Food and Drug Administration, HHS Pt. 446
(c) The batch for neomycin content, PART 446—TETRACYCLINE polymyxin B content, pH, and sterility. ANTIBIOTIC DRUGS (ii) Samples required: (a) The neomycin sulfate used in Subpart A—Bulk Drugs making the batch: Ten packages, each containing approximately 300 milli- Sec. grams. 446.10 Chlortetracycline hydrochloride. (b) The polymyxin B sulfate used in 446.10a Sterile chlortetracycline hydro- making the batch: Ten packages, each chloride. 446.15 Demeclocycline. containing approximately 300 milli- 446.16 Demeclocycline hydrochloride. grams 446.20 Doxycycline hyclate. (c) The batch: 446.20a Sterile doxycycline hyclate. (1) For all tests except sterility: A 446.21 Doxycycline monohydrate. minimum of six immediate containers. 446.42 Meclocycline sulfosalicylate. (2) For sterility testing: Twenty im- 446.50 Methacycline hydrochloride. mediate containers, collected at regu- 446.60 Minocycline hydrochloride. lar intervals throughout each filling 446.65 Oxytetracycline. operation. 446.65a Sterile oxytetracycline. 446.66 Oxytetracycline calcium. (b) Tests and methods of assay—(1) Po- 446.67 Oxytetracycline hydrochloride. tency—(i) Neomycin content. Proceed as 446.67a Sterile oxytetracycline hydro- directed in § 444.42a(b)(1), except pre- chloride. pare the sample as follows: Remove an 446.75a Sterile rolitetracycline. accurately measured portion and dilute 446.76a Sterile rolitetracycline nitrate. with 0.1M potassium phosphate buffer, 446.80 Tetracycline. pH 8.0, to the proper prescribed ref- 446.81 Tetracycline hydrochloride. erence concentration. The neomycin 446.81a Sterile tetracycline hydrochloride. 446.82 Tetracycline phosphate complex. content is satisfactory if it is not less than 90 percent nor more than 130 per- Subpart B—Oral Dosage Forms cent of the number of milligrams of ne- omycin that it is represented to con- 446.110 Chlortetracycline hydrochloride cap- tain. sules. (ii) Polymyxin B content. Remove an 446.115 Demeclocycline oral dosage forms. 446.115a Demeclocycline oral suspension. accurately measured portion and dilute 446.115b Demeclocycline for oral suspension. with 10-percent potassium phosphate 446.116 Demeclocyline hydrochloride oral buffer, pH 6.0, to a reference concentra- dosage forms. tion of 10 units of polymyxin B per mil- 446.116a Demeclocycline hydrochloride tab- liliter. Proceed as directed in lets. § 448.30a(b)(1) of this chapter, except 446.116b [Reserved] add to each concentration of the poly- 446.116c Demeclocycline hydrochloride cap- myxin B standard curve a quantity of sules. 446.120 Doxycycline hyclate oral dosage neomycin to yield the same concentra- forms. tion of neomycin as that present when 446.120a Doxycycline hyclate capsules. the sample is diluted to contain 10 446.120b Doxycycline calcium oral suspen- units of polymyxin B per milliliter. sion. The polymyxin B content is satisfac- 446.120c Doxycycline hyclate tablets. tory if it is not less than 90 percent nor 446.120d Doxycycline hyclate pellet–filled more than 130 percent of the number of capsules. units of polymyxin B that it is rep- 446.121 Doxycycline monohydrate oral dos- age forms. resented to contain. 446.121a Doxycycline monohydrate for oral (2) Sterility. Proceed as directed in suspension. § 436.20 of this chapter, using the meth- 446.121b Doxycycline monohydrate capsules. od described in paragraph (e)(1) of that 446.150 Methacycline hydrochloride oral section. dosage forms. (3) pH. Proceed as directed in 446.150a Methacycline hydrochloride cap- § 440.80a(b)(5)(ii) of this chapter, using sules. the undiluted sample. 446.150b Methacycline hydrochloride oral suspension. [39 FR 19045, May 30, 1974, as amended at 41 446.160 Minocycline hydrochloride oral dos- FR 56307, Dec. 28, 1976; 42 FR 18059, Apr. 5, age forms. 1977; 50 FR 19919, May 13, 1985] 446.160a Minocycline hydrochloride tablets.
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446.160b Minocycline hydrochloride cap- mic dosage forms. sules. 446.381a Tetracycline hydrochloride oph- 446.160c Minocycline hydrochloride oral sus- thalmic ointment. pension. 446.381b Tetracycline hydrochloride oph- 446.165 Oxytetracycline oral dosage forms. thalmic suspension. 446.165a Oxytetracycline tablets. 446.165b—446.165c [Reserved] Subpart E—Otic Dosage Forms 446.165d Oxytetracycline for oral suspen- sion. 446.467 Oxytetracycline hydrochloride-poly- 446.166 Oxytetracycline calcium oral sus- myxin B sulfate otic ointment. pension. 446.167 Oxytetracycline hydrochloride cap- Subpart F—Dermatologic Dosage Forms sules. 446.180 Tetracycline oral dosage forms. 446.510 Chlortetracycline hydrochloride 446.180a—446.180b [Reserved] ointment. 446.180c Tetracycline oral suspension. 446.542 Meclocycline sulfosalicylate cream. 446.181 Tetracycline hydrochloride oral dos- 446.567 Oxytetracycline hydrochloride der- age forms. matologic dosage forms. 446.181a—446.181c [Reserved] 446.567a [Reserved] 446.181d Tetracycline hydrochloride tablets. 446.567b Oxytetracycline hydrochloride- 446.181e Tetracycline hydrochloride cap- polymyxin B sulfate topical ointment. sules. 446.567c Oxytetracycline hydrochloride- 446.182 Tetracycline phosphate complex polymyxin B sulfate topical powder. capsules. 446.581 Tetracycline hydrochloride dermato- logic dosage forms. Subpart C—Injectable Dosage Forms 446.581a—446.581b [Reserved] 446.581c Tetracycline hydrochloride for top- 446.220 Doxycycline hyclate for injection. ical solution. 446.260 Sterile minocycline hydrochloride. 446.581d Tetracycline hydrochloride oint- 446.265 Oxytetracycline injection. ment. 446.267 Oxytetracycline hydrochloride for injection. Subpart G—Vaginal Dosage Forms 446.275 Rolitetracycline injectable dosage forms. 446.667 Oxytetracycline hydrochloride-poly- 446.275a Rolitetracycline for intravenous myxin B sulfate vaginal tablets. use. 446.275b Rolitetracycline for intramuscular Subpart H—Rectal Dosage Forms use. [Reserved] 446.276 Rolitetracycline nitrate injectable dosage forms. Subpart I [Reserved] 446.276a Rolitetracycline nitrate for intra- venous use. Subpart J—Certain Other Dosage Forms 446.276b Rolitetracycline nitrate for intramuscular use. [Reserved] 446.281 Tetracycline hydrochloride injectable dosage forms. AUTHORITY: 21 U.S.C. 357. 446.281a Sterile tetracycline hydrochloride. SOURCE: 39 FR 19076, May 30, 1974, unless 446.281c Tetracycline hydrochloride for otherwise noted. intramuscular use. 446.281d Tetracycline hydrochloride for in- travenous use. Subpart A—Bulk Drugs 446.282 Tetracycline phosphate complex for injection. § 446.10 Chlortetracycline hydro- chloride. Subpart D—Ophthalmic Dosage Forms (a) Requirements for certification—(1) 446.310 Chlortetracycline hydrochloride Standards of identity, strength, quality, ophthalmic ointment. and purity. Chlortetracycline hydro- 446.367 Oxytetracycline hydrochloride oph- chloride is [4S - (4α,4aα,5aα,6β, 12aα] - 7 thalmic dosage forms. - chloro - 4 - (dimethylamino) - 1,4, 446.367c Oxytetracycline hydrochloride-hy- 4a,5,5a,6,11,12a - octahydro - 3,6,10,12, drocortisone acetate ophthalmic suspen- 12a - pentahydroxy - 6 - methyl - 1,11 - sion. 446.367e Oxytetracycline hydrochloride- dioxo - 2 - polymyxin B sulfate ophthalmic oint- naphthacenecarboxamidemonohydro- ment. chloride. Chlortetracycline is produced 446.381 Tetracycline hydrochloride ophthal- by the growth of Streptomyces
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aureofaciens. It is a yellow powder. It is § 446.10a Sterile chlortetracycline hy- so purified and dried that: drochloride. (i) Its potency is not less than 900 (a) Requirements for certification—(1) micrograms per milligram. Standards of identity, strength, quality, (ii) [Reserved] and purity. Chlortetracycline hydro- (iii) Its loss on drying is not more chloride is [4S - (4α,4aα,5aα,6β,12aα)] - 7 than 2.0 percent. - chloro - 4 - (dimethylamino) - (iv) Its pH in an aqueous solution 1,4,4a,5,5a,6,11,12a - octahydro - containing 10 milligrams per milliliter 3,6,10,12,12a - pentahydroxy - 6 - methyl is not less than 2.3 and not more than - 1,11 - dioxo - 2 - 3.3. naphthacenecarboxamide (v) It is crystalline. monohydrochloride. Chlortetracycline (vi) It meets the identity test for is produced by the growth of chlortetracycline. Streptomyces aureofaciens. It is a yellow (2) Labeling. It shall be labeled in ac- powder. It is so purified and dried that: cordance with the requirements of (i) Its potency is not less than 900 § 432.5 of this chapter. micrograms per milligram. (3) Requests for certification; samples. (ii) It is sterile. In addition to complying with the re- (iii) It is nonpyrogenic. quirements of § 431.1 of this chapter, (iv) [Reserved] each such request shall contain: (v) It contains no depressor sub- (i) Results of tests and assays on the stances. batch for potency, loss on drying, pH, (vi) Its loss on drying is not more crystallinity, and identity. than 2.0 percent. (ii) Samples required: 10 packages, (vii) Its pH in an aqueous solution each containing approximately 300 mil- containing 10 milligrams per milliliter ligrams. is not less than 2.3 and not more than (b) Tests and methods of assay—(1) Po- 3.3. tency. Proceed as directed in § 436.106 of (viii) It is crystalline. this chapter, preparing the sample for (ix) It meets the identity test for assay as follows: Dissolve an accu- chlortetracycline. rately weighed sample in sufficient (2) Labeling. It shall be labeled in ac- 0.01N hydrochloric acid to obtain a con- cordance with the requirements of centration of 1,000 micrograms of § 432.5 of this chapter. chlortetracycline hydrochloride per (3) Requests for certification; samples. milliliter (estimated). Further dilute In addition to complying with the re- an aliquot of the stock solution with quirements of § 431.1 of this chapter, sterile distilled water to the reference each such request shall contain: (i) Results of tests and assays on the concentration of 0.06 microgram of batch for potency, sterility, pyrogens, chlortetracycline hydrochloride per depressor substances, loss on drying, milliliter (estimated). pH, crystallinity, and identity. (2) [Reserved] (ii) Samples required: (3) Loss on drying. Proceed as di- (a) For all tests except sterility: 10 rected in § 436.200(b) of this chapter. packages, each containing approxi- (4) pH. Proceed as directed in § 436.202 mately 300 milligrams. of this chapter, using an aqueous solu- (b) For sterility testing: 20 packages, tion containing 10 milligrams per mil- each containing approximately 300 mil- liliter. ligrams. (5) Crystallinity. Proceed as directed (b) Tests and methods of assay—(1) Po- in § 436.203(a) of this chapter. tency. Proceed as directed in § 436.106 of (6) Identity. To 1 milligram of sample, this chapter, preparing the sample for add 2.0 milliliters of concentrated sul- assay as follows: Dissolve an accu- furic acid. In the presence of chlor- rately weighed sample in sufficient tetracycline, a deep blue color is pro- 0.01N hydrochloric acid to obtain a con- duced that becomes dark green. centration of 1,000 micrograms of [43 FR 11154, Mar. 17, 1978; 43 FR 34456, Aug. chlortetracycline hydrochloride per 4, 1978, as amended at 50 FR 19920, May 13, milliliter (estimated). Further dilute 1985] an aliquot of the stock solution with
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sterile distilled water to the reference demeclocycline hydrochloride working concentration of 0.06 microgram of standard is 107.4±3.88. chlortetracycline hydrochloride per (vi) It is crystalline. milliliter (estimated). (vii) It passes the identity test. (2) Sterility. Proceed as directed in (2) Labeling. It shall be labeled in ac- § 436.20 of this chapter, using the meth- cordance with the requirements of od described in paragraph (e)(1) of that § 432.5 of this chapter. section, except use diluting fluid D in (3) Requests for certification; samples. lieu of diluting fluid A. In addition to complying with the re- (3) Pyrogens. Proceed as directed in quirements of § 431.1 of this chapter, § 436.32(b) of this chapter, using a solu- each such request shall contain: tion containing 5 milligrams of chlor- (i) Results of tests and assays on the tetracycline hydrochloride per milli- batch for potency, moisture, pH, ab- liter. sorptivity, crystallinity, and identity. (4) [Reserved] (ii) Samples required: 10 packages, (5) Depressor substances. Proceed as each containing approximately 250 mil- directed in § 436.35 of this chapter. ligrams. (6) Loss on drying. Proceed as directed (b) Tests and methods of assay—(1) Po- in § 436.200(b) of this chapter. tency. Proceed as directed in § 436.106 of (7) pH. Proceed as directed in § 436.202 this chapter, preparing the sample for of this chapter, using an aqueous solu- assay as follows: Dissolve an accu- tion containing 10 milligrams per mil- rately weighed sample in sufficient liliter. 0.1N hydrochloric acid to obtain a con- (8) Crystallinity. Proceed as directed centration of 1,000 micrograms of in § 436.203(a) of this chapter. demeclocycline hydrochloride per mil- (9) Identity. To 1.0 milligram of sam- liliter (estimated). Further dilute an ple, add 2.0 milliliters of concentrated aliquot of the stock solution with ster- sulfuric acid. In the presence of chlor- ile distilled water to the reference con- tetracycline, a deep blue color is pro- centration of 0.100 microgram of duced that becomes dark green. demeclocycline hydrochloride per mil- [43 FR 11154, Mar. 17, 1978; 43 FR 34456, Aug. liliter (estimated). 4, 1978, as amended at 46 FR 60568, Dec. 11, (2) [Reserved] 1981; 50 FR 19920, May 13, 1985] (3) Moisture. Proceed as directed in § 436.201 of this chapter. § 446.15 Demeclocycline. (4) pH. Proceed as directed in § 436.202 (a) Requirements for certification—(1) of this chapter, using an aqueous solu- Standards of identity, strength, quality, tion containing 10 milligrams per mil- and purity. Demeclocycline is [4S - liliter. (4α,4aα,5aα,6β,12aα)] - 7 - chloro - 4 - (5) Absorptivity. Determine the per- (dimethylamino) - 1,4,4a,5,5a,6,11, 12a - cent absorptivity of the sample rel- octahydro - 3,6,10,12,12a - pentahydroxy ative to that of the standard in the fol- - 1, 11 - dioxo - 2 - lowing manner: Dissolve an accurately naphthacenecarboxamide. It is so puri- weighed portion of approximately 40 fied and dried that: milligrams of the sample in 2 milli- (i) Its potency is not less than 970 liters of 0.1N HCl, dilute to exactly 250 micrograms of demeclocycline hydro- milliliters with distilled water, and chloride equivalent per milligram on mix thoroughly. Transfer a 10-milli- the anhydrous basis. liter aliquot of this solution to a 100- (ii) [Reserved] milliliter volumetric flask. Add about (iii) Its moisture content is not less 75 milliliters of distilled water and 5 than 4.3 percent and not more than 6.7 milliliters of 5N NaOH, dilute to vol- percent. ume with distilled water, and mix thor- (iv) Its pH is an aqueous solution oughly. Exactly 6 minutes after the ad- containing 10 milligrams per milliliter dition of the NaOH, determine the ab- is not less than 4 and not more than sorbance of the solution at a wave- 5.5. length of 380 nanometers, using a suit- (v) When calculated on the anhydrous able spectrophotometer and distilled basis, its absorptivity at 380 water as the blank. Treat a portion of nanometers relative to that of the the demeclocycline hydrochloride
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working standard in the same manner. tivity of the sample using the following Determine the percent relative absorp- calculation:
Absorbance of sample× Weight of standard in milligrams × Potency of standard in micrograms per milligram× 10 Percent relative = absorptivity Absorbance of standard× Weight of sample in milligrams× (100 − m )
where: m=percent moisture in the sample. (i) Results of tests and assays on the (6) Crystallinity. Proceed as directed batch for potency, loss on drying, pH, in § 436.203(a) of this chapter. absorptivity, crystallinity, and iden- tity. (7) Identity. Proceed as directed in (ii) Samples required: 10 packages, § 446.16(b)(7). The value yielded by cal- each containing approximately 250 mil- culation ranges between 0.97 and 1.17. ligrams. [39 FR 19076, May 30, 1974, as amended at 43 (b) Tests and methods of assay—(1) Po- FR 11155, Mar. 17, 1978; 43 FR 34456, Aug. 4, tency. Proceed as directed in § 436.106 of 1978; 46 FR 16683, Mar. 13, 1981; 50 FR 19920, this chapter, preparing the sample for May 13, 1985] assay as follows: Dissolve an accu- rately weighed sample in sufficient § 446.16 Demeclocycline hydro- 0.1N hydrochloric acid to obtain a con- chloride. centration of 1,000 micrograms of (a) Requirements for certification—(1) demeclocycline hydrochloride per mil- Standards of identity, strength, quality, liliter (estimated). Further dilute an and purity. Demeclocycline hydro- aliquot of the stock solution with ster- chloride is [4S - (4α 4aα,5aα,6β,12aα)] - 7 ile distilled water to the reference con- - chloro - 4 - (dimethylamino) - centration of 0.100 microgram of 1,4,4a,5,5a,6,11,12a - octahydro- demeclocycline hydrochloride per mil- 3,6,10,12,12a - pentahydroxy - 1,11 - liliter (estimated). dioxo - 2 - naphthacenecarboxamide (2) [Reserved] monohydrochloride. It is so purified (3) Loss on drying. Proceed as directed and dried that: in § 436.200(b) of this chapter. (i) Its potency is not less than 900 (4) pH. Proceed as directed in § 436.202 micrograms per milligram on the an- of this chapter, using an aqueous solu- hydrous basis. tion containing 10 milligrams per mil- (ii) [Reserved] liliter. (iii) Its loss on drying is not more (5) Absorptivity. Determine the per- than 2 percent. cent absorptivity of the sample rel- ative to that of the standard in the fol- (iv) Its pH in an aqueous solution lowing manner: Dissolve an accurately containing 10 milligrams per milliliter weighed portion of approximately 40 is not less than 2 and not more than 3. milligrams of the sample in 2 milli- (v) When calculated on the anhydrous liters of 0.1N HCl, dilute to exactly 250 basis, its absorptivity at 380 milliliters with distilled water, and nanometers relative to that of the mix thoroughly. Transfer a 10 milliliter demeclocycline hydrochloride standard aliquot of this solution to a 100-milli- ± is 100 4.2 percent. liter volumetric flask. Add about 75 (vi) It is crystalline. milliliters of distilled water and 5 mil- (vii) It passes the identity test. liliters of 5N NaOH, dilute to volume (2) Labeling. It shall be labeled in ac- with distilled water, and mix thor- cordance with the requirements of oughly. Exactly 6 minutes after the ad- § 432.5 of this chapter. dition of the NaOH, determine the ab- (3) Requests for certification; samples. sorbance of the solution at a wave- In addition to complying with the re- length of 380 nanometers, using a suit- quirements of § 431.1 of this chapter, able spectrophotometer and distilled each such request shall contain: water as the blank. Treat a portion of
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the working standard in the same man- sorptivity of the sample using the fol- ner. Determine the percent relative ab- lowing calculation:
Absorbance of sample× Weight of standard in milligrams× Potency of standard in micrograms per milligram ×10 Percent relative absorptivity = Absorbance of standard× Weight of sample in milligrams× (100 − m )
where: m=percent moisture in the sample. other add 10 milliliters of 3N HCl. Place (6) Crystallinity. Proceed as directed the acid-treated flasks into a boiling water batch for 20 minutes. Remove in § 436.203(a) of this chapter. the flasks and place in a cold water (7) Identity. Accurately weigh 40 mil- bath. When cool, dilute to volume with ligrams of the sample and place into a water and mix well. Treat a portion of 200-milliliter volumetric flask. Add 100 the standard in the same manner. milliliters of 0.1N HCl and place on a Using a suitable spectrophotometer, shaker until the sample is dissolved. place the 6N HCl-treated sample into Dilute to volume with 0.1N HCl and the reference cell and read against the mix well. Transfer a 5-milliliter aliquot 3N HCl-treated sample at a wavelength of the solution to each of two 50-milli- of 368 nanometers. Reverse the order of liter volumetric flasks. To one flask the cells in the cell holder and read at add 10 milliliters of 6N HCl and to the a wavelength of 430 nanometers.
()AA+ sample (milligrams of standard per milliliter) (100) 368 430 = 0.. 9 to 11 + − ()AA368 430 standard (milligrams of sample per milliliter) (100m )
where: m=percent moisture in the sample. (iv) Its pH in an aqueous solution containing 10 milligrams per milliliter [39 FR 19076, May 30, 1974, as amended at 43 is not less than 2.0 nor more than 3.0. FR 11155, Mar. 17, 1978; 43 FR 34456, Aug. 4, 1978; 50 FR 19920, May 13, 1985] (v) It contains not less than 82 nor more than 90 percent doxycycline on an § 446.20 Doxycycline hyclate. ‘‘as is’’ basis. (a) Requirements for certification—(1) (vi) It gives a positive identity test Standards of identity, strength, quality, for doxycycline hyclate. and purity. Doxycycline hyclate is [4S - (vii) It is crystalline. 4aα,4aα,5aα,5aα,6α,12aα]- 4 - (2) Labeling. It shall be labeled in ac- dimethylamino) -1,4,4a,5,5a,6,11,12a - cordance with the requirements of octahydro- 3,5,10,12,12a-pentahydroxy - § 432.5 of this chapter. 6 -methyl-1,11- dioxo -2 - (3) Requests for certification; samples. naphthacenecarboxamide In addition to complying with the re- hydrochloridehemiethanolate quirements of § 431.1 of this chapter, hemihydrate. It is so purified and dried each such request shall contain: that: (i) Results of tests and assays on the (i) Its potency is not less than 800 nor more than 920 micrograms of batch for potency, moisture, pH, doxycycline per milligram on an ‘‘as doxycycline content, identity, and is’’ basis. crystallinity. (ii) [Reserved] (ii) Samples required: 10 packages, (iii) Its moisture content is not less each containing approximately 300 mil- than 1.4 nor more than 2.75 percent. ligrams.
