameter). C21H27NO3·HCl. Column temperature: A constant temperature of about 40ºC. Mobile phase: Dissolve 4.6 g of sodium 1-nonanesulfonate Containers and storage Containers—Well-closed containers. and 2.3 g of phosphoric acid in water to make 1000 mL, and filter through a membrane filter with a pore size not exceeding Add the following: 0.45 µm. To 900 mL of the filtrate add 600 mL of acetonitrile. Flow rate: Adjust the flow rate so that the retention time of diphenyl phthalate is about 39 minutes. Propafenone Hydrochloride Tablets Time span of measurement: Beginning after the solvent peak プロパフェノン塩酸塩錠 to the retention time of diphenyl phthalate. System suitability 1— Propafenone Hydrochloride Tablets contain not less System performance: Dissolve 12 mg of Propafenone Hy- than 96.0% and not more than 104.0% of the labeled drochloride and 50 mg of isopropyl benzoate in 100 mL of amount of propafenone hydrochloride methanol. When the procedure is run with 10 µL of this solution (C21H27NO3·HCl: 377.90). under the above operating conditions 1, propafenone and isopropyl benzoate are eluted in this order with the resolution be- Method of preparation Prepare as directed under Tablets, tween these peaks being not less than 5. with Propafenone Hydrochloride. System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- Identification To a quantity of Propafenone Hydrochloride tions 1, the relative standard deviation of the peak area of Tablets, equivalent to 0.3 g of Propafenone Hydrochloride ac- propafenone is not more than 2.0%. cording to the labeled amount, add 60 mL of water, and disinte- Operating conditions 2— grate by warming. After cooling, centrifuge, and to 3 mL of the Detector, column and column temperature: Proceed as di- supernatant liquid add water to make 500 mL. Determine the rected in the operation conditions 1. absorption spectrum of this solution as directed under Ultravio- Mobile phase: Dissolve 7.33 g of sodium 1-decanesulfonate let-visible Spectrophotometry <2.24>: it exhibits maxima be- and 2.3 g of phosphoric acid in water to make 1000 mL, and fil- tween 247 nm and 251 nm, and between 302 nm and 306 nm. ter through a membrane filter with a pore size not exceeding Separately, determine the both maximal absorbances, A1 and A2, 0.45 µm. To 700 mL of the filtrate add 700 mL of acetonitrile. of the solution,: the ratio of A1/A2 is between 2.30 and 2.55. Flow rate: Adjust the flow rate so that the retention time of Uniformity of dosage units <6.02> Perform the test accord- diphenyl phthalate is about 11 minutes. ing to the following method: it meets the requirement of the Time span of measurement: About 2.5 times as long as the Content uniformity test. retention time of diphenyl phthalate. To 1 tablet of Propafenone Hydrochloride Tablets add 30 mL System suitability 2— of a mixture of water and acetonitrile (1:1), shake well to disin- System performance: Dissolve 12 mg of Propafenone Hy- tegrate, add a mixture of water and acetonitrile (1:1) to make drochloride and 50 mg of isopropyl benzoate in 100 mL of exactly 50 mL, and centrifuge. Pipet V mL of the supernatant methanol. When the procedure is run with 10 µL of this solution liquid, equivalent to about 6 mg of propafenone hydrochloride under the above operating conditions 2, propafenone and iso- (C H NO ·HCl), add exactly 5 mL of the internal standard so- propyl benzoate are eluted in this order with the resolution be- 21 27 3 lution, add methanol to make 50 mL, and use this solution as the tween these peaks being not less than 21. sample solution. Proceed as directed in the Assay. System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- Amount (mg) of propafenone hydrochloride tions 2, the relative standard deviation of the peak area of (C21H27NO3·HCl)

Supplement II, JP XV Official Monographs 2185

= WS × (QT/QS) × (10/V) WS: Amount (mg) of propafenone hydrochloride for assay

WS: Amount (mg) of propafenone hydrochloride for assay Internal standard solution—A solution of isopropyl benzoate in methanol (1 in 200) Internal standard solution—A solution of isopropyl benzoate in Operating conditions— methanol (1 in 200) Detector: An ultraviolet absorption photometer (wavelength: 254 nm). Dissolution <6.10> When the test is performed at 50 revolu- Column: A stainless steel column 4.6 mm in inside diameter tions per minute according to the Paddle method, using 900 mL and 15 cm in length, packed with octadecylsilanized silica gel of water as the dissolution medium, the dissolution rate in 30 for liquid chromatography (5 µm in particle diameter). minutes of Propafenone Hydrochloride is not less than 75%. Column temperature: A constant temperature of about 40ºC. Start the test with 1 tablet of Propafenone Hydrochloride Mobile phase: Dissolve 4.6 g of sodium 1-nonanesulfonate Tablets, withdraw not less than 20 mL of the medium at the and 2.3 g of phosphoric acid in water to make 1000 mL, and fil- specified minute after starting the test, and filter through a ter through a membrane filter with a pore size not exceeding membrane filter with a pore size not exceeding 0.5 µm. Discard 0.45 µm. To 900 mL of the filtrate add 600 mL of acetonitrile. the first 10 mL of the filtrate, pipet V mL of the subsequent fil- Flow rate: Adjust the flow rate so that the retention time of trate, add water to make exactly V´ mL so that each mL contains propafenone is about 8 minutes. about 67 µg of propafenone hydrochloride (C H NO ·HCl) 21 27 3 System suitability— according to the labeled amount, and use this solution as the System performance: When the procedure is run with 10 µL sample solution. Separately, weigh accurately about 13 mg of of the standard solution under the above operating conditions, propafenone hydrochloride for assay, previously dried at 105ºC propafenone and the internal standard are eluted in this order for 2 hours, dissolve in water to make exactly 200 mL, and use with the resolution between these peaks being not less than 5. this solution as the standard solution. Determine the absorb- System repeatability: When the test is repeated 6 times with ances, A and A , of the sample solution and standard solution at T S 10 µL of the standard solution under the above operating condi- 305 nm as directed under Ultraviolet-visible Spectrophotometry tions, the relative standard deviation of the ratio of the peak area <2.24>. of propafenone to that of the internal standard is not more than Dissolution rate (%) with respect to the labeled amount of 1.0%. propafenone hydrochloride (C H NO ·HCl) 21 27 3 Containers and storage Containers—Tight containers. = WS × (AT/AS) × (V´/V) × (1/C) × 450

WS: Amount (mg) of propafenone hydrochloride for assay C: Labeled amount (mg) of propafenone hydrochloride Propylthiouracil Tablets

(C21H27NO3·HCl) in 1 tablet プロピルチオウラシル錠 Assay To a quantity of Propafenone Hydrochloride Tablets, equivalent to 1.5 g of propafenone hydrochloride Add the following next to Identification: (C H NO ·HCl), add 70 mL of a mixture of water and acetoni- 21 27 3 Uniformity of dosage units <6.02> Perform the test accord- trile (1:1), shake well to disintegrate, shake well for another 5 ing to the following method: it meets the requirement of the minutes, add a mixture of water and acetonitrile (1:1) to make Content uniformity test. exactly 100 mL, and centrifuge. Pipet 4 mL of the supernatant To 1 tablet of Propylthiouracil Tablets add 3V/4 mL of 2nd liquid, and add methanol to make exactly 50 mL. Pipet 5 mL of fluid for dissolution test, treat with ultrasonic waves until the the solution, add exactly 5 mL of the internal standard solution, tablet is disintegrated, and add 2nd fluid for dissolution test to add methanol to make 50 mL, and use this solution as the sam- make exactly V mL so that each mL contains about 0.25 mg of ple solution. Separately, weigh accurately about 30 mg of propylthiouracil (C H N OS). Filter this solution through a propafenone hydrochloride for assay, previously dried at 105ºC 7 10 2 membrane filter with a pore size not exceeding 0.45 µm, discard for 2 hours, and dissolve in methanol to make exactly 50 mL. the first 5 mL of the filtrate, pipet 2 mL of the subsequent fil- Pipet 10 mL of this solution, add exactly 5 mL of the internal trate, add 2nd fluid for dissolution test to make exactly 100 mL, standard solution, add methanol to make 50 mL, and use this and use this solution as the sample solution. Proceed as directed solution as the standard solution. Perform the test with 10 µL in the Assay. each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the follow- Amount (mg) of propylthiouracil (C7H10N2OS) ing conditions, and calculate the ratios, Q and Q , of the peak T S = WS × (AT/AS) × (V/200) area of propafenone to that of the internal standard.

WS: Amount (mg) of propylthiouracil for assay Amount (mg) of propafenone hydrochloride

(C21H27NO3·HCl) = WS × (QT/QS) × 50

2186 Official Monographs Supplement II, JP XV Change the Dissolution and Assay to read: Protamine Sulfate Injection

Dissolution <6.10> When the test is performed at 75 revolu- プロタミン硫酸塩注射液 tions per minute according to the Paddle method using 900 mL of 2nd fluid for dissolution test as the dissolution medium, the Delete the Purity and Heparin-binding capacity, dissolution rate in 30 minutes of Propylthiouracil Tablets is not and change the Origin/limits of content to read: less than 80%. Start the test with 1 tablet of Propylthiouracil Tablets, with- Protamine Sulfate Injection is an aqueous solution draw not less than 20 mL of the medium at the specified minute for injection. after starting the test, and filter through a membrane filter with a It contains not less than 92.0% and not more than pore size not exceeding 0.8 µm. Discard the first 10 mL of the 108.0% of the labeled amount of Protamine Sulfate. It filtrate, pipet 5 mL of the subsequent filtrate, add the dissolution binds with not less than 100 Units of heparin per mg of medium to make exactly 50 mL, and use this solution as the the labeled amount. sample solution. Separately, weigh about 50 mg of propylthiouracil for assay, previously dried at 105ºC for 2 hours, and Identification (1) Dilute a volume of Protamine Sulfate In- dissolve in the dissolution medium to make exactly 1000 mL. jection, equivalent to 1 mg of Protamine Sulfate according to Pipet 5 mL of this solution, add the dissolution medium to make the labeled amount, with water to make 2 mL, and proceed as 50 mL, and use this solution as the standard solution. Proceed as directed in the Identification (1) under Protamine Sulfate. directed in the Assay. (2) Dilute a volume of Protamine Sulfate Injection, equivalent to 5 mg of Protamine Sulfate according to the labeled Dissolution rate (%) with respect to the labeled amount of amount, with water to make 1 mL, and proceed as directed in

propylthiouracil (C7H10N2OS) the Identification (2) under Protamine Sulfate. = WS × (AT/AS) × (1/C) × 90 Add the following next to the pH:

WS: Amount (mg) of propylthiouracil for assay Bacterial endotoxins <4.01> Less than 6.0 EU/mg. C: Labeled amount (mg) of propylthiouracil (C7H10N2OS) in 1 tablet Add the following next to the Extractable volume: Assay Weigh accurately the mass of not less than 20 Propyl- Foreign insoluble matter <6.06> Perform the test according thiouracil Tablets, and powder. Weigh accurately a portion of the to Method 1: it meets the requirement. powder, equivalent to about 50 mg of propylthiouracil (C7H10N2OS), add 150 mL of 2nd fluid for dissolution test, dis- Insoluble particulate matter <6.07> It meets the require- perse finely the particles with the aid of ultrasonic waves, and ment. add 2nd fluid for dissolution test to make exactly 200 mL. Filter this solution through a membrane filter with a pore size not ex- Sterility <4.06> Perform the test according to the Membrane ceeding 0.45 µm, discard the first 5 mL of the filtrate, pipet 2 filtration method: it meets the requirement. mL of the subsequent filtrate, add 2nd fluid for dissolution test to make exactly 100 mL, and use this solution as the sample so- Assay (1) Protein—Pipet a volume of Protamine Sulfate In- lution. Separately, weigh accurately about 50 mg of propyl- jection, equivalent to about 10 mg of Protamine Sulfate, transfer thiouracil for assay, previously dried at 105ºC for 2 hours, and to a Kjeldahl flask, evaporate on a water bath to dryness with dissolve in 2nd fluid for dissolution test to make exactly 200 mL. the aid of a current of air, determine the nitrogen as directed Pipet 2 mL of this solution, add 2nd fluid for dissolution test to under Nitrogen Determination <1.08>, and calculate the amount make 100 mL, and use this solution as the standard solution. of protein by converting 0.24 mg of nitrogen (N: 14.01) to 1 mg of protein. Determine the absorbance at 274 nm, AT and AS, of the sample solution and standard solution as directed under Ultravio- (2) Heparin-binding activity—Proceed the test as directed let-visible Spectrophotometry <2.24>. in the Heparin-binding capacity under Protamine Sulfate, changing the sample solution (a) as below, and determine the

Amount (mg) of propylthiouracil (C7H10N2OS) amount of heparin bound to 1 mg of protein by dividing by the = WS × (AT/AS) amount of protein. (i) Sample solution (a)—Pipet a volume of Protamine Sul- WS: Amount (mg) of propylthiouracil for assay fate Injection, equivalent to 15.0 mg of Protamine Sulfate according to the labeled amount, and add water to make exactly

100 mL. Repeat this procedure two more times, and designate

the solutions so obtained as the sample solutions (a1), (a2) and (a3).

Supplement II, JP XV Official Monographs 2187

Add the following: tion, pH 6.0 and methanol (7:7:6) to make exactly 20 mL. Pipet 2 mL of this solution, add a mixture of water, 0.05 mol/L phos- Rebamipide phate buffer solution, pH 6.0 and methanol (7:7:6) to make exactly 50 mL, and use this solution as the standard solution. Per- レバミピド form the test with exactly 10 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions. Determine each peak area of both solutions by the automatic integration method: the area of the peak of rebamipide m-chloro isomer, having the relative retention time of about 0.95 with respect to rebamipide,

and enantiomer from the sample solution, is not larger than 3/8 times the area of the peak of rebamipide from the standard solution.

C19H15ClN2O4: 370.79 Operating conditions— (2RS)-2-(4-Chlorobenzoylamino)-3-(2-oxo- Detector: An ultraviolet absorption photometer (wavelength: 1,2-dihydroquinolin-4-yl)propanoic acid [90098-04-7] 222 nm). Column: A stainless steel column 4.6 mm in inside diameter Rebamipide, when dried, contains not less than and 15 cm in length, packed with octadecylsilanized silica gel 99.0% and not more than 101.0% of C19H15ClN2O4. for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 25ºC. Description Rebamipide occurs as a white crystalline powder, Mobile phase: To 300 mL of phosphate buffer solution, pH 6.2, and has a bitter taste. add 750 mL of water. To 830 mL of this solution add 170 mL of It is soluble in N,N-dimethylformamide, very slightly soluble acetonitrile. in methanol and in ethanol (99.5), and practically insoluble in Flow rate: Adjust the flow rate so that the retention time of water. rebamipide is about 20 minutes. A solution of Rebamipide in N,N-dimethylformamide (1 in System suitability— 20) shows no optical rotation. Test for required detectability: Pipet 5 mL of the standard so- Melting point: about 291ºC (with decomposition). lution, and add a mixture of water, 0.05 mol/L phosphate buffer Identification (1) Determine the absorption spectrum of a solution, pH 6.0 and methanol (7:7:6) to make exactly 25 mL. solution of Rebamipide in methanol (7 in 100000) as directed Confirm that the peak area of rebamipide obtained from 10 µL under Ultraviolet-visible Spectrophotometry <2.24>, and com- of this solution is equivalent to 15 to 25% of that of rebamipide pare the spectrum with the Reference Spectrum: both spectra from 10 µL of the standard solution. exhibit similar intensities of absorption at the same wave- System performance: To 1 mL of the sample solution add a lengths. mixture of water, 0.05 mol/L phosphate buffer solution, pH 6.0 (2) Determine the infrared absorption spectrum of Re- and methanol (7:7:6) to make 100 mL. When the procedure is bamipide as directed in the potassium bromide disk method un- run with 10 µL of this solution under the above operating condi- der Infrared Spectrophotometry <2.25>, and compare the spec- tions, the number of theoretical plates and the symmetry factor trum with the Reference Spectrum: both spectra exhibit similar of the peak of rebamipide are not less than 11000 and not more intensities of absorption at the same wave numbers. than 1.2, respectively. (3) Perform the test with Rebamipide as directed under Flame System repeatability: When the test is repeated 6 times with Coloration Test <1.04>(2): a green color appears. 10 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of re- Purity (1) Chloride <1.03>—Dissolve 0.5 g of Rebamipide bamipide is not more than 2.0%. in 40 mL of N,N,-dimethylformamide, and add 6 mL of dilute (4) Related substances— Perform the test with exactly 10 nitric acid and water to make 50 mL. Perform the test using this µL each of the sample solution and standard solution obtained in solution as the test solution. Prepare the control solution as fol- (3) as directed under Liquid Chromatography <2.01> according lows : To 0.40 mL of 0.01 mol/L hydrochloric acid VS add 40 to the following conditions. Determine each peak area of both mL of N,N,-dimethylformamide, 6 mL of dilute nitric acid and solutions by the automatic integration method: each area of the water to make 50 mL (not more than 0.028%). peaks of rebamipide o-chloro isomer and debenzoylated isomer, (2) Heavy metals <1.07>—Proceed with 2.0 g of Rebamip- having the relative retention times of about 0.5 and about 0.7, ide according to Method 2, and perform the test. Prepare the respectively, with respect to rebamipide from the sample solu- control solution with 2.0 mL of Standard Lead Solution (not tion, is not larger than 3/8 times the peak area of rebamipide more than 10 ppm). from the standard solution, the area of each peak other than the (3) Rebamipide m-chloro isomer Dissolve 40 mg of Re- peak mentioned above is not larger than 1/4 times the peak area bamipide in a mixture of water, 0.05 mol/L phosphate buffer of rebamipide from the standard solution, and the total area of solution, pH 6.0, and methanol (7:7:6) to make 100 mL, and use the peaks other than rebamipide from the sample solution is not this solution as the sample solution. Pipet 2 mL of this solution, larger than the peak area of rebamipide from the standard solu- and add a mixture of water, 0.05 mol/L phosphate buffer solution. For the calculation, use the peak area of rebamipide

2188 Official Monographs Supplement II, JP XV o-chloro isomer, after multiplying by the response factor, 1.4. Add the following: Operating conditions— Detector: An ultraviolet absorption photometer (wavelength : Rebamipide Tablets 232 nm). Column: A stainless steel column 4.6 mm in inside diameter レバミピド錠 and 25 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Rebamipide Tablets contain not less than 95.0% and Column temperature: A constant temperature of about 40ºC. not more than 105.0% of the labeled amount of re- Mobile phase: Dissolve 2.44 g of sodium 1-decanesulfonate bamipide (C19H15ClN2O4: 370,79). in 1000 mL of water and to this solution add 1000 mL of Method of preparation Prepare as directed under Tablets, methanol and 10 mL of phosphoric acid. with Rebamipide. Flow rate: Adjust the flow rate so that the retention time of rebamipide is about 12 minutes. Identification To a quantity of powdered Rebamipide Tablets, Time span of measurement: About 3 times as long as the re- equivalent to 30 mg of Rebamipide according to the labeled tention time of rebamipide, beginning after the solvent peak. amount, add 5 mL of a mixture of methanol and ammonia solu- System suitability— tion (28) (9:1), shake for 10 minutes, centrifuge, and use the Test for required detectability: Pipet 5 mL of the standard so- supernatant liquid as the sample solution. Separately, dissolve lution, and add a mixture of water, 0.05 mol/L phosphate buffer 30 mg of rebamipide for assay in 5 mL of a mixture of methanol solution, pH 6.0, and methanol (7:7:6) to make exactly 50 mL. and ammonia solution (28) (9:1), and use this solution as the Confirm that the peak area of rebamipide obtained from 10 µL standard solution. Perform the test with these solutions as di- of this solution is equivalent to 7 to 13% of that of rebamipide rected under Thin-layer Chromatography <2.03>. Spot 5 µL from 10 µL of the standard solution. each of the sample solution and standard solution on a plate of System performance: Dissolve 20 mg of 4-chlorobenzoate in silica gel with fluorescent indicator for thin-layer chromatogra- methanol to make 50 mL. To 5 mL each of this solution and the phy. Develop the plate with a mixture of ethyl acetate, methanol sample solution add a mixture of water, 0.05 mol/L phosphate and formic acid (75:25:2) to a distance of about 10 cm, and buffer solution, pH 6.0, and methanol (7:7:6) to make 50 mL. air-dry the plate. Examine under ultraviolet light (main wave- When the procedure is run with 10 µL of this solution under the length: 254 nm): the principal spot obtained from the sample above operating conditions, rebamipide and 4-chlorobenzoate solution has the same Rf value as the spot from the standard so- are eluted in this order with the resolution between these peaks lution. being not less than 8. System repeatability: When the test is repeated 6 times with Uniformity of dosage units <6.02> Perform the test accord- 10 µL of the standard solution under the above operating condi- ing to the following method: it meets the requirement of the tions, the relative standard deviation of the peak area of re- Content uniformity test. bamipide is not more than 2.0%.relative response To 1 tablet of Rebamipide Tablets add 10 mL of water, shake (5) Residual solvent—Being specified separately. well for 10 minutes, add exactly 10 mL of the internal standard solution, add 10 mL of N,N-dimethylformamide, shake well for Loss on drying <2.41> Not more than 3.0% (1 g, 105ºC, 2 5 minutes, and add N,N-dimethylformamide to make 50 mL. hours). Centrifuge this solution, pipet V mL of the supernatant liquid, equivalent to 3 mg of rebamipide (C H ClN O ), and add 20 Residue on ignition <2.44> Not more than 0.1% (1 g). 19 15 2 4 mL of N,N-dimethylformamide and water to make 50 mL. Filter Assay Weigh accurately about 0.6 g of Rebamipide, previ- this solution through a membrane filter with a pore size not ex- ously dried, dissolve in 60 mL of N,N-dimethylformamide, and ceeding 0.5 µm, discard the first 1 mL of the filtrate, and use the titrate <2.50> with 0.1 mol/L potassium hydroxide VS until the subsequent filtrate as the sample solution. Separately, weigh color of the solution changes from pale yellow to color- accurately about 0.1 g of rebamipide for assay, previously dried less(indicator: 2 drops of phenol red TS). Perform a blank de- at 105ºC for 2 hours, dissolve in N,N-dimethylformamide, and termination in the same manner, and make any necessary cor- add exactly 10 mL of the internal standard solution and rection. N,N-dimethylformamide to make 50 mL. Pipet 1.5 mL of this solution, add 20 mL of N,N-dimethylformamide, add water to Each mL of 0.1 mol/L potassium hydroxide VS make 50 mL, and use this solution as the standard solution.

= 37.08 mg of C19H15ClN2O4 Proceed as directed in the Assay.

Containers and storage Containers—Well-closed containers. Amount (mg) of rebamipide (C19H15ClN2O4) Storage—Light-resistant. = WS × (QT/QS) × (3/2V)

WS: Amount (mg) of rebamipide for assay

Internal standard solution—A solution of acetanilide in N,N-dimethylformamide (1 in 150)

Supplement II, JP XV Official Monographs 2189

Dissolution <6.10> When the test is performed at 50 revolu- Internal standard solution—A solution of acetanilide in tions per minute according to the Paddle method using 900 mL N,N-dimethylformamide (1 in 20) of diluted disodium hydrogen phosphate-citric acid buffer solu- Operating conditions— tion (1 in 4), pH 6.0, as the dissolution medium, the dissolution Detector: An ultraviolet absorption photometer (wavelength: rate in 60 minutes of Rebamipide Tablets is not less than 75%. 254 nm) Start the test with 1 tablet of Rebamipide Tablets, withdraw Column: A stainless steel column 4.6 mm in inside diameter not less than 20 mL of the medium at the specified minute after and 15 cm in length, packed with octadecylsilanized silica gel starting the test, and filter through a membrane filter with a pore for liquid chromatography (5 µm in particle diameter). size not exceeding 0.45 µm. Discard the first 10 mL of the fil- Column temperature: A constant temperature of about 25ºC. trate, pipet V mL of the subsequent filtrate, add the dissolution Mobile phase: To 300 mL of phosphate buffer solution, pH medium to make exactly V´ mL so that each mL contains about 6.2, add 750 mL of water. To 830 mL of this solution add 170

22 µg of rebamipide (C19H15ClN2O4) according to the labeled mL of acetonitrile. amount, and use this solution as the sample solution. Separately, Flow rate: Adjust the flow rate so that the retention time of weigh accurately about 50 mg of rebamipide for assay, previ- rebamipide is about 20 minutes. ously dried at 105ºC for 2 hours, and dissolve in System suitability— N,N-dimethylformamide to make exactly 25 mL. Pipet 2 mL of System performance: When the procedure is run with 20 µL this solution, add the dissolution medium to make exactly 200 of the standard solution under the above operating conditions, mL, and use this solution as the standard solution. Perform the the internal standard and rebamipide are eluted in this order with test with the sample solution and standard solution as directed the resolution between these peaks being not less than 8. under Ultraviolet-visible Spectrophotometry <2.24>, using the System repeatability: When the test is repeated 6 times with dissolution medium as the blank, and determine the absorbances, 20 µL of the standard solution under the above operating condi-

AT and AS, at 326 nm. tions, the relative standard deviation of the ratio of the peak area of rebamipide to that of the internal standard is not more than Dissolution rate (%) with respect to the labeled amount of 1.0%. rebamipide (C19H15ClN2O4) = WS × (AT/AS) × (V´/V) × (1/C) × 36 Containers and storage Containers—Well-closed containers.

WS: Amount (mg) of rebamipide for assay C: Labeled amount (mg) of rebamipide (C19H15ClN2O4) in 1 Rice Starch tablet コメデンプン Assay To 10 Rebamipide Tablets add exactly V/5 mL of the internal standard solution and 50 mL of N,N-dimethylformamide, Delete the Description and Total ash, and change and disintegrate the tablets with the aid of ultrasonic waves. the Definition to read: Shake this solution for 5 minutes, add N,N-dimethylformamide to make V mL so that each mL contains about 10 mg of re- This monograph is harmonized with the European Pharma- bamipide (C19H15ClN2O4). Centrifuge this solution, and to 5 mL copoeia and the U.S. Pharmacopoeia. The parts of the text that ◆ of the supernatant liquid add N,N-dimethylformamide to make are not harmonized are marked with symbols ( ◆). 50 mL. To 2 mL of this solution add 20 mL of Rice starch consists of the starch granules obtained from the N,N-dimethylformamide and water to make 50 mL. Filter, if caryopsis of Oryza sativa Linné (Gramineae). necessary, through a membrane filter with a pore size not exceeding 0.5 µm, and use the filtrate as the sample solution. Add the following next to Definition: Separately, weigh accurately about 0.1 g of rebamipide for assay, ◆Description Rice Starch occurs as a white mass or powder. previously dried at 105ºC for 2 hours, dissolve in It is practically insoluble in water and in ethanol (99.5). N,N-dimethylformamide, and add exactly 2 mL of the internal ◆ standard solution and N,N-dimethylformamide to make 100 mL. Change the Identification to read: To 2 mL of this solution, add 20 mL of N,N-dimethylformamide and water to make 50 mL, and use this solution as the standard Identification (1) Examined under a microscope <5.01> solution. Perform the test with 20 µL each of the sample solution using a mixture of water and glycerin (1:1), Rice Starch presents and standard solution as directed under Liquid Chromatography polyhedral, simple grains 1-10 µm, mostly 4-6 µm, in size. <2.01> according to the following conditions, and calculate the These simple grains often gather in ellipsoidal, compound ratios, QT and QS, of the peak area of rebamipide to that of the grains 50-100 µm in diameter. The granules have a poorly visi- internal standard. ble central hilum and there are no concentric striations. Between orthogonally orientated polarizing plates or prisms, the starch Amount (mg) of rebamipide (C19H15ClN2O4) granules show a distinct black cross intersecting at the hilum. = WS × (QT/QS) × (V/100) (2) To 1 g of Rice Starch add 50 mL of water, boil for 1 minute, and allow to cool: a thin, cloudy mucilage is formed. W : Amount (mg) of rebamipide for assay S (3) To 1 mL of the mucilage obtained in (2) add 0.05 mL of

2190 Official Monographs Supplement II, JP XV diluted iodine TS (1 in 10): an orange-red to dark-blue color is hydrogen peroxide-sodium hydroxide TS in the test-tube. After produced which disappears on heating. 15 minutes, remove the funnel without interrupting the stream of carbon dioxide, and introduce through the opening into the Add the following next to the Identification: flask about 25 g of Rice Starch, accurately weighed, with the aid of 100 mL of water. Apply tap grease to the outside of the con- pH <2.54> To 5.0 g of Rice Starch add 25 mL of freshly nection part of the funnel, and load the funnel. Close the tap of boiled and cooled water, and mix gently for 1 minute to achieve the funnel, pour 80 mL of 2 mol/L hydrochloric acid TS into the suspension. Allow to stand for 15 minutes: the pH of the solu- funnel, open the tap to introduce the hydrochloric acid into the tion is 5.0 to 8.0. flask, and close the tap while several mL of the hydrochloric Change the Purity and Loss on drying to read: acid remains, in order to avoid losing sulfur dioxide. Place the flask in a water bath, and heat the mixture for 1 hour. Open the Purity (1) Iron—To 1.5 g of Rice Starch add 15 mL of 2 tap of the funnel and stop the flow of carbon dioxide and also mol/L hydrochloric acid TS, mix, filter, and use the filtrate as the heating and the cooling water. Transfer the contents of the the test solution. To 2.0 mL of Standard Iron Solution add water test-tube with the aid of a little water to a wide-necked conical to make 20 mL, and use this solution as the control solution. Put flask. Heat on a water-bath for 15 minutes and allow to cool. 10 mL each of the test solution and the control solution in test Add 0.1 mL of bromophenol blue TS, and titrate <2.50> with tubes, add 2 mL of a solution of citric acid (1 in 5) and 0.1 mL 0.1 mol/L sodium hydroxide VS until the color changes from of mercapto acetic acid, and mix. Add ammonia solution (28) to yellow to violet-blue lasting for at least 20 seconds. Perform a these solutions until the color of a litmus paper to change from blank determination in the same manner, and make any neces- red to blue, add water to make 20 mL, and mix. Transfer 10 mL sary correction. Calculate the amount of sulfur dioxide by ap- each of these solutions into test tubes, allow to stand for 5 min- plying the following formula: it is not more than 50 ppm. utes, and compare the color of these solutions against a white background: the color of the test solution is not more intense Amount (ppm) of sulfur dioxide = (V/W) × 1000 × 3.203 than that of the control solution (not more than 10 ppm). W: Amount (g) of the sample (2) Oxidizing substances—To 4.0 g of Rice Starch add 50 V: Amount (mL) of 0.1 mol/L sodium hydroxide VS con- mL of water, shake for 5 minutes, and centrifuge. To 30 mL of sumed the supernatant liquid add 1 mL of acetic acid (100) and 0.5 to 1.0 g of potassium iodide, shake, and allow to stand for 25 to 30 ◆(4) Foreign matter—Under a microscope <5.01>, Rice minutes in the dark. Add 1 mL of starch TS, and titrate <2.50> Starch does not contain starch granules of any other origin. It with 0.002 mol/L sodium thiosulfate VS until the starch-iodine may contain a minute quantity, if any, of fragments of the tissue color disappears. Perform a blank determination in the same of the original plant.◆ manner, and make any necessary correction. Not more than 1.4 mL of 0.002 mol/L sodium thiosulfate VS is required (not more Loss on drying <2.41> Not more than 15.0% (1 g, 130ºC, 90 than 20 ppm, calculated as H2O2). minutes). (3) Sulfur dioxide— (i) Apparatus Use as shown in the figure. Add the following next to the Loss on drying: Residue on ignition <2.44> Not more than 0.6% (1 g).

◆Containers and storage Containers—Well-closed contain- A: Boiling flask (500 mL) ers. B: Funnel (100 mL) ◆

C: Condenser D: Test tube Rokitamycin Tablets

ロキタマイシン錠

Add the following next to Containers and storage: Carbon dioxide Expiration date: 24 months after preparation.

The figures are in mm.

(ii) Procedure Introduce 150 mL of water into the boiling flask, close the tap of the funnel, and pass carbon dioxide through the whole system at a rate of 100 ± 5 mL per minute. Pass cooling water through the condenser, and place 10 mL of

Supplement II, JP XV Official Monographs 2191

the sample solution and standard solution at 600 nm as directed Add the following: under Ultraviolet-visible Spectrophotometry <2.24>, using a Sevoflurane solution, prepared with 4.0 mL of diluted 0.01 mol/L sodium hydroxide TS (1 in 20) in the same manner, as the blank: the セボフルラン absorbance of the sample solution is not more than that of the standard solution (not more than 1 ppm). Fluorine standard solution: Dissolve exactly 2.21 g of sodium fluoride in water to make exactly 1000 mL. Pipet 10 mL of this solution and add water to make exactly 1000 mL. Each mL of this solution contains 0.01 mg of fluorine (F). C H F O:200.05 4 3 7 (3) Related substances—Perform the test with 2 µL of Se- 1,1,1,3,3,3-Hexafluoro-2-(fluoromethoxy)propane voflurane as directed under Gas Chromatography <2.02> ac- [28523-86-6] cording to the following conditions. Determine each peak area Sevoflurane contains not less than 99.0% and not by the automatic integration method and calculate the amount of them by the area percentage method: the amount of the peak of more than 101.0% of C4H3F7O, calculated on the anhydrous basis. hexafluoroisopropyl methyl ether, having the relative retention time of about 0.84 with respect to sevoflurane, is not more than Description Sevoflurane is a clear, colorless, and mobile liq- 0.005%, the amount of each peak other than the peaks of se- uid. voflurane and hexafluoroisopropyl methyl ether is not more than It is very slightly soluble in water. 0.0025%, and the total amount of the peaks other than the peaks It is miscible with ethanol (99.5). of sevoflurane and hexafluoroisopropyl methyl ether is not more It is volatile and inflammable. than 0.005%. 20 Refractive index n D : 1.2745 – 1.2760 Operating conditions— Boiling point: about 58.6°C Detector, column, injection port temperature, detector temperature, carrier gas and split ratio: Proceed as directed in the Identification Transfer about 1 µL of Sevoflurane to a gas cell operating conditions in the Assay. having light path 10 cm in length, and determine the infrared Column temperature: Inject at a constant temperature of about absorption spectrum as directed in the gas sampling method un- 40°C, maintain the temperature for 10 minutes, raise at a rate of der Infrared Spectrophotometry <2.25>, and compare the spec- 10°C per minute to 200°C, and maintain at a constant tempera- trum with the Reference Spectrum or the spectrum of Sevoflu- ture of about 200ºC. rane Reference Standard: both spectra exhibit similar intensities Flow rate: Adjust the flow rate so that the retention time of of absorption at the same wave numbers. sevoflurane is about 7 minutes. Time span of measurement: About 6 times as long as the re- Specific gravity <2.56> d 20 : 1.510 - 1.530 20 tention time of sevoflurane. Purity (1) Acidity or alkalinity— To 50 mL of Sevoflurane System suitability― with 50 mL of freshly boiled and cooled water vigorously for 3 Test for required detectability: To 20 µL of Sevoflurane add minutes. Separate the water layer and use this solution as the o-xylene to make 20 mL. To 1 mL of this solution add o-xylene sample solution. To 20 mL of the sample solution add 1 drop of to make 20 mL, and use this solution as the solution for system bromocresol purple TS and 0.10 mL of 0.01 mol/L sodium hy- suitability test. Pipet 1 mL of the solution for system suitability droxide VS: a red-purple color develops. To 20 mL of the sam- test and add o-xylene to make exactly 10 mL. Confirm that the ple solution add 1 drop of bromocresol purple TS and 0.6 mL of peak area of sevoflurane obtained from 2 µL of this solution is 0.01 mol/L hydrochloric acid VS: a yellow color is produced. equivalent to 7 to 13% of the peak area of sevoflurane from the (2) Soluble fluoride—To 6 g of Sevoflurane add 12 mL of solution for system suitability test. diluted 0.01 mol/L sodium hydroxide TS (1 in 20), and shake System performance: When the procedure is run with 2 µL of for 10 minutes. Transfer 4.0 mL of diluted 0.01 mol/L sodium the solution for system suitability test under the above operating hydroxide solution (1 in 20) layer into a Nessler tube. Add 30 conditions, the number of theoretical plates and symmetry factor mL of a mixture of alizarin complexone TS, acetic of the peak of sevoflurane are not less than 6000 and not more acid-potassium acetate buffer solution, pH4.3 and cerium (III) than 1.5, respectively. nitrate TS (1:1:1), add water to make 50 mL, allow to stand for System repeatability: When the test is repeated 6 times with 2 60 minutes, and use this solution as the sample solution. Sepa- µL of the solution for system suitability test under the above op- rately, transfer 0.2 mL of the fluorine standard solution and 4.0 erating conditions, the relative standard deviation of the peak mL of diluted 0.01 mol/L sodium hydroxide TS (1 in 20) into a area of Sevoflurane is not more than 5.0%. Nessler tube, and add 30 mL of a mixture of alizarin complex- (4) Residual solvent―Being specified separately. one TS, acetic acid-potassium acetate buffer solution, pH4.3 and (5) Residue on evaporation―Evaporate 10 mL of Sevoflu- cerium (III) nitrate TS (1:1:1). Proceed in the same manner as rane, exactly measured, on a water bath to dryness, and dry at directed for the preparation of the sample solution, and use this 105°C for 2 hours: the mass of the residue is not more than 1.0 solution as the standard solution. Determine the absorbances of mg.

2192 Official Monographs Supplement II, JP XV

Water <2.48> 0.04 - 0.2 w/v% (5 mL, volumetric titration, Add the following: direct titration).

Assay Pipet 5 mL each of Sevoflurane and Sevoflurane Simvastatin Reference Standard (separately determine the water content シンバスタチン <2.48> using the same manner as Sevoflurane), to each add exactly 5 mL of dimethoxymethane as an internal standard, and use these solutions as the sample solution and standard solution, respectively. Perform the test with 1 µL each of the sample solution and standard solution as directed under Gas Chromatogra- phy <2.02> according to the following conditions, and calculate the ratios, QT and QS, of the peak area of sevoflurane to that of the internal standard. C25H38O5:418.57 Amount (mg) of sevoflurane (C4H3F7O) (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy- = VS × (QT / QS) × 1000 × 1.521 6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl- 1,2,3,7,8,8a-hexahydronaphthalen-1-yl VS: Amount (mL) of Sevoflurane Reference Standard, calcu- 2,2-dimethylbutanoate [79902-63-9] lated on the anhydrous basis. 20 Simvastatin contains not less than 98.0% and not 1.521: Specific gravity of Sevoflurane (d 20 ) more than 101.0% of C25H38O5, calculated on the dried Operating conditions— basis. Detector: A hydrogen flame-ionization detector. It may contain a suitable antioxidant. Column: A fused silica column 0.32 mm in inside diameter and 30 m in length, coated inside with cyanopropyl methyl- Description Simvastatin occurs as a white, crystalline powder. phenyl silicone for gas chromatography in 1.8 µm thickness. It is freely soluble in acetonitrile, in methanol and in ethanol Column temperature: 40°C (99.5), and practically insoluble in water. Injection port temperature: A constant temperature of about 200°C. Identification (1) Determine the absorption spectrum of a Detector temperature: A constant temperature of about 225°C. solution of Simvastatin in acetonitrile (1 in 100000) as directed Carrier gas: Helium. under Ultraviolet-visible Spectrophotometry <2.24> and com- Flow rate: Adjust the flow rate so that the retention time of pare the spectrum with the Reference Spectrum or the spectrum Sevoflurane is about 3 minutes. of a solution of Simvastatin Reference Standard prepared in the Split ratio: 1:20. same manner as the sample solution: both spectra exhibit similar System suitability― intensities of absorption at the same wavelengths. System performance: When the procedure is run with 1 µL of (2) Determine the infrared absorption spectrum of Simvas- the standard solution under the above operating conditions, se- tatin as directed in the potassium bromide disk method under voflurane and the internal standard are eluted in this order with Infrared Spectrophotometry <2.25>, and compare the spectrum the resolution between these peaks being not less than 3. with the Reference Spectrum or the spectrum of Simvastatin System repeatability: When the test is repeated 6 times with 1 Reference Standard: both spectra exhibit similar intensities of µL of the standard solution under the above operating conditions, absorption at the same wave numbers. the relative standard deviation of the ratio of the peak area of 20 sevoflurane to that of the internal standard is not more than Optical rotation <2.49> [a] D : +285 - +300º (50 mg calcu- 1.0 %. lated on the dried basis, acetonitrile, 10 mL, 100 mm).

Containers and storage Containers―Tight containers. Purity (1) Clarity and color of solution—Dissolve 1 g of Simvastatin in 10 mL of methanol: the solution is clear. Perform the test with this solution as directed under Ultraviolet-visible Spectrophotometry <2.24>: the absorbance at 440 nm is not more than 0.10. (2) Heavy metals <1.07>—To 1.0 g of Simvastatin add 2 mL of sulfuric acid, and heat gently to carbonize. After cooling, add 2 mL of nitric acid and 1 mL of sulfuric acid, heat gently until the white fumes no more evolve, and heat to incinerate at 500 to 600°C. If the incineration is not accomplished, add 0.5 mL of nitric acid, heat in the same manner as above, and ignite at 500 to 600°C to incinerate completely. After cooling, add 2 mL of hydrochloric acid, proceed with this solution according to Method 2, and perform the test. Prepare the control solution by

Supplement II, JP XV Official Monographs 2193 using the same quantities of the same reagents as directed for System repeatability: When the test is repeated 6 times with 5 the preparation of the test solution, and add 2.0 mL of Standard µL of the solution for system suitability test under the above Lead solution and water to make 50 mL (not more than 20 conditions, the relative standard deviation of the peak area of ppm). simvastatin is not more than 1.0 %. (3) Related substances―Dissolve 30 mg of Simvastatin in (4) Residual solvent―Being specified separately. 20 mL of a mixture of acetonitrile and 0.01 mol/L potassium Loss on drying <2.41> Not more than 0.5% (1 g, in vacuum dihydrogen phosphate TS, pH 4.0, (3:2), and use this solution as not exceeding 0.67 kPa, 60°C, 3 hours). the sample solution. Perform the test with 5 µL of the sample solution as directed under Liquid Chromatography <2.01> ac- Residue on ignition <2.44> Not more than 0.1% (1 g). cording to the following conditions. Determine each peak area Assay Weigh accurately about 30 mg each of Simvastatin and from the sample solution by the automatic integration method, Simvastatin Reference Standard (previously determine the loss and calculate the amount of them by the area percentage on drying <2.41> in the same manner as Simvastatin), dissolve method: the amounts of the peaks , having the relative retention each in a mixture of acetonitrile and 0.01 mol/L potassium di- times of about 0.45, about 0.80, about 2.42, and about 3.80 with hydrogen phosphate TS, pH 4.0, (3:2) to make exactly 20 mL, respect to simvastatin are not more than 0.2%, respectively; the and use these solutions as the sample solution and the standard amount of the peak wsith a relative retention time of about 2.38 solution, respectively. Perform the test with exactly 5 µL each of is not more than 0.3%; the amount of the peak with a relative the sample solution and standard solution as directed under Liq- retention time of about 0.60 is not more than 0.4%; and the uid Chromatography <2.01> according to the following condi- amount of each peak other than simvastatin and other than the tions, and determine the peak areas, A and A , of simvastatin peaks mentioned above is not more than 0.1%. Furthermore, the T S for each solution. total amount of the peaks other than simvastatin and other than the peak with relative retention time of about 0.60 with respect Amount (mg) of simvastatin (C25H38O5) = WS × (AT / AS) to simvastatin is not more than 1.0 %. Operating conditions— WS: Amount (mg) of Simvastatin Reference Standard , calcu- Detector, column, and column temperature: Proceed as di- lated on the dried basis rected in the operating conditions in the Assay. Operating conditions— Mobile phase A: A mixture of diluted phosphoric acid (1 in Detector: An ultraviolet absorption photometer (wavelength: 1000) and acetonitrile for liquid chromatography (1:1). 238 nm). Mobile phase B: A solution of phosphoric acid in acetonitrile Column: A stainless steel column 4.6 mm in inside diameter for liquid chromatography (1 in 1000). and 33 mm in length, packed with octadecylsilanized silica gel Flowing of mobile phase: Control the gradient by mixing the for liquid chromatography (3 µm in particle diameter). mobile phases A and B as directed in the following table. Column temperature: A constant temperature of about 25°C. Time after injec- Mobile phase A Mobile phase B Mobile phase: A mixture of diluted phosphoric acid (1 in tion of sample (vol%) (vol%) 1000) and acetonitrile for liquid chromatography (1:1). (min) Flow rate: Adjust the flow rate so that the retention time of 0 - 4.5 100 0 simvastatin is about 3 minutes. 4.5 - 4.6 100 → 95 0 → 5 System suitability― System performance: Dissolve 3 mg of lovastatin in 2 mL of 4.6 - 8.0 95 → 25 5 → 75 the standard solution. When the procedure is run with 5 µL of 8.0 - 11.5 25 75 this solution under the above operating conditions, lovastatin Flow rate: 3.0 mL per minute. and simvastatin are eluted in this order with the resolution be- Time span of measurement: About 5 times as long as the re- tween these peaks being not less than 3. tention time of simvastatin. System repeatability: When the test is repeated 6 times with 5 System suitability― µL of the standard solution under the above operating conditions, Proceed as directed in the system suitability in the Assay. the relative standard deviation of the peak area of simvastatin is Test for required detectability: Pipet 0.5 mL of the sample not more than 1.0 %. solution, add a mixture of acetonitrile and 0.01 mol/L potassium Containers and storage Containers―Tight containers. dihydrogen phosphate TS, pH 4.0 (3:2), to make exactly 100 mL, and use this solution as the solution for system suitability Storage—Under nitrogen atmosphere. test. Pipet 2 mL of the solution for system suitability test, add a mixture of acetonitrile and 0.01 mol/L potassium dihydrogen phosphate TS, pH 4.0 (3:2), to make exactly 10 mL. Confirm that the peak area of simvastatin obtained from 5 µL of this solution is equivalent to 16 to 24% of the peak area of simvastatin in the solution for system suitability test. System performance: Proceed as directed in the system suitability in the Assay.

2194 Official Monographs Supplement II, JP XV

Add the following: ride is 200 to 300 seconds: the maximum viscosity calculated on the dried basis is between 10.0 and 19.5 dL/g or between 25.0 Purified Sodium Hyaluronate and 55.0 dL/g.

精製ヒアルロン酸ナトリウム Purity (1) Clarity and color of solution—Dissolve 0.10 g of Purified Sodium Hyaluronate in 10 mL of water: the solution is clear and colorless. (2) Chloride <1.03>—Dissolve 0.20 g of Purified Sodium Hyaluronate in 15 mL of water, add 6 mL of dilute nitric acid, and heat on a water bath for 30 minutes. After cooling, add water to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution with 0.70 mL of 0.01 mol/L hydrochloric acid VS (not more than 0.124%). (3) Heavy metals <1.07>—Proceed with 1.0 g of Purified Sodium Hyaluronate according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead (C14H20NNaO11)n Solution (not more than 20 ppm). [9067-32-7] (4) Residual solvent—Being specified separately. (5) Protein—Weigh accurately about 20 mg of Purified So- Purified Sodium Hyaluronate is the sodium salt of dium Hyaluronate, calculated on the dried basis, dissolve in 1.0 glycosaminoglycans composed of disaccharide units of mL of dilute sodium hydroxide TS, and use this solution as the D-glucuronic acid and N-acetyl-D-glucosamine ob- sample solution. Separately, weigh accurately about 10 mg of tained from cockscomb or microorganisms. bovine serum albumin, dissolve in dilute sodium hydroxide TS It contains not less than 90.0% and not more than to make exactly 1000 mL, and use this solution as the standard 105.5% of sodium hyaluronate (C H NNaO ) , cal- 14 20 11 n solution. To 1.0 mL each of the sample solution and standard culated on the dried basis. solution add 5.0 mL of alkaline copper TS (2), immediately stir, It is composed of an average molecular mass of the allow to stand at room temperature for 10 minutes, add 0.5 mL sodium salt of hyaluronic acid between 500,000 and of diluted Folin’s TS (1 in 2), immediately stir, and allow to 1,200,000 or between 1,500,000 and 3,900,000. stand at room temperature for 30 minutes. Perform the test with The average molecular mass of Purified Sodium these solutions as directed under Ultraviolet-visible Spectro- Hyaluronate should be labeled. photometry <2.24>, using a solution, prepared with 1.0 mL of Description Purified Sodium Hyaluronate occurs as white dilute sodium hydrochloride in the same manner, as the blank: powder, granules or fibrous masses. the absorbance of the sample solution at 750 nm does not ex- It is sparingly soluble in water, and practically insoluble in ceed the absorbance of the standard solution (not more than ethanol (99.5). 0.05%). It is hygroscopic. (6) Nucleic acid— Determine the absorbance of a solution of 0.10 g Purified Sodium Hyaluronate in 50 mL of water as di- Identification (1) Determine the infrared absorption spec- rected under Ultraviolet-visible Spectrophotometry <2.24>, us- trum of Purified Sodium Hyaluronate, previously dried, as di- ing water as the blank: the absorbance at 260 nm is not more rected in the potassium bromide disk method under Infrared than 0.02. Spectrophotometry <2.25>, and compare the spectrum with the (7) Other acidic mucopolysaccharides—(In the case of Reference Spectrum: both spectra exhibit similar intensities of chicken-derived samples) Dissolve 0.25 g of Purified Sodium absorption at the same wave numbers. Hyaluronate in 100 mL of water, and use this solution as the (2) A solution of Purified Sodium Hyaluronate (1 in 1000) sample solution. Immerse a cellulose acetate membrane 6 cm in responds to the Qualitative Tests <1.09> (1) for sodium salt. length in 0.2 mol/L pirydine-formic acid buffer solution, pH 3.0. Take out the membrane and remove excessive buffer solution Viscosity <2.53> Weigh accurately an amount of Purified So- using a filter paper. Place the membrane in an electrophoresis dium Hyaluronate so that the downflowing time of its solution vessel saturated with 0.2 mol/L pyridine-formic acid buffer so- in 100 mL of 0.2 mol/L sodium chloride TS is 2.0 to 2.4 times lution, pH 3.0, and run at 0.5 mA/cm for 1 minute. Apply 2 µL longer than that of 0.2 mol/L sodium chloride TS, dissolve in of the sample solution to the membrane in an area 1 cm in width 0.2 mol/L sodium chloride TS to make exactly 100 mL, and use at 1.5 cm from the anode. Carry out electrophoresis at 0.5 this solution as the sample solution (1). Pipet 16 mL, 12 mL and mA/cm for 1 hour. After the electrophoresis, stain the membrane 8 mL of the sample solution (1), to each add 0.2 mol/L sodium by immersing it in Alcian blue staining solution for 10 to 20 chloride TS to make exactly 20 mL, and use these solutions as minutes. After staining, decolorize sufficiently with diluted ace- the sample solutions (2), (3) and (4), respectively. Perform the tic acid (100) (3 in 100): no bands other than the principal band test with the sample solutions (1), (2), (3) and (4) as directed appears. under Method 1 at 30 ± 0.1ºC using a Ubbelohde-type viscome- (8) Hemolytic streptococci—(In the case of microorgan- ter in which the downflowing time for 0.2 mol/L sodium chlo- ism-derived samples) Dissolve 0.5 g of Purified Sodium Hyalu-

Supplement II, JP XV Official Monographs 2195 ronate in sterile isotonic sodium chloride solution to make ex- lution at the wavelength of maximum absorption at 530 nm as actly 100 mL. Take 0.5 mL of this solution, apply to 2 blood directed under Ultraviolet-visible Spectrophotometry <2.24>, agar plates, respectively, using a Conradi stick, and incubate at using a solution, prepared with 1 mL of water in the same man- 37ºC for 48 hours: no hemolytic colonies appear, or if any, no ner, as the blank. streptococci are observed in the colony under a microscope. (9) Hemolysis—(In the case of microorganism-derived Amount (mg) of sodium hyaluronate [(C14H20NNaO11)a] samples) Dissolve 0.40 g of Purified Sodium Hyaluronate in = WS × (AT/AS) × 2.2786 sterile physiological saline to make exactly 100 mL. To 0.5 mL W : Amount (mg) of D-Glucuronolactone Reference Standard of this solution add 0.5 mL of 1% blood suspension, mix, allow S to stand at 37ºC for 2 hours, and, if necessary, centrifuge at 3000 Containers and storage Containers—Tight containers. revolutions per minute for 10 minutes: the erythrocytes precipi- Storage—Light-resistant, at not exceeding 15ºC. tate and the supernatant liquid is clear as in a blank determination performed in the same manner using 0.5 mL of isotonic sodium chloride as the blank and 0.5 mL of sterile purified water as the positive control. Sodium Iotalamate Injection

Loss on drying <2.41> Not more than 15.0% (0.1 g, reduced イオタラム酸ナトリウム注射液 pressure not exceeding 0.67 kPa, phosphorus (V) oxide, 60ºC, 5 Add the following next to Extractable volume: hours). Foreign insoluble matter <6.06> Perform the test according Microbial limit <4.05> The allowable limits of the total aero- to Method 1: it meets the requirement. bic microbial count and of the total combined yeasts/molds 2 1 count for Purified Sodium Hyaluronate are 10 CFU/g and 10 Insoluble particulate matter <6.07> It meets the require- CFU/g, respectively. ment.

Average molecular mass (1) In the case of the labeled av- Sterility <4.06> Perform the test according to the Direct erage molecular mass of between 500,000 and 1,200,000 method: it meets the requirement. Calculate the average molecular mass of Purified Sodium Hya- luronate according to the following equation: it is between 500,000 and 1,200,000. For [η], use the maximum viscosity un- Sodium Valproate der Viscosity Determination. バルプロ酸ナトリウム Average molecular mass = ([η] × 105 / 36)1/0.78 Change the Origin/limits of content, Description, (2) In the case of the labeled average molecular mass of Identification and Purity to read: between 1,500,000 and 3,900,000 Calculate the average molecular mass of Purified Sodium Sodium Valproate, when dried, contains not less Hyaluronate according to the following equation: it is between than 98.5% and not more than 101.0% of C8H15NaO2. 1,500,000 and 3,900,000. For [η], use the maximum viscosity Description Sodium Valproate occurs as a white, crystalline under Viscosity Determination. powder.

Average molecular mass = ([η] × 105 / 22.8)1/0.816 It is very soluble in water, freely soluble in ethanol (99.5) and in acetic acid (100). It is hygroscopic. Assay Weigh accurately about 50 mg of Purified Sodium Hyaluronate, and dissolve in water to make exactly 50 mL. Pi- Identification (1) To 5mL of a solution of Sodium Val- pet 1 mL of this solution, add water to make exactly 20 mL, and proate (1 in 20) add 1 mL of a solution of cobalt (II) nitrate use this solution as the sample solution. Separately, weigh accu- hexahydrate (1 in 20) and warm on a water bath: a purple precipitate is formed. rately about 20 mg of D-Glucuronolactone Reference Standard, previously dried (under reduced pressure not exceeding 0.67 (2) Dissolve 0.5 g of Sodium Valproate in 5 mL of water, kPa, silica gel, 24 hours), and dissolve in water to make exactly add 5 mL of diethyl ether and 1 mL of 2 mol/L hydrochloric 100 mL. Pipet 1 mL of this solution, add water to make exactly acid TS, and shake vigorously for 1 minute. Separate the diethyl 10 mL, and use this solution as the standard solution. Pipet 1 mL ether layer, dehydrate with anhydrous sodium sulfate, and filter. each of the sample solution and standard solution, gently add Evaporate the solvent of the filtrate, determine the infrared into the 5.0 mL of sodium tetraborate-sulfuric acid TS, previ- spectrum of the residue as directed in the liquid film method ously cooled in ice water, stir while cooling, heat in a water bath under Infrared Spectrophotometry <2.25>, and compare the for 10 minutes, and cool in ice water. To each solution add 0.2 spectrum with the Reference Spectrum: both spectra exhibit mL of carbazole TS, stir well, heat in a water bath for 15 min- similar intensities of absorption at the same wave numbers. utes, and cool in ice water to room temperature. Determine the (3) A solution of Sodium Valproate (1 in 10) responds to the Qualitative Tests <1.09> for sodium salt. absorbances, AT and AS, of the sample solution and standard so-

2196 Official Monographs Supplement II, JP XV

Purity (1) Heavy metals <1.07>―Dissolve 2.0 g of Sodium Method of preparation Prepare as directed under Syrups, Valproate in 44 mL of water, shake with 6 mL of dilute hydro- with Sodium Valproate. chloric acid, allow to stand for 5 minutes, and filter. Discard the first 5 mL of the filtrate, neutralize the subsequent 25 mL with Identification To a volume of Sodium Valproate Syrup, ammonia TS, and add 2 mL of dilute acetic acid and water to equivalent to 50 mg of Sodium Valproate according to the la- make 50 mL. Perform the test using this solution as the test so- beled amount, add water to make 10 mL. To 5 mL of this solu- lution. Prepare the control solution as follows: to 2.0 mL of tion add 1 mL of a solution of cobalt (II) nitrate hexahydrate (1 Standard Lead Solution add 2 mL of dilute acetic acid and water in 20) and warm on a water bath: a purple precipitate is formed. to make 50 mL (not more than 20 ppm). Microbial Limit Test <4.05> Acceptance criteria for the to- (2) Related substances―Dissolve 0.10 g of Sodium Val- tal aerobic microbial count and the total combined yeasts and proate in 10 mL of a mixture of formic acid and methyl acetate moulds are 102 CFU and 101 CFU per mL of Sodium Valproate (1:1), and use this solution as the sample solution. Pipet 1 mL of Syrup, respectively, with no Escherichia coli present. the sample solution, add a mixture of formic acid and methyl acetate (1:1) to make exactly 200 mL, and use this solution as Assay Pipet a volume of Sodium Valproate Syrup, equivalent the standard solution. Perform the test with exactly 2 µL each of to about 0.1 g of sodium valproate (C8H15NaO2) and add water the sample solution and standard solution as directed under Gas to make exactly 100 mL. Pipet 20 mL of this solution, add ex- Chromatography <2.02> according to the following conditions. actly 5 mL of internal standard solution, and use this solution as Determine each peak area of both solutions by automatic inte- the sample solution. Separately, weigh accurately about 50 mg gration method: the total area of the peaks other than the peak of of sodium valproate for assay , previously dried at 105°C for 3 valproic acid from the sample solution is not more than the peak hours, dissolve in water to make exactly 50 mL. Pipet 20 mL of area of valproic acid from the standard solution. this solution, add exactly 5 mL of the internal standard solution, Operating conditions— and use this solution as the standard solution. Perform the test Detector: A hydrogen flame-ionization detector. with 10 µL each of the sample solution and standard solution as Column: A glass column 3 mm in diameter and 2 m in length, directed under Liquid Chromatography <2.01> according to the packed with siliceous earth for gas chromatography (150 to 180 following conditions, and calculate the ratios, QT and QS, of the µm in particle diameter) coated with diethylene glycol adipate peak area of valproic acid to that of the internal standard. ester for gas chromatography and phosphoric acid at the ratios of 5% and 1%, respectively. Amount (mg) of sodium valproate (C8H15NaO2) Column temperature: A constant temperature of about 145°C. = WS × (QT / QS) × 2 Carrier gas: Nitrogen. WS: Amount (mg) of sodium valproate for assay Flow rate: Adjust the flow rate so that the retention time of valproic acid is about 7 minutes. Internal standard solution—A solution of ethyl parahydroxy- Time span of measurement: About 2 times as long as the re- benzoate in the mobile phase (1 in 50000) tention time of valproic acid, beginning after the solvent peak. Operating conditions— System suitability― Detector: An ultraviolet absorption photometer (wavelength: System performance: To 2 mL of the sample solution and 8 210 nm). µL of n-valerianic acid, add a mixture of formic acid and methyl Column: A stainless steel column 4.6 mm in inside diameter acetate (1:1) to make 10 mL. When the procedure is run with 2 and 15 cm in length packed with octadecylsilanized silica gel µL of this solution under the above operating conditions, for liquid chromatography (5 µm in particle diameter). n-valerianic acid and valproic acid are eluted in this order with Column temperature: A constant temperature of about 25°C. the resolution between these peaks being not less than 5. Mobile phase: A mixture of 0.05 mol/L sodium dihydrogen- System repeatability: Pipet 2 mL of the standard solution and phosphate TS, pH 3.0 and acetonitrile (1:1). add a mixture of formic acid and methyl acetate (1:1) to make Flow rate: Adjust the flow rate so that the retention time of exactly 10 mL. When the test is repeated 6 times with 2 µL of valproic acid is about 6 minutes. this solution under the above operating conditions, the relative System suitability― standard deviation of the peak area of valproic acid is not more System performance: When the procedure is run with 10 µL than 5.0%. of the standard solution under the above operating conditions, the internal standard and valproic acid are eluted in this order with the resolution between these peaks being not less than 7. Add the following: System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- Sodium Valproate Syrup tions, the relative standard deviation of the ratio of the peak area バルプロ酸ナトリウムシロップ of valproic acid to that of the internal standard is not more than 1.0%. Sodium Valproate Syrup contains not less than 95.0% and not more than 105.0% of the labeled Containers and storage Containers―Tight containers. amount of sodium valproate (C8H15NaO2: 166.19).