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(b) Tests and methods of assay—(1) Po- acid. Store in the refrigerator and use tency. Proceed as directed in § 436.106 of within 7 days. this chapter, preparing the sample for (iv) Preparation of sample. Accurately assay as follows: Dissolve an accu- weight about 50 milligrams of the sam- rately weighed sample in sufficient ple into a 5-milliliter volumetric flask 0.1N hydrochloric acid to obtain a con- and bring to volume with 0.05N meth- centration of 1,000 micrograms of anolic hydrochloric acid. doxycycline per milliliter (estimated). (v) Preparation of the chromatogram. Further dilute with sterile distilled Dip the chromatographic sheets into water to the reference concentration of pH 4.2 buffer and lightly blot each 0.100 microgram of doxycycline per sheet between clean nonfluorescing, milliliter (estimated). white blotters. Use separate sheets for (2) [Reserved] the doxycycline standard solution, for (3) Moisture. Proceed as directed in each doxycycline sample solution, and § 436.201 of this chapter. for blanks without standard or sample (4) pH. Proceed as directed in § 436.202 application. Care must be taken so of this chapter, using an aqueous solu- that the moist sheets do not become tion containing the equivalent of 10 too dry; a period of 5 to 10 minutes be- milligrams of doxycycline per milli- tween impregnating the paper and liter. placing it in the chromatographic (5) Doxycycline content—(i) Equip- chamber is usually satisfactory. Even- ment—(a) Sheet (chromatographic). ly apply a 0.100-milliliter aliquot of a Whatman No. 4 filter paper for chroma- doxycycline solution to the origin line tography, 15 × 57 centimeters. of a sheet as a 14-centimeter-long (b) Chamber (chromatographic). Square streak. Place the sheets in the chamber glass chromatography jar, 30 × 30 × 60 and develop them in a descending man- centimeters, equipped with 25-centi- ner for 2 hours. The doxycycline band meter troughs for descending chroma- should move approximately 12.5 centi- tography. meters from the origin line. Remove (ii) Preparation of solutions—(a) 0.05N the sheets from the chamber and air- Methanolic hydrochloric acid. Dilute 4.2 dry for about 10 minutes. milliliters of concentrated hydro- (vi) Processing the chromatogram. Ex- chloric acid to 1 liter with methanol. amine each sheet under 366-nanometer (b) pH 4.2 buffer. Mix 5.86 volumes of ultraviolet light. Outline the fluores- 0.1M citric acid with 4.14 volumes of cent bands with a pencil. The main 0.2M disodium phosphate. marked area should be approximately (c) Chromatographic system. Mix tolu- 10 × 15 centimeters in size. Outline ene, pyridine, and pH 4.2 buffer in volu- areas on the blank sheet approximately metric proportions of 20:3:10, respec- equal in size and in the same locations tively. Allow the phases to separate. as those outlined on the standard Place the upper phase in the troughs sheet. Exposure of the sheets to ammo- near the top of the chamber. Place the nia or other alkaline vapors must be lower phase in the bottom of the cham- avoided. Cut the marked areas from ber. Saturate the atmosphere of the the sheets and then cut them into ap- tightly sealed chamber for 24 hours be- proximately 2-centimeter squares. For fore use by placing white blotters on each sheet, place the squares from each two opposite sides of the chamber so of the following areas into separate 125- that their ends are immersed in the milliliter Erlenmeyer flasks: The main lower phase in the bottom of the cham- doxycycline band of the sample, the ber. Replace the solvent in troughs be- main doxycycline band of the standard, fore the chromatograms are to be de- all the other bands of the standard, the veloped. area of the blank sheet corresponding (iii) Preparation of the doxycycline to the main band of the standard, the standard solution. Accurately weigh other area of the blank sheet cor- about 50 milligrams of the doxycycline responding to the other bands of the working standard into a 5-milliliter standard. The time between removing volumetric flask and bring to volume the sheets from the chamber and plac- with 0.05N methanolic hydrochloric ing the squares into the Erlenmeyer
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flasks should be minimal, since exces- each of three 125-milliliter Erlenmeyer sive drying of the paper can lead to er- flasks. Add 50 milliliters of 0.05N meth- ratic elutions. anolic hydrochloric acid to each of (vii) Elution. To each flask add 50 these flasks. milliliters of 0.05N methanolic hydro- (ix) Absorbance measurement. Using a chloric acid and agitate on a recip- suitable spectrophotometer and 0.05N rocating shaker for 1 hour. Decant the methanolic hydrochloric acid as the contents of each flask into another reference solvent, determine the ab- flask by pouring through a small fun- sorbance of each eluate and of each nel fitted with a glass wool plug. doxycycline standard solution at the (viii) Doxycycline standard solution for absorption maximum at about 349 direct measurement of absorbance. Pi- nanometers. pette a 0.100-milliliter aliquot of the (x) Calculation of percent doxycycline doxycycline standard solution into in samples. Calculate as follows:
()A− A ) (W Percent = u b s × Doxycycline content of doxycycline − the working standard ()As A b ) (W u
where: where: Au=Absorbance of the eluate from the main Ac=Absorbance of the eluate from sections doxycycline band of the sample sheet. of the standard chromatogram contain- As=Absorbance of the eluate from the main ing nondoxycycline 349 nanometers-ab- doxycycline band on the standard sorbing contaminants. sheet. Acb=Absorbance of the eluates from the Ab=Absorbance of the eluate from the area sections of the blank sheets cor- of the blank sheet corresponding to the responding to those sections of the area of the doxycycline band of the nondoxycycline-absorbing contami- standard sheet. nants of the standard sheets. Wu=Weight in milligrams of sample. (6) Identity. Proceed as directed in Ws=Weight in milligrams of doxycycline working standard. § 436.211 of this chapter, using the 0.25 potassium bromide mixture described (xi) Recovery of the doxycycline stand- in paragraph (b)(1) of that section. ard from the chromatogram. As follows: (7) Crystallinity. Proceed as directed in § 436.203(a) of this chapter. As− Ab 100 Percent recovery = × [39 FR 19076, May 30, 1974, as amended at 43 AF FR 11155, Mar. 17, 1978; 50 FR 19920, May 13, p 1985] where: Ap=Absorbance of the doxycycline stand- § 446.20a Sterile doxycycline hyclate. ard solution described in paragraph (a) Requirements for certification—(1) (b)(5)(viii) of this section. Standards of identity, strength, equality, F=The fractional purity of doxycycline and purity. Sterile doxycycline hyclate standard solution described in para- α α α α α α graph (b)(5)(xii) of this section. is [4S - (4 ,4a ,5 ,5a ,6 12a )] - 4 - (dimethylamino) - 1,4,4a,5,5a,6,11,12a - If the recovery of the doxycycline octahydro - 3,5,10,12,12a - pentahydroxy standard from the chromatogram is - 6 - methyl - 1,11 - dioxo - 2 - less than 95 percent, repeat the chro- naphthacenecarboxamide hydro- matogram. chloride hemiethanolate hemihydrate. (xii) Determination of the fractional pu- It is so purified and dried that: rity of the doxycycline working standard. (i) Its potency is not less than 800 nor Determine F by means of the following more than 920 micrograms of equation: doxycycline per milligram on an ‘‘as is’’ basis. Ac− Acb (ii) It is sterile. F = 1− (iii) It is nonpyrogenic. Ac− Acb + As − Ab (iv) [Reserved]
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(v) It contains no depressor sub- (7) pH. Proceed as directed in § 436.202 stances. of this subchapter, using an aqueous (vi) Its moisture content is not less solution containing the equivalent of than 1.4 nor more than 2.75 percent. 10 milligrams of doxycycline per milli- (vii) Its pH in an aqueous solution liter. containing 10 milligrams per milliliter (8) Doxycycline content. Proceed as di- is not less than 2.0 nor more than 3.0. rected in § 446.20(b)(5). (viii) It contains not less than 82 nor (9) Identity. Proceed as directed in more than 90 percent doxycycline on an § 436.211 of this subchapter, using the ‘‘as is’’ basis. 0.25 potassium bromide mixture de- (ix) It gives a positive identity test scribed in paragraph (b)(1) of that sec- for doxycycline hyclate. tion. (x) It is crystalline. (10) Crystallinity. Proceed as directed (2) Labeling. It shall be labeled in ac- in § 436.203(a) of this subchapter. cordance with the requirements of § 432.5 of this subchapter. [39 FR 19076, May 30, 1974, as amended at 43 FR 11155, Mar. 17, 1978; 46 FR 60568, Dec. 11, (3) Requests for certification; samples. 1981; 50 FR 19920, May 13, 1985] In addition to complying with the re- quirements of § 431.1 of this subchapter, § 446.21 Doxycycline monohydrate. each such request shall contain: (a) Requirements for certification—(1) (i) Results of tests and assays on the Standards of identity, strength, quality, batch for potency, sterility, pyrogens, and purity. Doxycycline monohydrate depressor substances, moisture, pH, is [4S - (4α,4aα,5α,5aα,6α,12aα)] - 4 - doxycycline content, identity, and (dimethylamino) - 1,4,4a,5,5a,6,11, - 12a - crystallinity. octahydro - 3,5,10,12,12a - pentahydroxy (ii) Samples required: - 6 - methyl - 1,11 - dioxo - 2 - naphtha (a) For all tests except sterility: 12 - cenecarboxamide monohydrate. It is packages, each containing approxi- so purified and dried that: mately 300 milligrams. (i) Its potency is not less than 880 (b) For sterility testing: 20 packages, micrograms nor more than 980 each containing approximately 300 mil- micrograms of doxycycline per milli- ligrams. gram on an ‘‘as is’’ basis. (b) Tests and methods of assay—(1) Po- tency. Proceed as directed in § 436.106 of (ii) [Reserved] this chapter, preparing the sample for (iii) Its moisture content is not less assay as follows: Dissolve an accu- than 3.6 percent nor more than 4.6 per- rately weighed sample in sufficient cent. 0.1N hydrochloric acid to obtain a con- (iv) Its pH in an aqueous suspension centration of 1,000 micrograms of containing the equivalent of 10 milli- doxycycline per milliliter (estimated). grams of doxycycline per milliliter is Further dilute with sterile distilled not less than 5.0 nor more than 6.5. water to the reference concentration of (v) It contains not less than 90 per- 0.100 microgram of doxycycline per cent nor more than 98 percent milliliter (estimated). doxycycline on an ‘‘as is’’ basis. (2) Sterility. Proceed as directed in (vi) It gives a positive identity test § 436.20 of this subchapter, using the for doxycycline monohydrate. method described in paragraph (e)(1) of (vii) It is crystalline. that section, except use diluting fluid (2) Labeling. It shall be labeled in ac- D in lieu of diluting fluid A. cordance with the requirements of (3) Pyrogens. Proceed as directed in § 432.5 of this chapter. § 436.32(a) of this subchapter, using a (3) Requests for certification; samples. solution containing 7.5 milligrams of In addition to complying with the re- doxycycline per milliliter. quirements of § 431.1 of this chapter, (4) [Reserved] each such request shall contain: (5) Depressor substances. Proceed as (i) Results of tests and assays on the directed in § 436.35 of this subchapter. batch for potency, moisture, pH, (6) Moisture. Proceed as directed in doxycycline content, identity, and § 436.201 of this subchapter. crystallinity.
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(ii) Samples of the batch: 10 pack- (3) Requests for certification; samples. ages, each containing approximately In addition to complying with the re- 300 milligrams. quirements of § 431.1 of this chapter, (b) Tests and methods of assay—(1) Po- each such request shall contain: tency. Proceed as directed in § 436.106 of (i) Results of tests and assays on po- this chapter, preparing the sample for tency, moisture, pH, and crystallinity. assay as follows: Dissolve an accu- (ii) Samples required: 10 packages, rately weighed sample in sufficient each containing approximately 300 mil- 0.1N hydrochloric acid to obtain a con- ligrams. centration of 1,000 micrograms of (b) Tests and methods of assay—(1) Po- doxycycline per milliliter (estimated). tency. Use either of the following meth- Further dilute with sterile distilled ods; however, the results obtained from water to the reference concentration of the high-pressure liquid chroma- 0.100 microgram of doxycycline per tography method shall be conclusive. milliliter (estimated). (i) High-pressure liquid chroma- (2) [Reserved] tography. Proceed as directed in (3) Moisture. Proceed as directed in § 436.329 of this chapter. § 436.201 of this chapter. (ii) Microbiological turbidimetric assay. (4) pH. Proceed as directed in § 436.202 Proceed as directed in § 436.106 of this of this chapter, using an aqueous sus- chapter, preparing the sample for assay pension containing the equivalent of 10 as follows: Dissolve an accurately milligrams of doxycycline per milli- weighed portion of the sample in suffi- liter. cient 0.01N methanolic hydrochloric (5) Doxycycline content. Proceed as di- acid (solution 13) to obtain a stock so- rected in § 446.20(b)(5). lution of convenient concentration. (6) Identity. Proceed as directed in Further dilute an aliquot of the stock § 436.211 of this chapter, using the 0.25 solution with distilled water to the ref- potassium bromide mixture described erence concentration of 0.06 microgram in paragraph (b)(1) of that section. of meclocycline per milliliter (esti- (7) Crystallinity. Proceed as directed mated). in § 436.203(a) of this chapter. (2) Moisture. Proceed as directed in [39 FR 19076, May 30, 1974, as amended at 43 § 436.201 of this chapter. FR 11155, Mar. 17, 1978; 45 FR 16476, Mar. 14, (3) pH. Proceed as directed in § 436.202 1980; 50 FR 19920, May 13, 1985] of this chapter, using an aqueous sus- pension containing 10 milligrams of § 446.42 Meclocycline sulfosalicylate. meclocycline per milliliter. (a) Requirements for certification—(1) (4) Crystallinity. Proceed as directed Standards of identity, strength, quality, in § 436.203(a) of this chapter. and purity. Meclocycline sulfosalicylate is the sulfosalicylate [46 FR 3836, Jan. 16, 1981] salt of 7-chloro-4-(dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro- § 446.50 Methacycline hydrochloride. 3,5,10,12,12a-pentahydroxy-6-methylene- (a) Requirements for certification—(1) 1,11-dioxo-2-naphthacenecarboxamide. Standards of identity, strength, quality, It is so purified and dried that: and purity. Methacycline hydrochloride (i) Its potency is not less than 620 is [4S - (4α,4aα,5α,5aα, - 12aα)] - 4 - micrograms of meclocycline per milli- (dimethylamino) - 1,4,4a,5,5a,6,11,12a - gram on an ‘‘as is’’ basis. octahydro - 3,5,10,12,12a - pentahydroxy (ii) Its moisture content is not more - 6 - methylene - 1,11 - dioxo - 2 - than 4.0 percent. naphthacenecar - boxamide (iii) Its pH is in an aqueous suspen- monohydrochloride. It is so purified sion containing 10 milligrams per mil- and dried that: liliter is not less than 2.5 and not more (i) Its potency is not less than 832 than 3.5. micrograms of methacycline per milli- (iv) It is crystalline. gram on an ‘‘as is’’ basis. (2) Labeling. It shall be labeled in ac- (ii) [Reserved] cordance with the requirements of (iii) Its moisture content is not more § 432.5 of this chapter. than 2 percent.
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(iv) Its pH in an aqueous solution nanometers. Determine the percent ab- containing 10 milligrams per milliliter sorptivity of the sample relative to the is not less than 2.0 nor more than 3.0. absorptivity of the standard using the (v) Its absorptivity at the absorption following calculations: maximum of 345 nanometers relative to Percent relative absorptivity=(Absorbance of that of the methacycline working sample×weight in milligrams of stand- standard similarly treated is 92.4±4 per- ards×potency of standard in micrograms cent. per milligram)/(Absorbance of stand- (vi) It gives a positive result to the ard×weight in milligrams of sample×10) identity test for methacycline hydro- (6) Identity. The absorption spectrum chloride. between the wavelength of 250 and 400 (vii) It is crystalline. nanometers, determined as directed in (2) Labeling. It shall be labeled in ac- paragraph (b)(5) of this section, com- cordance with the requirements of pares qualitatively with that of the § 432.5(b) of this chapter. methacycline standard. (3) Requests for certification; samples. (7) Crystallinity. Proceed as directed In addition to complying with the re- in § 436.203(a) of this chapter. quirements of § 431.1 of this chapter, each such request shall contain: [39 FR 19076, May 30, 1974, as amended at 43 (i) Results of tests and assays on the FR 11155, Mar. 17, 1978; 50 FR 19920, May 13, batch for potency, moisture, pH, ab- 1985] sorptivity, identity, and crystallinity. (ii) Samples of the batch: 10 pack- § 446.60 Minocycline hydrochloride. ages, each containing 300 milligrams. (a) Requirements for certification—(1) (b) Tests and methods of assay—(1) Po- Standards of identity, strength, quality, tency. Proceed as directed in § 436.106 of and purity. Minocycline hydrochloride this chapter, preparing the sample for is [4S-(4α,4aα,5aα,12aα)]-4,7-bis assay as follows: Dissolve an accu- (dimethylamino)-1,4,4a,5,5a,6,11, - 12a- rately weighed sample in sufficient octahydro-3,10,12, - 12a-tetrahydroxy- sterile distilled water to obtain a stock 1,11-dioxo-2-naphthacenecarboxamide solution of convenient concentration. monohydrochloride. It is so purified Further dilute an aliquot of the stock and dried that: solution with sterile distilled water to (i) Its potency is not less than 890 the reference concentration of 0.06 micrograms per milligram and not microgram of methacycline per milli- more than 950 micrograms per milli- liter (estimated). gram on the anhydrous basis. (2) [Reserved] (ii) [Reserved] (3) Moisture. Proceed as directed in (iii) Its moisture content is not less § 436.201 of this chapter. than 4.3 percent and not more than 8.0 (4) pH. Proceed as directed in § 436.202 percent. of this chapter, using an aqueous solu- (iv) Its pH in an aqueous solution tion containing 10 milligrams of containing 10 milligrams of methacycline per milliliter. minocycline per milliliter is not less (5) Absorptivity. Determine the ab- than 3.5 and not more than 4.5. sorbance of the sample and standard (v) Its epi-minocycline content is not solutions in the following manner: Dis- more than 1.2 percent. solve approximately 50 milligrams each (vi) It gives a positive identity test of the sample and standard in 100 milli- for minocycline hydrochloride. liters of 0.01N methanolic hydrochloric (vii) It is crystalline. acid. Transfer a 10-milliliter aliquot to (viii) Its residue on ignition is not a 250-milliliter volumetric flask and di- more than 0.15 percent. lute to volume with 0.01N methanolic (ix) The absorptivity at 560 hydrochloric acid. Using a suitable nanometers of an aqueous solution con- spectrphotometer and 0.01N methanolic taining 10 milligrams of minocycline hydrochloric acid as the blank, scan hydrochloride per milliliter is not the absorption spectrum between the more than 0.006. wavelengths of 250 and 400 nanometers. (2) Labeling. It shall be labeled in ac- Determine the absorbance of each solu- cordance with the requirements of tion at the maxima, ca. 345 § 432.5 of this chapter.
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(3) Requests for certification; samples. (prepared as described in paragraph In addition to complying with the re- (b)(1)(i)(c) of this section) to obtain a quirements of § 431.1 of this chapter, solution containing 500 micrograms of each such request shall contain: minocycline activity per milliliter. Use (i) Results of tests and assays on the this standard solution within 3 hours of batch for potency, moisture, pH, epi- preparation. minocycline content, identity, crys- (b) Sample solution. Dissolve an accu- tallinity, residue on ignition, and ab- rately weighed sample in sufficient mo- sorptivity. bile phase to obtain a solution contain- (ii) Samples required: 10 packages, ing 500 micrograms of minocycline ac- each containing approximately 300 mil- tivity per milliliter (estimated). Use ligrams. this solution within 3 hours of prepara- (b) Tests and methods of assay—(1) tions. Minocycline potency. Proceed as di- (iii) System suitability requirements— rected in § 436.216 of this chapter, using (a) Asymmetry factor. Calculate the ambient temperature, an ultraviolet asymmetry factor (As), measured at a detection system operating at a wave- point 5 percent of the peak height from length of 280 nanometers, a 4.6-milli- the baseline, as follows: meter × 3-centimeter guard column + containing 10-micrometer diameter = a b RP–8 Lichrosorb, a 4.6-millimeter × 15- As centimeter analytical column packed 2a with octyl silane chemically bonded to where: porous microsilica particles, 5 microm- a=Horizontal distance from point of ascent eters in diameter, a flow rate of 2.9 mil- to point of maximum peak height; and liliters per minute, and a known injec- b=Horizontal distance from the point of max- tion volume of 10 microliters. Re- imum peak height to point of descent. agents, working standard and sample The asymmetry factor (As)is satisfactory if solutions, system suitability require- it is not less than 0.9 and not more than 1.35. ments, and calculations are as follows: (b) Efficiency of the column. From the (i) Reagents—(a) 0.1 M Disodium ethyl- number of theoretical plates (n) cal- enediamine-tetraacetate (EDTA). Accu- culated as described in § 436.216(c)(2) rately weigh 37.22 grams of disodium calculate the reduced plate height (hr) ethylenediaminetetraacetate into a as follows: 1,000-milliliter volumetric flask. Dis- solve in and dilute to mark with deion- = (L )(10 , 000 ) ized water. hr (b) 0.2 M Ammonium oxalate. Accu- (n )( d p ) rately weigh 28.42 grams of ammonium where: oxalate into a 1,000-milliliter volu- metric flask. Dissolve in and dilute to L=Length of the column in centimeters; mark with deionized water. n=number of theoretical plates; and dp=Average diameter of the particles in ana- (c) Mobile phase. Mix 250 milliliters of lytical column packing in micrometers. dimethylformamide, 200 milliliters of 0.1M disodium ethylenediaminetetra- The absolute efficiency (hr) is satisfac- acetate and 550 milliliters of 0.2M am- tory if it is not more than 50 for the monium oxalate. (5:4:11). Allow the so- minocycline peak. lution to cool to room temperature and (c) Resolution. Dissolve 50 milligrams then adjust the pH to 6.2 to 6.3 with of minocycline hydrochloride in 25 mil- 0.4M tetrabutylammonium hydroxide. liliters of deionized water. Pipet 5 mil- Filter and degas the mobile phase just liliters of this solution into a 25-milli- prior to its introduction into the liter volumetric flask and heat on a chomatographic pumping system. steam bath for 60 minutes. Transfer the (ii) Preparations of working standard, contents of the flask to a small beaker sample and resolution testing solutions— and evaporate to dryness. Dissolve the (a) Working standard solution. Dissolve residue in mobile phase, transfer to a an accurately weighed portion of the 25-milliliter volumetric flask, dilute to minocycline hydrocholoride working mark with mobile phase, mix, and fil- standard with sufficient mobile phase ter through Whatman No. 1 filter
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paper. Use this solution to determine working standard solution in the resolution factor. The resolution micrograms per milliliter; (R) between the peaks for minocycline Cu=Milligrams of minocycline sample per milliliter of sample solution; and and epi-minocycline is satisfactory if it m=Percent moisture content of the sample. is not less than 2.0. (d) Coefficient of variation (relative (2) [Reserved] standard deviation). The coefficient of (3) Moisture. Proceed as directed in variation (SR in percent) of 5 replicate § 436.201 of this chapter. injections is satisfactory if it is not (4) pH. Proceed as directed in § 436.202 more than 2.0 percent. of this chapter, using an aqueous solu- (e) Capacity factor (k′). Calculate the tion containing 10 milligrams of capacity factor (k′) for minocycline as minocycline per milliliter. follows: (5) Epi-minocycline content. Proceed as directed in paragraph (b)(1) of this sec- − tion. Calculate the epi-minocycline tr t o k′ = content as follows: to ()A ×100 where: Percent Epi-minocycline = epi tr=Retention time of minocycline in minutes; and ()Atotal to=Column dead time in minutes, which is es- where: timated from the following equation: Aepi=Area of the epi-minocycline peak in the chromatogram of the sample; and 2 (31416 . )(DL )( )( 0 . 75 ) Atotal=The sum of the areas of all the peaks = eluting after the solvent front. t o 4F (6) Identity. Proceed as directed in where: § 436.211 of this chapter, using a 0.5 per- D=Column diameter in centimeters; cent potassium bromide disc prepared L=Column length in centimeters; as described in paragraph (b)(1) of that 0.75=Average total column porosity; and section. F=Flow rate in milliliters per minute. (7) Crystallinity. Proceed as directed The capacity factor (k′) for minocycline in § 436.203(a) of this chapter. is satisfactory if it is not less than 6.2 (8) Residue on ignition. Proceed as di- and not more than 11.5. rected in § 436.207(b) of this chapter. If the system suitability require- (9) Absorptivity. Accurately weigh ments have been met, then proceed as about 1 gram of sample into a 100-milli- described in § 436.216(b) of this chapter. liter volumetric flask, dissolve, and di- Alternate chromatographic conditions lute to mark with deionized water. De- are acceptable provided reproducibility termine the absorbance of this solution and resolution are comparable to the on a suitable spectrophotometer at 560 system. However, the sample prepara- nanometers (nm) using 5-centimeter tion described in paragraph (b)(1)(ii)(b) cells with water in the reference cell. of this section should not be changed. Calculate the absorptivity as follows: (iv) Calculations—Calculate the (A )() 100 micrograms of minocycline per milli- Absorptivity at 560 = 560 gram of sample as follows: nm (grams of sample) (1,000)(5) Micrograms of AP× ×100 minocycline = u s [39 FR 19076, May 30, 1974, as amended at 43 AC× ×()100 − m FR 11156, Mar. 17, 1978; 43 FR 34456, Aug. 4, per milligram s u 1978; 44 FR 22058, Apr. 13, 1979; 50 FR 19920, where: May 13, 1985; 53 FR 32607, Aug. 26, 1988; 53 FR Au=Area of the minocycline peak in the chro- 39839, Oct. 12, 1988; 54 FR 47205, Nov. 13, 1989] matogram of the sample (at a retention time equal to that observed for the § 446.65 Oxytetracycline. standard); (a) Requirements for certification—(1) As=Area of the minocycline peak in the chro- matogram of the minocycline working Standards of identity, strength, quality, standard; and purity. Oxytetracycline is [4S- Ps=Minocycline activity in the minocycline (4α,4aα,5α,5aα,6β,12aα)]-4-(dimeth- 773