Supplement II, JP XV Official Monographs 2197

ing conditions, and determine the peak areas, A and A , of the Add the following: T S valproic acid in each solution. Sodium Valproate Tablets Dissolution rate (%) with respect to the labeled amount of バルプロ酸ナトリウム錠 sodium valproate (C8H15NaO2) = WS × (AT / AS)×(V ´/ V )×(1 / C)× 180 Sodium Valproate Tablets contain not less than 95.0% and not more than 105.0% of the labeled WS: Amount (mg) of sodium valproate for assay C: Labeled amount (mg) of sodium valproate (C H NaO ) in amount of sodium valproate (C8H15NaO2: 166.19). 8 15 2 1 tablet. Method of preparation Prepare as directed under Tablets, with Sodium Valproate. Operating conditions— Proceed as directed in the Assay. Identification To a quantity of powdered Sodium Valproate System suitability― Tablets, equivalent to 0.5 g of Sodium Valproate according to System performance: When the procedure is run with 50 µL the labeled amount, add 10 mL of water, shake well, and centri- of the standard solution under the above operating conditions, fuge. To 5 mL of the supernatant liquid add 1 mL of a solution the number of theoretical plates and symmetry factor of the peak of cobalt (II) nitrate hexahydrate (1 in 20) and warm on a water of valproic acid are not less than 3000 and not more than 2.0, bath: a purple precipitate is formed. respectively. System repeatability: When the test is repeated 6 times with Uniformity of dosage units <6.02> Perform the test accord- 50 µL of the standard solution under the above operating condi- ing to the following method: it meets the requirement of the tions, the relative standard deviation of the peak area of valproic Content uniformity test. acid is not more than 1.5%. To 1 tablet of Sodium Valproate Tablets add 7 V/10 mL of the mobile phase, shake vigorously, add the mobile phase to Assay Weigh accurately the mass of not less than 20 Sodium make exactly V mL so that each mL contains about 1 mg of so- Valproate Tablets, and powder. Weigh accurately a portion of dium valproate (C8H15NaO2), and centrifuge. Filter the super- the powder, equivalent to about 0.2 g of sodium valproate natant liquid, pipet 20 mL of the filtrate, add exactly 5 mL of (C8H15NaO2), add about 160 mL of the mobile phase, shake the internal standard solution, shake vigorously, and use this well, add the mobile phase to make exactly 200 mL, and centri- solution as the sample solution. Proceed as directed in the As- fuge. Filter the supernatant liquid, pipet 20 mL of the filtrate, say. add exactly 5 mL of the internal standard solution, and use this solution as the sample solution. Separately, weigh accurately Amount (mg) of sodium valproate (C8H15NaO2) about 0.1 g of sodium valproate for assay, previously dried at = WS × (QT / QS) × (V / 100) 105°C for 3 hours, and dissolve in the mobile phase to make exactly 100 mL. Pipet 20 mL of this solution, add exactly 5 mL WS: Amount (mg) of sodium valproate for assay of the internal standard solution, and use this solution as the Internal standard solution―A solution of ethyl parahydroxy- standard solution. Perform the test with 10 µL each of the sam- benzoate in the mobile phase (1 in 50000) ple solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions, Dissolution <6.10> When the test is performed at 50 revolu- and calculate the ratios, QT and QS, of the peak area of valproic tions per minute according to the Paddle method using the acid to that of the internal standard. sinker, using 900 mL of water as the dissolution medium, the dissolution rate in 30 minutes of Sodium Valproate Tablets is Amount (mg) of sodium valproate (C8H15NaO2) not less than 85%. = WS × (QT / QS) × 2 Start the test with 1 tablet of Sodium Valproate Tablets, W : Amount (mg) of sodium valproate for assay withdraw not less than 20 mL of the medium at the specified S minute after starting the test, and filter through a membrane fil- Internal standard solution―A solution of ethyl parahydroxy- ter with a pore size not exceeding 0.45 µm. Discard the first 10 benzoate in the mobile phase (1 in 50000) mL of the filtrate, pipet V mL of the subsequent filtrate, add Operating conditions— water to make exactly V´ mL so that each mL contains about Detector: An ultraviolet absorption photometer (wavelength: 0.11 mg of sodium valproate (C8H15NaO2), according to the la- 210 nm). beled amount, and use this solution as the sample solution. Column: A stainless steel column 4.6 mm in inside diameter Separately, weigh accurately about 0.11 mg of sodium valproate and 15 cm in length, packed with octadecylsilanized silica gel for assay, previously dried at 105°C for 3 hours, and dissolve in for liquid chromatography (5 µm in particle diameter). water to make exactly 50 mL. Pipet 5 mL of this solution, add Column temperature: A constant temperature of about 25°C water to make exactly 50 mL of the solution, and use this solu- Mobile phase: A mixture of 0.05 mol/L sodium dihydrogen- tion as the standard solution. Perform the test with exactly 50 µL phosphate TS, pH 3.0 and acetonitrile (1:1). each of the sample solution and standard solution as directed Flow rate: Adjust the flow rate so that the retention time of under Liquid Chromatography <2.01> according to the follow-

2198 Official Monographs Supplement II, JP XV valproic acid is about 6 minutes. Insoluble particulate matter <6.07> It meets the require- System suitability― ment. System performance: When the procedure is run with 10 µL of the standard solution under the above operating conditions, Sterility <4.06> Perform the test according to the Membrane the internal standard and valproic acid are eluted in this order filtration method: it meets the requirement. with the resolution between these peaks being not less than 7. Assay Perform the test according to the Cylinder-plate method System repeatability: When the test is repeated 6 times with as directed under Microbial Assay for Antibiotics<4.02> ac- 10 µL of the standard solution under the above operating condi- cording to the following conditions. tions, the relative standard deviation of the ratio of the peak area (i) Test organisms, culture medium and standard solu- of valproic acid to that of the internal standard is not more than tions—Proceed as directed in the Assay under Streptomycin 1.0%. Sulfate. Containers and storage Containers―Tight containers. (ii) Sample solution Take 10 containers of Streptomycin Sulfate for Injection, and weigh accurately the mass of the contents. Weigh accurately an amount of the contents, equivalent to Add the following: 1 g (potency) of Streptomycin Sulfate, and dissolve in water to make exactly 200 mL. Take exactly a suitable amount of this Streptomycin Sulfate for Injection solution, add 0.1 mol/L phosphate buffer solution, pH 8.0, to make a solutions so that each mL contains 8 µg (potency) and 2 注射用ストレプトマイシン硫酸塩 µg (potency), and use these solutions as the high concentration Streptomycin Sulfate for Injection is a preparation sample solution and the low concentration sample solution, respectively. for injection, which is dissolved before use. It contains not less than 90.0% and not more than Containers and storage Containers―Hermetic containers. 110.0% of the labeled potency of streptomycin (C21H39N7O12: 581.57).

Method of preparation Prepare as directed under Injections, Add the following: with Streptomycin Sulfate. Sulindac Description Streptomycin Sulfate for Injection occurs as a スリンダク white or light yellowish white masses or powder.

Identification Peform the test as directed in the Identification (2) under Streptomycin Sulfate.

Osmotic pressure ratio Being specified separately. pH <2.54> The pH of a solution prepared by dissolving an amount of Streptomycin Sulfate for Injection, equivalent to 2.0 and enantiomer g (potency) of Streptomycin Sulfate according to the labeled C20H17FO3S:356.41 amount, in 10 mL of water is 5.0 to 7.0. (1Z)-(5-Fluoro-2-methyl-1-{4-[(RS)- methylsulfinyl]benzylidene}-lH-inden-3-yl)acetic acid Purity Clarity and color of solution—Dissolve an amount of [38194-50-2] Streptomycin Sulfate for Injection, equivalent to 1.0 g (potency) of Streptomycin Sulfate according to the labeled amount, in 3 Sulindac, when dried, contains not less than 99.0% mL of water: The solution is clear, and the absorbance of this and not more than 101.0% of C20H17FO3S. solution at 400 nm, determined as directed under Ultravio- Description Sulindac occurs as a yellow, crystalline powder. let-visible Spectrophotometry <2.24>, is not more than 0.50. It is sparingly soluble in methanol and in ethanol (99.5), and Loss on drying <2.41> Not more than 4.0 % (0.5 g, reduced practically insoluble in water. pressure not exceeding 0.67 kPa, 60°C, 3 hours). A solution of Sulindac in methanol (1 in 100) shows no optical rotation. Bacterial endotoxins <4.01> Less than 0.10 EU/mg (po- Melting point: about 184°C (with decomposition). tency). Identification (1) Dissolve 15 mg of Sulindac in 1000 mL Uniformity of dosage units <6.02> It meets the requirement of a solution of hydrochloric acid in methanol (1 in 120). De- of the Mass Variation Test. termine the absorption spectrum of this solution as directed under the Ultraviolet-visible Spectrophotometry <2.24> and Foreign insoluble matter <6.06> Perform the test according compare the spectrum with the Reference Spectrum: both spec- to Method 2: it meets the requirement. tra exhibit similar intensities of absorption at the same wave-

Supplement II, JP XV Official Monographs 2199 lengths. Add the following: (2) Determine the infrared absorption spectrum of Sulindac as directed in the potassium bromide disc method under Infrared Tacrolimus Hydrate Spectrophotometry <2.25>, and compare the spectrum with the タクロリムス水和物 Reference Spectrum: both spectra exhibit similar intensities of absorption at the same wave numbers.

Purity (1) Heavy metals <1.07>―Proceed with 2.0 g of Su- lindac according to Method 2 and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than 10 ppm). (2) Arsenic <1.11>―Prepare the test solution with 1.0 g of Sulindac according to Method 3 and perform the test (not more than 2 ppm). (3) Related substances―Dissolve 0.25 g of Sulindac in 10 mL of methanol and use this solution as the sample solution. Pipet 1 mL of this solution and add methanol to make exactly 100 mL. Pipet 5 mL, 4 mL and 2 mL of this solution, to each C44H69NO12·H2O:822.03 add methanol to make exactly 10 mL, and use these solutions as (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)- the standard solution (1), standard solution (2) and standard so- 5,19-Dihydroxy-3-{(1E)-2-[(1R,3R,4R)-4-hydroxy- lution (3). Perform the test with these solutions as directed un- 3-methoxycyclohexyl]-1-methylethenyl}-14,16-dimethoxy- der Thin-layer Chromatography <2.03>. Spot 4µL each of the 4,10,12,18-tetramethyl-8-(prop-2-en-1-yl)-15,19-epoxy- sample solution, standard solution (1), standard solution (2) and 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a- standard solution (3) on a plate of silica gel for thin-layer chro- hexadecahydro-3H-pyrido[2,1-c][1,4]oxaazacyclotricosine- matography. Develop the plate with a mixture of ethyl acetate 1,7,20,21(4H,23H)-tetrone monohydrate [109581-93-3] and acetic acid (100) (97:3) to a distance of about 17 cm, and air-dry the plate. Examine under ultraviolet light (main wave- Tacrolimus Hydrate contains not less than 98.0% length: 254 nm): the spots other than the principal spot from the and not more than 102.0% of tacrolimus (C44H69NO12: sample solution are not more intense than the spot from the 804.02), calculated on the anhydrous basis. standard solution (1), and the total intensity of spots other than the principal spot from the sample solution is not more than Description Tacrolimus Hydrate occurs as a white crystal or 1.0% calculated on the basis of intensities of the spots from the crystalline powder. standard solution (1), standard solution (2) and standard solution It is very soluble in methanol and in ethanol (99.5), freely (3). soluble in N,N-dimethylformamide and in ethanol (95), and (4) Residual solvent―Being specified separately. practically insoluble in water.

Loss on drying <2.41> Not more than 0.5% (1 g, in vacuum Identification (1) Dissolve 5 mg of Tacrolimus Hydrate in 1 not exceeding 0.7 kPa, 100°C, 2 hours). mL of ethanol (95), add 1 mL of 1,3-dinitrobenzene TS and 1 mL of sodium hydroxide TS, and shake: a red-purple color de- Residue on ignition <2.44> Not more than 0.1% (1 g, plati- velops. num crucible). (2) Determine the infrared absorption spectrum of Tac- rolimus Hydrate as directed in the paste method under Infrared Assay Weigh accurately about 0.3 g of Sulindac, previously Spectrophotometry <2.25>, and compare the spectrum with the dried, dissolve in 50 mL of methanol and titrate <2.50> with 0.1 Reference Spectrum or the spectrum of Tacrolimus Reference mol/L sodium hydroxide VS (potentiometric titration). Perform Standard: both spectra exhibit similar intensities of absorption at a blank determination in the same manner, and make any nec- the same wave numbers. essary correction. 20 Optical rotation <2.49> [α] D : -110 ‐ -115º (0.2 g calcu- Each mL of 0.1 mol/L sodium hydroxide VS lated on the anhydrous basis, N,N-dimethylformamide, 20 mL, = 35.64 mg of C20H17FO3S 100 mm).

Containers and storage Containers―Tight containers. Purity (1) Heavy metals <1.07>―Proceed with 2.0 g of Tacrolimus Hydrate according to Method 2, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solu- tion (not more than 10 ppm). (2) Related substances―Being specified separately. (3) Residual solvent―Being specified separately.

Water <2.48> 1.9 – 2.5% (0.5 g, volumetric titration, direct

2200 Official Monographs Supplement II, JP XV titration). Add the following: Residue on ignition <2.44> Not more than 0.1% (1 g). Tazobactam Isomer Being specified separately. タゾバクタム

Assay Weigh accurately about 25 mg each of Tacrolimus Hy- drate and Tacrolimus Reference Standard (separately determine the water content <2.48> in the same manner as Tacrolimus Hydrate) and dissolve each in 15 mL of ethanol (99.5), to each add exactly 10 mL of the internal standard, add 25 mL of water, C H N O S: 300.29 allow to stand for 6 hours, and use these solutions as the sample 10 12 4 5 (2S,3S,5R)-3-Methyl-7-oxo-3-(1H-1,2,3-triazol- solution and standard solution, respectively. Perform the test 1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic with 10 µL each of the sample solution and standard solution as acid 4,4-dioxide [89786-04-9] directed under Liquid Chromatography <2.01> according to the following conditions, and calculate the ratios, QT and QS, of the Tazobactam contains not less than 980 µg and not peak area of tacrolimus to that of the internal standard. more than 1020 µg (potency) per 1 mg, calculated on the anhydrous basis. The potency of Tazobactam is Amount (mg) of tacrolimus (C44H69NO12) = WS × (QT / QS) expressed as mass (potency) of C10H12N4O5S. WS: Amount (mg) of Tacrolimus Reference Standard, calculated on the anhydrous basis. Description Tazobactam occurs as a white to pale yellowish white, crystalline powder. Internal standard solution―A solution of heptyl parahydroxy- It is freely soluble in dimethylsulfoxide and in N, benzoate in ethanol (99.5) (3 in 4000) N-dimethylformamide, and slightly soluble in water, in metha- Operating conditions— nol and in ethanol (99.5). Detector: An ultraviolet absorption photometer (wavelength: It dissolves in a solution of sodium hydrogen carbonate (3 in 220 nm). 100). Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel Identification (1) Determine the infrared absorption spec- for liquid chromatography (5 µm in particle diameter). trum of Tazobactam as directed in the potassium bromide disk Column temperature: Constant temperature of about 50°C. method under the Infrared Spectrophotometry <2.25>, and Mobile phase: A mixture of water, 2-propanol for liquid compare the spectrum with the Reference Spectrum or the spec- chromatography and tetrahydrofuran for liquid chromatography trum of Tazobactam Reference Standard: both spectra exhibit (5:2:2). similar intensities of absorption at the same wave numbers. Flow rate: Adjust the flow rate so that the retention time of (2) Determine the spectrum of a solution of Tazobactam in tacrolimus is about 10 minutes. deuterated dimethylsulfoxide for nuclear magnetic resonance System suitability― spectroscopy (1 in 35) as directed under the Nuclear Magnetic System performance: When the procedure is run with 10 µL Resonance Spectroscopy <2.21> (1H), using tetramethylsilane of the standard solution under the above operating conditions, for nuclear magnetic resonance spectroscopy as an internal ref- tacrolimus and the internal standard are eluted in this order with erence compound: it exhibits a single signal A at around δ 1.3 the resolution between these peaks being not less than 6. ppm, and double signals, B and C, at around δ 7.8 ppm and at System repeatability: When the test is repeated 6 times with around δ 8.1 ppm. The ratio of the integrated intensity of each 10 µL of the standard solution under the above operating condi- signal, A:B:C, is about 3:1:1. tions, the relative standard deviation of the ratio of the peak area Optical rotation <2.49> 20: +162 − +167º (1 g calculated of tacrolimus to that of internal standard is not more than 1.0%. [α]D on the anhydrous basis, N, N-dimethylformamide, 100 mL, 100 Containers and storage Containers―Well-closed containers. mm).

Purity (1) Clarity and color of solution－Dissolve 1.0 g of Tazobactam in 10 mL of sodium hydrogen carbonate (3 in 100) : the solution is clear. Perform the test with the solution as directed under Ultraviolet-visible Spectrophotometry <2.24> : the absorbance at 420 nm is not more than 0.14. (2) Heavy metals <1.07> －Proceed with 1.0 g of Tazo- bactam according to Method 2, and perform the test. Prepare the control solution with 1.0 mL of Standard Lead Solution (not more than 10 ppm). (3) Related substances－This operation must be performed quickly. Dissolve 50 mg of Tazobactam in 20 mL of the mobile

Supplement II, JP XV Official Monographs 2201 phase, and use this solution as the sample solution. Pipet 1 mL tion, add water to make 100 mL, and use these solutions as the of the sample solution, add the mobile phase to make exactly sample solution and the standard solution, respectively. Perform 100 mL, and use this solution as the standard solution (1). Pipet the test with 10 µL each of the sample solution and the standard 1 mL of the standard solution (1), add the mobile phase to make solution as directed under the Liquid Chromatography <2.01> exactly 10 mL, and use this solution as the standard solution (2). according to the following conditions, and determine the ratios,

Perform the test with exactly 50 µL each of the sample solution, QT and QS, of the peak areas of tazobactam to that of the inter- the standard solution (1) and the standard solution (2) as di- nal standard. rected under the Liquid Chromatography <2.01> according to Amount [µg (potency)] of tazobactam (C10H12N4O5S) the following conditions. Determine each peak area form these = Ws×(QT /QS)×1000 solutions by the automatic integration method: the area of the Ws: Amount [mg (potency)] of Tazobactam Reference Stan- peak, having the relative retention time of about 0.17 with re- dard spect to tazobactam, obtained from the sample solution is not larger than 4/5 times the peak area of tazobactam from the stan- Internal standard solution－A solution of phenylalanine (1 in dard solution (1), the peak area other than the peak of tazobac- 400). tam and the peak having the relative retention time of about 0.17 Operating conditions－ with respect to tazobactam from the sample solution is not lar- Detector: An ultraviolet absorption photometer (wavelength: ger than the peak area of tazobactam from the standard solution 210 nm). (2), and the total area of the peaks other than the peak of tazo- Column: A stainless steel column 4.6 mm in inside diameter bactam and the peak having the relative retention time of about and 25 cm in length, packed with octadecylsilanized silica gel 0.17 with respect of tazobactam from the sample solution is not for liquid chromatography (10 µm in particle diameter). larger than 2 times the peak area of tazobactam from the stan- Column temperature: A constant temperature of about 25°C. dard solution (2). Mobile phase: Disssolve 1.32 g of diammonium hydrogen Operating conditions－ phosphate in 750 mL of water, adjust the pH to 2.5 with phos- Detector, column, column temperature, mobile phase, and phoric acid, add water to make 1000 mL, and add 25 mL of flow rate: Proceed as directed in the operating conditions in the acetonitrile. Assay. Flow rate: Adjust the flow rate so that the retention time of Time span of measurement: About 3 times as long as the re- tazobactam is about 10 minutes. tention time of tazobactam. System suitability－ System suitability－ System performance: When the procedure is run with 10 µL Test for required detectability: Pipet 1 mL of the standard so- of the standard solution under the above operating conditions, lution (1), and add the mobile phase to make exactly 20 mL. the internal standard, the internal standard and tazobactam are Confirm that the peak area of tazobactam obtained from 50 µL eluted in this order with the resolution between these peaks be- of this solution is equivalent to 3 to 7% of that of tazobactam ing not less than 4. from the standard (1). System repeatability: When the test is repeated 6 times with System performance: When the procedure is run with 50 µL 10 µL of the standard solution under the above operating condi- of the standard solution (1) under the above operating conditions, the relative standard deviation of the ratios of the peak tions, the number of theoretical plates and the symmetry factor area of tazobactam to that of the internal standard is not more of the peak of tazobactam are not less than 2000 and 0.8 -1.2, than 1.0%. respectively. Containers and storage Containers―Tight containers. System repeatability: When the test is repeated 6 times with 50 µL of the standard solution (1) under the above operating condi- Expiration date 24 months after preparation. tions, the relative standard deviations of the peak area of tazobactam is not more than 1.0%. (4) Residual solvent Being specified separately. Teicoplanin

Water <2.48> Not more than 0.5% (1 g, volumetric titration, テイコプラニン direct titration. Use a mixture of formamide for water determination and methanol for water determination (3:1) instead of Change the Origin/limits of content to read: methanol for water determination). Teicoplanin is a mixture of glycopeptide substances Residue on ignition <2.44> Not more than 0.1% (1 g). having antibacterial activity produced by the growth of Actinoplanes teichomyceticus. Bacterial endotoxins <4.01> Less than 0.04 EU/mg (po- It contains not less than 900 µg (potency) and not tency). more than 1120 µg (potency) per 1 mg, calculated on the anhydrous, de-sodium chloride and de-residual Assay Weigh accurately an amount of Tazobactam and Tazo- solvents basis. The potency of Teicoplanin is ex- bactam Reference Standard, equivalent to about 50 mg (po- pressed as mass (potency) of teicoplanin (C72～89H68～ tency), dissolve in exactly 10 mL of the internal standard solu- 99Cl2N8～9O28～33).

2202 Official Monographs Supplement II, JP XV

Add the following: (3) Related substances―Dissolve 30 mg of Teprenone in 6 mL of hexane, and use this solution as the sample solution. Per- Teprenone form the test with 3 µL of the sample solution as directed under Gas Chromatography <2.02> according to the following condi- テプレノン tions. Determine each peak area from the sample solution by the automatic integration method and calculate the amounts of them by the area percentage method: the peak area of the di-cis isomer of teprenone, having the relative retention time of about 0.8 with respect to the all-trans isomer of teprenone, is not more than 0.5%, and each area of the peaks for the mono-cis and all-trans isomers of the teprenone and for those other than mentioned above is not more than 0.2 %. Furthermore, the total area C23H38O:330.55 of the peaks other than the mono-cis, all-trans and di-cis isomers (5E,9E,13E)-6,10,14,18-Tetramethylnonadeca- of teprenone is not more than 1.0 %. 5,9,13,17-tetraen-2-one Operating conditions— (5Z,9E,13E)-6,10,14,18-Tetramethylnonadeca- Detector, column, column temperature, carrier gas and flow 5,9,13,17-tetraen-2-one rate: Proceed as directed in the operating conditions in the As- [6809-52-5] say. Time span of measurement: About 2 times as long as the re- Teprenone contains not less than 97.0% and not tention time for the all-trans isomer of teprenone beginning after more than 101.0% of C H O. 23 38 the solvent peak. Teprenone is comprised of mono-cis and all-trans System suitability― isomers, with their ratio being about 2:3. Test for required detectability: To 1 mL of the sample solu- Description Teprenone occurs as a colorless to slightly yel- tion add hexane to make 100 mL, and use this solution as the lowish clear oily liquid, with slight, characteristic odor. solution for system suitability test. Pipet 1 mL of the solution It is miscible with ethanol (99.5), with ethyl acetate and with for system suitability test, and add hexane to make exactly 10 hexane. mL. Confirm that the sum of the peak areas of the mono-cis and It is practically insoluble in water. all-trans isomers of teprenone obtained from 3 µL of this solu- It is oxidized by air, and gradually turns yellow. tion is 7 to 13% of the peak areas of the mono-cis and all-trans isomers of teprenone from the solution for system suitability Identification (1) To 2 mL of a solution of Teprenone in test. ethanol (99.5) (1 in 100) add 1 mL of a solution of phospho- System performance: When the procedure is run with 3 µL of molybdic acid n-hydrate in acetic acid (100) (1 in 100), heat in a the solution for system suitability test under the above operating water bath for 5 minutes, and continue heating with addition of conditions, the mono-cis and all-trans isomers of teprenone are 5 to 6 drops of sulfuric acid: blue to bluish green color develops. eluted in this order with the resolution between these peaks be- (2) To 2 mL of a solution of Teprenone in ethanol (99.5) (1 ing not less than 1.1. in 100) add 2 mL of 2,4-dinitrophenylhydrazine TS, and shake: System repeatability: When the test is repeated 6 times with 3 a yellow to orange-yellow precipitate is formed. µL of the solution for system suitability test under the above (3) Determine the infrared absorption spectrum of Te- operating conditions, the relative standard deviation of the sum prenone as directed in the liquid film method under Infrared of the peak areas of the mono-cis and all-trans isomers of te- Spectrophotometry <2.25>, and compare the spectrum with the prenone is not more than 3.0%. Reference Spectrum or the spectrum of Teprenone Reference (4) Residual solvent―Being specified separately. Standard: both spectra exhibit similar intensities of absorption at the same wave numbers. Residue on ignition <2.44> Not more than 0.1% (1 g).

20 Isomer ratio Dissolve 30 mg of Teprenone in 6 mL of hexane, Refractive index <2.45> n D : 1.485 – 1.491 and use this solution as the sample solution. Perform the test 20 Specific gravity <2.56> d20 : 0.882 – 0.890 with 3 µL of the sample solution as directed under Gas Chro- matography <2.02> according to the following conditions. De- Purity (1) Clarity and color of solution―To 1.0 mL of Te- termine the areas of two adjacent peaks, Aa and Ab, having re- prenone add 9 mL of ethanol (99.5) and shake: the solution is tention times of about 18 minutes, where Aa is the peak of the clear, and its absorbance at 400 nm determined as directed un- mono-cis isomer, having the shorter retention time, and Ab is the der Ultraviolet-visible Spectrophotometry <2.24> is not more peak area of the all-trans isomer, having the longer retention than 0.02. time: Aa/Ab is 0.60 to 0.70. (2) Heavy metals <1.07>―Proceed with 1.0 g of Te- Operating conditions— prenone according to Method 2 and perform the test. Prepare the Proceed as directed in the Assay. control solution with 2.0 mL of Standard Lead Solution (not System suitability― more than 20 ppm). Proceed as directed in the system suitability in the Purity (3).

Supplement II, JP XV Official Monographs 2203

Assay Weigh accurately about 50 mg each of Teprenone and Teprenone Reference Standard, dissolve each in exactly 5 mL of the internal standard solution, add ethyl acetate to make 50 mL, Testosterone Propionate Injection and use these solutions as the sample solution and standard solution, respectively. Perform the test with 3 µL each of the sam- テストステロンプロピオン酸エステル注射液 ple solution and standard solution as directed under Gas Chro- matography <2.02> according to the following conditions, and Add the following next to Foreign insoluble matter: calculate the ratios, QT and QS, of the peak area of teprenone (sum of the peak areas of mono-cis and all-trans isomers) to that Insoluble particulate matter <6.07> Perform the test ac- of the internal standard. cording to Method 2: it meets the requirement. Amount (mg) of teprenone (C H O) = W × (Q /Q ) 23 38 S T S

WS: Amount (mg) of Teprenone Reference Standard Add the following: Internal standard solution—A solution of di-n-butyl phthalate in ethyl acetate (1 in 100) Tiapride Hydrochloride Operating conditions— チアプリド塩酸塩 Detector: A hydrogen flame-ionization detector. Column: A glass column 4 mm in inside diameter and 2 m in length, packed with 149 to 177 µm siliceous earth for gas chromatography coated in 5% with polyethylene glycol 2-nitroterephthalate. Column temperature: Constant temperature of about 210°C. Carrier gas: Nitrogen or helium. C15H24N2O4S·HCl: 364.89 Flow rate: Adjust the flow rate so that the retention time of N-[2-(Diethylamino)ethyl]-2-methoxy- the peak of the all-trans isomer of teprenone, the larger of the 5-(methylsulfonyl)benzamide monohydrochloride two main peaks, having the retention time about 18 minutes, [51012-33-0] becomes 19 minutes. Tiapride Hydrochloride, when dried, contains not System suitability― less than 99.0% and not more than 101.0% of System performance: When the procedure is run with 3 µL of C H N O S·HCl. the standard solution under the above operating conditions, the 15 24 2 4 internal standard and the mono-cis and all-trans isomers of te- Description Tiapride Hydrochloride occurs as a white to prenone are eluted in this order with the resolution between the slightly yellowish white crystal or crystalline powder. mono-cis and all-trans isomers being not less than 1.1. It is very soluble in water, freely soluble in acetic acid (100), System repeatability: When the test is repeated 6 times with 3 soluble in methanol, slightly soluble in ethanol (99.5) and very µL of the standard solution under the above operating conditions, slightly soluble in acetic anhydride. the relative standard deviation of the ratio of the sum of the peak It dissolves in 0.1 mol/L hydrochloric acid TS. areas of the mono-cis and all-trans isomers of teprenone to that of the internal standard is not more than 1.0%. Identification (1) Determine the absorption spectrum of a solution of Tiapride Hydrochloride in 0.1 mol/L hydrochloric Containers and storage Containers—Tight Containers. acid TS (1 in 10000) as directed under Ultraviolet-visible Spec- Storage conditions―Under Nitrogen atmosphere at 2 to 8°C. trophotometry <2.24>, and compare the spectrum with the Ref- erence Spectrum: both spectra exhibit similar intensities of absorption at the same wavelengths. Testosterone Enanthate Injection (2) Determine the infrared absorption spectrum of Tiapride Hydrochloride as directed in the potassium chloride disk method テストステロンエナント酸エステル注射液 under Infrared Spectrophotometry <2.25>: both spectra exhibit similar intensities of absorption at the same wave numbers. Add the following next to Extractable volume: (3) A solution of Tiapride Hydrochloride (1 in 20) responds Foreign insoluble matter <6.06> Perform the test according to Qualitative Tests <1.09> for chloride. to Method 1: it meets the requirement. Purity (1) Heavy metals <1.07>―Proceed with 1 g of Insoluble particulate matter <6.07> Perform the test ac- Tiapride Hydrochloride according to Method 1 and perform the cording to Method 2: it meets the requirement. test. Prepare the control solution with 2.0 mL of Standard Lead Solution (not more than 20 ppm). Sterility <4.06> Perform the test according to the Membrane (2) Related substances―Dissolve 0.20 g of Tiapride Hy- filtration method: it meets the requirement. drochloride in 10 mL of methanol and use this solution as the

2204 Official Monographs Supplement II, JP XV sample solution. Pipet 1 mL of the sample solution, and add til the tablet is disintegrated, and add 4V/10 mL of methanol. To methanol to make exactly 100 mL. Pipet 1 mL of this solution, this solution add exactly V/10 mL of the internal standard solu- add methanol to make exactly 10 mL, and use this solution as tion, shake for 30 minutes, and add methanol to make V mL so the standard solution. Perform the test with these solutions as that each mL contains about 1 mg of tiapride (C15H24N2O4S). directed under Thin-layer Chromatography <2.03>. Spot rap- Centrifuge this solution for 10 minutes, and use the supernatant idly10 µL each of the sample solution and standard solution on a liquid as the sample solution. Proceed as directed in the Assay. plate of silica gel with fluorescent indicator for thin-layer chromatography under a stream of nitrogen. Develop the plate with a Amount (mg) of tiapride (C15H24N2O4S) mixture of water, 1-butanol and acetic acid (100) (2:2:1) to a = WS × (QT/QS) × (V/100) × 0.900 distance of about 10 cm, and air-dry, and then dry the plate at W : Amount (mg) of tiapride hydrochloride for assay 80°C for 30 minutes. Examine under ultraviolet light (main S wavelength: 254 nm): the spots other than the principal spot Internal standard solution—A solution of methyl parahydroxy- from the sample solution are not more intense than the spot benzoate in methanol (1 in 500) from the standard solution. (3) Residual solvent―Being specified separately. Dissolution Being specified separately.

Loss on drying <2.41> Not more than 0.5% (1 g, 105°C, 2 Assay Weigh accurately the mass of not less than 20 Tiapride hours). Hydrochloride Tablets and powder. Weigh accurately a portion of the powder, equivalent to about 0.1 g of tiapride Residue on ignition <2.44> Not more than 0.1% (1 g). (C15H24N2O4S), add about 10 mL of 0.1 mol/L hydrochloric acid TS and 40 mL of methanol, add exactly 10 mL of the in- Assay Weigh accurately about 0.4 g of Tiapride Hydrochlo- ternal standard solution, shake for 30 minutes, and add methanol ride, previously dried, dissolve in 50 mL of a mixture of acetic to make 100 mL. Centrifuge this solution and use the super- anhydride and acetic acid (100) (7:3), and titrate <2.50> with natant liquid as the sample solution. Separately, weigh accu- 0.1 mol/L perchloric acid VS (potentiometric titration). Perform rately about 0.11 g of tiapride chloride for assay, previously a blank determination in the same manner, and make any nec- dried at 105°C for 2 hours, dissolve in 10 mL of 0.1 mol/L hy- essary correction. drochloric acid TS, add exactly 10 mL of the internal standard Each mL of 0.1 mol/L perchloric acid VS solution, add methanol to make 100 mL, and use this solution as the standard solution. Perform the test with 5 µL each of the = 36.49 mg of C15H24N2O4S·HCl sample solution and standard solution as directed under liquid Containers and storage Containers―Well-closed containers. chromatography <2.01> according to the following conditions,

and calculate the ratios, QT and QS, of the peak area of Tiapride to that of the internal standard. Add the following:

Amount (mg) of tiapride (C15H24N2O4S) Tiapride Hydrochloride Tablets = WS × (QT/QS) × 0.900

チアプリド塩酸塩錠 WS: Amount (mg) of tiapride chloride for assay

Tiapride Hydrochloride Tablets contain not less than Internal standard solution—A solution of methyl parahydroxy- 95.0% and not more than 105.0% of the labeled benzoate in methanol (1 in 500) Operating conditions— amount of tiapride (C15H24N2O4S: 328.43) Detector: An ultraviolet absorption photometer (wavelength: Method of preparation Prepare as directed under Tablets, 254 nm). with Tiapride Hydrochloride. Column: A stainless steel column 4 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel Identification To a quantity of powdered Tiapride Hydro- for liquid chromatography (5 µm in particle diameter). chloride Tablets, equivalent to 10 mg of tiapride (C15H24N2O4S) Column temperature: Constant temperature of about 25°C. according to the labeled amount, add 100 mL of 0.1 mol/L hy- Mobile phase: Dissolve 11.2 g of sodium perchlorate in 800 drochloric acid TS, shake well, and filter. Determine the absorp- mL of water, add 5 mL of diluted perchloric acid (17 in 2000). tion spectrum of the filtrate as directed under Ultraviolet-visible To 800 mL of this solution add 200 mL of acetonitrile. Spectrophotometry <2.24>: it exhibits a maximum between 286 Flow rate: Adjust the flow rate so that the retention time of nm and 290 nm. tiapride is about 8 minutes. System suitability― Uniformity of dosage units <6.02> Perform the test accord- System performance: When the procedure is run with 5 µL of ing to the following method: it meets the requirement of the the standard solution under the above operating conditions, Content uniformity test. tiapride and the internal standard are eluted in this order with To 1 tablet of Tiapride Hydrochloride Tablets add V/10 mL of the resolution between these peaks being not less than 8. 0.1 mol/L hydrochloric acid TS, treat with ultrasonic waves un-

Supplement II, JP XV Official Monographs 2205

System repeatability: When the test is repeated 6 times with 5 Add the following: µL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of the peak area of Tosufloxacin Tosilate Hydrate tiapride to that of the internal standard is not more than 1.0%. トスフロキサシントシル酸塩水和物 Containers and storage Containers―Well-closed containers.

Tolbutamide Tablets

トルブタミド錠

Add the following next to Identification:

Uniformity of dosage units <6.02> It meets the requirement and enantiomer of the Mass variation test.

C19H15F3N4O3·C7H8O3S·H2O: 594.56 Change the Dissolution to read: 7-[(3RS)-3-Aminopyrrolidin-1-yl]-1-(2,4-difluorophenyl)- 6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic Dissolution <6.10> When the test is performed at 100 revolu- acid monotosylate monohydrate [115964-29-9, anhydride] tions per minute according to the Paddle method, using 900 mL of phosphate buffer solution, pH 7.4, as the dissolution medium, Tosufloxacin Tosilate Hydrate contains not less than the dissolution rate in 30 minutes of Tolbutamide Tablets is not 98.5% and not more than 101.0% of tosufloxacin tosi- less than 80%. late (C19H15F3N4O3·C7H8O3S: 576.54), calculated on Start the test with 1 tablet of Tolbutamide Tablets, withdraw the anhydrous basis. not less than 20 mL of the medium at the specified minute after Description Tosufloxacin Tosilate Hydrate occurs as a white starting the test, and filter through a membrane filter with a pore to pale yellowish white, crystalline powder. size not exceeding 0.8 µm. Discard the first 10 mL of the filtrate, It is freely soluble in N,N-dimethylformamide, sparingly pipet V mL of the subsequent filtrate, add water to make exactly soluble in methanol, and practically insoluble in water and in V´ mL so that each mL contains about 10 µg of tolbutamide ethanol (99.5). (C12H18N2O3S) according to the labeled amount, and use this A solution of Tosufloxacin Tosilate Hydrate in methanol (1 in solution as the sample solution. Separately, weigh accurately 100) shows no optical rotation. about 50 mg of Tolbutamide Reference Standard, previously Melting point: about 254°C (with decomposition). dried at 105°C for 3 hours, dissolve in 10 mL of methanol, and add the dissolution medium to make exactly 100 mL. Pipet 2 Identification (1) Tosufloxacin Tosilate Hydrate shows a mL of this solution, add water to make exactly 100 mL, and use light bluish-white fluorescence under ultraviolet light (main this solution as the standard solution. Perform the test with the wavelength 254 nm). sample solution and standard solution as directed under Ultra- (2) Proceed 10 mg of Tosufloxacin Tosilate Hydrate as di- violet-visible Spectrophotometry <2.24>, and determine the rected under Oxygen Flask Combustion Method <1.06>, using a absorbances, AT and AS, at 226 nm. mixture of 0.5 mL of 0.01 mol/L sodium hydroxide TS and 20 mL of water as the absorbing liquid: the solution responds to the Dissolution rate (%) with respect to the labeled amount of Qualitative Tests <1.09> (2) for fluoride. tolbutamide (C12H18N2O3S) (3) Determine the absorption spectrum of a solution of To- = WS × (AT/AS)× (V´/V ) × (1/C) × 18 sufloxacin Tosilate Hydrate in a mixture of methanol and so-

WS: Amount (mg) of Tolbutamide Reference Standard dium hydroxide TS (49:1) (1 in 100000) as directed under Ul- traviolet-visible Spectrophotometry <2.24>, and compare the C: Labeled amount (mg) of tolbutamide (C12H18N2O3S) in 1 spectrum with the Reference Spectrum or the spectrum of a so- tablet lution of Tosufloxacin Tosilate Hydrate Reference Standard

prepared in the same manner as the sample solution: both spec-

tra exhibit similar intensities of absorption at the same wavelengths. (4) Determine the infrared absorption spectrum of Tosu- floxacin Tosilate Hydrate as directed in the paste method under Infrared Spectrophotometry <2.25>, and compare the spectrum with the Reference Spectrum or the spectrum of Tosufloxacin Tosilate Hydrate Reference Standard: both spectra exhibit similar intensities of absorption at the same wave numbers.

2206 Official Monographs Supplement II, JP XV

Purity (1) Chloride <1.03>―Dissolve 1.0 g of Tosufloxacin Time after injec- Mobile phase A Mobile phase B Tosilate Hydrate in 40 mL of N,N-dimethylformamide, and add tion of sample (vol%) (vol%) 6 mL of dilute nitric acid and N,N-dimethylformamide to make (min) 50 mL. Perform the test using this solution as the test solution. 0 - 1 100 0 Prepare the control solution with 0.20 mL of 0.01 mol/L hydro- 1 - 16 100 → 0 0 → 100 chloric acid VS, 6 mL of dilute nitric acid and 16 - 35 0 100 N,N-dimethylformamide to make 50 mL (not more than 0.007%). Flow rate: 0.5 mL per minute. (2) Heavy metals <1.07>―Proceed with 1.0 g of Tosu- Time span of measurement: About 5 times as long as the re- floxacin Tosilate Hydrate according to Method 4, and perform tention time of tosufloxacin. the test. Prepare the control solution with 2.0 mL of Standard System suitability― Lead Solution (not more than 20 ppm). Test for required detectability: Pipet 5 mL of the standard so- (3) Arsenic <1.11>―Prepare the test solution with 1.0 g of lution, and add mobile phase A to make exactly 20 mL. Confirm Tosufloxacin Tosilate Hydrate according to Method 4, and per- that the peak area of tosufloxacin obtained from 20 µL of this form the test under the condition of the ignition temperature be- solution is equivalent to 18 to 32% of the peak area of tosuflox- ing between 750 and 850°C, and add 10 mL of diluted hydro- acin from the standard solution. chloric acid to residue (not more than 2 ppm). System performance: When the procedure is run with 20 µL (4) Related substances―Dissolve10 mg of Tosufloxacin of the standard solution under the above operating conditions, Tosilate Hydrate in 12 mL of mobile phase B, add water to the number of theoretical plates and symmetry factor of the peak make 25 mL, and use this solution as the sample solution. Pipet of tosufloxacin are not less than 10000 and not more than 1.5, 5 mL of this solution, and add mobile phase A to make exactly respectively. 100 mL. Pipet 2 mL of this solution, add mobile phase A to System repeatability: When the test is repeated 6 times with make exactly 50 mL, and use this solution as the standard solu- 20 µL of the standard solution under the above operating condition. Perform the test with exactly 20 µL each of the sample so- tions, the relative standard deviation of the peak area of tosu- lution and standard solution as directed under Liquid Chroma- floxacin is not more than 2.0%. tography <2.01> according to the following conditions. Deter- (5) Residual solvent Being specified separately. mine each peak area of both solutions by automatic integration Water <2.48> 2.5 – 3.5% (30 mg, coulometric titration). method: the area of each peak other than the peaks of tosylic acid and tosufloxacin from the sample solution is not more than Assay Weigh accurately about 30 mg each of Tosufloxacin 3/4 of the peak area of tosufloxacin from the standard solution, Tosilate Hydrate and Tosufloxacin Tosilate Hydrate Reference and the total area of the peaks other than those of tosylic acid Standard (separately determine the water content <2.48> in the and tosufloxacin from the sample solution is not larger than 2.5 same manner as Tosufloxacin Tosilate Hydrate), and dissolve times the peak area of tosufloxacin from the standard solution. each in methanol to make exactly 100 mL. Pipet 20 mL each of Operating conditions— these solutions, to each add exactly 4 mL of the internal stan- Detector: An ultraviolet absorption photometer (wavelength: dard solution and methanol to make 100 mL, and use these so- 272 nm). lutions as the sample solution and standard solution, respec- Column: A stainless steel column 3.0 mm in inside diameter tively. Perform the test with 10 µL each of the sample solution and 15 cm in length, packed with octadecylsilanized silica gel and standard solution as directed under Liquid Chromatography for liquid chromatography (5 µm in particle diameter). <2.01> according to the following conditions, and calculate the Column temperature: Constant temperature of about 35ºC ratios, QT and QS, of the peak area of tosufloxacin to that of the Mobile phase A: To 300 to 500 mL of water add slowly 100 internal standard. mL of methanesulfonic acid under ice-cooling, add slowly 100 mL of triethylamine under ice-cooling too, and add water to Amount (mg) of tosufloxacin tosilate make 1000 mL. To 10 mL of this solution add 143 mL of water, (C19H15F3N4O3·C7H8O3S) 40 mL of acetonitrile and 7 mL of 1 mol/L dipotassium hydro- = WS × (QT/QS) gen phosphate TS for buffer solution. Mobile phase B: To 300 to 500 mL of water add slowly 100 WS: Amount (mg) of Tosufloxacin Tosilate Reference Stan- mL of methanesulfonic acid under ice-cooling, add slowly 100 dard, calculated on the anhydrous basis. mL of triethylamine under ice-cooling too, and add water to Internal standard solution—A solution of methyl parahydroxy- make 1000 mL. To 10 mL of this solution add 100 mL of ace- benzoate in methanol (1 in 800) tonitrile, 83 mL of water and 7 mL of 1 mol/L dipotassium hy- Operating conditions— drogen phosphate TS for buffer solution. Detector: An ultraviolet absorption photometer (wavelength: Flowing of mobile phase: Control the gradient by mixing the 270 nm). mobile phases A and B as directed in the following table. Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Column temperature: Constant temperature of about 40ºC.

Supplement II, JP XV Official Monographs 2207

Mobile phase: To a mixture of 0.02 mol/L phosphate buffer = WS × (QT/QS)× (V/20) × 1.031 solution, pH 3.5, and a solution of dibutylamine in methanol (1 in 2500) (3:1) add diluted phosphoric acid (1 in 10) to adjust the WS: Amount (mg) of Tosufloxacin Tosilate Reference Stan- pH to 3.5. dard, calculated on the anhydrous basis. Flow rate: Adjust the flow rate so that the retention time of Internal standard solution—A solution of methyl parahydroxy- tosufloxacin is about 20 minutes. benzoate in methanol (1 in 800) System suitability― System performance: When the procedure is run with 10 µL Dissolution <6.10> When the test is performed at 50 revolu- of the standard solution under the above operating conditions, tions per minute according to the Paddle method, using 900 mL the internal standard and tosufloxacin are eluted in this order of water as the dissolution medium, the dissolution rate in 90 with the resolution between these peaks being not less than 2.5. minutes of Tosufloxacin Tosilate Tablets is not less than 65%. System repeatability: When the test is repeated 6 times with Start the test with 1 tablet of Tosufloxacin Tosilate Tablets, 10 µL of the standard solution under the above operating condi- withdraw not less than 20 mL of the medium at the specified tions, the relative standard deviation of the ratio of the peak area minute after starting the test, and filter through a membrane fil- of tosufloxacin to that of the internal standard is not more than ter with a pore size not exceeding 0.5 µm. Discard the first 10 1.0%. mL of the filtrate, pipet V mL of the subsequent filtrate, add 0.05 mol/L acetic acid-sodium acetate buffer solution, pH 4.0, Containers and storage Containers―Tight containers. to make exactly V´ mL so that each mL contains about 17 µg of

tosufloxacin tosilate hydrate (C19H15F3N4O3·7H8O3S·H2O) ac- Add the following: cording to the labeled amount, and use this solution as the sample solution. Separately, weigh accurately about 21 mg of Tosu- Tosufloxacin Tosilate Tablets floxacin Tosilate Reference Standard (separately determine the water content <2.48> in the same manner as Tosufloxacin Tosi- トスフロキサシントシル酸塩錠 late Hydrate), and dissolve in N,N-dimethylformamide to make exactly 25 mL. Pipet 2 mL of this solution, add 0.05 mol/L ace- Tosufloxacin Tosilate Tablets contain not less than tic acid-sodium acetate buffer solution, pH 4.0, to make exactly 95.0% and not more than 105.0% of the labeled 100 mL, and use this solution as the standard solution. Perform amount of tosuflozacin tosilate hydrate the test with the sample solution and standard solution as di- (C19H15F3N4O3·C7H8O3S·H2O: 594.56). rected under Ultraviolet-visible Spectrophotometry <2.24>, using 0.05 mol/L acetic acid-sodium acetate buffer solution, pH Method of preparation Prepare as directed under Tablets, 4.0, as the blank, and determine the absorbances, AT and AS, at with Tosufloxacin Tosilate Hydrate. 346 nm.

Identification To a quantity of powdered Tosufloxacin Tosi- Dissolution rate (%) with respect to the labeled amount of late Tablets, equivalent to 75 mg of Tosufloxacin Tosilate Hy- tosufloxacin tosilate hydrate (C19H15F3N4O3·C7H8O3S·H2O) drate according to the labeled amount, add 200 mL of a mixture = WS × (AT/AS) × (V´/V) × (1/C) × 72 × 1.031 of methanol and sodium hydroxide TS (49:1), shake well, and centrifuge. To 2 mL of the supernatant liquid add 100 mL of a WS: Amount (mg) of Tosufloxacin Tosilate Reference Stan- mixture of methanol and sodium hydroxide TS (49:1). Deter- dard, calculated on the anhydrous basis. mine the absorption spectrum of this solution as directed under C: Labeled amount (mg) of tosufloxacin tosilate hydrate

Ultraviolet-visible Spectrophotometry <2.24>: it exhibits (C19H15F3N4O3·C7H8O3S·H2O) in 1 tablet maxima between 260 nm and 264 nm, between 341 nm and 345 nm, and between 356 nm and 360 nm. Assay Weigh accurately the mass of not less than 20 Tosu- floxacin Tosilate Tablets, and powder. Weigh accurately a por- Uniformity of dosage units <6.02> Perform the test accord- tion of the powder, equivalent to about 0.15 g of tosufloxacin ing to the following method: it meets the requirement of the tosilate hydrate (C19H15F3N4O3·C7H8O3S·H2O), add 10 mL of Content uniformity test. water and methanol to make exactly 100 mL, shake for 10 min- To 1 tablet of Tosufloxacin Tosilate Tablets add V/10 mL of utes, and centrifuge. Pipet 4 mL of the supernatant liquid, add water and shake until the tablet is disintegrated. Add methanol exactly 4 mL of the internal standard solution and methanol to to make exactly V mL so that each mL contains about 1.5 mg of make 100 mL, and use this solution as the sample solution. tosufloxacin tosilate hydroxide (C19H15F3N4O3·C7H8O3S·H2O). Separately, weigh accurately about 30 mg of Tosufloxacin To- Shake this solution for 10 minutes, and centrifuge. Pipet 4 mL silate Reference Standard (separately determine the water con- of the supernatant liquid, add exactly 4 mL of the internal stan- tent <2.48> in the same manner as Tosufloxacin Tosilate Hy- dard solution and methanol to make 100 mL, and use this solu- drate), add 2 mL of water, and dissolve in methanol to make tion as the sample solution. Proceed as directed in the Assay. exactly 100 mL. Pipet 20 mL of this solution, add exactly 4 mL of the internal standard solution and methanol to make 100 mL, Amount (mg) of tosufloxacin tosilate hydrate and use this solution as the standard solution. Perform the test (C19H15F3N4O3·C7H8O3S·H2O) with 10 µL each of the sample solution and standard solution as

2208 Official Monographs Supplement II, JP XV directed under Liquid Chromatography <2.01> according to the frared Spectrophotometry <2.25>, and compare the spectrum following conditions, and calculate the ratios, QT and QS, of the with the Reference Spectrum or the spectrum of Troxipide Ref- peak area of tosufloxacin to that of the internal standard. erence Standard: both spectra exhibit similar intensities of absorption at the same wave numbers. Amount (mg) of tosufloxacin tosilate hydrate

(C19H15F3N4O3·C7H8O3S·H2O) Melting point <2.60> 177‐181°C = WS × (QT/QS)× 5 × 1.031 Purity (1) Chloride <1.03>―Dissolve 1.0 g of Troxipide in

WS: Amount (mg) of Tosufloxacin Tosilate Reference Stan- 30 mL of methanol, and add 6 mL of dilute nitric acid and water dard, calculated on the anhydrous basis. to make 50 mL. Perform the test using this solution as the test solution. Prepare the control solution as follows: to 0.25 mL of Internal standard solution—A solution of methyl parahydroxy- 0.01 mol/L hydrochloric acid VS add 30 mL of methanol, 6 mL benzoate in methanol (1 in 800) of dilute nitric acid and water to make 50 mL (not more than Operating conditions— 0.009%). Proceed as directed in the operating conditions in the Assay (2) Heavy metals <1.07>―Moisten 2.0 mg of Troxipide under Tosufloxacin Tosilate. with 1 mL of sulfuric acid, and gently heat until charred. After System suitability― cooling, add 2 mL of nitric acid, carefully heat until white Proceed as directed in the system suitability in the Assay un- fumes are no longer evolved, and perform the test according to der Tosufloxacin Tosilate. Method 2. Prepare the control solution as follows: evaporate 1 mL of sulfuric acid, 2 mL of nitric acid and 2 mL of hydrochlo- Containers and storage Containers―Well-closed containers. ric acid on a water bath and then on a sand bath to dryness, and

moisten the residue with 3 drops of hydrochloric acid. Proceed Add the following: in the same manner for the preparation of the test solution, and add 2.0 mL of Standard Lead Solution and water to make 50 mL Troxipide (not more than 10 ppm). (3) Related substances―Dissolve 0.20 g of Troxipide in 10 トロキシピド mL of methanol, and use this solution as the sample solution. Pipet 2 mL of this solution, and add methanol to make exactly 100 mL. Pipet 2 mL of this solution, add methanol to make exactly 20 mL, and use this solution as the standard solution. Per- form the test with these solutions as directed under Thin-layer Chromatography <2.03>. Spot 5 µL each of the sample solution and standard solution on a plate of silica gel with fluorescent in- and enantiomer dicator for thin-layer chromatography. Develop the plate with a mixture of methanol, ethyl acetate, water, hexane and ammonia C15H22N2O4: 294.35 water (28) (20:20:5:5:1) to a distance of about 10 cm, and 3,4,5-Trimethoxy-N-[(3RS)-piperidin-3-yl]benzamide air-dry the plate. Examine under ultraviolet light (main wave- [30751-05-4] length: 254 nm): the number of the spots other than the principal spot obtained from the sample solution is not more than three, Troxipide, when dried, contains not less than 98.5% and they are not more intense than the spot from the standard and not more than 101.0% of C H N O 15 22 2 4. solution. Description Troxipide occurs as a white, crystalline powder. (4) Residual solvent―Being specified separately. It is freely soluble in acetate (100), soluble in methanol, Loss on drying <2.41> Not more than 1.0% (1 g, 105°C, 2 sparingly soluble in ethanol (99.5) and slightly soluble in water. hours). It dissolves in 0.1 mol/L hydrochloric acid TS. A solution of Troxipide in 1 mol/L hydrochloric acid TS (1 in Residue on ignition <2.44> Not more than 0.1% (1 g). 5) shows no optical rotation. Assay Weigh accurately about 0.6 g of Troxipide, previously Identification (1) Determine the absorption spectrum of a dried, dissolve in 40 mL of acetic acid (100), and titrate <2.50> solution of Troxipide in 0.1 mol/L hydrochloric acid TS (1 in with 0.1 mol/L perchloric acid VS (potentiometric titration). 62500) as directed under Ultraviolet-visible Spectrophotometry Perform a blank determination in the same manner, and make <2.24>, and compare the spectrum with the Reference Spectrum any necessary correction. or the spectrum of a solution of Troxipide Reference Standard prepared in the same manner as the sample solution: both spec- Each mL of 0.1 mol/L perchloric acid VS tra exhibit similar intensities of absorption at the same wave- = 29.44 mg of C15H22N2O4 lengths. (2) Determine the infrared absorption spectrum of Troxip- Containers and storage Containers―Tight containers. ide as directed in the potassium bromide disk method under In-

Supplement II, JP XV Official Monographs 2209

Add the following: sample solution and standard solution as directed under Ultra- violet-visible Spectrophotometry <2.24>, and determine the Troxipide Fine Granules absorbances, AT and AS, at 258 nm.