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ylamino)-1,4,4a,5,5a,6,11,12a-octa - sults obtained from the micro- hydro- 3,5,6,10,12,12a-hexahydroxy-6- biological turbidimetric assay shall be methyl- 1,11-dioxo-2-naphthacenecar - conclusive. boxamide dihydrate. Oxytetracycline is (i) Microbiological turbidimetric assay. produced by the growth of Streptomyces Proceed as directed in § 436.106 of this rimosus. It is so purified and dried that: chapter, preparing the sample for assay (i) Its potency is not less than 832 as follows: Dissolve an accurately micrograms of oxytetracycline per mil- weighed sample in sufficient 0.1N hy- ligram on an ‘‘as is’’ basis. drochloric acid to obtain a concentra- (ii) [Reserved] tion of 1,000 micrograms of oxytetra- (iii) Its moisture content is not less cycline per milliliter (estimated). Fur- than 6 percent and not more than 9 per- ther dilute an aliquot of the stock solu- cent. tion with sterile distilled water to the (iv) Its pH in an aqueous suspension reference concentration of 0.24 containing 10 milligrams per milliliter microgram of oxytetracycline per mil- is not less than 4.5 and not more than liliter (estimated). 7.0. (ii) Chemical assay. Proceed as di- (v) When calculated on an anhydrous rected in § 436.320 of this chapter. basis its absorptivity at 353 (2) [Reserved] nanometers relative to that of the oxy- (3) Moisture. Proceed as directed in tetracycline working standard simi- § 436.201 of this chapter. larly treated is 100±4 percent. (4) pH. Proceed as directed in § 436.202 (vi) It gives a positive result to an of this chapter, using an aqueous sus- identity test for oxytetracycline. pension containing 10 milligrams per (vii) It is crystalline. milliliter. (2) Labeling. It shall be labeled in ac- (5) Absorptivity. Determine the ab- cordance with the requirements of sorbance of the sample and standard § 432.5 of this chapter. solutions in the following manner: Dis- (3) Requests for certification; samples. solve approximately 50 milligrams each In addition to complying with the re- of the sample and standard in 250 milli- quirements of § 431.1 of this chapter, liters of 0.1N hydrochloric acid. Trans- each such request shall contain: fer a 10-milliliter aliquot to a 100-milli- (i) Results of tests and assays on the liter volumetric flask and dilute to vol- batch for potency, moisture, pH, ab- ume with 0.1N hydrochloric acid. Using sorptivity, identity, and crystallinity. a suitable spectrophotometer and 0.1N (ii) Samples required: 10 packages, hydrochloric acid as the blank, deter- each containing approximately 300 mil- mine the absorbance of each solution ligrams. at 353 nanometers. Determine the per- (b) Tests and methods of assay—(1) Po- cent absorptivity of the sample rel- tency. Assay for potency by either of ative to the absorptivity of the stand- the following methods; however, the re- ard using the following calculations:
Absorbance of sample × Percent relative = Milligrams of standard ×Potency of standard in × 10 absorptivity Absorbance of standard micrograms per milligram − ×Milligrams of sample 100 m
where: m = Percent moisture in the sample. (7) Crystallinity. Proceed as directed (6) Identity. To about 1 milligram of in § 436.203(a) of this chapter. sample, add 2 milliliters of sulfuric [43 FR 11156, Mar. 17, 1978, as amended at 50 acid; a light-red color is produced when FR 19920, May 13, 1985] oxytetracycline is present. § 446.65a Sterile oxytetracycline. (a) Requirements for certification—(1) Standards of identity, strength, quality,
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and purity. Sterile oxytetracycline is chapter, preparing the sample for assay [4S - (4α,4aα,5α,5aα,6β,12aα)] - 4 - as follows: Dissolve an accurately (dimethylamino) - 1,4,4a,5,5a,6,11, 12a - weighed sample in sufficient 0.1N hy- octahydro - 3,5,6,10,12,12a - drochloric acid to obtain a concentra- hexahydroxy - 6 - methyl - 1,11 - dioxo tion of 1,000 micrograms of oxytetra- - 2 - naphthacenecarboxamide dihy- cycline per milliliter (estimated). Fur- drate. Oxytetracycline is produced by ther dilute an aliquot of the stock solu- the growth of Streptomyces rimosus. It is tion with sterile distilled water to the so purified and dried that: reference concentration of 0.24 (i) Its potency is not less than 832 microgram of oxytetracycline per micrograms of oxytetracycline per mil- milli- liter (estimated). ligram on an ‘‘as is’’ basis. (ii) Chemical assay. Proceed as di- (ii) It is sterile. rected in § 436.320 of this chapter. (iii) It is nonpyrogenic. (2) Sterility. Proceed as directed in (iv) [Reserved] § 436.20 of this chapter, using the meth- (v) It contains no depressor sub- od described in paragraph (e)(1) of that stances. section, except use diluting fluid D in (vi) Its moisture content is not less lieu of diluting fluid A. than 6 percent and not more than 9 per- (3) Pyrogens. Proceed as directed in cent. § 436.32(b) of this chapter, using a solu- (vii) Its pH in an aqueous suspension tion containing 5.0 milligrams of oxy- containing 10 milligrams per milliliter tetracycline per milliliter prepared by is not less than 4.5 and not more than dissolving 40 milligrams in 2.0 milli- 7.0. liters of 0.1N hydrochloric acid and di- (viii) When calculated on an anhy- luting with the required amount of drous basis, its absorptivity at 353 sterile, pyrogen-free distilled water. nanometers relative to that of the (4) [Reserved] oxytet- racycline working standard similarly treated, is 100±4 percent. (5) Depressor substances. Proceed as (ix) It gives a positive result to an directed in § 436.35 of this chapter, pre- identity test for oxytetracycline. paring the sample by dissolving 40 mil- (x) It is crystalline. ligrams in 2.0 milliliters of 0.1N hydro- (2) Labeling. It shall be labeled in ac- chloric acid and diluting with the re- cordance with the requirements of quired amount of sterile distilled § 432.5 of this chapter. water. (3) Requests for certification; samples. (6) Moisture. Proceed as directed in In addition to complying with the re- § 436.201 of this chapter. quirements of § 431.1 of this chapter, (7) pH. Proceed as directed in § 436.202 each such request shall contain: of this chapter, using an aqueous sus- (i) Results of tests and assays on the pension containing 10 milligrams per batch for potency, sterility, pyrogens, milliliter. depressor substances, moisture, pH, ab- (8) Absorptivity. Determine the ab- sorptivity, identity, and crystallinity. sorbance of the sample and standard (ii) Samples required: solutions in the following manner: Dis- (a) For all tests except sterility: 10 solve approximately 50 milligrams each packages, each containing approxi- of the sample and standard in 250 milli- mately 300 milligrams. liters of 0.1N hydrochloric acid. Trans- (b) For sterility testing: 20 packages, fer a 10-milliliter aliquot to a 100-milli- each containing approximately 300 mil- liter volumetric flask, and dilute to ligrams. volume with 0.1N hydrochloric acid. (b) Tests and methods of assay—(1) Po- Using a suitable spectrophotometer tency. Assay for potency by either of and 0.1N hydrochloric acid as the the following methods; however, the re- blank, determine the absorbance of sults obtained from the micro- each solution at 353 nanometers. Deter- biological turbidimetric assay shall be mine the percent absorptivity of the conclusive. sample relative to the absorptivity of (i) Microbiological turbidimetric assay. the standard using the following cal- Proceed as directed in § 436.106 of this culations:
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Absorbance of sample × Percent relative = Milligrams of standard ×Potency of standard in × 10 absorptivity Absorbance of standard micrograms per milligram − ×Milligrams of sample 100 m
where: m =Percent moisture in the sample. (3) Requests for certification; samples. (9) Identity. To about 1 milligram of In addition to complying with the re- sample, add 2 milliliters of sulfuric quirements of § 431.1 of this chapter, acid; a light-red color is produced when each such request shall contain: oxytetracycline is present. (i) Results of tests and assays on the (10) Crystallinity. Proceed as directed batch for potency, moisture, pH, cal- in § 436.203(a) of this chapter. cium content, identity, and crystallin- ity. [43 FR 11156, Mar. 17, 1978; 43 FR 34456, Aug. (ii) Samples required: 10 packages, 4, 1978, as amended at 46 FR 60568, Dec. 11, 1981; 50 FR 19920, May 13, 1985] each containing approximately 300 mil- ligrams. § 446.66 Oxytetracycline calcium. (b) Tests and methods of assay—(1) Po- (a) Requirements for certification—(1) tency. Assay for potency by either of Standards of identity, strength, quality, the following methods; however, the re- and purity. Oxytetracycline calcium is sults obtained from the micro- [4S-(4α,4aα,5α,5aα,6β,12αβ)]-4- biological turbidimetric assay shall be (dimethylamino)-1,4,4a,5,5a,6,11, 12a- conclusive. octahydro-3,5,6,10,12,12a-hexa hydroxy- (i) Microbiological turbidimetric assay. 6-methyl-1,11-dioxo- 2- Proceed as directed in § 436.106 of this naphthacenecarboxamide calcium salt. chapter, preparing the sample for assay Oxytetracycline is produced by the as follows: Dissolve an accurately growth of Streptomyces rimosus. It is so weighed sample in sufficient 0.1N hy- purified and dried that: drochloric acid to obtain a concentra- (i) Its potency is equivalent to not tion of 1,000 micrograms of oxytetra- less than 865 micrograms of oxytetra- cycline per milliliter (estimated). Fur- cycline per milligram on an anhydrous ther dilute an aliquot of the stock solu- basis. tion with sterile distilled water to the r- (ii) [Reserved] reference concentration of 0.24 (iii) Its moisture content is not less microgram of oxytetracycline per mil- than 8 percent and not more than 14 liliter (estimated). percent. (ii) Chemical assay. Proceed as di- (iv) Its pH in an aqueous suspension rected in § 436.320 of this chapter. containing 25 milligrams per milliliter (2) [Reserved] is not less than 6.0 and not more than (3) Moisture. Proceed as directed in 8.0 § 436.201 of this chapter. (v) Its calcium content as the (4) pH. Proceed as directed in § 436.202 sulfated ash is not less than 3.85 per- of this chapter, using a saturated aque- cent and not more than 4.35 percent on ous suspension containing 25 milli- an anhydrous basis. grams per milliliter. (vi) It gives a positive identity test. (5) Calcium content. Proceed as di- (vii) It is crystalline. rected in § 436.207(b) of this chapter, ex- (2) Labeling. It shall be labeled in ac- cept from the weight of residue ob- cordance with the requirements of tained calculate the calcium content § 432.5 of this chapter. as follows:
Weight of residue ×0. 29435 × 100 × 100 Percent calcium = Weight of sample (anhydrous basis) ×()100 − m
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where: m = Percent moisture in the sample. absorptivity, identity, and crystallin- (6) Identity. To about 1 milligram of ity. sample, add 2 milliliters of sulfuric (ii) Samples required: 10 packages, acid; a light-red color is produced when each containing approximately 300 mil- oxytetracycline is present. ligrams. (7) Crystallinity. Proceed as directed (b) Tests and methods of assay—(1) Po- in § 436.203(a) of this chapter. tency. Assay for potency by either of [43 FR 11157, Mar. 17, 1978; 43 FR 34456, Aug. the following methods; however, the re- 4, 1978, as amended at 50 FR 19920, May 13, sults obtained from the micro- 1985] biological turbidimetric assay shall be conclusive. § 446.67 Oxytetracycline hydro- (i) Microbiological turbidimetric assay. chloride. Proceed as directed in § 436.106 of this (a) Requirements for certification—(1) chapter, preparing the sample for assay Standards of identity, strength, quality, as follows: Dissolve an accurately and purity. Oxytetracycline hydro- weighed sample in sufficient 0.1N hy- α α α α β α chloride is [4S-(4 ,4a ,5 ,5a , 6 ,12a ,)] drochloric acid to obtain a concentra- - 4 - (dimethylamino) - 1,4,4a,5, 5a,6, 11, tion of 1,000 micrograms of oxytetra- 12a - octahydro - 3,5,6,10,12,12a - cycline per milliliter (estimated). Fur- hexahydroxy - 6 - methyl - 1,11 - dioxo ther dilute an aliquot of the stock solu- - 2 - naphthacenecarboxamide monohydrochloride. Oxytetracycline is tion with sterile distilled water to the produced by the growth of Streptomyces reference concentration of 0.24 rimosus. It is so purified and dried that: microgram of oxytetracycline per (i) Its potency is not less than 835 milli- liter (estimated). micrograms of oxytetracycline per mil- (ii) Chemical assay. Proceed as di- ligram on an anhydrous basis. rected in § 436.320 of this chapter. (ii) [Reserved] (2) [Reserved] (iii) Its loss on drying is not more (3) Loss on drying. Proceed as di- than 2 percent. rected in § 436.200(b) of this chapter. (iv) Its pH in an aqueous solution (4) pH. Proceed as directed in § 436.202 containing 10 milligrams per milliliter of this chapter, using an aqueous solu- is not less than 2.0 and not more than tion containing 10 milligrams per mil- 3.0. liliter. (v) When calculated on an anhydrous (5) Absorptivity. Determine the ab- basis, its absorptivity at 353 sorbance of the sample and standard nanometers relative to that of the oxy- tetracycline standard similarly treated solutions in the following manner: Dis- is 92.5±4.3 percent. solve approximately 50 milligrams each (vi) It gives a positive result to an of the sample and standard in 250 milli- identity test for oxytetracycline. liters of 0.1N hydrochloric acid. Trans- (vii) It is crystalline. fer a 10-milliliter aliquot to a 100-milli- (2) Labeling. It shall be labeled in ac- liter volumetric flask and dilute to vol- cordance with the requirements of ume with 0.1N hydrochloric acid. Using § 432.5 of this chapter. a suitable spectrophotometer and 0.1N (3) Requests for certification; samples. hydrochloric acid as the blank, deter- In addition to complying with the re- mine the absorbance of each solution quirements of § 431.1 of this chapter, at 353 nanometers. Determine the per- each such request shall contain: cent absorptivity of the sample rel- (i) Results of tests and assays on the ative to the absorptivity of the stand- batch for potency, loss on drying, pH, ard, using the following calculations:
Absorbance of sample × Percent relative = Milligrams of standard ×Potency of standard in × 10 absorptivity Absorbance of standard micrograms per milligram − ×Milligrams of sample 100 m
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where: m = Percent moisture in the sample. (ii) Samples required: (6) Identity. To about 1 milligram of (a) For all tests except sterility: 10 sample, add 2 milliliters of sulfuric packages, each containing approxi- acid; a light-red color is produced when mately 300 milligrams. oxytetracycline is present. (b) For sterility testing: 20 packages, (7) Crystallinity. Proceed as directed each containing approximately 300 mil- in § 436.203(a) of this chapter. ligrams. [43 FR 11157, Mar. 17, 1978; 43 FR 34456, Aug. (b) Tests and methods of assay—(1) Po- 4, 1978, as amended at 50 FR 19920, May 13, tency. Assay for potency by either of 1985] the following methods; however, the re- sults obtained from the micro- § 446.67a Sterile oxytetracycline hy- biological turbidimetric assay shall be drochloride. conclusive. (a) Requirements for certification—(1) (i) Microbiological turbidimetric assay. Standards of identity, strength, quality, Proceed as directed in § 436.106 of this and purity. Sterile oxytetracycline hy- chapter, preparing the sample for assay drochloride is [4S - as follows: Dissolve an accurately (4α,4aα,5α,5aα,6β,12α)] - 4 - weighed sample in sufficient 0.1N hy- (dimethylamino) - 1,4,4a,5,5a,6,11,12a - drochloric acid to obtain a concentra- octahydro - 3,5,6,10,12,12a - tion of 1,000 micrograms of oxytetra- hexahydroxy - 6 - methyl - 1,11 - dioxo cycline per milliliter (estimated). Fur- - 2 - naphthacenecarboxamide ther dilute an aliquot of the stock solu- monohydrochloride. It is produced by tion with sterile distilled water to the the growth of Streptomyces rimosus. It is reference concentration of 0.24 so purified and dried that: microgram of oxytetracycline per mil- (i) Its potency is not less than 835 liliter (estimated). micrograms of oxytetracycline per mil- (ii) Chemical assay. Proceed as di- ligram on an anhydrous basis. rected in § 436.320 of this chapter. (ii) It is sterile. (2) Sterility. Proceed as directed in (iii) It is nonpyrogenic. § 436.20 of this chapter, using the meth- (iv) [Reserved] od described in paragraph (e)(1) of that (v) It contains no depressor sub- section, except use diluting fluid D in stances. lieu of diluting fluid A. (vi) Its loss on drying is not more (3) Pyrogens. Proceed as directed in than 2.0 percent. § 436.32(b) of this chapter, using a solu- (vii) Its pH in an aqueous solution tion containing 5 milligrams of oxytet- containing 10 milligrams per milliliter racycline per milliliter. is not less than 2.0 and not more than 3.0. (4) [Reserved] (viii) When calculated on an anhy- (5) Depressor substances. Proceed as drous basis, its absorptivity at 353 directed in § 436.35 of this chapter. nanometers relative to that of the oxy- (6) Loss on drying. Proceed as di- tetracycline working standard simi- rected in § 436.200(b) of this chapter. larly treated is 92.5±4.3 percent. (7) pH. Proceed as directed in § 436.202 (ix) It gives a positive result to an of this chapter, using an aqueous solu- identity test for oxytetracycline. tion containing 10 milligrams per mil- (x) It is crystalline. liliter. (2) Labeling. It shall be labeled in ac- (8) Absorptivity. Determine the ab- cordance with the requirements of sorbance of the sample and standard § 432.5 of this chapter. solutions in the following manner: Dis- (3) Requests for certification; samples. solve approximately 50 milligrams each In addition to complying with the re- of the sample and standard in 250 milli- quirements of § 431.1 of this chapter, liters of 0.1N hydrochloric acid. Trans- each such request shall contain: fer a 10-milliliter aliquot to a 100-milli- (i) Results of tests and assays on the liter volumetric flask and dilute to vol- batch for potency, sterility, pyrogens, ume with 0.1N hydrochloric acid. Using depressor substances, loss on drying, a suitable spectrophotometer and 0.1N pH, absorptivity, identity, and crys- hydrochloric acid as the blank, deter- tallinity. mine the absorbance of each solution
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at 353 nanometers. Determine the per- ative to the absorptivity of the stand- cent absorptivity of the sample rel- ard using the following calculations:
Absorbance of sample × Percent relative = Milligrams of standard ×Potency of standard in × 10 absorptivity Absorbance of standard micrograms per milligram − ×Milligrams of sample 100 m
where: m = Percent moisture in the sample. (3) Requests for certification; samples. (9) Identity. To about 1 milligram of In addition to complying with the re- sample, add 2 milliliters of sulfuric quirements of § 431.1 of this subchapter, acid; a light-red color is produced when each such request shall contain: oxytetracycline is present. (i) Results of tests and assays on the (10) Crystallinity. Proceed as directed batch for potency, sterility, pyrogens, in § 436.203(a) of this chapter. depressor substances, moisture, pH, crystallinity, absorptivity, and iden- [43 FR 11158, Mar. 17, 1978; 43 FR 34456, Aug. tity. 4, 1978, as amended at 46 FR 60568, Dec. 11, (ii) Samples required: 1981; 50 FR 19920, May 13, 1985] (a) For all tests except sterility: 10 § 446.75a Sterile rolitetracycline. packages, each containing approxi- mately 500 milligrams. (a) Requirements for certification—(1) Standards of identity, strength, quality, (b) For sterility testing: 20 packages, and purity. Sterile rolitetracycline is each containing approximately 300 mil- [4S-(4α,4aα,5aα,6β,12aα)] - 4 - ligrams. (dimethylamino) - 1,4,4a,5,5a,6,11,12a - (b) Tests and methods of assay—(1) Po- octahydro - 3,6,10,12,12a - pentahydroxy tency. Proceed as directed in § 436.106 of - 6 - methyl - 1,11 - dioxo - N - (1 - this chapter, preparing the sample for pyrrolidinylmethyl) - 2 - assay as follows: Dissolve an accu- naphthacenecarboxamide. It is so puri- rately weighed portion of the sample in fied and dried that: sufficient methyl alcohol to give a so- (i) Its potency is not less than 900 lution containing 1 milligram of micrograms per milligram on the an- rolitetracycline per milliliter (esti- hydrous basis. mated). Further dilute an aliquot of (ii) It is sterile. the stock solution with sterile distilled (iii) It is nonpyrogenic. water to the reference concentration of (iv) [Reserved] 0.24 microgram of rolitetracycline per (v) It contains no depressor sub- milliliter (estimated). stances. (2) Sterility. Proceed as directed in (vi) Its moisture content is not more § 436.20 of this subchapter, using the than 3.0 percent. method described in paragraph (e)(1) of (vii) Its pH in an aqueous solution that section, except use diluting fluid containing 10 milligrams per milliliter D in lieu of diluting fluid A. is not less than 7 and not more than 9, (3) Pyrogens. Proceed as directed in and such solution is substantially § 436.32(b) of this subchapter, using a clear. solution containing 5.0 milligrams of (viii) It is crystalline. rolitetracycline per milliliter. (ix) When calculated on an anhydrous (4) [Reserved] basis, its absorptivity at 380 (5) Depressor substances. Proceed as nanometers relative to that of the directed in § 436.35 of this subchapter. rolitetracycline standard similarly (6) Moisture. Proceed as directed in treated is 100±4.4 percent. § 436.201 of this subchapter. (x) It passes the identity test. (7) pH. Proceed as directed in § 436.202 (2) Labeling. It shall be labeled in ac- of this subchapter, using an aqueous cordance with the requirements of solution containing 10 milligrams per § 432.5 of this subchapter. milliliter.
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(8) Crystallinity. Proceed as directed umetric flasks. Add approximately 75 in § 436.203(a) of this subchapter. milliliters of distilled water and 5.0 (9) Absorptivity. Determine the ab- milliliters of 5N NaOH to each flask, sorbance of the sample and standard and then dilute to volume with water solutions in the following manner: Dis- and mix thoroughly. Exactly 6 minutes solve an accurately weighed portion of after the addition of the NaOH, deter- approximately 40 milligrams each of mine the absorbance of each solution the sample and standard in approxi- at 380 nanometers, using a suitable mately 150 milliliters of distilled water spectrophotometer and distilled water and mix thoroughly. Dilute each to ex- as the blank. Determine the percent actly 250 milliliters with distilled absorptivity of the sample relative to water and mix thoroughly. Transfer a 10.0-milliliter aliquot of each of these the absorptivity of the standard using solutions to separate 100-milliliter vol- the following calculations:
Absorbance of sample× weight of standard in milligrams× potency of standard in micrograms per milligram ×10 Percent relative absorptivity = Absorbance of standard× weight of sample in milligrams× (100 − m )
where m=percent moisture in the sample. (iv) [Reserved] (10) Identity. Place approximately 100 (v) It contains no depressor sub- milligrams of the sample to be tested stances. in a test tube, and 5 milliliters of 1N (vi) Its moisture content is not more NaOH, and heat gently to boiling for than 5.0 percent. about 15 seconds. (The musty, (vii) Its pH in an aqueous solution aminelike odor of pyrrolidine is detect- containing 10 milligrams per milliliter able.) Allow to cool to room tempera- is not less than 3.5 and not more than ture. A deep burgundy-red color of the 5.5. clear solution indicates the presence of (viii) It is crystalline. rolitetracycline. (ix) When calculated on an anhydrous basis, its absorptivity at 380 [39 FR 19076, May 30, 1974, as amended at 43 nanometers relative to that of the FR 11158, Mar. 17, 1978; 43 FR 34456, Aug. 4, 1978; 46 FR 60568, Dec. 11, 1981; 50 FR 19920, rolitetracycline standard treated is May 13, 1985] 89.2±4.0 percent. (x) It gives a positive result to the § 446.76a Sterile rolitetracycline ni- identity tests for rolitetracycline ni- trate. trate. (a) Requirements for certification—(1) (2) Labeling. It shall be labeled in ac- Standards of identity, strength, quality, cordance with the requirements of and purity. Sterile rolitetracycline ni- § 432.5 of this subchapter. trate is [4S-(4α,4aα,5aα,6β, 12aα)] - 4 - (3) Requests for certification; samples. (dimethylamino) - 1,4,4a,5,5a,6,11,12a - In addition to complying with the re- octahydro - 3,6,10,12,12a - pentahydroxy quirements of § 431.1 of this chapter, - 6 - methyl - 1,11 - dioxo - N - (1 - each such request shall contain: pyrrolidinylmethyl) - 2 - (i) Results of tests and assays on the naphthacenecarboxamide mononitrate batch for potency, sterility, pyrogens, sesquihydrate. It is so purified and depressor substances, moisture, pH, dried that: crystallinity, absorptivity, and iden- (i) It contains not less than 765 tity. micrograms of rolitetracycline per mil- (ii) Samples required: ligram on an ‘‘as is’’ basis. (a) For all tests except sterility: 10 (ii) It is sterile. packages, each containing approxi- (iii) It is nonpyrogenic. mately 500 milligrams.
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(b) For sterility testing: 20 packages, solution containing 10 milligrams per each containing approximately 300 mil- milliliter. ligrams. (8) Crystallinity. Proceed as directed (b) Tests and methods of assay—(1) Po- in § 436.203(a) of this subchapter. tency. Proceed as directed in § 436.106 of (9) Absorptivity. Determine the ab- this chapter, preparing the sample for sorbance of the sample and standard assay as follows: Dissolve an accu- solutions in the following manner: Dis- rately weighed sample in sufficient solve an accurately weighed portion of sterile distilled water to obtain a stock solution of convenient concentration. approximately 40 milligrams each of Further dilute an aliquot of the stock the sample and standard in approxi- solution with sterile distilled water to mately 150 milliliters of distilled water the reference concentration of 0.24 and mix thoroughly. Dilute each to ex- microgram of rolitetracycline per mil- actly 250 milliliters with distilled liliter (estimated). water and mix thoroughly. Transfer a (2) Sterility. Proceed as directed in 10.0-milliliter aliquot of each of these § 436.20 of this subchapter, using the solutions to representative 100-milli- method described in paragraph (e)(1) of liter volumetric flasks. Add about 75 that section, except use diluting fluid milliliters of distilled water and 5.0 D in lieu of diluting fluid A. milliliters of 5N NaOH to each and then (3) Pyrogens. Proceed as directed in dilute to volume with water and mix § 436.32(b) of this subchapter, using a thoroughly. Exactly 6 minutes after solution containing 5.0 milligrams of the addition of the NaOH, determine rolitetracycline per milliliter. the absorbance of each solution at 380 (4) [Reserved] nanometers, using a suitable spectro- (5) Depressor substances. Proceed as photometer and distilled water as the directed in § 436.35 of this subchapter. (6) Moisture. Proceed as directed in blank. Determine the percent absorp- § 436.201 of this subchapter. tivity of the sample relative to the ab- (7) pH. Proceed as directed in § 436.202 sorptivity of the standard using the of this subchapter, using an aqueous following calculations:
Absorbance of sample× weight of standard in milligrams× potency of standard in micrograms per milligram× 10 Percent relative absorptivity = Absorbance of standard× weight of sample in milligrams×() 100 − m
where: m=percent moisture in the sample. 10-percent solution of nitron (1,4-di- (10) Identity—(i) Rolitetracycline. Place phenyl-3,5-endo-anilino-4,5-dihydro- 7 approximately 100 milligrams of the 1,2,4-triazole) C20H16N4 in 1N acetic sample to be used in a test tube, add 5 acid. Allow to cool. A heavy precipitate milliliters of 1N NaOH, and heat gently indicates the presence of nitrate. to boiling for about 15 seconds. (The [39 FR 19076, May 30, 1974, as amended at 43 musty, amine-like odor of pyrrolidine FR 11159, Mar. 17, 1978; 46 FR 60568, Dec. 11, is detectable.) Allow to cool to room 1981; 50 FR 19920, May 13, 1985] temperature. A deep burgundy-red color of the clear solution indicates the § 446.80 Tetracycline. presence of rolitetracycline. (a) Requirements for certification—(1) (ii) Nitrate identity. Transfer approxi- Standards of identity, strength, quality, mately 1 gram of sample to a 250-milli- and purity. Tetracycline is [4S - liter beaker, add 100 milliliters of water, and acidify with 1 milliliter of 7 Nitron is available from J. T. Baker Lab- acetic acid. Heat to boiling and, with oratory Chemicals, North Phillipsburg, N.J. constant stirring, add 10 milliliters of a 08865.