トロキシピド細粒 Dissolution rate (%) with respect to the labeled amount of troxipide (C15H22N2O4) Tiapride Fine Granules contain not less than 93.0% = (WS/WT) × (AT/AS) × (1/C) × 450 and not more than 107.0% of the labeled amount of W : Amount (mg) of Troxipide standard for assay troxipide (C15H22N2O4: 294.35). S WT: Amount (mg) of Troxipide for Assay Method of preparation Prepare as directed under Powders, C: Labeled amount (mg) of troxipide (C15H22N2O4) in 1 g with Troxipide. Particle Size <6.03> It meets the requirement. Identification To a quantity of Troxipide Fine Granules, equivalent to 20 mg of Troxipide according to the labeled Assay Weigh accurately an amount of Troxipide Fine Gran- amount, add 100 mL of 0.1 mol/L hydrochloric acid TS, stir, ules, equivalent to about 0.5 g of troxipide (C15H22N2O4), add and filter. To 4 mL of the filtrate add 0.1 mol/L hydrochloric 200 mL of 0.1 mol/L hydrochloric acid TS, stir for 10 minutes, acid TS to make 50 mL. Determine the absorption spectrum of and add 0.1 mol/L hydrochloric acid TS to make exactly 250 this solution as directed under Ultraviolet-visible Spectropho- mL. Centrifuge this solution, pipet 5 mL of the supernatant liq- tometry <2.24>: it exhibits a maximum between 256 nm and uid, add 0.1 mol/L hydrochloric acid TS to make exactly 10 mL. 260 nm. Pipet 2 mL of this solution, add exactly 3 mL of the internal standard solution, add water to make 100 mL, and use this solu- Uniformity of dosage units <6.02> Perform the test accord- tion as the sample solution. Separately, weigh accurately about ing to the following method: Tiapride Fine Granules in sin- 25 mg of Troxipide Reference Standard, previously dried at gle-unit containers meet the requirement of the Content uni- 105°C for 2 hours, and dissolve in 0.1 mol/L hydrochloric acid formity test. TS to make exactly 25 mL. Pipet 2 mL of this solution, add ex- Take out the entire content of 1 pack of Troxipide Fine Gran- actly 3 mL of the internal standard solution, add water to make ules, add 80 mL of 0.1 mol/L hydrochloric acid TS, stir for 10 100 mL, and use this solution as the standard solution. Perform minutes, and add 0.1 mol/L hydrochloric acid TS to make ex- the test with 20 µL each of the sample solution and standard so- actly V mL so that each mL contains about 1 mg of troxipide lution as directed under Liquid Chromatography <2.01> ac-

(C15H22N2O4). Centrifuge this solution, pipet 2 mL of the su- cording to the following conditions, and calculate the ratios, QT pernatant liquid, add exactly 3 mL of the internal standard solu- and QS, of the peak area of troxipide to that of the internal stan- tion, add water to make 100 mL, and use this solution as the dard. sample solution. Proceed as directed in the Assay. Amount (mg) of troxipide (C15H22N2O4) Amount (mg) of troxipide (C15H22N2O4) = WS × (QT/QS) × 20 = WS × (QT/QS) × (V/25) WS: Amount (mg) of Troxipide Reference Standard WS: Amount (mg) of Troxipide Reference Standard Internal standard solution—A solution of 4-aminoacetophenone Internal standard solution—A solution of 4-aminoacetophenone in 0.1 mol/L hydrochloric acid TS (3 in 2000). in 0.1 mol/L hydrochloric acid TS (3 in 2000). Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: Dissolution <6.10> When the test is performed at 50 revolu- 258 nm). tions per minute according to the Paddle method, using 900 mL Column: A stainless steel column 4.6 mm in inside diameter of water as the dissolution medium, the dissolution rate in 60 and 15 cm in length, packed with octadecylsilanized silica gel minutes of Troxipide Fine Granules is not less than 85%. for liquid chromatography (5 µm in particle diameter). Weigh accurately an amount of Troxipide Fine Granules, Column temperature: Constant temperature of about 30ºC. equivalent to about 0.1 g of Troxipide (C15H22N2O4) according Mobile phase: To diluted phosphoric acid (1 in 500) add di- to the labeled amount, start the test, withdraw not less than 20 ethylamine to adjust the pH to 3.0. To 1500 mL of this solution mL of the medium at the specified minute, and filter through a add 100 mL of methanol and 50 mL of tetrahydronfuran. membrane filter with a pore size not exceeding 0.8 µm. Discard Flow rate: Adjust the flow rate so that the retention time of the first 10 mL of the filtrate, pipet 4 mL of the subsequent fil- troxipide is about 7 minutes. trate, add water to make exactly 20 mL, and use this solution as System suitability― the sample solution. Separately, weigh accurately about 20 mg System performance: When the procedure is run with 20 µL of Troxipide Reference Standard, previously dried at 105°C for of standard solution under the above operating conditions, 2 hours, and dissolve in water to make exactly 200 mL. Pipet 4 troxipide and the internal standard are eluted in this order with mL of this solution, add water to make exactly 20 mL, and use the resolution between these peaks being not less than 3. this solution as the standard solution. Perform the test with the System repeatability: When the test is repeated 6 times with

2210 Official Monographs Supplement II, JP XV

20 µL of the standard solution under the above operating condi- (C15H22N2O4) according to the labeled amount, and use this so- tions, the relative standard deviation of the ratio of the peak area lution as the sample solution. Separately weigh accurately about of troxipide to that of the internal standard is not more than 20 mg of Troxipide Reference Standard, previously dried at 1.0%. 105°C for 2 hours, and dissolve in water to make exactly 200 mL. Pipet 4 mL of this solution, add water to make exactly 20 Containers and storage Containers―Tight containers. mL, and use this solution as the standard solution. Perform the test with the sample solution and standard solution as directed

under Ultraviolet-visible Spectrophotometry <2.24>, and de- Add the following: termine the absorbances, AT and AS, at 258 nm.

Troxipide Tablets Dissolution rate (%) with respect to the labeled amount of

troxipide (C15H22N2O4) トロキシピド錠 = WS × (AT/AS) × (V´/V ) × (1/C) × 90 Troxipide Tablets contain not less than 95.0% and WS: Amount (mg) of Troxipide Reference Standard not more than 105.0% of the labeled amount of troxip- C: Labeled amount (mg) of Troxipide (C15H22N2O4) in 1 tab- ide (C15H22N2O4: 294.35). let

Method of preparation Prepare as directed under Tablets, Assay Weigh accurately the mass of not less than 20 Troxip- with Troxipide. ide Tablets, and powder. Weigh accurately a portion of the powder, equivalent to about 1 g of troxipide (C H N O ), add Identification Weigh accurately an amount of powdered 15 22 2 4 150 mL of 0.1 mol/L hydrochloric acid TS, shake for 30 min- Troxipide Tablets, equivalent to 0.1 g of Troxipide according to utes, add 0.1 mol/L hydrochloric acid TS to make exactly 250 the labeled amount, add 250 mL of 0.1 mol/L hydrochloric acid mL. Centrifuge this solution, pipet 5 mL of the supernatant liq- TS, shake, and filter. To 4 mL of the filtrate add 0.1 mol/L hy- uid, and add 0.1 mol/L hydrochloric acid TS to make exactly 20 drochloric acid TS to make 100 mL. Determine the absorption mL. Pipet 2 mL of this solution, add exactly 3 mL of the inter- spectrum of this solution as directed under Ultraviolet-visible nal standard solution and water to make 100 mL, and use this Spectrophotometry <2.24>: it exhibits maximum between 256 solution as the sample solution. Separately, weigh accurately nm and 260 nm. about 25 mg of Troxipide Reference Standard, previously dried Uniformity of dosage units <6.02> Perform the test accord- at 105°C for 2 hours, and dissolve in 0.1 mol/L hydrochloric ing to the following method: it meets the requirement of the acid TS to make exactly 25 mL. Pipet 2 mL of this solution, add Content uniformity test. exactly 3 mL of the internal standard solution and water to make To 1 tablet of Troxipide Tablets add 90 mL of 0.1 mol/L hy- 100 mL, and use this solution as the standard solution. Perform drochloric acid TS, shake well to disintegrate, shake for another the test with 20 µL each of the sample solution and standard so- 10 minutes, and add 0.1 mol/L hydrochloric acid TS to make lution as directed under Liquid Chromatography <2.01> ac- exactly V mL so that each mL contains about 1 mg of troxipide cording to the following conditions, and calculate the ratios, QT and Q , of the peak area of troxipide to that of the internal stan- (C15H22N2O4). Pipet 2 mL of the supernatant liquid, add exactly S 3 mL of the internal standard solution, add water to make 100 dard. mL, and use this solution as the sample solution. Proceed as di- Amount (mg) of troxipide (C H N O ) rected in the Assay. 15 22 2 4 = WS × (QT/QS) × 40

Amount (mg) of troxipide (C15H22N2O4) WS: Amount (mg) of Troxipide Reference Standard = WS × (QT/QS) × (V/25) Internal standard solution—A solution of 4-aminoacetophenone W : Amount (mg) of Troxipide Reference Standard S in 0.1 mol/L hydrochloric acid TS (3 in 2000). Internal standard solution—A solution of 4-aminoacetophenone Operating conditions— in 0.1 mol/L hydrochloric acid TS (3 in 2000). Detector: An ultraviolet absorption photometer (wavelength: 258 nm). Dissolution <6.10> When the test is performed at 50 revolu- Column: A stainless steel column 4.6 mm in inside diameter tions per minute according to the Paddle method, using 900 mL and 15 cm in length, packed with octadecylsilanized silica gel of water as the dissolution medium, the dissolution rate in 30 for liquid chromatography (5 µm in particle diameter). minutes of Troxipide Tablets is not less than 70%. Column temperature: Constant temperature of about 30 °C. Start the test with 1 tablet of Troxipide Tablets, withdraw not Mobile phase: To 1500 mL of diluted phosphoric acid (1 in less than 20 mL of the medium at the specified minute after 500) add diethylamine to adjust the pH to 3.0. To this solution starting the test, and filter through a membrane filter with a pore add 100 mL of methanol and 50 mL of tetrahydronfuran. size not exceeding 0.8 µm. Discard the first 10 mL of the filtrate, Flow rate: Adjust the flow rate so that the retention time of pipet V mL of the subsequent filtrate, add water to make exactly troxipide is about 7 minutes. V´ mL so that each mL contains about 22 µg of troxipide System suitability―

Supplement II, JP XV Official Monographs 2211

System performance: When the procedure is run with 20 µL Amount (mg) of ubenimex (C16H24N2O4S) of the standard solution under the above operating conditions, = WS × (QT / QS) × (1 / V) × (15 / 2) troxipide and the internal standard are eluted in this order with the resolution between these peaks being not less than 3. WS: Amount (mg) of ubenimex for assay System repeatability: When the test is repeated 6 times with Internal standard solution—A solution of ethyl parahydroxy- 20 µL of the standard solution under the above operating condi- benzoate in a mixture of water and acetonitrile (7:3) (1 in 2000) tions, the relative standard deviation of the ratio of the peak area Operating conditions— of troxipide to that of the internal standard is not more than Proceed as directed in the Assay. 1.0%. System suitability— Containers and storage Containers―Tight containers. System performance: When the procedure is run with 20 µL of the standard solution under the above operating conditions, ubenimex and the internal standard are eluted in this order with Add the following: the resolution between these peaks being not less than 10. System repeatability: When the test is repeated 6 times with Ubenimex Capsules 20 µL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of the peak area ウベニメクスカプセル of ubenimex to that of the internal standard is not more than 2.0%. Ubenimex Capsules contain not less than 93.0% and not more than 107.0% of the labeled amount of uben- Dissolution <6.10> When the test is performed at 50 revolu- imex (C16H24N2O4: 308.37). tions per minute according to the Paddle method using the sinker, using 900 mL of water as the dissolution medium, the Method of preparation Prepare as directed under Capsules, dissolution rate in 30 minutes of Ubenimex Capsules is not less with Ubenimex. than 70 %. Start the test with 1 capsule of Ubenimex Capsules, withdraw Identification To a quantity of the contents of Ubenimex not less than 20 mL of the medium at the specified minute after Capsules, equivalent to 25 mg of Ubenimex according to the starting the test, and filter through a membrane filter with a pore labeled amount, add water to make 50 mL, shake well, and filter. size not exceeding 0.45 µm. Discard the first 10 mL of the fil- Determine the absorption spectrum of the filtrate as directed trate, pipet V mL of the subsequent filtrate, add a mixture of under Ultraviolet-visible Spectrophotometry <2.24>: it exhibits water and acetonitrile (7:3) to make exactly V´ mL so that each maxima between 250 nm and 254 nm, between 255 nm and 259 mL contains about 11 µg of ubenimex (C H N O ) according nm, and between 261 nm and 265 nm. 16 24 2 4 to labeled amount, and use this solution as the sample solution. Uniformity of dosage units <6.02> Perform the test accord- Separately, weigh accurately about 22mg of ubenimex for assay, ing to the following method: it meets the requirement of the previously dried in vacume at 80°C for 4 hours, and dissolve in Content uniformity test. a mixture of water and acetonitrile (7:3) to make exactly 100 To 1 capsule of Ubenimex Capsules add 30 mL of a mixture mL. Pipet 5 mL of this solution, add a mixture of water and of water and acetonitrile (7:3), shake well for 30 minutes, and acetonitrile (7:3) to make exactly 100 mL, and use this solution add a mixture of water and acetonitrile (7:3) to make exactly 50 as the standard solution. Perform the test with exactly 50 µL mL. Centrifuge this solution and filter the supernatant liquid each of the sample solution and standard solution as directed through a membrane filter with a pore size not exceeding 0.45 under Liquid Chromatography <2.01> according to the follow- µm. Discard the first 5 mL of the filtrate, pipet V mL of the ing conditions, and determine the peak areas, AT and AS, of subsequent filtrate, equivalent to about 3 mg of ubenimex ubenimex in each solution. (C H N O ), add exactly 4 mL of the internal standard solu- 16 24 2 4 Dissolution rate (%) with respect to the labeled amount of tion, add a mixture of water and acetonitrile (7:3) to make 50 ubenimex (C H N O ) mL, and use this solution as the sample solution. Separately, 16 24 2 4 = W × (A / A ) ×(V ′/ V ) × (1 / C) × 45 weigh accurately about 20 mg of ubenimex for assay, previously S T S dried at 80°C for 4 hours under reduced pressure, and dissolve WS: Amount (mg) of ubenimex for assay in a mixture of water and acetonitrile (7:3) to make exactly 100 C: Labeled amount (mg) of ubenimex (C16H24N2O4) in 1 mL. Pipet 15 mL of this solution, add exactly 4 mL of the inter- capsule nal standard solution, add a mixture of water and acetonitrile (7:3) to make 50 mL, and use this solution as the standard solu- Operating conditions— tion. Perform the test with 20 µL each of the sample solution It meets test requirements directed in the assay. and standard solution as directed under Liquid Chromatography System suitability— <2.01> according to the following conditions, and calculate the System performance: When the procedure is run with condi- ratios, QT and QS, of the peak area of ubenimex to that of the tions described above for 50 µL of the standard solution, the internal standard. number of theoretical plates and symmetry factor for Ubenimex are not less than 3000 and not more than 2.0, respectively.

2212 Official Monographs Supplement II, JP XV System repeatability: When the test is repeated 6 times with Ursodeoxycholic Acid 50 µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of Ubeni- ウルソデオキシコール酸 mex is not more than 2.0%. Change the Origin/limits of content, Description, Assay To 10 Ubenimex capsules add 140 mL of a mixture of Identification, and Purity and Assay to read: water and acetonitrile (7:3), shake well for 30 minutes, and add a mixture of water and acetonitrile (7:3) to make exactly 200 Ursodeoxycholic Acid, when dried, contains not less mL. Centrifuge this solution, and filter. Discard the first 20 mL than 98.5% and not more than 101.0% of C24H40O4. of the filtrate, pipet a volume of the subsequent filtrate, equiva- Description Ursodeoxycholic Acid occurs as a white crystal lent to about 7.5 mg of ubenimex (C16H24N2O4), add exactly 10 mL of the internal standard solution, add a mixture of water and or powder, with bitter taste. acetonitrile (7:3) to make 50 mL, and use this solution as the It is freely soluble in methanol, in ethanol (99.5) and in acetic sample solution. Separately, weigh accurately about 30 mg of acid (100), and practically insoluble in water. ubenimex for assay, previously dried at 80°C for 4 hours under Identification Determine the infrared absorption spectrum of reduced pressure, dissolve in a mixture of water and acetonitrile Ursodeoxycholic Acid as directed in the potassium bromide disk (7:3) to make exactly 20 mL. Pipet 5 mL of this solution, add method under Infrared Spectrophotometry <2.25>, and compare exactly 10 mL of the internal standard solution, add a mixture of the spectrum with the Reference Spectrum: both spectra exhibit water and acetonitrile (7:3) to make 50 mL, and use this solution similar intensities of absorption at the same wave numbers. as the standard solution. Perform the test with 20 µL each of the sample solution and standard solution as directed under liquid Purity (1) Sulfate <1.14>—Dissolve 2.0 g of Ursodeoxy- chromatography <2.01> according to the following conditions, cholic Acid in 20 mL of acetic acid (100), add water to make and calculate the ratios, QT and QS, of the peak area of ubeni- 200 mL, and allow to stand for 10 minutes. Filter this solution, mex to that of the internal standard. discard the first 10 mL of the filtrate, and use the subsequent filtrate as the sample solution. To 40 mL of the sample solution Amount (mg) of ubenimex (C H N O S) 16 24 2 4 add 1 mL of dilute hydrochloric acid and water to make 50 mL. = W × (Q / Q ) × (1 / 4) S T S Perform the test using this solution as the test solution. Prepare the control solution with 0.40 mL of 0.005 mol/L sulfuric acid WS: Amount (mg) of ubenimex for assay by adding 4 mL of acetic acid (100), 1 mL of dilute hydrochlo- Internal standard solution—A solution of ethyl parahy- ric acid and water to make 50 mL (not more than 0.048%). droxybenzoate in mixture of water and acetonitrile (7:3) (1 in (2) Heavy metal <1.07>—Proceed with 1.0 g of Ursode- 2000) oxycholic Acid according to Method 2 and perform the test. Operating conditions— Prepare the control solution with 2.0 mL of Standard Lead Solu- Detector: An ultraviolet absorption photometer (wavelength: tion (not more than 20 ppm). 200 nm). (3) Barium—To 2.0 g of Ursodeoxychollic Acid add 100 Column: A stainless steel column 4.6 mm in inside diameter mL of water and 2 mL of hydrochloric acid, boil for 2 minutes, and 15 cm in length, packed with octadecylsilanized silica gel allow it to cool, filter, and wash the filter with water until to get for liquid chromatography (5 µm in particle diameter). 100 mL of the filtrate. To 10 mL of the filtrate add 1 mL of di- Column temperature: Constant temperature of about 30 °C. lute sulfuric acid: no turbidity is appeared. Mobile phase: A mixture of diluted phosphoric acid and ace- (4) Related substances—Dissolve 0.10 g of Ursodeoxy- tonitrile for liquid chromatography (83:17) (1 in 100). cholic Acid in 1 mL of methanol, add acetone to make exactly Flow rate: Adjust the flow rate so that the retention time of 10 mL, and use this solution as the sample solution. Pipet 1 mL ubenimex is about 8 minutes. of this solution, and add acetone to make exactly 100 mL. Pipet System suitability— 1 mL and 2 mL of this solution, to each add acetone to make System performance: When the procedure is run with 20 µL exactly 20 mL, and use these solutions as the standard solution of the standard solution under the above operating conditions, (A) and standard solution (B), respectively. Separately, dissolve ubenimex and the internal standard are eluted in this order with 50 mg of chenodeoxycholic acid for thin-layer chromatography the resolution between these peaks being not less than 10. in 5 mL of methanol, add acetone to make exactly 50 mL. Pipet System repeatability: When the test is repeated 6 times with 2 mL of this solution, add acetone to make exactly 20 mL, and 20 µL of the standard solution under the above operating condi- use this solution as the standard solution (1). Furthermore, dis- tions, the relative standard deviation of the ratio of the peak area solve 25 mg of lithocholic acid for thin-layer chromatography in of ubenimex to that of the internal standard is not more than 5 mL of methanol, and add acetone to make exactly 50 mL. Pi- 1.0%. pet 2 mL of this solution, and add acetone to make exactly 20 mL. Pipet 2 mL of this solution, add acetone to make exactly 10 Containers and storage Containers―Tight containers. mL, and use this solution as standard solution (2). Perform the test with these solutions as directed under Thin-layer Chroma- tography <2.03>. Spot 10µL each of the sample solution, stan-

Supplement II, JP XV Official Monographs 2213 dard solution (1), standard solution (2), standard solution (A) at 120°C for 30 minutes, immediately splay evenly a solution of and standard solution (B) on a plate of silica gel for thin-layer phosphomolybdic acid n-hydrate in ethanol (99.5) (1 in 5), and chromatography. Develop the plate with a mixture of isooctane, heat at 120ºC for 3 to 5 minutes: the principle spot obtained ethanol (99.5), ethyl acetate and acetic acid (100) (10:6:3:1) to a from the sample solution and the spot from the standard solution distance of about 15 cm, and air-dry the plate. Dry the plate show a blue color and the same Rf value. further at 120°C for 30 minutes, and immediately spray evenly the solution which was prepared by dissolving 5 g of phospho- Dissolution <6.10> When the test is performed at 50 revolu- molybdic acid n-hydrate in about 50 mL of ethanol (99.5), to tions per minute according to the Paddle method, using 900 mL which 5 mL of sulfuric acid is dropped in and add ethanol (99.5) of the 2nd fluid for dissolution test as the test solution, the dis- to make 100 mL, and heat at 120°C for 3 to 5 minutes: the spots solution rate in 15 minutes of Ursodeoxycholic Acid Granules is from the sample solution corresponding to the spots obtained not less than 80 %. from the standard solution (1) and (2) are not more intense than Start the test by taking the exact amount that correspond to the spots from the standard solutions (1) and (2), the spots other about 50 mg of ursodeoxycholic acid (C24H40O4) according to than the principal spot from the sample solution and other than labeled amount and withdraw not less than 20 mL of the me- those mentioned above are not intense than the spots obtained dium at the specified time, and filter through a membrane filter from the standard solution (B), and the total amount of the spots with a pore size not exceeding 0.45 µm. Discard first 10 mL of other than the principal spot from the sample solution and other the filtrate, then use the subsequent filtrate as the sample solu- than those mentioned above, which is calculated by the com- tion. Separately, weigh accurately about 22 mg of ursodeoxy- parison with the spots obtained from the standard solutions (A) cholic acid for array, previously dried at 105°C for 2 hours, and and (B), is not more than 0.25%. dissolve in acetonitrile to make exactly 100 mL of the solution. Pipet 5 mL of this solution, add test solution to prepare exactly Assay Weigh accurately about 0.5 g of Ursodeoxycholic Acid, 20 mL of standard solution. Perform the test with 100 µL each previously dried, dissolve in 40 mL of ethanol (95) and 20 mL of sample solution and standard solution as directed under Liq- of water, and titrate <2.50> with 0.1 mol/L sodium hydroxide uid Chromatography <2.01> according to the following condi-

VS (potentiometric titration). Perform a blank determination in tions, and determine the peak areas, AT and AS, of ursodeoxy- the same manner, and make any necessary correction. cholic acid in each solution.

Each mL of 0.1 mol/L sodium hydroxide VS Dissolution rate (%) with respect to the labeled amount of

= 39.26 mg of C24H40O4 ursodeoxycholic acid (C24H40O4) = (WS / WT) × (AT/ AS ) × (1 / C) × 225

Add the following: WS: Amount (mg) of ursodeoxycholic acid for assay WT: Amount (g) of Ursodeoxycholic Acid Glanules Ursodeoxycholic Acid Granules C: Labeled amount (mg) of ursodeoxycholic acid (C24H40O4) ウルソデオキシコール酸顆粒 in 1 g

Ursodeoxycholic Acid Granules contain not less Operating conditions— than 95.0% and not more than 105.0% of the labeled Proceed as directed in the Assay. System suitability— amount of ursodeoxycholic acid (C24H40O4: 392.57). System performance: When the procedure is run with 100 µL Method of preparation Prepare as directed under Granules, of the standard solution under the above operating conditions, with Ursodeoxycholic Acid. the number of theoretical plates and symmetry factor of the peak of ursodeoxycholic acid are not less than 3000 and not more Identification To a quantity of powdered Ursodeoxycholic than 2.0, respectively. Acid Granules, equivalent to 20 mg of Ursodeoxycholic Acid System repeatability: When the test is repeated 6 times with according to the labeled amount, add 10 mL of methanol, and 100 µL of the standard solution under the above operating con- shake for 20 minutes. Centrifuge this solution, pipet 4 mL of the ditions, the relative standard deviation of the peak area of urso- supernatant liquid, and distil under reduced pressure. To the deoxycholic acid is not more than 2.0 %. residue add 4 mL of acetone, disperse with ultrasonic waves, centrifuge, and use the supernatant liquid as the sample solution. Particle Size <6.03> It meets the requirement. Separately, dissolve 10 mg of ursodeoxycholic acid in 5 mL of acetone, and use this solution as the standard solution. Perform Assay Weigh accurately an amount of powdered Ursodeoxy- the test with these solutions as directed under Thin-layer Chro- cholic Acid Granules, equivalent to about 0.1 g of ursodeoxy- matography <2.03>. Spot 10 µL of the sample solution and cholic acid (C24H40O4) according to labeled amount, add exactly standard solution on a plate of silica gel for thin-layer chroma- 20 mL of the internal standard solution, shake for 10 minutes, tography. Develop the plate with a mixture of isooctane, ethanol and centrifuge. Filter the supernatant liquid through a membrane (99.5), ethyl acetate and acetic acid (100) (10:6:3:1) to a dis- filter with a pore size not exceeding 0.45 µm, and use the filtrate tance of about 15 cm, and air-dry the plate. Dry the plate further as the sample solution. Separately, weigh accurately about 0.1 g

2214 Official Monographs Supplement II, JP XV of ursodeoxycholic acid for assay, previously dried at 105°C for supernatant liquid, and distil under reduced pressure. To the 2 hours, dissolve in 20 mL of the internal standard solution, and residue add 4 mL of acetone, disperse with ultrasonic waves, use this solution as the standard solution. Perform the test with centrifuge, and use the remaining supernatant liquid as the sam- 10 µL each of the sample solution and standard solution as di- ple solution. Separately, dissolve 10 mg of ursodeoxycholic acid rected under Liquid Chromatography <2.01> according to the in 5 mL of acetone, and use this solution as the standard solu- following conditions, and calculate the ratios, QT and QS, of the tion. Perform the test with these solutions as directed under peak area of ursodeoxycholic acid to that of the internal stan- Thin-layer Chromatography <2.03>. Spot 10 µL each of the dard. sample solution and standard solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of Amount (mg) of ursodeoxycholic acid (C24H40O4) isooctane, ethanol (99.5), ethyl acetate and acetic acid (100) = WS × (QT / QS) (10:6:3:1) to a distance of about 15 cm, and air-dry the plate. Dry the plate further at 120°C for 30 minutes, and immediately W : Amount (mg) of ursodeoxycholic acid for assay S splay evenly a solution of phosphomolybdic acid n-hydrate in Internal standard solution— A solution of ethyl parahydroxy- ethanol (95) (1 in 5) on the plate, and heat at 120ºC for 3 to 5 benzoate in diluted methanol (4 in 5) (7 in 200000). minutes: the principal spot obtained from the sample solution Operating conditions— and the spot from the standard solution show a blue color and Detector: An ultraviolet absorption photometer (wavelength: the same Rf value. 210 nm). Uniformity of dosage units <6.02> Perform the test accord- Column: A stainless steel column 4.6 mm in inside diameter and ing to the following method: it meets the requirement of the 15 cm in length, packed with octadecylsilanized silica gel for Content uniformity test. liquid chromatography (5 µm in particle diameter). Take 1 tablet of Ursodeoxycholic Acid Tablets and add ex- Column temperature: Constant temperature of about 40 °C. actly V mL of the internal standard solution so that each mL Mobile phase: A mixture of diluted phosphoric acid (1 in 500) contains about 5 mg of ursodeoxycholic acid (C H O ), dis- and acetonitrile for liquid chromatography (11:9). 24 40 4 perse it with ultrasonic waves, then agitate to mix for 10 more Flow rate: Adjust the flow rate so that the retention time of minutes and then centrifuge. Filter the clear supernatant solution ursodeoxycholic acid is about 6 minutes. through a membrane filter with a pore size not exceeding 0.45 System suitability— µm, and use this filtrate as the sample solution. System performance: When the procedure is run with 10 µL Proceed as directed in the operating conditions in the Assay of the standard solution under the above operating conditions, ursodeoxycholic acid and the internal standard are eluted in this Amount (mg) of ursodeoxycholic acid (C24H40O4) order with the resolution between these peaks being not less = WS × (QT / QS) × (V / 20) than 8.

System repeatability: When the test is repeated 6 times with WS: Amount (mg) of ursodeoxycholic acid for assay 10 µL of the standard solution under the above operating conditions, the relative standard deviation of the ratio of the peak area Internal standard solution—A solution of ethyl parahydroxy- of ursodeoxycholic acid to that of the internal standard is not benzoate in diluted methanol (4 in 5) (7 in 200000). more than 1.0%. Dissolution <6.10> When the test is performed at 50 revolu- Containers and storage Containers—Tight containers. tions per minute according to the Paddle method, using 900 mL of the 2nd fluid for dissolution test as the dissolution medium, the dissolution rate of a 50-mg Ursodeoxycholic Acid tablet in Add the following: 30 minutes and a 100-mg tablet in 45 minutes are not less than 80% and not less than 70%, respectively. Ursodeoxycholic Acid Tablets Start the test with one tablet of Ursodeoxycholic Acid Tablets, ウルソデオキシコール酸錠 withdraw not less than 20 mL of the medium at the specified time after starting the test, and filter through a membrane filter Ursodeoxycholic Acid Tablets contain not less than with a pore size not exceeding 0.45 µm. Discard 10 mL of the 95.0% and not more than 105.0% of the labeled first filtrate and pipet V mL of the subsequent filtrate. Add dis- amount of Ursodeoxycholic Acid (C24H40O4: 392.57). solution medium to make exactly V´ mL so that each mL contains about 56 µg of ursodeoxycholic acid (C24H40O4) according Method of preparation Prepare as directed under Tablets, to the labeled amount, and use the solution as the sample solu- with Ursodeoxycholic Acid. tion. Separately weigh accurately about 22 mg of ursodeoxycholic acid for assay, previously dried at 105°C for 2 hours, and Identification To a quantity of powdered Ursodeoxycholic dissolve in acetonitrile to make exactly 100 mL. Pipet 5 mL of Acid Tablets, equivalent to 20 mg of Ursodeoxycholic Acid ac- this solution, add dissolution medium to make exactly 20 mL, cording to the labeled amount, add 10 mL of methanol, and and use this solution as the standard solution. Perform the test shake for 20 minutes. Centrifuge this solution, pipet 4 mL of the with exactly 100 µL each of sample solution and standard solu-

Supplement II, JP XV Official Monographs 2215 tion as directed under Liquid Chromatography <2.01> accord- System suitability— ing to the following conditions, and determine the peak areas, System performance: When the procedure is run with 10 µL

AT and AS, of ursodeoxycholic acid in each solution. of the standard solution according to the above operating conditions, ursodeoxycholic acid and the internal standard are eluted Dissolution rate (%) with respect to the labeled amount of in this order with the resolution between these peaks being not ursodeoxycholic acid (C24H40O4) less than 8. = WS × (AT / AS) + (V ′/ V ) + (1 / C) × 225 System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- W : Amount (mg) of ursodeoxycholic acid for assay S tions, the relative standard deviation of the ratio of the peak area C: Labeled amount (mg) of ursodeoxycholic acid in 1 tablet of ursodeoxycholic acid to that of the internal standard is not (C H O ) 24 40 4 more than 1.0%. Operating conditions— Containers and storage Containers—Tight containers. Proceed as directed in the operating conditions in the Assay. System suitability— System performance: When the procedure is run with 100 µL Vasopressin Injection of the standard solution under the above operating condition, the number of theoretical plates and symmetry factor of the peak of バソプレシン注射液 ursodeoxycholic acid are not less than 3000 and not more than 2.0, respectively. Add the following next to Purity: System repeatability: When the test is repeated 6 times with 100 µL of the standard solution under the above operating con- Bacterial endotoxins <4.01> Less than 15 EU / Vasopressin ditions, the relative standard deviation of the peak area of urso- unit deoxycholic acid is not more than 2.0 %. Add the following next to Extractable volume: Assay Weigh accurately the mass of not less than 20 Ursode- Foreign insoluble matter <6.06> Perform the test according oxycholic Acid Tablets, and powder. Weigh accurately a portion to Method 1: it meets the requirement. of the powder, equivalent to about 0.1 g of ursodeoxycholic acid (C24H40O4), add exactly 20 mL of the internal standard solution, Insoluble particulate matter <6.07> It meets the require- shake for 10 minutes, and centrifuge. Filter the supernatant liq- ment. uid through a membrane filter with a pore size not exceeding Sterility <4.06> Perform the test according to the Membrane 0.45 µm, and use the filtrate as the sample solution. Separately, filtration method: it meets the requirement. weigh accurately about 0.1 g of ursodeoxycholic acid for assay, previously dried at 105°C for 2 hours, dissolve in exactly 20 mL of the internal standard solution, and use this solution as the Warfarin Potassium Tablets standard solution. Perform the test with 10 µL each of the sample solution and standard solution as directed under Liquid ワルファリンカリウム錠 Chromatography <2.01> according to the following conditions, and calculate the ratios, QT and QS, of the peak area of ursode- Add the following next to Uniformity of dosage oxycholic acid to that of the internal standard. units:

Amount (mg) of ursodeoxycholic acid (C24H40O4) Dissolution <6.10> When the test is performed at 50 revolu- = WS × (QT / QS) tions per minute according to the Paddle method, using 900 mL of water as the dissolution medium, the dissolution rates of WS: Amount (mg) of ursodeoxycholic acid for assay 0.5-mg, 1-mg and 2-mg tablets in 15 minutes and of 5-mg tablets in 30 minutes are not less than 80%. Internal standard solution—A solution of ethyl parahydroxy- Start the test with 1 tablet of Warfarin Potassium Tablets, benzoate in diluted methanol (4 in 5) (7 in 200000). withdraw not less than 20 mL of the medium at the specified Operating conditions— minute after starting the test, and filter through a membrane fil- Detector: An ultraviolet absorption photometer (wavelength: ter with a pore size not exceeding 0.45 µm. Discard the first 10 210 nm). mL of the filtrate, pipet V mL of the subsequent filtrate, add Column: A stainless steel column 4.6 mm in inside diameter water to make exactly V´ mL so that each mL contains about and 15 cm in length, packed with octadecylsilanized silica gel 0.56 µg of warfarin potassium (C H KO ) according to the la- for liquid chromatography (5 µm in particle diameter). 19 15 4 beled amount, and use this solution as the sample solution. Column temperature: Constant temperature of about 40°C. Separately, weigh accurately about 22 mg of Warfarin Potas- Mobile phase: A mixture of diluted phosphoric acid (1 in sium Reference Standard, previously dried at 105°C for 3 hours, 500) and acetonitrile for liquid chromatography (11:9). and dissolve in water to make exactly 100 mL. Pipet 5 mL of Flow rate: Adjust the flow rate so that the retention time of this solution, and add water to make exactly 100 mL. Pipet 5 ursodeoxycholic acid is about 6 minutes. mL of this solution, add water to make exactly 100 mL, and use

2216 Official Monographs Supplement II, JP XV this solution as the standard solution. Perform the test with 100 cross intersecting at the hilum. µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the follow- Add the following next to item (3) in the section on Purity. ing conditions, and determine the peak areas, AT and AS, of warfarin from each solution. Purity ◆(4) Foreign matter—Under a microscope <5.01>, Dissolution rate (%) with respect to the labeled amount of Wheat Starch does not contain starch granules of any other origin. warfarin potassium (C19H15KO4) ◆ = WS × (AT / AS) × (V ′/ V ) × (1 / C) × (9 / 4)

WS: Amount (mg) of Warfarin Potassium Reference Standard Zinc Sulfate Hydrate C: Labeled amount (mg) of warfarin potassium (C19H15KO4) in 1 tablet 硫酸亜鉛水和物

Operating conditions— Change the Description and Identification to Detector: An ultraviolet absorption photometer (wavelength: read: 283 nm). Description Zinc Sulfate Hydrate occurs as colorless crystals Column: A stainless steel column 4.6 mm in inside diameter or white crystalline powder. and 15 cm in length, packed with octadecylsilanized silica gel It is very soluble in water, and very slightly soluble in ethanol for liquid chromatography (5 µm in particle diameter). (99.5). Column temperature: A constant temperature of about 35°C. It effloresces in dry air. Mobile phase: A mixture of methanol, water and phosphoric acid (700:300:1). Identification (1) A solution of Zinc Sulfate Hydrate (1 in Flow rate: Adjust the flow rate so that the retention time of 20) responds to the Qualitative Tests <1.09> for zinc salt. warfarin is about 6 minutes. (2) A solution of Zinc Sulfate Hydrate (1 in 20) responds to System suitability— the Qualitative Tests <1.09> for sulfate. System performance: When the procedure is run with 100 µL of the standard solution under the above conditions, the number Add the following next to the Identification: of theoretical plates and the symmetry factor of the peak of warfarin are not less than 2000 and not more than 2.0, respec- pH <2.54> Dissolve 1.0 g of Zinc Sulfate Hydrate in 20 mL tively. of water: the pH of the solution is between 4.4 and 6.0. System repeatability: When the test is repeated 6 times with 100 µL of the standard solution under the above operating con- Change the Purity (1) to read: ditions, the relative standard deviation of the peak area of warfarin is not more than 2.0%. Purity (1) Clarity and color of solution―Dissolve 0.25 g of Zinc Sulfate Hydrate in 5 mL of water: the solution is clear and Wheat Starch colorless.

コムギデンプン Add the following next to the Purity: Change the Origin/limits of content and the Iden- Loss on drying <2.41> Not less than 35.5% and not more tification (1) to read: than 38.5% (1 g, 105°C, 3 hours). Wheat Starch consists of the starch granules obtained from caryopsis of wheat, Triticum aestivum Linné (Gramineae).

Identification (1) Examine under a microscope <5.01> using a mixture of water and glycerinol (1:1), Wheat Starch presents large and small granules, and, very rarely, intermediate sizes. The large granules, usually 10-60 µm in diameter, are discoid or, more rarely, reniform when seen face-on. The central hilum and striations are invisible or barely visible and the granules sometimes show cracks on the edges. Seen in profile, the granules are elliptical and fusiform and the hilum appears as a slit along the main axis. The small granules, rounded or polyhedral, are 2-10 µm in diameter. Between orthogonally oriented polarizing plates or prisms, the granules show a distinct black

Supplement II, JP XV Official Monographs 2217

Add the following: exactly 100 mL. Pipet 2 mL of this solution, add methanol to make exactly 20 mL, and use this solution as the standard solu- Zolpidem Tartrate tion. Perform the test with exactly 5 µL each of the sample solution and standard solution as directed under Liquid Chromatog- ゾルピデム酒石酸塩 raphy <2.01> according to the following conditions. Determine each peak area of both solutions by the automatic integration method: each area of the peak other than the peak of zolpidem from the sample solution is not more than the peak area of zolpidem from the standard solution. Operating conditions— Detector: A ultraviolet absorption photometer (wavelength: 254 nm). Column: A stainless steel tube 4.6 mm in inside diameter and (C H N O) ·C H O :764.87 19 21 3 2 4 6 6 7.5 cm in length, packed with octadecylsilanized silica gel for N,N,6–Trimethyl–2–(4– liquid chromatography (5 µm in particle diameter). methylphenyl)imidazo[1,2–a]pyridine–3-acetamide Column temperature: A constant temperature of about 25°C. hemi–(2R,3R)–tartrate [99294–93–6] Mobile phase: To 4.9 g of phosphoric acid add 1000 mL of Zolpidem Tartrate contains not less than 98.5% and water, and adjust the pH to 5.5 with triethylamine. To 11 vol- not more than 101.0% of zolpidem tartrate umes of this solution add 5 volumes of methanol and 4 volumes of acetonitrile. [(C19H21N3O)2·C4H6O6)], calculated on the anhydrous basis. Flow rate: Adjust the flow rate so that the retention time of zolpidem is about 5 minutes. Description Zolpidem Tartrate occurs as a white, crystalline Time span of measurement: About 5 times as long as the re- powder. tention time of zolpidem. It is freely soluble in acetic acid (100), soluble in System suitability— N,N-dimethylformamide and in methanol, sparingly soluble in System performance: Dissolve 10 mg each of Zolpidem Tar- water, and slightly soluble in ethanol (99.5) and in acetic anhy- trate and benzyl parahydroxybenzoate in 100 mL of methanol. dride. When the procedure is run with 5 µL of this solution under the It dissolves in 0.1 mol/L hydrochloric acid TS. above operating conditions, zolpidem and benzyl parahydroxy- It gradually changes to yellow in color on exposure to light. benzoate are eluted in this order with the resolution between these peaks being not less than 9. 20 Optical rotation [α] D : About +1.8° (1 g, System repeatability: When the test is repeated 6 times with 5 N,N-dimethylformamide, 20 mL, 100 mm). µL of the standard solution under the above operating conditions, the relative standard deviation of the peak area of zolpidem is Identification (1) Dissolve 50 mg of Zolpidem Tartrate in 5 not more than 5.0%. mL of acetic acid (100) and add 3 drops of Dragendorff’s TS: an (3) Residual solvent―Being specified separately. orange precipitate is formed. (2) Determine the absorption spectrum of a solution of Zol- Water <2.48> Not more than 3.0% (0.5 g, volumetric titration, pidem Tartrate in 0.1 mol/L hydrochloric acid TS (1 in 100000) direct titration). as directed under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spectrum: both Residue on ignition <2.44> Not more than 0.1% (1 g). spectra exhibit similar intensities of absorption at the same wavelengths. Assay Weigh accurately about 0.4 g of Zolpidem Tartrate, (3) Determine the infrared absorption spectrum of Zolpidem dissolve in 100 mL of a mixture of acetic anhydride and acetic Tartrate as directed in the potassium bromide disk method under acid (100) (7:3) and titrate <2.50> with 0.1 mol/L perchloric the Infrared Spectrophotometry <2.25>, and compare the spec- acid VS (potentiometric titration). Perform a blank determina- trum with the Reference Spectrum: both spectra exhibit similar tion in the same manner, and make any necessary correction. intensities of absorption at the same wave numbers. Each mL of 0.1 mol/L perchloric acid VS (4) A solution of Zolpidem Tartrate in methanol (1 in 10) = 38.24 mg of (C H N O) ·C H O responds to the Qualitative Tests <1.09> (3) for tartrate. 19 21 3 2 4 6 6 Containers and storage Containers—Tight containers Purity (1) Heavy metals <1.07>—Proceed with 2.0 g of Storage conditions―Light-resistant Zolpidem Tartrate according to Method 4, and perform the test. Prepare the control solution with 2.0 mL of Standard Lead Solu- tion (not more than 10 ppm). (2) Related substances—Dissolve 10 mg of Zolpidem Tar- trate in 20 mL of methanol and use this solution as the sample solution. Pipet 1 mL of this solution, and add methanol to make

Crude Drugs

Apricot Kernel System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating condi- キョウニン tions, the relative standard deviation of the peak area of amygdalin is not more than 1.5%. Change the Origin to read: Apricot Kernel is the seed of Prunus armeniaca Astragalus Root Linné or Prunus armeniaca Linné var. ansu Maxi- mowicz (Rosaceae). オウギ It contains not less than 2.0% of amygdalin, calculated on the basis of dried material. Add the following next to Description:

Add the following next to the Purity: Identification Put 1 g of pulverized Astragalus Root in a glass-stoppered centrifuge tube, add 5 mL of potassium hydrox- Loss on drying <5.01> Not more than 7.0% (6 hours). ide TS and 5 mL acetonitrile, and stop the vial tightly. After Component determination Weigh accurately 0.5 g of ground shaking this for 10 minutes, centrifuge, and use the upper layer Apricot Kernel, add 40 mL of diluted methanol (9 in 10), heat as the sample solution. Separately, dissolve 1 mg of astraga- immediately under a reflux condenser on a water bath for 30 loside IV for thin-layer chromatography in 2 mL of methanol, minutes, and cool. Filter the mixture, add diluted methanol (9 in and use this solution as the standard solution. Perform the test 10) to make exactly 50 mL. Pipet 5 mL of this solution, add wa- with these solutions as directed under Thin-layer Chromatogra- ter to make exactly 10 mL, filter, and use the filtrate as the sam- phy <2.03>. Spot 10 µL of the sample solution and standard so- ple solution. Separately, weigh accurately about 10 mg of lution on a plate of silica gel for thin-layer chromatography. amygdalin for component determination, previously dried in a Develop the plate with a mixture of ethyl acetate, methanol and desiccator (silica gel) for not less than 24 hours, dissolve in di- water (20:5:4) to a distance of about 10 cm, and air-dry the plate. luted methanol (1 in 2) to make exactly 50 mL, and use this so- Spray evenly diluted sulfuric acid on the plate, heat at 105°C for lution as the standard solution. Perform the test with 10 µL each 5 minutes, and examine under ultraviolet light (main wave- of the sample solution and standard solution as directed under length: 365 nm): one of the spot among the several spots from Liquid Chromatography <2.01> according to the following con- the sample solution has the same color tone and Rf value with the brownish yellow fluorescent spot from the standard solution. ditions, and determine the peak areas, AT and AS, of amygdalin in each solution.

Amount (mg) of amygdalin = WS × (AT/AS) × 2 Bear Bile

WS : Amount (mg) of amygdalin for component determination ユウタン Operating conditions― Detector: An ultraviolet absorption photometer (wavelength: Change the Identification to read: 210 nm) Identification To 0.1 g of pulverized Bear Bile, add 5 mL of Column: A stainless steel column 4.6 mm in inside diameter methanol, heat on a water bath for 10 minutes, centrifuge after and 15 cm in length, packed with octadecylsilianized silica gel cooling, and use the supernatant liquid as the sample solution. for liquid chromatography (5 µm in particle diameter). Separately, dissolve 10 mg of sodium tauroursodeoxycholate for Column temperature: A constant temperature of about 45°C. thin-layer chromatography in 5 mL of methanol, and use this as Mobile phase: A mixture of 0.05 mol/L sodium dihydrogen the standard solution. Perform the test with these solutions as phosphate TS and methanol (5:1). directed under Thin-layer Chromatography <2.03>. Spot 5 µL Flow rate: 0.8 mL per minute (the retention time of amygda- each of the sample solution and standard solution on a plate of lin is about 12 minutes). silica gel for thin-layer chromatography. Develop the plate with System suitability― a mixture of acetic acid (100), toluene and water (10:10:1) to a System performance: When the procedure is run with 10 µL distance of about 10 cm, and air-dry the plate. Spray evenly di- of the standard solution under the above operating conditions, luted sulfuric acid on the plate, and heat at 105°C for 10 min- the number of theoretical plates and the symmetry factor of the utes: one of the spot among the several spots from the sample peak of amygdalin are not less than 5000 and not more than 1.5, solution has the same color tone and R value with the spot from respectively. f the standard solution. 2219 2220 Crude Drugs Supplement II, JP XV Add the following next to the Identification: Powdered Calumba

Purity Other animal biles—Use the sample solution obtained コロンボ末 in the Identification as the sample solution. Separately, dissolve 10 mg of sodium glycocholate for thin-layer chromatography Change the Purity to read: and 20 mg of powdered porcine bile for thin-layer chromatography in 5 mL of methanol, and use these solutions as the stan- Purity (1) Heavy metals <1.07> Proceed with 3.0 g of dard solution (1) and standard solution (2) respectively. Perform Powdered Calumba according to Method 3, and perform the test. the test with these solutions as directed in the Identification: Prepare the control solution with 3.0 mL of Standard Lead Solu- Spots from the sample solution correspond to neither the spot of tion (not more than 10 ppm). glycocholic acid from the standard solution (1) nor the (2) Arsenic <1.11> Prepare the test solution with 0.40 g of gray-brown to black spot of powdered porcine bile at around Rf Powdered Calumba according to Method 4, and perform the test 0.3 from the standard solution (2). (not more than 5 ppm).

Bupleurum Root Cardamon

サイコショウズク

Change the Identification (2) to read: Change the another title in Japanese of the monograph as follows: Identification (2) To 1.0 g of the pulverized Bupleurum Root, add 10 mL of methanol, and boil gently under a reflux 小豆宼 condenser on a water bath for 15 minutes. After cooling, centrifuge, and use the filtrate as the sample solution. Separately, dis- 小豆蔲 solve 1 mg of saikosaponin a for thin-layer chromatography in 1 mL of methanol, and use this solution as the standard solution. Perform the test with these solutions as directed under Cornus Fruit Thin-layer Chromatography <2.03>. Spot 10 µL each of the サンシュユ sample solution and standard solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of Change the Origin to read: ethyl acetate, ethanol (99.5) and water (8:2:1) to a distance of about 10 cm, and air-dry the plate. Spray evenly Cornus Fruit is the pulp of the pseudocarp of Cornus 4-dimethylaminobenzaldehyde TS on the plate, and heat at officinalis Siebold et Zuccarini (Cornaceae). 105°C for 5 minutes: one of the spot among the several spots It contains not less than 0.4% of loganin, calculated from the sample solution has the same color tone and Rf value on the basis of dried material. with the gray-brown spot from the standard solution, accompa- nied by the adjacent yellow-red spot above. Add the following next to Extract Content: Component determination Weigh accurately about 1 g of Calumba fine cuttings of Cornus Fruit (separately determine the loss on drying <5.01>), put in a glass-stoppered centrifuge tube, sus- コロンボ pend in 30 mL of diluted methanol (1 in 2), shake for 20 minutes, centrifuge, and separate the supernatant liquid. To the Change the Purity to read: residue, add 30 mL of diluted methanol (1 in 2), and repeat the above process twice more. Combine all the extracts, add diluted Purity (1) Heavy metals <1.07> Proceed with 3.0 g of methanol (1 in 2) to make exactly 100 mL, and use this solution pulverized Calumba according to Method 3, and perform the as the sample solution. Separately, weigh accurately about 10 test. Prepare the control solution with 3.0 mL of Standard Lead mg of loganin for component determination, previously dried in Solution (not more than 10 ppm). a desiccator (silica gel) for 24 hours, dissolve in diluted metha- (2) Arsenic <1.11> Prepare the test solution with 0.40 g of nol (1 in 2) to make exactly 100 mL, and use this solution as the pulverized Calumba according to Method 4, and perform the standard solution. Perform the test with 10 µL each of the sam- test (not more than 5 ppm). ple solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions,

and determine the peak areas, AT and AS, of loganin in each solution.

Amount (mg) of loganin = WS × (AT/AS)

Supplement II, JP XV Crude Drugs 2221

WS : Amount (mg) of loganin for component determination Add the following:

Operating conditions― Detector: An ultraviolet absorption photometer (wavelength: Goshajinkigan Extract 238 nm) 牛車腎気丸エキス Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilianized silica gel Goshajinkigan Extract contains not less than 4 mg and not for liquid chromatography (5 µm in particle diameter). more than 16 mg of loganin, not less than 6 mg and not more Column temperature: A constant temperature of about 50°C. than 18 mg of peoniflorin (C23H28O11: 480.46), and not less than Mobile phase: A mixture of water, acetonitrile and methanol 0.2 mg (for preparation prescribed Powdered Processed Aconite (55:4:1). Root 1) of total alkaloids (as benzoylmesaconine hydrochloride Flow rate: Adjust the flow rate so that the retention time of and 14-anisoylaconine hydrochloride, or as benzoylmesaconine loganin is about 25 minutes. hydrochloride and benzoylhypaconine hydrochloride) or not less System suitability― than 0.1 mg (for preparation prescribed Powdered Processed System performance: When the procedure is run with 10 µL Aconite Root 2) of total alkaloids (as benzoylmesaconine hy- of the standard solution under the above operating conditions, drochloride and benzoylhypaconine hydrochloride) per the ex- the number of theoretical plates and the symmetry factor of the tract prepared as directed in the Method of preparation. peak of loganin are not less than 5000 and not more than 1.5, respectively. Method of preparation Prepare a dry extract or viscous ex- System repeatability: When the test is repeated 6 times with tract as directed under Extracts, with 5 g of Rehmannia Root, 3 10 µL of the standard solution under the above operating condi- g of Cornus Fruit, 3 g of Dioscorea Rhizome, 3 g of Alisma tions, the relative standard deviation of the peak area of loganin Rhizome, 3 g of Poria Sclerotium, 3 g of Moutan Bark, 1 g of is not more than 1.5%. Cinnamon Bark, 1 g of Powdered Processed Aconite Root 1 or Powdered Processed Aconite Root 2 of “Powdered Processed Aconite Root”, 3 g of Achyranthes Root and 3 g of Plantago Daiokanzoto Extract Seed.

大黄甘草湯エキス Description Goshajinkigan Extract occurs as brown to black-brown powder or viscous extract. It has slightly a charac- Change the Origin to read: teristic odor and a slightly acid taste.

Daiokanzoto Extract contains not less than 3.5 mg of Identification (1) To 1.0 g of the dry extract (or 3.0 g of the viscous extract), add 10 mL of water, shake, then add 30 mL of sennoside A (C42H38O20: 862.74) and not less than 9 mg and not more than 27 mg (for preparation pre- methanol, shake, centrifuge, and use the supernatant liquid as scribed 1 g of Glycyrrhiza) or not less than 18 mg and the sample solution. Perform the test with the sample solution as not more than 54 mg (for preparation prescribed 2 g of directed under Thin-layer Chromatography <2.03>. Spot 5 µL of the sample solution on a plate of silica gel for thin-layer chro- Glycyrrhiza) of glycyrrhizic acid (C42H62O16: 822.93) per the extract prepared as directed in the Method of matography. Develop the plate with a mixture of water, metha- preparation. nol and 1-butanol (1:1:1) to a distance of about 10 cm, and air-dry the plate. Spray evenly 4-methoxybenzaldehyde-sulfuric acid TS on the plate, heat at 105°C for 5 minutes, and allow to Eleutherococcus Senticosus cool; a dark-green spot is observed at around Rf 0.6 (Rehmannia Root). Rhizome (2) To 2.0 g of the dry extract (or 6.0 g of the viscous extract), add 10 mL of water, shake, then add 5 mL of 1-butanol, シゴカ shake, centrifuge, and use the supernatant liquid as the sample solution. Separately, dissolve 1 mg of loganin for thin-layer Add the following next to Identification: chromatography in 1 mL of methanol, and use the solution as Purity (1) Heavy metals <1.07> Proceed with 3.0 g of the standard solution. Perform the test with these solutions as pulverized Eleutherococcus Senticosus Rhizome according to directed under Thin-layer Chromatography <2.03>. Spot 10 µL Method 3, and perform the test. Prepare the control solution of the sample solution and 2 µL of the standard solution on a with 3.0 mL of Standard Lead Solution (not more than 10 ppm). plate of silica gel for thin-layer chromatography. Develop the (2) Arsenic <1.11> Prepare the test solution with 0.40 g of plate with a mixture of ethyl acetate, water and formic acid pulverized Eleutherococcus Senticosus Rhizome according to (6:1:1) to a distance of about 10 cm, and air-dry the plate. Spray Method 4, and perform the test (not more than 5 ppm). evenly 4-methoxybezaldehyde-sulfuric acid TS on the plate, and heat at 105°C for 2 minutes: one of the spot among the several

spots from the sample solution has the same color tone and Rf value with the purple spot from the standard solution (Cornus Fruit).