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(4α,4aα,5aα,6β,12aα)] - 4 - (b) Tests and methods of assay—(1) Po- (dimethylamino) - 1,4,4a,5,5a,6,11,12a - tency. Proceed as directed in § 436.106 of octahydro - 3,6,10,12,12a - pentahydroxy this chapter, preparing the sample for - 6 - methyl - 1,11 - dioxo - 2 - assay as follows: Dissolve an accu- naphthacenecarboxamide. It is so puri- rately weighed sample in sufficient fied and dried that: 0.1N hydrochloric acid to obtain a con- (i) Its potency is not less than 975 centration of 1,000 micrograms of tetra- micrograms per milligram on the an- cycline hydrochloride per milliliter (es- hydrous basis. timated). Further dilute an aliquot of (ii) [Reserved] the stock solution with sterile distilled (iii) Its moisture content is not more water to the reference concentration of than 13 percent. 0.24 microgram of tetracycline hydro- (iv) Its pH in an aqueous suspension containing 10 milligrams per milliliter chloride per milliliter (estimated). is not less than 3.0 and not more than (2) [Reserved] 7.0. (3) Moisture. Proceed as directed in (v) When calculated on the anhydrous § 436.201 of this chapter. basis, its absorptivity at 380 (4) pH. Proceed as directed in § 436.202 nanometers relative to that of the tet- of this chapter, using an aqueous sus- racycline hydrochloride working stand- pension containing 10 milligrams per ard similarly treated is 108.2±3.75 per- milliliter. cent. (5) Absorptivity. Dissolve approxi- (vi) Its 4-epianhydrotetracycline con- mately 40 milligrams of the sample (as tent is not more than 2.0 percent. the anhydrous compound), accurately (vii) It is crystalline. weighed, in 2.0 milliliters of 0.1N hydro- (viii) It passes the identity test for chloric acid and dilute with distilled tetracycline. water to 250 milliliters. Transfer a 10.0- (2) Labeling. In addition to the re- milliliter aliquot of this solution to a quirements of § 432.5 of this chapter, 100-milliliter volumetric flask, add ap- each package shall bear on its label or labeling the statement ‘‘For use only proximately 75 milliliters of distilled in the manufacture of nonparenteral water and 5.0 milliliters of 5N NaOH, drugs.’’ dilute to volume with water and mix (3) Requests for certification; samples. thoroughly. Treat a sample of the tet- In addition to complying with the re- racycline hydrochloride working stand- quirements of § 431.1 of this chapter, ard in the same manner. Exactly 6 min- each such request shall contain: utes after the addition of the NaOH, de- (i) Results of tests and assays on the termine the absorbance of each solu- batch for potency, moisture, pH, ab- tion at 380 nanometers, using a suit- sorptivity, 4-epianhydrotetra- cycline able spectrophotometer and distilled content, crystallinity, and identity. water as the blank. Determine the per- (ii) Samples required: 10 packages, cent absorptivity of the sample rel- each containing approximately 60 mil- ative to the absorptivity of the stand- ligrams. ard using the following calculations:
Absorbance of sample Milligrams of standard Potency of standard 10 Percent relative × × × absorptivity = in micrograms Absorbance of standard Milligrams of sample per milligram 100 − m
where: m = Percent moisture in the sample. (8) Identity. Proceed as directed in (6) 4-Epianhydrotetracycline. Proceed § 436.308 of this chapter. as directed in § 436.309 of this chapter. [43 FR 11159, Mar. 17, 1978; 43 FR 34456, Aug. (7) Crystallinity. Proceed as directed 4, 1978, as amended at 50 FR 19920, May 13, in § 436.203(a) of this chapter. 1985]
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§ 446.81 Tetracycline hydrochloride. (b) Tests and methods of assay—(1) Po- (a) Requirements for certification—(1) tency. Proceed as directed in § 436.106 of Standards of identity, strength, quality, this chapter, preparing the sample for and purity. Tetracycline hydrochloride assay as follows: Dissolve an accu- is [4S-(4α,4aα,5aα,6β, 12aα)] - 4 - rately weighed sample in sufficient (dimethylamino) - 1,4,4a,5,5a,6,11,12a - 0.1N hydrochloric acid to obtain a con- octahydro - 3,6,10,12,12a - pentahydroxy centration of 1,000 micrograms of tetra- - 6 - methyl - 1,11 - dioxo - 2 - cycline hydrochloride per milliliter (es- naphthacenecarboxamide timated). Further dilute an aliquot of monohydrochloride. It is so purified the stock solution with sterile distilled and dried that: water to the reference concentration of (i) Its potency is not less than 900 0.24 microgram of tetracycline hydro- micrograms per milligram. chloride per milliliter (estimated). (ii) [Reserved] (2) [Reserved] (iii) Its loss on drying is not more (3) Loss on drying. Proceed as directed than 2 percent. in § 436.200(b) of this chapter. (iv) Its pH in an aqueous solution (4) pH. Proceed as directed in § 436.202 containing 10 milligrams per milliliter of this chapter, using an aqueous solu- is not less than 1.8 and not more than tion containing 10 milligrams per mil- 2.8. liliter. (v) When calculated on the anhydrous (5) Absorptivity. Dissolve approxi- basis, its absorptivity at 380 mately 40 milligrams of the sample, ac- nanometers relative to that of the tet- curately weighed, in approximately 150 racycline hydrochloride working stand- milliliters of distilled water by mixing ard similarly treated is 100±4 percent. thoroughly. Dilute to 250 milliliters (vi) Its 4-epianhydrotetracycline con- tent is not more than 2.0 percent. with distilled water and mix thor- (vii) It is crystalline. oughly. Transfer a 10.0 milliliter ali- (viii) It passes the identity test for quot of this solution to a 100-milliliter tetracycline. volumetric flask, add about 75 milli- (2) Labeling. It shall be labeled in ac- liters of distilled water and 5.0 milli- cordance with the requirements of liters of 5N NaOH, dilute to volume § 432.5 of this chapter. with water, and mix thoroughly. Treat (3) Requests for certification; samples. a sample of the tetracycline hydro- In addition to complying with the re- chloride working standard in the same quirements of § 431.1 of this chapter, manner. Exactly 6 minutes after the each such request shall contain: addition of the NaOH, determine the (i) Results of tests and assays on the absorbance of each solution at 380 batch for potency, loss on drying, pH, nanometers, using a suitable spectro- absorptivity, 4-epianhydrotetracycline photometer and distilled water as the content, crystallinity, and identity. blank. Determine the percent absorp- (ii) Samples required: 10 packages, tivity of the sample relative to the ab- each containing approximately 300 mil- sorptivity of the standard using the ligrams. following calculations:
Absorbance of sample Milligrams of standard Potency of standard 10 Percent relative × × × absorptivity = in micrograms Absorbance of standard Milligrams of sample per milligram 100 − m
where: m = Percent moisture in the sample. (8) Identity. Proceed as directed in (6) 4-Epianhydrotetracycline. Proceed § 436.308 of this chapter. as directed in § 436.309 of this chapter. [43 FR 11159, Mar. 17, 1978, as amended at 50 (7) Crystallinity. Proceed as directed FR 19920, May 13, 1985] in § 436.203(a) of this chapter.
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§ 446.81a Sterile tetracycline hydro- (1) For all tests except sterility: 10 chloride. packages, each containing approxi- (a) Requirements for certification—(1) mately 300 milligrams. Standards of identity, strength, quality, (2) For sterility testing: 20 packages, and purity. Tetracycline hydrochloride each containing approximately 300 mil- is [4S - (4α,4aα,5aα,6β, 12aα)] - 4 - ligrams. dimethylamino) - 1,4,4a,5,5a,6,11,12a - (b) If the batch is packaged for dis- octahydro - 3,6,10,12,12a - pentahydroxy pensing. - 6 - methyl - 1,11 - dioxo - 2 - (1) For all tests except sterility: A naphthacene - carboxamide minimum of 10 immediate containers. monohydrochloride. It is so purified (2) For sterility testing: 20 immediate and dried that: containers, collected at regular inter- (i) Its potency is not less than 900 vals throughout each filling operation. micrograms of tetracycline hydro- (b) Tests and methods of assay—(1) Po- chloride per milligram. If it is pack- tency. Proceed as directed in § 436.106 of aged for dispensing, its content is sat- this chapter, preparing the sample for isfactory if it is not less than 90 per- assay as follows: Dissolve an accu- cent and not more than 115 percent of rately weighed sample in sufficient the number of milligrams of tetra- 0.1N hydrochloric acid to obtain a cycline hydrochloride that it is rep- stock solution containing 1,000 resented to contain. micrograms of tetracycline hydro- (ii) It is sterile. chloride per milliliter (estimated); (iii) It is nonpyrogenic. also, if it is packaged for dispensing, (iv) [Reserved] reconstitute as directed in the labeling. (v) It contains no depressor sub- Then using a suitable hypodermic nee- stances. dle and syringe, remove all of the (vi) Its loss on drying is not more withdrawable contents if it is rep- than 2 percent. resented as a single dose container; or, (vii) Its pH in an aqueous solution if the labeling specifies the amount of containing 10 milligrams per milliliter potency in a given volume of the re- is not less than 1.8 and not more than sultant preparation, remove an accu- 2.8. rately measured representative portion (viii) When calculated on the anhy- from each container. Dilute the sample drous basis, its absorptivity at 380 thus obtained with sufficient 0.1N hy- nanometers relative to that of the tet- drochloric acid to obtain a stock solu- racycline hydrochloride working stand- tion of convenient concentration con- ard similarly treated is 100±4 percent. taining not less than 150 micrograms of (ix) Its 4-epianhydrotetracycline con- tetracycline hydrochloride per milli- tent is not more than 2.0 percent. liter (estimated). Further dilute an ali- (x) It is crystalline. quot of the stock solution with sterile (xi) It passes the identity test for tet- distilled water to the reference con- racycline. centration of 0.24 microgram of tetra- (2) Labeling. It shall be labeled in ac- cycline hydrochloride per milliliter (es- cordance with the requirements of timated). § 432.5 of this chapter. (2) Sterility. Proceed as directed in (3) Requests for certification; samples. § 436.20 of this chapter, using the meth- In addition to complying with the re- od described in paragraph (e)(1) of that quirements of § 431.1 of this chapter, section, except use diluting fluid D in each such request shall contain: lieu of diluting fluid A. (i) Results of tests and assays on the (3) Pyrogens. Proceed as directed in batch for potency, sterility, pyrogens, § 436.32(b) of this chapter, using a [so– depressor substances, loss on drying, ]lution containing 5.0 milligrams of te– pH, absorptivity, 4- [tracycline] hydrochloride per milli- epianhydrotetracycline content, crys- liter. tallinity, and identity. (4) [Reserved] (ii) Samples required: (5) Depressor substances. Proceed as (a) If the batch is packaged for re- directed in § 436.35 of this chapter. packing or for use in the manufacture (6) Loss on drying. Proceed as di- of another drug: rected in § 436.200(b) of this chapter.
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(7) pH. Proceed as directed in § 436.202 milliliters of 5N NaOH, dilute to vol- of this chapter, using an aqueous solu- ume with water, and mix thoroughly. tion containing 10 milligrams per mil- Treat a sample of the tetracycline hy- liliter. drochloride working standard in the (8) Absorptivity. Dissolve approxi- same manner. Exactly 6 minutes after mately 40 milligrams of the sample, ac- the addition of the NaOH, determine curately weighed, in approximately 150 the absorbance of each solution at 380 milliliters of distilled water by mixing nanometers, using a suitable spectro- thoroughly. Dilute to 250 milliliters photometer and distilled water as the with distilled water and mix thor- blank. Determine the percent absorp- oughly. Transfer a 10.0-milliliter ali- tivity of the sample relative to the ab- quot of this solution to a 100-milliliter volumetric flask, add approximately 75 sorptivity of the standard using the milliliters of distilled water and 5.0 following calculation:
Absorbance of sample Milligrams of standard Potency of standard 10 Percent relative × × × absorptivity = in micrograms Absorbance of standard Milligrams of sample per milligram 100 − m
where: m = Percent moisture in the sample. racycline hydrochloride working stand- ± (9) 4-Epianhydrotetracycline. Proceed ard similarly treated is 82.0 4.9 per- as directed in § 436.309 of this chapter. cent. (10) Crystallinity. Proceed as directed (vi) Its 4-epianhydrotetracycline con- in § 436.203(a) of this chapter. tent is not more than 2.0 percent. (11) Identity. Proceed as directed in (vii) It passes the identity test, show- § 436.308 of this chapter. ing a presence of phosphate, a content of not more than 0.2 percent chloride, [43 FR 11160, Mar. 17, 1978; 43 FR 34456, Aug. and a content of not more than 1 per- 4, 1978, as amended at 44 FR 31636, June 1, 1979; 46 FR 60568, Dec. 11, 1981; 50 FR 19920, cent tetracycline base. May 13, 1985] (viii) It is crystalline. (2) Labeling. In addition to the re- § 446.82 Tetracycline phosphate com- quirements of § 432.5 of this chapter, plex. each such package shall bear on its (a) Requirements for certification—(1) label or labeling the statement ‘‘For Standards of identity, strength, quality, use only in the manufacture of non- and purity. Tetracycline phosphate parenteral drugs’’. complex is [4S-(4α,4aα,5aα,6β, 12aα)] - 4 (3) Requests for certification; samples. - (dimethylamino) - 1,4,4a,5,5a,6,11,12a - In addition to complying with the re- octahydro - 3,6,10,12,12a - pentahydroxy quirements of § 431.1 of this chapter, - 6 - methyl - 1,11 - dioxo - 2 - each such request shall contain: naphthacenecarboxamide phosphate (i) Results of tests and assays on the complex. It is so purified and dried batch for potency, moisture, pH, ab- that: sorptivity, 4-epianhydro tetracycline (i) Its potency is not less than 750 content, identity, and crystallinity. micrograms per milligram on the an- (ii) Samples required: 10 packages, hydrous basis. each containing approximately 60 mil- (ii) [Reserved] ligrams. (iii) Its moisture content is not more (b) Tests and methods of assay—(1) Po- than 9 percent. tency. Proceed as directed in § 436.106 of (iv) Its pH in an aqueous suspension this chapter, preparing the sample for containing 10 milligrams per milliliter assay as follows: Dissolve an accu- is not less than 2.0 and not more than rately weighed sample in sufficient 4.0. 0.1N hydrochloric acid to obtain a con- (v) When calculated on the anhydrous centration of 1,000 micrograms of tetra- basis, its absorptivity at 380 cycline hydrochloride per milliliter (es- nanometers relative to that of the tet- timated). Further dilute an aliquot of
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the stock solution with sterile distilled milliliter aliquot of this solution to a water to the reference concentration of 100-milliliter volumetric flask, add 0.24 microgram of tetracycline hydro- about 75 milliliters of distilled water chloride per milliliter (estimated). and 5.0 milliliters of 5N NaOH, dilute to (2) [Reserved] volume with water, and mix thor- (3) Moisture. Proceed as directed in oughly. Treat a sample of the tetra- § 436.201 of this chapter. cycline hydrochloride working stand- (4) pH. Proceed as directed in § 436.202 ard in the same manner. Exactly 6 min- of this chapter, using a suspension con- utes after the addition of NaOH, deter- taining 10 milligrams of the sample per mine the absorbance of each solution milliliter. at 380 nanometers, using a suitable (5) Absorptivity. Dissolve approxi- spectrophotometer and distilled water mately 40 milligrams of the sample, ac- as the blank. Determine the percent curately weighed, in 2.0 milliliters of absorptivity of the sample relative to 0.1N HCl and dilute to 250 milliliters the absorptivity of the standard using with distilled water. Transfer a 10.0 the following calculations:
Absorbance of sample Milligrams of standard Potency of standard 10 Percent relative × × × absorptivity = in micrograms Absorbance of standard Milligrams of sample per milligram 100 − m
where: m = Percent moisture in the sample. (2) Purified dioxane: Pass the dioxane (6) 4-Epianhydrotetracycline. Proceed through a column of Amberlite IRA 400 as directed in § 436.309 of this chapter. (OH–) resin or equivalent. (7) Identity—(i) Presence of phosphate. (3) Perchloric acid, 0.01N: Dilute 0.84 Prepare a filtrate as follows: Suspend milliliter of 70 percent perchloric acid 100 milligrams of the sample in 10 mil- to 1,000 milliliters with purified liliters of distilled water and filter a dioxane; standardize at least once small portion by gravity. Transfer 1.0 every 2 days, as follows: Weigh accu- milliliter of the filtrate to a 100-milli- rately about 70 milligrams of liter glass-stoppered cylinder, add 10.0 diphenylguanidine, and dissolve in 50 milliliters of distilled water, 2.0 milli- milliliters of ethyl alcohol in a 250-mil- liters of ammonium molybdate test so- liliter flask. Add two drops of methyl lution, 1.0 milliliter of stannous chlo- red, and titrate with the perchloric ride test solution, and 10.0 milliliters of acid solution until the yellow color isobutyl alcohol-benzene mixture (1:1 changes to orange. Deduct the volume ratio), all in the order named. Shake of the perchloric acid consumed by 50 vigorously for 1 minute, allow the lay- milliliters of the ethyl alcohol, and ers to separate, and examine the top calculate the normality. Each 2.113 organic layer. In the presence of phos- milligrams of diphenylguanidine is phate, the top layer turns blue. equivalent to 1 milliliter of 0.01N per- (ii) Chloride content. To 1.0 milliliter chloric acid. of the filtrate prepared as directed in the first sentence of paragraph (b)(7)(i) (4) Methyl red indicator: Dissolve 100 of this section, add 1 drop of silver ni- milligrams of methyl red in 100 milli- trate test solution and 1 drop of nitric liters of methyl alcohol. acid. Any turbidity produced is not (b) Procedure. Place an accurately greater than that obtained by similarly weighed 1-gram sample into a 50-milli- treating 1.0 milliliter of 0.057N hydro- liter Erlenmeyer flask, add 10.0 milli- chloric acid. liters of purified dioxane and shake the (iii) Determination of percent tetra- mixture manually for about 2 minutes. cycline base. This test is used to deter- Allow to settle, decant all the super- mine the quantity of tetracycline natant liquid into a 50-milliliter poly- present as base in mixtures with phos- ethylene centrifuge tube, cover with phate salts. Parafilm (or equivalent), and cen- (a) Reagents—(1) 1,4-Dioxane. trifuge until clear (about 3 minutes).
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Pipette 5.0 milliliters of the clear, su- yl red as the indicator. The endpoint is pernatant solution into a 50-milliliter the last color change to orange when a beaker, stir magnetically, and titrate drop of titrant is added. Calculate the with 0.01N perchloric acid, using meth- percent tetracycline base as follows:
Milliliters of acid used× Normality × 0.4445 × 200 Percent tetracycline base = Weight of sample
(8) Crystallinity. Proceed as directed (b) The batch: A minimum of 36 cap- in § 436.203(a) of this chapter. sules. [43 FR 11161, Mar. 17, 1978; 43 FR 34456, Aug. (b) Test and methods of assay—(1) Po- 4, 1978, as amended at 50 FR 19920, May 13, tency. Proceed as directed in § 436.106 of 1985] this chapter, preparing the sample for assay as follows: Place a representative Subpart B—Oral Dosage Forms number of capsules into a high-speed glass blender jar containing sufficient § 446.110 Chlortetracycline hydro- 0.01N hydrochloric acid to give a stock chloride capsules. solution of convenient concentration. (a) Requirements for certification—(1) Blend for 3 to 5 minutes. Remove an al- Standards of identity, strength, quality, iquot of the stock solution and further and purity. Chlortetracycline hydro- dilute with sterile distilled water to chloride capsules are composed of the reference concentration of 0.06 chlortetracycline hydrochloride and microgram of chlortetracycline hydro- one or more suitable and harmless chloride per milliliter (estimated). diluents, lubricants, and fillers. Each (2) Loss on drying. Proceed as directed capsule contains 50, 100, or 250 milli- in § 436.200(b) of this chapter. grams of chlortetracycline hydro- [43 FR 11162, Mar. 17, 1978; 43 FR 34456, Aug. chloride. The potency is satisfactory if 4, 1978, as amended at 50 FR 19920, May 13, it is not less than 90 percent and not 1985] more than 120 percent of the number of milligrams of chlortetracycline hydro- § 446.115 Demeclocycline oral dosage chloride that it is represented to con- forms. tain. The loss on drying is not more than 1 percent. The chlortetracycline § 446.115a Demeclocycline oral suspen- hydrochloride used conforms to the sion. standards prescribed by § 446.10(a)(1). (a) Requirements for certification—(1) (2) Labeling. It shall be labeled in ac- Standards of identity, strength, quality, cordance with the requirements of and purity. Demeclocycline oral sus- § 432.5 of this chapter. pension is composed of demeclocycline (3) Requests for certification; samples. with or without one or more suitable In addition to complying with the re- and harmless buffer substances, sus- quirements of § 431.1 of this chapter, pending and stabilizing agents, and each such request shall contain: preservatives suspended in a suitable (i) Results of tests and assays on: and harmless vehicle. Each milliliter (a) The chlortetracycline hydro- contains demeclocycline equivalent to chloride used in making the batch for 15 milligrams of demeclocycline hydro- potency, loss on drying, pH, crystallin- chloride. Its potency is satisfactory if ity, and identity. it is not less than 90 percent and not (b) The batch for potency and loss on more than 125 percent of the number of drying. milligrams of demeclocycline hydro- (ii) Samples required: chloride equivalent that it is rep- (a) The chlortetracycline hydro- resented to contain. The pH is not less chloride used in making the batch: 10 than 4 and not more than 5.8. The packages, each containing approxi- demeclocycline used conforms to the mately 300 milligrams. standards prescribed by § 446.15(a)(1).
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(2) Labeling. It shall be labeled in ac- than 90 percent and not more than 120 cordance with the requirements of percent of the number of milligrams of § 432.5 of this chapter. demeclocycline hydrochloride equiva- (3) Requests for certification; samples. lent that it is represented to contain. In addition to complying with the re- Its moisture content is not more than quirements of § 431.1 of this chapter, 5 percent. The demeclocycline used each such request shall contain: conforms to the standards prescribed (i) Results of tests and assays on: by § 446.15(a)(1). (a) The demeclocycline used in mak- (2) Labeling. It shall be labeled in ac- ing the batch for potency, moisture, cordance with the requirements of pH, absorptivity, crystallinity, and § 432.5 of this chapter. identity. (3) Requests for certification; samples. (b) The batch for potency and pH. In addition to complying with the re- (ii) Samples required: quirements of § 431.1 of this chapter, (a) The demeclocycline used in mak- each such request shall contain: ing the batch: 10 packages, each con- (i) Results of tests and assays on: taining approximately 250 milligrams. (a) The demeclocycline used in mak- (b) The batch: A minimum of five im- ing the batch for potency, moisture, mediate containers. pH, absorptivity, crystallinity, and (b) Tests and methods of assay—(1) Po- identity. tency. Proceed as directed in § 436.106 of (b) The batch for potency and mois- this chapter, preparing the sample for ture. assay as follows: Transfer an accu- (ii) Samples required: rately measured representative portion (a) The demeclocycline used in mak- of the well-shaken suspension to an ap- ing the batch: 10 packages, each con- propriate-sized volumetric flask and di- taining approximately 250 milligrams. lute to volume with 0.1N hydrochloric (b) The batch: A minimum of five im- acid to obtain a stock solution of con- mediate containers. venient concentration containing not (b) Tests and methods of assay—(1) Po- less than 150 micrograms of tency. Proceed as directed in § 436.106 of demeclocycline hydrochloride per mil- this chapter, preparing the sample for liliter (estimated). Mix well. Further assay as follows: Reconstitute as di- dilute an aliquot of the stock solution rected in the labeling. Transfer an ac- with sterile distilled water to the ref- curately measured representative por- erence concentration of 0.100 tion of the well-shaken suspension to microgram of demeclocycline hydro- an appropriate-sized volumetric flask chloride per milliliter (estimated). and dilute to volume with 0.1N hydro- (2) pH. Proceed as directed in § 436.202 chloric acid to obtain a stock solution of this chapter, using the undiluted of convenient concentration containing sample. not less than 150 micrograms of [39 FR 19076, May 30, 1974, as amended at 43 demeclocycline per milliliter (esti- FR 11162, Mar. 17, 1978; 43 FR 50677, Oct. 31, mated). Further dilute an aliquot of 1978; 50 FR 19920, May 13, 1985] the stock solution with sterile distilled water to the reference concentration of § 446.115b Demeclocycline for oral sus- 0.100 microgram of demeclocycline hy- pension. drochloride per milliliter (estimated). (a) Requirements for certification—(1) (2) Moisture. Proceed as directed in Standards of identity, strength, quality, § 436.201 of this chapter. and purity. Demeclocycline for oral suspension is composed of [39 FR 19076, May 30, 1974, as amended at 43 FR 11162, Mar. 17, 1978; 50 FR 19920, May 13, demeclocycline with or without one or 1985] more suitable and harmless buffer sub- stances, preservatives, diluents, color- § 446.116 Demeclocycline hydro- ings, and flavorings. When reconsti- chloride oral dosage forms. tuted as directed in the labeling, each milliliter contains demeclocycline § 446.116a Demeclocycline hydro- equivalent to 15 milligrams of chloride tablets. demeclocycline hydrochloride. Its po- (a) Requirements for certification—(1) tency is satisfactory if it is not less Standards of identity, strength, quality,
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and purity. Demeclocycline hydro- (3) Disintegration time. Proceed as di- chloride tablets are composed of rected in § 436.212 of this chapter. demeclocycline hydrochloride with one [39 FR 19076 , May 30, 1974, as amended at 43 or more suitable and harmless diluents, FR 11162, Mar. 17, 1978; 50 FR 19920, May 13, lubricants, binders, and flavorings. 1985] Each tablet contains 75 milligrams, 150 milligrams, or 300 milligrams of § 446.116b [Reserved] demeclocycline hydrochloride. Its po- tency is satisfactory if it is not less § 446.116c Demeclocycline hydro- than 90 percent and not more than 125 chloride capsules. percent of the number of milligrams of (a) Requirements for certification—(1) demeclocycline hydrochloride that it is Standards of identity, strength, quality, represented to contain. Its loss on dry- and purity. Demeclocycline hydro- ing is not more than 2 percent. It shall chloride capsules are composed of disintegrate within 30 minutes. The demeclocycline hydrochloride, with demeclocycline hydrochloride used one or more suitable and harmless conforms to the standards prescribed diluents and lubricants, enclosed in a by § 446.16(a)(1). gelatin capsule. Each capsule contains (2) Labeling. It shall be labeled in ac- 75 milligrams, 150 milligrams, or 300 cordance with the requirements of milligrams of demeclocycline hydro- § 432.5 of this chapter. chloride. Its potency is satisfactory if (3) Requests for certification; samples. it is not less than 90 percent and not In addition to complying with the re- more than 125 percent of the number of quirements of § 431.1 of this chapter, milligrams of demeclocycline hydro- each such request shall contain: chloride that it is represented to con- (i) Results of tests and assays on: tain. Its loss on drying is not more than 2 percent, except that if starch is (a) The demeclocycline hydrochloride used as a diluent the loss on drying is used in making the batch for potency, not more than 8 percent. The loss on drying, pH, absorptivity, crys- demeclocycline hydrochloride used tallinity, and identity. conforms to the standards prescribed (b) The batch for potency, loss on by § 446.16(a)(1). drying, and disintegration time. (2) Labeling. It shall be labeled in ac- (ii) Samples required: cordance with the requirements of (a) The demeclocycline hydrochloride § 432.5 of this chapter. used in making the batch: 10 packages, (3) Requests for certification; samples. each containing approximately 250 mil- In addition to complying with the re- ligrams. quirements of § 431.1 of this chapter, (b) The batch: A minimum of 36 tab- each such request shall contain: lets. (i) Results of tests and assays on: (b) Tests and methods of assay—(1) Po- (a) The demeclocycline hydrochloride tency. Proceed as directed in § 436.106 of used in making the batch for potency, this chapter, preparing the sample for loss on drying, pH, absorptivity, crys- assay as follows: Place a representative tallinity, and identity. number of tablets into a high-speed (b) The batch for potency and loss on glass blender jar containing sufficient drying. 0.1N hydrochloric acid to give a stock (ii) Samples required: solution of convenient concentration (a) The demeclocycline hydrochloride containing not less than 150 used in making the batch: 10 packages, micrograms of demeclocycline hydro- each containing approximately 250 mil- chloride per milliliter (estimated). ligrams. Blend for 3 to 5 minutes. Remove an al- (b) The batch: A minimum of 30 cap- iquot of the stock solution and further sules. dilute with sterile distilled water to (b) Tests and methods of assay—(1) Po- the reference concentration of 0.100 tency. Proceed as directed in § 436.106 of microgram of demeclocycline hydro- this chapter, preparing the sample for chloride per milliliter (estimated). assay as follows: Place a representative (2) Loss on drying. Proceed as directed number of capsules into a high-speed in § 436.200(b) of this chapter. glass blender jar containing sufficient
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0.1N hydrochloric acid to give a stock containing approximately 300 milli- solution of convenient concentration grams. containing not less than 150 (b) The batch: A minimum of 36 cap- micrograms of demeclocycline hydro- sules. chloride per milliliter (estimated). (b) Tests and methods of assay—(1) Po- Blend for 3 to 5 minutes. Remove an al- tency. Proceed as directed in § 436.106 of iquot of the stock solution and further this chapter, preparing the sample for dilute with sterile distilled water to assay as follows: Blend a representa- the reference concentration of 0.100 tive number of capsules in a high-speed microgram of demeclocycline hydro- glass blender jar containing 0.1N hydro- chloride per milliliter (estimated). chloric acid to obtain a stock solution (2) Loss on drying. Proceed as directed of convenient concentration containing in § 436.200(b) of this chapter. not less than 150 micrograms of doxycycline per milliliter (estimated). [39 FR 19076, May 30, 1974, as amended at 43 FR 11162, Mar. 17, 1978; 50 FR 19920, May 13, Blend for 3 to 5 minutes. Remove an al- 1985] iquot of the stock solution and further dilute with sterile distilled water to § 446.120 Doxycycline hyclate oral dos- the reference concentration of 0.100 age forms. microgram of doxycycline per milli- liter (estimated). § 446.120a Doxycycline hyclate cap- (2) Moisture. Proceed as directed in sules. § 436.201 of this chapter. (a) Requirements for certification—(1) (3) Identity. Proceed as directed in Standards of identity, strength, quality, § 436.308 of this chapter, except prepare and purity. Doxycycline hyclate cap- the standard and sample solutions as sules are composed of doxycycline follows: Dissolve precise amounts of hyclate and one or more suitable and the doxycycline capsule contents and harmless lubricants and diluents en- of the doxycycline working standard in closed in a gelatin capsule. Each cap- methanol and further dilute each solu- sule contains doxycycline hyclate tion to a concentration of 1 milligram equivalent to either 50, 100, or 300 milli- of doxycycline per milliliter. Prepare grams of doxycycline. Its potency is the sample-standard mixed solution by satisfactory if it is not less than 90 per- mixing equal volumes of the final cent and not more than 120 percent of standard and sample solutions. The the number of milligrams of standard and sample must each doxycycline that it is represented to produce a major, yellow fluorescent contain. The moisture content is not spot with the same Rf value, and the more than 5.0 percent. It passes the standard-sample mixed solution must identity test for the presence of the show no separation of major spots. doxycycline moiety. The doxycycline [39 FR 19076, May 30, 1974. Redesignated at 39 hyclate used conforms to the standards FR 41250, Nov. 26, 1974, and amended at 43 FR prescribed by § 446.20. 11162, Mar. 17, 1978; 44 FR 20667, Apr. 6, 1979; (2) Labeling. It shall be labeled in ac- 50 FR 19920, May 13, 1985] cordance with the requirements of § 432.5 of this chapter. § 446.120b Doxycycline calcium oral (3) Requests for certification; samples. suspension. In addition to the requirements of (a) Requirements for certification—(1) § 431.1 of this chapter, each such re- Standards of identity, strength, quality, quest shall contain: and purity. Doxycycline calcium oral (i) Results of tests and assays on: suspension is prepared from (a) The doxycycline hyclate used in doxycycline hyclate and contains one making the batch for potency, mois- or more suitable and harmless buffer ture, pH, doxycycline content, iden- substances, preservatives, diluents, sol- tity, and crystallinity. vents, colorings, and flavorings. Its po- (b) The batch for potency, moisture, tency is satisfactory if it is not less and identity. than 90 percent and not more than 125 (ii) Samples required: percent of the number of milligrams of (a) The doxycycline hyclate used in doxycycline that it is represented to making the batch: 10 packages, each contain. Its pH is not less than 6.5 and
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not more than 8.0. It passes the iden- orescent spot with the same Rf value, tity test for the presence of the and the sample-standard mixed solu- doxycycline moiety. The doxycycline tion must show no separation of major hyclate used conforms to the standards spots. prescribed by § 446.20(a)(1). [39 FR 41250, Nov. 11, 1974, as amended at 45 (2) Labeling. It shall be labeled in ac- FR 16476, Mar. 14, 1980; 50 FR 19920, May 13, cordance with the requirements of 1985] § 432.5 of this chapter. (3) Requests for certification; samples. § 446.120c Doxycycline hyclate tablets. In addition to complying with the re- (a) Requirements for certification—(1) quirements of § 431.1 of this chapter, Standards of identity, strength, quality, each such request shall contain: and purity. Doxycycline hyclate tablets (i) Results of tests and assays on: contain doxycycline hyclate with or (a) The doxycycline hyclate used in without one or more disintegrants, lu- making the batch for potency, mois- bricants, colorings, and coating sub- ture, pH, doxycycline content, iden- stances. Each tablet contains tity, and crystallinity. doxycycline hyclate equivalent to 50 or (b) The batch for potency, pH, and 100 milligrams of doxycycline. Its po- identity. tency is satisfactory if it is not less (ii) Samples required: than 90 percent and not more than 120 (a) The doxycycline hyclate used in percent of the number of milligrams of making the batch: 10 packages, each doxycycline that it is represented to containing approximately 300 milli- contain. Its moisture content is not grams. more than 5.0 percent. It passes the dis- (b) The batch: A minimum of 6 imme- solution test. It passes the identity diate containers. test. The doxycycline hyclate conforms (b) Tests and methods of assay—(1) Po- to the standards prescribed by tency. Proceed as directed in § 436.106 of § 446.20(a)(1). this chapter, preparing the sample for (2) Labeling. It shall be labeled in ac- assay as follows: Transfer an appro- cordance with the requirements of priate aliquot of the suspension to a § 432.5 of this chapter. volumetric flask and dissolve with suf- (3) Requests for certification; samples. ficient 0.1N hydrochloric acid to give a In addition to complying with the re- stock solution of convenient con- quirements of § 431.1 of this chapter, centration (containing not less than each such request shall contain: 150 micrograms of doxycycline per mil- (i) Results of tests and assays on: liliter in acid). Further dilute an ali- (a) The doxycycline hyclate used in quot of the stock solution with sterile making the batch for potency, mois- distilled water to the reference con- ture, pH, doxycycline content, iden- centration of 0.100 microgram of tity, and crystallinity. doxycycline per milliliter (estimated). (b) The batch for potency, moisture, (2) pH. Proceed as directed in § 436.202 dissolution, and identity. of this chapter, using the undiluted (ii) Samples required: sample. (a) The doxycycline hyclate used in (3) Identity. Proceed as directed in making the batch: 10 packages, each § 436.308 of this chapter, except prepare containing approximately 300 milli- the standard and sample solutions as grams. follows: Dissolve precise amounts of (b) The batch: A minimum of 100 tab- the doxycycline calcium oral suspen- lets. sion and of the doxycycline working (b) Tests and methods of assay—(1) Po- standard in methanol and further di- tency. Proceed as directed in § 436.106 of lute each solution with methanol to a this chapter, preparing the sample for concentration of 1 milligram of assay as follows: Place a representative doxycycline per milliliter. Prepare the number of tablets into a high-speed sample-standard mixed solution by glass blender jar containing 0.1N hydro- mixing equal volumes of the final con- chloric acid to obtain a stock solution centration of the sample and standard of convenient concentration containing solutions. The sample and standard not less than 150 micrograms of must each produce a major, yellow flu- doxycycline per milliliter (estimated).
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Blend for 3 to 5 minutes. Remove an al- grams of doxycycline that it is rep- iquot of the stock solution and further resented to contain. The moisture con- dilute with sterile distilled water to tent is not more than 5.0 percent. It the reference concentration of 0.100 passes the acid resistance test. It microgram of doxycycline per milli- passes the dissolution test. The liter (estimated). doxycycline hyclate conforms to the (2) Moisture. Proceed as directed in standards prescribed by § 446.20(a)(1). § 436.201 of this chapter. (2) Labeling. It shall be labeled in ac- (3) Dissolution. Proceed as directed in cordance with the requirements of § 436.215 of this chapter, except: § 432.5 of this chapter. (i) In lieu of paragraph (a) of that (3) Requests for certification; samples. section, a distance of 4.5±0.5 centi- In addition to complying with the re- meters should be maintained between quirements of § 431.1 of this chapter, the lower edge of the stirring blade and each such request shall contain: the lowest inner surface of the vessel (i) Results of tests and assays on: during the test; and (a) The doxycycline hyclate used in (ii) In lieu of paragraph (d) of that making the batch for potency, safety, section, use the interpretation de- moisture, pH, doxycycline content, scribed in the United States Pharma- identity, and crystallinity. copeia XX dissolution test. The quan- (b) The batch for potency, moisture, tity, Q (the amount of doxycycline dis- acid resistance, and dissolution. solved) is 55 percent at 60 minutes and (ii) Samples, if required by the Direc- 85 percent at 90 minutes. tor, Center for Drug Evaluation and (4) Identity. Proceed as directed in Research: § 436.308 of this chapter, except prepare (a) The doxycycline hyclate used in the sample and standard solutions as making the batch: 10 packages, each follows: Grind tablet to a powder. Dis- containing approximately 300 milli- solve precise amount of the grams. doxycycline tablet and of the doxycycline working standard in meth- (b) The batch: A minimum of 100 cap- anol and further dilute each solution to sules. a concentration of 1 milligram of (b) Tests and methods of assay—(1) Po- doxycycline per milliliter. Prepare the tency. Proceed as directed in § 436.106 of sample-standard mixed solution by this chapter, preparing the sample for mixing equal volumes of the final assay as follows: Place a representative standard and sample solutions. The number of capsules into a high-speed standard and sample must each glass blender jar containing 0.1N hydro- produce a major, yellow fluorescent chloric acid to obtain a stock solution of convenient concentration containing spot with the same Rf value and the standard-sample mixed solution must not less than 150 micrograms of show no separation of major spots. doxycycline per milliliter (estimated). Blend for 3 to 5 minutes. Remove an al- [46 FR 7273, Jan. 23, 1981, as amended at 48 iquot of the stock solution and further FR 23813, May 27, 1983; 48 FR 51293, Nov. 8, dilute with sterile distilled water to 1983; 50 FR 19920, May 13, 1985] the reference concentration of 0.100 § 446.120d Doxycycline hyclate pellet- microgram of doxycycline per milli- filled capsules. liter (estimated). (2) Moisture. Proceed as directed in (a) Requirements for certification—(1) § 436.201 of this chapter. Standards of identity, strength, quality, and purity. Doxycycline hyclate pellet- (3) Acid resistance. Proceed as directed filled capsules contain pellets which in § 436.543 of this chapter. are composed of doxycycline hyclate (4) Dissolution. Empty the contents of and suitable and harmless diluents, one pellet-filled capsule into the bas- binders, and lubricants. Each capsule ket and proceed as directed in § 436.544 contains doxycycline hyclate equiva- of this chapter. The quantity Q (the lent to 100 milligrams of doxycycline. amount of doxycycline dissolved) is 85 Its potency is satisfactory if it is not percent at 30 minutes. less than 90 percent and not more than [50 FR 41679, Oct. 15, 1985, as amended at 55 120 percent of the number of milli- FR 11584, Mar. 29, 1990]
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§ 446.121 Doxycycline monohydrate lution of convenient concentration oral dosage forms. containing not less than 150 micrograms of doxycycline per milli- § 446.121a Doxycycline monohydrate liter (estimated). Further dilute an ali- for oral suspension. quot of the stock solution with sterile (a) Requirements for certification—(1) distilled water to the reference con- Standards of identity, strength, quality, centration of 0.100 microgram of and purity. Doxycycline monohydrate doxycycline per milliliter (estimated). for oral suspension is doxycycline (2) Moisture. Proceed as directed in monohydrate with one or more suitable § 436.201 of this chapter. and harmless buffer substances, pre- (3) pH. Reconstitute as directed in servatives, diluents, colorings, and the labeling and proceed as directed in flavorings. Its moisture content is not § 436.202 of this chapter, using the undi- more than 3 percent. It passes the iden- luted sample. tity test for the presence of the (4) Identity. Proceed as directed in doxycycline moiety. When prepared as § 436.308 of this chapter, except prepare directed in the labeling, each milliliter the standard and sample solutions as contains the equivalent of 5 milligrams follows: Dissolve precise amounts of of doxycycline and its pH is not less the doxycycline monohydrate for oral than 5.0 and not more than 6.5. Its po- suspension and of the doxycycline tency is satisfactory if it is not less working standard in methanol and fur- than 90 percent and not more than 125 ther dilute each solution to a con- percent of the number of milligrams of centration of 1 milligram of doxycycline that it is represented to doxycycline per milliliter. Prepare the contain. The doxycycline monohydrate sample-standard mixed solution by used conforms to the standards pre- mixing equal volumes of the final con- scribed by § 446.21(a)(1). centration of the sample and standard (2) Labeling. In addition to the label- solutions. The sample and standard ing requirements of § 432.5 of this chap- must each produce a major, yellow flu- ter, this drug shall be labeled orescent spot with the same Rf value ‘‘doxycycline for oral suspension’’. and the sample-standard mixed solu- (3) Requests for certification; samples. tion must show no separation of major In addition to the requirements of spots. § 431.1 of this chapter, each such re- [39 FR 19076, May 30, 1974, as amended at 43 quest shall contain: FR 11163, Mar. 17, 1978; 50 FR 19920, May 13, (i) Results of tests and assays on: 1985. Redesignated at 55 FR 6637, Feb. 26, (a) The doxycycline monohydrate 1990] used in making the batch for potency, moisture, pH, doxycycline content, § 446.121b Doxycycline monohydrate identity, and crystallinity. capsules. (b) The batch for potency, moisture, (a) Requirements for certification—(1) pH, and identity. Standards of identity, strength, quality, (ii) Samples required: and purity. Doxycycline monohydrate (a) The doxycycline monohydrate capsules are composed of doxycycline used in making the batch: 10 packages, monohydrate and one or more suitable each containing approximately 300 mil- and harmless lubricants and diluents ligrams. enclosed in a gelatin capsule. Each cap- (b) The batch: A minimum of six im- sule contains doxycycline monohydrate mediate containers. equivalent to 100 milligrams of (b) Tests and methods of assay—(1) Po- doxycycline. Its potency is satisfactory tency. Proceed as directed in § 436.106 of if it is not less than 90 percent and not this chapter, preparing the sample for more than 120 percent of the number of assay as follows: Reconstitute the sam- milligrams of doxycycline that it is ple as directed in the labeling. Transfer represented to contain. The moisture an accurately measured representative content is not more than 5.5 percent. It portion of the well-shaken suspension passes the dissolution test. It passes to an appropriate-sized volumetric the identity test. The doxycycline flask and dilute to volume with 0.1N monohydrate used conforms to the hydrochloric acid to obtain a stock so- standards prescribed by § 446.21.
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(2) Labeling. It shall be labeled in ac- (ii) Preparation of working standard, cordance with the requirements of sample, and resolution test solutions—(A) § 432.5 of this chapter. Working standard solution. Dissolve an (3) Requests for certification; samples. accurately weighed portion of the In addition to complying with the re- doxycycline hyclate working standard quirements of § 431.1 of this chapter, in sufficient 0.1N hydrochloric acid to each such request shall contain: obtain a known concentration of about (i) Results of tests and assays on: 1,000 micrograms of doxycycline per (A) The doxycycline monohydrate milliliter. Further dilute with distilled used in making the batch for potency, water to a concentration of 40 moisture, pH, doxycycline content, micrograms of doxycycline activity per identity, and crystallinity. milliliter. Filter through a membrane (B) The batch for potency, moisture, filter of 0.5 micron or finer porosity. dissolution, and identity. (B) Sample solution. Remove, as com- pletely as possible, the contents of a (ii) Samples, if required by the Cen- representative number of capsules. Mix ter for Drug Evaluation and Research: the combined contents and transfer an (A) The doxycycline monohydrate accurately weighed portion of the pow- used in making the batch: 10 packages, der, equivalent to about 100 milligrams each containing approximately 300 mil- of doxycycline, to a 100-milliliter volu- ligrams. metric flask. Add 20 milliliters of 0.1N (B) The batch: A minimum of 100 cap- hydrochloric acid and sonicate for 5 sules. minutes. Dilute to mark with 0.1N hy- (b) Tests and methods of assay—(1) drochloric acid. Further quantitatively Doxycycline potency. Proceed as di- dilute an aliquot of this solution with rected in § 436.216 of this chapter, using distilled water to a concentration of 40 ambient temperature, an ultraviolet micrograms of doxycycline activity per detection system operating at a wave- milliliter (estimated). Filter through a length of 280 nanometers, a 4.6-milli- membrane filter of 0.5 micron or finer meter X 3-centimeter guard column porosity. Content uniformity analyses containing 5- to 10-micrometer diame- may be obtained from sample solutions ter octyl silane chemically bonded to prepared as above except that the con- totally porous microsilica particles, a tents of one capsule are quantitatively 3.9-millimeter X 30-centimeter analyt- transferred to the 100-milliliter volu- ical column packed with octadecyl sil- metric flask. ane chemically bonded to porous silica (C) Resolution test solution. Dissolve 50 or ceramic microparticles, 5 to 10 mi- milligrams of doxycycline in 25 milli- crometers in diameter, a flow rate of liters of distilled water. Pipet 5 milli- 1.5 milliliters per minute, and a 10- liters of this solution into a 25-milli- microliter loop injector. Reagents, liter volumetric flask and heat on a working standard and sample solu- steam bath for 60 minutes. Transfer the tions, system suitability requirements, contents of the flask to a small beaker and calculations are as follows: and evaporate to dryness. Dissolve the (i) Reagents—(A) 0.1M sodium phos- residue in distilled water, transfer to a phate buffer. Prepare a solution con- 25-milliliter volumetric flask, dilute to taining 13.8 grams of monobasic sodium mark with distilled water, mix, and fil- phosphate per liter of distilled water. ter through Whatman No. 1 filter (B) Mobile phase. Mix 450 milliliters paper. Use this solution to determine of 0.1M monobasic sodium phosphate the resolution factor. and 550 milliliters of methanol. Add 3 (iii) System suitability requirements— milliliters of N,N-dimethyl-n- (A) Asymmetry factor. Calculate the octylamine. Adjust the pH to 8.0 with asymmetry factor (As), measured at a 5N sodium hydroxide. Filter the mobile point 5 percent of the peak height from phase through a suitable glass filter or the baseline, as follows: equivalent that is capable of removing particulate contamination to 1 micron + = a b in diameter. Degas the mobile phase As just prior to its introduction into the 2a chromatograph pumping system. where:
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a=Horizontal distance from point of ascent met, then proceed as described in to a point of a maximum peak height; § 436.216(b) of this chapter. Alternate and chromatographic conditions are ac- b=Horizontal distance from the point of max- ceptable provided reproducibility and imum peak height to point of descent. resolution are comparable to the sys-
The asymmetry factor (As) is satisfac- tem described. However, the sample tory if it is not less than 1.4 and not preparation described in paragraph more than 2.0 (b)(1)(ii)(B) of this section should not (B) Efficiency of the column. From the be changed. number of theoretical plates (n) cal- (iv) Calculations. Calculate the culated as described in § 436.216(c)(2) of doxycycline content as follows: this chapter calculate the reduced A× P × d plate height (hr) as follows: Milligramsof doxycycline= u s ( )( ) per capsule A×1, 000 × n = L 10, 000 s hr where: (n )( dp ) Au=Area of the doxycycline peak in the chro- matogram of the sample (at a retention where: time equal to that observed for the L=Length of the column in centimeters; standard); n=number of theoretical plates; and As=Area of the doxycycline peak in the chro- dp=Average diameter of the particles in ana- matogram of the working standard; lytical column packing in micrometers. Ps=Doxycycline activity in the doxycycline working standard solution in The absolute efficiency (hr) is satisfac- micrograms per milliliter; tory if it is not more than 37.5 for the d=Dilution factor of the sample; and doxycycline peak. n=Number of capsules in the sample assayed. (C) The resolution (R) between peaks (2) Moisture. Proceed as directed in for doxycycline and epi-doxycycline is § 436.201 of this chapter. satisfactory if it is not less than 1.5. (3) Dissolution. Proceed as directed in (D) Coefficient of variation (relative § 436.215 of this chapter. The quantity Q standard deviation). The coefficient of (the amount of doxycycline dissolved) variation (SR in percent) of 5 replicate is 85 percent at 60 minutes. injections is satisfactory if it is not (4) Identity. The high-pressure liquid more than 2.0 percent. chromatogram of the sample deter- ′ (E) Capacity factor (k ). Calculate the mined in paragraph (b)(1) of this sec- ′ capacity factor (k ) for doxycycline as tion compares qualitatively to that of follows: the doxycycline working standard. t− t [55 FR 6637, Feb. 26, 1990] k′ = r o t § 446.150 Methacycline hydrochloride o oral dosage forms. where:
tr=Retention time of doxycycline in minutes; § 446.150a Methacycline hydrochloride and capsules. to=Column dead time in minutes, which is es- (a) Requirements for certification—(1) timated from the following equation: Standards of identity, strength, quality, 2 and purity. Methacycline hydrochloride = (3.1416)(DL )( )(0.75) capsules are composed of methacycline to hydrochloride and one or more suitable 4F and harmless lubricants and diluents where: enclosed in a gelatin capsule. Each cap- D=Column diameter in centimeters; sule contains methacycline hydro- L=Column length in centimeters; chloride equivalent to either 70 milli- 0.75=Average total column porosity; and F=Flow rate in milliliters per minute. grams of methacycline, 140 milligrams of methacycline, or 280 milligrams of The capacity factor (k′) for doxycycline methacycline. Its potency is satisfac- is satisfactory if it is not less than 1.5 tory if it is not less than 90 percent and and not more than 2.5. If the system not more than 120 percent of the num- suitability requirements have been ber of milligrams of methacycline that
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it is represented to contain. The mois- 125 percent of the number of milli- ture content is not more than 7.5 per- grams of methacycline that it is rep- cent. The methacycline hydrochloride resented to contain. Its pH is not less used conforms to the standards pre- than 6.5 nor more than 8.0. The scribed by § 446.50(a)(1). methacycline hydrochloride used con- (2) Labeling. It shall be labeled in ac- forms to the standards prescribed by cordance with the requirements of § 446.50(a)(1). § 432.5 of this chapter. (2) Labeling. It shall be labeled in ac- (3) Requests for certification; samples. cordance with the requirements of In addition to the requirements of § 432.5 of this chapter. § 431.1 of this chapter, each such re- (3) Requests for certification; samples. quest shall contain: In addition to the requirements of (i) Results of tests and assays on: § 431.1 of this chapter, each such re- (a) The methacycline hydrochloride quest shall contain: used in making the batch for potency, (i) Results of tests and assays on: moisture, pH, absorptivity, identity, (a) The methacycline hydrochloride and crystallinity. used in making the batch for potency, (b) The batch for potency and mois- moisture, pH, absorptivity, identity, ture. and crystallinity. (ii) Samples required: (a) The methacycline hydrochloride (b) The batch for potency and pH. used in making the batch: 10 packages, (ii) Samples required. each containing approximately 300 mil- (a) The methacycline hydrochloride ligrams. used in making the batch: 10 packages, (b) The batch: A minimum of 30 cap- each containing approximately 300 mil- sules. ligrams. (b) Tests and methods of assay—(1) Po- (b) The batch: A minimum of 5 imme- tency. Proceed as directed in § 436.106 of diate containers. this chapter, preparing the sample for (b) Tests and methods of assay—(1) Po- assay as follows: Blend a representa- tency. Proceed as directed in § 436.106 of tive number of capsules in a high-speed this chapter, preparing the sample for glass blender jar containing sufficient assay as follows: Transfer an accu- sterile distilled water to give a stock rately measured representative portion solution of convenient concentration. of the well-shaken suspension to an ap- Further dilute an aliquot of the stock propriate-sized volumetric flask, and solution with sterile distilled water to dilute to volume with sterile distilled the reference concentration of 0.06 water. Mix well. Remove an aliquot of microgram of methacycline per milli- the stock solution and further dilute liter (estimated). with sterile distilled water to the ref- (2) Moisture. Proceed as directed in erence concentration of 0.06 microgram § 436.201 of this chapter. of methacycline per milliliter (esti- mated). [39 FR 19076, May 30, 1974, as amended at 43 FR 11163, Mar. 17, 1978; 46 FR 46313, Sept. 18, (2) pH. Proceed as directed in § 436.202 1981; 50 FR 19920, May 13, 1985] of this chapter using the undiluted sample. § 446.150b Methacycline hydrochloride oral suspension. [39 FR 19076, May 30, 1974, as amended at 43 FR 11163, Mar. 17, 1978; 50 FR 19920, May 13, (a) Requirements for certification—(1) 1985] Standards of identity, strength, quality, and purity. Methacycline hydrochloride § 446.160 Minocycline hydrochloride oral suspension contains methacycline oral dosage forms. hydrochloride and one or more suitable and harmless buffers, dispersants, § 446.160a Minocycline hydrochloride diluents, colorings, flavorings, and pre- tablets. servatives. It contains methacycline (a) Requirements for certification—(1) hydrochloride equivalent to 14 milli- Standards of identity, strength, quality, grams of methacycline per milliliter. and purity. Minocycline hydrochloride Its potency is satisfactory if it is not tablets are composed of minocycline less than 90 percent and not more than hydrochloride and one or more suitable
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and harmless diluents, binders, lubri- cants, coloring, and coating sub- Milligrams of × × Au P s d stances. Each tablet contains minocycline = × × minocycline hydrochloride equivalent per milliliter As 1,000 5 to 100 milligrams of minocycline. Its where: potency is satisfactory if it contains Au=Area of the minocycline peak in the chro- not less than 90 percent and not more matogram of the sample (at a retention than 115 percent of the number of milli- time equal to that observed for the grams of minocycline that it is rep- standard); resented to contain. Its moisture con- As=Area of the minocycline peak in the chro- tent is not more than 12 percent. The matogram of the minocycline working tablets disintegrate within 30 minutes. standard; The minocycline hydrochloride used Ps=Minocycline activity in the minocycline working standard solution in conforms to the standards prescribed micrograms per milliliter; by § 446.60(a)(1). d = Dilution factor of the sample; and (2) Labeling. It shall be labeled in ac- n = Number of tablets in the sample assayed. cordance with the requirements of § 432.5 of this chapter. (2) Moisture. Proceed as directed in § 436.201 of this chapter. (3) Requests for certification; samples. (3) Disintegration time. Proceed as di- In addition to complying with the re- rected in § 436.212 of this chapter, using quirements of § 431.1 of this chapter, the procedure described in paragraph each such request shall contain: (e)(1) of that section. (i) Results of tests and assays on: (a) The minocycline hydrochloride [39 FR 19076, May 30, 1974, as amended at 43 used in making the batch for potency, FR 11163, Mar. 17, 1978; 44 FR 22058, Apr. 13, moisture, pH, epi-minocycline content, 1979; 50 FR 19920, May 13, 1985; 53 FR 32609, Aug. 26, 1988] identity, crystallinity, residue on igni- tion, and absorptivity. § 446.160b Minocycline hydrochloride (b) The batch for potency, moisture, capsules. and disintegration time. (a) Requirements for certification—(1) (ii) Samples required: Standards of identity, strength, quality, (a) The minocycline hydrochloride and purity. Minocycline hydrochloride used in making the batch: 10 packages, capsules are composed of minocycline each containing approximately 300 mil- hydrochloride and one or more suitable ligrams. and harmless lubricants and diluents (b) The batch: A minimum of 36 tab- enclosed in a gelatin capsule. Each cap- lets. sule contains minocycline hydro- (b) Tests and methods of assay—(1) Po- chloride equivalent to 50 or 100 milli- tency. Proceed as directed in grams of minocycline. Its potency is § 446.60(b)(1) of this part, except prepare satisfactory if it is not less than 90 per- the sample solution and calculate the cent and not more than 115 percent of minocycline potency as follows: the number of milligrams of (i) Sample solution. Grind a represent- minocycline that it is represented to ative number of tablets in a mortar contain. Its moisture content is not and pestle. Wash the ground tablets more than 12 percent. The minocycline into a volumetric flask containing mo- hydrochloride used conforms to the bile phase (described in standards prescribed by § 446.60(a)(1). § 446.60(b)(1)(i)(c) of this part) and shake (2) Labeling. It shall be labeled in ac- to dissolve. Dilute with mobile phase cordance with the requirements of to give a stock solution of convenient § 432.5 of this chapter. concentration. Filter the stock solu- (3) Requests for certification; samples. tion. Further dilute using mobile phase In addition to complying with the re- to obtain a solution containing 500 quirements of § 431.1 of this chapter, micrograms of minocycline activity each such request shall contain: per milliliter (estimated). Use this so- (i) Results of tests and assays on: lution within 3 hours of preparation. (a) The minocycline hydrochloride (ii) Calculations. Calculate the used in making the batch for potency, minocycline content as follows: moisture, pH, epi-minocycline content,
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identity, crystallinity, residue on igni- § 446.160c Minocycline hydrochloride tion, and absorptivity. oral suspension. (b) The batch for potency and mois- (a) Requirements for certification—(1) ture. Standards of identity, strength, quality, (ii) Samples required: and purity. Minocycline hydrochloride (a) The minocycline hydrochloride oral suspension is minocycline hydro- used in making the batch: 10 packages, chloride with one or more suitable each containing approximately 300 mil- flavorings, wetting agents, preserva- ligrams. tives, and diluents in an aqueous vehi- (b) The batch: A minimum of 30 cap- cle. Each milliliter contains sules. minocycline hydrochloride equivalent (b) Tests and methods of assay—(1) Po- to 10 milligrams of minocycline. Its po- tency. Proceed as directed in tency is satisfactory if it is not less § 446.60(b)(1) of this part, except prepare than 90 percent and not more than 130 the sample solution and calculate the percent of the number of milligrams of minocycline potency as follows: minocycline that it is represented to (i) Sample solution. Open a representa- contain. Its pH is not less than 7.0 and tive number of capsules and empty the not more than 9.0. The minocycline hy- drochloride used conforms to the contents into a volumetric flask con- standards prescribed by § 446.60(a)(1). taining mobile phase (described in (2) It shall be labeled in ac- § 446.60(b)(1)(i)(c) of this part) and shake Labeling. cordance with the requirements of to dissolve. Dilute with mobile phase § 432.5 of this subchapter. to give a stock solution of convenient (3) Requests for certification; samples. concentration. Filter the stock solu- In addition to complying with the re- tion. Remove an aliquot of the stock quirements of § 431.1 of this chapter, solution and further dilute with mobile each such request shall contain: phase to obtain a solution containing (i) Results of tests and assays on: 500 micrograms of minocycline activity (a) The minocycline hydrochloride per milliliter (estimated). Use this so- used in making the batch for potency, lution within 3 hours of preparation. moisture, pH, epi-minocycline content, (ii) Calculations. Calculate the identity, crystallinity, residue on igni- minocycline content as follows: tion, and absorptivity. (b) The batch for potency and pH. Milligrams of A× P × d minocycline = u s (ii) Samples required: × × (a) The minocycline hydrochloride per capsule As 1, 000 n used in making the batch: 10 packages, where: each containing approximately 300 mil- Au= Area of the minocycline peak in the ligrams. chromatogram of the sample (at a reten- (b) The batch: A minimum of five im- tion time equal to that observed for the mediate containers. standard); (b) Tests and methods of assay—(1) Po- A = Area of the minocycline peak in the s tency. Proceed as directed in chromatogram of the minocycline work- ing standard: § 446.60(b)(1) of this part, except prepare the sample solution and calculate the Ps= Minocycline activity in the minocycline working standard solution in minocycline potency as follows: micrograms per milliliter; (i) Sample solution. Transfer an accu- d = Dilution factor of the sample; and rately measured 5-milliliter portion of n = Number of capsules in the sample as- the well-shaken suspension to a 100- sayed. milliliter volumetric flask. Dilute to (2) Moisture. Proceed as directed in § 436.201 mark with mobile phase (described in of this chapter. § 446.60(b)(1)(i)(c) of this part) and mix [39 FR 19076, May 30, 1974, as amended at 43 well. Filter this solution and use with- FR 11163, Mar. 17, 1978; 44 FR 22058, Apr. 13, in 3 hours of its preparation. 1979; 50 FR 19920, May 13, 1985; 53 FR 32609, (ii) Calculations. Calculate the Aug. 26, 1988] minocycline content as follows:
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(a) The oxytetracycline used in mak- A× P × d Milligramsof minocycline = u s ing the batch: 10 packages, each con- per milliliter A ×1, 000 × 5 taining approximately 300 milligrams. s (b) The batch: A minimum of 36 tab- where: lets. Au= Area of the minocycline peak in the (b) Tests and methods of assay—(1) Po- chromatogram of the sample (at a reten- tency. Proceed as directed in § 436.106 of tion time equal to that observed for the standard); this chapter, preparing the sample for assay as follows: Place a representative As= Area of the minocycline peak in the chromatogram of the minocycline work- number of tablets into a high-speed ing standard: glass blender jar containing sufficient
Ps= Minocycline activity in the minocycline 0.1N hydrochloric acid to obtain a working standard solution in stock solution of convenient con- micrograms per milliliter; and centration containing not less than 150 d = Dilution factor of the sample. micrograms of oxytetracycline per mil- (2) pH. Proceed as directed in § 436.202 of liliter (estimated). Blend for 3 to 5 min- this subchapter, using the undiluted sample. utes. Remove an aliquot of the stock [39 FR 19076, May 30, 1974, as amended at 43 solution and further dilute with sterile FR 11163, Mar. 17, 1978; 44 FR 22058, Apr. 13, distilled water to the reference con- 1979; 50 FR 19920, May 13, 1985; 53 FR 32609, centration of 0.24 microgram of oxytet- Aug. 26, 1988] racycline per milliliter (estimated). § 446.165 Oxytetracycline oral dosage (2) Moisture. Proceed as directed in forms. § 436.201 of this chapter. (3) Disintegration time. Proceed as di- § 446.165a Oxytetracycline tablets. rected in § 436.212 of this chapter, using (a) Requirements for certification—(1) the method described in paragraph Standards of identity, strength, quality, (e)(1) of that section. and purity. Oxytetracycline tablets are [43 FR 11163, Mar. 17, 1978; 43 FR 34456, Aug. tablets composed of oxytetracycline 4, 1978, as amended at 50 FR 19920, May 13, and one or more suitable and harmless, 1985] diluents, binders, lubricants, colorings, and coating substances. The potency of §§ 446.165b—446.165c [Reserved] each tablet is 250 milligrams of oxytet- racycline. Its potency is satisfactory if § 446.165d Oxytetracycline for oral sus- it is not less than 90 percent and not pension. more than 120 percent of the number of (a) Requirements for certification—(1) milligrams of oxytetracycline that it is Standards of identity, strength, quality, represented to contain. The moisture and purity. Oxytetracycline for oral content is not more than 7.5 percent. suspension is oxytetracycline with one They shall disintegrate within 1 hour. or more suitable and harmless buffer The oxytetracycline used conforms to substances, preservatives, diluents, the standards prescribed by colorings, and flavorings. When pre- § 446.65(a)(1). pared as directed in the labeling, each (2) Labeling. It shall be labeled in ac- milliliter contains 50 milligrams of ox- cordance with the requirements of ytetracycline. Its potency is satisfac- § 432.5 of this chapter. tory if it is not less than 90 percent and (3) Requests for certification; samples. not more than 115 percent of the num- In addition to complying with the re- ber of milligrams of oxytetracycline quirements of § 431.1 of this chapter, that it is represented to contain. Its each such request shall contain: loss on drying is not more than 2 per- (i) Results of tests and assays on: cent. When reconstituted as directed in (a) The oxytetracycline used in mak- the labeling, its pH is not less than 5.5 ing the batch for potency, moisture, and not more than 7.5. The oxytetra- pH, absorptivity, identity, and crys- cycline used conforms to the standards tallinity. prescribed by § 446.65(a)(1). (b) The batch for potency, moisture, (2) Labeling. It shall be labeled in ac- and disintegration time. cordance with the requirements of (ii) Samples required: § 432.5 of this chapter.
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(3) Requests for certification; samples. oxytetracycline. Its potency is satis- In addition to complying with the re- factory if it is not less than 90 percent quirements of § 431.1 of this chapter, and not more than 120 percent of the each such request shall contain: number of milligrams of oxytetra- (i) Results of tests and assays on: cycline that it is represented to con- (a) The oxytetracycline used in mak- tain. Its pH is not less than 5.0 and not ing the batch for potency, moisture, more than 8.0. The oxytetracycline cal- pH, absorptivity, identity, and crys- cium used conforms to the standards tallinity. prescribed by § 446.66(a)(1). (b) The batch for potency, loss on (2) Labeling. It shall be labeled in ac- drying, and pH. cordance with the requirements of (ii) Samples required: § 432.5 of this chapter. (a) The oxytetracycline used in mak- (3) Requests for certification; samples. ing the batch: 10 packages, each con- In addition to complying with the re- taining approximately 300 milligrams. quirements of § 431.1 of this chapter, (b) The batch: A minimum of six im- each such request shall contain: mediate containers. (i) Results of tests and assays on: (b) Tests and methods of assay—(1) Po- (a) The oxytetracycline calcium used tency. Proceed as directed in § 436.106 of in making the batch for potency, mois- this chapter, preparing the sample for ture, pH, calcium content, identity, assay as follows: Reconstitute as di- and crystallinity. rected in the labeling. Transfer an ac- (b) The batch for potency and pH. curately measured representative por- (ii) Samples required: tion of the well-shaken suspension to (a) The oxytetracycline calcium used an appropriate-sized volumetric flask in making the batch: 10 packages, each and dilute to volume with 0.1N hydro- containing approximately 300 milli- chloric acid to obtain a stock solution grams. of convenient concentration containing (b) The batch: A minimum of five im- not less than 150 micrograms of oxytet- mediate containers. racycline per milliliter (estimated). (b) Tests and methods of assay—(1) Po- Mix well. Further dilute an aliquot of tency. Proceed as directed in § 436.106 of the stock solution with sterile distilled this chapter, preparing the sample for water to the reference concentration of assay as follows: Transfer an accu- 0.24 microgram of oxytetracycline per rately measured representative portion milliliter (estimated). of the sample to an appropriate-sized (2) Loss on drying. Proceed as directed volumetric flask and dilute to volume in § 436.200(b) of this chapter. with 0.1N hydrochloric acid to give a (3) pH. Reconstitute as directed in stock solution of convenient con- the labeling and proceed as directed in centration containing not less than 150 § 436.202 of this chapter. micrograms of oxytetracycline per mil- liliter (estimated). Mix well. Remove [43 FR 11164, Mar. 17, 1978, as amended at 48 FR 51293, Nov. 8, 1983; 50 FR 19920, May 13, an aliquot of the stock solution and 1985] further dilute with sterile distilled water to the reference concentration of § 446.166 Oxytetracycline calcium oral 0.24 microgram of oxytetracycline per suspension. milliliter (estimated). (a) Requirements for certification—(1) (2) pH. Proceed as directed in § 436.202 Standards of identity, strength, quality, of this chapter, using the undiluted and purity. Oxytetracycline calcium sample. oral suspension contains oxytetra- [43 FR 11164, Mar. 17, 1978 as amended at 43 cycline calcium with one or more suit- FR 50677, Oct. 31, 1978; 45 FR 16476, Mar. 14, able and harmless buffer substances, 1980; 50 FR 19920, May 13, 1985] suspending and stabilizing agents, flavorings, colorings, solvents, and pre- § 446.167 Oxytetracycline hydro- servatives suspended in a suitable and chloride capsules. harmless vehicle. It may contain N- (a) Requirements for certification—(1) acetyl glucosamine. Each milliliter Standards of identity, strength, quality, contains a quantity of oxytetracycline and purity. Oxytetracycline hydro- calcium equivalent to 25 milligrams of chloride capsules are gelatin capsules
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containing oxytetracycline hydro- of paragraph (a) of that section, a dis- chloride with or without one or more tance of 4.5±0.5 centimeters should be suitable and harmless buffers, preserv- maintained between the lower edge of atives, diluents, binders, and lubri- the stirring blade and the lowest inner cants. They may contain glucosamine surface of the vessel during the test. hydrochloride. Each capsule contains The quantity Q (the amount of oxytet- 50 milligrams, 100 milligrams, 125 milli- racycline dissolved) is 60 percent with- grams, or 250 milligrams of oxytetra- in 30 minutes and 85 percent within 60 cycline. Its potency is satisfactory if it minutes. is not less than 90 percent and not more than 120 percent of the number of [43 FR 11164, Mar. 17, 1978, as amended at 44 milligrams of oxytetracycline that it is FR 48189, Aug. 17, 1979; 47 FR 32938, July 30, 1982; 48 FR 51293, Nov. 3, 1983; 49 FR 37058, represented to contain. The loss on Sept. 21, 1984; 50 FR 19920, May 13, 1985] drying is not more than 5.0 percent. It passes the dissolution test. The oxytet- § 446.180 Tetracycline oral dosage racycline hydrochloride used conforms forms. to the standards prescribed by § 446.67(a)(1). §§ 446.180a—446.180b [Reserved] (2) Labeling. It shall be labeled in ac- cordance with the requirements of § 446.180c Tetracycline oral suspen- § 432.5 of this chapter. sion. (3) Requests for certification; samples. (a) Requirements for certification—(1) In addition to the requirements of Standards of identity, strength, quality, § 431.1 of this chapter, each such re- and purity. Tetracycline oral suspen- quest shall contain: sion is composed of tetracycline with (i) Results of tests and assays on: or without one or more suitable and (a) The oxytetracycline hydro- harmless buffer substances, suspending chloride used in making the batch for and stabilizing agents, and preserva- potency, loss on drying, pH, absorptiv- tives, suspended in a suitable and ity, identity, and crystallinity. harmless vehicle. Each milliliter con- (b) The batch for potency, loss on tains tetracycline equivalent to 25 mil- drying, and dissolution. ligrams of tetracycline hydrochloride. (ii) Samples required: Its potency is satisfactory if it con- (a) The oxytetracycline hydro- tains the equivalent of not less than 90 chloride used in making the batch: 10 percent and not more than 125 percent packages, each containing approxi- of the number of milligrams of tetra- mately 300 milligrams. cycline hydrochloride that it is rep- (b) The batch: A minimum of 30 cap- resented to contain. Its pH is not less sules. than 3.5 and not more than 6.0. Its 4- (b) Tests and methods of assay—(1) Po- epianhydrotetracycline content is not tency. Proceed as directed in § 436.106 of more than 5.0 percent. The tetracycline this chapter, preparing the sample for used conforms to the standards pre- assay as follows: Place a representative scribed by § 446.80(a)(1). number of capsules into a high-speed (2) Labeling. It shall be labeled in ac- glass blender jar containing sufficient cordance with the requirements of 0.1N hydrochloric acid to give a stock § 432.5 of this chapter. solution of convenient concentration containing not less than 150 (3) Requests for certification; samples. micrograms of oxytetracycline per mil- In addition to complying with the re- liliter (estimated). Blend for 3 to 5 min- quirements of § 431.1 of this chapter, utes. Remove an aliquot of the stock each such request shall contain: solution and further dilute with sterile (i) Results of tests and assays on: distilled water to the reference con- (a) The tetracycline used in making centration of 0.24 microgram of oxytet- the batch for potency, moisture, pH, racycline per milliliter (estimated). absorptivity, 4-epianhydrotetracycline (2) Loss on drying. Proceed as directed content, crystallinity, and identity. in § 436.200(b) of this chapter. (b) The batch for potency, pH, and 4- (3) Dissolution. Proceed as directed in epianhydrotetracycline content. § 436.215 of this chapter, except in lieu (ii) Samples required:
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(a) The tetracycline used in making hydrochloride used conforms to the the batch: 10 packages, each containing standards prescribed by § 446.81(a)(1). approximately 300 milligrams. (2) Labeling. It shall be labeled in ac- (b) The batch: A minimum of 5 imme- cordance with the requirements of diate containers. § 432.5 of this chapter. (b) Tests and methods of assay—(1) Po- (3) Requests for certification; samples. tency. Proceed as directed in § 436.106 of In addition to complying with the re- this chapter, preparing the sample for quirements of § 431.1 of this chapter, assay as follows: Transfer an accu- each such request shall contain: rately measured representative portion (i) Results of tests and assays on: of the well-shaken suspension to an ap- (a) The tetracycline hydrochloride propriate-sized volumetric flask and di- lute to volume with 0.1N hydrochloric used in making the batch for potency, acid to give a stock solution of conven- loss on drying, pH, absorptivity, 4- ient concentration containing not less epianhydrotetracycline content, crys- than 150 micrograms of tetracycline tallinity, and identity. hydrochloride per milliliter (esti- (b) The batch for potency, loss on mated). Mix well. Remove an aliquot of drying, dissolution, and 4- the stock solution and further dilute epianhydrotetracycline content. with sterile distilled water to the ref- (ii) Samples required: erence concentration of 0.24 microgram (a) The tetracycline hydrochloride of tetracycline hydrochloride per milli- used in making the batch: 10 packages, liter (estimated). each containing approximately 300 mil- (2) pH. Proceed as directed in § 436.202 ligrams. of this chapter, using the undiluted (b) The batch: A minimum of 36 tab- suspension. lets. (3) 4-Epianhydrotetracycline. Proceed (b) Tests and methods of assay—(1) Po- as directed in § 436.309(b) of this chap- tency. Proceed as directed in § 436.106 of ter. this chapter, preparing the sample for [43 FR 11164, Mar. 17, 1978; 43 FR 34456, Aug. assay as follows: Place a representative 4, 1978, as amended at 45 FR 16472, 16476, Mar. number of tablets into a high-speed 14, 1980; 50 FR 19920, May 13, 1985] glass blender jar containing sufficient 0.1N hydrochloric acid to obtain a § 446.181 Tetracycline hydrochloride oral dosage forms. stock solution of convenient con- centration containing not less than 150 §§ 446.181a—446.181c [Reserved] micrograms of tetracycline hydro- chloride per milliliter (estimated). § 446.181d Tetracycline hydrochloride Blend for 3 to 5 minutes. Remove an al- tablets. iquot of the stock solution and further (a) Requirements for certification—(1) dilute with sterile distilled water to Standards of identity, strength, quality, the reference concentration of 0.24 and purity. Tetracycline hydrochloride microgram of tetracycline hydro- tablets contain tetracycline hydro- chloride per milliliter (estimated). chloride with or without one or more (2) Loss on drying. Proceed as directed buffer substances, preservatives, in § 436.200(b) of this chapter. diluents, binders, lubricants, colorings, (3) Dissolution. Proceed as directed in and flavorings. Each tablet contains § 436.215 of this chapter, except in lieu 250 milligrams or 500 milligrams of tet- of paragraph (a) of that section, a dis- racycline hydrochloride. Its potency is ± satisfactory if it contains not less than tance of 4.5 0.5 centimeters should be 90 percent and not more than 125 per- maintained between the lower edge of cent of the number of milligrams of the stirring blade and the lowest inner tetracycline hydrochloride that it is surface of the vessel during the test. represented to contain. Its loss on dry- The quantity Q (the amount of tetra- ing is not more than 3.0 percent. It cycline hydrochloride dissolved) is 60 passes the dissolution test. Its 4- percent within 30 minutes and 85 per- epianhydrotetracycline content is not cent within 60 minutes. more than 3.0 percent. The tetracycline