2222 Crude Drugs Supplement II, JP XV

(3) To 2.0 g of the dry extract (or 6.0 g of the viscous ex- Separately, dissolve 1 mg of (E)-2-methoxycinnamaldehyde for tract), add 10 mL of sodium carbonate TS, shake, then add 10 thin-layer chromatography in 1 mL of methanol, and use this mL of diethyl ether, shake, centrifuge, and use the supernatant solution as the standard solution. Perform the test with these so- liquid as the sample solution. Separately, dissolve 1 mg of Alisol lutions as directed under Thin-layer Chromatography <2.03>. A for thin-layer chromatography in 1 mL of methanol, and use Spot 20 µL of the sample solution and 2 µL of the standard solu- the solution as the standard solution. Perform the test with these tion on a plate of silica gel for thin-layer chromatography. De- solutions as directed under Thin-layer Chromatography <2.03>. velop the plate with a mixture of hexane and ethyl acetate (2:1) Spot 20 µL of the sample solution and 2µL of the standard solu- to a distance of about 10 cm, and air-dry the plate. Examine un- tion on a plate of silica gel for thin-layer chromatography. De- der ultraviolet light (main wavelength: 365 nm): one of the spot velop the plate with a mixture of ethyl acetate, hexane and ace- among several spots from the sample solution has the same tic acid (100)(10:10:3) to a distance of about 10 cm, and air-dry color tone and Rf value with the bluish white fluorescent spot the plate. Spray evenly vanillin-sulfuric acid TS on the plate, from the standard solution. heat at 105°C for 5 minutes, and allow to cool: one of the spot (6) To 3.0 g of the dry extract (or 9.0 g of the viscous ex- among the several spots from the sample solution has the same tract), add 20 mL of diethyl ether and 2 mL of ammonia TS, color tone and Rf value with the purple spot from the standard shake for 10 minutes, centrifuge, and evaporate the supernatant solution (Alisma Rhizome). liquid under reduced pressure. Add 1 mL of acetonitrile to the (4) To 2.0 g of the dry extract (or 6.0 g of the viscous ex- residue, and use this solution as the sample solution. Separately, tract), add 10 mL of water, shake, then add 5 mL of diethyl ether, dissolve 1 mg of benzoylmesaconine hydrochloride for shake, centrifuge, and use the supernatant liquid as the sample thin-layer chromatography in 10 mL of ethanol (99.5), and use solution. Separately, dissolve 1 mg of paeonol for thin-layer this solution as the standard solution. Perform the test with these chromatography in 1 mL of methanol, and use the solution as solutions as directed under Thin-layer Chromatography <2.03>. the standard solution. Perform the test with these solutions as Spot 20 µL of the sample solution and 10 µL of the standard so- directed under Thin-layer Chromatography <2.03>. Spot 20 µL lution on a plate of silica gel for thin-layer chromatography. of the sample solution and 2µL of the standard solution on a Develop the plate with a mixture of 1-butanol, water and acetic plate of silica gel for thin-layer chromatography. Develop the acid (100)(4:2:1) to a distance of about 10 cm, and air-dry the plate with a mixture of hexane and diethyl ether (5:3) to a dis- plate. Spray evenly Dragendorff’s TS for spraying on the plate, tance of about 10 cm, and air-dry the plate. Spray evenly and air-dry the plate. Then spray evenly sodium nitrite TS on the 4-methoxybezaldehyde-sulfuric acid TS on the plate, and heat at plate: one of the spot among the several spots from the sample

105°C for 5 minutes: one of the spot among the several spots solution has the same color tone and Rf value with the yel- from the sample solution has the same color tone and Rf value low-brown spot from the standard solution (Powdered Proc- with the orange spot from the standard solution (Moutan Bark). essed Aconite Root). (5) Perform the test according to the following (i) or (ii) (7) To 2.0 g of the dry extract (or 6.0 g of the viscous ex- (Cinnamon Bark). tract), add 10 mL of water, shake, then add 5 mL of 1-butanol, (i) Put 10 g of the dry extract (or 30 g of the viscous ex- shake, centrifuge, and use the supernatant liquid as the sample tract) in a 300 mL hard-glass flask, add 100 mL of water and 1 solution. Separately, to 0.3 g of pulverized Plantago Seed for mL of silicone resin, connect the apparatus for essential oil de- thin-layer chromatography, add 1 mL of methanol, heat on a termination, and heat to boil under a reflux condenser. The water bath for 3 minutes, centrifuge after cooling, and use the graduated tube of the apparatus is to be previously filled with supernatant liquid as the standard solution. Perform the test with water to the standard line, and 2 mL of hexane is added to the these solutions as directed under Thin-layer Chromatography graduated tube. After heating under reflux for 1 hour, separate 1 <2.03>. Spot 10 µL each of the sample solution and standard mL of the hexane layer, add 0.5 mL of sodium hydroxide TS, solution on a plate of silica gel for thin-layer chromatography. shake, centrifuge, and use the supernatant liquid as the sample Develop the plate with a mixture of acetone, ethyl acetate, water solution. Separately, dissolve 1 mg of (E)-cinnamaldehyde for and acetic acid (100) (10:10:3:1) to a distance of about 10 cm, thin-layer chromatography in 1 mL of methanol, and use this and air-dry the plate. Spray evenly solution as the standard solution. Perform the test with these so- 4-methoxybezaldehyde-sulfuric acid TS on the plate, and heat at lutions as directed under Thin-layer Chromatography <2.03>. 105°C for 5 minutes: one of the spot among the several spots

Spot 50 µL of the sample solution and 2 µL of the standard solu- from the sample solution has the same color tone and Rf value tion on a plate of silica gel for thin-layer chromatography. De- (around 0.3) with the deep blue spot from the standard solution velop the plate with a mixture of hexane, diethyl ether and (Plantago Seed). methanol (15:5:1) to a distance of about 10 cm, and air-dry the (8) To 2.0 g of the dry extract (or 6.0 g of the viscous ex- plate. Spray evenly 2,4-dinitrophenylhydrazine TS on the plate: tract), add 10 mL of water, shake, then add 5 mL of 1-butanol, one of the spot among the several spots from the sample solu- shake, centrifuge, and use the supernatant liquid as the sample tion has the same color tone and Rf value with the yel- solution. Separately, to 2 g of Achyranthes Root for thin-layer low-orange spot from the standard solution. chromatography, add 10 mL of water, shake, then add 10 mL of (ii) To 2.0 g of dry extract (or 6.0 g of the viscous extract), 1-butanol, shake, centrifuge, and use the supernatant liquid as add 10 mL of water, shake, then add 5 mL of hexane, shake, the standard solution. Perform the test with these solutions as centrifuge, and use the supernatant liquid as the sample solution. directed under Thin-layer Chromatography <2.03>. Spot 20 µL

Supplement II, JP XV Crude Drugs 2223 each of the sample solution and standard solution on a plate of System suitability― silica gel for thin-layer chromatography. Develop the plate with System performance: When the procedure is run with 20 µL a mixture of 1-propanol, ethyl acetate and water (4:4:3) to a of aconitum diester alkaloids standard solution for purity under distance of about 10 cm, and air-dry the plate. Spray evenly di- the above operating conditions, using 254 nm, mesaconitine, luted sulfuric acid on the plate and heat at 105°C for 5 minutes: hypaconitine, aconitine and jesaconitine are eluted in this order, one of the spot among the several spots from the sample solu- and each resolution between their peaks is not less than 1.5 re- tion has the same color tone and Rf value (around 0.4) with the spectively. dark red spot from the standard solution (Achyranthes Root). System repeatability: When the test is repeated 6 times with 20 µL of the standard solution under the above operating condi- Purity (1) Heavy metals <1.07> Prepare the test solution tions, using 231 nm, the relative standard deviation of the peak with 1.0 g of the dry extract (or an amount of the viscous extract, height of mesaconitine is not more than 1.5%. equivalent to 1.0 g of the dried substance) as directed in the Ex- tracts (4) under General Rules for Preparations, and perform the Loss on drying <2.41> The dry extract: Not more than 9.0% test (not more than 30 ppm). (1 g, 105°C, 5 hours). (2) Arsenic <1.11> Prepare the test solution with 0.67 g of The viscous extract: Not more than 66.7% (1 g, 105°C, 5 the dry extract (or an amount of the viscous extract, equivalent hours). to 0.67 g of the dried substance) according to Method 3, and perform the test (not more than 3 ppm). Total ash <5.01> Not more than 9.0%, calculated on the dried basis. (3) Aconitum diester alkaloids (aconitine, jesaconitine, hypaconitine and mesaconitine)— Weigh accurately 1.0 g of the Assay (1) Loganin―Weigh accurately about 0.5 g of the dry dry extract (or an amount of the viscous extract, equivalent to extract (or an amount of the viscous extract, equivalent to about 1.0 g of the dried substance), add 20 mL of diethyl ether, shake, 0.5 g of the dried substance), add exactly 50mL of diluted then add 3.0 mL of 0.1 mol/L hydrochloric acid TS and shake methanol (1 in 2), shake for 15 minutes, filter, and use the fil- for 10 minutes. Centrifuge this solution, remove the upper layer, trate as the sample solution. Separately, weigh accurately 10 mg then add 20 mL of diethyl ether, proceed in the same manner as of loganin for component determination, previously dried in a described above, and remove the upper layer. To the water layer, desiccator (silica gel) for not less than 24 hours, and dissolve in add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shake diluted methanol (1 in 2) to make exactly 100 mL, and use this for 30 minutes, centrifuge, and take the supernatant liquid. To solution as the standard solution. Perform the test with exactly the water layer, add 1.0 mL of ammonia TS and 20 mL of di- 10 µL each of the sample solution and standard solution as diethyl ether, and repeat the above process twice more. Combine rected under Liquid Chromatography <2.01> according to the all the supernatant liquids, and evaporate to dryness under re- following conditions, and determine the peak areas, AT and AS, duced pressure. Dissolve the residue with exactly 10 mL of a of loganin. mixture of phosphate buffer solution for processed aconite root and acetonitrile (1:1). Centrifuge this solution, and use the su- Amount (mg) of loganin = WS × (AT / AS) × (1/2) pernatant liquid as the sample solution. Separately, pipet 1 mL WS: Amount (mg) of loganin for component determination of aconitum diester alkaloids standard solution for purity, add a mixture of phosphate buffer solution for processed aconite root Operating conditions― and acetonitrile (1:1) to make exactly 10 mL, and use this solu- Detector: An ultraviolet absorption photometer (wavelength: tion as the standard solution. Perform the test with exactly 40 µL 238 nm) each of the sample solution and standard solution as directed Column: A stainless steel column 4.6 mm in inside diameter under Liquid Chromatography <2.01> according to the follow- and 15 cm in length, packed with octadecylsilanized silica gel ing conditions: the heights of the peaks corresponding to aco- for liquid chromatography (5 µm in particle diameter). nitine, jesaconitine, hypaconitine and mesaconitine from the Column temperature: A constant temperature of about 50°C. sample solution are not higher than the respective heights cor- Mobile phase: A mixture of water, acetonitrile and methanol responding to aconitine, jesaconitine, hypaconitine and mesaco- (55:4:1). nitine from the standard solution. Flow rate: 1.2 mL per minute (the retention time of loganin is Operating conditions― about 25 minutes). Detector: An ultraviolet absorption photometer (wavelength: System suitability― 231 nm for aconitine, hypaconitine and mesaconitine; 254 nm System performance: When the procedure is run with 10 µL for jesaconitine). of the standard solution under the above operating conditions, Column: A stainless steel column 4.6 mm in inside diameter the number of theoretical plates and symmetry factor of the peak and 15 cm in length, packed with octadecylsilanized silica gel of loganin are not less than 5000 and not more than 1.5, respec- for liquid chromatography (5 µm in particle diameter). tively. Column temperature: A constant temperature of about 40°C. System repeatability: When the test is repeated 6 times with Mobile phase: A mixture of phosphate buffer for processed 10 µL of the standard solution under the above operating condi- aconite root and tetrahydrofuran (183:17). tions, the relative standard deviation of the peak area of loganin Flow rate: 1.0 mL per minute (the retention time of mesaco- is not more than 1.5%. nitine is about 31 minutes). (2) Peoniflorin―Weigh accurately about 0.5 g of the dry

2224 Crude Drugs Supplement II, JP XV extract (or an amount of the viscous extract, equivalent to about mination as directed under Liquid Chromatography <2.01> ac- 0.5 g of the dried substance), add exactly 50 mL of diluted cording to the following conditions. Determine the peak areas of methanol (1 in 2), shake for 15 minutes, filter, and use the fil- benzoylmesaconine, benzoylhypaconine and 14-anisoylaconine, trate as the sample solution. Separately, weigh accurately about ATM and ASM, ATH and ASH, as well as ATA and ASA, in each solu- 10 mg of Peoniflorin Reference Standard (separately determine tion, respectively. the water), and dissolve in diluted methanol (1 in 2) to make Amount (mg) of benzoylmesaconine hydrochloride exactly 100 mL, and use this solution as the standard solution. = C × (A / A ) × 10 Perform the test with exactly 10 µL each of the sample solution SM TM SM and standard solution as directed under Liquid Chromatography Amount (mg) of benzoylhypaconine hydrochloride <2.01> according to the following conditions, and determine the = CSH × (ATH / ASH) × 10 peak areas, AT and AS, of peoniflorin.

Amount (mg) of 14-anisoylaconine hydrochloride Amount (mg) of peoniflorin (C23H28O11) = CSA × (ATA / ASA) × 10 = WS × (AT / AS) × (1/2) C : Concentration (mg/mL) of benzoylmesaconine hydro- W : Amount (mg) of Peoniflorin Reference Standard, calcu- SM S chloride for component determination in aconitum lated on the anhydrous basis monoester alkaloids standard solution TS for compo- Operating conditions― nent determination Detector: An ultraviolet absorption photometer (wavelength: C : Concentration (mg/mL) of benzoylhypaconine hydro- 232 nm) SH chloride for component determination in aconitum Column: A stainless steel column 4.6 mm in inside diameter monoester alkaloids standard solution TS for component and 15 cm in length, packed with octadecylsilanized silica gel determination for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 20°C. CSA: Concentration (mg/mL) of 14-anisoylaconine hydro- Mobile phase: A mixture of water, acetonitrile and phosphoric chloride for component determination in aconitum acid (850:150:1). monoester alkaloids standard solution TS for component Flow rate: 1.0 mL per minute (the retention time of peoniflo- determination rin is about 9 minutes). System suitability― Operating conditions― System performance: Dissolve 1 mg each of Peoniflorin Ref- Detector: An ultraviolet absorption photometer (wavelength: erence Standard and albiflorin in diluted methanol (1 in 2) to 231 nm for benzoylhypaconine and benzoylmesaconine; 254 nm make 10 mL. When the procedure is run with 10 µL of this solu- for 14-anisoylaconine). tion under the above operating conditions, albiflorin and Column: A stainless steel column 4.6 mm in inside diameter peoniflorin are eluted in this order with the resolution between and 15 cm in length, packed with octadecylsilanized silica gel these peaks being not less than 2.5. for liquid chromatography (5 µm in particle diameter). System repeatability: When the test is repeated 6 times with Column temperature: A constant temperature of about 40°C. 10 µL of the standard solution under the above operating condi- Mobile phase: A mixture of phosphate buffer solution for tions, the relative standard deviation of the peak area of processed aconite root and tetrahydrofuran (183:17). peoniflorin is not more than 1.5%. Flow rate: 1.0 mL per minute (the retention time of benzoyl- (3) Total alkaloids―Weigh accurately about 1 g of the dry mesaconine is about 15 minutes). extract (or an amount of the viscous extract, equivalent to about System suitability― 1 g of the dried substance), add 20 mL of diethyl ether, shake, System performance: When the procedure is run with 20 µL then add 3.0 mL of 0.1 mol/L hydrochloric acid TS, and shake of the aconitum monoester alkaloids standard solution TS for for 10 minutes. Centrifuge this solution, remove the upper layer, component determination under the above operating conditions, then add 20 mL of diethyl ether, proceed in the same manner as the number of theoretical plates and the symmetry factor of the described above, and remove the upper layer. To the water layer, peak of benzoylmesaconine are not less than 5000 and not more add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shake than 1.5, respectively. for 30 minutes, centrifuge, and take the supernatant liquid. To System repeatability: When the test is repeated 6 times with the water layer, add 1.0 mL of ammonia TS and 20 mL of di- 20 µL of the aconitum monoester alkaloids standard solution TS ethyl ether, and repeat the above process twice more. Combine for component determination under the above operating condi- all the supernatant liquids, and evaporate to dryness under re- tions, the relative standard deviation of the peak areas of ben- duced pressure. Dissolve the residue with a mixture of phos- zoylmesaconine, benzoylhypaconine and 14-anisoylaconine is phate buffer solution for processed aconite root and acetonitrile not more than 1.5%. (1:1) to make exactly 10 mL. Centrifuge this solution, and use Container and storage Containers―Tight containers. the supernatant liquid as the sample solution. Perform the test with exactly 20 µL each of the sample solution and the aconitum monoester alkaloids standard solution TS for component deter-

Supplement II, JP XV Crude Drugs 2225

Add the following: shake, centrifuge, and use the supernatant liquid as the sample solution. Separately, dissolve 1 mg of loganin for thin-layer Hachimijiogan Extract chromatography in 1 mL of methanol, and use the solution as the standard solution. Perform the test with the sample solution 八味地黄丸エキス and standard solution as directed under Thin-layer Chromatog- raphy <2.03>. Spot 10 µL of the sample solution and 2 µL of the Hachimijiogan Extract contains not less than 4 mg and not standard solution on a plate of silica gel for thin-layer chroma- more than 16 mg of loganin, not less than 6 mg and not more tography. Develop the plate with a mixture of ethyl acetate, wa- than 18 mg (for preparation prescribed 3 g of Moutan Bark) or ter and formic acid (6:1:1) to a distance of about 10 cm, and not less than 5 mg and not more than 15 mg (for preparation air-dry the plate. Spray evenly 4-methoxybezaldehyde-sulfuric prescribed 2.5 g of Moutan Bark) of peoniflorin (C23H28O11: acid TS on the plate, and heat at 105ºC for 2 minutes: one of the 480.46), and not less than 0.7 mg (for preparation prescribed 1 g spot among the several spots from the sample solution has the of Processed Aconite Root 1) of total alkaloids (as benzoylme- same color tone and Rf value with the purple spot from the saconine hydrochloride and 14-anisoylaconine hydrochloride), standard solution (Cornus Fruit). or not less than 0.2 mg (for preparation prescribed 1 g of Pow- (3) To 2.0 g of the dry extract (or 6.0 g of the viscous ex- dered Processed Aconite Root 1) of total alkaloids (as benzoyl- tract), add 10 mL of sodium carbonate TS, shake, then add 10 mesaconine hydrochloride and 14-anisoylaconine hydrochloride, mL of diethyl ether, shake, centrifuge, and use the supernatant or as benzoylmesaconine hydrochloride and benzoylhypaconine liquid as the sample solution. Separately, dissolve 1 mg of Alisol hydrochloride), or not less than 0.1 mg (for preparation pre- A for thin-layer chromatography in 1 mL of methanol, and use scribed 1 g of Powdered Processed Aconite Root 2) of total al- the solution as the standard solution. Perform the test with these kaloids (as benzoylmesaconine hydrochloride and benzoylhy- solutions as directed under Thin-layer Chromatography <2.03>. paconine hydrochloride), or not less than 0.1 mg (for prepara- Spot 20 µL of the sample solution and 2µL of the standard solution prescribed 0.5 g of Powdered Processed Aconite Root 1) of tion on a plate of silica gel for thin-layer chromatography. De- total alkaloids (as benzoylmesaconine hydrochloride and velop the plate with a mixture of ethyl acetate, hexane and ace- 14-anisoylaconine hydrochloride, or as benzoylmesaconine hy- tic acid (100) (10:10:3) to a distance of about 10 cm, and air-dry drochloride and benzoylhypaconine hydrochloride) per the ex- the plate. Spray evenly vanillin-sulfuric acid TS on the plate, tract prepared as directed in the Method of preparation. heat at 105ºC for 5 minutes, and allow to cool: one of the spot Method of preparation Prepare a dry extract or viscous ex- among the several spots from the sample solution has the same tract as directed under Extracts, with 5 g of Rehmannia Root, 3 color tone and Rf value with the purple spot from the standard g of Cornus Fruit, 3 g of Dioscorea Rhizome, 3 g of Alisma solution (Alisma Rhizome). Rhizome, 3 g of Poria Sclerotium, 3 g of Moutan Bark, 1 g of (4) To 2.0 g of the dry extract (or 6.0 g of the viscous ex- Cinnamon Bark, and 1 g of Processed Aconit Root 1 of “Proc- tract), add 10 mL of water, shake, then add 5 mL of diethyl ether, essed Aconit Root” or Powdered Processed Aconit Root 1 or shake, centrifuge, and use the supernatant liquid as the sample Powdered Processed Aconit Root 2 of “Powdered Processed solution. Separately, dissolve 1 mg of paeonol for thin-layer Aconit Root”, or with 6 g of Rehmannia Root, 3 g of Cornus chromatography in 1 mL of methanol, and use the solution as Fruit, 3 g of Dioscorea Rhizome, 3 g of Alisma Rhizome, 3 g of the standard solution. Perform the test with these solutions as Poria Sclerotium, 2.5 g of Moutan Bark, 1 g of Cinnamon Bark, directed under Thin-layer Chromatography <2.03>. Spot 20 µL and 0.5 g of Powdered Processed Aconit Root 1 of “Powdered of the sample solution and 2 µL of the standard solution on a Processed Aconit Root”. plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of hexane and diethyl ether (5:3) to a dis- Description Hachimijiogan Extract occurs as grayish brown tance of about 10 cm, and air-dry the plate. Spray evenly to black-brown powder or viscous extract. It has a characteristic 4-methoxybezaldehyde-sulfuric acid TS on the plate, and heat at odor and a slightly bitter and acid taste. 105ºC for 5 minutes: one of the spot among the several spots Identification (1) To 1.0 g of the dry extract (or 3.0 g of the from the sample solution has the same color tone and Rf value viscous extract), add 10 mL of water, shake, then add 30 mL of with the orange spot from the standard solution (Moutan Bark ). methanol, shake, centrifuge, and use the supernatant liquid as (5) Perform the test according to the following (i) or (ii) the sample solution. Perform the test with these solutions as di- (Cinnamon Bark). rected under Thin-layer Chromatography <2.03>. Spot 5 µL of (i) Put 10 g of the dry extract (or 30 g of the viscous ex- the sample solution on a plate of silica gel for thin-layer chro- tract) in a 300 mL hard-glass flask, add 100 mL of water and 1 matography. Develop the plate with a mixture of water, metha- mL of silicone resin, connect the apparatus for essential oil de- nol and 1-butanol (1:1:1) to a distance of about 10 cm, and termination, and heat to boil under a reflux condenser. The air-dry the plate. Spray evenly 4-methoxybezaldehyde-sulfuric graduated tube of the apparatus is to be previously filled with acid TS on the plate, heat at 105ºC for 5 minutes, and allow to water to the standard line, and 2 mL of hexane is added to the graduated tube. After heating under reflux for 1 hour, separate 1 cool; a dark-green spot is observed at around Rf 0.6 (Rehmannia Root). mL of the hexane layer, add 0.5 mL of sodium hydroxide TS, (2) To 2.0 g of the dry extract (or 6.0 g of the viscous ex- shake, centrifuge, and use the supernatant liquid as the sample tract), add 10 mL of water, shake, then add 5 mL of 1-butanol, solution. Separately, dissolve 1 mg of (E)-cinnamaldehyde for

2226 Crude Drugs Supplement II, JP XV thin-layer chromatography in 1 mL of methanol, and use this 1.0 g of the dried substance), add 20 mL of diethyl ether, shake, solution as the standard solution. Perform the test with these so- then add 3.0 mL of 0.1 mol/L hydrochloric acid TS and shake lutions as directed under Thin-layer Chromatography <2.03>. for 10 minutes. Centrifuge this solution, remove the upper layer, Spot 50 µL of the sample solution and 2 µL of the standard solu- then add 20 mL of diethyl ether, proceed in the same manner as tion on a plate of silica gel for thin-layer chromatography. De- described above, and remove the upper layer. To the water layer, velop the plate with a mixture of hexane, diethyl ether and add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shake methanol (15:5:1) to a distance of about 10 cm, and air-dry the for 30 minutes, centrifuge, and take the supernatant liquid. To plate. Spray evenly 2,4-dinitrophenylhydrazine TS on the plate: the water layer, add 1.0 mL of ammonia TS and 20 mL of dione of the spot among the several spots from the sample solu- ethyl ether, and repeat the above process twice more. Combine tion has the same color tone and Rf value with the yel- all the supernatant liquids, and evaporate to dryness under re- low-orange spot from the standard solution. duced pressure. Dissolve the residue with exactly 10 mL of a (ii) To 2.0 g of dry extract (or 6.0 g of the viscous extract), mixture of phosphate buffer solution for processed aconite root add 10 mL of water, shake, then add 5 mL of hexane, shake, and acetonitrile (1:1). Centrifuge this solution, and use the su- centrifuge, and use the supernatant liquid as the sample solution. pernatant liquid as the sample solution. Separately, pipet exactly Separately, dissolve 1 mg of (E)-2-methoxycinnamaldehyde for 1 mL of aconitum diester alkaloids standard solution for purity, thin-layer chromatography in 1 mL of methanol, and use this add a mixture of phosphate buffer solution for processed aconite solution as the standard solution. Perform the test with these so- root and acetonitrile (1:1) to make exactly 10 mL, and use this lutions as directed under Thin-layer Chromatography <2.03>. solution as the standard solution. Perform the test with exactly Spot 20 µL of the sample solution and 2 µL of the standard solu- 40 µL each of the sample solution and standard solution as di- tion on a plate of silica gel for thin-layer chromatography. De- rected under Liquid Chromatography <2.01> according to the velop the plate with a mixture of hexane and ethyl acetate (2:1) following conditions: the heights of the peaks corresponding to to a distance of about 10 cm, and air-dry the plate. Examine un- aconitine, jesaconitine, hypaconitine and mesaconitine from the der ultraviolet light (main wavelength: 365 nm): one of the spot sample solution are not higher than the respective heights cor- among several spots from the sample solution has the same responding to aconitine, jesaconitine, hypaconitine and mesaco- color tone and Rf value with the bluish white fluorescent spot nitine from the standard solution. from the standard solution. Operating conditions― (6) To 3.0 g of the dry extract (or 9.0 g of the viscous ex- Detector: An ultraviolet absorption photometer (wavelength: tract), add 20 mL of diethyl ether and 2 mL of ammonia TS, 231 nm for aconitine, hypaconitine and mesaconitine; 254 nm shake for 10 minutes, centrifuge, and evaporate the supernatant for jesaconitine). liquid under reduced pressure. Add 1 mL of acetonitrile to the Column: A stainless steel column 4.6 mm in inside diameter residue, and use this solution as the sample solution. Separately, and 15 cm in length, packed with octadecylsilanized silica gel dissolve 1 mg of benzoylmesaconine hydrochloride for for liquid chromatography (5 µm in particle diameter). thin-layer chromatography in 10 mL of ethanol (99.5), and use Column temperature: A constant temperature of about 40ºC. this solution as the standard solution. Perform the test with these Mobile phase: A mixture of phosphate buffer for processed solutions as directed under Thin-layer Chromatography <2.03>. aconite root and tetrahydrofuran (183:17). Spot 20 µL of the sample solution and 10 µL of the standard so- Flow rate: 1.0 mL per minute (the retention time of mesaco- lution on a plate of silica gel for thin-layer chromatography. nitine is about 31 minutes). Develop the plate with a mixture of 1-butanol, water and acetic System suitability― acid (100) (4:2:1) to a distance of about 10 cm, and air-dry the System performance: When the procedure is run with 20 µL plate. Spray evenly Dragendorff’s TS for spraying on the plate, of aconitum diester alkaloids standard solution for purity under and air-dry the plate. Then spray evenly sodium nitrite TS on the the above operating conditions, using 254 nm, mesaconitine, plate : one of the spot among the several spots from the sample hypaconitine, aconitine and jesaconitine are eluted in this order, solution has the same color tone and Rf value with the yel- and each resolution between their peaks is not less than 1.5 re- low-brown spot from the standard solution (Processed Aconite spectively. Root or Powdered Processed Aconite Root). System repeatability: When the test is repeated 6 times with 20 µL of the standard solution under the above operating condi- Purity (1) Heavy metals <1.07> Prepare the test solution tions, using 231 nm, the relative standard deviation of the peak with 1.0 g of the dry extract (or an amount of the viscous extract, height of mesaconitine is not more than 1.5 %. equivalent to 1.0 g of the dried substance) as directed in the Ex- tracts (4) under General Rules for Preparations, and perform the Loss on drying <2.41> The dry extract: Not more than 8.5 % test (not more than 30 ppm). (1 g, 105ºC, 5 hours). (2) Arsenic <1.11> Prepare the test solution with 0.67 g of The viscous extract: Not more than 66.7% (1 g, 105ºC, 5 the dry extract (or an amount of the viscous extract, equivalent hours). to 0.67 g of the dried substance) according to Method 3, and perform the test (not more than 3 ppm). Total ash <5.01> Not more than 10.0%, calculated on the (3) Aconitum diester alkaloids (aconitine, jesaconitine, hy- dried basis. paconitine and mesaconitine)— Weigh accurately 1.0 g of the Assay (1) Loganin―Weigh accurately about 0.5 g of the dry dry extract (or an amount of the viscous extract, equivalent to

Supplement II, JP XV Crude Drugs 2227 extract (or an amount of the viscous extract, equivalent to about Column: A stainless steel column 4.6 mm in inside diameter 0.5 g of the dried substance), add exactly 50 mL of diluted and 15 cm in length, packed with octadecylsilanized silica gel methanol (1 in 2), shake for 15 minutes, filter, and use the fil- for liquid chromatography (5 µm in particle diameter). trate as the sample solution. Separately, weigh accurately 10 mg Column temperature: A constant temperature of about 20ºC. of loganin for component determination, previously dried in a Mobile phase: A mixture of water, acetonitrile and phosphoric desiccator (silica gel) for not less than 24 hours, and dissolve in acid (850:150:1). diluted methanol (1 in 2) to make exactly 100 mL, and use this Flow rate: 1.0 mL per minute (the retention time of peoniflo- solution as the standard solution. Perform the test with exactly rin is about 9 minutes). 10 µL each of the sample solution and standard solution as di- System suitability― rected under Liquid Chromatography <2.01> according to the System performance: Dissolve 1 mg each of Peoniflorin Ref- following conditions, and determine the peak areas, AT and As, erence Standard and albiflorin in diluted methanol (1 in 2) to of loganin. make 10 mL. When the procedure is run with 10 µL of this solu-

tion under the above operating conditions, albiflorin and Amount (mg) of loganin = W × (A / A ) × (1/2) S T s peoniflorin are eluted in this order with the resolution between these peaks being not less than 2.5. WS: Amount (mg) of loganin for component determination System repeatability: When the test is repeated 6 times with Operating conditions― 10 µL of the standard solution under the above operating condi- Detector: An ultraviolet absorption photometer (wavelength: tions, the relative standard deviation of the peak area of 238 nm) peoniflorin is not more than 1.5%. Column: A stainless steel column 4.6 mm in inside diameter (3) Total alkaloids―Weigh accurately about 1 g of the dry and 15 cm in length, packed with octadecylsilanized silica gel extract (or an amount of the viscous extract, equivalent to about for liquid chromatography (5 µm in particle diameter). 1 g of the dried substance), add 20 mL of diethyl ether, shake, Column temperature: A constant temperature of about 50ºC. then add 3.0 mL of 0.1 mol/L hydrochloric acid TS, and shake Mobile phase: A mixture of water, acetonitrile and methanol for 10minutes. Centrifuge this solution, remove the upper layer, (55:4:1). then add 20 mL of diethyl ether, proceed in the same manner as Flow rate: 1.2 mL per minute (the retention time of loganin is described above, and remove the upper layer. To the water layer, about 25 minutes). add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shake System suitability― for 30 minutes, centrifuge, and take the supernatant liquid. To System performance: When the procedure is run with 10 µL the water layer, add 1.0 mL of ammonia TS and 20 mL of di- of the standard solution under the above operating conditions, ethyl ether, and repeat the above process twice more. Combine the number of theoretical plates and symmetry factor of the peak all the supernatant liquids, and evaporate to dryness under re- of loganin are not less than 5000 and not more than 1.5, respec- duced pressure. Dissolve the residue with a mixture of phos- tively. phate buffer solution for processed aconite root and acetonitrile System repeatability: When the test is repeated 6 times with (1:1) to make exactly 10 mL. Centrifuge this solution, and use 10 µL of the standard solution under the above operating condi- the supernatant liquid as the sample solution. Perform the test tions, the relative standard deviation of the peak area of loganin with exactly 20 µL each of the sample solution and the aconitum is not more than 1.5%. monoester alkaloids standard solution TS for component deter- (2) Peoniflorin―Weigh accurately about 0.5 g of the dry ex- mination as directed under Liquid Chromatography <2.01> ac- tract (or an amount of the viscous extract, equivalent to about cording to the following conditions. Determine the peak areas of 0.5 g of the dried substance), add exactly 50 mL of diluted benzoylmesaconine, benzoylhypaconine and 14-anisoylaconine, methanol (1 in 2), shake for 15 minutes, filter, and use the fil- ATM and ASM, ATH and ASH, as well as ATA and ASA, in each solu- trate as the sample solution. Separately, weigh accurately about tion, respectively. 10 mg of Peoniflorin Reference Standard (separately determine the water), and dissolve in diluted methanol (1 in 2) to make Amount (mg) of benzoylmesaconine hydrochloride exactly 100 mL, and use this solution as the standard solution. = CSM × (ATM / ASM) × 10 Perform the test with exactly 10 µL each of the sample solution Amount (mg) of benzoylhypaconine hydrochloride and standard solution as directed under Liquid Chromatography = C × (A / A ) × 10 <2.01> according to the following conditions, and determine the SH TH SH peak areas, AT and As, of peoniflorin. Amount (mg) of 14-anisoylaconine hydrochloride = C × (A / A ) × 10 Amount (mg) of peoniflorin (C23H28O11) SA TA SA = WS × (AT / AS) × (1/2) CSM: Concentration (mg/mL) of benzoylmesaconine hydrochloride for component determination in aconitum WS: Amount (mg) of Peoniflorin Reference Standard, calculated on the anhydrous basis monoester alkaloids standard solution TS for component determination Operating conditions― Detector: An ultraviolet absorption photometer (wavelength: CSH: Concentration (mg/mL) of benzoylhypaconine hydro- 232 nm) chloride for component determination in aconitum

2228 Crude Drugs Supplement II, JP XV monoester alkaloids standard solution TS for compo- Japanese Valerian nent determination カノコソウ CSA: Concentration (mg/mL) of 14-anisoylaconine hydrochloride for component determination in aconitum Change the Purity to read: monoester alkaloids standard solution TS for component determination Purity (1) Heavy metals <1.07> Proceed with 3.0 g of

pulverized Japanese Valerian according to Method 3, and per- Operating conditions― form the test. Prepare the control solution with 3.0 mL of Stan- Detector: An ultraviolet absorption photometer (wavelength: dard Lead Solution (not more than 10 ppm). 231 nm for benzoylhypaconine and benzoylmesaconine; 254 nm (2) Arsenic <1.11> Prepare the test solution with 0.40 g of for 14-anisoylaconine). pulverized Japanese Valerian according to Method 4, and per- Column: A stainless steel column 4.6 mm in inside diameter form the test (not more than 5 ppm). and 15 cm in length, packed with octadecylsilanized silica gel for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 40ºC. Mobile phase: A mixture of phosphate buffer solution for Powdered Japanese Valerian processed aconite root and tetrahydrofuran (183:17). カノコソウ末 Flow rate: 1.0 mL per minute (the retention time of benzoylmesaconine is about 15 minutes). Change the Purity to read: System suitability― System performance: When the procedure is run with 20 µL Purity (1) Heavy metals <1.07> Proceed with 3.0 g of of the aconitum monoester alkaloids standard solution TS for Powdered Japanese Valerian according to Method 3, and per- component determination under the above operating conditions, form the test. Prepare the control solution with 3.0 mL of Stan- the number of theoretical plates and the symmetry factor of the dard Lead Solution (not more than 10 ppm). peak of benzoylmesaconine are not less than 5000 and not more (2) Arsenic <1.11> Prepare the test solution with 0.40 g of than 1.5, respectively. Powdered Japanese Valerian according to Method 4, and per- System repeatability: When the test is repeated 6 times with form the test (not more than 5 ppm). 20 µL of the aconitum monoester alkaloids standard solution TS for component determination under the above operating conditions, the relative standard deviation of the peak areas of ben- Kakkonto Extract zoylmesaconine, benzoylhypaconine and 14-anisoylaconine is not more than 1.5%. 葛根湯エキス

Container and storage Containers－Tight containers. Change the Origin to read:

Kakkonto Extract contains not less than 9 mg and Hochuekkito Extract not more than 27 mg (for preparation prescribed 3 g of Ephendra Herb) or not less than 12 mg and not more 補中益気湯エキス than 36 mg (for preparation prescribed 4 g of Ephendra Herb) of total alkaloids [ephedrine (C10H15NO: 165.23) Change the Origin to read: and pseudoephedrine (C10H15NO: 165.23)], not less than 14 mg and not more than 56 mg (for preparation Hochuekkito Extract contains not less than 16 mg prescribed 2 g of Peony Root) of peoniflorin and not more than 64 mg of hesperidin, not less than (C23H28O11: 480.46) or not less than 21 mg and not 0.3 mg and not more than 1.2 mg (for preparation pre- more than 84 mg (for preparation prescribed 3 g of scribed 1 g of Bupleurum Root) or not less than 0.6 mg Peony Root), and not less than 19 mg and not more and not more than 2.4 mg (for preparation prescribed 2 than 57 mg of glycyrrhizic acid (C42H62O16: 822.93) g of Bupleurum Root) of saikoponin b2, and not less per the extract prepared as directed in the Method of than12 mg and not more than 36 mg of grycyrrhizic preparation. acid (C42H62O16: 822.93) per the extract prepared as directed in the Method of preparation.

Supplement II, JP XV Crude Drugs 2229 Lithospermum Root <1.09> (1), (2) and (3) for calcium salt.

シコン Purity (1) Heavy metals <1.07> To 2.0 g of pulverized Longgu, add 5 mL of water, shake, add gradually 6 mL of hy- Change the Purity to read: drochloric acid, evaporate on a water bath to dryness, dissolve the residue in 50 mL of water, and filter. To 25 mL of the filtrate, Purity (1) Heavy metals <1.07> Proceed with 3.0 g of add 2 mL of dilute acetic acid, 1 drop of ammonia TS and water pulverized Lithospermum Root according to Method 3, and to make 50 mL. Perform the test with this solution as the test perform the test. Prepare the control solution with 3.0 mL of solution. Separately, evaporate 3 mL of hydrochloric acid on a Standard Lead Solution (not more than 10 ppm). water bath to dryness, add 2 mL of dilute acetic acid, 2.0 mL of (2) Arsenic <1.11> Prepare the test solution with 0.40 g of Standard Lead Solution and water to make 50 mL, and use this pulverized Lithospermum Root according to Method 4, and solution as the control solution (not more than 20 ppm). perform the test (not more than 5 ppm). When being shown as extracts, infusions and decoctions on the label, the procedure and the limit are as follows. To 20.0 g of pulverized Longgu, add 80 mL of water, shake Add the following: occasionally on a water bath, heat to make about 40 mL, allow to cool, and filter. Proceed with this solution according to Longan Aril Method 3, and perform the test. To the control solution, add 1.0 mL of Standard Lead Solution (not more than 0.5 ppm). Longan Arillus リュウガンニク Nuphar Rhizome Longan Aril is the aril of Euphoria longana La- marck (Sapindaceae). センコツ

Description Depressed ellipsoidal aril, 1 - 2 cm in length, Change the Purity to read: about 1 cm in width; yellowish red-brown to blackish brown; Purity (1) Petiole―The amount of the petioles contained in soft in texture and mucous; when immersed in water, Nuphar Rhizome does not exceed 3.0%. bell-shaped, with the tip split in several parts. (2) Heavy metals <1.07> Proceed with 3.0 g of pulverized Odor, characteristic; taste, sweet. Nuphar Rhizome according to Method 3, and perform the test. Under a microscope <5.01>, a transverse section reveals the Prepare the control solution with 3.0 mL of Standard Lead Solu- outmost layer composed of a single-layered epidermis, beneath tion (not more than 10 ppm). this observed parenchyma consisting of depressed parenchyma (3) Arsenic <1.11> Prepare the test solution with 0.4 g of cells; the innermost layer composed of slightly thick-walled pulverized Nuphar Rhizome according to Method 4, and per- epidermis; parenchyma contains red-brown to brown contents as form the test (not more than 5 ppm). well as solitary crystals, amorphous crystals and sand crystals of (4) Foreign matter <5.01> The amount of foreign matter calcium oxalate. other than the petioles is not more than 1.0%. Identification To 1 g of coarse cuttings of Longan Aril, add 10 mL of water, shake thoroughly, and filter. To 3 mL of the filtrate, add 3 mL of Fehling solution, and heat on a water bath: a Add the following: red precipitate is produced. Nutmeg Total ash <5.01> Not more than 5.0%. Myristicae Semen Extract content <5.01> Dilute ethanol-soluble extract: Not less than 75.0%. ニクズク

Nutmeg is the seed of Myristica fragrans Houttuyn Longgu (Myristicaceae), usually from which the seed coat has been removed. リュウコツ Description Ovoid-globose to ellipsoidal seeds, 1.5 - 3.0 cm Change (2) of the Identification and (1) of the Pu- in length, 1.3 - 2.0 cm in diameter; externally grayish brown, rity to read: with wide and shallow longitudinal furrows and fine wrinkles; usually, grayish white to grayish yellow and slightly protruding Identification (2) The turbid solution obtained in (1) has a hilum at one end, grayish brown to dark brown and slightly characteristic odor. Filtrate this solution and neutralize with concave chalaza at the other end; cross section has a marble-like ammonia TS: this solution responds to the Qualitative Tests appearance with the dark brown thin perisperm extending ir-

2230 Crude Drugs Supplement II, JP XV regularly into the light yellowish white to light brown en- luted methanol (1 in 2) to make exactly 50 mL, and use this so- dosperm. lution as the standard solution. Perform the test with 10 µL each Odor, characteristic and strong; taste, acrid and slightly bitter. of the sample solution and standard solution as directed under Under a microscope <5.01>, a transverse section reveals per- Liquid Chromatography <2.01> according to the following con- isperm composed of outer and inner layers, the outer layer ditions, and determine the peak areas, AT and AS, of amygdalin composed of parenchyma containing dark red-brown contents in each solution. and the inner layer composed of parenchyma containing red-brown contents with a number of large oil cells and scat- Amount (mg) of amygdalin = WS × (AT/AS) × 2 tered vascular bundles; in parenchyma cells of endosperm, sim- W : Amount (mg) of amygdalin for component determination ple or compound starch grains and aleurone grains observed. S Operating conditions― Identification To 1 g of pulverized Nutmeg, add 5 mL of Detector: An ultraviolet absorption photometer (wavelength: methanol, allow to stand for 10 minutes with occasional shaking, 210 nm) filtrate, and use the filtrate as the sample solution. Separately, Column: A stainless steel column 4.6 mm in inside diameter dissolve 2 mg of myristicin for thin-layer chromatography in 1 and 15 cm in length, packed with octadecylsilianized silica gel mL of ethanol (95), and use this solution as the standard solution. for liquid chromatography (5 µm in particle diameter). Perform the test with these solutions as directed under Column temperature: A constant temperature of about 45°C. Thin-layer Chromatography <2.03>. Spot 5 µL each of the sam- Mobile phase: A mixture of 0.05 mol/L sodium dihydrogen ple solution and standard solution on a plate of silica gel for phosphate TS and methanol (5:1). thin-layer chromatography. Develop the plate with a mixture of Flow rate: 0.8 mL per minute (the retention time of amygda- hexane and acetone (9:1) to a distance of about 10 cm, and lin is about 12 minutes). air-dry the plate. Spray evenly diluted sulfuric acid on the plate, System suitability― and heat at 105°C for 5 minutes: one of the spot among the sev- System performance: When the procedure is run with 10 µL eral spots from the sample solution has the same color tone and of the standard solution under the above operating conditions, R value with the red-purple spot from the standard solution. f the number of theoretical plates and the symmetry factor of the Loss on drying <5.01> Not more than 16.0% (6 hours). peak of amygdalin are not less than 5000 and not more than 1.5, respectively. Total ash <5.01> Not more than 2.5%. System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating conditions, Essential oil content <5.01> When the test is performed with the relative standard deviation of the peak area of amygdalin is 10.0 g of pulverized Nutmeg, the essential oil content is not less not more than 1.5%. than 0.5 mL. Powdered Peach Kernel Peach Kernel トウニン末トウニン Change the Origin to read: Change the Origin to read: Powdered Peach Kernel is the powder of Peach Peach Kernel is the seed of Prunus persica Batsch Kernel. or Prunus persica Batsch var. davidiana Maximowicz It contains not less than 1.2% of amygdalin, calcu- (Rosaceae). lated on the basis of dried material. It contains not less than 1.2% of amygdalin, calculated on the basis of dried material. Add the following next to the Acid-insoluble ash:

Add the following next to the Purity: Component determination Weigh accurately 0.5 g of Pow- dered Peach Kernel, add 40 mL of diluted methanol (9 in 10), Loss on drying <5.01> Not more than 8.0% (6 hours). heat immediately under a reflux condenser on a water bath for 30 minutes, and cool. Filter the mixture, add diluted methanol (9 Component determination Weigh accurately 0.5 g of ground in 10) to make exactly 50 mL. Pipet 5 mL of this solution, add Peach Kernel, add 40 mL of diluted methanol (9 in 10), heat water to make exactly 10 mL, filter, and use the filtrate as the immediately under a reflux condenser on a water bath for 30 sample solution. Separately, weigh accurately about 10 mg of minutes, and cool. Filter the mixture, add diluted methanol (9 in amygdalin for component determination, previously dried in a 10) to make exactly 50 mL. Pipet 5 mL of this solution, add wa- desiccator (silica gel) for not less than 24 hours, dissolve in di- ter to make exactly 10 mL, filter, and use the filtrate as the sam- luted methanol (1 in 2) to make exactly 50 mL, and use this so- ple solution. Separately, weigh accurately about 10 mg of lution as the standard solution. Perform the test with 10 µL each amygdalin for component determination, previously dried in a of the sample solution and standard solution as directed under desiccator (silica gel) for not less than 24 hours, dissolve in di-

Supplement II, JP XV Crude Drugs 2231

Liquid Chromatography <2.01> according to the following con- Add the following next to the Acid-insoluble ash: ditions, and determine the peak areas, AT and AS, of amygdalin in each solution. Component determination Weigh accurately about 0.2 g of freshly prepared pulverized Perilla Herb, put in a Amount (mg) of amygdalin = WS × (AT/AS) × 2 glass-stoppered centrifuge tube, add 20 mL of methanol, shake for 10 minutes, centrifuge, and separate the supernatant liquid. WS : Amount (mg) of amygdalin for component determination To the residue, add 20 mL of methanol, and proceed in the same Operating conditions― manner. Combine all the extracts, add methanol to make exactly Detector: An ultraviolet absorption photometer (wavelength: 50 mL, and use this solution as the sample solution. Separately, 210 nm) weigh accurately about 10 mg of perillaldehyde for component Column: A stainless steel column 4.6 mm in inside diameter determination, and dissolve in methanol to make exactly 100 and 15 cm in length, packed with octadecylsilianized silica gel mL. Weigh accurately 10 mL of this solution, add methanol to for liquid chromatography (5 µm in particle diameter). make exactly 100 mL, and use this solution as the standard so- Column temperature: A constant temperature of about 45°C. lution. Perform the test with 10 µL each of the sample solution Mobile phase: A mixture of 0.05 mol/L sodium dihydrogen and standard solution as directed under Liquid Chromatography phosphate TS and methanol (5:1). <2.01> according to the following conditions, and determine the

Flow rate: 0.8 mL per minute (the retention time of amygda- peak areas, AT and AS, of perillaldehyde in each solution. lin is about 12 minutes). Amount (mg) of perillaldehyde = W × (A / A ) × (1/20) System suitability― S T S System performance: When the procedure is run with 10 µL WS: Amount (mg) of perillaldehyde for component determi- of the standard solution under the above operating conditions, nation the number of theoretical plates and the symmetry factor of the peak of amygdalin are not less than 5000 and not more than 1.5, Operating conditions― respectively. Detector: An ultraviolet absorption photometer (wavelength: System repeatability: When the test is repeated 6 times with 10 230 nm) µL of the standard solution under the above operating conditions, Column: A stainless steel column 4.6 mm in inside diameter the relative standard deviation of the peak area of amygdalin is and 15 cm in length, packed with octadecylsilanized silica gel not more than 1.5%. for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 40°C. Mobile phase: A mixture of water and acetonitrile (13:7). Perilla Herb Flow rate: 1.0 mL per minute System suitability― ソヨウ System performance: Dissolve 1 mg of (E)-asarone in the standard solution to make exactly 50 mL. When the procedure is Delete the Essential oil content and change the run with 10 µL of this solution under the above operating condi- Origin and the Identification to read: tions, perillaldehyde and (E)-asarone are eluted in this order with the resolution between these peaks being not less than 1.5. Perilla Herb is the leaves and the tips of branches of System repeatability: When the test is repeated 6 times with Perilla frutescens Britton var. acuta Kudo or Perilla 10 µL of the standard solution under the above operating condi- frutescens Britton var. crispa Decaisne (Labiatae). tions, the relative standard deviation of the peak area of per- It contains not less than 0.08% of perillaldehyde, illaldehyde is not more than 1.5%. calculated on the basis of dried material.

Identification To 0.6 g of pulverized Perilla Herb, add 10 mL Add the following: of diethyl ether, shake for 15 minutes, filter, and use the filtrate as the sample solution. Separately, dissolve 1 mg of perillaldehyde for thin-layer chromatography in 10 mL of methanol, and Pogostemon Herb use this solution as the standard solution. Perform the test with Pogostemoni Herba these solutions as directed under Thin-layer Chromatography <2.03>. Spot 10 µL each of the sample solution and standard カッコウ solution on a plate of silica gel for thin-layer chromatography. Develop the plate with a mixture of hexane and ethyl acetate Pogostemon Herb is the terrestrial part of Pogoste- (3:1) to a distance of about 10 cm, and air-dry the plate. Spray mon cablin Bentham (Labiatae). evenly 4-methoxybenzaldehyde-sulfuric acid-acetic acid-ethanol TS for spray on the plate, and heat at 105°C for 2 minutes: one Description Stems with opposite leaves, leaves wrinkled and of the spot among the several spots from the sample solution has shriveled. When smoothed by immersion in water, leaves are obovate to ovate-oblong, 2.5-10 cm in length, 2.5-7 cm in width, the same color tone and Rf value with the red-purple spot from the standard solution. with obtusely serrate margins and petioles at the cuneate bases; the upper surface of leaves dark brown, the lower surface gray-

2232 Crude Drugs Supplement II, JP XV ish brown, both sides covered densely with hairs. Stems are Quercus Bark square, solid, grayish green, covered with grayish to yellowish white hairs; the pith broad, whitish, spongy. Under a magnifying Quercus Cortex glass, leaf reveales hairs, glandular hairs and glandular scales. Odor, distinct; taste, slightly bitter. ボクソク Under a microscope <5.01>, a transverse section of petiole reveals central portion of the adaxial side protruding remarkably, Quercus Bark is the bark of Quercus acutissima with collenchyma cells beneath epidermis; vascular bundles at Carruthers, Quercus serrata Murray, Quercus mongo- the center divided into two groups. Under a microscope <5.01>, lica Fischer ex Ledebour var. crispula Ohashi or a transverse section of the midvein of lamina reveals the adaxial Quercus variabilis Blume (Fagaceae). side protruding remarkably, with collenchyma cells beneath Description Plate-like or semi-tubular pieces of bark, 5 - 15 epidermis; vascular bundles at the center arranged in fan-shape. mm in thickness; externally grayish brown to dark brown, with Under a microscope <5.01>, a transverse section of stem reveals thick periderm and longitudinal coarse splits; internally brown several-cells-layered collenchyma beneath epidermis, occasion- to light brown, with longitudinal ridges, the transverse section ally with cork layer developed; beneath cortex, collateral vascu- brown to light brown, white small spots composed of stone cells lar bundles arranged in a circle, phloem fibers in groups ob- in groups observed sporadically. served at the outer portion of phloem; oil droplets observed in Almost odorless, tasteless. parenchymat cells of cortex,, needle, solitary or columnar crys- Under a microscope <5.01>, a transverse section reveals a tals of calcium oxalate in parenchyma cells of pith. cork layer with scattered cork stone cells; in secondary cortex Identification To 0.5 g of pulverized Pogostemon Herb, add 5 fiber bundles lined almost stepwide, large groups of stone cells mL of methanol, shake for 3 minutes, filter, and use the filtrate arranged irregularly; in parenchyma aggregate crystals of cal- as the sample solution. Perform the test with the sample solution cium oxalate scattered; adjacent to stone cells and fiber cells, as directed under Thin-layer Chromatography <2.03>. Spot 5 µL cells containing solitary crystals of calcium oxalate observed, of the sample solution on a plate of silica gel for thin-layer and these cells form crystal cell rows in a longitudinal section. chromatography, develop the plate with a mixture of hexane and acetone (9:1) to a distance of about 10 cm, and air-dry the plate. Identification To 2 g of pulverized Quercus Bark, add 10 mL Spray evenly vanillin-sulfuric acid TS on the plate, and heat at of ethyl acetate, shake for 10 minutes, and centrifuge to remove ethyl acetate. Add 10 mL of acetone to the residue, shake for 10 105°C; a red spot appears at around Rf 0.4. minutes, centrifuge, and use the supernatant liquid as the sample Loss on drying <5.01> Not more than 15.0% (6 hours). solution. Perform the test with this solution as directed under Thin-layer Chromatography <2.03>. Spot 10 µL of the sample Total ash <5.01> Not more than 13.0%. solution on a plate of silica gel for thin-layer chromatography, develop the plate with a mixture of ethyl acetate, methanol and Acid-insoluble ash <5.01> Not more than 3.0%. water (7:2:1) to a distance of about 10 cm, and air-dry the plate. Essential oil content <5.01> When the test is performed with Examine under ultraviolet light (main wavelength: 365 nm): 50.0 g of pulverized Pogostemon Herb in a flask with 1 mL of Two consecutive fluorescent spots in different colors are ob- silicon resin added, the essential oil content is not less than 0.3 served at around Rf 0.4. Then, spray evenly diluted sulfuric acid mL. on the plate, heat at 105ºC. Examine under ultraviolet light (main wavelength: 365 nm): one of these spots produces fluorescence.

Polygonatum Rhizome Loss on drying <5.01> Not more than 11.0% (6 hours).

オウセイ Total ash <5.01> Not more than 8.5%.

Add the following next to Identification: Acid-insoluble ash <5.01> Not more than 0.5%.

Purity (1) Heavy metals <1.07> Proceed with 3.0 g of pulverized Polygonutum Rhizome according to Method 3, and perform the test. Prepare the control solution with 3.0 mL of Standard Lead Solution (not more than 10 ppm). (2) Arsenic <1.11> Prepare the test solution with 0.40 g of pulverized Polygonutum Rhizome according to Method 4, and perform the test (not more than 5 ppm).

Supplement II, JP XV Crude Drugs 2233

Add the following: nol, treat with ultrasonic waves for 30 minutes, and add methanol to make exactly 50 mL. Centrifuge this solution, take ex- Royal Jelly actly 2 mL of the supernatant liquid, add exactly 2 mL of the internal standard solution, then add 25 mL of water and methanol Apilac to make exactly 50 mL, and use this solution as the sample solution. Separately, weigh accurately about 10 mg of ローヤルゼリー 10-hydroxy-2-(E)-decenoic acid for component determination, dissolve in methanol to make exactly 100 mL. To exactly 3 mL Royal Jelly is the viscous liquid or its dried sub- of this solution, add exactly 2 mL of the internal standard solu- stance secreted by the secreting gland on the head of tion, then add 25 mL of water and methanol to make exactly 50 Apis mellifera Linné or Apis cerana Fabricius (Api- mL, and use this solution as the standard solution. Perform the dae). test with 10 µL each of the sample solution and standard solu- It contains not less than 4.0% and not more than tion as directed under Liquid Chromatography <2.01> according 8.0% of 10-hydroxy-2-(E)-decenoic acid, calculated on to the following conditions, and calculate the ratios, Q and Q , the basis of dried material. T S of the peak area of 10-hydroxy-2-(E)-decenoic acid to that of Description Slightly viscous liquid or powder, milky white to the internal standard. light yellow in color. Odor, characteristic; taste, astringent and Amount (mg) of 10-hydroxy-2-(E)-decenoic acid acid. = WS × (QT/QS) × (3/4) Identification To a portion of Royal Jelly, equivalent to 0.2 g W : Amount (mg) of 10-hydroxy-2-(E)-decenoic acid for of dried substance, add 5 mL of water, 1 mL of dilute hydro- S component determination chloric acid and 10 mL of diethyl ether, shake for 15 minutes, and centrifuge. Take the diethyl ether layer, evaporate under re- Internal standard solution—A solution of propyl parahydroxy- duced pressure, dissolve the residue in 5 mL of methanol, and benzoate in methanol (1 in 5000) use this solution as the sample solution. Separately, dissolve 2 Operating conditions— mg of 10-hydroxy-2-(E)-decenoic acid for thin-layer chroma- Detector: An ultraviolet absorption photometer (wavelength: tography in 1 mL of methanol, and use this solution as the stan- 215 nm) dard solution. Perform the test with these solutions as directed Column: A stainless steel column 4.6 mm in inside diameter under Thin-layer Chromatography <2.03>. Spot 20 µL each of and 15 cm in length, packed with octadecylsilanized silica gel the sample solution and standard solution on a plate of silica gel for liquid chromatography (5 µm in particle diameter). with fluorescent indicator for thin-layer chromatography, de- Column temperature: A constant temperature of about 50°C. velop the plate with a mixture of 1-propanol and ammonia solu- Mobile phase: A mixture of water, methanol and phosphoric tion (28) (7:3) to a distance of about 10 cm, and air-dry the plate. acid (550:450:1) Examine under ultraviolet light (main wavelength: 254 nm): the Flow rate: Adjust the flow rate so that the retention time of spot from the sample solution has the same color tone and Rf 10-hydroxy-2-(E)-decenoic acid is about 10 minutes. value with the dark purple spot from the standard solution. System suitability― System performance: When the procedure is run with 10 µL Purity (1) Heavy metals <1.07> Proceed with a portion of of the standard solution under the above operating conditions, Royal Jelly, equivalent to 1.0 g of the dried substance, according 10-hydroxy-2-(E)-decenoic acid and the internal standard are to Method 3, and perform the test. Prepare the control solution eluted in this order with the resolution between these peaks be- with 3.0 mL of Standard Lead Solution (not more than 30 ppm). ing not less than 6. (2) Arsenic <1.11> Prepare the test solution with an System repeatability: When the test is repeated 6 times with amount of Royal Jelly, equivalent to 0.40 g of the dried sub- 10 µL of the standard solution under the above operating condi- stance according to Method 3, and perform the test (not more tions, the relative standard deviation of the ratio of the peak area than 5 ppm). of 10-hydroxy-2-(E)-decenoic acid to that of the internal stan- Loss on drying <5.01> The slightly viscous liquid: Not less dard is not more than 1.0%. than 57.0% and not more than 77.0% (6 hours). Container and storage Containers―Tight containers. The powder: Not less than 7.0% and not more than 13.0% (6 Storage―At not exceeding 10°C hours)

Total ash <5.01> Not more than 4.0%, calculated on the dried basis.

Acid-insoluble ash <5.01> Not more than 0.5%, calculated on the dried basis.

Component determination Weigh a portion of Royal Jelly, equivalent to 0.2 g of the dried substance, add 20 mL of metha-

2234 Crude Drugs Supplement II, JP XV Saposhnikovia Root Powdered Senega

ボウフウセネガ末

Add the following next to the Description: Change the Purity to read:

Identification To 1 g of pulverized Saposhnikovia Root, add 5 Purity (1) Heavy metals <1.07> Proceed with 3.0 g of mL of methanol, shake for 10 minutes, filter, and use the filtrate Powdered Senega according to Method 3, and perform the test. as the sample solution. Separately, dissolve 1 mg of Prepare the control solution with 3.0 mL of Standard Lead Solu- 4´-O-glucosyl-5-O-methylvisamminol for thin-layer chroma- tion (not more than 10 ppm). tography in 1 mL of methanol, and use this solution as the stan- (2) Arsenic <1.11> Prepare the test solution with 0.40 g of dard solution. Perform the test with these solutions as directed Powdered Senega according to Method 4, and perform the test under Thin-layer Chromatography <2.03>. Spot 5 µL each of (not more than 5 ppm). the sample solution and standard solution on a plate of silica gel (3) Foreign matter―Under a microscope <5.01>, stone with fluorescent indicator for thin-layer chromatography, de- cells, starch grains or crystals of calcium oxalate are not ob- velop the plate with a mixture of ethyl acetate, methanol and served. water (10:2:1) to a distance of about 10 cm, and air-dry the plate. Examine under ultraviolet light (main wavelength: 254 nm): one of the spot among several spots from the sample solution has the Add the following: same color tone and Rf value with the blue spot from the standard solution. Shimbuto Extract

真武湯エキス Scopolia Rhizome Shimbuto Extract contains not less than 26 mg and not more ロートコン than 78 mg of peoniflorin (C23H28O11: 480.46), not less than 0.5 mg and not more than 2.0 mg (for preparation prescribed 0.8 g Change the Purity to read: of Ginger) or not less than 0.6 mg and not more than 2.4 mg (for preparation prescribed 1 g of Ginger) or not less than 0.9 mg Purity (1) Heavy metals <1.07> Proceed with 3.0 g of and not more than 3.6 mg (for preparation prescribed 1.5 g of pulverized Scopolia Rhizome according to Method 3, and per- Ginger) of [6]-gingerol, and not less than 0.7 mg (for prepara- form the test. Prepare the control solution with 4.5 mL of Stan- tion prescribed 1 g of Processed Aconite Root 1) of total alka- dard Lead Solution (not more than 15 ppm). loids (as benzoylmesaconine hydrochloride and (2) Arsenic <1.11> Prepare the test solution with 0.40 g of 14-anisoylaconine hydrochloride) or not less than 0.2 mg (for pulverized Scopolia Rhizome according to Method 4, and per- preparation prescribed 1 g of Powdered Processed Aconite Root form the test (not more than 5 ppm). 1) of total alkaloids (as benzoylmesaconine hydrochloride and 14-anisoylaconine hydrochloride, or as benzoylmesaconine hydrochloride and benzoylhypaconine hydrochloride) or not less Senega than 0.1 mg (for preparation prescribed 1 g of Powdered Proc- セネガ essed Aconite Root 2) of total alkaloids (as benzoylmesaconine hydrochloride and 14-benzoylhypacomine hydrochloride) or not Change the Purity to read: less than 0.1 mg (for preparation prescribed 0.5 g of Powdered Processed Aconite Root 1) of total alkaloids (as benzoylmesa- Purity (1) Stem—The amount of the stems contained in conine hydrochloride and 14-anisoylaconine hydrochloride, or Senega does not exceed 2.0%. as benzoylmesaconine hydrochloride and benzoylhypaconine (2) Heavy metals <1.07> Proceed with 3.0 g of pulverized hydrochloride) per the extract prepared as directed in the Senega according to Method 3, and perform the test. Prepare the Method of preparation. control solution with 3.0 mL of Standard Lead Solution (not more than 10 ppm). Method of preparation Prepare a dry extract or viscous ex- (3) Arsenic <1.11> Prepare the test solution with 0.40 g of tract as directed under Extracts, with 5 g of Poria Sclerotium, 3 pulverized Senega according to Method 4, and perform the test g of Paeony Root, 3 g of Atractylodes Rhizome, 1 g of Ginger (not more than 5 ppm). and 1 g Processed Aconit Root 1 of “Processed Aconit Root”, or (4) Foreign matter <5.01> The amount of foreign matter with 5 g of Poria Sclerotium, 3 g of Paeony Root, 3 g of Atrac- other than the stems is not more than 1.0%. tylodes Lancea Rhizome, 1 g of Ginger and 1 g of Powdered Processed Aconit Root 1 of “Powdered Processed Aconit Root”,

or with 5 g of Poria Sclerotium, 3 g of Paeony Root, 3 g of Atractylodes Rhizome, 0.8 g of Ginger and 1 g of Powdered Processed Aconit Root 2 of “Powdered Processed Aconit Root”,

Supplement II, JP XV Crude Drugs 2235 or with 4 g of Poria Sclerotium, 3 g of Paeony Root, 3 g of zome). Atractylodes Lancea Rhizome, 1.5 g of Ginger and 0.5 g of (4) To 1.0 g of Shimbuto Extract, add 10 mL of water, shake, Powdered Processed Aconit Root 1 of “Powdered Processed then add 25 mL of diethyl ether, and shake. Take the diethyl Aconit Root”. ether layer, evaporate the layer under reduced pressure, add 2 mL of diethyl ether to the residue, and use this solution as the Description Shimbuto Extract occurs as light yellow-brown to sample solution. Separately, dissolve 1 mg of [6]-gingerol for brown powder. It has slightly a characteristic odor and a hot and thin-layer chromatography in 1 mL of methanol, and use this bitter taste. solution as the standard solution. Perform the test with these solutions as directed under Thin-layer Chromatography <2.03>. Identification (1) To 2.0 g of Shimbuto Extract, add 10 mL Spot 10 µL of the sample solution and 5 µL of the standard solu- of water, shake, then add 5 mL of 1-butanol, shake, centrifuge, tion on a plate of silica gel for thin-layer chromatography. De- and use the supernatant liquid as the sample solution. Separately, velop the plate with a mixture of ethyl acetate and hexane (1:1) dissolve 1 mg of Peoniflorin Reference Standard in 1 mL of to a distance of about 10 cm, and air-dry the plate. Spray evenly methanol, and use this solution as the standard solution. Perform 4-dimethylaminobenzaldehyde TS for spraying on the plate, the test with these solutions as directed under Thin-layer Chro- heated at 105°C for 5 minutes and allowed to cool: one of the matography <2.03>. Spot 5 µL each of the sample solution and spot among the several spots from the sample solution has the standard solution on a plate of silica gel for thin-layer chroma- same color tone and R value with the blue-green spot from the tography. Develop the plate with a mixture of ethyl acetate, f standard solution (Ginger). methanol and water (20:3:2) to a distance of about 10 cm, and (5) To 3.0 g of Shimbuto Extract, add 20 mL of diethyl air-dry the plate. Spray evenly 4-methoxybezaldehyde-sulfuric ether and 2 ml of ammonia TS, shake for 10 minutes, centrifuge, acid TS on the plate, and heat at 105°C for 5 minutes: one of the and take the supernatant liquid. Evaporate the supernatant liquid spot among the several spots from the sample solution has the under reduced pressure, add 1 mL of acetonitrile to the residue, same color tone and R value with the purple spot from the f and use this solution as the sample solution. Separately, dissolve standard solution (Peony Root). 1 mg of benzoylmesaconine hydrochloride for thin-layer chro- (2) (For preparation prescribed Atractylodes Rhizome) To matography in 10 mL of ethanol (99.5), and use this solution as 1.0 g of Shimbuto Extract, add 10 mL of water, shake, then add the standard solution. Perform the test with these solutions as 25 mL of diethyl ether, and shake. Take the diethyl ether layer, directed under Thin-layer Chromatography <2.03>. Spot 20 µL evaporate the layer under reduced pressure, add 2 mL of diethyl of the sample solution and 10 µL of the standard solution on a ether to the residue, and use this solution as the sample solution. plate of silica gel for thin-layer chromatography. Develop the Separately, dissolve 1 mg of atractylenolide III for thin-layer plate with a mixture of 1-butanol, water and acetic acid (100) chromatography in 2 mL of methanol, and use this solution as (4:2:1) to a distance of about 10 cm, and air-dry the plate. Spray the standard solution. Perform the test with these solutions as evenly Dragendorff’s TS for spraying on the plate, and air-dry directed under Thin-layer Chromatography <2.03>. Spot 5 µL the plate. Then spray evenly sodium nitrite TS on the plate: one each of the sample solution and standard solution on a plate of of the spot among the several spots from the sample solution has silica gel for thin-layer chromatography. Develop the plate with the same color tone and R value with the yellow-brown spot a mixture of ethyl acetate and hexane (1:1) to a distance of f from the standard solution (Processed Aconite Root or Pow- about 10 cm, and air-dry the plate. Spray evenly diluted sulfuric dered Processed Aconite Root). acid on the plate, heat at 105°C for 5 minutes, and examine under ultraviolet light (main wavelength: 365 nm): one of the spot Purity (1) Heavy metals <1.07> Prepare the test solution among the several spots from the sample solution has the same with 1.0g of Shimbuto Extract as directed in the Extracts (4) color tone and Rf value with the bluish white fluorescent spot under General Rules for Preparations, and perform the test (not from the standard solution (Atractylodes Rhizome). more than 30 ppm). (3) (For preparation prescribed Atractylodes Lancea Rhi- (2) Arsenic <1.11> Prepare the test solution with 0.67 g of zome) To 2.0 g of Shimbuto Extract, add 10 mL of water, Shimbuto Extract according to Method 3, and perform the test shake, then add 25 mL of hexane, and shake. Take the hexane (not more than 3 ppm). layer, add anhydrous sodium sulfate to dry, and filter. Evaporate (3) Aconitum diester alkaloids (aconitine, jesaconitine, hy- the filtrate under reduced pressure, add 2 mL of hexane to the paconitine and mesaconitine)—Weigh accurately 1.0 g of residue, and use this solution as the sample solution. Perform Shimbuto Extract, add 20 mL of diethyl ether, shake, then add the test with the sample solution as directed under Thin-layer 3.0 mL of 0.1 mol/L hydrochloric acid TS and shake for 10 Chromatography <2.03>. Spot 20 µL of the sample solution on a minutes. Centrifuge this solution, remove the upper layer, then plate of silica gel with fluorescent indicator for thin-layer chro- add 20 mL of diethyl ether, proceed in the same manner as de- matography, develop the plate with a mixture of hexane and scribed above, and remove the upper layer. To the water layer, acetone (7:1) to a distance of about 10 cm, and air-dry the plate. add 1.0 mL of ammonia TS and 20 mL of diethyl ether, shake Examine under ultraviolet light (main wavelength: 254 nm): a for 30 minutes, centrifuge, and take the supernatant liquid. To dark purple spot is observed at around Rf 0.4. The spot shows a the water layer, add 1.0 mL of ammonia TS and 20 mL of di- greenish brown color after being sprayed evenly ethyl ether, and repeat the above process twice more. Combine 4-dimethylaminobenzaldehyde TS for spraying, heated at 105°C all the supernatant liquids, and evaporate to dryness under re- for 5 minutes and allowed to cool (Atractylodes Lancea Rhi- duced pressure. Dissolve the residue with exactly 10 mL of a

2236 Crude Drugs Supplement II, JP XV mixture of phosphate buffer solution for processed aconite root lated on the anhydrous basis and acetonitrile (1:1). Centrifuge this solution, and use the su- Operating conditions― pernatant liquid as the sample solution. Separately, pipet 1 mL Detector: An ultraviolet absorption photometer (wavelength: of aconitum diester alkaloids standard solution for purity, add a 232 nm) mixture of phosphate buffer solution for processed aconite root Column: A stainless steel column 4.6 mm in inside diameter and acetonitrile (1:1) to make exactly 10 mL, and use this solu- and 15 cm in length, packed with octadecylsilanized silica gel tion as the standard solution. Perform the test with exactly 40 µL for liquid chromatography (5 µm in particle diameter). each of the sample solution and standard solution as directed Column temperature: A constant temperature of about 20°C. under Liquid Chromatography <2.01> according to the follow- Mobile phase: A mixture of water, acetonitrile and phosphoric ing conditions: the heights of the peaks corresponding to aco- acid (850:150:1). nitine, jesaconitine, hypaconitine and mesaconitine from the Flow rate: 1.0 mL per minute (the retention time of peoniflo- sample solution are not higher than the respective heights cor- rin is about 9 minutes). responding to aconitine, jesaconitine, hypaconitine and mesaco- System suitability― nitine from the standard solution. System performance: Dissolve 1 mg each of Peoniflorin Ref- Operating conditions― erence Standard and albiflorin in diluted methanol (1 in 2) to Detector: An ultraviolet absorption photometer (wavelength: make 10 mL. When the procedure is run with 10 µL of this 231 nm for aconitine, hypaconitine and mesaconitine; 254 nm standard solution under the above operating conditions, albiflo- for jesaconitine). rin and peoniflorin are eluted in this order with the resolution Column: A stainless steel column 4.6 mm in inside diameter between these peaks being not less than 2.5. and 15 cm in length, packed with octadecylsilanized silica gel System repeatability: When the test is repeated 6 times with for liquid chromatography (5 µm in particle diameter). 10 µL of the standard solution under the above operating condi- Column temperature: A constant temperature of about 40°C. tions, the relative standard deviation of the peak area of Mobile phase: A mixture of phosphate buffer for processed peoniflorin is not more than 1.5%. aconite root and tetrahydrofuran (183:17). (2) [6]-gingerol―Weigh accurately about 0.5 g of Shimbuto Flow rate: 1.0 mL per minute (the retention time of mesaco- Extract, add exactly 50 mL of diluted methanol (7 in 10), shake nitine is about 31 minutes). for 15 minutes, filter, and use the filtrate as the sample solution. System suitability― Separately, weigh accurately about 10 mg of [6]-gingerol for System performance: When the procedure is run with 20 µL component determination, dissolve in diluted methanol to make of aconitum diester alkaloids standard solution for purity under exactly 100 mL. Pipet 5 mL of this solution, add methanol to the above operating conditions, using 254 nm, mesaconitine, make exactly 50 mL, and use this solution as the standard solu- hypaconitine, aconitine and jesaconitine are eluted in this order, tion. Perform the test with exactly 10 µL each of the sample so- and each resolution between their peaks is not less than 1.5 re- lution and standard solution as directed under Liquid Chroma- spectively. tography <2.01> according to the following conditions, and de- System repeatability: When the test is repeated 6 times with termine the peak areas, A and A , of [6]-gingerol. 20 µL of the standard solution under the above operating condi- T S tions, using 231 nm, the relative standard deviation of the peak Amount (mg) of [6]-gingerol = WS × (AT / AS) × (1/20) height of mesaconitine is not more than 1.5%.

WS: Amount (mg) of [6]-gingerol for component determina- Loss on drying <2.41> Not more than 7.0% (1 g, 105°C, 5 tion hours). Operating conditions― Total ash <5.01> Not more than 10.0%. Detector: An ultraviolet absorption photometer (wavelength: 282 nm) Assay (1) Peoniflorin―Weigh accurately about 0.5 g of Column: A stainless steel column 4.6 mm in inside diameter Shimbuto Extract, add exactly 50 mL of diluted methanol (1 in and 15 cm in length, packed with octadecylsilanized silica gel 2), shake for 15 minutes, filter, and use the filtrate as the sample for liquid chromatography (5 µm in particle diameter). solution. Separately, weigh accurately about 10 mg of Peoniflo- Column temperature: A constant temperature of about 30°C. rin Reference Standard (separately determine the water), and Mobile phase: A mixture of water, acetonitrile and phosphoric dissolve in diluted methanol (1 in 2) to make exactly 100 mL, acid (620:380:1). and use this solution as the standard solution. Perform the test Flow rate: 1.0 mL per minute (the retention time of with exactly 10 µL each of the sample solution and standard so- [6]-gingerol is about 15 minutes). lution as directed under Liquid Chromatography <2.01> ac- System suitability― cording to the following conditions, and determine the peak ar- System performance: When the procedure is run with 10 µL eas, A and A , of peoniflorin. T S of the standard solution under the above operating conditions, the number of theoretical plates and the symmetry factor of the Amount (mg) of peoniflorin (C23H28O11) peak of [6]-gingerol are not less than 5000 and not more than = WS × (AT / AS) × (1/2) 1.5, respectively.

WS: Amount (mg) of Peoniflorin Reference Standard, calcu- System repeatability: When the test is repeated 6 times with

Supplement II, JP XV Crude Drugs 2237

10 µL of the standard solution under the above operating condi- Flow rate: 1.0 mL per minute (the retention time of benzoyl- tions, the relative standard deviation of the peak area of mesaconine is about 15 minutes). [6]-gingerol is not more than 1.5%. System suitability― (3) Total alkaloids―Weigh accurately about 1 g of Shim- System performance: When the procedure is run with 20 µL buto Extract, add 20 mL of diethyl ether, shake, then add 3.0 mL of the aconitum monoester alkaloids standard solution TS for of 0.1 mol/L hydrochloric acid TS, and shake for 10 minutes. component determination under the above operating conditions, Centrifuge this solution, remove the upper layer, then add 20 the number of theoretical plates and the symmetry factor of the mL of diethyl ether, proceed in the same manner as described peak of benzoylmesaconine are not less than 5000 and not more above, and remove the upper layer. To the water layer, add 1.0 than 1.5, respectively. mL of ammonia TS and 20 mL of diethyl ether, shake for 30 System repeatability: When the test is repeated 6 times with minutes, centrifuge, and take the supernatant liquid. To the wa- 20 µL of the aconitum monoester alkaloids standard solution TS ter layer, add 1.0 mL of ammonia TS and 20 mL of diethyl ether, for component determination under the above operating condi- and repeat the above process twice more. Combine all the su- tions, the relative standard deviation of the peak areas of ben- pernatant liquids, and evaporate to dryness under reduced pres- zoylmesaconine, benzoylhypaconine and 14-anisoylaconine is sure. Dissolve the residue with a mixture of phosphate buffer not more than 1.5%. solution for processed aconite root and acetonitrile (1:1) to make exactly 10 mL. Centrifuge this solution, and use the su- Container and storage Containers－Tight containers. pernatant liquid as the sample solution. Perform the test with exactly 20 µL each of the sample solution and the aconitum monoester alkaloids standard solution TS for component deter- Turmeric mination as directed under Liquid Chromatography <2.01> according to the following conditions. Determine the peak areas of ウコン benzoylmesaconine, benzoylhypaconine and 14-anisoylaconine, Change the Origin and the identification to read: ATM and ASM, ATH and ASH, as well as ATA and ASA, in each solution, respectively. Turmeric is the rhizome of Curcuma Longa Linné Amount (mg) of benzoylmesaconine hydrochloride (Zingiberaceae) with or without cork layers, usually with the application of blanching. = CSM × (ATM / ASM) × 10 It contains not less than 1.0% and not more than Amount (mg) of benzoylhypaconine hydrochloride 5.0% of total curcuminoids (curcumin, demethoxycur-

= CSH × (ATH / ASH) × 10 cumin and bisdemethoxycurcumin), calculated on the basis of dried material. Amount (mg) of 14-anisoylaconine hydrochloride

= CSA × (ATA / ASA) × 10 Identification (1) To 0.5 g of pulverized Turmeric, add 20 mL of methanol, shake for 15 minutes, filter, and use the filtrate CSM: Concentration (mg/mL) of benzoylmesaconine hydro- as the sample solution. Perform the test with the sample solution chloride for component determination in aconitum as directed under Thin-layer Chromatography <2.03>. Spot 5 µL monoester alkaloids standard solution TS for compo- of the sample solution on a plate of silica gel for thin-layer nent determination chromatography. Develop the plate with a mixture of ethyl acetate, hexane and acetic acid (100) (70:30:1) to a distance about C : Concentration (mg/mL) of benzoylhypaconine hydro- SH 10 cm, and air-dry the plate: a yellow spot appears at around R chloride for component determination in aconitum f 0.4. monoester alkaloids standard solution TS for compo- (2) To 0.2 g of pulverized Turmeric, add 25 mL of a mixture nent determination of methanol and acetic acid (100) (99:1), centrifuge after shaking for 20 minutes, and separate the supernatant liquid. Perform CSA: Concentration (mg/mL) of 14-anisoylaconine hydrochloride for component determination in aconitum the test as directed in the Component Determination, and meas- monoester alkaloids standard solution for TS compo- ure the peak areas of curcumin, demethoxycurcumin and bis- nent determination demethoxycurcumin: the peak area of curcumin is larger than the peak area of demethoxycurcumin and is larger than 0.69 Operating conditions― times the peak area of bisdemethoxycurcumin. Detector: An ultraviolet absorption photometer (wavelength: 231 nm for benzoylhypaconine and benzoylmesaconine; 254 nm Add the following next to Extract Content: for 14-anisoylaconine). Column: A stainless steel column 4.6 mm in inside diameter Component determination Weigh accurately about 0.2 g of and 15 cm in length, packed with octadecylsilanized silica gel pulverized Turmeric, add 25 mL of a mixture of methanol and for liquid chromatography (5 µm in particle diameter). acetic acid (100) (99:1), shake for 20 minutes, centrifuge, and Column temperature: A constant temperature of about 40°C. separate the supernatant liquid. To the residue, add 25 mL of a Mobile phase: A mixture of phosphate buffer solution for mixture of methanol and acetic acid (100) (99:1), and proceed in processed aconite root and tetrahydrofuran (183:17). the same manner as described above. Combine all the extracts,

2238 Crude Drugs Supplement II, JP XV add methanol to make exactly 50 mL, and use this solution as as directed under Thin-layer Chromatography <2.03>. Spot 5 µL the sample solution. Separately, weigh accurately about 10 mg of the sample solution on a plate of silica gel for thin-layer of curcumin for component determination, and dissolve in chromatography. Develop the plate with a mixture of ethyl ace- methanol to make exactly 50 mL. Weigh accurately 10 mL of tate, hexane and acetic acid (100) (70:30:1) to a distance about this solution, add methanol to make exactly 50 mL, and use this 10 cm, and air-dry the plate: a yellow spot appears at around Rf solution as the standard solution. Perform the test with exactly 0.4. 10 µL each of the sample solution and standard solution as de- (2) To 0.2 g of Powdered Turmeric, add 25 mL of a mixture scribed under Liquid Chromatography <2.01> according to the of methanol and acetic acid (100) (99:1), centrifuge after shak- following conditions, and determine the peak areas, ATC, ATD ing for 20 minutes, and separate the supernatant liquid. Perform and ATD of curcumin, demethoxycurcumin and bisdemethoxy- the test as directed in the Component Determination, and meas- curcumin in the sample solution as well as the peak area AS of ure the peak areas of curcumin, demethoxycurcumin and bis- curcumin in the standard solution. demethoxycurcumin: the peak area of curcumin is larger than the peak area of demethoxycurcumin and is larger than 0.69 Amount (mg) of total curcuminoids (curcumin, demethoxy- times the peak area of bisdemethoxycurcumin. curcumin and bisdemethoxycurcumin)

= WS × {( ATC + ATD + ATB × 0.69) / AS} × (1 / 5) Add the following next to Extract Content:

WS: Amount (mg) of curcumin for component determination Component determination Weigh accurately about 0.2 g of

Powdered Turmeric, add 25 mL of a mixture of methanol and Operating conditions― acetic acid (100) (99:1), shake for 20 minutes, centrifuge, and Detector: An ultraviolet absorption photometer (wavelength: separate the supernatant liquid. To the residue, add 25 mL of a 245 nm) mixture of methanol and acetic acid (100) (99:1), and proceed in Column: A stainless steel column 4.6 mm in inside diameter the same manner as described above. Combine all the extracts, and 15 cm in length, packed with octadecylsilianized silica gel add methanol to make exactly 50 mL, and use this solution as for liquid chromatography (5 µm in particle diameter). the sample solution. Separately, weigh accurately about 10 mg Column temperature: A constant temperature of about 40°C. of curcumin for component determination, and dissolve in Mobile phase: A mixture of water, acetonitrile and acetic acid methanol to make exactly 50 mL. Weigh accurately 10 mL of (100) (56:43:1). this solution, add methanol to make exactly 50 mL, and use this Flow rate: 1.0 mL per minute (the retention time of curcumin solution as the standard solution. Perform the test with exactly is about 11 minutes). 10 µL each of the sample solution and standard solution as de- System suitability― scribed under Liquid Chromatography <2.01> according to the System performance: Dissolve 1 mg each of curcumin, de- following conditions, and determine the peak areas, A , A methoxycurcumin and bisdemethoxycurcumin for component TC TD and A of curcumin, demethoxycurcumin and bisdemethoxy- determination in methanol to make 5 mL. When the procedure is TB curcumin in the sample solution as well as the peak area A of run with 10 µL of this solution under the above operating condi- S curcumin in the standard solution. tions, bisdemethoxycurcumin, demethoxycurcumin and curcumin are eluted in this order with the resolution among these Amount (mg) of total curcuminoids (curcumin, demethoxy- peaks being not less than 1.5. curcumin and bisdemethoxycurcumin

System repeatability: When the test is repeated 6 times with = WS ×{( ATC + ATD + ATB × 0.69) / AS} × (1 / 5) 10 µL of the standard solution under the above operating condi- WS: Amount (mg) of curcumin for component determination tions, the relative standard deviation of curcumin is not more than 1.5%. Operating conditions— Detector: An ultraviolet absorption photometer (wavelength: 245 nm) Powdered Turmeric Column: A stainless steel column 4.6 mm in inside diameter and 15 cm in length, packed with octadecylsilianized silica gel ウコン末 for liquid chromatography (5 µm in particle diameter). Column temperature: A constant temperature of about 40°C. Change the Origin and the Identification to read: Mobile phase: A mixture of water, acetonitrile and acetic acid Powdered Turmeric is the powder of Turmeric. (100) (56:43:1). It contains not less than 1.0% and not more than Flow rate: 1.0 mL/per minute (the retention time of curcumin 5.0% of total curcuminoids (curcumin, demethoxycur- is about 11 minutes). cumin and bisdemethoxycurcumin), calculated on the System suitability― basis of dried material. System performance: Dissolve 1 mg each of curcumin, demethoxycurcumin and bisdemethoxycurcumin for component Identification (1) To 0.5 g of Powdered Turmeric, add 20 determination in methanol to make 5 mL. When the procedure is mL of methanol, shake for 15 minutes, filter, and use the filtrate run with 10 µL of this solution under the above operating condi- as the sample solution. Perform the test with the sample solution tions, bisdemethoxycurcumin, demethoxycurcumin and curcu-

Supplement II, JP XV Crude Drugs 2239 min are eluted in this order with the resolution among these peaks being not less than 1.5. System repeatability: When the test is repeated 6 times with 10 µL of the standard solution under the above operating conditions, the relative standard deviation of curcumin is not more than 1.5%.

Zanthoxylum Fruit

サンショウ

Change the Total ash to read:

Total ash <5.01> Not more than 8.0%.

Powdered Zanthoxylum Fruit

サンショウ末

Change the Total ash to read:

Total ash <5.01> Not more than 8.0%

Infrared Reference Spectra

Supplement II, JP XV Infrared Reference Spectra 2243

Change to read the following Infrared Reference Spectrum:

L-Arginine

2244 Infrared Reference Spectra Supplement II, JP XV

Add the following 51 spectra:

Aciclovir

L-Alanine

Amiodarone Hydrochloride

Supplement II, JP XV Infrared Reference Spectra 2245

Aprindine Hydrochloride

Argatroban Hydrate

Betaxolol Hydrochloride

2246 Infrared Reference Spectra Supplement II, JP XV

Cadralazine

Cinoxacin

Clebopride Malate

Supplement II, JP XV Infrared Reference Spectra 2247

Danazol

Diflucortolone Valerate

Doxazosin Mesilate

2248 Infrared Reference Spectra Supplement II, JP XV

Droxidopa

Ecabet Sodium Hydrate

Ethenzamide

Supplement II, JP XV Infrared Reference Spectra 2249

Flopropione

Fludrocortisone Acetate

Flutamide

2250 Infrared Reference Spectra Supplement II, JP XV

Flutoprazepam

Gefarnate

Gliclazide

Supplement II, JP XV Infrared Reference Spectra 2251

Imidapril Hydrochloride

Indapamide

Ipriflavone

2252 Infrared Reference Spectra Supplement II, JP XV

Irsogladine Maleate

Ketoconazole

Levofloxacin Hydrate

Supplement II, JP XV Infrared Reference Spectra 2253

Losartan Potassium

L-Lysine Acetate

Mosapride Citrate Hydrate

2254 Infrared Reference Spectra Supplement II, JP XV

Phenobarbital

Pimozide

Pioglitazone Hydrochloride

Supplement II, JP XV Infrared Reference Spectra 2255

Prazosin Hydrochloride

Prednisolone Sodium Phosphate

Probucol

2256 Infrared Reference Spectra Supplement II, JP XV

Procainamide Hydrochloride

Propafenone Hydrochloride

Rebamipide

Supplement II, JP XV Infrared Reference Spectra 2257

Sevoflurane

Simvastatin

Purified Sodium Hyaluronate

2258 Infrared Reference Spectra Supplement II, JP XV

Sulindac

Tacrolimus Hydrate

Tazobactam

Supplement II, JP XV Infrared Reference Spectra 2259

Teprenone

Tiapride Hydrochloride

Tosufloxacin Tosilate Hydrate

2260 Infrared Reference Spectra Supplement II, JP XV

Troxipide

Ursodeoxycholic Acid

Zolpidem Tartrate

Ultraviolet-visible Reference Spectra

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2263

Add the following 41 spectra:

Aciclovir

Amiodarone Hydrochloride

Aprindine Hydrochloride

2264 Ultraviolet-visible Reference Spectra Supplement II, JP XV

Argatroban Hydrate

Betaxolol Hydrochloride

Cadralazine

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2265

Calcitonin（Salmon）

Cinoxacin

Clebopride Malate

2266 Ultraviolet-visible Reference Spectra Supplement II, JP XV

Danazol

Diflucortolone Valerate

Doxazosin Mesilate

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2267

Droxidopa

Ecabet Sodium Hydrate

Ethenzamide

2268 Ultraviolet-visible Reference Spectra Supplement II, JP XV

Fludrocortisone Acetate

Flutamide

Flutoprazepam

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2269

Gliclazide

Indapamide

Ipriflavone

2270 Ultraviolet-visible Reference Spectra Supplement II, JP XV

Irsogladine Maleate

Ketoconazole

Levofloxacin Hydrate

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2271

Losartan Potassium

Mosapride Citrate Hydrate

Phenobarbital

2272 Ultraviolet-visible Reference Spectra Supplement II, JP XV

Pimozide

Pioglitazone Hydrochloride

Prazosin Hydrochloride

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2273

Prednisolone Sodium Phosphate

Probucol

Progesterone

2274 Ultraviolet-visible Reference Spectra Supplement II, JP XV

Propafenone Hydrochloride

Rebamipide

Simvastatin

Supplement II, JP XV Ultraviolet-visible Reference Spectra 2275

Sulindac

Tiapride Hydrochloride

Tosufloxacin Tosilate Hydrate

2276 Ultraviolet-visible Reference Spectra Supplement II, JP XV

Troxipide

Zolpidem Tartrate

General Information

GENERAL INFORMATION

8. International Harmonization Implemented in the Japanese Pharmacopoeia Fifteenth Edition

Add the following:

June 2008 (Rev.1)

Harmonized items JP15 (Supplement II) Remarks

Bulk Density and Tapped Density of 3.01 Determination of Bulk and Tapped Powders Densities (Introduction) JP’s particular description: Explanation of this test method.

Bulk density Bulk density Method 1: Measurement in a graduated Method 1: Measurement in a Graduated cylinder Cylinder

Procedure Procedure Method 2: Measurement in a volumeter Method 2: Measurement in a Volumeter Apparatus Apparatus Procedure Procedure Method 3: Measurement in a vessel Method 3: Measurement in a Vessel Apparatus Apparatus Procedure Procedure Tapped density Tapped density Method 1 Method 1 Apparatus Apparatus Procedure Procedure Method 2 Method 2 Procedure Procedure

Method 3 Method 3 Procedure Procedure Measures of powder compressibility Measures of powder compressibility

2279 2280 General Information Supplement II, JP XV

May 2007

Harmonized items JP15 (Supplement II) Remarks

Gas Pycnometric Density of Solids 3.03 Powder Particle Density Determi- . nation

(Introduction) (Introduction) JP’s particular description: application of this test method

Apparatus 1. Apparatus Calibration of apparatus The range of temperature during the measurement is described in the Proce- dure.

Method 2. Procedure Expression of the results 2. Procedure

October 2006

Harmonized items JP15 (Supplement II) Remarks

Rice Starch Rice Starch

Definition Definition Identification A Identification (1) Identification B Identification (2) Identification C Identification (3) pH pH Iron Purity (1) Iron Loss on drying Loss on drying Sulphated ash Residue on ignition Oxidising substances Purity (2) Oxidizing substances Sulphur dioxide Purity (3) Sulfur dioxide

May 2007

Harmonized items JP15 (Supplement II) Remarks

GENERAL INFORMATION

Powder Fineness Powder Fineness

Supplement II, JP XV General Information 2281

Change to read: pneumoniae ATCC15531 or equivalent species or strains) and one of which should be an arginine hydrolyser (i.e., M. orale 14. Mycoplasma Testing for Cell ATCC23714 or equivalent species or strains). The mycoplasma strains used for the positive control tests should be those with a Substrates used for the Production low number of passages obtained from an official or suitably of Biotechnological/Biological accredited agency, and handled appropriately. Inoculate the culture medium with 100 colony-forming units (CFU) or 100 Products color-changing units (CCU) or less.

This document describes the currently available methods of 3. Culture and Observation mycoplasma testing that should be performed for cell substrates 1) Inoculate no less than 0.2 mL of test sample (cell suspen- that are used in the manufacture of biotechnological/biological sion) in evenly distributed amounts over the surface of each of products. two or more agar plates. After the surfaces of the inoculated Methods suggested for detection of mycoplasma are, A. cul- plates are dried, the plates should be incubated under mi- ture method, B. indicator cell culture method, and C. poly- croaerophilic conditions in an atmosphere of nitrogen contain- merase chain reaction (PCR) method. ing 5 to 10 percent carbon dioxide and adequate humidity at 36 Mycoplasma testing should be performed on the master cell ± 1ºC for no less than 14 days. bank (MCB) and the working cell bank (WCB), as well as on 2) Inoculate no less than 10 mL of the test sample (cell sus- the cell cultures used during the manufacturing process of the pension) into each of one or more vessels containing 100 mL of product. For the assessment of these cells, mycoplasma testing broth medium, and incubate at 36 ± 1ºC. should be performed using both methods A and B. Method B, If the culture medium for the sample cells contains any however, does not detect only DNA derived from mycoplasma. growth-inhibiting factors, such as antibiotics, these factors must Therefore, if a positive result is obtained only from method B, be removed. A method such as centrifugation is recommended method C can be used to determine whether mycoplasma is ac- for this purpose. Refer to the Validation tests for tually present. When method C is used, it is necessary to dem- growth-inhibiting factors described in the Minimum Require- onstrate the rationale for determining a negative result. In such a ments for Biological Products for the detection of case, the sensitivity and specificity of the method, the appropri- growth-inhibiting factors. ateness of the sample preparation, and the suitability of the se- 3) Subculture 0.2 mL of broth culture from each vessel on lection of the test method, including selection of reagents, reac- the 3rd, 7th, and 14th days of incubation onto two or more agar tion conditions and primers should be taken into account. plates. The plates should be incubated microaerophilically at 36 Prior to mycoplasma testing, the sample should be tested to ± 1ºC for no less than 14 days. detect the presence of any factors inhibiting the growth of my- 4) Examination of all plates for mycoplasma colonies coplasma. If such growth-inhibiting factors are detected they should be done microscopically on the 7th and 14th day at 100 should be neutralized or eliminated by an appropriate method, times magnification or greater. such as centrifugation or cell passage. If the test will be performed within 24 hours of obtaining the B. Indicator Cell Culture Method sample, the sample should be stored at a temperature between Using Vero cell culture substrate, pretest the suitability of the 2ºC and 8ºC. If more than 24 hours will elapse before the test is method using an inoculum of 100 CFU or 100 CCU or less of M. performed, the sample should be stored at –60ºC or lower. hyorhinis (ATCC29052, ATCC17981 or equivalent species or If mycoplasma is detected, additional testing to identify the strains) and M. orale (ATCC23714 or equivalent species or species may be helpful in determining the source of contamina- strains). tion. An equivalent indicator cell substrate and suitable mycoplasma strains may be acceptable if data demonstrate at least A. Culture Method equal sensitivity for the detection of known mycoplasma con- 1. Culture Medium taminants. The mycoplasma strains should be those with a low Both agar plates and broth are used. Each lot of agar and number of passages obtained from an official or suitably accred- broth medium should be free of antibiotics except for penicillin. ited agency, and handled appropriately, and the unit of inocula- Refer to the Minimum Requirements for Biological Products tion should be determined before use. The cell substrate used regarding selection of the culture media. Other culture media should be obtained from a qualified cell bank and certified to be may be used if they fulfill the requirements described in the fol- mycoplasma free. The acquired cells should be carefully cul- lowing section 2. tured and propagated, and sufficient volumes of seed stock should be prepared with the proper precautions to avoid my- 2. Suitability of Culture Medium coplasma contamination. The stock should be tested for my- Each lot of medium should be examined for mycoplasma coplasma contamination using at least one of the methods de- growth-promoting properties. To demonstrate the capacity of the scribed in this document, then frozen for storage. For each test a media to detect known mycoplasma, each test should include new container from the stock should be thawed and used within control cultures of at least two known species or strains of my- 6 passages. coplasma, one of which should be a dextrose fermenter (i.e., M. Indicator cell cultures should be grown on cover slips sub-

2282 General Information Supplement II, JP XV merged in culture dishes or equivalent containers for one day. 12) Examine by epifluorescence microscopy at 400 to 600 Inoculate no less than 1 mL of the test sample (cell culture su- times magnification or greater. pernatant) into two or more of the culture dishes. 13) Compare the microscopic appearance of the test sample The test should include a negative (non-infected) control and with that of the negative and positive controls. two positive mycoplasma controls, such as M. hyorhinis 14) The test result is judged to be positive if there are more (ATCC29052, ATCC17981 or equivalent species or strains) and than 5 cells per 1000 (0.5%) that have minute fluorescent spots M. orale (ATCC23714 or equivalent species or strains). Use an that appear to surround, but are outside, the cell nucleus. inoculum of 100 CFU or 100 CCU or less for the positive controls. C. Polymerase Chain Reaction (PCR) Detection Method Incubate the cell cultures for 3 to 6 days at 36 ± 1ºC in an at- The PCR method is a highly specific method that enables the mosphere of air containing 5 percent carbon dioxide. detection of trace amounts of mycoplasma DNA, and has come Examine the cell cultures after fixation for the presence of to be widely used in recent years as a means of detecting my- mycoplasma by epifluorescence microscopy (400 to 600 times coplasma contamination. However, the sensitivity and specific- magnification or greater) using a DNA-binding fluorochrome, ity depend on the procedure employed, and a positive result such as bisbenzimidazole or an equivalent stain. Compare the from PCR does not always indicate the presence of viable my- microscopical appearance of the test cultures with that of the coplasma. negative and positive controls. The PCR method is based on amplifying DNA extracted from the cell culture with specific primers so that the presence of the Procedure target DNA is detected. A two-step PCR (nested PCR) is rec- 1) Aseptically place a sterilized glass cover slip into each ommended in order to increase sensitivity and specificity. The cell culture dish (35 mm diameter). tests should include both a positive control (such as M. hy- 2) Prepare Vero cell suspension in Eagle’s minimum essen- orhinis (ATCC29052, ATCC17981 or equivalent species or tial medium containing 10 percent bovine calf serum at a con- strains) of 100 CFU or 100 CCU or less) and a negative control. centration of 1 × 104 cells per 1 mL. The bovine calf serum Mycoplasma DNA from the sample of cells or cell cultures is should be tested and confirmed to be free from mycoplasma amplified using primers which should be able to amplify some prior to use. common conserved mycoplasma DNA sequence. The amplifica- 3) Inoculate aliquots of 2 mL of the Vero cell suspension tion should be performed using an appropriate heat-resistant into each culture dish. Ensure that the cover slips are completely DNA polymerase, and suitable conditions. The amplified DNA submerged, and not floating on the surface of the culture me- can be identified after agarose gel electrophoresis, followed by dium. Incubate the cultures at 36 ± 1ºC in an atmosphere of air ethidium bromide staining and UV irradiation of the gel. containing 5 percent carbon dioxide for one day, so that the cells For this method, it is important to use primers that are spe- are attached to the glass cover slip. cific to mycoplasma by choosing base sequences that are 4) Replace 2 mL of the culture medium with fresh medium, well-conserved for a wide range of mycoplasma species, for then add 0.5 mL of the test sample (cell culture supernatant) to example, the spacer region between the 16S-23S ribosome each of two or more culture dishes. Perform the same procedure genes. for the positive (2 types of mycoplasma, such as M. hyorhinis It is recommended that a two-step PCR using nested primers (ATCC29052, ATCC17981 or equivalent species or strains) and should be performed to increase the sensitivity and specificity, if M. orale (ATCC23714 or equivalent species or strains)) and the one-step PCR is negative. negative controls. The primers to be selected for the second stage of a two-step 5) Incubate the cultures for 3 to 6 days at 36 ± 1ºC in an PCR are nested primers from the inner portion of the sequence. atmosphere of air containing 5 percent carbon dioxide. The outer and inner primers should have proven effectiveness 6) Remove the culture medium from the culture dishes, and and specificity as described in publications or be validated ex- add 2 mL of a mixture of acetic acid (100) and methanol (1:3) perimentally. (fixative) to each dish; then, allow them to stand for 5 minutes. It is possible to increase the accuracy of the detection of my- 7) Remove the fixative from each dish, then add the same coplasma DNA by performing PCR tests after cultivation of amount of fixative again, and leave the dishes to stand for 10 mycoplasma that may be present in samples using Vero cells. minutes. The following is an example of a two-step PCR procedure. 8) Remove the fixative and then completely air-dry all the The reagents and reaction conditions in this example are not ex- dishes. clusive. If the suitability of other reagents and conditions is 9) Add 2 mL of bisbenzamide fluorochrome staining solu- verified, they may be used. If another procedure is used, the tion to each culture dish. Cover the dishes and let them stand at procedure should be justified and documented in detail, and the room temperature for 30 minutes. information provided should include the sensitivity and speci- 10) Aspirate the staining solution and rinse each dish with 2 ficity of the method. mL of distilled water 3 times. Take out the glass cover slips and dry them. Example Procedure 11) Mount each cover slip with a drop of a mounting fluid. 1. Preparation of template Blot off surplus mounting fluid from the edges of the cover 1) Place 600 µL of the test cell suspension (if necessary, slips. subcultured with Vero cells) in a tube and dissolve the cells with

Supplement II, JP XV General Information 2283

0.1% SDS or an equivalent. Add an equal volume (600 µL) of 4. Second stage of a two-step PCR TE (10 mmol/L tris-hydrochloric acid (pH 8.0), 1 mmol/L 1) Make a mixture of the heat-resistant DNA polymerase, EDTA) buffer-saturated phenol, and mix. dNTP solution, inner primer, and reaction buffer solution (in- 2) Centrifuge at 15,000 min-1 for 5 minutes at room cluding Mg ions), and place 99 µL in each tube. temperature. 2) Add 1 µL of the first stage PCR product from each tube 3) Transfer 400 µL of the supernatant to another tube, and to a tube containing the second stage PCR solution (99 µL). add 10 µL of 3 mol/L sodium acetate. 3) Perform the DNA amplification by repeating 30 cycles of 4) Add 1 mL (2.5 volumes) of ethanol (95) and stir thor- denaturation at 94ºC for 30 seconds, annealing at an appropriate oughly. Ice the mixture for 15 minutes, then centrifuge at 15,000 temperature for the primer (55ºC for the primer in this example), min-1 for 10 minutes at 4ºC. and elongation at 72ºC for 2 minutes. 5) Discard the supernatant and rinse the precipitate once or twice with 200 to 300 µL of 80% ethanol. Remove the rinse so- 5. Agarose gel electrophoresis lution using a pipet. Centrifuge at 15,000 min-1 for 10 minutes at 1) Mix 10 µL of each of the first stage and second stage 4ºC, then remove the supernatant thoroughly and dry up the PCR products with 2 µL of an appropriate dye as a migration precipitate. marker, and perform 1% agarose gel electrophoresis. 6) Dissolve the precipitate in 40 µL of distilled water. 2) Stain the gel with ethidium bromide and take a photo- graph under UV irradiation. 2. Perform the same procedure for the positive and negative 3) The test is judged to be positive if a DNA band is de- controls tected.

3. First stage of a two-step PCR [An Example of Primer] 1) Make a mixture of the heat-resistant DNA polymerase, For mycoplasma detection dNTP solution, outer primer, and reaction buffer solution (in- Outer primer cluding Mg ions), and place 90 µL in each tube. F1:5´-ACACCATGGGAG(C/T)TGGTAAT-3´ 2) Add 10 µL of the template prepared as above to each R1:5´-CTTC(A/T)TCGACTT(C/T)CAGACCCAAGG-C tube containing the first stage PCR solution (90 µL). AT-3´ 3) Perform the DNA amplification by repeating 30 cycles of Inner primer denaturation at 94ºC for 30 seconds, annealing at an appropriate F2:5´-GTG(G/C)GG(A/C)TGGATCACCTCCT-3´ temperature for the primer (55ºC for the primer in this example), R2:5´-GCATCCACCA(A/T)A(A/T)AC(C/T)CTT-3´ and elongation at 72ºC for 2 minutes. ( ) indicates a mixture.

[PCR reaction solution] [First stage] [Second stage] dNTP solution (1.25 mol each) 16 µL 16 µL Primer (10 pmol/µL) F1 2 µL F2 2 µL Primer (10 pmol/µL) R1 2 µL R2 2 µL Heat-resistant DNA polymerase (1 U/µL) 2 µL 2 µL Reaction buffer solution 25 mmol/L magnesium chloride hexahydrate 8 µL 8 µL 10-fold buffer solution* 10 µL 10 µL Sterile distilled water 50 µL 59 µL

*Composition of 10-fold buffer solution 2-amino-2-hydroxymethyl-1,3-propanediol- hydrochloric acid (pH 8.4) 100 mmol/L Potassium chloride 500 mmol/L Magnesium chloride hexahydrate 20 mmol/L Gelatin 0.1 g/L 3) Replace the culture media with fresh media, and add 0.5 [Method of cultivating mycoplasma within Vero cells] mL of the test sample (cell culture supernatant) to each of two or 1) Use at least two cell culture dishes for each of the test more Vero cell culture dishes. Perform the same procedure for sample, positive control and negative control. the positive (such as 100 CFU or 100 CCU or less of M. hy- 2) Into each cell culture dish (35 mm diameter), inoculate 2 orhinis (ATCC29052, ATCC17981 or equivalent species or 4 mL of the Vero cell suspension (1 × 10 cells per 1 mL) in Ea- strains)) and negative controls. gle’s minimum essential medium containing 10 percent bovine 4) Incubate the Vero cell culture dishes for the test sample, calf serum (tested in advance using the PCR method to verify positive and negative controls for 3 to 6 days at 36 ± 1ºC in an that it does not contain any detectable mycoplasma DNA). In- atmosphere of air containing 5 percent carbon dioxide. cubate the cultures at 36 ± 1ºC in an atmosphere of air containing 5 percent carbon dioxide for one day.

2284 General Information Supplement II, JP XV

Add the following: fective means to perform pharmaceutical manufacturing process control online. 32. Near Infrared Spectrometry 1. Equipment Near-infrared spectrophotometers can either be a distributed Near infrared spectrometry (NIR) is one of spectroscopic near-infrared spectrophotometer or a Fourier transform 1) methods used to qualitatively and quantitatively evaluate sub- near-infrared spectrophotometer . Interference filter-type stances from analysis of data obtained by determining their ab- near-infrared spectrophotometers that use interference filter in sorption spectrum of light in the near-infrared range. the spectrometry section are also available, however, this type The near-infrared range lies between the visible light and in- of equipment is hardly used in the field of pharmaceutical qual- frared light, typically of wavelengths (wave numbers) between ity control. 750 and 2500 nm (13333 – 4000 cm-1). The absorption of 1.1 Distributed near-infrared spectrophotometer near-infrared light occurs due to harmonic overtones from nor- This equipment is comprised of light source section, sample mal vibration or combination tones in the infrared range (4000 section, spectrometry section, photometry section, signal proc- to 400 cm-1), primarily absorption of O-H, N-H, C-H and S-H essing section, data processing section, display-record-output that involve hydrogen atoms, in particular. For instance the section. Halogen lamps, tungsten lamps, light emitting diodes asymmetrical stretching vibration of N-H occurs in the vicinity and other such devices that can emit high intensity near-infrared of 3400 cm-1, but the absorption due to the first harmonic over- light in a stable manner are used in the light source section. The tone occurs in the vicinity of 6600 cm-1 (wavelength 1515 nm), sample section is comprised of a sample cell and a sample which is near double 3400 cm-1. holder. Equipment that have an optical fiber section that is Absorption in the near-infrared range is far weaker than ab- comprised of optical fibers and a collimator are equipped with a sorption due to normal vibration that occurs in the infrared function for transmitting light to sample section, which is re- range. Furthermore, in comparison with visible light, motely located away from the spectrophotometer main unit. near-infrared light has longer wavelength, which makes it pos- Quartz is ordinarily used as material for optical fibers. sible for the light to penetrate to a depth of several mm into The spectrometry section is intended to extract light of re- solid specimens, including fine particles. This method is often quired wavelength, using dispersive devices and is comprised of utilized as a nondestructive analysis, as changes occurring with slits, mirrors and dispersive devices. Potential dispersive de- absorbed light spectrum (transmitted light or reflected light) in vices include prisms, diffraction grating, acousto-optical tunable this process provide physical and chemical information pertain- filters (AOTF), or liquid crystal tunable filters (LCTF). ing to specimens. The photometry section is comprised of detectors and ampli- Conventional spectrometry, such as calibration curve method, fiers. Sensors include semiconductor detectors (silicon, lead sul- is used as a method for analyzing near-infrared absorption spec- fide, indium-gallium-arsenic, indium-antimony), as well as trum whenever applicable. Ordinarily, however, chemometrics photomultiplier tubes. Detecting methods that use semiconduc- methods are used for analysis. Chemometrics ordinarily involve tor detectors generally perform detections with single elements, quantification of chemical data, as well as numerical and statis- but there are also occasions where array-type detectors that use tical procedures for computerization of information. Chemom- multiple elements are used. Such detectors are capable of si- etrics for near-infrared spectrometry includes various types of multaneously detecting multiple wavelengths (wave numbers). multivariate analysis such as multiple regression analysis, to The signal processing section separates signals required for perform qualitative or quantitative evaluation of active sub- measurements from output signals fed by amplifiers and then stances. outputs such isolated signals. The data processing section per- Near-infrared spectrometry is used as a rapid and nondestruc- forms data conversions and spectral analysis, etc. The dis- tive method of analysis that replaces conventional and estab- play-record-output section outputs data, analysis results and data lished analysis methods for water determinations or substance processing results to a printer. verifications. It is necessary to perform a comparison test to 1.2 Fourier transform near-infrared spectrophotometer evaluate this method against an existing analysis method, to The configuration of the equipment is fundamentally same as verify that this method is equivalent to such existing analysis that of the distributed-type equipment described in Section 1.1, method, before using this analysis method as a quality evalua- except for the spectrometry section and the signal processing tion test method in routine tests. section. Applications of near-infrared spectrometry in the pharmaceu- The spectrometry section is comprised of interferometers, tical field include qualitative or quantitative evaluation of ingre- sampling signal generators, detectors, amplifiers, A/D conver- dients, additives or water contents of active substances or sion devices, etc. Interferometers include Michelson interfer- preparations. Furthermore, near-infrared spectrometry can also ometers, transept interferometers and polarization interferome- be used for evaluation of physical conditions of substances, such ters. The signal processing section is equipped with functions as crystal forms, crystallinity, particle diameters. It is also pos- that are required for spectrometer, as well as a function for sible to perform spectrometry on samples that are located in a translating acquired interference waveform (interferogram) into remote location away from equipment main units, without sam- absorption spectrum by Fourier transformation. pling, by using optical fibers. It can therefore be used as an ef-

Supplement II, JP XV General Information 2285

2. Determination Ar = log (1 / r) = log (Ir / I) There are three types of measurement methods that are used with near-infrared spectrometry: transmittance method, diffuse The intensity of diffuse reflectance spectrum can also be ex- reflectance method and transmittance reflectance method. The pressed with the Kubelka-Munk (K-M) function. The K-M selection of measurement methods relies on the shape of sam- function is derived, based on the existence of a sample with suf- ples and applications. The transmittance method or diffuse re- ficient thickness, and expressed in terms of light scattering coef- flectance method is used for solid samples, including fine parti- ficient, which is determined by absorptivity, grain size, shape cles. The transmittance method or transmittance reflectance and fill condition (compression). method is used for liquid samples. This method is applied to solid samples, including fine parti- 2.1 Transmittance method cles, and requires a diffuse reflector. The degree of decay for incident light intensity as the light 2.3 Transmittance reflectance method from a light source passes through a sample, is represented as The transmittance reflectance method is a combination of the transmittance rate T (%) or absorbance A with the transmittance transmittance method and reflectance method. A mirror is used method. to re-reflect a light that has passed through a sample in order to A sample is placed in the light path between a light source and a take a measurement of transmittance reflectance rate, T* (%). detector, the arrangement of which is ordinarily same as that of Light path must be twice the thickness of the sample. On the the spectroscopic method. other hand, the light reflected off a mirror and enters into a detector is used as the control light. When this method is applied T = 100 t to suspended samples, however, a metal plate or a ceramic re- -αcl T = I / I0 = 10 flector with rough surface that causes diffuse reflectance is used I0: Incident light intensity instead of a mirror. I: Transmitted light intensity Transmittance reflectance absorbance (A*) is obtained by the α: Absorptivity following formula with this method: c: Solution concentration l: Layer length (sample thickness) T* = 100 t* * t = I / IT A = -log t = log (1 / t) = log (I0 / I) = αcl I: Intensity of transmitted and reflected light, in cases where a sample is placed

This method is applied for taking measurements of samples lT: Intensity of reflected light, in cases where is no sample that are liquids and solutions. Quartz glass cells and flow cells are used, with the layer length of 1 – 5 mm along. Furthermore, A* = log (1 / t*) this method can also be applied for taking measurements of samples that are solids, including fine particles. It is also known This is a method that is applied to solid samples, including as diffuse transmittance method. Selecting appropriate layer fine particles, as well as liquids and suspended samples. The length is critical for this method, since the transmitted light in- thickness of a sample must be adjusted when applying this tensity varies depending on grain sizes and surface conditions of method to a solid sample. Ordinarily adjustment is made by set- samples. ting absorbance to 0.1 – 2 (transmittance of 79 – 1%), which 2.2 Diffuse reflectance method provides the best linearity and S/N ratio of detector. A cell with The ratio of the reflection light intensity I, emitted from the appropriate layer length, according to the grain size of the fine sample in a wide reflectance range and a control reflection light particle, must be selected when applying the method to a fine intensity Ir emitted from surface of a substance, is expressed as particle sample. reflectance R (%) with the diffuse reflectance method. The near-infrared light penetrates to a depth of several mm into solid 3. Factors that affect spectrum samples, including fine particles. In that process, transmission, Following items must be considered as factors that can affect refraction, reflection and dispersion are repeated, and diffusion spectrum when applying near-infrared spectrometry, particularly takes place, but a portion of the diffused light is emitted again when conducting quantitative analysis. from the surface of the sample and captured by a detector. The 3.1 Sample temperature A significant change (wavelength shift, for example) can oc- spectrum for the diffuse reflectance absorbance (Ar) can ordinarily be obtained by plotting logarithm of inverse numbers for re- cur when the temperature varies by a several degree (°C). Care flectance (1/r) against wavelengths (wave numbers). must be taken, particularly when the sample is a solution or contains water. R = 100 r 3.2 Water or residual solvent Water or residual solvent contents of a sample, as well as r= I / Ir I: Reflection light intensity of light, diffuse reflected off the water (humidity) in the environment wherein measurements are sample taken, can potentially significantly affect absorption band of the near-infrared range. Ir: Control reflection light intensity of light emitted from surface of reference substance 3.3 Sample thickness The thickness of a sample is a factor for spectral changes and

2286 General Information Supplement II, JP XV therefore needs to be controlled at a certain thickness. A sample (layer length: 1.0 mm) can be used, when taking measurements may be considered to be of adequate thickness for the diffuse with transmittance method that involve the use of dichloro- reflectance method, however, if the thickness is less than a cer- methane as reference. The absorption peak of steam at 7306.7 tain amount, for example, the sample may have to be placed on cm-1 can be used with a Fourier transformation-type spectro- a support plate with high reflectance to take measurements by photometer, as its wave number resolution ability is high. the transmittance reflectance method. Other substances can also be used as reference, so long as 3.4 Fill condition of sample their adequacy for the purpose can be verified. The condition of sample fill can potentially affect spectrum, 4.2 Spectroscopic linearity when taking measurements of samples that are solids or fine Appropriate standard plates, such as plate-shaped polymer particles. Care must be taken when filling samples in a cell, to impregnated with varying concentrations of carbon (car- ensure that a certain amount is filled through a specific proce- bon-doped polymer standards), can be used to evaluate spectro- dure. scopic linearity. In order to verify linearity, however, standard 3.5 Optical characteristics of samples plates with no less than 4 levels of concentration within the re- When a sample is physically, chemically or optically uneven, flectance of 10 – 90% must be used. When measurements are relatively large beam size must be used, multiple samples must expected to be taken with absorbance of no less than 1.0, it is be used, measurements must be taken at multiple points on the necessary to add standard plates with reflectance of either 2% or same sample, or a sample must be pulverized to ensure averag- 5% or both. ing of the sample. Grain size, fill condition, as well as roughness In order to plot absorbance (AOBS) of such standard plates at of surface can also affect fine particle samples. locations in the vicinity of wavelengths 1200 nm, 1600 nm and