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(4) 4-Epianhydrotetracycline. Proceed number of capsules into a high-speed as directed in § 436.309 of this chapter. glass blender jar containing sufficient 0.1N hydrochloric acid to obtain a [43 FR 11165, Mar. 17, 1978, as amended at 44 FR 48189, Aug. 17, 1979; 47 FR 32938, July 30, stock solution of convenient con- 1982; 48 FR 51293, Nov. 8, 1983; 49 FR 37058, centration containing not less than 150 Sept. 21, 1984; 50 FR 19920, May 13, 1985] micrograms of tetracycline hydro- chloride per milliliter (estimated). § 446.181e Tetracycline hydrochloride Blend for 3 to 5 minutes. Remove an al- capsules. iquot of the stock solution and further (a) Requirements for certification—(1) dilute with sterile distilled water to Standards of identity, strength, quality, the reference concentration of 0.24 and purity. Tetracycline hydrochloride microgram of tetracycline hydro- capsules are composed of tetracycline chloride per milliliter (estimated). hydrochloride with or without one or (2) Loss on drying. Proceed as directed more suitable and harmless buffer sub- in § 436.200(b) of this chapter. stances, preservatives, diluents, bind- (3) 4-Epianhydrotetracycline. Proceed ers, lubricants, colorings, and as directed in § 436.309 of this chapter. flavorings enclosed in a gelatin cap- (4) Dissolution. Proceed as directed in sule. Each capsule contains 50, 100, 125, § 436.215 of this chapter except in lieu of 250, or 500 milligrams of tetracycline paragraph (a) of that section, a dis- hydrochloride. Its potency is satisfac- tance of 4.5±0.5 centimeters should be tory if it is not less than 90 percent and maintained between the lower edge of not more than 125 percent of the num- the stirring blade and the lowest inner ber of milligrams of tetracycline hy- surface of the vessel during the test. drochloride that it is represented to The quantity Q (the amount of tetra- contain. Its loss on drying is not more cycline hydrochloride dissolved), ex- than 4 percent. Its 4- cept for the 500-milligram capsule, is 60 epianhydrotetracycline content is not percent within 30 minutes and 85 per- more than 3.0 percent. It passes the dis- cent within 60 minutes. For the 500- solution test. The tetracycline hydro- milligram capsule, the quantity Q is 50 chloride used conforms to the stand- percent within 30 minutes, 70 percent ards prescribed by § 446.81(a)(1). within 60 minutes, and 85 percent with- (2) Labeling. It shall be labeled in ac- in 90 minutes. cordance with the requirements of [43 FR 11166, Mar. 17, 1978, as amended at 44 § 432.5 of this chapter. FR 48189, Aug. 17, 1979; 47 FR 32938, July 30, (3) Requests for certification; samples. 1982; 48 FR 51293, Nov. 8, 1983; 49 FR 37058, In addition to complying with the re- Sept. 21, 1984; 50 FR 19920, May 13, 1985] quirements of § 431.1 of this chapter, each such request shall contain: § 446.182 Tetracycline phosphate com- (i) Results of tests and assays on: plex capsules. (a) The tetracycline hydrochloride (a) Requirements for certification—(1) used in making the batch for potency, Standards of identity, strength, quality, loss on drying, pH, absorptivity, 4- and purity. Tetracycline phosphate epianhydrotetracycline content, crys- complex capsules contain tetracycline tallinity, and identity. phosphate complex with or without one (b) The batch for potency, loss on or more buffer substances, preserva- drying, 4-epianhydrotetracycline con- tives, diluents, binders, lubricants, tent, and dissolution. colorings, and flavorings enclosed in a (ii) Samples required: gelatin capsule. Each capsule contains (a) The tetracycline hydrochloride tetracycline phosphate complex equiv- used in making the batch: 10 packages, alent to 50, 100, 125, 250, or 500 milli- each containing approximately 300 mil- grams of tetracycline hydrochloride. ligrams. Its potency is satisfactory if it con- (b) The batch: A minimum of 30 cap- tains the equivalent of not less than 90 sules. percent and not more than 125 percent (b) Tests and methods of assay—(1) Po- of the number of milligrams of tetra- tency. Proceed as directed in § 436.106 of cycline hydrochloride that it is rep- this chapter, preparing the sample for resented to contain. Its loss on drying assay as follows: Place a representative is not more than 9.0 percent. Its 4-
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epianhydrotetracycline content is not and purity. Doxycycline hyclate for in- more than 3.0 percent. The tetracycline jection is a dry mixture of doxycycline phosphate complex used conforms to hyclate and a buffer substance. Its po- the standards prescribed by § 446.82 tency is satisfactory if it is not less (a)(1). than 90 percent and not more than 120 (2) Labeling. It shall be labeled in ac- percent of the number of milligrams of cordance with the requirements of doxycycline that it is represented to § 432.5 of this chapter. contain. It is sterile. It is (3) Requests for certification, samples. nonpyrogenic. It contains no depressor In addition to complying with the re- substances. Its loss on drying is not quirements of § 431.1 of this chapter, more than 2.0 percent. Its pH when re- each such request shall contain: constituted as directed in the labeling (i) Results of tests and assays on: is not less than 1.8 and not more than (a) The tetracycline phosphate com- 3.3. It passes the identity test for the plex used in making the batch for po- presence of the doxycycline moiety. tency, moisture, pH, absorptivity, 4- The doxycycline hyclate used conforms epianhydrotetracycline content, iden- to the standards prescribed by tity, and crystallinity. § 446.20a(a)(1). (b) The batch for potency, loss on (2) Labeling. It shall be labeled in ac- drying, and 4-epianhydrotetracycline cordance with the requirements of content. § 432.5 of this subchapter. (ii) Samples required: (3) Requests for certification: samples. (a) The tetracycline phosphate com- In addition to complying with the re- plex used in making the batch: 10 pack- quirements of § 431.1 of this subchapter, ages, each containing approximately each such request shall contain: 300 milligrams. (i) Results of tests and assays on: (b) The batch: A minimum of 30 cap- (a) The doxycycline hyclate used in sules. making the batch for potency, mois- (b) Tests and methods of assay—(1) Po- ture, pH, doxycycline content, iden- tency. Proceed as directed in § 436.106 of tity, and crystallinity. this chapter, preparing the sample for (b) The batch for potency, sterility, assay as follows: Place a representative pyrogens, depressor substances, loss on number of capsules into a high-speed drying, pH, and identity. glass blender jar containing sufficient (ii) Samples required: 0.1N hydrochloric acid to obtain a (a) The doxycycline hyclate used in stock solution of convenient con- making the batch: 10 packages, each centration containing not less than 150 containing approximately 300 milli- micrograms of tetracycline hydro- grams. chloride per milliliter (estimated). (b) The batch: Blend for 3 to 5 minutes. Remove an al- (1) For all tests except sterility: A iquot of the stock solution and further minimum of 20 immediate containers. dilute with sterile distilled water to (2) For sterility testing: 20 immediate the reference concentration of 0.24 containers, collected at regular inter- microgram of tetracycline per milli- vals throughout each filling operation. liter (estimated). (b) Tests and methods of assay—(1) Po- (2) Loss on drying. Proceed as directed Proceed as directed in § 436.106 of in § 436.200(b) of this chapter. tency. (3) 4-Epianhydrotetracycline. Proceed this subchapter, preparing the sample as directed in § 436.309 of this chapter. for assay as follows: Reconstitute as di- rected in the labeling. Using a suitable [43 FR 11166, Mar. 17, 1978, as amended at 50 hypodermic needle and syringe, remove FR 19920, May 13, 1985] all of the withdrawable contents from each container if it is represented as a Subpart C—Injectable Dosage single-dose container; or if the labeling Forms specifies the amount of potency in a given volume of the resultant prepara- § 446.220 Doxycycline hyclate for injec- tion, remove an accurately measured tion. representative portion from each con- (a) Requirements for certification—(1) tainer. Dilute the solution thus ob- Standards of identity, strength, quality, tained with sufficient 0.1N hydrochloric
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acid to give a stock solution of conven- contain. It is sterile. It is ient concentration (containing not less nonpyrogenic. It contains no depressor than 150 micrograms of doxycycline in substance. Its moisture content is not acid). Further dilute an aliquot of the more than 3.0 percent. Its pH in an stock solution with sterile distilled aqueous solution containing 10 milli- water to the reference concentration of grams per milliliter is not less than 2.0 0.100 microgram of doxycycline per and not more than 3.5. The minocycline milliliter (estimated). hydrochloride used conforms to the (2) Sterility. Proceed as directed in standards prescribed by § 446.60(a)(1). § 436.20 of this subchapter, using the (2) Labeling. It shall be labeled in ac- method described in paragraph (e)(1) of cordance with the requirements of that section, except use diluting fluid § 432.5 of this chapter. D in lieu of diluting fluid A. (3) Requests for certification; samples. (3) Pyrogens. Proceed as directed in In addition to complying with the re- § 436.32(a) of this subchapter, using a quirements of § 431.1 of this chapter, solution containing 7.5 milligrams of each such request shall contain: doxycycline per milliliter. (i) Results of tests and assays on: (4) [Reserved] (a) The minocycline hydrochloride (5) Depressor substances. Proceed as used in making the batch for potency, directed in § 436.35 of this subchapter. moisture, pH, epi-minocycline content, (6) Loss on drying. Proceed as directed identity, crystallinity, residue on igni- in § 436.200(a) of this subchapter. tion, and absorptivity. (7) pH. Proceed as directed in § 436.202 (b) The batch for potency, sterility, of this subchapter, using the drug re- pyrogens, depressor substances, mois- constituted as directed in the labeling. ture, and pH. (8) Identity. Proceed as directed in (ii) Samples required: § 436.308 of this subchapter, except pre- (a) The minocycline hydrochloride pare the standard and sample solutions used in making the batch: 10 packages, as follows: Dissolve precise amounts of each containing approximately 300 mil- the doxycycline hyclate for injection ligrams. and of the doxycycline working stand- (b) The batch: ard in methanol and further dilute (1) For all tests except sterility: A each solution to a concentration of 1 minimum of 10 immediate containers. milligram of doxycycline per milliliter. (2) For sterility testing: 20 immediate Prepare the sample-standard mixed so- containers, collected at regular inter- lution by mixing equal volumes of the vals throughout each filling operation. final concentration of the sample and (b) Tests and methods of assay—(1) Po- standard solutions. The sample and tency. Proceed as directed in standard must each produce a major, § 446.60(b)(1) of this part, except prepare yellow fluorescent spot with the same the sample solution and calculate the Rf value and the sample-standard minocycline potency as follows: mixed solution must show no separa- (i) Sample solution. Reconstitute as tion of major spots. directed in the labeling. Using a suit- [39 FR 19076, May 30, 1974, as amended at 43 able hypodermic needle and syringe, FR 11166, Mar. 17, 1978; 43 FR 34457, Aug. 4, remove the withdrawable contents 1978; 46 FR 60568, Dec. 11, 1981; 50 FR 19920, from each container represented as a May 13, 1985] single-dose container; or if the labeling specifies the amount of potency in a § 446.260 Sterile minocycline hydro- given volume of the resultant prepara- chloride. tion, withdraw an accurately measured (a) Requirements for certification—(1) representation portion from each con- Standards of identity, strength, quality, tainer. Dilute the sample thus obtained and purity. Sterile minocycline hydro- with sufficient mobile phase (described chloride is a lyophilized powder of in § 446.60(b)(1)(i)(c) of this part) to give minocycline hydrochloride. Its potency a stock solution of convenient con- is satisfactory if it is not less than 90 centration. Filter the stock solution. percent and not more than 120 percent Further dilute an aliquot of this stock of the number of milligrams of solution with mobile phase to obtain a minocycline that it is represented to solution containing 500 micrograms of
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minocycline activity per milliliter (es- tion containing 10 milligrams of timated). Use this solution within 3 minocycline per milliliter. hours of preparation. [39 FR 19076, May 30, 1974, as amended at 43 (ii) Calculations—(a) Calculate the FR 11166, Mar. 17, 1978; 43 FR 34457, Aug. 4, minocycline content of the single-dose 1978; 44 FR 22058, Apr. 13, 1979; 46 FR 60568, vial as follows: Dec. 11, 1981; 50 FR 19920, May 13, 1985; 53 FR 32609, Aug. 26, 1988; 54 FR 47205, Nov. 13, 1989] × × Milligrams of minocycline Au P s d = § 446.265 Oxytetracycline injection. per single-dose vial × As 1, 000 (a) Requirements for certification—(1) where: Standards of identity, strength, quality,
Au= Area of the minocycline peak in the and purity. Oxytetracycline injection is chromatogram of the sample (at a reten- a solution of oxytetracycline with or tion time equal to that observed for the without one or more suitable and standard); harmless buffer substances, anesthet- As= Area of the minocycline peak in the ics, preservatives, antioxidants, chromatogram of the minocycline work- complexing agents, and solvents. Each ing standard: milliliter contains 50 milligrams or 125 Ps= Minocycline activity in the minocycline working standard solution in milligrams of oxytetracycline. Its po- micrograms per milliliter; and tency is satisfactory if it is not less d = Dilution factor of the sample. than 90 percent and not more than 120 percent of the number of milligrams of (b) Calculate the minocycline con- oxytetracycline that it is represented tent of the multiple-dose vial as fol- to contain. It is sterile. It is lows: nonpyrogenic. It contains no depressor substances. Its pH is not less than 8.0 Milligrams of × × Au P s d and not more than 9.0. The oxytetra- minocycline per = cycline used conforms to the standards × × multiple-dose vial As 1, 000 n prescribed by § 446.65a(a)(1), except ste- where: rility, pyrogens, and depressor sub- stances. Au= Area of the minocycline peak in the chromatogram of the sample (at a reten- (2) Labeling. It shall be labeled in ac- tion time equal to that observed for the cordance with the requirements of standard); § 432.5 of this chapter. As= Area of the minocycline peak in the (3) Requests for certification; samples. chromatogram of the minocycline work- In addition to complying with the re- ing standard: quirements of § 431.1 of this chapter, Ps= Minocycline activity in the minocycline each such request shall contain: working standard solution in micrograms per milliliter; (i) Results of tests and assays on: d = Dilution factor of the sample. (a) The oxytetracycline used in mak- n = Volume of sample solution assayed. ing the batch for potency, moisture, pH, absorptivity, identity, and crys- (2) Sterility. Proceed as directed in tallinity. § 436.20 of this chapter, using the meth- (b) The batch for potency, sterility, od described in paragraph (e)(1) of that pyrogens, depressor substances, and section. pH. (3) Pyrogens. Proceed as directed in (ii) Samples required: § 436.32(b) of this chapter, using a solu- (a) The oxytetracycline used in mak- tion containing 5 milligrams per milli- ing the batch: 10 packages, each con- liter. taining approximately 300 milligrams. (4) [Reserved] (b) The batch: (5) Depressor substances. Proceed as (1) For all tests except sterility: A directed in § 436.35 of this chapter. minimum of 10 immediate containers. (6) Moisture. Proceed as directed in (2) For sterility testing: 20 immediate § 436.201 of this chapter, using the sam- containers, collected at regular inter- ple preparation described in paragraph vals throughout each filling operation. (d)(4) of that section. (b) Tests and methods of assay—(1) Po- (7) pH. Proceed as directed in § 436.202 tency. Proceed as directed in § 436.106 of of this chapter, using an aqueous solu- this chapter, preparing the sample for
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assay as follows: Transfer an accu- (3) Requests for certification; samples. rately measured representative quan- In addition to complying with the re- tity of the sample to an appropriate- quirements of § 431.1 of this chapter, sized volumetric flask. Dilute to vol- each such request shall contain: ume with 0.1N hydrochloric acid to ob- (i) Results of tests and assays on: tain a stock solution of convenient (a) The oxytetracycline hydro- concentration containing not less than chloride used in making the batch for 150 micrograms of oxytetracycline per potency, loss on drying, pH, absorptiv- milliliter (estimated). Further dilute ity, identity, and crystallinity. an aliquot of the stock solution with (b) The batch for potency, sterility, sterile distilled water to the reference pyrogens, depressor substances, loss on concentration of 0.24 microgram of ox- drying, and pH. ytetracycline per milliliter (esti- (ii) Samples required: mated). (a) The oxytetracycline hydro- (2) Sterility. Proceed as directed in chloride used in making the batch: 10 § 436.20 of this chapter, using the meth- packages, each containing approxi- od described in paragraph (e)(1) of that mately 300 milligrams. section. (b) The batch: (3) Pyrogens. Proceed as directed in (1) For all tests except sterility: A § 436.32(b) of this chapter, using a solu- minimum of 10 immediate containers. tion containing 5.0 milligrams of oxy- (2) For sterility testing: 20 immediate tetracycline per milliliter. containers, collected at regular inter- (4) [Reserved] vals throughout each filling operation. (5) Depressor substances. Proceed as (b) Tests and methods of assay—(1) Po- directed in § 436.35 of this chapter. tency. Proceed as directed in § 436.106 of this chapter, preparing the sample for (6) pH. Proceed as directed in § 436.202 assay as follows: Reconstitute as di- of this chapter, using the undiluted so- rected in the labeling. Then, using a lution. suitable hypodermic needle and sy- [43 FR 11166, Mar. 17, 1978, as amended at 46 ringe, promptly remove all the FR 60568, Dec. 11, 1981; 48 FR 51293, Nov. 8, withdrawable contents if it is rep- 1983; 50 FR 19920, May 13, 1985] resented as a single dose container; or, if the labeling specifies the amount of § 446.267 Oxytetracycline hydro- potency in a given volume of the re- chloride for injection. sultant preparation, remove an accu- (a) Requirements for certification—(1) rately measured representative portion Standards of identity, strength, quality, from the container. Dilute the sample and purity. Oxytetracycline hydro- thus obtained with sufficient 0.1N hy- chloride for injection is a dry mixture drochloric acid to obtain a stock solu- of oxytetracycline hydrochloride and a tion of convenient concentration con- suitable buffer substance. Its potency taining not less than 150 micrograms of is satisfactory if it is not less than 90 oxytetracycline per milliliter (esti- percent and not more than 115 percent mated). Further dilute an aliquot of of the number of milligrams of oxytet- the stock solution with sterile distilled racycline that it is represented to con- water to the reference concentration of tain. It is sterile. It is nonpyrogenic. It 0.24 microgram of oxytetracycline per contains no depressor substances. Its milliliter (estimated). loss on drying is not more than 3.0 per- (2) Sterility. Proceed as directed in cent. Its pH in an aqueous solution § 436.20 of this chapter, using the meth- containing 25 milligrams per milliliter od described in paragraph (e)(1) of that is not less than 1.8 and not more than section, except use diluting fluid D in 2.8. The oxytetracycline hydrochloride lieu of diluting fluid A. used conforms to the standards pre- (3) Pyrogens. Proceed as directed in scribed by § 446.67a(a)(1), except steril- 436.32(b) of this chapter, using a solu- ity, pyrogens, and depressor sub- tion containing 5.0 milligrams per mil- stances. liliter. (2) Labeling. It shall be labeled in ac- (4) [Reserved] cordance with the requirements of (5) Depressor substances. Proceed as § 432.5 of this chapter. directed in § 436.35 of this chapter,
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using the diluent recommended by the (2) For sterility testing: 20 immediate manufacturer in the labeling for the containers, collected at regular inter- drug. vals throughout each filling operation. (6) Loss on drying. Proceed as directed (b) Tests and methods of assay—(1) Po- in § 436.200(b) of this chapter. tency. Proceed as directed in § 436.106 of (7) pH. Proceed as directed in § 436.202 this subchapter, preparing the sample of this chapter, using an aqueous solu- for assay as follows: Reconstitute the tion containing 25 milligrams per mil- sample as directed in the labeling. liliter. Using a suitable hypodermic needle and syringe, remove all of the [43 FR 11167, Mar. 17, 1978, as amended at 46 FR 60568, Dec. 11, 1981; 50 FR 19920, May 13, withdrawable contents if it is rep- 1985] resented as a single dose container; or if the labeling specifies the amount of § 446.275 Rolitetracycline injectable potency in a given volume of the re- dosage forms. sultant preparation, remove an accu- rately measured representative portion § 446.275a Rolitetracycline for intra- from each container. Dilute the sample venous use. thus obtained with sufficient distilled (a) Requirements for certification—(1) water to obtain a stock solution of con- Standards of identity, strength, quality, venient concentration. Further dilute and purity. Rolitetracycline for intra- an aliquot of the stock solution with venous use is a dry mixture of distilled water to the reference con- rolitetracycline and one or more suit- centration of 0.24 microgram of able buffer substances. Its potency is rolitetracycline per milliliter (esti- satisfactory if it is not less than 90 per- mated). cent and not more than 115 percent of (2) Sterility. Proceed as directed in the number of milligrams of § 436.20 of this subchapter, using the rolitetracycline that it is represented method described in paragraph (e)(1) of to contain. It is sterile. It is that section, except use diluting fluid nonpyrogenic. It contains no depressor D in lieu of diluting fluid A. substances. Its loss on drying is not (3) Pyrogens. Proceed as directed in more than 5 percent. When reconsti- § 436.32(b) of this subchapter, using a tuted as directed in the labeling, its pH solution containing 5.0 milligrams of is not less than 3.0 and not more than rolitetracycline per milliliter. 4.5. The rolitetracycline used conforms (4) [Reserved] to the standards prescribed by (5) Depressor substances. Proceed as § 446.75a(a)(1). directed in § 436.35 of this subchapter. (2) Labeling. It shall be labeled in ac- (6) Loss on drying. Proceed as directed cordance with the requirements of in § 436.200(b) of this chapter. § 432.5 of this subchapter. (7) pH. Proceed as directed in § 436.202 (3) Requests for certification; samples. of this subchapter, using a solution In addition to complying with the re- prepared as directed in the labeling. quirements of § 431.1 of this subchapter, [39 FR 19076, May 30, 1974, as amended at 43 each such request shall contain: FR 11167, Mar. 17, 1978; 46 FR 46313, Sept. 18, (i) Results of tests and assays on: 1981; 46 FR 60568, Dec. 11, 1981; 50 FR 19920, (a) The rolitetracycline used in mak- May 13, 1985] ing the batch for potency, moisture, pH, crystallinity, absorptivity, and § 446.275b Rolitetracycline for identity. intramuscular use. (b) The batch for potency, sterility, (a) Requirements for certification—(1) pyrogens, depressor substances, loss on Standards of identity, strength, quality, drying, and pH. and purity. Rolitetracycline for (ii) Samples required: intramuscular use is a dry mixture of (a) The rolitetracycline used in mak- rolitetracycline and one or more suit- ing the batch: 10 packages, each con- able buffer substances and anesthetic taining approximately 500 milligrams. agents. Its potency is satisfactory if it (b) The batch: is not less than 90 percent and not (1) For all tests except sterility: A more than 115 percent of the number of minimum of 10 immediate containers. milligrams of rolitetracycline that it is
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represented to contain. It is sterile. It (3) Pyrogens. Proceed as directed in is nonpyrogenic. Its loss on drying is § 436.32(b) of this subchapter, using a not more than 5 percent. When recon- solution containing 5.0 milligrams of stituted as directed in the labeling, its rolitetracycline per milliliter. pH is not less than 3.0 and not more (4) Loss on drying. Proceed as directed than 4.5. The rolitetracycline used con- in § 436.200(b) of this subchapter. forms to the standards prescribed by (5) pH. Proceed as directed in § 436.202 § 446.75a(a)(1). of this subchapter, using a solution (2) Labeling. It shall be labeled in ac- prepared as directed in the labeling. cordance with the requirements of [39 FR 19076, May 30, 1974, as amended at 43 § 432.5 of this subchapter. FR 11167, Mar. 17, 1978; 46 FR 46313, Sept. 18, (3) Requests for certification; samples. 1981; 46 FR 60568, Dec. 11, 1981; 50 FR 19920, In addition to complying with the re- May 13, 1985] quirements of § 431.1 of this subchapter, each such request shall contain: § 446.276 Rolitetracycline nitrate (i) Results of tests and assays on: injectable dosage forms. (a) The rolitetracycline used in mak- ing the batch for potency, depressor § 446.276a Rolitetracycline nitrate for substances, moisture, pH, crystallinity, intravenous use. absorptivity, and identity. (a) Requirements for certification—(1) (b) The batch for potency, sterility, Standards of identity, strength, quality, pyrogens, loss on drying, and pH. and purity. Rolitetracycline nitrate for (ii) Samples required: intravenous use is a dry mixture of (a) The rolitetracycline used in mak- rolitetracycline nitrate and one or ing the batch: 10 packages, each con- more suitable buffer substances. Its po- taining approximately 500 milligrams. tency is satisfactory if it contains not (b) The batch: less than 90 percent and not more than (1) For all tests except sterility: A 115 percent of the number of milli- minimum of 10 immediate containers. grams of rolitetracycline that it is rep- (2) For sterility testing: 20 immediate resented to contain. It is sterile. It is containers, collected at regular inter- nonpyrogenic. It contains no depressor vals throughout each filling operation. substances. Its loss on drying is not (b) Tests and methods of assay—(1) Po- more than 5 percent. When reconsti- tency. Proceed as directed in § 436.106 of tuted as directed in the labeling, its pH this subchapter, preparing the sample is not less than 2.5 nor more than 4.0. for assay as follows: Reconstitute the The rolitetracycline nitrate used con- sample as directed in the labeling. forms to the standards prescribed by Then using a suitable hypodermic nee- § 446.76a(a)(1). dle and syringe, remove all of the (2) Labeling. It shall be labeled in ac- withdrawable contents if it is rep- cordance with the requirements of resented as a single dose container; or § 432.5 of this subchapter. if the labeling specifies the amount of (3) Requests for certification; samples. potency in a given volume of the re- In addition to complying with the re- sultant preparation, remove an accu- quirements of § 431.1 of this subchapter, rately measured representative portion each such request shall contain: from each container. Dilute the sample (i) Results of tests and assays on: thus obtained with sufficient distilled (a) The rolitetracycline nitrate used water to obtain a stock solution of con- in making the batch for potency, mois- venient concentration. Further dilute ture, pH, crystallinity, absorptivity, an aliquot of the stock solution with and identity. distilled water to the reference con- (b) The batch for potency, sterility, centration of 0.24 microgram of pyrogens, depressor substances, loss on rolitetracycline per milliliter (esti- drying, and pH. mated). (ii) Samples required: (2) Sterility. Proceed as directed in (a) The rolitetracycline nitrate used § 436.20 of this subchapter, using the in making the batch: 10 packages, each method described in paragraph (e)(1) of containing approximately 500 milli- that section, except use diluting fluid grams. D in lieu of diluting fluid A. (b) The batch:
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(1) For all tests except sterility: A cent and not more than 115 percent of minimum of 10 immediate containers. the number of milligrams of (2) For sterility testing: 20 immediate rolitetracycline that it is represented containers, collected at regular inter- to contain. It is sterile. It is vals throughout each filling operation. nonpyrogenic. Its loss on drying is not (b) Tests and methods of assay—(1) Po- more than 5 percent. When reconsti- tency. Proceed as directed in § 436.106 of tuted as directed in the labeling, its pH this subchapter, preparing the sample is not less than 2.5 nor more than 4.0. for assay as follows: Reconstitute the The rolitetracycline nitrate used con- sample as directed in the labeling. forms to the standards prescribed by Using a suitable hypodermic needle and § 446.76a(a)(1). syringe, remove all of the (2) Labeling. It shall be labeled in ac- withdrawable contents if it is [repre- cordance with the requirements of ]sented as a single dose container; or if § 432.5 of this subchapter. the labeling specifies the amount of po- (3) Requests for certification; samples. tency in a given volume of the result- In addition to complying with the re- ant preparation, remove an accurately quirements of § 431.1 of this subchapter, measured representative portion from each such request shall contain: each container. Dilute the sample thus (i) Results of tests and assays on: obtained with sufficient distilled water (a) The rolitetracycline nitrate used to obtain a stock solution of conven- in making the batch for potency, de- ient concentration. Further dilute an pressor substances, moisture, pH, crys- aliquot of the stock solution with dis- tallinity, absorptivity, and identity. tilled water to the reference concentra- (b) The batch for potency, sterility, tion of 0.24 microgram of pyrogens, loss on drying, and pH. rolitetracycline per milliliter (esti- mated). (ii) Samples required: (2) Sterility. Proceed as directed in (a) The rolitetracycline nitrate used § 436.20 of this subchapter, using the in making the batch: 10 packages, each method described in paragraph (e)(1) of containing approximately 500 milli- that section, except use diluting fluid grams. D in lieu of diluting fluid A. (b) The batch: (3) Pyrogens. Proceed as directed in (1) For all tests except sterility: A § 436.32(b) of this subchapter, using a minimum of 10 immediate containers. solution containing 5.0 milligrams of (2) For sterility testing: 20 immediate rolitetracycline per milliliter. containers, collected at regular inter- (4) [Reserved] vals throughout each filling operation. (5) Depressor substances. Proceed as (b) Tests and methods of assay—(1) Po- directed in § 436.35 of this chapter. tency. Proceed as directed in § 436.106 of (6) Loss on drying. Proceed as directed this subchapter, preparing the sample in § 436.200(b) of this subchapter. for assay as follows: Reconstitute the (7) pH. Proceed as directed in § 436.202 sample as directed in the labeling. of this subchapter, using a solution Then using a suitable hypodermic nee- prepared as directed in the labeling. dle and syringe, remove all of the [39 FR 19076, May 30, 1974, as amended at 43 withdrawable contents if it is rep- FR 11168, Mar. 17, 1978; 43 FR 34457, Aug. 4, resented as a single-dose container; or 1978; 46 FR 46313, Sept. 18, 1981; 46 FR 60568, if the labeling specifies the amount of Dec. 11, 1981; 50 FR 19920, May 13, 1985] potency in a given volume of the re- sultant preparation, remove an accu- § 446.276b Rolitetracycline nitrate for rately measured representative portion intramuscular use. from each container. Dilute the sample (a) Requirements for certification—(1) thus obtained with sufficient distilled Standards of identity, strength, quality, water to obtain a stock solution of con- and purity. Rolitetracycline nitrate for venient concentration. Further dilute intramuscular use is a dry mixture of an aliquot of the stock solution with rolitetracycline nitrate, one or more distilled water to the reference con- suitable buffer substances, and lido- centration of 0.24 microgram of caine hydrochloride. Its potency is sat- rolitetracycline per milliliter (esti- isfactory if it is not less than 90 per- mated).