3.6 Crystal forms 2000 nm against absorbance (AREF) assigned to each standard Variations in crystal structures (crystal forms) can also affect plate, verifications must be made to ensure that the gradient of spectrum linearity obtained are within the range 1.0±0.05 for each of In cases where multiple crystal forms exist, it is necessary to these wavelengths and 0±0.05 for ordinate intercept. have consideration for characteristics of samples to be consid- 4.3 Spectrophotometric noise ered and care must be taken to ensure that even standard sam- The spectrophotometric noise of the equipment can be ples for calibration curve method have diversified distributions checked using appropriate reflectance standard plates, such as similar to that of samples that are subject to analysis. white-colored reflecting ceramic tiles or reflective thermoplastic 3.7 Temporal changes in characteristics of samples resin (such as polytetrafluoroethylene). Samples can potentially undergo chemical, physical or optical 4.3.1 High flux noise property changes, due to passing of time or storage after sam- Spectrophotometric noise is evaluated by using standard pling, and such changes affect spectrum in a subtle manner. For plates with high reflectance, such as reflectance of 99%. Stan- instance even with identical samples, if elapsed times differ, dard plates are used to take measurements for both samples and then their characteristics of near-infrared spectrum can vary sig- control samples. The average value obtained from calculation of nificantly. In creating calibration curves, therefore, measure- mean square root (RMS) of noise for each 100 nm segments in ments must be taken offline in a laboratory or online in manu- the wavelength range of 1200 – 2200 nm must not be more than facturing process (or inline) and samples for calibration curves 0.3 x 10-3 and individual values must not exceed 0.8 x 10-3. must be prepared with adequate considerations for the passing 2 1 / 2 of time before measurements are taken. RMS = {1 / N • Σ (Ai - Am) }

2, 3) 4 Control of equipment performance N: Number of measurement points per segment 4.1 Accuracy of wavelengths (wave numbers) Ai: Absorbance at each measurement point of segment The accuracy of wavelengths (wave numbers) of an equip- Am: Average absorbance for segment ment is derived from the deviation of substances for which peak absorption wavelengths (wave numbers) have been defined, 4.3.2 Low flux noise such as polystyrene, mixture of rare earth oxides (dysprosium, Spectrophotometric noise is evaluated by using standard holmium and erbium; 1:1:1) or steam, from the figures indicated plates with low reflectance, such as reflectance of 10%, when on the equipment. Tolerance figures in the vicinity of 3 peaks the amount of light is low. In such cases, light source, optical are ordinarily set in the following manner: system, detector and electronic circuit systems all have some 1200 ± 1 nm (8300 ± 8 cm-1) impact on noise. Similar to the cases of high flux noise, the av- 1600 ± 1 nm (6250 ± 4 cm-1) erage value obtained from calculation of RMS for each 100 nm 2000 ± 1.5 nm (5000 ± 4 cm-1) segments in the wavelength range of 1200 – 2200 nm must not Since the location of absorption peaks vary, depending on the be more than 1.0 x 10-3 and individual values must not exceed substance used as reference, absorption peaks of wavelengths 2.0 x 10-3. (wave numbers) that are closest to the above 3 peaks are selected for suitability evaluations. A mixture of rare earth oxides, 5. Application to qualitative or quantitative analysis for instance, would indicate characteristic absorption peaks at Unlike in the infrared range, mainly harmonic overtones and 1261 nm, 1681 nm and 1971 nm. combinations manifest as spectrum in the near-infrared range. Absorption peaks at 1155 nm, 1417 nm, 1649 nm, 2352 nm Such absorbance spectrums are often observed as overlay of

Supplement II, JP XV General Information 2287 absorption bands of functional groups and atomic groups. The tions as variables, such as wavelength correlation method, re- near-infrared spectrometry, therefore, differs from conventional sidual sum of squares, range sum of squares, along with factor analysis methods and it is usually necessary to establish analysis analysis method, cluster analysis method, discriminant analysis methods that correspond to each application, by preparing method, as well as SIMCA (soft independent modeling of class model analysis methods using methodologies of chemometrics, analogy). such as multivariate analysis. It is also possible to consider the overall near-infrared absorp- Characteristics of near-infrared absorption spectrum must be tion spectrum as a single pattern and to identify parameters ob- emphasized and effects of complexities of spectrums, as well as tained by applying multivariate analysis methods or characteris- overlay of absorption bands must be reduced by performing tic wavelength (wave number) peaks of the sample substance as mathematical preprocesses, such as primary or secondary spec- indices for monitoring, for the purpose of manufacturing proc- tral differentiation processes or normalizations, which becomes ess control for active substances or preparations. one of vital procedures in establishing analysis methods that use 5.2 Quantitative analysis methodologies of chemometrics. While there are many Quantitative analysis uses spectrums of sample groups and chemometrics methodologies and mathematical preprocessing analysis values obtained through the existing and established methods for data, appropriate combinations must be selected analysis methods, to obtain quantitative models with method- that suit the purposes of intended analysis. ologies of chemometrics. These are used to calculate concentra- Evaluation of validity based on analysis parameters is ordi- tions of individual ingredients and material values of samples narily required for the analysis validation when establishing a being measured, using conversion formulas. Chemometrics near-infrared analysis method. Selection of parameters that are methodologies for obtaining quantitative models include multi- appropriate for applications must be made for its intended use. ple regression analysis method, main ingredient regression Furthermore, following issues must be considered, in confor- analysis method and PLS (partial least squares) regression mity with attributes of the near-infrared spectrometry. analysis method. (i) Whether or not wavelengths (wave numbers) intended In cases where the composition of a sample is simple, confor the particular analysis method, are suitable for evaluation of centrations of ingredients in the sample that are subject to characteristics of a sample in performing analysis under given analysis can be calculated, by plotting a calibration curve using conditions. the absorbance of a specific wavelength (wave number) or the (ii) Whether or not the method is adequately robust to deal correlating relationship between the parameters and concentra- with variables such as handling of samples (for instance fill tion, using samples for preparation of calibration curves with condition for fine particle samples, etc.) and configuration ma- known concentrations (calibration curve method). trix. (iii) Whether or not about the same level of accuracy or Reference precision can be obtained, in comparison with the existing and 1) General Rules for Near-infrared Spectrophotometric established analysis methods, which are available as standards. Analysis, JIS K 0134 (2002), Japanese Industrial Standards (iv) Sustaining and managing performance of an analysis 2) Near-infrared Spectrophotometry, 2.2.40, European Phar- method, once established, are critical. Continuous and system- macopoeia 5.0 (2005) atic maintenance and inspection work must therefore be imple- 3) Near-infrared Spectrophotometry, <1119>, US Pharmaco- mented. Furthermore, it must be determined whether or not ap- poeia 30 (2007) propriate evaluation procedures are available to deal with change controls or implementation of re-validation on changes made in manufacturing processes or raw materials, as well as Add the following: changes arising from replacement of major components in equipment. 33. Rapid counting of microbes (v) Whether or not there are appropriate evaluation procedures in place to verify validity of transferring implementation using fluorescent staining of an analysis, which presupposes the use of a specific equipment, from such originally intended equipment to another This chapter provides rapid methods using fluorescence equipment (model transfer) for the purpose of sharing the analy- staining for the quantitative estimation of viable microorgan- sis method. isms. Incubation on an agar medium has been widely used for 5.1 Qualitative analysis quantitative estimation of viable microorganisms, but a number Qualitative analysis, such as verification of substances, is of environmental microorganisms of interest are not easy to performed after preparing a reference library that includes in- grow in culture under usual conditions, thus new microbial deter-lot variations within tolerance range and chemometrics tection methods based on fluorescence or luminescence have methodologies, such as multivariate analysis, have been estab- been developed. In the fluorescence staining method, microor- lished. Minute quality characteristic variations between lots can ganisms are stained with fluorescent dye, and can easily be de- also be estimated by using this method. tected and counted with various sorts of apparatus, such as a Furthermore, multivariate analysis includes direct analysis fluorescence microscope or flow cytometer. Methods are avail- methods that consider wavelengths (wave numbers) and absorp- able to detect total microorganisms, including both dead and viable cells, or to detect only cells with a specified bioactivity

2288 General Information Supplement II, JP XV by choosing the dye reagent appropriately. Nucleic acid staining (ii) Membrane filters (poresize: 0.2 µm); A suitable filter that reagents, which bind with DNA or RNA, detect all cells con- can trap particles on the surface can be used such as polycar- taining nucleic acids, whether they are live or dead. This tech- bonate filter, alumina filter, etc. nique is the most fundamental for the fluorescence staining (iii) Glass slide method. On the other hand, fluorescent vital staining methods (iv) Cover glass target the respiratory activity of the microorganism and the ac- (v) Ocular micrometer for counting (with 10 x 10 grids) tivity of esterase, which is present universally in microorgan- 1.3 Procedure isms. In the microcolony method, microcolonies in the early An example of the procedure using fluorescence microscope is stage of colony formation are counted. The CFDADAPI double described below. staining method and the microcolony method are described be- 1.3.1 Preparation of samples low. These methods can give higher counts than the other tech- Prepare samples by ensuring that microbes are dispersed evenly niques, because these rapid and accurate techniques provide in the liquid (water or buffer solution). quantitative estimation of viable microorganisms based on a 1.3.2 Filtration very specific definition of viability, which may be different Set a membrane filter (poresize: 0.2 µm) on the funnel of the from that implicit in other methods. The procedures of these filtering equipment. Filter an appropriate amount of sample to methods described here may be changed as experience with the trap microbes in the sample on the filter. methods is accumulated. Therefore, other reagents, instruments 1.3.3 Staining and apparatus than those described here may also be used if Pour sufficient amount of buffer solution for CFDA staining, there is a valid reason for so doing. mixed to provide final concentration of 150 µg/mL of CFDA and 1 µg/mL of DAPI, into the funnel of the filtering equipment 1. CFDADAPI double staining method and allow staining in room temperature for 3 minutes, then filter Fluorescein diacetate (FDA) reagents are generally used for the liquid by suction. Pour in sufficient amount of aseptic water, the detection of microorganisms possessing esterase activity. suction filter and remove excess fluorescent reagent left on the These reagents are hydrolyzed by intracellular esterase, and the filter. Thoroughly dry the filter. hydrolyzed dye exhibits green fluorescence under blue excita- 1.3.4 Slide preparation tion light (about 490 nm). Modified FDAs such as carboxyfluo- Put one drop of immersion oil for fluorescence microscope on rescein diacetate (CFDA) are used because of the low stainabil- the glass slide. Place the air dried filter over it, with the filtering ity of gramnegative bacteria with FDA. The principle of the side on the top. Then put one drop of immersion oil for fluores- CFDADAPI double staining method, which also employs a nu- cence microscope on the surface of the filter, place a cover glass. cleic acid staining reagent, 4´,6-diamidino-2-phenylindole Put another drop of immersion oil for fluorescence microscope (DAPI), is as follows. on the cover glass when using an oilimmersion objective lens. The nonpolar CFDA penetrates into the cells and is hydro- 1.3.5 Counting lyzed to fluorescent carboxyfluorescein by intracellular esterase. Observe and count under fluorescence microscope, with 1000 The carboxyfluorescein is accumulated in the living cells due to magnification. In case of CFDADAPI double staining method, its polarity, and therefore green fluorescence due to carboxy- count the microorganisms (with esterase activity) exhibiting fluorescein occurs when cells possessing esterase activity are green fluorescence under the blue excitation light first to avoid illuminated with blue excitation light. No fluorescent carboxy- color fading by the ultraviolet light, then count the microorgan- fluorescein is produced with dead cells, since they are unable to isms (with DNA) exhibiting blue fluorescence under the ultra- hydrolyze CFDA. On the other hand, DAPI binds preferentially violet excitation light in the same microscopic field. Count the to the adenine and thymine of DNA after penetration into both organisms exhibiting fluorescence on more than 20 randomly viable and dead microorganisms, and consequently all of the selected fields among 100 grids observed through an ocular mi- organisms containing DNA exhibit blue fluorescence under ul- crometer of the microscope, and calculate the total number of traviolet excitation light. Therefore, this double staining method organisms using the following formula. The area of the micro- enables to count specifically only live microorganisms possess- scopic field should be previously determined with the ocular ing esterase activity under blue excitation light, and also to de- and objective micrometers. The amount of the sample to be fil- termine the total microbial count (viable and dead microorgan- tered must be adjusted so that the cell number per field is be- isms) under ultraviolet excitation light. tween 10 and 100. It might be necessary to reprepare the sample 1.1 Apparatus in certain instances. (In such case that the average count number 1.1.1 Fluorescence microscope or fluorescence observation is not more than 2 organisms per field, or where more than 5 apparatus . Various types of apparatus for counting fluores- fields are found which have no organism per field, it is assumed cencestained microorganisms are available. Appropriate filters that the microorganism count is below the detection limit.). are provided, depending on the fluorescent dye reagents used. A fluorescence microscope, laser microscope, flow cytometer, and Number of microbes (cells/mL) various other types of apparatus may be used for fluorescence = {(average number of microbes per visual field) x (area of observation. filtration)} / {( amount (mL) of sample filtered) x ( area of 1.2 Instruments one microscopic field)} (i) Filtering equipment (funnels, suction flasks, suction pumps) 1.4 Reagents and test solutions

Supplement II, JP XV General Information 2289

(i) Aseptic water in the liquid (water or buffer solution). Filter water through a membrane filter with 0.2 µm pore size to 2.3.2 Filtration remove particles, then sterilize it by heating in an autoclave at Set a membrane filter (pore size: 0.2 µm)on the funnel of the 121ºC for 15 minutes. Water for injection may be used. filtering equipment. Filter an appropriate amount of sample to (ii) CFDA solution, 10 mg/mL trap microbes in the sample on the filter. Dissolve 50 mg of CFDA in dimethylsulfoxide to prepare a 5 2.3.3 Incubation mL solution. Store at -20°C in light shielded condition. Remove the filter from the filtering equipment and place it (iii) Buffer solution for CFDA staining with filtering side facing up on a culture medium avoiding for- Mix 5 g of sodium chloride with 0.5 mL of 0.1 mol/L ethyl- mation of airbubbles between the filter and the medium. Incu- enediaminetetraacetic aciddisodium dihydrogen test solution bate at a suitable temperature for appropriate hours in a dark and diluted disodium hydrogen phosphate test solution (1 in 3) place. It should be noted that the appropriate incubation condi- to prepare 100 mL of solution. Add sodium dihydrogen phos- tions (such as medium, incubation temperature and/or incuba- phate dihydrate solution (1 in 64) to adjust the pH level to 8.5. tion time) are different, depending on the sample. Filter the solution through a membrane filter with a pore size of 2.3.4 Fixation 0.2 µm. Soak filter paper with an appropriate amount of neutral buff- (iv) DAPI solution, 10 µg/mL ered formaldehyde test solution, then place the filter that has Dissolve 10 gm of DAPI in 100 mL of aseptic water. Dilute been removed from the culture medium on top with filtering this solution 10 times with aseptic water and filter through a side up, and allow to remain at room temperature for more than membrane filter with a pore size of 0.2 µm. Store at 4°C in light 30 minutes to fix the microcolonies. shielded condition. 2.3.5 Staining (v) Immersion oil for fluorescence microscope Soak filter paper with an appropriate amount of staining solution (such as1 µg/mL of DAPI, 2% polyoxyethylenesorbitan 2. Microcolony method monolaurate), then place the filter on top with filtering side up, Microcolonies, which are in early stages of colony formation, and then leave at room temperature, light shielded for 10 min- are fluorescently stained, then observed and counted under utes to stain microcolonies. Wash the filter by placing it with the fluorescence microscope or other suitable systems. This method filtering side facing up on top of a filter paper soaked with asep- enables to count the number of proliferative microorganisms, tic water for 1 minute. Thoroughly air dry the filter. with short incubation time. In this method, the organisms are 2.3.6 Slide preparation trapped on a membrane filter, the filter is incubated on a me- Put one drop of immersion oil for fluorescence microscope on dium for a short time, and the microcolonies are counted. By the slide glass. Place an air dried filter over it, with the filtering this method, even colonies which are undetectable with the na- side on the top. Then, put one drop of immersion oil for fluo- ked eye can be identified, so viable organisms can be counted rescence microscope on top, place a cover glass. rapidly and with high precision. 2.3.7 Counting Various nucleic acid staining reagents can be used for staining Count the organisms exhibiting fluorescence on more than 20 of microcolonies. randomly selected fields among the 100 grids observed through 2.1 Apparatus an ocular micrometer of the microscope, and calculate the total 2.1.1 Fluorescence microscope or fluorescence observation number of organisms using the following formula. The area of apparatus. the microscopic field should be previously determined with the Various types of apparatus for counting fluorescencestained ocular and objective micrometers. microorganisms are available. Appropriate filters are provided, (In such case that the average count number is not more than 2 depending on the fluorescence dye reagents used. A fluores- microcolonies per field, or where more than 5 fields are found cence microscope, laser microscope and various other types of which have no microcolony per field, it is assumed that the mi- apparatus may be used for fluorescence observation. croorganism count is below the detection limit.). 2.2 Instruments (i) Filtering equipment (funnels, suction flasks, suction Number of microcolonies (cells/mL) pumps) = {(average number of microcolonies per visual field) x (area (ii) Membrane filters (pore size: 0.2 µm); A suitable filter that of filtration)} / {( amount (mL) of sample filtered) x (area of can trap particles on the surface can be used such as polycar- one microscopic field)} bonate filter, alumina filter, etc. (iii) Glass slide 2.4 Reagents and test solutions (iv) Cover glass (i) Aseptic water (v) Filter paper (No. 2) Filter water through a membrane filter with 0.2 µm pore size (vi) Ocular micrometer for counting (with 10 x 10 grids) to remove particles, and sterilize it by heating in an autoclave at 2.3 Procedure 121ºC for 15 minutes. Water for injection may be used. An example of the procedure using a fluorescence micro- (ii) Staining solution scope is described below. Dissolve 10 gm of DAPI in 100 mL of aseptic water. Dilute 2.3.1 Preparation of samples the solution 10 times with aseptic water and filter through a Prepare samples by ensuring that microbes are dispersed evenly membrane filter with pore size of 0.2 µm. Store at 4°C in light

2290 General Information Supplement II, JP XV shielded condition. Dissolve polyoxyethylene sorbitan (1) Allowable limit of system repeatability monolaurate to the final concentration of 2%, when using. It is described in the section of system suitability in “Liquid (iii) Neutral buffered formaldehyde solution (4w/v% formal- Chromatography” that “In principle, total number of replicate dehyde solution; neutrally buffered). injections should be 6.”, and “The allowable limit of “System (iv) Immersion oil for fluorescence microscope repeatability” should be set at an appropriate level based on the data when suitability of the method for the evaluation of quality of the drug was verified, and the precision necessary for the quality test.” 34. System Suitability Based on the above description, an allowable limit of system repeatability for 6 replicate injections should be set in consid- In order to ensure the reliability on the results of drug analy- eration with the following descriptions. However, in the case ses, it is essential to verify that the test method to be applied to that the test method prescribed in the JP monograph is used for the test, including the method prescribed in the Japanese Phar- the test, the allowable limit of system repeatability prescribed in macopoeia (JP), can give the results adequate for its intended the monograph should be applied. use using the analytical system in the laboratory in which the test is to be performed, then to carry out system suitability test- Assay for drug substance (for drug substance with the con- ing for confirming that the analytical system maintains the state tent nearby 100%): An adequate allowable limit should be suitable for the quality test. set at the level that the chromatographic system is able to

give the precision suitable for the evaluation of variation in 1. Definition and role of system suitability the content of active ingredient within and among the “System Suitability” is the concept for ensuring that the per- batches of drug substance. For example, the allowable formance of the analytical system is as suitable for the analysis limit of “not more than 1.0%” is usually recommended for of the drug as was at the time when the verification of the test the drug substances whose width of content specification method was performed using the system. are not more than 5%, as is in the case of content specifi- Usually, system suitability testing should be carried out at cation of 98.0-102.0% which is often observed in the assay every series of drug analysis. The test procedures and accep- using liquid chromatography. tance criteria of system suitability testing must be prescribed in Assay for drug products: An adequate allowable limit should the test methods of drugs. The results of drug analyses are not be set considering the width of content specification of the acceptable unless the requirements of system suitability have drug product and the allowable limit prescribed in the as- been met. say of drug substance (when the drug product is analyzed System suitability testing is an integral part of test methods by a method with the same chromatographic conditions as using analytical instruments, and based on the concept that the those used for the analysis of drug substance). equipments, electronic data processing systems, analytical op- Purity test for related substances: An adequate allowable erations, samples to be analyzed and operators constitute an in- limit should be set considering the concentration of active tegral system that can be evaluated, when the test procedures ingredients in the solution used for the system suitability and acceptance criteria of system suitability testing are pre- testing. In the case that a solution with active ingredient scribed in the test methods. concentration of 0.5-1.0% is used for the test of system

repeatability, an allowable limit of “not more than 2.0%” is 2. Points to consider in setting system suitability usually recommended. Parameters of system suitability testing to be prescribed in the test method depend on the intended use and type of analytical Recommendations for allowable limits described above method. Since system suitability testing is to be carried out in a should not be applicable to gas chromatography. routine manner, it is preferable to select the parameters necessary for ensuring that the analytical system maintains the state (2) Method for decreasing the number of replicate injec- suitable for the analysis of the drug and to prescribe its test pro- tions without losing the quality of system repeatability test- cedure able to carry out easily and rapidly. ing For example, in the case of quantitative purity tests using liq- It is described in the section of system suitability in “Liquid uid chromatography or gas chromatography, the evaluation of Chromatography” that “In principle, total number of replicate parameters such as “System performance” (to confirm the abil- injections should be 6. However, in the case that a long time is ity to analyze target substance specifically), “System repeatabil- necessary for one analysis, such as the analysis using the gradi- ity” (to confirm that the degree of variation in the analytical re- ent method, or the analysis of samples containing late eluting sults of target substance in replicate injections is within the al- components, it may be acceptable to decrease the number of lowable limit) and “Test for required detectability” (to confirm replicate injections by adopting new allowable limit of “System the linearity of chromatographic response around the specifica- repeatability” which can guarantee a level of “System repeat- tion limit) are usually required. ability” equivalent to that at 6 replicate injections.” The followings are supplements to the section of system In consideration of the above description, a method for de- suitability prescribed in “Liquid Chromatography”. creasing the number of replicate injections without losing the

Supplement II, JP XV General Information 2291 quality of system repeatability testing is adopted. One can set of test equivalent to that of test at n=6. the test for system repeatability with reduced number of repli- However, it should be kept in mind that since decrease in the cate injections by utilizing this method, if necessary, and can number of replicate injections results in increase in the weight also apply it as an alternative for the method prescribed in a of each injection, it becomes more important to perform the test monograph. by the experienced operator, and to maintain the equipment in a The following table shows the allowable limits to be attained suitable state. in the test at 3-5 replicate injections (n=3-5) to keep the quality

Table Allowable limits to be attained in the test at 3-5 replicate injections (n=3-5) to keep the quality of test equivalent to that of test at n=6 * Allowable limit (RSD) Allowable limit prescribed in the test 1% 2% 3% 4% 5% 10% of n=6 n=5 0.88% 1.76% 2.64% 3.52% 4.40% 8.81% Allowable limit to n=4 0.72% 1.43% 2.15% 2.86% 3.58% 7.16% be attained n=3 0.47% 0.95% 1.42% 1.89% 2.37% 4.73% * The probability for inadequate analytical systems to meet the requirements of system suitability testing, is supposed to be 5%.

3. Points to consider at the change of analytical system 35. Powder Fineness (Change control of analytical system) When the test method and analytical system verified is con- This classification is harmonized with the European Pharma- tinuously used for the quality test without any change, it is suf- copoeia and the U.S. Pharmacopoeia. ficient to confirm the compliance to the requirements of system A simple descriptive classification of powder fineness is pro- suitability at every series of drug analysis. vided in this chapter. Sieving is most suitable where a majority However, when the test is performed for a long period, a of the particles are larger than about 75 µm, although it can be situation in which some changes in the analytical system are in- used for some powders having smaller particle sizes where the evitable, may occur. These changes don’t affect the quality of meth——od can be validated. Light diffraction is also a widely the product itself, but they affect the scale in the evaluation of used technique for measuring the size of a wide range of parti- product quality. If the change in the analytical system may in- cles. duce a significant deviation of the scale, it may lead to the ac- Where the cumulative distribution has been determined by ceptance of products with inadequate quality and/or the rejec- analytical sieving or by application of other methods, particle tion of products with adequate quality. Thus, at the time of size may be characterized in the following manner: change in the analytical system, it is necessary to check whether the change is appropriate or not, to avoid the deviation of the x90: particle size corresponding to 90% of the cumulative un- scale in the evaluation of product quality. dersize distribution

In the case of the change of test method, it is required to per- x50: median particle size (ie: 50% of the particles are smaller form an adequate validation depending on the extent of the and 50% of the particles are larger) change. x10: particle size corresponding to 10% of the cumulative un- On the other hand, in the case of the change of analytical sys- dersize distribution tem in a laboratory, such as renewal of apparatus or column of liquid chromatography, and the change of operator, it is neces- It is recognized that the symbol d is also widely used to des- sary to perform at least system suitability testing using the sys- ignate these values. Therefore, the symbols d90, d50, d10 may be tem after change, and to confirm that the equivalency of the re- used. sults before and after change. The following parameters may be defined based on the cu- In the case that equivalent results would not be obtained after mulative distribution. change, for example, when a renewal of column of liquid chro- Qr(x): cumulative distribution of particles with a dimension less matograph may induce a significant change of elution pattern, than or equal to x where the subscript r reflects the distribution such as the reversal of elution order between target ingredient of type the test and substance for checking resolution, it is required to perform a revalidation of the analytical system for the test using new column, since it is uncertain whether the specificity and/or other validation characteristics necessary for estimating target ingredient is kept or not.

2292 General Information Supplement II, JP XV

Qr(x) = 0.90 when x = x90 r Distribution Type Qr(x) = 0.50 when x = x50 0 Number Qr(x) = 0.10 when x = x10 1 Length An alternative but less informative method of classifying pow- 2 Area der fineness is by use of the descriptive terms in the following 3 Volume table.

Therefore, by definition:

Classification of Powders by Fineness

Descriptive Term x50 (µm) Cumulative Distribution by volume basis, Q3(x)

Coarse >355 Q3(355) <0.50

Moderately Fine 180 – 355 Q3(180) <0.50 and Q3(355) ≥0.50

Fine 125 – 180 Q3(125) <0.50 and Q3(180) ≥0.50

Very Fine ≤125 Q3(125) ≥0.50

INDEX

Page citations refer to the pages of the Supplement II, to the pages of the Supple- ment I, and to the pages of the JP XV main volume, including those where the text being revised in the Supplements originally appeared. This Supplement II com- mences with page 2041 and succeeding Supplements will continue to be paged in sequence.

1 - 1788 Main Volume of JP XV 1789 - 2040 Supplement I 2041 - 2322 Supplement II

Powdered, 1253 Amikacin Sulfate, 296 A Ajmaline, 278 Injection, 1830 Tablets, 279, 1826 Aminoacetic Acid, 704 Absorptive Ointment, 265 Akebia Stem, 1253 Aminobenzylpenicillin, 307 Acacia, 1251 Alacepril, 279 Anhydrous, 306 Powdered, 1251 Tablets, 280 Hydrate, 307 Acebutolol Hydrochloride, 265 L-Alanine, 2076 Sodium, 308 Aceglutamide Aluminum, 266 Albumin Tannate, 282 Aminophylline Acemetacin, 1825 Alcohol, 638 Hydrate, 297 Capsules, 2073 Dehydrated, 639 Injection, 297, 1831, 2079 Tablets, 2074 for Disinfection, 640 Amiodarone Hydrochloride, 2079 Acetaminophen, 267 Aldioxa, 282 Tablets, 2081 Acetazolamide, 268 Alimemazine Tartrate, 283 Amitriptyline Hydrochloride, 298 Acetic Acid, 268 Alisma Rhizome, 1253 Tablets, 299, 1831 Glacial, 269 Powdered, 1253 Amlexanox, 1831 Acetohexamide, 269 Allopurinol, 284 Tablets, 1833 Acetylcholine Chloride for Injection, Tablets, 2078 Amlodipine Besilate, 1834 271, 1825 Alminoprofen, 1826 Tablets, 2082 Acetylsalicylic Acid, 318 Tablets, 1827 Ammonia Water, 299 Tablets, 319 Aloe, 1254 Amobarbital, 300 Achyranthes Root, 1252 Powdered, 1255 Sodium for Injection, 300 Aciclovir, 2075 Alpinia Officinarum Rhizome, 1256, Amomum Seed, 1256 Aclarubicin Hydrochloride, 272 1937 Powdered, 1256 Acrinol Alprazolam, 284 Amorphous Insulin Zinc Injection and Zinc Oxide Oil, 273 Alprenolol Hydrochloride, 285 (Aqueous Suspension), 764 and Zinc Oxide Ointment, 274 Alprostadil, 286 Amosulalol Hydrochloride, 1835 Hydrate, 274 Alfadex, 287 Tablets, 1836 Actinomycin D, 275 Injection, 1828 Amoxapine, 301 Adrenaline, 276 Alum, 292 Amoxicillin Injection, 276 Solution, 293 Capsules, 2083 Solution, 277 Aluminum Hydrate, 302, 2085 Adsorbed Acetylsalicylate, 319 Amphotericin B, 303 Diphtheria-Purified Pertussis-Tetanus Hydroxide Gel, Dried, 288 for Injection, 304 Combined Vaccine, 596 Hydroxide Gel Fine Granules, Dried, Syrup, 305 Diphtheria-Tetanus Combined Toxoid, 289, 2079 Tablets, 305 596 Monostearate, 291 Ampicillin Diphtheria Toxoid for Adult Use, Potassium Sulfate, Dried, 292 Anhydrous, 306 596 Potassium Sulfate Hydrate, 292 Ethoxycarbonyloxyethyl Hydrochlo- Habu-venom Toxoid, 716 Silicate, Natural, 289 ride, 329 Hepatitis B Vaccine, 716 Silicate, Synthetic, 290 Hydrate, 307 Purified Pertussis Vaccine, 980 Sucrose Sulfate Ester, 1118 Sodium, 308 Tetanus Toxoid, 1156 Amantadine Hydrochloride, 293 Sodium for Injection, 1838 Afloqualone, 277 Ambenonium Chloride, 294 Ampicillinphthalidyl Hydrochloride, Agar, 1252 Amidotrizoic Acid, 295 1138 2293 2294 Index Supplement II, JP XV

Amyl Nitrite, 309 B Biperiden Hydrochloride, 366 Anemarrhena Rhizome, 1256, 1937 Bisacodyl, 367 Anesthamine, 644 Bacampicillin Hydrochloride, 329 Suppositories, 368, 1843 Anesthetic Ether, 641 Bacitracin, 330 Bismuth Angelica Dahurica Root, 1257, 1937 Baclofen, 331 Subgallate, 368 Anhydrous Tablets, 332, 1841 Subnitrate, 369 Aminobenzylpenicillin, 306 Bamethan Sulfate, 333 Bisoprolol Fumarate, 1843 Ampicillin, 306 Barbital, 333 Tablets, 1844 Caffeine, 386 Barium Sulfate, 334 Bitter Citric Acid, 514 Bear Bile, 1262, 2219 Cardamon, 1265 Dibasic Calcium Phosphate, 396, Bearberry Leaf, 1262 Orange Peel, 1265 1874 Beclometasone Dipropionate, 335 Tincture, 1266 Ethanol, 639 Beef Tallow, 336 Bleomycin Lactose, 802, 1900 Beeswax Hydrochloride, 370 Antipyrine, 310 White, 336 Sulfate, 372 Apricot Kernel, 1257, 1937, 2219 Yellow, 336 Boric Acid, 374 Water, 1257 Bekanamycin Sulfate, 337 Bromazepam, 374 Aprindine Hydrochloride, 2085 Belladonna Bromhexine Hydrochloride, 375 Capsules, 2086 Extract, 1263, 1939 Bromocriptine Mesilate, 376 Aralia Rhizome, 1937 Root, 1263 Bromovalerylurea, 377 Arbekacin Sulfate, 311 Benidipine Hydrochloride, 338 Bucillamine, 377 Injection, 312 Tablets, 339 Tablets, 1845 Areca, 1258 Benincasa Seed, 1264 Bucumolol Hydrochloride, 378 Argatroban Hydrate, 2087 Benoxinate Hydrochloride, 951 Bufetolol Hydrochloride, 379 L-Arginine, 313 Benserazide Hydrochloride, 340 Bufexamac, 380 Hydrochloride, 313 Bentonite, 341 Cream, 380 Hydrochloride Injection, 314, 1839 Benzalkonium Chloride, 342 Ointment, 381 Aromatic Castor Oil, 415 Concentrated Solution 50, 343 Buformin Hydrochloride, 1846 Arotinolol Hydrochloride, 314 Solution, 342 Enteric-coated Tablets, 1847 Arsenical Paste, 315 Benzbromarone, 343 Tablets, 1849 Arsenic Trioxide, 316 Benzethonium Chloride, 344 Bumetanide, 382 Arsenous Acid, 316 Solution, 345 Bunazosin Hydrochloride, 383 Artemisia Capillaris Flower, 1258 Benzocaine, 644 Bupleurum Root, 1266, 2220 Ascorbic Acid, 316 Benzoic Acid, 345 Bupranolol Hydrochloride, 383 Injection, 317, 1839 Benzoin, 1265 Buprenorphine Hydrochloride, 1850 Powder, 317 Benzyl Burdock Fruit, 1267 Asiasarum Root, 1259, 1938 Alcohol, 346 Burnt Alum, 292 Asparagus Tuber, 1259, 1938 Benzoate, 347 Busulfan, 384 L-Aspartic Acid, 318 Benzylpenicillin Butropium Bromide, 385 Aspirin, 318 Benzathine Hydrate, 348 Butyl Parahydroxybenzoate, 386 Aluminum, 319 Potassium, 349 Tablets, 319 Potassium for Injection, 1841 C Aspoxicillin Hydrate, 320 Berberine Astragalus Root, 1260, 2219 Chloride Hydrate, 351 Cacao Butter, 386 Astromicin Sulfate, 322 Tannate, 352 Cadralazine, 2091 Atenolol, 323 Betahistine Mesilate, 353, 1842 Tablets, 2092 Atractylodes Tablets, 354 Caffeine Lancea Rhizome, 1260 Betamethasone, 355 and Sodium Benzoate, 388 Lancea Rhizome, Powdered, 1260 Dipropionate, 358 Anhydrous, 386 Rhizome, 1261, 1938 Sodium Phosphate, 359 Hydrate, 387 Rhizome, Powdered, 1261, 1939 Tablets, 356, 2090 Calciferol, 624 Atropine Sulfate Valerate, 360 Calcitonin (Salmon), 2093 Hydrate, 324 Valerate and Gentamicin Sulfate Calcium Injection, 324 Cream, 361 Carbonate, Precipitated, 389 Azathioprine, 325 Valerate and Gentamicin Sulfate Chloride Hydrate, 390 Tablets, 326, 2088 Ointment, 362 Chloride Injection, 390, 1851 Azelastine Hydrochloride, 1839 Bethanechol Chloride, 363 Folinate, 391, 1851 Granules, 2089 Betaxolol Hydrochloride, 2090 Gluconate Hydrate, 391 Azithromycin Hydrate, 327 Bezafibrate, 364 Hydroxide, 392 Aztreonam, 328 Sustained Release Tablets, 365 Lactate Hydrate, 393 for Injection, 1840 Bifonazole, 366 Leucovorin, 391 Biotin, 1842 Oxide, 393

Supplement II, JP XV Index 2295

Pantothenate, 394 Calcium, 409, 2097 Cefpodoxime Proxetil, 461 Paraaminosalicylate Granules, 394 Sodium, 410, 2097 Cefroxadine Paraaminosalicylate Hydrate, 395 Carmofur, 411 for Syrup, 2103 Polystyrene Sulfonate, 398 Carnauba Wax, 411 Hydrate, 462 Stearate, 400 Carteolol Hydrochloride, 412 Cefsulodin Sodium, 464 Calumba, 1267, 1939, 2220 Carumonam Sodium, 412 Ceftazidime Powdered, 1268, 1939, 2220 Cassia Seed, 1271 for Injection, 1856 Camellia Oil, 400 Castor Oil, 414 Hydrate, 466 Camostat Mesilate, 400, 1852 Aromatic, 415 Cefteram Pivoxil, 468 d-Camphor, 401 Catalpa Fruit, 1271 Fine Granules, 469 dl-Camphor, 402 Cefaclor, 415 Tablets, 2104 Capsicum, 1268 Capsules, 416 Ceftibuten Hydrate, 470 and Salicylic Acid Spirit, 1270 Compound Granules, 419, 2097 Ceftizoxime Sodium, 471 Powdered, 1269 Fine Granules, 417 Ceftriaxone Sodium Hydrate, 472 Tincture, 1269 Cefadroxil, 421 Cefuroxime Capsules, 403 Capsules, 1852 Axetil, 474 Capsules for Syrup, 1853 Sodium, 476 Acemetacin, 2073 Cefalexin, 422 Cellacefate, 480, 2105 Amoxicillin, 2083 Cefalotin Sodium, 423, 1854 Cellulose Aprindine Hydrochloride, 2086 Cefapirin Sodium, 424 Microcrystalline, 477, 2105 Cefaclor, 416 Cefatrizine Propylene Glycolate, 425, Powdered, 480, 2105 Cefadroxil, 1852 1854 Celmoleukin (Genetical Recombination), Cefalexin, 2098 Cefazolin Sodium, 426 481 Cefdinir, 435 for Injection, 1854 Cetanol, 484 Cefixime, 2101 Hydrate, 428 Cetirizine Hydrochloride, 1856 Cinoxacin, 2106 Cefbuperazone Sodium, 429 Tablets, 1857 Clindamycin Hydrochloride, 520, Cefcapene Pivoxil Hydrochloride Cetraxate Hydrochloride, 485 2018 Fine Granules, 432 Chenodeoxycholic Acid, 486 Clofibrate, 526 Hydrate, 430 Chloral Hydrate, 487 Clorazepate Dipotassium, 1869 Tablets, 433 Chloramphenicol, 487 Doxifluridine, 604 Cefdinir, 434 Palmitate, 488 Droxidopa, 2119 Capsules, 435 Sodium Succinate, 489 Flopropione, 667 Fine Granules, 436 Chlordiazepoxide, 490 Flurazepam, 678 Cefaclor Compound Granules, 2097 Powder, 491 Indometacin, 756, 1893 Cefalexin Tablets, 492, 1858 Nizatidine, 1913 Capsules, 2098 Chlorhexidine Rifampicin, 1065 for Syrup, 2099 Gluconate Solution, 493 Roxatidine Acetate Hydrochloride Cefatrizine Propylene Glycolate for Hydrochloride, 493 Extended-release, 1071 Syrup, 2100 Chlorinated Lime, 494 Sodium Iodide (123I), 1103 Cefditoren Pivoxil, 437 Chlormadinone Acetate, 494 Sodium Iodide (131I), 1103 Fine Granules, 438 Chlorobutanol, 495 Sulpiride, 1132 Tablets, 438 Chlorphenesin Carbamate, 496, 1858 Tranexamic Acid, 1192 Cefepime Dihydrochloride Tablets, 1859 Ubenimex, 2211 for Injection, 441 Chlorpheniramine Vitamin A, 1230 Hydrate, 439 and Calcium Powder, 497 Vitamin A Oil, 1230 Cefixime, 442 Maleate, 498 Captopril, 403 Capsules, 2101 Maleate Injection, 499 Carbamazepine, 404 Cefmenoxime Hydrochloride, 443 Maleate Powder, 499 Carbazochrome Sodium Sulfonate Cefmetazole Sodium, 445 Maleate Tablets, 500 Hydrate, 405 for Injection, 1855 d-Chlorpheniramine Maleate, 501 Carbetapentane Citrate, 974 Cefminox Sodium Hydrate, 446 Chlorpromazine Hydrochloride, 502 Carbetapentene Citrate, 974 Cefodizime Sodium, 447 Injection, 503, 1860 Carbidopa Hydrate, 406 Cefoperazone Sodium, 448 Tablets, 503, 1861 L-Carbocisteine, 407 Cefotaxime Sodium, 449 Chlorpropamide, 504 Carbolic Acid, 985 Cefotetan, 451 Tablets, 505, 1861 for Disinfection, 986 Cefotiam Cholecalciferol, 506 Liquefied, 986 Hexetil Hydrochloride, 453 Cholera Vaccine, 506 Carbon Dioxide, 407 Hydrochloride, 455 Cholesterol, 507 Carboxymethylcellulose, 408 Hydrochloride for Injection, 456 Chorionic Gonadotrophin, 707 Calcium, 409 Cefozopran Hydrochloride, 457 for Injection, 708 Sodium, 410 for Injection, 458 Chrysanthemum Flower, 1271 Cardamon, 1271, 2220 Cefpiramide Sodium, 458 Cibenzoline Succinate, 1861 Carmellose, 408 Cefpirome Sulfate, 460 Tablets, 1862

2296 Index Supplement II, JP XV

Ciclacillin, 507 Coconut Oil, 535 Cycloserine, 551 Ciclosporin, 509 Codeine Phosphate Cyperus Rhizome, 1280, 1942 A, 509 Hydrate, 536 Powdered, 1280, 1942 Cilastatin Sodium, 509 Powder, 1%, 536 Cyproheptadine Hydrochloride Hydrate, Cilazapril Powder, 10%, 537 551 Hydrate, 1863 Tablets, 537, 2109 L-Cysteine, 1871 Tablets, 1864 Cod Liver Oil, 538 Hydrochloride Hydrate, 1872 Cilostazol, 511 Coix Seed, 1276 Cytarabine, 552 Tablets, 512, 1866 Powdered, 1276 Cimetidine, 513 Colchicine, 538 D Cimicifuga Rhizome, 1272, 1939 Colistin Cinchocaine Hydrochloride, 569 Sodium Methanesulfonate, 540 Daiokanzoto Extract, 1280, 2221 Cinnamon Sulfate, 541 Danazol, 2112 Bark, 1272 Colophonium, 1347 Dantrolene Sodium Hydrate, 553 Bark, Powdered, 1273 Compound Daunorubicin Hydrochloride, 553 Oil, 1273 Acrinol and Zinc Oxide Oil, 273 Deferoxamine Mesilate, 554, 1873 Cinoxacin, 2105 Diastase and Sodium Bicarbonate Dehydrated Alcohol, 639 Capsules, 2106 Powder, 567 Dehydrocholate Sodium Injection, 557 Cisplatin, 513 Hycodenone Injection, 952 Dehydrocholic Acid, 556 Citric Acid Iodine Glycerin, 770 Injection, 557, 1873 Anhydrous, 514 Methyl Salicylate Spirit, 879 Purified, 556 Hydrate, 515 Oxycodone and Atropine Injection, Demethylchlortetracycline Hydrochlo- Citrus Unshiu Peel, 1273 953 ride, 558 Clarithromycin, 516 Oxycodone Injection, 952 Dental Tablets, 517 Phellodendron Powder for Cataplasm, Antiformin, 310 Clebopride Malate, 2107 1332 Iodine Glycerin, 771 Clemastine Fumarate, 519 Rhubarb and Senna Powder, 1346 Paraformaldehyde Paste, 969 Clematis Root, 1274, 1939 Salicylic Acid Spirit, 1080 Phenol with Camphor, 987 Clindamycin Hydrochloride, 519, Scopolia Extract and Diastase Powder, Sodium Hypochlorite Solution, 310 2108 1355 Triozinc Paste, 1210 Capsules, 520, 2108 Thianthol and Salicylic Acid Solution, Dermatol, 368 Clindamycin Phosphate, 521 1165 Deslanoside, 559 Injection, 1866 Vitamin B Powder, 1230 Injection, 560, 1873 Clinofibrate, 522 Concentrated Dexamethasone, 560 Clobetasol Propionate, 1867 Glycerin, 703 Dextran Clocapramine Hydrochloride Hydrate, Glycerol, 703 40, 561, 1873 523 Condurango, 1276 40 Injection, 562 Clofedanol Hydrochloride, 524 Fluidextract, 1277, 1940 70, 563 Clofibrate, 525 Coptis Rhizome, 1277, 1940 Sulfate Sodium Sulfur 5, 564 Capsules, 526 Powdered, 1278, 1940 Sulfate Sodium Sulfur 18, 565 Clomifene Citrate, 526 Corn Dextrin, 565 Tablets, 527, 2109 Oil, 542 Dextromethorphan Hydrobromide Clomipramine Hydrochloride, 528 Starch, 542, 2110 Hydrate, 566 Clonazepam, 528 Cornus Fruit, 1279, 2220 Diagnostic Sodium Citrate Solution, Clonidine Hydrochloride, 529 Cortisone Acetate, 543 1100 Cloperastine Hydrochloride, 530 Corydalis Tuber, 1279, 1940 Diastase, 567 Clorazepate Dipotassium, 1868 Powdered, 1940 and Sodium Bicarbonate Powder, Capsules, 1869 Crataegus Fruit, 1941 567 Clotiazepam, 531 Creosote, 544, 1870 Diazepam, 567 Clotrimazole, 532 Wood, 2110 Dibasic Clove, 1274 Cresol, 544 Calcium Phosphate, Anhydrous, 396, Oil, 1275 Solution, Saponated, 545 1874 Powdered, 1274 Croconazole Hydrochloride, 546 Calcium Phosphate Hydrate, 396, Cloxacillin Sodium Hydrate, 533 Croscarmellose Sodium, 546, 2112 1875 Cloxazolam, 534 Crude Glycyrrhiza Extract, 1297, 1943 Sodium Phosphate Hydrate, 568 CMC, 408 Crystalline Insulin Zinc Injection Dibekacin Sulfate, 569 Calcium, 409 (Aqueous Suspension), 765 Ophthalmic Solution, 2113 Sodium, 410 Crystal Violet, 881 Dibucaine Hydrochloride, 569 Cnidium Cyanamide, 548 Dichlorphenamide, 571 Monnieri Fruit, 1275 Cyanocobalamin, 548, 1870 Tablets, 572 Rhizome, 1275, 1939 Injection, 549, 1871 Diclofenac Sodium, 570 Rhizome, Powdered, 1276, 1940 Cyclopentolate Hydrochloride, 549 Diclofenamide, 571 Cocaine Hydrochloride, 535 Cyclophosphamide Hydrate, 550

Supplement II, JP XV Index 2297

Tablets, 572 Doxazosin Mesilate, 2117 Enteric-Coated Tablets, 1882, 2125 Dicloxacillin Sodium Hydrate, 573 Doxifluridine, 604 Ethylsuccinate, 629 Diethylcarbamazine Citrate, 574 Capsules, 604 Lactobionate, 629 Tablets, 574, 2113 Doxorubicin Hydrochloride, 605 Stearate, 630 Diethylstilbestrol Diphosphate, 683 for Injection, 1877 Estazolam, 631 Tablets, 684 Doxycycline Hydrochloride Hydrate, Estradiol Benzoate, 631 Difenidol Hydrochloride, 575 606 Injection, 632 Diflucortolone Valerate, 2114 Dried Injection (Aqueous Suspension), Digenea, 1280 Aluminum Hydroxide Gel, 288 633, 2125 Digitoxin, 576 Aluminum Hydroxide Gel Fine Gran- Estriol, 633 Tablets, 576 ules, 289 Injection (Aqueous Suspension), Digoxin, 578, 2115 Aluminum Potassium Sulfate, 292 634, 2125 Injection, 579, 2116 Sodium Carbonate, 1096 Tablets, 635 Tablets, 580, 2116 Sodium Sulfite, 1109 Etacrynic Acid, 636 Dihydrocodeine Phosphate, 581 Thyroid, 1171 Tablets, 636 Powder, 1%, 582 Yeast, 1241 Ethacridine Lactate, 274 Powder, 10%, 582 Droperidol, 608 Ethambutol Hydrochloride, 637 Dihydroergotamine Mesilate, 583 Droxidopa, 2118 Ethanol, 638 Dihydroergotoxine Mesilate, 584 Capsules, 2119 Anhydrous, 639 Dilazep Hydrochloride Hydrate, 586 Fine Granules, 2120 for Disinfection, 640 Diltiazem Hydrochloride, 586 Dydrogesterone, 609 Ethenzamide, 640, 2125 Dilute Tablets, 610 Ether, 641 Hydrochloric Acid, 726 Anesthetic, 641 Iodine Tincture, 769 E Ethinylestradiol, 642, 2125 Diluted Opium Powder, 940 Tablets, 642 Dimemorfan Phosphate, 588 Ethionamide, 643 Ecabet Sodium Dimenhydrinate, 588 Ethosuximide, 644 Granules, 2121 Tablets, 589, 2117 Ethoxybenzamide, 640 Hydrate, 2122 Dimercaprol, 590 Ethyl Ecarazine Hydrochloride, 1185 Injection, 590 Aminobenzoate, 644 Ecothiopate Iodide, 610 Dimorpholamine, 591 Cysteine Hydrochloride, 645 Edrophonium Chloride, 611 Injection, 591 L-Cysteine Hydrochloride, 645 Injection, 612, 1878 Dinoprost, 592 Icosapentate, 646 EDTA Sodium Hydrate, 598 Dionin, 648 Parahydroxybenzoate, 647 Elcatonin, 612 Dioscorea Rhizome, 1282, 1942 Ethylenediamine, 648 Eleutherococcus Senticosus Rhizome, Powdered, 1282, 1942 Ethylmorphine Hydrochloride Hydrate, 1283, 2221 Diphenhydramine, 593 648 Emorfazone, 1878 and Bromovalerylurea Powder, 593 Etidronate Disodium, 649 Tablets, 2123 Hydrochloride, 594 Tablets, 650 Enalapril Maleate, 1879 ,Phenol and Zinc Oxide Liniment, Etilefrine Hydrochloride, 650 Tablets, 1880 595 Tablets, 651 Enflurane, 615 Tannate, 595 Etizolam, 652 Enoxacin Hydrate, 616 Diphenylhydantoin, 991 Fine Granules, 1883 Enviomycin Sulfate, 616 Powder, 992 Tablets, 1884 Eperisone Hydrochloride, 618 Sodium for Injection, 92 Etodolac, 653 Ephedra Herb, 1283 Tablets, 992 Etoposide, 653 Ephedrine Hydrochloride, 619 Diphtheria Eucalyptus Oil, 654 Injection, 619, 1882 Tetanus Combined Toxoid, 596 Eucommia Bark, 1284 Powder, 620 Toxoid, 596 Evodia Fruit, 1285 Powder, 10%, 620 Dipyridamole, 597 Exsiccated Gypsum, 1298 Tablets, 621, 1882, 2124 Disodium Edetate Hydrate, 598 Extract Epimedium Herb, 1284 Disopyramide, 598 Belladonna, 1263, 1939 Epinephrine, 276 Distigmine Bromide, 599 Daiokanzoto, 1280, 2221 Injection, 276 Tablets, 600, 2117 Glycyrrhiza, 1296, 1943 Solution, 277 Disulfiram, 600 Goshajinkigan, 2221 Epirizole, 621 Dobutamine Hydrochloride, 601 Crude Glycyrrhiza, 1297, 1943 Epirubicin Hydrochloride, 622 Dolichos Seed, 1282 Hachimijiogan, 2225 Ergocalciferol, 624 Domperidone, 1876 Hangekobokuto, 1943 Ergometrine Maleate, 625 Dopamine Hydrochloride, 602 Hochuekkito, 1298, 1945 Injection, 625, 2125 Injection, 602, 1877 Kakkonto, 1308, 1950, 2228 Tablets, 626 Dover's Powder, 1324 Kamishoyosan, 1310, 1952 Ergotamine Tartrate, 627 Doxapram Hydrochloride Hydrate, Keishibukuryogan, 1955 Erythromycin, 627 603 Nux Vomica, 1322, 1960

2298 Index Supplement II, JP XV

Ryokeijutsukanto, 1347, 1965 Flutoprazepam, 2129 Ophthalmic Solution, 2133 Saireito, 1349 Tablets, 2130 Gentian, 1290, 1943 Scopolia, 1353, 1967 Foeniculated Ammonia Spirit, 1286 and Sodium Bicarbonate Powder, Shimbuto, 2234 Folic Acid, 680 1290 Injection, 681, 1888 Japanese, 1306, 1949 F Tablets, 681, 1888 Powdered, 1290, 1943 Formalin, 681 Powdered, Japanese, 1306, 1949 Water, 682 Geranium Herb, 1291 Famotidine, 655 Formoterol Fumarate Hydrate, 682 Powdered, 1291 for Injection, 656, 1885 Forsythia Fruit, 1286 Ginger, 1291 Powder, 657, 2125 Fosfestrol, 683, 1888 Powdered, 1292 Tablets, 657 Tablets, 684, 1888 Ginseng, 1292 Faropenem Sodium Fosfomycin Powdered, 1293 for Syrup, 659, 1886, 2126 Calcium Hydrate, 685 Glacial Acetic Acid, 269 Hydrate, 658, 1885 Sodium, 686 Glehnia Root, 1294, 1943 Tablets, 660, 1886, 2126 Sodium for Injection, 687, 2131 Glibenclamide, 699 Felbinac, 1887 Fradiomycin Sulfate, 688 Gliclazide, 2134 Fenbufen, 660 Freeze-dried Glucose, 700 Fennel, 1285 BCG Vaccine (for Percutaneous Use), Injection, 701, 1889 Oil, 1286 335 L-Glutamine, 1889 Powdered, 1285 Botulism Antitoxin, Equine, 374 Glutathione, 701 Fentanyl Citrate, 661 Diphtheria Antitoxin, Equine, 596 Glycerin, 702 Ferrous Sulfate Hydrate, 661 Habu Antivenom, Equine, 716 and Potash Solution, 704 Fine Granules Inactivated Tissue Culture Rabies Concentrated, 703 Cefaclor, 417 Vaccine, 1054 Glycerol, 702 Cefcapene Pivoxil Hydrochloride, Japanese Encephalitis Vaccine, 786 Concentrated, 703 432 Live Attenuated Measles Vaccine, Glyceryl Monostearate, 704 Cefdinir, 436 843 Glycine, 704 Cefditoren Pivoxil, 438 Live Attenuated Mumps Vaccine, Glycyrrhiza, 1295 Cefteram Pivoxil, 469 902 Extract, 1296, 1943 Dried Aluminum Hydroxide Gel, Live Attenuated Rubella Vaccine, Extract, Crude, 1297, 1943 289, 2079 1074 Powdered, 1296 Droxidopa, 2120 Mamushi Antivenom, Equine, 841 Gonadorelin Acetate, 705 Etizolam, 1883 Smallpox Vaccine, 1091 Gonadotrophin Irsogladine Maleate, 2148 Smallpox Vaccine Prepared in Cell Chorionic, 707 Troxipide, 2209 Culture, 1091 for Injection, Chorionic, 708 Flavin Adenine Dinucleotide Sodium, Tetanus Antitoxin, Equine, 1156 for Injection, Human Chorionic, 708 662 Fritillaria Bulb, 1287, 1942 Human Chorionic, 707 Flavoxate Hydrochloride, 664 Fructose, 689 Human Menopausal, 708 Flomoxef Sodium, 664 Injection, 689, 1888 Serum, 710 for Injection, 666 Furosemide, 690 for Injection, Serum, 711 Flopropione, 667, 2126 Injection, 2131 Goshajinkigan Extract, 2221 Capsules, 667 Tablets, 691 Gramicidin, 712 Flucytosine, 668 Fursultiamine Hydrochloride, 692 Granules Fludiazepam, 669 Azelastine Hydrochloride, 2089 Fludrocortisone Acetate, 2127 Calcium Paraaminosalicylate, 394 Fluidextract G Cefaclor Compound, 419, 2097 Condurango, 1277, 1940 Ecabet Sodium, 2121 Platycodon, 1334, 1962 Gabexate Mesilate, 693, 1889 Ursodeoxycholic Acid, 2213 Uva Ursi, 1371, 1969 β-Galactosidase Pas-calcium Granules, 394 Flunitrazepam, 670 (Aspergillus), 694 Griseofulvin, 713 Fluocinolone Acetonide, 670 (Penicillium), 695 Tablets, 1890, 2135 Fluocinonide, 672 Gallium (67Ga) Citrate Injection, 696 Guaiacol Glyceryl Ether, 714 Fluorescein Sodium, 673 Gambir, 1287 Guaifenesin, 714 Fluorometholone, 673 Powdered, 1287 Guanabenz Acetate, 715 Fluorouracil, 674 Gardenia Fruit, 1288 Guanethidine Sulfate, 716 Fluoxymesterone, 675 Powdered, 1288 Gypsum, 1297 Fluphenazine Enanthate, 676 Gas Gangrene Antitoxin, Equine, 696 Flurazepam, 677 Gastrodia Tuber, 1289, 1943 Capsules, 678 Gefarnate, 2132 H Hydrochloride, 678 Gelatin, 696 Flurbiprofen, 679 Purified, 697 Hachimijiogan Extract, 2225 Flutamide, 2128 Gentamicin Sulfate, 698 Haloperidol, 717

Supplement II, JP XV Index 2299

Tablets, 718 Idarubicin Hydrochloride, 745 Chlorpromazine Hydrochloride, 503, Halothane, 719 for Injection, 746 1860 Haloxazolam, 719 Idoxuridine, 747 Chorionic Gonadotrophin for, 708 Hangekobokuto Extract, 1943 Ophthalmic Solution, 747, 1893 Clindamycin Phosphate, 1866 Hemp Fruit, 1298 Ifenprodil Tartrate, 748 Cyanocobalamin, 549, 1871 Heparin Calcium, 2135 Imidapril Hydrochloride, 2140 Dehydrocholate Sodium, 557 Heparin Sodium, 721, 2137 Tablets, 2141 Dehydrocholic Acid, 557, 1873 Injection, 722 Imipenem Deslanoside, 560, 1873 Hochuekkito Extract, 1298, 1945, and Cilastatin for Injection, 750 Dextran 40, 562 2228 Hydrate, 749 Digoxin, 579, 2116 Homatropine Hydrobromide, 722 Imipramine Hydrochloride, 751 Dimercaprol, 590 Homochlorcyclizine Hydrochloride, Tablets, 752, 1893 Dimorpholamine, 591 723 Immature Orange, 1302 Diphenylhydantoin Sodium for, 992 Honey, 1301 Imperata Rhizome, 1302, 1949 Dopamine Hydrochloride, 602, 1877 Houttuynia Herb, 1302 Indapamide, 2143 Doxorubicin Hydrochloride for, Human Tablets, 2144 1877 Chorionic Gonadotrophin, 707 Indenolol Hydrochloride, 753 Edrophonium Chloride, 612, 1878 Chorionic Gonadotrophin for Injec- Indigocarmine, 754 Ephedrine Hydrochloride, 619, 1882 tion, 708 Injection, 755, 2145 Epinephrine, 276 Menopausal Gonadotrophin, 708, Indium (111In) Chloride Injection, 755 Ergometrine Maleate, 625, 2125 2137 Indometacin, 755 Estradiol Benzoate, 632 Normal Immunoglobulin, 724 Capsules, 756, 1893 Famotidine for, 656, 1885 Hycoato Injection, 953 Suppositories, 757, 2145 Flomoxef Sodium for, 666 Hydralazine Hydrochloride, 724 Influenza HA Vaccine, 758 Folic Acid, 681, 1888 for Injection, 724, 2138 Injection Fosfomycin Sodium for, 687, 2131 Powder, 725 Acetylcholine Chloride for, 271, Fructose, 689, 1888 Tablets, 725, 1890 1825 Furosemide, 2131 Hydrochloric Acid, 725 Adrenaline, 276 Gallium (67Ga) Citrate, 696 Dilute, 726 Alprostadil, 1828 Glucose, 701, 1889 Lemonade, 727 Amikacin Sulfate, 1830 Heparin Sodium, 722 Hydrochlorothiazide, 727 Aminophylline, 297, 1831, 2079 Human Chorionic Gonadotrophin for, Hydrocortisone, 728 Amobarbital Sodium for, 300 708 Acetate, 729 Amphotericin B for, 304 Hycoato, 953 and Diphenhydramine Ointment, Ampicillin Sodium for, 1838 Hycodenone, Compound, 952 730 Estradiol Benzoate, (Aqueous Hydralazine Hydrochloride for, 724, Butyrate, 730 Suspension), 633, 2125 2138 Sodium Phosphate, 731, 2139 Estriol, (Aqueous Suspension), 634, Idarubicin Hydrochloride for, 746 Sodium Succinate, 732 2125 Imipenem and Cilastatin for, 750 Succinate, 733 Insulin Zinc, (Aqueous Suspension), Indigocarmine, 755, 2145 Hydrocotarnine Hydrochloride 763 Indium (111In) Chloride, 755 Hydrate, 734 Insulin Zinc, Amorphous, (Aqueous Insulin, 762 Hydrogenated Oil, 735 Suspension), 764 Iodinated (131I) Human Serum Albu- Hydrophilic Insulin Zinc, Crystalline, (Aqueous min, 768 Ointment, 735 Suspension), 765 Isepamicin Sulfate Injection, 2150 Petrolatum, 981 Insulin Zinc Protamine, (Aqueous Isoniazid, 781, 2151 Hydrous Lanolin, 807 Suspension), 766 Isotonic Sodium Chloride, 1098 Hydroxocobalamin Acetate, 736 Isophane Insulin, (Aqueous Suspen- Levallorphan Tartrate, 814, 1900 Hydroxypropylcellulose, 736, 2139 sion), 762 Lidocaine, 818, 2157 Low Substituted, 2139 Arbekacin Sulfate, 312 Lidocaine Hydrochloride, 818, 2157 Hydroxypropylmethylcellulose, 741 L-Arginine Hydrochloride, 314, Magnesium Sulfate, 839, 1900 Hydroxyzine 1839 D-Mannite, 842 Hydrochloride, 739 Ascorbic Acid, 317, 1839 D-Mannitol, 842, 1903 Pamoate, 739 Atropine Sulfate, 324 Meglumine Amidotrizoate, 851 Hymecromone, 740 Aztreonam for, 1840 Meglumine Iotalamate, 852, 2161 Hypromellose, 741, 2140 Benzylpenicillin Potassium for, 1841 Meglumine Sodium Amidotrizoate, Phthalate, 743, 1891, 2140 Calcium Chloride, 390, 1851 853, 2161 Cefazolin Sodium for, 1854 Meglumione Sodium Iodamide, 854 I Cefepime Dihydrochloride for, 441 Mepivacaine Hydrochloride, 860, Cefmetazole Sodium for, 1855 2161 Cefotiam Hydrochloride for, 456 Meropenem for, 2162 Ibudilast, 1892 Cefozopran Hydrochloride for, 458 Metenolone Enanthate, 866 Ibuprofen, 744 Ceftazidime for, 1856 Minocycline Hydrochloride for, Ichthammol, 744 Chlorpheniramine Maleate, 499 1904, 2163

2300 Index Supplement II, JP XV

Mitomycin C for, 1905 Testosterone Propionate, 1155, 2203 Suspension), 762 Morphine and Atropine, 899 Thallium (201Tl) Chloride, 1158 l-Isoprenaline Hydrochloride, 782 Morphine Hydrochloride, 901, 2165 Thiamine Chloride Hydrochloride, Isopropanol, 783 Neostigmine Methylsulfate, 910, 1161, 1930 Isopropyl Alcohol, 783 1912 Thiamylal Sodium for, 1164 Isopropylantipyrine, 783 Nicardipine Hydrochloride, 912, Thiopental Sodium for, 1167, 1930 Isosorbide, 784 1912 Tobramycin, 1930 Dinitrate, 785 Nicotinic Acid, 921, 1912 Tranexamic Acid, 1193 Dinitrate Tablets, 786, 2151 Noradrenaline, 931, 1915 Tubocurarine Chloride Hydrochloride, Isotonic Noradrenaline Hydrochloride, 931 1213, 1931 Salt Solution, 1098 Norepinephrine, 931 Tubocurarine Hydrochloride, 1213 Sodium Chloride Injection, 1098 Norepinephrine Hydrochloride, 931 Vancomycin Hydrochloride for, Sodium Chloride Solution, Operidine, 981 1223 1098,1893 Opium Alkaloids and Atropine, 942 Vasopressin, 1223, 2215 Isoxsuprine Hydrochloride, 1894 Opium Alkaloids and Scopolamine, Vinblastine Sulfate for, 1227 Tablets, 1895 943 Vitamin B1 Hydrochloride, 1161 Itraconazole, 1896 Opium Alkaloids Hydrochlorides, 942 Vitamin B2 Phosphate Ester, 1062 Oxycodone and Atropine, Compound, Vitamin B6, 1048 J 953 Vitamin B12, 549 Oxycodone, Compound, 952 Vitamin C, 317 Japanese Oxytocin, 960 Water for, 1235, 1934 Angelica Root, 1305 Ozagrel Sodium for, 1917 Weak Opium Alkaloids and Scopola- Angelica Root, Powdered, 1305 Papaverine Hydrochloride, 965, mine, 945 Encephalitis Vaccine, 786 1918 Xylitol, 1241, 1935 Encephalitis Vaccine, Freeze-dried, Peplomycin Sulfate for, 1918 Insulin, 758 786 Pethidine Hydrochloride, 981, 1918 Human (Genetical Recombination), Gentian, 1306, 1949 Phenolsulfonphthalein, 988, 2169 760 Gentian, Powdered, 1306, 1949 Phenytoin Sodium for, 992 Injection, 762 Valerian, 1306, 1950, 2228 Piperacillin Sodium for, 998 Zinc Injection (Aqueous Suspension), Valerian, Powdered, 1307, 1950, Prednisolone Sodium Succinate for, 763 2228 1025, 1921 Amorphous, 764 Josamycin, 786 Procainamide Hydrochloride, 1029, Crystalline, 765 Propionate, 788 2179 Zinc Protamine Injection (Aqueous Tablets, 1897, 2152 Procaine Hydrochloride, 1030 Suspension), 766 Jujube, 1307 Progesterone, 1034, 2182 Iodamide, 767 Seed, 1307 Protamine Sulfate, 1042, 1922, 2186 Iodinated (131I) Human Serum Albumin Pyridoxine Hydrochloride, 1048, Injection, 768 1922 Iodine, 768 K Reserpine, 1056, 1922 Salicylic Acid and Phenol Spirit, Riboflavin Phosphate, 1062 772 Kainic Acid Riboflavin Sodium Phosphate, 1062, Tincture, 769 and Santonin Powder, 790 1922 Iodoform, 773 Hydrate, 789 Serum Gonadotrophin for, 711 Iopamidol, 773 Kakkonto Extract, 1308, 1950, 2228 Sodium Bicarbonate, 1094, 1925 Iotalamic Acid, 774 Kallidinogenase, 790 0.9% Sodium Chloride, 1098 Iotroxic Acid, 775 Kamishoyosan Extract, 1310, 1952 10% Sodium Chloride, 1098, 1925 Ipecac, 1303, 1949 Kanamycin Sodium Chromate (51Cr), 1099 Powdered, 1303, 1949 Monosulfate, 793 Sodium Citrate, for Transfusion, Syrup, 1304 Sulfate, 794 1099, 1926 Ipratropium Bromide Hydrate, 776 Kaolin, 795 Sodium Iodohippurate (131I), 1103 Ipriflavone, 2145 Keishibukuryogan Extract, 1955 Sodium Iotalamate, 1103, 2195 Tablets, 2146 Ketamine Hydrochloride, 795 Sodium Pertechnetate (99mTc), 1105 Iproveratril Hydrochloride, 1225 Ketoconazole, 2152 Sodium Thiosulfate, 1110, 1927 Ilsogladine Maleate, 2147 Cream, 2153 Streptomycin Sulfate for, 2198 Fine Granules, 2148 Lotion, 2154 Sulfobromophthalein Sodium, 1130 Tablets, 2149 Solution, 2155 Sulpyrine, 1134, 1927 Isepamicin Sulfate, 777 Ketoprofen, 796 Suxamethonium Chloride for, 1137, Injection, 2150 Ketotifen Fumarate, 797 1928 Isoflurane, 778 Kitasamycin, 798 Suxamethonium Chloride, 1138, L-Isoleucine, 780 Acetate, 799 1928 Isoniazid, 780 Tartrate, 800 Teceleukin for, (Genetical Recombi- Injection, 781, 2151 nation), 1148, 1929 Tablets, 781, 2151 Testosterone Enanthate, 1154, 2203 Isophane Insulin Injection (Aqueous

Supplement II, JP XV Index 2301

L Lonicera Leaf and Stem, 1314 Sodium Iodamide Injection, 854 Loquat Leaf, 1314 Melphalan, 855 Labetalol Hydrochloride, 1898 Lorazepam, 827 Menatetrenone, 855 Tablets, 1899 Losartan Potassium, 2158 Mentha Lactic Acid, 801 Lotion Herb, 1317 Lactose, 803 Ketoconazole, 2154 Oil, 1318 Anhydrous, 802, 1900, 2155 Sulfur and Camphor, 1130 Water, 1318 Hydrate, 803, 2156 Low Substituted Hydroxypropylcellu- dl-Menthol, 856 Lactulose, 804 lose, 738, 2139 l-Menthol, 857 Lanatoside C, 805 Loxoprofen Sodium Hydrate, 828 Mepenzolate Bromide, 857 Tablets, 806 Lycium Mepirizole, 621 Lanolin Bark, 1315, 1959 Mepitiostane, 858 Hydrous, 807 Fruit, 1315 Mepivacaine Hydrochloride, 859 Purified, 808 Lysine Hydrochloride, 829 Injection, 860, 2161 Lard, 808 L-Lysine Acetate, 2159 Mequitazine, 861 Latamoxef Sodium, 809 L-Lysine Hydrochloride, 829 Merbromin, 862 Lauromacrogol, 810 Lysozyme Hydrochloride, 830 Solution, 863 Lemonade Mercaptopurine Hydrate, 861 Hydrochloric Acid, 727 M Mercurochrome, 862 Lenampicillin Hydrochloride, 810 Solution, 863 Meropenem Leonurus Herb, 1958 Macrogol for Injection, 2162 L-Leucine, 812 400, 830 Hydrate, 863 Leucomycin, 798 1500, 831 Mestranol, 864 Acetate, 799 4000, 832 Metenolone Tartrate, 800 6000, 832 Acetate, 865 Levallorphan Tartrate, 813 20000, 833 Enanthate, 866 Injection, 814, 1900 Ointment, 833 Enanthate Injection, 866 Levodopa, 814 Magnesium Metformin Hydrochloride, 867 Levofloxacin Hydrate, 2156 Carbonate, 834 Tablets, 867 Levomepromazine Maleate, 815 Oxide, 835 Methamphetamine Hydrochloride, 868 Levothyroxine Sodium Silicate, 836 L-Methionine, 869 Hydrate, 816 Stearate, 837 Methotrexate, 869 Tablets, 817 Sulfate Hydrate, 838 Methoxsalen, 870 Lidocaine, 818 Sulfate Injection, 839, 1900 Methylbenactyzium Bromide, 871 Hydrochloride Injection, 818 Sulfate Mixture, 839 Methylcellulose, 871, 2163 Injection, 818, 2157 Magnolia Methyldopa Light Bark, 1315, 1959 Hydrate, 873 Anhydrous Silicic Acid, 1087 Bark, Powderd, 1316, 1959 Tablets, 874, 1903 Liquid Paraffin, 967 Flower, 1317 dl-Methylephedrine Hydrochloride, Lilium Bulb, 1958 Mallotus Bark, 1317 875 Limaprost Alfadex, 819 Maltose Hydrate, 840 Powder, 876 Liniment Manidipine Hydrochloride, 1900 Powder, 10%, 876 Diphenhydramine, Phenol and Zinc Tablets, 1902 Methylergometrine Maleate, 876 Oxide, 595 D-Mannite Injection, 842 Tablets, 877 Lincomycin Hydrochloride D-Mannitol, 841 Methyl Hydrate, 820 Injection, 842, 1903 Parahydroxybenzoate, 878 Injection, 2157 Maprotiline Hydrochloride, 842 Salicylate, 881 Lindera Root, 1313, 1959 Meclofenoxate Hydrochloride, 843 Methylprednisolone, 879 Liothyronine Sodium, 821 Mecobalamin, 844 Succinate, 880 Tablets, 822 Medazepam, 845, 1903 Methylrosanilinium Chloride, 881 Liquefied Medicinal Methyltestosterone, 882 Carbolic Acid, 986 Carbon, 845 Tablets, 883 Phenol, 986 Soap, 846 Meticrane, 884 Liquid Paraffin, 966 Mefenamic Acid, 847 Metildigoxin, 885 Lisinopril Mefloquine Hydrochloride, 848 Metoclopramide, 886 Hydrate, 823 Mefruside, 849 Tablets, 886 Tablets, 824 Tablets, 849, 1903 Metoprolol Tartrate, 887 Lithium Carbonate, 826 Meglumine, 850 Tablets, 888 Lithospermum Root, 1313, 1959, 2228 Amidotrizoate Injection, 851 Metronidazole, 889 Live Oral Poliomyelitis Vaccine, 1005 Iotalamate Injection, 852, 2161 Tablets, 889 Longan Aril, 2229 Sodium Amidotrizoate Injection, Metyrapone, 890 Longgu, 1313, 2229 853, 2161 Mexiletine Hydrochloride, 891

2302 Index Supplement II, JP XV

Miconazole, 892 Tablets, 918, 2168 Injection, 981 Nitrate, 893 Nicorandil, 919, 1912 Ophiopogon Tuber, 1324 Microcrystalline Cellulose, 477 Nicotinamide, 919 Ophthalmic Solution Micronomicin Sulfate, 893 Nicotinic Acid, 920 Dibekacin Sulfate, 2113 Midecamycin, 894 Injection, 921, 1912 Gentamicin Sulrate, 2133 Acetate, 895 Nifedipine, 922 Idoxuridine, 747, 1893 Migrenin, 896 Nilvadipine, 923 Silver Nitrate, 1088 Minocycline Hydrochloride, 897 Tablets, 924 Zinc Sulfate, 1247 for Injection, 1904, 2163 Nitrazepam, 925 Opium Tablets, 2163 Nitrendipine, 926 Ipecac Powder, 1324 Mitomycin C, 898 Tablets, 927 Powdered, 939 for Injection, 1905 Nitrogen, 928 Tincture, 940 Mizoribine, 1906 Nitroglycerin Tablets, 928 Opium Alkaloids Tablets, 1907 Nitrous Oxide, 929 and Atropine Injection, 942 Monobasic Calcium Phosphate Nizatidine, 1912 and Scopolamine Injection, 943 Hydrate, 397 Capsules, 1913 Hydrochlorides, 941 Monosodium Trichloroethyl Phosphate, Noradrenaline, 930 Hydrochlorides Injection, 942 1202 Hydrochloride Injection, 931 Orange Syrup, 1203 Injection, 931, 1915 Oil, 946 Morphine Norepinephrine, 930 Peel Syrup, 1325 and Atropine Injection, 899 Hydrochloride Injection, 931 Peel Tincture, 1325 Hydrochloride Hydrate, 900 Injection, 931 Orciprenaline Sulfate, 946 Hydrochloride Injection, 901, 2165 Norethisterone, 932, 2168 Oriental Bezoar, 1325 Hydrochloride Tablets, 902, 1908, Norfloxacin, 932 Oxapium Iodide, 947 2165 Norgestrel, 933 Oxaprozin, 948 Mosapride Citrate and Ethinylestradiol Tablets, 934 Oxazolam, 948 Hydrate, 2165 Nortriptyline Hydrochloride, 935 Oxetacaine, 949 Tablets, 2166 Noscapine, 936 Oxethazaine, 949 Moutan Bark, 1318 Hydrochloride Hydrate, 937 Oxprenolol Hydrochloride, 950 Powdered, 1319 Notopterygium Rhizome, 1321, 1960 Oxybuprocaine Hydrochloride, 951 Mulberry Bark, 1320, 1960 Nuphar Rhizome, 1321, 1960, 2229 Oxycodone Hydrochloride Hydrate, Mupirocin Calcium Hydrate, 902 Nutmeg, 2229 951 Nux Vomica, 1321 Oxydol, 954 N Extract, 1322, 1960 Oxygen, 955 Extract Powder, 1323 Oxymetholone, 956 Tincture, 1323 Oxytetracycline Hydrochloride, 956 Nabumetone, 1908 Nystatin, 937 Oxytocin, 958 Tablets, 1910 Injection, 960 Nadolol, 904 Oyster Shell, 1326 Nafamostat Mesilate, 1911 O Powdered, 1326 Nalidixic Acid, 905 Ozagrel Sodium, 1916 Naloxone Hydrochloride, 906 Ofloxacin, 938 for Injection, 1917 Naphazoline Ointment and Chlorpheniramine Solution, 906 Absorptive, 265 Hydrochloride, 907 Acrinol and Zinc Oxide, 274 P Nitrate, 908 Betamethasone Valerate and Gen- Naproxen, 908 tamicin Panax Japonicus Rhizome, 1326, 1960 Narcotine, 936 Sulfate, 362 Powdered, 1327, 1960 Hydrochloride, 937 Bufexamac, 381 Pancreatin, 961 Natamycin, 994 Ointment (continued) Pancuronium Bromide, 962 Natural Aluminum Silicate, 289 Hydrocortisone and Diphenhydramine, Panipenem, 962 Nelumbo Seed, 1320 730 Pantethine, 964 Neomycin Sulfate, 688 Hydrophilic, 735 Papaverine Hydrochloride, 965 Neostigmine Methylsulfate, 909 Macrogol, 833 Injection, 965, 1918 Injection, 910, 1912 Polyethylene Glycol, 833 Paracetamol, 267 Netilmicin Sulfate, 910 Simple, 1089 Paraffin, 966 Nicardipine Hydrochloride, 911 Sulfur, Salicylic Acid and Thianthol, Light Liquid, 967 Injection, 912, 1912 1131 Liquid, 966 Nicergoline, 913 White, 1238 Paraformaldehyde, 968 Powder, 914 Zinc Oxide, 1246 Parnaparin Sodium, 969 Tablets, 915 Olive Oil, 939 Pas-calcium Niceritrol, 916 Omeprazole, 1915 Granules, 394 Nicomol, 917 Operidine, 980 Hydrate, 395

Supplement II, JP XV Index 2303

Paste Pindolol, 995 Powder Arsenical, 315 Pinellia Tuber, 1333 Ascorbic Acid, 317 Paraformaldehyde, Dental, 969 Pioglitazone Hydrochloride, 2172 Chlordiazepoxide, 491 Triozinc, Dental, 1210 Pipemidic Acid Hydrate, 996, 2173 Chlorpheniramine and Calcium, 497 Peach Kernel, 1327, 1961, 2230 Piperacillin Chlorpheniramine Maleate, 499 Powdered, 1327, 1961, 2230 Hydrate, 1919 Codeine Phosphate, 1%, 536 Peanut Oil, 971 Sodium, 997 Codeine Phosphate, 10%, 537 Penbutolol Sulfate, 972 Sodium for Injection, 998 Diastase and Sodium Bicarbonate, Penicillin G Potassium, 349 Piperazine 567 Pentazocine, 972 Adipate, 999 Diastase and Sodium Bicarbonate, Pentobarbital Calcium, 973 Phosphate Hydrate, 999 Compound, 567 Pentoxyverine Citrate, 974 Phosphate Tablets, 1000 Dihydrocodeine Phosphate, 1%, 582 Peony Root, 1328 Pirarubicin, 1000 Dihydrocodeine Phosphate, 10%, 582 Powdered, 1329 Pirenoxine, 1001 Diluted Opium, 940 Peplomycin Sulfate, 975 Pirenzepine Hydrochloride Hydrate, Diphenhydramine and for Injection, 1918 1002 Bromovalerylurea, 593 Perilla Herb, 1329, 1961, 2231 Piroxicam, 1003 Diphenylhydantoin, 992 Perphenazine, 977 Pivmecillinam Hydrochloride, 1004 Dover's, 1324 Maleate, 978 Tablets, 2173 Ephedrine Hydrochloride, 620 Maleate Tablets, 979 Plantago Ephedrine Hydrochloride, 10%, 620 Tablets, 977 Herb, 1334 Famotidine, 657, 2125 Pethidine Hydrochloride, 980 Seed, 1334 Gentian and Sodium Bicarbonate, Injection, 981, 1918 Platycodon 1290 Petrolatum Fluidextract, 1334, 1962 Hydralazine Hydrochloride, 725 Hydrophilic, 981 Root, 1334 Kainic Acid and Santonin, 790 White, 981 Root, Powdered, 1335 dl-Methylephedrine Hydrochloride, Yellow, 982 Polyethylene Glycol 876 Petroleum Benzin, 982 400, 830 dl-Methylephedrine Hydrochloride, Peucedanum Root, 1961 1500, 831 10%, 876 Pharbitis Seed, 1330 4000, 832 Nicergoline, 914 Phellodendron, 6000, 832 Nux Vomica Extract, 1323 Albumin Tannate and Bismuth Subni- 20000, 833 Opium Ipecac, 1324 trate Ointment, 833 Phellodendron, Albumin Tannate Powder, 1332 Pogostemon Herb, 2231 and Bismuth Subnitrate, 1332 Bark, 1330 Polygala Root, 1335, 1962 Phenobarbital, 985 Bark, Powdered, 1331 Powdered, 1335, 1962 Phenobarbital, 10%, 985, 2168 Phenazone, 310 Polygonatum Rhizome, 1336, 2232 Phenytoin, 992, 2169 Phenethicillin Potassium, 983 Polygonum Root, 1336, 1962 Reserpine, 1057 Phenobarbital, 984, 2168 Polymixin B Sulfate, 1006 Reserpine, 0.1%, 1057 Powder, 985 Polyoxyethylene Lauryl Alcohol Ether, Rhubarb and Senna, Compound, 1346 Powder, 10%, 985, 2168 810 Riboflavin, 1060 Phenol, 985 Polyoxyl 40 Stearate, 1007 Salicylated Alum, 1078 and Zinc Oxide Liniment, 987 Polyporus Sclerotium, 1336, 1962 Scopolia Extract, 1354 for Disinfection, 986 Powdered, 1337, 1963 Scopolia Extract and Carbon, 1355 Liquefied, 986 Polysorbate 80, 1007 Scopolia Extract and Diastase, Com- Phenolated Water, 987 Polyvidone, 1015 pound, 1355 for Disinfection, 987 Polyvinylpyrrolidone, 1015 Scopolia Extract and Ethyl Phenolsulfonphthalein, 988 Poria Sclerotium, 1337 Aminobenzoate, 1355 Injection, 988, 2169 Powdered, 1337 Scopolia Extract, Paparerine and L-Phenylalanine, 989 Potash Soap, 1007 Ethyl Aminobenzoate, 1356 Phenylbutazone, 990 Potassium Swertia and Sodium Bicarbonate, Phenylephrine Hydrochloride, 990 Bromide, 1008 1367 Phenytoin, 991 Canrenoate, 1008 Thiamine Chloride Hydrochloride, Powder, 992, 2169 Carbonate, 1009 1162 Sodium for Injection, 992 Chloride, 1009 Vitamin B, Compound, 1230 Tablets, 992, 2170 Clavulanate, 1010 Vitamin B1 Hydrochloride, 1162 Phytomenadione, 993 Hydroxide, 1012 Vitamin B2, 1060 Phytonadione, 993 Iodide, 1013 Vitamin C, 317 Picrasma Wood, 1333 Permanganate, 1013 Zinc Oxide Starch, 1246 Powdered, 1333 Sulfate, 1014 Powdered Pilocarpine Hydrochloride, 994 Potato Starch, 1014, 2174 Acacia, 1251 Pimaricin, 994 Povidone, 1015 Agar, 1253 Pimozide, 2171 Iodine, 1017 Alisma Rhizome, 1253

2304 Index Supplement II, JP XV

Aloe, 1255 Sodium Succinate for Injection, Injection, 1048, 1922 Amomum Seed, 1256 1025, 1921 Pyroxylin, 1049 Atractylodes Lancea Rhizome, 1260 Sodium Phosphate, 2176 Pyrrolnitrin, 1049 Atractylodes Rhizome, 1261, 1939 Succinate, 1024 Calumba, 1268, 1939, 2220 Tablets, 1022 Q Capsicum, 1269 Primidone, 1026 Cellulose, 480, 2105 Probenecid, 1027 Quercus Bark, 2232 Cinnamon Bark, 1273 Tablets, 1027, 2177 Quick Lime, 393 Clove, 1274 Probucol, 2177 Quinidine Sulfate Hydrate, 1050 Cnidium Rhizome, 1276, 1940 Procainamide Hydrochloride, 1028, Quinine Coix Seed, 1276 2179 Ethyl Carbonate, 1051 Coptis Rhizome, 1278, 1940 Injection, 1029, 2179 Hydrochloride Hydrate, 1052 Corydalis Tuber, 1940 Tablets, 1029, 2180 Sulfate Hydrate, 1053 Cyperus Rhizome, 1280, 1942 Procaine Hydrochloride, 1030 Dioscorea Rhizome, 1282, 1942 Injection, 1030 Fennel, 1285 Procarbazine Hydrochloride, 1031 R Gambir, 1287 Procaterol Hydrochloride Hydrate, Gardenia Fruit, 1288 1032 Ranitidine Hydrochloride, 1054 Gentian, 1290, 1943 Processed Rape Seed Oil, 1055 Geranium Herb, 1291 Aconite Root, 1338, 1963 Rebamipide, 2187 Ginger, 1292 Aconite Root, Powdered, 1339, 1963 Tablets, 2188 Ginseng, 1293 Ginger, 1341, 1964 Red Ginseng, 1342 Glycyrrhiza, 1296 Prochlorperazine Maleate, 1033 Rehmannia Root, 1343, 1964 Ipecac, 1303, 1949 Tablets, 1033, 2181 Reserpine, 1055 Japanese Angelica Root, 1305 Progesterone, 1034, 2182 Injection, 1056, 1922 Japanese Gentian, 1306, 1949 Injection, 1034, 2182 Powder, 1057 Japanese Valerian, 1307, 1950, 2228 Proglumide, 1035 Powder, 0.1%, 1057 Magnolia Bark, 1316, 1959 Promethazine Hydrochloride, 1036 Tablets, 1057 Moutan Bark, 1319 Propafenone Hydrochloride, 2183 Retinol Opium, 939 Tablets, 2184 Acetate, 1058 Oyster Shell, 1326 Propantheline Bromide, 1036 Palmitate, 1059 Panax Japonicus Rhizome, Propranolol Hydrochloride, 1037 Rhubarb, 1344 1327,1960 Tablets, 1038 Powdered, 1345 Peach Kernel, 1327, 1961, 2230 Propyl Parahydroxybenzoate, 1039 Riboflavin, 1059 Peony Root, 1329 Propylene Glycol, 1039 Butyrate, 1060 Phellodendron Bark, 1331 Propylthiouracil, 1040 Rice Starch, 2189 Picrasma Wood, 1333 Tablets, 1040, 2185 Phosphate, 1061 Platycodon Root, 1335 Propyphenazone, 783 Phosphate Injection, 1062 Polygala Root, 1335, 1962 Prostaglandin Powder, 1060 Polyporus Sclerotium, 1337, 1963 E1, 286 Sodium Phosphate, 1061 Poria Sclerotium, 1337 E1 α-Cyclodextrin Clathrate Sodium Phosphate Injection, 1062, Processed Aconite Root, 1339, Compound, 287 1922 1963 F2α, 592 Ribostamycin Sulfate, 1063 Rhubarb, 1345 Protamine Sulfate, 1041, 1921 Rice Starch, 1346 Rose Fruit, 1346 Injection, 1042, 1922, 2186 Rifampicin, 1064 Scutellaria Root, 1359, 1967 Prothionamide, 1042 Capsules, 1065 Senega, 1361, 1968, 2234 Protirelin, 1043 Ringer's Solution, 1066, 1922 Senna Leaf, 1362 Tartrate Hydrate, 1044 Ritodrine Hydrochloride, 1067 Smilax Rhizome, 1364, 1968 Prunella Spike, 1341 Tablets, 1068 Sophora Root, 1364, 1969 Pueraria Root, 1341 Rokitamycin, 1069 Sweet Hydrangea Leaf, 1365 Pullulan, 1045 Tablets, 1923, 2190 Swertia Herb, 1366 Purified Rose Fruit, 1346 Tragacanth, 1369 Dehydrocholic Acid, 556 Powdered, 1346 Turmeric, 1969, 2238 Gelatin, 697 Rosin, 1347 Zanthoxylum Fruit, 1371, 2239 Lanolin, 808 Roxatidine Acetate Hydrochloride, Pranoprofen, 1018 Shellac, 1085 1070 Pravastatin Sodium, 1018 Sodium Hyaluronate, 2194 Extended-release Capsules, 1071 Prazepam, 1020 Water, 1236 Roxithromycin, 1073, 1923 Tablets, 1021 Water, Sterile, 1236 Royal Jelly, 2233 Prazosin Hydrochloride, 2174 Pyrantel Pamoate, 1045 Ryokeijutsukanto Extract, 1347, 1965 Precipitated Calcium Carbonate, 389 Pyrazinamide, 1046 Prednisolone, 1021 Pyridostigmine Bromide, 1047 Acetate, 1023 Pyridoxine Hydrochloride, 1047

Supplement II, JP XV Index 2305

S Sisomicin Sulfate, 1090 Epinephrine, 277 Slaked Lime, 392 Glycerin and Potash, 704 Saccharated Pepsin, 1074 Smilax Rhizome, 1364, 1968 Isotonic Salt, 1098 Saccharin, 1075 Powdered, 1364, 1968 Isotonic Sodium Chloride, 1098, Sodium, 1076 Sodium 1893 Sodium Hydrate, 1076 Acetate Hydrate, 1091 Ketoconazole, 2155 Safflower, 1348 Aurothiomalate, 1092 Merbromin, 863 Saffron, 1349 Benzoate, 1093 Mercurochrome, 863 Saireito Extract, 1349 Bicarbonate, 1093 Naphazoline and Chlorpheniramine, Salazosulfapyridine, 1077 Bicarbonate and Bitter Tincture 906 Salbutamol Sulfate, 1078 Mixture, 1364 Ringer's, 1066, 1922 Salicylated Alum Powder, 1078 Bicarbonate Injection, 1094, 1925 Saponated Cresol, 545 Salicylic Acid, 1079, 1924 Bisulfite, 1094 Silver Protein, 1089 Borate, 1095 Sodium Citrate, Diagnostic, 1100 Plaster, Adhesive, 1080 131 Spirit, 1080 Bromide, 1095 Sodium Iodide ( I), 1103 Santonin, 1081 Carbonate, Dried, 1096 D-Sorbitol, 1113 Saponated Cresol Solution, 545 Carbonate Hydrate, 1096 Thianthol and Salicylic Acid, Com- Saposhnikovia Root, 1352, 1966, 2234 Chloride, 1097 pound, 1165 Sappan Wood, 1352 Chloride Injection, 0.9%, 1098 Tolnaftate, 1189 Saussurea Root, 1352, 1966 Chloride Injection, 10%, 1098, 1925 Sophora Root, 1364, 1968 Schisandra Fruit, 1352 Chloride Solution, Isotonic, 1098, Powdered, 1364, 1969 1893 Sorbitan Sesquioleate, 1111 Schizonepeta Spike, 1353 51 Scopolamine Chromate ( Cr) Injection, 1099 D-Sorbitol, 1112 Butylbromide, 1082 Citrate Hydrate, 1099 Solution, 1113 Hydrobromide Hydrate, 1083 Citrate Injection for Transfusion, Soybean Oil, 1113 Scopolia Extract, 1353, 1967 1099, 1926 Spectinomycin Hydrochloride Hydrate, and Carbon Powder, 1355 Citrate Solution, Diagnostic, 1100 1114 and Ethyl Aminobenzoate Powder, Cromoglicate, 1100 Spiramycin Acetate, 1114 1355 Fusidate, 1101 Spirit and Tannic Acid Suppositories, Hyaluronate, Purified, 2194 Capsicum and Salicylic Acid, 1270 1357 Hydrogen Sulfite, 1094 Foeniculated Ammonia, 1286 ,Papaverine and Ethyl Aminobenzoate Hydroxide, 1101 Iodine Salicylic Acid and Phenol, Powder, 1356 Iodide, 1102 772 Iodide (123I) Capsules, 1103 Methyl Salicylate, Compound, 879 Powder, 1354 131 Rhizome, 1357, 1967, 2234 Iodide ( I) Capsules, 1103 Salicylic Acid, 1080 Iodide (131I) Solution, 1103 Salicylic Acid, Compound, 1080 Scutellaria Root, 1358, 1967 131 Powdered, 1359, 1967 Iodohippurate ( I) Injection, 1103 Spironolactone, 1116 Senega, 1360, 1968, 2234 Iotalamate Injection, 1103, 2195 Starch Powdered, 1361, 1968, 2234 Lauryl Sulfate, 1104 Corn, 542, 2110 Metabisulfite, 1108 Glycolate, Sodium, 1926 Syrup, 1361 99m Senna Leaf, 1361 Pertechnetate ( Tc) Injection, Potato, 1014, 2174 Powdered, 1362 1105 Rice, 1346, 2189 Picosulfate Hydrate, 1105 Wheat, 1237, 2216 L-Serine, 1925 Serrapeptase, 1083 Polystyrene Sulfonate, 1106 Stearic Acid, 1116 Serum Gonadotrophin, 710 Prasterone Sulfate Hydrate, 1107 Stearyl Alcohol, 1117 for Injection, 711 Pyrosulfate, 1108 Sterile Purified Water, 1236 Sesame Oil, 1084 Salicylate, 1108 Streptomycin Sulfate, 1117 Sevoflurane, 2191 Starch Glycolate, 1926 for Injection, 2198 Shellac Sulfite, Dried, 1109 Sucralfate Hydrate, 1118 Purified, 1085 Thiosulfate Hydrate, 1109 Sucrose, 1120 Shimbuto Extract, 2234 Thiosulfate Injection, 1110, 1927 Sulbactam Sodium, 1122, 1927 Siccanin, 1086 Valproate, 1110, 2195 Sulbenicillin Sodium, 1123 Silver Valproate Syrup, 2196 Sulfadiazine Silver, 1124 Nitrate, 1088 Valproate Tablets, 2197 Sulfafurazole, 1128 Nitrate Ophthalmic Solution, 1088 Solution Sulfamethizole, 1125 Protein, 1088 Adrenaline, 277 Sulfamethoxazole, 1126 Protein Solution, 1089 Alum, 293 Sulfamonomethoxine Hydrate, 1126 Simple Benzalkonium Chloride, 342 Sulfasalazine, 1077 Ointment, 1089 Benzethonium Chloride, 345 Sulfinpyrazone, 1127, 1927 Syrup, 1089 Chlorhexidine Gluconate, 493 Tablets, 1128, 1927 Simvastatin, 2192 Cresol, 545 Sulfisomezole, 1126 Sinomenium Stem, 1363 Dental Sodium Hypochlorite, 310 Sulfisoxazole, 1128 Diagnostic Sodium Citrate, 1100 Sulfobromophthalein Sodium, 1129

2306 Index Supplement II, JP XV

Injection, 1130 Amitriptyline Hydrochloride, 299, Folic Acid, 681, 1888 Sulfur, 1130 1831 Fosfestrol, 684, 1888 and Camphor Lotion, 1130 Amlexanox, 1833 Furosemide, 691 Salicylic Acid and Thianthol Oint- Amlodipine Besilate, 2082 Griseofulvin, 1890, 2135 ment, 1131 Amosulalol Hydrochloride, 1836 Haloperidol, 718 Sulindac, 2198 Amphotericin B, 305 Hydralazine Hydrochloride, 725, Sulpiride, 1131 Aspirin, 319 1890 Capsules, 1132 Azathioprine, 326, 2088 Imidapril Hydrochloride, 2141 Tablets, 1132 Baclofen, 332, 1841 Imipramine Hydrochloride, 752, Sulpyrine Benidipine Hydrochloride, 339 1893 Hydrate, 1133 Betahistine Mesilate, 354 Indapamide, 2144 Injection, 1134, 1927 Betamethasone, 356, 2090 Ipriflavone, 2146 Sultamicillin Tosilate Hydrate, Bezafibrate Sustained Release, 365 Irsogladine Maleate, 2149 1134,1927 Bisoprolol Fumarate, 1844 Isoniazid, 781, 2151 Sultiame, 1136 Bucillamine, 1845 Isosorbide Dinitrate, 786, 2151 Suppositories Buformine Hydrochloride, 1849 Isoxsuprine Hydrochloride, 1895 Bisacodyl, 368, 1843 Buformine Hydrochloride Josamycin, 1897, 2152 Indometacin, 757, 2145 Entericcoated, 1847 Labetalol Hydrochloride, 1899 Scopolia Extract and Tannic Acid, Cadralazine, 2092 Lanatoside C, 806 1357 Cefcapene Pivoxil Hydrochloride, Levothyroxine Sodium, 817 Suxamethonium Chloride 433 Liothyronine Sodium, 822 for Injection, 1137, 1928 Cefditoren Pivoxil, 438 Lisinopril, 824 Hydrate, 1137 Cefteram Pivoxil, 2104 Manidipine Hydrochloride, 1902 Injection, 1138, 1928 Cetirizine Hydrochloride, 1857 Mefruside, 849, 1903 Sweet Hydrangea Leaf, 1365 Chlordiazepoxide, 492, 1858 Metformin Hydrochloride, 867 Powdered, 1365 Chlorphenesin Carbamate, 1859 Methyldopa, 874, 1903 Swertia Chlorpheniramine Maleate, 500 Methylergometrine Maleate, 877 and Sodium Bicarbonate Powder, Chlorpromazine Hydrochloride, 503, Methyltestosterone, 883 1367 1861 Metoclopramide, 886 Herb, 1365 Chlorpropamide, 505, 1861 Metoprolol Tartrate, 888 Herb, Powdered, 1366 Cibenzoline Succinate, 1862 Metronidazole, 889 Synthetic Cilazapril, 1864 Minocycline Hydrochloride, 2163 Aluminum Silicate, 290 Cilostazol, 512, 1866 Mizoribine, 1907 Camphor, 402 Clarithromycin, 517 Morphine Hydrochloride, 902, 1908, Syrup Clomifene Citrate, 527, 2109 2165 Amphotericin B, 305 Codeine Phosphate, 537, 2109 Mosapride Citrate, 2166 Cefadroxil for, 1853 Dichlorphenamide, 572 Nabumetone, 1910 Cefalexin, 2099 Diclofenamide, 572 Nicergoline, 915 Cefatrizine Propylene Glycolate for, Diethylcarbamazine Citrate, 574, Nicomol, 918, 2168 2100 2113 Nilvadipine, 924 Cefroxadine for, 2103 Diethylstilbestrol Diphosphate, 684 Nitrendipine, 927 Faropenem Sodium for, 659, 1886, Digitoxin, 576 Nitroglycerin, 928 2126 Digoxin, 580, 2116 Norgestrel and Ethinylestradiol, 934 Ipecac, 1304 Dimenhydrinate, 589, 2117 Perphenazine, 977 Monosodium Trichloroethyl Phos- Diphenylhydantoin, 992 Perphenazine Maleate, 979 phate, 1203 Distigmine Bromide, 600, 2117 Phenytoin, 992, 2170 Orange Peel, 1325 Dydrogesterone, 610 Piperazine Phosphate, 1000 Senega, 1361 Emorfazone, 2123 Pivmecillinam Hydrochloride, 2173 Simple, 1089 Enalapril Maleate, 1880 Prazepam, 1021 Sodium Valproate, 2196 Ephedrine Hydrochloride, 621, 1882, Prednisolone, 1022 Triclofos Sodium, 1203 2124 Probenecid, 1027, 2177 Ergometrine Maleate, 626 Procainamide Hydrochloride, 1029, T Erythromycin Enteric-Coated, 1882, 2180 2125 Prochlorperazine Maleate, 1033, Estriol, 635 2181 Tablets Etacrynic Acid, 636 Propafenone Hydrochloride, 2184 Acemetacin, 2074 Ethinylestradiol, 642 Propranolol Hydrochloride, 1038 Acetylsalicylic Acid, 319 Etidronate Disodium, 650 Propylthiouracil, 1040, 2185 Ajmaline, 279, 1826 Etilefrine Hydrochloride, 651 Rebamipide, 2188 Alacepril, 280 Etizolam, 1884 Reserpine, 1057 Allopurinol, 2078 Famotidine, 657 Ritodrine Hydrochloride, 1068 Alminoprofen, 1827 Faropenem Sodium, 660, 1886, 2126 Rokitamycin, 1923, 2190 Amiodarone Hydrochloride, 2081 Flutoprazepam, 2130 Sodium Valproate, 2197

Supplement II, JP XV Index 2307

Sulfinpyrazone, 1128, 1927 Thrombin, 1170 Trihexyphenidyl Hydrochloride, 1204 Sulpiride, 1132 Thymol, 1170 Tablets, 1204 Thiamazole, 1160 Tiapride Hydrochloride, 2203 Trimebutine Maleate, 1206 Tiapride Hydrochloride, 2204 Tablets, 2204 Trimetazidine Hydrochloride, 1207, Tiaramide Hydrochloride, 1172 Tiaramide Hydrochloride, 1171 1931 Tipepidine Hibenzate, 1177, 1930 Tablets, 1172 Tablets, 1207 Tolbutamide, 1188, 2205 Ticlopidine Hydrochloride, 1173 Trimethadione, 1208 Tosufloxacin Tosilate, 2207 Timepidium Bromide Hydrate, 1174 Tablets, 1209 Tranexamic Acid, 1193 Timolol Maleate, 1174 Trimetoquinol Hydrochloride Hydrate, Trichlormethiazide, 1199 Tincture 1209 Trihexyphenidyl Hydrochloride, Bitter, 1266 Tropicamide, 1211 1204 Capsicum, 1269 Troxipide, 2208 Trimetazidine Hydrochloride, 1207 Iodine, 769 Fine Granules, 2209 Trimethadione, 1209 Iodine, Dilute, 769 Tablets, 2210 Troxipide, 2210 Nux Vomica, 1323 L-Tryptophan, 1211 Ursodeoxycholic Acid, 2214 Opium, 940 Tubocurarine Chloride Hydrochloride Verapamil Hydrochloride, 1226 Orange Peel, 1325 Hydrate, 1212, 1931 Voglibose, 1232 Tinidazole, 1175 Injection, 1213, 1931 Warfarin Potassium, 1234, 2215 Tipepidine Hibenzate, 1176 Tubocurarine Hydrochloride, 1212 Zaltoprofen, 1243 Tablets, 1177, 1930 Injection, 1213 Tacrolimus Hydrate, 2199 Titanium Oxide, 1178 Tulobuterol Hydrochloride, 1213 Talampicillin Hydrochloride, 1138 Tizanidine Hydrochloride, 1179 Turmeric, 1367, 1969, 2237 Talc, 1139, 1928 Toad Venom, 1368 Powdered, 1969, 2238 Tamsulosin Hydrochloride, 1140 Tobramycin, 1180 Turpentine Oil, 1214 Tannic Acid, 1141 Injection, 1930 L-Tyrosine, 1931 Tartaric Acid, 1141 Tocopherol, 1181 Taurine, 1142 Acetate, 1182 U Tazobactam, 2200 Calcium Succinate, 1183 Teceleukin Nicotinate, 1184 Ubenimex, 1932 for Injection (Genetical Recombina- dl-α-Tocopherol, 1181 Capsules, 2211 tion), 1148, 1929 Acetate, 1182 Ubidecarenone, 1214 (Genetical Recombination), 1143 Nicotinate, 1184 Ulinastatin, 1215 Tegafur, 1149 Todralazine Hydrochloride Hydrate, Uncaria Hook, 1370 Teicoplanin, 1150, 2201 1185 Urapidil, 1217 Teprenone, 2202 Tofisopam, 1186 Urea, 1218 Terbutaline Sulfate, 1153 Tolazamide, 1187 Urokinase, 1219 Testosterone Tolbutamide, 1188 Ursodeoxycholic Acid, 1220, 2212 Enanthate, 1154 Tablets, 1188, 2205 Granules, 2213 Enanthate Injection, 1154, 2203 Tolnaftate, 1189 Tablets, 2214 Propionate, 1155 Solution, 1189 Uva Ursi Fluidextract, 1371, 1969 Propionate Injection, 1155, 2203 Tolperisone Hydrochloride, 1190 Tetracaine Hydrochloride, 1156 Tosufloxacin Tosilate Tetracycline Hydrochloride, 1157 Hydrate, 2205 V Thallium (201Tl) Chloride Injection, Tablets, 2207 1158 Tragacanth, 1369 Vaccine Theophylline, 1158 Powdered, 1369 BCG, Freeze-dried, (for Percutaneous Thiamazole, 1159 Tranexamic Acid, 1191 Use), 335 Tablets, 1160 Capsules, 1192 Cholera, 506 Thiamine Injection, 1193 Diphtheria-Purified Pertussis-Tetanus Chloride Hydrochloride, 1160 Tablets, 1193 Combined, Adsorbed, 596 Chloride Hydrochloride Injection, Trapidil, 1194 Hepatitis B, Adsorbed, 716 1161, 1930 Trepibutone, 1195 Inactivated Tissue Culture Rabies, Chloride Hydrochloride Powder, Tretoquinol Hydrochloride, 1209 Freeze-dried, 1054 1162 Triamcinolone, 1195 Influenza HA, 758 Nitrate, 1162 Acetonide, 1196 Japanese Encephalitis, 786 Thiamylal Sodium, 1163 Triamterene, 1197 Japanese Encephalitis, Freeze-dried, for Injection, 1164 Tribulus Fruit, 1369 786 Thianthol, 1165 Trichlormethiazide, 1198 Live Attenuated Measles, Thiopental Sodium, 1166 Tablets, 1199 Freeze-dried, 843 for Injection, 1167, 1930 Trichomycin, 1201 Live Attenuated Mumps, Freeze-dried, Thioridazine Hydrochloride, 1168 Trichosanthes Root, 1369 902 Thiotepa, 1168 Triclofos Sodium, 1202 Live Attenuated Rubella, Freeze-dried, L-Threonine, 1169 Syrup, 1203 1074

2308 Index Supplement II, JP XV

Live Oral Poliomyelitis, 1005 Vitamin C, 316 Wood Creosote, 1870, 2110 Purified Pertussis, Adsorbed, 980 Injection, 317 Smallpox, Freeze-dried, 1091 Powder, 317 X Smallpox, Freeze-dried, Prepared in Vitamin D2, 624 Cell Culture, 1091 Vitamin D , 506 3 Xylitol, 1240 Weil's Disease and Akiyami Com- Vitamin E, 1181 Injection, 1241, 1935 bined, 1237 Acetate, 1182 L-Valine, 1221 Calcium Succinate, 1183 Vancomycin Hydrochloride, 1221 Nicotinate, 1184 Y for Injection, 1223 Vitamin K1, 993 Vasopressin Injection, 1223, 2215 Voglibose, 1231 Yellow Verapamil Hydrochloride, 1225 Tablets, 1232 Beeswax, 336 Tablets, 1226 Petrolatum, 982 Vinblastine Sulfate, 1226 W for Injection, 1227 Z Vincristine Sulfate, 1228, 1933 Warfarin Potassium, 1233 Vitamin A Tablets, 1234, 2215 Zaltoprofen, 1242 Acetate, 1058 Water, 1235 Tablets, 1243 Capsules, 1230 for Injection, 1235, 1934 Zanthoxylum Fruit, 1371, 2239 Oil, 1229 Purified, 1236 Powdered, 1371, 2239 Oil Capsules, 1230 Sterile Purified, 1236 Zedoary, 1372, 1969 Palmitate, 1059 Weak Opium Alkaloids and Scopola- Zidovudine, 1935 Vitamin B 1 mine Injection, 945 Zinc Hydrochloride, 1160 Weil's Disease and Akiyami Combined Chloride, 1244 Hydrochloride Injection, 1161 Vaccine, 1237 Oxide, 1245 Hydrochloride Powder, 1162 Wheat Starch, 1237, 2216 Oxide Oil, 1245 Nitrate, 1162 White Oxide Ointment, 1246 Vitamin B , 1059 2 Beeswax, 336 Oxide Starch Powder, 1246 Phosphate Ester, 1061 Ointment, 1238 Sulfate Hydrate, 1246, 2216 Phosphate Ester Injection, 1062 Petrolatum, 981 Sulfate Ophthalmic Solution, 1247 Powder, 1060 Shellac, 1085 Zinostatin Stimalamer, 1247 Vitamin B , 1047 6 Soft Sugar, 1121 Zolpidem Tartrate, 2217 Injection, 1048 Whole Human Blood, 1238 Vitamin B , 548 12 Wine, 1238 Injection, 549

INDEX IN LATIN NAME

A Pulverata, 1268 F Cannabis Fructus, 1298 Achyranthis Radix, 1252 Capsici Fructus, 1268 Fel Ursi, 1262 Adeps Pulveratus, 1269 Foeniculi Fructus, 1285 Lanae Rurificatus, 808 Cardamomi Fructus, 1271 Pulveratus, 1285 Suillus, 808 Carthami Flos, 1348 Forsythiae Fructus, 1286 Agar, 1252 Caryophylli Flos, 1274 Fossilia Ossis Mastodi, 1313 Pulveratum, 1253 Pulveratus, 1274 Fritillariae Bulbus, 1287 Akebiae Caulis, 1253 Cassiae Semen, 1271 Catalpae Fructus, 1271 Alismatis Rhizoma, 1253 G Pulveratum, 1253 Cera Aloe, 1254 Alba, 336 Gambir, 1287 Pulverata, 1255 Carnauba, 411 Pulveratum, 1287 Alpiniae Flava, 336 Gardeniae Fructus, 1288 Fructus, 1265 Chrysanthemi Flos, 1271 Pulveratus, 1288 Officinari Rhizoma, 1256 Cimicifugae Rhizoma, 1272 Gastrodiae Tuber, 1289 Amomi Semen, 1256 Cinnamomi Cortex, 1272 Gentianae Pulveratum, 1256 Pulveratus, 1273 Radix, 1290 Amylum Clematidis Radix, 1274 Radix Pulverata, 1290 Maydis, 542 Cnidii Scabrae Radix, 1306 Oryzae, 1346 Monnieris Fructus, 1275 Scabrae Radix Pulverata, 1306 Solani, 1014 Rhizoma, 1275 Geranii Herba, 1291 Tritici, 1237 Rhizoma Pulveratum, 1276 Pulverata, 1291 Anemarrhenae Rhizoma, 1256 Coicis Semen, 1276 Ginseng Radix, 1292 Angelicae Radix, 1305 Pulveratum, 1276 Pulverata, 1293 Pulverata, 1305 Condurango Cortex, 1276 Rubra, 1342 Apilac, 2233 Coptidis Rhizoma, 1277 Glehniae Radix cum Rhizoma, 1294 Araliae Cordatae Rhizoma, 1937 Pulveratum, 1278 Glycyrrhizae Radix, 1295 Arctii Fructus, 1267 Corni Fructus, 1279 Pulverata, 1296 Arecae Semen, 1258 Corydalis Tuber, 1279 Gummi Arabicum, 1251 Armeniacae Semen, 1257 Pulveratum, 1940 Pulveratum, 1251 Artemisiae Capillaris Flos, 1258 Crataegi Fructus, 1941 Gypsum Asiasari Radix, 1259 Crocus, 1349 Exsiccatum, 1298 Asparagi Tuber, 1259 Curcumae Rhizoma, 1367 Fibrosum, 1297 Astragali Radix, 1260 Purveratum, 1969 Atractylodis Cyperi Rhizoma, 1280 Lanceae Rhizoma, 1260 Pulveratum, 1280 H Lanceae Rhizoma Pulveratum, 1260 Rhizoma, 1261 D Houttuyniae Herba, 1302 Rhizoma Pulveratum, 1261 Hydrangeae Dulcis Folium, 1365 Aurantii Digenea, 1280 Pulveratum, 1365 Bobilis Pericarpium, 1273 Dioscoreae Rhizoma, 1282 Fructus Immaturus, 1302 Pulveratum, 1282 I Pericarpium, 1265 Dolichi Semen, 1282 Imperatae Rhizoma, 1302 B E Ipecacuanhae Radix, 1303 Pulverata, 1303 Belladonnae Radix, 1263 Eleutherococci senticosi Rhizoma, Benincasae Semen, 1264 1283 L Benzoinum, 1265 Ephdrae Herba, 1283 Bezoar Bovis, 1325 Epimedii Herba, 1284 Leonuri Herba, 1958 Bufonis Venenum, 1368 Eriobotryae Folium, 1314 Lilii Bulbus, 1958 Bupleuri Radix, 1266 Eucommiae Cortex, 1284 Linderae Radix, 1313 Evodiae Fructus, 1285 Lithospermi Radix, 1313 C Extractum Belladonnae, 1263 Lonicerae Folium Cum Caulis, 1314 Longan Arillus, 2229 Calumbae Radix, 1267 Lycii

2309 2310 Index in Latin Name Supplement II, JP XV

Cortex, 1315 Pulverata, 1329 Scopoliae Rhizoma, 1357 Fructus, 1315 Panacis Japonici Rhizoma, 1326 Scutellariae Radix, 1358 Pulveratum, 1327 Pulverata, 1359 M Perillae Herba, 1329 Senegae Radix, 1360 Persicae Semen, 1327 Pulverata, 1361 Pulveratum, 1327 Sennae Folium, 1361 Magnoliae Peucedani Radix, 1961 Pulveratum, 1362 Cortex, 1315 Pharbitidis Semen, 1330 Sevum Bovinum, 336 Cortex Pulveratus, 1316 Phellodendri Cortex, 1330 Sinomeni Caulis et Rhizoma, 1363 Flos, 1317 Pulveratus, 1331 Smilacis Rhizoma, 1364 Malloti Cortex, 1317 Picrasmae Lignum, 1333 Pulveratum, 1364 Mel, 1301 Pulveratum, 1333 Sophorae Radix, 1364 Menthae Herba, 1317 Pinelliae Tuber, 1333 Pulverata, 1364 Mori Cortex, 1320 Plantaginis Strychni Semen, 1321 Moutan Cortex, 1318 Herba, 1334 Swertiae Herba, 1365 Pulveratus, 1319 Semen, 1334 Pulverata, 1366 Myristicae Semen, 2229 Platycodi Radix, 1334 Syrupus Pulverata, 1335 Ipecacuanha, 1304 N Pogostemoni Herba, 2231 Senegae, 1361 Polygalae Radix, 1335 Nelumbis Semen, 1320 Pulverata, 1335 T Notopterygii Rhizoma, 1321 Polygonati Rhizoma, 1336 Nupharis Rhizoma, 1321 Polygoni Multiflori Radix, 1336 Tinctura Amara, 1266 Polyporus, 1336 Tragacantha, 1369 Pulveratus, 1337 O Pulverata, 1369 Poria, 1337 Tribuli Fructus, 1369 Pulveratum, 1337 Oleum Trichosanthis Radix, 1369 Arachidis, 971 Processi Aconiti Radix, 1338 Pulverata, 1339 Aurantii, 946 U Cacao, 386 Prunellae Spica, 1341 Camelliae, 400 Puerariae Radix, 1341 Uncariae Uncis Cum Ramulus, 1370 Caryophylli, 1275 Uvae Ursi Folium, 1262 Cinnamomi, 1273 Q Cocois, 535 Eucalypti, 654 Quercus Cortex, 2232 V Foeniculi, 1286 Maydis, 542 R Valerianae Radix, 1306 Menthae Japonicae, 1318 Pulverata, 1307 Olivae, 939 Rehmanniae Radix, 1343 Rapae, 1055 Resina Pini, 1347 Z Ricini, 414 Rhei Rhizoma, 1344 Sesami, 1084 Pulveratum, 1345 Zanthoxyli Fructus, 1371 Sojae, 1113 Rosae Fructus, 1346 Pulveratus, 1371 Terebinthinae, 1214 Pulveratus, 1346 Zedoariae Rhizoma, 1372 Ophiopogonis Tuber, 1324 Zingiberis Opium Pulveratum, 939 Processum Rhizoma, 1341 Ostreae Testa, 1326 S Rhizoma, 1291 Pulverata, 1326 Saposhnikoviae Radix, 1352 Rhizoma Pulveratum, 1292 Sappan Lignum, 1352 Zizyphi P Saussureae Radix, 1352 Fructus, 1307 Schisandrae Fructus, 1352 Semen, 1307 Paeoniae Radix, 1328 Schizonepetae Spica, 1353

INDEX IN JAPANESE

注射液 943 アロエ末 1255 アアヘン散 940 アロチノロール塩酸塩 314 アヘンチンキ 940 アロプリノール 284 アヘン･トコン散 1324 アロプリノール錠 2078 亜鉛華デンプン 1246 アヘン末 939 安息香酸 345 亜鉛華軟膏 1246 アマチャ 1365 安息香酸ナトリウム 1093 アカメガシワ 1317 アマチャ末 1365 安息香酸ナトリウムカフェインアクチノマイシン D 275 アマンタジン塩酸塩 293 388 アクラルビシン塩酸塩 272 アミオダロン塩酸塩 2079 安息香酸ベンジル 347 アクリノール･亜鉛華軟膏 274 アミオダロン塩酸塩錠 2081 アンソッコウ 1265 アクリノール水和物 274 アミカシン硫酸塩 296 アンチピリン 310 アクリノール･チンク油 273 アミカシン硫酸塩注射液 1830 アンピシリン水和物 307 アシクロビル 2075 アミドトリゾ酸 295 アンピシリンナトリウム 308 アザチオプリン 325 アミドトリゾ酸ナトリウムメグルミアンベノニウム塩化物 294 アザチオプリン錠 326, 2088 ン注射液 853, 2161 アンモニア･ウイキョウ精 1286 亜酸化窒素 929 アミドトリゾ酸メグルミン注射液アンモニア水 299 アジスロマイシン水和物 327 851 アンレキサノクス 1831 アジマリンアジマリン錠 278 279, アミトリプチリン塩酸塩 298 アンレキサノクス錠 1833 1826 アミトリプチリン塩酸塩錠亜硝酸アミル 309 299,1831 アスコルビン酸イ 316 アミノ安息香酸エチル 644 アスコルビン酸散 317 アミノフィリン水和物 297 アスコルビン酸注射液イオウ 317, 1839 アミノフィリン注射液 297, 1831 1130 アズトレオナムイオウ･カンフルローション 328 アムホテリシン B 303 1130 アストロマイシン硫酸塩イオウ･サリチル酸･チアントール軟 322 アムホテリシン B 錠 305 アスパラギン酸膏 L- 318 アムホテリシン B シロップ 305 1131 アスピリンイオタラム酸 318 アムロジピンベシル酸塩 1834 774 アスピリンアルミニウムイオタラム酸ナトリウム注射液 319 アムロジピンベシル酸塩錠 2082 アスピリン錠 319 アモキサピン 301 1103, 2195 アスポキシシリン水和物イオタラム酸メグルミン注射液 320 アモキシシリンカプセル 2083 アセグルタミドアルミニウム 266 アモキシシリン水和物 302, 2084 852, 2161 アセタゾラミドイオトロクス酸 268 アモスラロール塩酸塩 1835 775 アセトアミノフェンイオパミドール 267 アモスラロール塩酸塩錠 1836 773 アセトヘキサミドイクタモール 269 アモバルビタール 300 744 アセブトロール塩酸塩イコサペント酸エチル 265 アラセプリル 279 646 アセメタシンイセパマイシン硫酸塩 1825 アラセプリル錠 280 777 アセメタシンカプセルイセパマイシン硫酸塩注射液 2073 L-アラニン 2076 2150 アセメタシン錠イソクスプリン塩酸塩 2074 アラビアゴム 1251 1894 アゼラスチン塩酸塩イソクスプリン塩酸塩錠 1839 アラビアゴム末 1251 1895 アゼラスチン塩酸塩顆粒イソソルビド 2089 アリメマジン酒石酸塩 283 784 アセンヤクイソニアジド 1287 アルガトロバン水和物 2087 780 アセンヤク末イソニアジド錠 1287 亜硫酸水素ナトリウム 1094 781, 2151 アテノロールイソニアジド注射液 323 L-アルギニン 313 781, 2151 アドレナリンイソフェンインスリン水性懸濁注射 276 L-アルギニン塩酸塩 313 アドレナリン液液 277 L-アルギニン塩酸塩注射液 762 アドレナリン注射液イソフルラン 276 314,1839 778 アトロピン硫酸塩水和物イソプレナリン塩酸塩 324 アルジオキサ 282 l- 782 アトロピン硫酸塩注射液イソプロパノール 324 アルプラゾラム 284 783 アプリンジン塩酸塩イソプロピルアンチピリン 2085 アルプレノロール塩酸塩 285 783 アプリンジン塩酸塩カプセルイソロイシン 2086 アルプロスタジル 286 L- 780 亜ヒ酸パスタ 315 アルプロスタジルアルファデクスイダルビシン塩酸塩 745 アフロクアロンイドクスウリジン 277 287 747 アヘンアルカロイド･アトロピン注イドクスウリジン点眼液アルプロスタジル注射液 1828 747, 1893 射液イトラコナゾール 942 アルベカシン硫酸塩 311 1896 アヘンアルカロイド塩酸塩イフェンプロジル酒石酸塩 941 アルベカシン硫酸塩注射液 312 748 アヘンアルカロイド塩酸塩注射液イブジラストアルミノプロフェン 1826 1892 イブプロフェン 942 アルミノプロフェン錠 1827 744 アヘンアルカロイド･スコポラミンイプラトロピウム臭化物水和物アロエ 1254

2311 2312 Index in Japanese Supplement II, JP XV

776 エストラジオール安息香酸エステル 626 イプリフラボン 2145 注射液 632 エルゴメトリンマレイン酸塩注射液イプリフラボン錠 2146 エストリオール 633 625, 2125 イミダプリル塩酸塩 2140 エストリオール錠 635 塩化亜鉛 1244 イミダプリル塩酸塩錠 2141 エストリオール水性懸濁注射液塩化インジウム(111In)注射液 755 イミプラミン塩酸塩 751 634, 2125 塩化カリウム 1009 イミプラミン塩酸塩錠 752, 1893 エタクリン酸 636 塩化カルシウム水和物 390 イミペネム水和物 749 エタクリン酸錠 636 塩化カルシウム注射液 390, 1851 イルソグラジンマレイン酸塩 2147 エタノール 638 塩化タリウム(201Tl)注射液 1158 イルソグラジンマレイン酸塩細粒エタンブトール塩酸塩 637 塩化ナトリウム 1097 2148 エチオナミド 643 10%塩化ナトリウム注射液イルソグラジンマレイン酸塩錠エチゾラム 652 1098,1925 2149 エチゾラム細粒 1883 エンゴサク 1279, 1940 イレイセン 1274, 1939 エチゾラム錠 1884 エンゴサク末 1940 インジゴカルミン 754 エチドロン酸二ナトリウム 649 塩酸 725 インジゴカルミン注射液 755, 2145 エチドロン酸二ナトリウム錠 650 塩酸リモナーデ 727 インスリン 758 エチニルエストラジオール 642, エンビオマイシン硫酸塩 616 インスリン亜鉛水性懸濁注射液 2125 エンフルラン 615 763 エチニルエストラジオール錠 642 インスリン注射液 762 L-エチルシステイン塩酸塩 645 オインダパミド 2143 エチルモルヒネ塩酸塩水和物 648 インダパミド錠 2144 エチレフリン塩酸塩 650 オウギインチンコウ 1258 エチレフリン塩酸塩錠 651 1260, 2219 オウゴンインデノロール塩酸塩 753 エチレンジアミン 648 1358, 1967 オウゴン末インドメタシン 755 エデト酸ナトリウム水和物 598 1359, 1967 黄色ワセリンインドメタシンカプセル 756, 1893 エーテル 641 982 オウセイインドメタシン坐剤 757, 2145 エカベトナトリウム顆粒 2121 1336, 2232 オウバクインフルエンザ HA ワクチン 758 エカベトナトリウム水和物 2121 1330 オウバク･タンナルビン･ビスマス散インヨウカク 1284 エテンザミド 640, 2125 エトスクシミド 644 1332 オウバク末エトドラク 653 1331 ウオウレンエトポシド 653 1277, 1940 オウレン末エドロホニウム塩化物 611 1278, 1940 ウイキョウオキサゾラム 1285 エドロホニウム塩化物注射液 612, 948 ウイキョウ末オキサピウムヨウ化物 1285 1878 947 ウイキョウ油オキサプロジン 1286 エナラプリルマレイン酸塩 1879 948 ウコンオキシコドン塩酸塩水和物 1367, 1969, 2237 エナラプリルマレイン酸塩錠 1880 951 ウコン末オキシテトラサイクリン塩酸塩 1969, 2238 エノキサシン水和物 616 ウベニメクス 1932 エピリゾール 621 956 ウベニメクスカプセルオキシトシン 2211 エピルビシン塩酸塩 622 958 ウヤクオキシトシン注射液 1313, 1959 エフェドリン塩酸塩 619 960 ウラピジルオキシドール 1217 エフェドリン塩酸塩散 10% 620 954 ウリナスタチンオキシブプロカイン塩酸塩 1215 エフェドリン塩酸塩錠 621, 1882, 951 ウルソデオキシコール酸オキシメトロン 2212 2124 956 ウルソデオキシコール酸錠オキセサゼイン 2214 エフェドリン塩酸塩注射液 949 ウルソデオキシコール酸顆粒オクスプレノロール塩酸塩 185, 619,1882 950 オザグレルナトリウム 1220, 2213 エペリゾン塩酸塩 618 1916 ウロキナーゼオフロキサシン 1219 エモルファゾン 1878 938 ウワウルシオメプラゾール 1262 エモルファゾン錠 2123 1915 ウワウルシ流エキスオリブ油 1371, 1969 エリスロマイシン 627 939 エリスロマイシンエチルコハク酸エオルシプレナリン硫酸塩 946 オレンジ油エステル 629 946 エリスロマイシンステアリン酸塩オンジ 1335, 1962 オンジ末 1335, 1962 エイジツ 1346 630 エイジツ末 1346 エリスロマイシン腸溶錠 1882, 液状フェノール 986 2125 カエコチオパートヨウ化物 610 エリスロマイシンラクトビオン酸塩エスタゾラム 631 629 カイニン酸･サントニン散 790 エストラジオール安息香酸エステルエルカトニン 612 カイニン酸水和物 789 631 エルゴカルシフェロール 624 カオリン 795 エストラジオール安息香酸エステルエルゴタミン酒石酸塩 627 カカオ脂 386 水性懸濁注射液 633, 2125 エルゴメトリンマレイン酸塩 625 加香ヒマシ油 415 エルゴメトリンマレイン酸塩錠

Supplement II, JP XV Index in Japanese 2313

カゴソウ 1341 乾燥破傷風ウマ抗毒素 1156 グラミシジン 712 カシュウ 1336, 1962 乾燥はぶウマ抗毒素 716 クラリスロマイシン 516 ガジュツ 1372, 1969 乾燥 BCG ワクチン 335 クラリスロマイシン錠 517 加水ラノリン 807 乾燥ボツリヌスウマ抗毒素 374 グリクラジド 2134 ガスえそウマ抗毒素 696 乾燥まむしウマ抗毒素 841 グリシン 704 カッコウ 2231 乾燥硫酸アルミニウムカリウムグリセオフルビン 713 カッコン 1341 292 グリセオフルビン錠 1890, 2135 葛根湯エキス 1308, 1950, 2228 カンゾウ 1295 グリセリン 702 カドララジン 2091 カンゾウエキス 1296, 1943 グリセリンカリ液 704 カドララジン錠 2092 カンゾウ粗エキス 1297, 1943 クリノフィブラート 522 過テクネチウム酸ナトリウム(99mTc) カンゾウ末 1296 グリベンクラミド 699 注射液 1105 カンテン 1252 クリンダマイシン塩酸塩 519, 2108 果糖 689 カンテン末 1253 クリンダマイシン塩酸塩カプセル果糖注射液 689, 1888 含糖ペプシン 1074 520, 2108 カナマイシン一硫酸塩 793 d-カンフル 401 クリンダマイシンリン酸エステルカナマイシン硫酸塩 794 dl-カンフル 402 521 カノコソウ 1306, 1950, 2228 肝油 538 クリンダマイシンリン酸エステル注カノコソウ末 1307, 1950, 2228 カンレノ酸カリウム 1008 射液 1866 カフェイン水和物 387 グルコン酸カルシウム水和物 391 カプセル 403 キグルタチオン 701 カプトプリル 403 L-グルタミン 1889 ガベキサートメシル酸塩 693, 1889 クレオソート 544 希塩酸過マンガン酸カリウム 1013 726 クレゾール 544 キキョウ加味逍遙散エキス 1310, 1952 1334 クレゾール水 545 キキョウ末カモスタットメシル酸塩 400, 1852 1335 クレゾール石ケン液 545 キキョウ流エキス b-ガラクトシダーゼ（アスペルギル 1334, 1962 クレボプリドリンゴ酸塩 2107 キクカス） 694 1271 クレマスチンフマル酸塩 519 キササゲ b-ガラクトシダーゼ（ペニシリウム） 1271 クロカプラミン塩酸塩水和物 523 キジツ 695 1302 クロキサシリンナトリウム水和物キシリトールカリジノゲナーゼ 790 1240 533 キシリトール注射液カリ石ケン 1007 1241, 1935 クロキサゾラム 534 キタサマイシンカルシトニン（サケ） 2093 798 クロコナゾール塩酸塩 546 キタサマイシン酢酸エステルカルテオロール塩酸塩 412 799 クロスカルメロースナトリウムキタサマイシン酒石酸塩カルナウバロウ 411 800 546, 2112 キニジン硫酸塩水和物カルバゾクロムスルホン酸ナトリウ 1050 クロチアゼパム 531 キニーネエチル炭酸エステルム水和物 405 1051 クロトリマゾール 532 キニーネ塩酸塩水和物カルバマゼピン 404 1052 クロナゼパム 528 キニーネ硫酸塩水和物カルビドパ水和物 406 1053 クロニジン塩酸塩 529 牛脂 L-カルボシステイン 407 336 クロフィブラート 525 吸水軟膏カルメロース 408, 2097 265 クロフィブラートカプセル 526 キョウカツカルメロースカルシウム 409, 2097 1321, 1960 クロフェダノール塩酸塩 524 キョウニンカルメロースナトリウム 410, 2097 1257, 1937, 2219 クロベタゾールプロピオン酸エステキョウニン水カルモナムナトリウム 412 1257 ル 1867 希ヨードチンキカルモフール 411 769 クロペラスチン塩酸塩 530 金チオリンゴ酸ナトリウムカロコン 1369 1092 クロミフェン塩酸塩錠 2109 カンキョウ 1341, 1964 クロミフェンクエン酸塩 526 乾燥亜硫酸ナトリウム 1109 ククロミフェンクエン酸塩錠 527 乾燥甲状腺 1171 クロミプラミン塩酸塩 528 51 乾燥酵母 1241 グアイフェネシン 714 クロム酸ナトリウム( Cr)注射液乾燥細胞培養痘そうワクチン 1091 グアナベンズ酢酸塩 715 1099 乾燥ジフテリアウマ抗毒素 596 グアネチジン硫酸塩 716 クロモグリク酸ナトリウム 1100 乾燥弱毒生おたふくかぜワクチングアヤコールスルホン酸カリウムクロラゼプ酸二カリウム 1868 902 1011 クロラゼプ酸二カリウムカプセル乾燥弱毒生風しんワクチン 1074 クエン酸ガリウム(67Ga)注射液 696 1869 乾燥弱毒生麻しんワクチン 843 クエン酸水和物 515 クロラムフェニコール 487 乾燥水酸化アルミニウムゲル 288 クエン酸ナトリウム水和物 1099 クロラムフェニコールコハク酸エス乾燥水酸化アルミニウムゲル細粒クコシ 1315 テルナトリウム 489 289, 2079 クジン 1364, 1968 クロラムフェニコールパルミチン酸乾燥組織培養不活化狂犬病ワクチンクジン末 1364, 1969 エステル 488 1054 苦味重曹水 1364 クロルジアゼポキシド 490 乾燥炭酸ナトリウム 1096 苦味チンキ 1266 クロルジアゼポキシド散 491 乾燥痘そうワクチン 1091 クラブラン酸カリウム 1010 クロルジアゼポキシド錠 492, 1858 乾燥日本脳炎ワクチン 786 クロルフェニラミン･カルシウム散

2314 Index in Japanese Supplement II, JP XV

497 サルブタモール硫酸塩 1078 クロルフェニラミンマレイン酸塩コ酸化亜鉛 1245 498 酸化カルシウム 393 d-クロルフェニラミンマレイン酸塩酸化チタン 1178 501 コウカ 1348 酸化マグネシウム 835 クロルフェニラミンマレイン酸塩散硬化油 735 サンキライ 1364, 1968 499 コウジン 1342 サンキライ末 1364, 1968 クロルフェニラミンマレイン酸塩錠合成ケイ酸アルミニウム 290 サンザシ 1941 500 コウブシ 1280, 1942 三酸化ヒ素 316 クロルフェニラミンマレイン酸塩注コウブシ末 1280, 1942 サンシシ 1288 射液 499 コウボク 1315, 1959 サンシシ末 1288 クロルフェネシンカルバミン酸エスコウボク末 1316, 1959 サンシュユ 1279, 2220 テル 496, 1858 ゴオウ 1325 サンショウ 1371, 2239 クロルフェネシンカルバミン酸エスコカイン塩酸塩 535 サンショウ末 1371, 2239 テル錠 1859 ゴシツ 1252 酸素 955 クロルプロパミド 504 牛車腎気丸エキス 2221 サンソウニン 1307 クロルプロパミド錠 505, 1861 ゴシュユ 1285 サントニン 1081 クロルプロマジン塩酸塩 502 コデインリン酸塩散 1% 536 サンヤク 1282, 1942 クロルプロマジン塩酸塩錠コデインリン酸塩散 10% 537 サンヤク末 1282, 1942 503,1861 コデインリン酸塩錠 537, 2109 コデインリン酸塩水和物 536 クロルプロマジン塩酸塩注射液シ 503,1860 ゴナドレリン酢酸塩 705 クロルヘキシジン塩酸塩 493 ゴボウシ 1267 クロルヘキシジングルコン酸塩液ゴマ油 1084 ジアスターゼ 567 ジアスターゼ･重曹散 493 ゴミシ 1352 567 ジアゼパムクロルマジノン酢酸エステル 494 コムギデンプン 1237, 2216 567 シアナミドクロロブタノール 495 コメデンプン 1346, 2189 548 コリスチンメタンスルホン酸ナトリシアノコバラミン 548, 1870 ウム 540 シアノコバラミン注射液 549, 1871 ケコリスチン硫酸塩 541 ジエチルカルバマジンクエン酸塩コルチゾン酢酸エステル 543 574, 2113 ケイガイ 1353 コルヒチン 538 ジエチルカルバマジンクエン酸塩錠経口生ポリオワクチン 1005 コレカルシフェロール 506 574 ケイ酸マグネシウム 836 コレステロール 507 ジオウ 1343, 1964 軽質無水ケイ酸 1087 コレラワクチン 506 歯科用アンチホルミン 310 軽質流動パラフィン 967 コロンボ 1267, 1939, 2220 歯科用トリオジンクパスタ 1210 桂枝茯苓丸エキス 1955 コロンボ末 1268, 1939, 2220 歯科用パラホルムパスタ 969 ケイヒ 1272 コンズランゴ 1276 歯科用フェノール･カンフル 987 ケイヒ末 1273 コンズランゴ流エキス 1277, 1940 歯科用ヨード･グリセリン 771 ケイヒ油 1273 ジギトキシン 576 ケタミン塩酸塩 795 サジギトキシン錠 576 結晶性インスリン亜鉛水性懸濁注射シクラシリン 507 液 765 ジクロキサシリンナトリウム水和物結晶セルロース 477, 2105 サイクロセリン 551 573 血清性性腺刺激ホルモン 710 サイコ 1266, 2220 シクロスポリン 508 ケツメイシ 1271 サイシン 1259, 1938 ジクロフェナクナトリウム 570 ケトコナゾール 2152 柴苓湯エキス 1349 ジクロフェナミド 571 ケトコナゾール液 2155 酢酸 268 ジクロフェナミド錠 572 ケトコナゾールクリーム 2153 酢酸ナトリウム水和物 1091 シクロペントラート塩酸塩 549 ケトコナゾールローション 2154 サッカリン 1075 シクロホスファミド水和物 550 ケトチフェンフマル酸塩 797 サッカリンナトリウム水和物 1076 シゴカ 1283, 2221 ケトプロフェン 796 サフラン 1349 ジゴキシン 578, 2115 ケノデオキシコール酸 486 サラシ粉 494 ジゴキシン錠 580, 2116 ゲファルナート, 105, 2132 サラシミツロウ 336 ジゴキシン注射液 579, 2116 ケンゴシ 1330 サラゾスルファピリジン 1077 ジコッピ 1315, 1959 ゲンタマイシン硫酸塩 698 サリチル酸 1079, 1924 シコン 1313, 1959, 2228 ゲンタマイシン硫酸塩点眼液 2133 サリチル酸精 1080 次硝酸ビスマス 369 ゲンチアナ 1290, 1943 サリチル酸ナトリウム 1108 ジスチグミン臭化物 599 ゲンチアナ･重曹散 1290 サリチル酸絆創膏 1080 ジスチグミン臭化物錠 600, 2117 ゲンチアナ末 1290, 1943 サリチル酸メチル 881 L-システイン 1871 ゲンノショウコ 1291 サリチル･ミョウバン散 1078 L-システイン塩酸塩水和物 1872 ゲンノショウコ末 1291 ザルトプロフェン 1242 シスプラチン 513 ザルトプロフェン錠 1243 ジスルフィラム 600

Supplement II, JP XV Index in Japanese 2315

ジソピラミド 598 ショウキョウ 1291 スリンダク 2198 シソマイシン硫酸塩 1090 ショウキョウ末 1292 スルタミシリントシル酸塩水和物シタラビン 552 硝酸イソソルビド 785 1134, 1927 シッカニン 1086 硝酸イソソルビド錠 786, 2151 スルチアム 1136 シツリシ 1369 硝酸銀 1088 スルバクタムナトリウム 1122, 1927 ジドブジン 1935 硝酸銀点眼液 1088 スルピリド 1131 ジドロゲステロン 609 常水 1235 スルピリドカプセル 1132 ジドロゲステロン錠 610 ショウズク 1271, 2220 スルピリド錠 1132 シノキサシン 2105 焼セッコウ 1298 スルピリン水和物 1133 シノキサシンカプセル 2106 消毒用エタノール 640 スルピリン注射液 1134, 1927 ジノスタチンスチマラマー 1247 消毒用フェノール 986 スルファジアジン銀 1124 ジノプロスト 592 消毒用フェノール水 987 スルファメチゾール 1125 ジヒドロエルゴタミンメシル酸塩ショウマ 1272, 1939 スルファメトキサゾール 1126 583 ジョサマイシン 786 スルファモノメトキシン水和物ジヒドロエルゴトキシンメシル酸塩ジョサマイシン錠 1897, 2152 1126 584 ジョサマイシンプロピオン酸エステスルフイソキサゾール 1128 ジヒドロコデインリン酸塩 581 ル 788 スルフィンピラゾン 1127, 1927 ジヒドロコデインリン酸塩散 1% シラザプリル錠 1864 スルフィンピラゾン錠 1128, 1927 582 シラザプリル水和物 1863 スルベニシリンナトリウム 1123 ジヒドロコデインリン酸塩散 10% シラスタチンナトリウム 509 スルホブロモフタレインナトリウム 582 ジラゼプ塩酸塩水和物 586 1129 ジピリダモール 597 ジルチアゼム塩酸塩 586 スルホブロモフタレインナトリウムジフェニドール塩酸塩 575 シロスタゾール 511 注射液 1130 ジフェンヒドラミン 593 シロスタゾール錠 512, 1866 ジフェンヒドラミン塩酸塩 594 シロップ用セファトリジンプロピレセジフェンヒドラミン･バレリル尿素ングリコール 2100 散 593 シロップ用セファドロキシル 1853 成人用沈降ジフテリアトキソイドジフェンヒドラミン･フェノール･亜シロップ用セファレキシン 2099 鉛華リニメント 595 シロップ用セフロキサジン 2103 596 精製水ジブカイン塩酸塩 569 シロップ用ファロペネムナトリウム 1236 精製ゼラチンジフテリアトキソイド 596 2126 697 ジフテリア破傷風混合トキソイドシロップ用ファロペネムナトリウム精製セラック 1085 精製デヒドロコール酸 596 659, 1886 556 精製白糖ジフルコルトロン吉草酸エステルシンイ 1317 1120 精製ヒアルロン酸ナトリウム 2114 親水軟膏 735 2194 精製ラノリンシプロヘプタジン塩酸塩水和物親水ワセリン 981 808 生理食塩液 551 診断用クエン酸ナトリウム液 1100 1098, 1893 石油ベンジンジベカシン硫酸塩 569 シンバスタチン 2192 982 セタノールジベカシン硫酸塩点眼液 2113 真武湯エキス 2234 484 セチリジン塩酸塩シベンゾリンコハク酸塩 1861 1856 セチリジン塩酸塩錠シベンゾリンコハク酸塩錠 1862 1857 スセッコウシメチジン 513 1297 セトラキサート塩酸塩ジメモルファンリン酸塩 588 485 水酸化カリウムセネガジメルカプロール 590 1012 1360, 1968, 2234 水酸化カルシウムセネガシロップジメルカプロール注射液 590 392 1361 水酸化ナトリウムセネガ末ジメンヒドリナート 588 1101 1361, 1968, 2234 スキサメトニウム塩化物水和物セファクロルジメンヒドリナート錠 589, 2117 415 セファクロルカプセル次没食子酸ビスマス 368 1137 416 スキサメトニウム塩化物注射液セファクロル細粒ジモルホラミン 591 417 セファクロル複合顆粒ジモルホラミン注射液 591 1138, 1928 419, 2097 弱アヘンアルカロイド･スコポラミスクラルファート水和物 1118 セファゾリンナトリウム 426 スコポラミン臭化水素酸塩水和物セファゾリンナトリウム水和物ン注射液 945 シャクヤク 1328 1083 428 ステアリルアルコールセファトリジンプロピレングリコーシャクヤク末 1329 1117 ステアリン酸ルジャショウシ 1275 1116 425, 1854 ステアリン酸カルシウムセファドロキシルシャゼンシ 1334 400 421 ステアリン酸ポリオキシルセファドロキシルカプセルシャゼンソウ 1334 40 1007 1852 ステアリン酸マグネシウムセファピリンナトリウム臭化カリウム 1008 837 424 ストレプトマイシン硫酸塩セファレキシン臭化ナトリウム 1095 1117 422 スピラマイシン酢酸エステルセファレキシンカプセルジュウヤク 1302 1114 2098 スピロノラクトンセファロチンナトリウムシュクシャ 1256 1116 423, 1854 スペクチノマイシン塩酸塩水和物セフィキシムシュクシャ末 1256 442 セフィキシムカプセル酒石酸 1141 1114 2101

2316 Index in Japanese Supplement II, JP XV

セフェピム塩酸塩水和物 439 ソウジュツ末 1260 チオリダジン塩酸塩 1168 セフォジジムナトリウム 447 ソウハクヒ 1320, 1960 チオ硫酸ナトリウム水和物 1109 セフォゾプラン塩酸塩 457 ソボク 1352 チオ硫酸ナトリウム注射液 1110, セフォタキシムナトリウム 449 ソヨウ 1329, 1961, 2231 1927 セフォチアム塩酸塩 455 ソルビタンセスキオレイン酸エステチクセツニンジン 1326, 1960 セフォチアムヘキセチル塩酸塩ル 1111 チクセツニンジン末 1327, 1960 453 ゾルピデム酒石酸塩 2217 チクロピジン塩酸塩 1173 セフォテタン 451 D-ソルビトール 1112 チザニジン塩酸塩 1179 セフォペラゾンナトリウム 448 D-ソルビトール液 1112 窒素 928 セフカペンピボキシル塩酸塩細粒チニダゾール 1175 432 タチペピジンヒベンズ酸塩 1176 セフカペンピボキシル塩酸塩錠チペピジンヒベンズ酸塩錠 433 1177,1930 ダイオウセフカペンピボキシル塩酸塩水和物 1344 チメピジウム臭化物水和物 1174 大黄甘草湯エキス 430 1280, 2221 チモ 1256, 1937 ダイオウ末セフジトレンピボキシル 437 1345 チモール 1170 ダイズ油セフジトレンピボキシル細粒 438 1113 チモロールマレイン酸塩 1174 タイソウセフジトレンピボキシル錠 438 1307 注射用アズトレオナム 1840 ダウノルビシン塩酸塩セフジニル 434 553 注射用アセチルコリン塩化物 271, タウリンセフジニルカプセル 435 1142 1825 タクシャセフジニル細粒 436 1253 注射用アムホテリシン B 304 タクシャ末セフスロジンナトリウム 464 1253 注射用アモバルビタールナトリウムタクロリムス水和物セフタジジム水和物 466 2199 300 タゾバクタムセフチゾキシムナトリウム 471 2200 注射用アンピシリンナトリウムダナゾールセフチブテン水和物 470 2112 1838 タムスロシン塩酸塩セフテラムピボキシル 468 1140 注射用イダルビシン塩酸塩 746 タランピシリン塩酸塩セフテラムピボキシル細粒 469 1138 注射用イミペネム･シラスタチンナタルクセフテラムピボキシル錠 2104 1139, 1928 トリウム 750 炭酸カリウムセフトリアキソンナトリウム水和物 1009 注射用オザグレルナトリウム 1917 炭酸水素ナトリウム 472 1093 注射用血清性性腺刺激ホルモン 711 炭酸水素ナトリウム注射液セフピラミドナトリウム 458 注射用水 1235, 1934 セフピロム硫酸塩 460 1094,1925 注射用スキサメトニウム塩化物炭酸ナトリウム水和物セフブペラゾンナトリウム 429 1096 1137, 1928 炭酸マグネシウムセフポドキシムプロキセチル 461 834 注射用ストレプトマイシン硫酸塩炭酸リチウムセフミノクスナトリウム水和物 826 2198 単シロップ 446 1089 注射用セファゾリンナトリウムダントロレンナトリウム水和物セフメタゾールナトリウム 445 1854 セフメノキシム塩酸塩 443 553 注射用セフェピム塩酸塩 441 単軟膏セフロキサジン水和物 462 1089 注射用セフォゾプラン塩酸塩 458 タンニン酸セフロキシムアキセチル 474 1141 注射用セフォチアム塩酸塩 456 タンニン酸アルブミンセフロキシムナトリウム 476 282 注射用セフタジジム 1856 タンニン酸ジフェンヒドラミンセボフルラン 2191 注射用セフメタゾールナトリウムセラセフェート 480, 2105 595 1855 タンニン酸ベルベリンゼラチン 696 352 注射用チアミラールナトリウムセラペプターゼ 1083 1164 L-セリン 1925 チ注射用チオペンタールナトリウムセルモロイキン（遺伝子組換え） 1167, 1930 481 チアプリド塩酸塩 176, 2203 注射用テセロイキン（遺伝子組換え）センキュウ 1275, 1939 チアプリド塩酸塩錠 177, 2204 1148, 1929 センキュウ末 1276, 1940 チアマゾール 1159 注射用ドキソルビシン塩酸塩 1877 ゼンコ 1961 チアマゾール錠 1160 注射用バンコマイシン塩酸塩 1223 センコツ 1321, 1960, 2229 チアミラールナトリウム 1163 注射用ヒト絨毛性性腺刺激ホルモンセンソ 1368 チアミン塩化物塩酸塩 1160 708 センナ 1361 チアミン塩化物塩酸塩散 1162 注射用ヒドララジン塩酸塩 724, センナ末 1362 チアミン塩化物塩酸塩注射液 1161, 2138 センブリ 1365 1930 注射用ピペラシリンナトリウムセンブリ･重曹散 1367 チアミン硝化物 1162 998 センブリ末 1366 チアラミド塩酸塩 1171 注射用ビンブラスチン硫酸塩 1227 チアラミド塩酸塩錠 1172 注射用ファモチジン 656, 1885 ソチアントール 1165 注射用フェニトインナトリウムチオテパ 1168 992 注射用プレドニゾロンコハク酸エスソウジュツチオペンタールナトリウム 1166 1260 テルナトリウム 1025, 1921

Supplement II, JP XV Index in Japanese 2317

注射用フロモキセフナトリウムテストステロンプロピオン酸エステトドララジン塩酸塩水和物 1185 666 ル 1155 ドパミン塩酸塩 602 注射用ペプロマイシン硫酸塩 1918 テストステロンプロピオン酸エステドパミン塩酸塩注射液 602, 1877 注射用ベンジルペニシリンカリウムル注射液 1155, 2203 トフィソパム 1186 1841 デスラノシド 559 ドブタミン塩酸塩 601 注射用ホスホマイシンナトリウムデスラノシド注射液 560, 1873 トブラマイシン 1180 687, 2131 テセロイキン（遺伝子組換え） 1143 トブラマイシン注射液 1930 注射用マイトマイシン C 1905 テトラカイン塩酸塩 1156 トラガント 1369 注射用ミノサイクリン塩酸塩 1904, テトラサイクリン塩酸塩 1157 トラガント末 1369 2163 デヒドロコール酸 556 トラザミド 1187 注射用メロペネム 2162 デヒドロコール酸注射液 557, 1873 トラネキサム酸 1191 チョウジ 1274 デフェロキサミンメシル酸塩トラネキサム酸カプセル 1192 チョウジ末 1274 554,1873 トラネキサム酸錠 1193 チョウジ油 1275 テプレノン 2202 トラネキサム酸注射液 1193 チョウトウコウ 1370 デメチルクロルテトラサイクリン塩トラピジル 1194 チョレイ 1336, 1962 酸塩 558 トリアムシノロン 1195 チョレイ末 1337, 1963 テルブタリン硫酸塩 1153 トリアムシノロンアセトニド 1196 L-チロジン 1931 テレビン油 1214 トリアムテレン 1197 チンク油 1245 天然ケイ酸アルミニウム 289 トリクロホスナトリウム 1202 沈降ジフテリア破傷風混合トキソイデンプングリコール酸ナトリウムトリクロホスナトリウムシロップド 596 1926 1203 沈降精製百日せきジフテリア破傷風テンマ 1289, 1943 トリクロルメチアジド 1198 混合ワクチン 596 テンモンドウ 1259, 1938 トリクロルメチアジド錠 1199 沈降精製百日せきワクチン 980 トリコマイシン 1201 沈降炭酸カルシウム 389 ト L-トリプトファン 1211 沈降破傷風トキソイド 1156 トリヘキシフェニジル塩酸塩 1204 沈降はぶトキソイド 716 トリヘキシフェニジル塩酸塩錠トウガシ沈降 B 型肝炎ワクチン 716 1264 1204 トウガラシチンピ 1273 1268 トリメタジオン 1208 トウガラシ･サリチル酸精 1270 トリメタジオン錠 1209 トウガラシチンキ 1269 トリメタジジン塩酸塩 1207, 1931 ツトウガラシ末 1269 トリメタジジン塩酸塩錠 1207 トウキ 1305 トリメトキノール塩酸塩水和物ツバキ油トウキ末 400 1305 1209 トウニンツボクラリン塩化物塩酸塩水和物 1327, 1961, 2230 トリメブチンマレイン酸塩 1206 トウニン末 1212, 1931 1327, 1961, 2230 トルナフタート 1189 トウヒツボクラリン塩化物塩酸塩注射液 1265 トルナフタート液 1189 トウヒシロップ 1213, 1931 1325 トルブタミド 1188 トウヒチンキツロブテロール塩酸塩 1213 1325 トルブタミド錠 1188, 2205 トウモロコシデンプン 542, 2110 トルペリゾン塩酸塩 1190 トウモロコシ油テ 542 L-トレオニン 1169 ドキサゾシンメシル酸塩 2117 トレピブトン 1195 ドキサプラム塩酸塩水和物 603 ドロキシドパ 2118 テイコプラニン 1150, 2201 ドキシサイクリン塩酸塩水和物低置換度ヒドロキシプロピルセルドロキシドパカプセル 2119 606 ドロキシドパ細粒 2120 ロース 738, 2139 ドキシフルリジン 604 トロキシピド 2208 テオフィリン 1158 ドキシフルリジンカプセル 604 トロキシピド細粒 2209 テガフール 1149 ドキソルビシン塩酸塩 605 トロキシピド錠 2210 デキサメタゾン 560 ドクカツ 1937 トロピカミド 1211 デキストラン 40 561, 1873 トコフェロール 1181 ドロペリドール 608 デキストラン 40 注射液 562 トコフェロールコハク酸エステルカトロンビン 1170 デキストラン 70 563 ルシウム 1183 豚脂 808 デキストラン硫酸エステルナトリウトコフェロール酢酸エステル 1182 ドンペリドン 1876 ムイオウ 5 564 トコフェロールニコチン酸エステルデキストラン硫酸ナトリウムイオウ 1184 18 565 トコン 1303, 1949 ナデキストリン 565 トコンシロップ 1304 デキストロメトルファン臭化水素酸トコン末 1303, 1949 ナイスタチン 937 塩水和物 566 トスフロキサシントシル酸塩錠ナタネ油 1055 テストステロンエナント酸エステル 179, 2207 ナドロール 904 1154 トスフロキサシントシル酸塩水和物ナファゾリン塩酸塩 907 テストステロンエナント酸エステル 178, 2205 ナファゾリン･クロルフェニラミン注射液 1154, 2203 トチュウ 1284 液 906

2318 Index in Japanese Supplement II, JP XV

ナファゾリン硝酸塩 908 ノルエチステロン 932, 2168 ナファモスタットメシル酸塩 1911 ノルゲストレル 933 ヒナブメトン 1908 ノルゲストレル･エチニルエストラナブメトン錠 1910 ジオール錠 934 ナプロキセン 908 ノルトリプチリン塩酸塩 935 ピオグリタゾン塩酸塩 2172 ナリジクス酸 905 ノルフロキサシン 932 ビオチン 1842 ナロキソン塩酸塩 906 ピコスルファートナトリウム水和物 1105 ハビサコジル 367 ビサコジル坐剤 368, ニ 1843 バイモ 1287, 1942 ビソプロロールフマル酸塩 1843 ニガキ 1333 バカンピシリン塩酸塩 329 ビソプロロールフマル酸塩錠 1844 ニガキ末 1333 白色セラック 1085 ビタミン A 油 1229 ニカルジピン塩酸塩 911 白色軟膏 1238 ビタミン A 油カプセル 1230 ニカルジピン塩酸塩注射液白色ワセリン 981 ヒトインスリン（遺伝子組換え） 912,1912 白糖 1121 760 ニクズク 2229 バクモンドウ 1324 ヒト下垂体性性腺刺激ホルモンニコチン酸 920 バクロフェン 331 708, 2137 ニコチン酸アミド 919 バクロフェン錠 332, 1841 ヒト絨毛性性腺刺激ホルモン 707 ニコチン酸注射液 921, 1912 バシトラシン 330 人全血液 1238 ニコモール 917 バソプレシン注射液 1223, 2215 人免疫グロブリン 724 ニコモール錠 918, 2168 八味地黄丸エキス 2225 ヒドララジン塩酸塩 724 ニコランジル 919, 1912 ハチミツ 1301 ヒドララジン塩酸塩散 725 ニザチジン 1912 ハッカ 1317 ヒドララジン塩酸塩錠 725, 1890 ニザチジンカプセル 1913 ハッカ水 1318 ヒドロキシジン塩酸塩 739 二酸化炭素 407 ハッカ油 1318 ヒドロキシジンパモ酸塩 739 ニセリトロール 916 パップ用複方オウバク散 1332 ヒドロキシプロピルセルロースニセルゴリン 913 パニペネム 962 736, 2139 ニセルゴリン散 914 パパベリン塩酸塩 965 ヒドロキソコバラミン酢酸塩 736 ニセルゴリン錠 915 パパベリン塩酸塩注射液 965, 1918 ヒドロクロロチアジド 727 ニトラゼパム 925 ハマボウフウ 1294, 1943 ヒドロコタルニン塩酸塩水和物ニトレンジピン 926 バメタン硫酸塩 333 734 ニトレンジピン錠 927 パラアミノサリチル酸カルシウム顆ヒドロコルチゾン 728 ニトログリセリン錠 928 粒 394 ヒドロコルチゾンコハク酸エステルニフェジピン 922 パラアミノサリチル酸カルシウム水 733 日本脳炎ワクチン 786 和物 395 ヒドロコルチゾンコハク酸エステル乳酸 801 パラオキシ安息香酸エチル 647 ナトリウム 732 乳酸カルシウム水和物 393 パラオキシ安息香酸ブチル 386 ヒドロコルチゾン酢酸エステル乳糖水和物 803, 2156 パラオキシ安息香酸プロピル 1039 729 尿素 1218 パラオキシ安息香酸メチル 878 ヒドロコルチゾン･ジフェンヒドラニルバジピン 923 パラフィン 966 ミン軟膏 730 ニルバジピン錠 924 パラホルムアルデヒド 968 ヒドロコルチゾン酪酸エステルニンジン 1292 L-バリン 1221 730 ニンジン末 1293 パルナパリンナトリウム 969 ヒドロコルチゾンリン酸エステルナニンドウ 1314 バルビタール 333 トリウム 731, 2139 バルプロ酸ナトリウム 1110, 2195 ピブメシリナム塩酸塩 1004 ネバルプロ酸ナトリウムシロップピブメシリナム塩酸塩錠 2173 2196 ヒプロメロース 741, 2140 バルプロ酸ナトリウム錠 2197 ヒプロメロースフタル酸エステルネオスチグミンメチル硫酸塩 909 バレイショデンプン 1014, 2173 ネオスチグミンメチル硫酸塩注射液 743, 1891, 2140 ハロキサゾラム 719 ピペミド酸水和物 996, 2173 910, 1912 ハロタン 719 ピペラシリン水和物 1919 ネチルマイシン硫酸塩 910 ハロペリドール 717 ピペラシリンナトリウム 997 ハロペリドール錠 718 ピペラジンアジピン酸塩 999 ノパンクレアチン 961 ピペラジンリン酸塩錠 1000 パンクロニウム臭化物 962 ピペラジンリン酸塩水和物 999 濃グリセリン 703 ハンゲ 1333 ビペリデン塩酸塩 366 濃ベンザルコニウム塩化物液 50 半夏厚朴湯エキス 1943 ビホナゾール 366 343 バンコマイシン塩酸塩 1221 ヒマシ油 414 ノスカピン 936 パンテチン 964 ピマリシン 994 ノスカピン塩酸塩水和物 937 パントテン酸カルシウム 394 ヒメクロモン 740 ノルアドレナリン 930 ピモジド 2171 ノルアドレナリン注射液 931, 1915 ビャクゴウ 1958

Supplement II, JP XV Index in Japanese 2319

ビャクシ 1257, 1937 複方チアントール･サリチル酸液プルラン 1045 ビャクジュツ 1261, 1938 1165 フルルビプロフェン 679 ビャクジュツ末 1261, 1939 複方ビタミン B 散 1230 ブレオマイシン塩酸塩 370 氷酢酸 269 複方ヨード･グリセリン 770 ブレオマイシン硫酸塩 372 ピラジナミド 1046 複方ロートエキス･ジアスターゼ散プレドニゾロン 1021 ピラルビシン 1000 1355 プレドニゾロンコハク酸エステルピランテルパモ酸塩 1045 ブクモロール塩酸塩 378 1024 ピリドキシン塩酸塩 1047 ブクリョウ 1337 プレドニゾロン酢酸エステル 1023 ピリドキシン塩酸塩注射液ブクリョウ末 1337 プレドニゾロンリン酸エステルナト 1048,1922 ブシ 1338, 1963 リウム 2176 ピリドスチグミン臭化物 1047 フシジン酸ナトリウム 1101 プレドニゾロン錠 1022 ピレノキシン 1001 ブシ末 1339, 1963 プロカインアミド塩酸塩 1028, ピレンゼピン塩酸塩水和物 1002 ブシラミン 377 2179 ピロ亜硫酸ナトリウム 1108 ブシラミン錠 1845 プロカインアミド塩酸塩錠 1029, ピロカルピン塩酸塩 994 ブスルファン 384 2180 ピロキシカム 1003 ブチルスコポラミン臭化物 1082 プロカインアミド塩酸塩注射液ピロキシリン 1049 ブドウ酒 1238 1029, 2179 ピロールニトリン 1049 ブドウ糖 700 プロカイン塩酸塩 1030 ビワヨウ 1314 ブドウ糖注射液 701, 1889 プロカイン塩酸塩注射液 1030 ビンクリスチン硫酸塩 1228, 1933 ブトロピウム臭化物 385 プロカテロール塩酸水和物 1032 ピンドロール 995 ブナゾシン塩酸塩 383 プロカルバジン塩酸塩 1031 ビンブラスチン硫酸塩 1226 ブフェキサマク 380 プログルミド 1035 ビンロウジ 1258 ブフェキサマククリーム 380 プロクロルペラジンマレイン酸塩ブフェキサマク軟膏 381 1033 フブフェトロール塩酸塩 379 プロクロルペラジンマレイン酸塩錠ブプラノロール塩酸塩 383 1033, 2181 ブプレノルフィン塩酸塩 1850 プロゲステロン 1034, 2182 ファモチジン 655 ブホルミン塩酸塩 1846 プロゲステロン注射液 1034, 2182 ファモチジン散 657, 2125 ブホルミン塩酸塩錠 1849 フロセミド 690 ファモチジン錠 657 ブホルミン塩酸塩腸溶錠 1847 フロセミド錠 691 ファロペネムナトリウム錠ブメタニド 382 フロセミド注射液 2131 660,1886, 2126 フラジオマイシン硫酸塩 688 プロタミンインスリン亜鉛水性懸濁ファロペネムナトリウム水和物プラステロン硫酸エステルナトリウ注射液 766 658,1885 ム水和物 1107 プロタミン硫酸塩 1041, 1921 フィトナジオン 993 プラゼパム 1020 プロタミン硫酸塩注射液 1042, フェニトイン 991 プラゼパム錠 1021 1922, 2186 フェニトイン散 992, 2169 プラゾシン塩酸塩 2174 プロチオナミド 1042 フェニトイン錠 992, 2170 プラノプロフェン 1018 プロチレリン 1043 フェニルアラニン L- 989 プラバスタチンナトリウム 1018 プロチレリン酒石酸塩水和物 1044 フェニルブタゾン 990 フラビンアデニンジヌクレオチドナプロテイン銀 1088 フェニレフリン塩酸塩 990 トリウム 662 プロテイン銀液 1089 フェネチシリンカリウム 983 フラボキサート塩酸塩 664 プロパフェノン塩酸塩 2183 フェノバルビタール 984, 2168 プリミドン 1026 プロパフェノン塩酸塩錠 2184 フェノバルビタール散 10% 985, フルオキシメステロン 675 プロパンテリン臭化物 1036 2168 フルオシノニド 672 プロピルチオウラシル 1040 フェノール 985 フルオシノロンアセトニド 670 プロピルチオウラシル錠 1040, フェノール･亜鉛華リニメント 987 フルオレセインナトリウム 673 2185 フェノール水 987 フルオロウラシル 674 プロピレングリコール 1039 フェノールスルホンフタレインフルオロメトロン 673 プロブコール 2177 988 フルジアゼパム 669 プロプラノロール塩酸塩 1037 フェノールスルホンフタレイン注射フルシトシン 668 プロプラノロール塩酸塩錠 1038 液 988, 2169 フルスルチアミン塩酸塩 692 フロプロピオン 667, 2126 フェルビナク 1887 フルタミド 2128 フロプロピオンカプセル 667 フェンタニルクエン酸塩 661 フルトプラゼパム 2129 プロベネシド 1027 フェンブフェン 660 フルトプラゼパム錠 2130 プロベネシド錠 1027, 2177 複方アクリノール･チンク油 273 フルドロコルチゾン酢酸エステルブロマゼパム 374 複方オキシコドン･アトロピン注射 2127 ブロムヘキシン塩酸塩 375 液 953 フルニトラゼパム 670 プロメタジン塩酸塩 1036 複方オキシコドン注射液 952 フルフェナジンエナント酸エステルフロモキセフナトリウム 664 複方サリチル酸精 1080 676 ブロモクリプチンメシル酸塩 376 複方サリチル酸メチル精 879 フルラゼパム 677 ブロモバレリル尿素 377 複方ジアスターゼ･重曹散 567 フルラゼパム塩酸塩 678 粉末セルロース 480, 2105 複方ダイオウ･センナ散 1346 フルラゼパムカプセル 678

2320 Index in Japanese Supplement II, JP XV

ヘボウコン 1302, 1949 ミホウ酸 374 ホウ砂 1095 ベカナマイシン硫酸塩 337 ミグレニン 896 抱水クロラール 487 ベクロメタゾンプロピオン酸エステミクロノマイシン硫酸塩 893 ボウフウ 1352, 1966, 2234 ル 335 ミコナゾール 892 ボクソク 2232 ベザフィブラート 364 ミコナゾール硝酸塩 893 ボグリボース 1231 ベザフィブラート徐放錠 365 ミゾリビン 1906 ボグリボース錠 1232 ベタキソロール塩酸塩 2090 ミゾリビン錠 1907 ホスフェストロール 683, 1888 ベタネコール塩化物 363 ミツロウ 336 ホスフェストロール錠 684, 1888 ベタヒスチンメシル酸塩 353, 1842 ミデカマイシン 894 ホスホマイシンカルシウム水和物ベタヒスチンメシル酸塩錠 354 ミデカマイシン酢酸エステル 895 685 ベタメタゾン 355 ミノサイクリン塩酸塩 897 ホスホマイシンナトリウム 686 ベタメタゾン吉草酸エステル 360 ミノサイクリン塩酸塩錠 2163 ボタンピ 1318 ベタメタゾン吉草酸エステル･ゲンミョウバン水 293 ボタンピ末 1319 タマイシン硫酸塩クリーム 361 補中益気湯エキス 1298, 1945, 2228 ベタメタゾン吉草酸エステル･ゲンポビドン 1015 ムタマイシン硫酸塩軟膏 362 ポビドンヨード 1017 ベタメタゾンジプロピオン酸エステホマトロピン臭化水素酸塩 722 無晶性インスリン亜鉛水性懸濁注射ル 358 ホミカ 1321 液ベタメタゾン錠 356, 2090 764 ホミカエキス 1322, 1960 ベタメタゾンリン酸エステルナトリ無水アンピシリン 306 ホミカエキス散 1323 無水エタノールウム 359 639 ホミカチンキ 1323 無水カフェインペチジン塩酸塩 980 386 ホモクロルシクリジン塩酸塩 723 無水クエン酸ペチジン塩酸塩注射液 981, 1918 514 ポリスチレンスルホン酸カルシウム無水乳糖ベニジピン塩酸塩 338 802, 1900, 2155 398 無水リン酸水素カルシウムベニジピン塩酸塩錠 339 ポリスチレンスルホン酸ナトリウムヘパリンカルシウム 2135 396,1874 1106 ムピロシンカルシウム水和物ヘパリンナトリウム 721, 2137 902 ポリソルベート 80 1007 ヘパリンナトリウム注射液 722 ホリナートカルシウム 391, 1851 ペプロマイシン硫酸塩 975 メポリミキシン B 硫酸塩 1006 ベラドンナエキス 1263, 1939 ホルマリン 681 ベラドンナコン 1263 ホルマリン水 682 メキシレチン塩酸塩 891 ベラパミル塩酸塩 1225 ホルモテロールフマル酸塩水和物メキタジン 861 ベラパミル塩酸塩錠 1226 682 メグルミン 850 ペルフェナジン 977 ボレイ 1326 メクロフェノキサート塩酸塩 843 ペルフェナジン錠 977 ボレイ末 1326 メコバラミン 844 ペルフェナジンマレイン酸塩 978 メシル酸塩ガベキサート 693 ペルフェナジンマレイン酸塩錠メストラノール 864 979 マメダゼパム 845, 1903 ベルベリン塩化物水和物 351 メタンフェタミン塩酸塩 868 ベンザルコニウム塩化物 342 マイトマイシン C 898 L-メチオニン 869 ベンザルコニウム塩化物液 342 マオウ 1283 メチクラン 884 ベンジルアルコール 346 マーキュロクロム 862 メチラポン 890 ベンジルペニシリンカリウム 349 マーキュロクロム液 863 dl-メチルエフェドリン塩酸塩 875 ベンジルペニシリンベンザチン水和マクリ 1280 dl-メチルエフェドリン塩酸塩散 10% 物 348 マクロゴール 400 830 876 ヘンズ 1282 マクロゴール 1500 831 メチルエルゴメトリンマレイン酸塩ベンズブロマロン 343 マクロゴール 4000 832 876 ベンゼトニウム塩化物 344 マクロゴール 6000 832 メチルエルゴメトリンマレイン酸塩ベンゼトニウム塩化物液 345 マクロゴール 20000 833 錠 877 ベンセラジド塩酸塩 340 マクロゴール軟膏 833 メチルジゴキシン 885 ペンタゾシン 972 マシニン 1298 メチルセルロース 871, 2163 ペントキシベリンクエン酸塩 974 麻酔用エーテル 641 メチルテストステロン 882 ベントナイト 341 マニジピン塩酸塩 1900 メチルテストステロン錠 883 ペントバルビタールカルシウムマニジピン塩酸塩錠 1902 メチルドパ錠 874, 1903 973 マプロチリン塩酸塩 842 メチルドパ水和物 873 ペンブトロール硫酸塩 972 マルトース水和物 840 メチルプレドニゾロン 879 D-マンニトール 841 メチルプレドニゾロンコハク酸エスホ D-マンニトール注射液 842, 1903 テル 880 メチルベナクチジウム臭化物 871 メチルロザニリン塩化物ボウイ 1363 881 滅菌精製水 1236

Supplement II, JP XV Index in Japanese 2321

メテノロンエナント酸エステルヨリボフラビンリン酸エステルナトリ 866 ウム注射液 1062, 1922 メテノロンエナント酸エステル注射リマプロストアルファデクス 819 ヨウ化カリウム 1013 液 866 リュウガンニク 2229 ヨウ化ナトリウム 1102 メテノロン酢酸エステル 865 リュウコツ 2229 ヨウ化ナトリウム(123I)カプセルメトキサレン 870 リュウコツ 1313 1103 メトクロプラミド 886 硫酸亜鉛水和物 1246, 2216 ヨウ化ナトリウム(131I)液 1103 メトクロプラミド錠 886 硫酸亜鉛点眼液 1247 ヨウ化ナトリウム(131I)カプセルメトトレキサート 869 硫酸アルミニウムカリウム水和物 1103 メトプロロール酒石酸塩 887 292 ヨウ化人血清アルブミン(131I)注射液メトプロロール酒石酸塩錠 888 硫酸カリウム 1014 768 メトホルミン塩酸塩 867 硫酸鉄水和物 661 ヨウ化ヒプル酸ナトリウム(131I)注射メトホルミン塩酸塩錠 867 硫酸バリウム 334 液 1103 メトロニダゾール 889 硫酸マグネシウム水 839 葉酸 680 メトロニダゾール錠 889 硫酸マグネシウム水和物 838 葉酸錠 681, 1888 メナテトレノン 855 硫酸マグネシウム注射液 839, 1900 葉酸注射液 681, 1888 メピチオスタン 858 リュウタン 1306, 1949 ヨウ素 768 メピバカイン塩酸塩 859 リュウタン末 1306, 1949 ヨクイニン 1276 メピバカイン塩酸塩注射液 860, 流動パラフィン 966 ヨクイニン末 1276 2161 リョウキョウ 1256, 1937 ヨーダミド 767 メフェナム酸 847 苓桂朮甘湯エキス 1347, 1965 ヨーダミドナトリウムメグルミン注メフルシド 849 リンゲル液 1066, 1922 射液 854 メフルシド錠 849, 1903 リンコマイシン塩酸塩水和物 820 ヨード･サリチル酸･フェノール精メフロキン塩酸塩 848 リンコマイシン塩酸塩注射液 2157 772 メペンゾラート臭化物 857 リン酸水素カルシウム水和物ヨードチンキ 769 メルカプトプリン水和物 861 396,1875 ヨードホルム 773 メルファラン 855 リン酸水素ナトリウム水和物 568 メロペネム水和物 863 リン酸二水素カルシウム水和物 dl-メントール 856 ラ 397 l-メントール 857 ラウリル硫酸ナトリウム 1104 レモラウロマクロゴール 810 ラクツロース 804 レセルピン 1055 ラタモキセフナトリウム 809 木クレオソート 1870, 2110 レセルピン散 0.1% 1057 ラッカセイ油 971 モクツウ 1253 レセルピン錠 1057 ラナトシド C 805 モサプリドクエン酸塩錠 2166 レセルピン注射液 1056, 1922 ラナトシド C 錠 806 モサプリドクエン酸塩水和物 2165 レチノール酢酸エステル 1058 ラニチジン塩酸塩 1054 モッコウ 1352, 1966 レチノールパルミチン酸エステルラベタロール塩酸塩 1898 モノステアリン酸アルミニウム 1059 ラベタロール塩酸塩錠 1899 291 レナンピシリン塩酸塩 810 モノステアリン酸グリセリン 704 レバミピド 2187 モルヒネ･アトロピン注射液 899 リレバミピド錠 2188 モルヒネ塩酸塩錠 902, 1908, 2165 レバロルファン酒石酸塩 813 モルヒネ塩酸塩水和物 900 リオチロニンナトリウム 821 レバロルファン酒石酸塩注射液モルヒネ塩酸塩注射液 901, 2165 リオチロニンナトリウム錠 822 814,1900 リシノプリル錠 824 レボチロキシンナトリウム錠 817 ヤリシノプリル水和物 823 レボチロキシンナトリウム水和物 L-リジン塩酸塩 829 816 リジン酢酸塩レボドパ 814 ヤクチ 1265 L- 2159 リゾチーム塩酸塩 830 レボフロキサシン水和物 2156 ヤクモソウ 1958 リドカイン 818 レボメプロマジンマレイン酸塩薬用石ケン 846 リドカイン注射液 818, 2157 815 薬用炭 845 リトドリン塩酸塩 1067 レンギョウ 1286 ヤシ油 535 リトドリン塩酸塩錠 1068 レンニク 1320 リファンピシン 1064 ユリファンピシンカプセル 1065 ロリボスタマイシン硫酸塩 1063 リボフラビンユウタン 1262, 2219 1059 L-ロイシン 812 ユーカリ油 654 リボフラビン散 1060 ロキサチジン酢酸エステル塩酸塩リボフラビン酪酸エステル輸血用クエン酸ナトリウム注射液 1060 1070 1099, 1926 リボフラビンリン酸エステルナトリロキサチジン酢酸エステル塩酸塩徐ユビデカレノン 1214 ウム 1061

2322 Index in Japanese Supplement II, JP XV

放カプセル 1071 ロキシスロマイシン 1073, 1923 ロキソプロフェンナトリウム水和物 828 ロキタマイシン 1069 ロキタマイシン錠 1923, 2190 ロサルタンカリウム 2158 ロジン 1347 ロートエキス 1353, 1967 ロートエキス･アネスタミン散 1355 ロートエキス･カーボン散 1355 ロートエキス散 1353 ロートエキス･タンニン坐剤 1357 ロートエキス･パパベリン･アネスタミン散 1356 ロートコン 1357, 1967, 2234 ロラゼパム 827 ローヤルゼリー 2233

ワ

ワイル病秋やみ混合ワクチン 1237 ワルファリンカリウム 1233 ワルファリンカリウム錠 1234, 2215