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(2) Sterility. Proceed as directed in (2) Labeling. It shall be labeled in ac- § 436.20 of this subchapter, using the cordance with the requirements of method described in paragraph (e)(1) of § 432.5 of this chapter. that section, except use diluting fluid (3) Requests for certification; samples. D in lieu of diluting fluid A. In addition to complying with the re- (3) Pyrogens. Proceed as directed in quirements of § 431.1 of this chapter, § 436.32(b) of this subchapter, using a each such request shall contain: solution containing 5.0 milligrams of (i) Results of tests and assays on: rolitetracycline per milliliter. (a) The tetracycline hydrochloride (4) Loss on drying. Proceed as directed used in making the batch for potency, in § 436.200(b) of this subchapter. depressor substances, loss on drying, pH, absorptivity, 4- (5) pH. Proceed as directed in § 436.202 epianhydrotetracycline content, crys- of this subchapter, using a solution tallinity, and identity. prepared as directed in the labeling. (b) The batch for potency, sterility, [39 FR 19076, May 30, 1974, as amended at 43 pyrogens, loss on drying, pH, and 4- FR 11168, Mar. 30, 1978; 46 FR 46313, Sept. 18, epianhydrotetracycline content. 1981; 46 FR 60568, Dec. 11, 1981; 50 FR 19920, (ii) Samples required: May 13, 1985] (a) The tetracycline hydrochloride used in making the batch: 10 packages, § 446.281 Tetracycline hydrochloride each containing approximately 300 mil- injectable dosage forms. ligrams. (b) The batch: A minimum of 10 im- § 446.281a Sterile tetracycline hydro- mediate containers. chloride. (b) Tests and methods of assay—(1) Po- The requirements for certification tency. Proceed as directed in § 436.106 of and the tests and methods of assay for this chapter, preparing the sample for sterile tetracycline hydrochloride assay as follows: Reconstitute the sam- packaged for dispensing are described ple as directed in the labeling. Then, in § 446.81a. using a suitable hypodermic needle and syringe, remove all the withdrawable § 446.281c Tetracycline hydrochloride contents if it is represented as a single for intramuscular use. dose container; or, if the labeling speci- (a) Requirements for certification—(1) fies the amount of potency in a given Standards of identity, strength, quality, volume of the resultant preparation, and purity. Tetracycline hydrochloride remove an accurately measured rep- for intramuscular use is a dry mixture resentative portion from each con- of tetracycline hydrochloride, magne- tainer. Dilute the sample thus obtained sium chloride, or magnesium ascorbate with sufficient 0.1N hydrochloric acid and one or more suitable buffer sub- to obtain a stock solution of conven- ient concentration containing not less stances, with or without one or more than 150 micrograms of tetracycline suitable preservatives and anesthetic hydrochloride per milliliter (esti- agents, and with or without one or mated). Further dilute an aliquot of more suitable solubilizers and stabiliz- the stock solution with sterile distilled ers. Its potency is satisfactory if it is water to the reference concentration of not less than 90 percent and not more 0.24 microgram of tetracycline hydro- than 115 percent of the number of milli- chloride per milliliter (estimated). grams of tetracycline hydrochloride (2) Sterility. Proceed as directed in that it is represented to contain. It is § 436.20 of this chapter, using the meth- sterile. It is nonpyrogenic. Its loss on od described in paragraph (e)(1) of that drying is not more than 5.0 percent. Its section, except use diluting fluid D in pH in an aqueous solution containing lieu of diluting fluid A. 10 milligrams per milliliter is not less (3) Pyrogens. Proceed as directed in than 2.0 and not more than 3.0. Its 4- § 436.32(b) of this chapter, using a solu- epianhydrotetracycline content is not tion containing 5.0 milligrams of tetra- more than 3.0 percent. The tetracycline cycline hydrochloride per milliliter. hydrochloride used conforms to the (4) Loss on drying. Proceed as directed standards prescribed by § 446.81a(a)(1). in § 436.200(b) of this chapter.
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(5) pH. Proceed as directed in § 436.202 (b) Tests and methods of assay—(1) Po- of this chapter, using an aqueous solu- tency. Proceed as directed in § 436.106 of tion containing 10 milligrams per mil- this chapter, preparing the sample for liliter. assay as follows: Reconstitute the sam- (6) 4-Epianhydrotetracycline. Proceed ple as directed in the labeling. Then, as directed in § 436.309 of this chapter. using a suitable hypodermic needle and syringe, remove all of the withdrawal [44 FR 31636, June 1, 1979, as amended at 46 contents if it is represented as a single FR 60568, Dec. 11, 1981; 47 FR 13326, Mar. 30, 1982; 50 FR 19920, May 13, 1985] dose container; or, if the labeling speci- fies the amount of potency in a given § 446.281d Tetracycline hydrochloride volume of the resultant preparation, for intravenous use. remove an accurately measured rep- resentative portion from each con- (a) Requirements for certification—(1) tainer. Dilute the sample thus obtained Standards of identity, strength, quality, with sufficient 0.1N hydrochloric acid and purity. Tetracycline hydrochloride to obtain a stock solution of conven- for intravenous use is a dry mixture of ient concentration containing not less tetracycline hydrochloride with one or than 150 micrograms of tetracycline more suitable and harmless stabilizing hydrochloride per milliliter (esti- agents. Its potency is satisfactory if it mated). Further dilute an aliquot of contains not less than 90 percent and the stock solution with sterile distilled not more than 115 percent of the num- water to the reference concentration of ber of milligrams of tetracycline hy- 0.24 microgram of tetracycline hydro- drochloride that it is represented to chloride per milliliter (estimated). contain. It is sterile. It is nonpyrogenic. It contains no depressor (2) Sterility. Proceed as directed in substances. Its loss on drying is not § 436.20 of this chapter, using the meth- more than 5.0 percent. Its pH in an od described in paragraph (e)(1) of that aqueous solution containing 10 milli- section, except use diluting fluid D in grams per milliliter is not less than 2.0 lieu of diluting fluid A. and not more than 3.0. Its 4- (3) Pyrogens. Proceed as directed in epianhydrotetracycline content is not § 436.32(b) of this chapter, using a solu- more than 3.0 percent. The tetracycline tion containing 5.0 milligrams of tetra- hydrochloride used conforms to the cycline hydrochloride per milliliter. standards prescribed by § 446.81a(a)(1). (4) [Reserved] (2) Labeling. It shall be labeled in ac- (5) Depressor substances. Proceed as cordance with the requirements of directed in § 436.35 of this chapter. § 432.5 of this chapter. (6) Loss on drying. Proceed as directed (3) Requests for certification; samples. in § 436.200(b) of this chapter. In addition to complying with the re- (7) pH. Proceed as directed in § 436.202 quirements of § 431.1 of this chapter, of this chapter, using an aqueous solu- each such request shall contain: tion containing 10 milligrams per mil- (i) Results of tests and assays on: liliter. (a) The tetracycline hydrochloride (8) 4-Epianhydrotetracycline. Proceed used in making the batch for potency, as directed in § 436.309 of this chapter. loss on drying, pH, absorptivity, 4- [44 FR 31636, June 1, 1979, as amended at 46 epianhydrotetracycline content, FR 60568, Dec. 11, 1981; 47 FR 13326, Mar. 30, cystallinity, and identity. 1982; 50 FR 19920, May 13, 1985] (b) The batch for potency, sterility, pyrogens, depressor substances, loss on § 446.282 Tetracycline phosphate com- drying, pH, and 4- plex for injection. epianhydrotetracycline content. (a) Requirements for certification—(1) (ii) Samples required: Standards of identity, strength, quality, (a) The tetracycline hydrochloride and purity. Tetracycline phosphate used in making the batch: 10 packages, complex for injection is a dry mixture each containing approximately 300 mil- of tetracycline phosphate complex, ligrams. magnesium chloride or magnesium (b) The batch: A minimum for 10 im- ascorbate and one or more suitable mediate containers. buffer substances, with or without one
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or more suitable preservatives and an- than 150 micrograms of tetracycline esthetic agents, and with or without hydrochloride per milliliter (esti- one or more suitable solubilizers and mated). Further dilute an aliquot of stabilizers. Its potency is satisfactory the stock solution with sterile distilled if it contains not less than 90 percent water to the reference concentration of and not more than 115 percent of the 0.24 microgram of tetracycline hydro- number of milligrams of tetracycline chloride per milliliter (estimated). hydrochloride that it is represented to (2) Sterility. Proceed as directed in contain. It is sterile. It is § 436.20 of this chapter, using the meth- nonpyrogenic. Its loss on drying is not od described in paragraph (e)(1) of that more than 5 percent. Its pH in an aque- section, except use 50 milligrams in ous solution containing 10 milligrams lieu of 300 milligrams of sample. per milliliter is not less than 2.0 and (3) Pyrogens. Proceed as directed in not more than 3.0. Its 4- § 436.32(b) of this chapter, using a solu- epianhydrotetracycline content is not tion containing 5.0 milligrams of tetra- more than 3.0 percent. The tetracycline cycline hydrochloride per milliliter. phosphate complex conforms to the (4) Loss on drying. Proceed as directed standards prescribed by § 446.82(a)(1), in § 436.200(b) of this chapter. and it contains no depressor substance. (2) Labeling. It shall be labeled in ac- (5) pH. Proceed as directed in § 436.202 cordance with the requirements of of this chapter, using an aqueous solu- § 432.5 of this chapter. tion containing 10 milligrams per mil- (3) Requests for certification; samples. liliter. In addition to complying with the re- (6) Depressor substances in the tetra- quirements of § 431.1 of this chapter, cycline phosphate complex used in making each such request shall contain: the batch. Proceed as directed in § 436.35 (i) Results of tests and assays on: of this chapter. Prepare the test solu- (a) The tetracycline phosphate com- tion by dissolving 40 milligrams of plex used in making the batch for po- sample in 2.0 milliliters of 0.1N hydro- tency, moisture, pH, depressor sub- chloric acid and diluting with sterile stances, absorptivity, 4- distilled water (diluent 3) to the pre- epianhydrotetracycline content, iden- scribed concentration. tity, and crystallinity. (7) 4-Epianhydrotetracycline. Proceed (b) The batch for potency, sterility, as directed in § 436.309 of this chapter. pyrogens, loss on drying, pH, and 4- [43 FR 11168, Mar. 17, 1978, as amended at 46 epianhydrotetracycline content. FR 60568, Dec. 11, 1981; 50 FR 19920, May 13, (ii) Samples required: 1985] (a) The tetracycline phosphate com- plex used in making the batch: 10 pack- ages, each containing approximately Subpart D—Ophthalmic Dosage 300 milligrams, and one package con- Forms taining approximately 1 gram. (b) The batch: A minimum of 10 im- § 446.310 Chlortetracycline hydro- chloride ophthalmic ointment. mediate containers. (b) Tests and methods of assay—(1) Po- (a) Requirements for certification—(1) tency. Reconstitute the sample as di- Standards of identity, strength, quality, rected in the labeling. Then, using a and purity. Chlortetracycline hydro- suitable hypodermic needle and sy- chloride ophthalmic ointment contains ringe, remove all the withdrawable chlortetracycline hydrochloride in a contents if it is represented as a single- suitable and harmless ointment base. dose container; or, if the labeling speci- Each gram contains 10 milligrams of fies the amount of potency in a given chlortetracycline hydrochloride. Its volume of the resultant preparation, potency is satisfactory if it contains remove an accurately measured rep- not less than 90 percent and not more resentative portion from each con- than 125 percent of the number of milli- tainer. Dilute the sample thus obtained grams of chlortetracycline hydro- with sufficient 0.1N hydrochloric acid chloride that it is represented to con- to obtain a stock solution of conven- tain. It is sterile. Its moisture content ient concentration containing not less is not more than 0.5 percent. It passes
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the test for metal particles. The chlor- (4) Metal particles. Proceed as directed tetracycline hydrochloride used con- in § 436.206 of this chapter. forms to the standards prescribed by [43 FR 11169, Mar. 17, 1978, as amended at 50 § 446.10a(a)(1). FR 19920, May 13, 1985] (2) Labeling. It shall be labeled in ac- cordance with the requirements of § 446.367 Oxytetracycline hydro- § 432.5 of this chapter. chloride ophthalmic dosage forms. (3) Requests for certification; samples. In addition to complying with the re- § 446.367c Oxytetracycline hydro- quirements of § 431.1 of this chapter, chloride-hydrocortisone acetate ophthalmic suspension. each such request shall contain: (i) Results of tests and assays on: (a) Requirements for certification—(1) (a) The chlortetracycline hydro- Standards of identity, strength, quality, chloride used in making the batch for and purity. Oxytetracycline hydro- potency, loss on drying, pH, crystallin- chloride-hydrocortisone acetate oph- ity, and identity. thalmic suspension is oxytetracycline hydrochloride and hydrocortisone ace- (b) The batch for potency, sterility, tate in a suitable and harmless oil base moisture, and metal particles. containing aluminum tristearate. Each (ii) Samples required: milliliter contains oxytetracycline hy- (a) The chlortetracycline hydro- drochloride equivalent to 5 milligrams chloride used in making the batch: 10 of oxytetracycline and 15 milligrams of packages, each containing approxi- hydrocortisone acetate. Its potency is mately 300 milligrams. satisfactory if it contains not less than (b) The batch: 90 percent and not more than 115 per- (1) For all tests except sterility: A cent of the number of milligrams of ox- minimum of 15 immediate containers. ytetracycline that it is represented to (2) For sterility testing: 20 immediate contain. It is sterile. Its moisture con- containers, collected at regular inter- tent is not more than 1 percent. The vals throughout each filling operation. oxytetracycline hydrochloride used (b) Tests and methods of assay—(1) Po- conforms to the standards prescribed tency. Proceed as directed in § 436.106 of by § 446.67a (a)(1). this chapter, preparing the sample for (2) Labeling. It shall be labeled in ac- assay as follows: Place an accurately cordance with the requirements of weighed representative portion of the § 432.5 of this chapter. sample into a separatory funnel con- (3) Requests for certification; samples. taining approximately 50 milliliters of In addition to complying with the re- peroxide-free ether. Shake the sample quirements of § 431.1 of this chapter, and ether until homogeneous. Add 20 to each such request shall contain: 25 milliliters of 0.01N hydrochloric acid (i) Results of tests and assays on: and shake well. Allow the layers to (a) The oxytetracycline hydro- separate. Remove the acid layer and re- chloride used in making the batch for peat the extraction procedure with potency, loss on drying, pH, absorptiv- each of three more 20- to 25-milliliter ity, crystallinity, and identity. quantities of 0.01N hydrochloric acid. (b) The batch for potency, sterility, Combine the extractives in a suitable and moisture. volumetric flask and dilute to volume (ii) Samples required: with 0.01N hydrochloric acid. Further (a) The oxytetracycline hydro- dilute an aliquot with sterile distilled chloride used in making the batch: 10 water to the reference concentration of packages, each containing approxi- 0.06 microgram of chlortetracycline hy- mately 300 milligrams. drochloride per milliliter (estimated). (b) The batch: (2) Sterility. Proceed as directed in (1) For all tests except sterility: A § 436.20 of this chapter, using the meth- minimum of five immediate contain- od described in paragraph (e)(3) of that ers. section. (2) For sterility testing: 20 immediate (3) Moisture. Proceed as directed in containers collected at regular inter- § 436.201 of this chapter. vals throughout each filling operation.
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(b) Tests and methods of assay—(1) Po- (2) Labeling. It shall be labeled in ac- tency. Proceed as directed in § 436.106 of cordance with the requirements of this chapter, preparing the sample for § 432.5 of this chapter. assay as follows: Place an accurately (3) Requests for certification; samples. measured, representative portion of the In addition to complying with the re- sample into a high-speed glass blender quirements of § 431.1 of this chapter, jar containing 1.0 milliliter of poly- each such request shall contain: sorbate 80 and sufficient 0.1N hydro- (i) Results of tests and assays on: chloric acid to obtain a stock solution (a) The oxytetracycline hydro- of convenient concentration containing chloride used in making the batch for not less than 150 micrograms of oxytet- potency, loss on drying, pH, absorptiv- racycline per milliliter (estimated). ity, crystallinity, and identity. Blend for 3 to 5 minutes. Further dilute (b) The polymyxin B sulfate used in an aliquot with sterile distilled water making the batch for potency, pH, loss to the reference concentration of 0.24 on drying, residue on ignition, and microgram of oxytetracycline per mil- identity. liliter (estimated). (c) The batch for oxytetracycline (2) Sterility. Proceed as directed in content, polymyxin B content, steril- § 436.20 of this chapter, using the meth- ity, moisture, and metal particles. od described in paragraph (e)(2) of that (ii) Samples required: section, except use 0.25 milliliter of the (a) The oxytetracycline hydro- sample in lieu of 1.0 milliliter. chloride used in making the batch: 10 (3) Moisture. Proceed as directed in packages, each containing approxi- § 436.201 of this chapter. mately 300 milligrams. [43 FR 11169, Mar. 17, 1978, as amended at 50 (b) The polymyxin B sulfate used in FR 19920, May 13, 1985] making the batch: 10 packages, each containing approximately 300 milli- § 446.367e Oxytetracycline hydro- grams. chloride-polymyxin B sulfate oph- (c) The batch: thalmic ointment. (1) For all tests except sterility: A (a) Requirements for certification—(1) minimum of 16 immediate containers. Standards of identity, strength, quality, (2) For sterility testing: 20 immediate and purity. Oxytetracycline hydro- containers collected at regular inter- chloride-polymyxin B sulfate ophthal- vals throughout each filling operation. mic ointment is oxytetracycline hydro- (b) Tests and methods of assay—(1) Po- chloride and polymyxin B sulfate in a tency—(i) Oxytetracycline content. Pro- suitable and harmless ointment base. ceed as directed in § 436.106 of this chap- Each gram contains oxytetracycline ter, preparing the sample for assay as hydrochloride equivalent to 5 milli- follows: Place an accurately weighed grams of oxytetracycline and poly- representative portion of the sample myxin B sulfate equivalent to 10,000 into a separatory funnel containing ap- units of polymyxin B. Its oxytetra- proximately 50 milliliters of peroxide- cycline content is satisfactory if it is free ether. Shake the ointment and not less than 90 percent and not more ether until homogeneous. Add 20 to 25 than 120 percent of the number of milli- milliliters of 0.1N hydrochloric acid grams of oxytetracycline that it is rep- and shake well. Allow the layers to resented to contain. Its polymyxin B separate. Remove the acid layer and re- content is satisfactory if it is not less peat the extraction procedure with than 90 percent and not more than 125 each of three more 20- to 25-milliliter percent of the number of units of poly- quantities of 0.1N hydrochloric acid. myxin B that it is represented to con- Combine the acid extractives in a suit- tain. It is sterile. Its moisture content able volumetric flask and dilute to vol- is not more than 1 percent. It passes ume with 0.1N hydrochloric acid to ob- the test for metal particles. The oxy- tain a stock solution of convenient tetracycline hydrochloride used con- concentration containing not less than forms to the standards prescribed by 150 micrograms of oxytetracycline per § 446.67a (a)(1). The polymyxin B sulfate milliliter (estimated). Further dilute used conforms to the standards pre- an aliquot of the stock solution with scribed by § 448.30a(a)(1) of this chapter. sterile distilled water to the reference
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concentration of 0.24 microgram of ox- cycline hydrochloride that it is rep- ytetracycline per milliliter (esti- resented to contain. It is sterile. Its mated). moisture content is not more than 0.5 (ii) Polymyxin B content. Proceed as percent. It passes the test for metal directed in § 436.105 of this chapter, pre- particles. The tetracycline hydro- paring the sample for assay as follows: chloride used conforms to the stand- Weigh accurately 0.5 to 1 gram of the ards prescribed by § 446.81a(a)(1). ointment and place into a 15-milliliter (2) Labeling. It shall be labeled in ac- centrifuge tube. Add 10 milliliters of cordance with the requirements of peroxide-free ether. Stir until contents § 432.5 of this chapter. are homogeneous and centrifuge for 10 (3) Requests for certification; samples. minutes at 3,000 revolutions per In addition to complying with the re- minute. Decant the supernatant ether. quirements of § 431.1 of this chapter, Repeat washing and centrifugation each such request shall contain: steps once more. Add 10 milliliters of (i) Results of tests and assays on: acetone, stir until contents are homo- (a) The tetracycline hydrochloride geneous, and centrifuge for 10 minutes used in making the batch for potency, at 3,000 revolutions per minute. Decant loss on drying, pH, absorptivity, crys- the supernatant acetone. Repeat ace- tallinity, and identity. tone wash and centrifugation once (b) The batch for potency, sterility, more. Continue acetone washings until moisture, and metal particles. the yellow color in the residue dis- (ii) Samples required: appears. Add 3 to 4 drops of polysorbate (a) The tetracycline hydrochloride 80 to the residue and mix well. Gently used in making the batch: 10 packages, wash the residue into a 100-milliliter each containing approximately 300 mil- volumetric flask with 10 percent potas- ligrams. sium phosphate buffer, pH 6.0 (solution (b) The batch: 6), and further dilute with solution 6 to (1) For all tests except sterility: A the reference concentration of 10 units minimum of 15 immediate containers. of polymyxin B per milliliter (esti- (2) For sterility testing: 20 immediate mated). containers, collected at regular inter- (2) Sterility. Proceed as directed in vals throughout each filling operation. § 436.20 of this chapter, using the meth- (b) Tests and methods of assay—(1) Po- od described in paragraph (e)(3) of that tency. Proceed as directed in § 436.106 of section. this chapter, preparing the sample for (3) Moisture. Proceed as directed in assay as follows: Place an accurately § 436.201 of this chapter. weighed representative portion of the (4) Metal particles. Proceed as directed sample into a separatory funnel con- in § 436.206 of this chapter. taining approximately 50 milliliters of peroxide-free ether. Shake the sample [43 FR 11170, Mar. 17, 1978; 43 FR 34457, Aug. and ether until homogeneous. Add 20 to 4, 1978, as amended at 50 FR 19920, May 13, 1985] 25 milliliters of 0.1N hydrochloric acid and shake well. Allow the layers to § 446.381 Tetracycline hydrochloride separate. Remove the acid layer and re- ophthalmic dosage forms. peat the extraction procedure with each of 3 more 20- to 25-milliliter quan- § 446.381a Tetracycline hydrochloride tities of 0.1N hydrochloric acid. Com- ophthalmic ointment. bine the extractives in a suitable volu- (a) Requirements for certification—(1) metric flask and fill to volume with Standards of identity, strength, quality, 0.1N hydrochloric acid to obtain a and purity. Tetracycline hydrochloride stock solution of convenient con- ophthalmic ointment contains tetra- centration containing not less than 150 cycline hydrochloride in a suitable and micrograms of tetracycline hydro- harmless ointment base. Each gram chloride per milliliter (estimated). Fur- contains 10 milligrams of tetracycline ther dilute an aliquot with sterile dis- hydrochloride. Its potency is satisfac- tilled water to the reference concentra- tory if it contains not less than 90 per- tion of 0.24 micrograms of tetracycline cent and not more than 125 percent of hydrochloride per milliliter (esti- the number of milligrams of tetra- mated).
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(2) Sterility. Proceed as directed in assay as follows: Place an accurately § 436.20 of this chapter, using the meth- measured representative portion of the od described in paragraph (e)(3) of that sample into a high-speed glass blender section. jar with 1 milliliter polysorbate 80 and (3) Moisture. Proceed as directed in sufficient 0.1N hydrochloric acid to § 436.201 of this chapter. give a stock solution of convenient (4) Metal particles. Proceed as directed concentration containing not less that in § 436.206 of this chapter. 150 micrograms of tetracycline hydro- chloride per milliliter (estimated). [43 FR 11170, Mar. 17, 1978, as amended at 50 FR 19920, May 13, 1985] Blend for 3 to 5 minutes. Remove an al- iquot and further dilute with sterile § 446.381b Tetracycline hydrochloride distilled water to the reference con- ophthalmic suspension. centration of 0.24 microgram of tetra- (a) Requirements for certification—(1) cycline hydrochloride per milliliter (es- Standards of identity, strength, quality, timated). and purity. Tetracycline hydrochloride (2) Sterility. Proceed as directed in ophthalmic suspension contains tetra- § 436.20 of this chapter, using the meth- cycline hydrochloride in a suitable and od described in paragraph (e)(3) of that harmless oily base. Each milliliter con- section. (3) Moisture. Proceed as directed in tains 10 milligrams of tetracycline hy- § 436.201 of this chapter. drochloride. Its potency is satisfactory if it contains not less than 90 percent [43 FR 11171, Mar. 17, 1978, as amended at 46 and not more than 125 percent of the FR 46313, Sept. 18, 1981; 50 FR 19920, May 13, number of milligrams of tetracycline 1985] hydrochloride that it is represented to contain. It is sterile. Its moisture con- Subpart E—Otic Dosage Forms tent is not more than 0.5 percent. The tetracycline hydrochloride used con- § 446.467 Oxytetracycline hydro- forms to the standards prescribed by chloride-polymyxin B sulfate otic ointment. § 446.81a(a)(1). (2) Labeling. It shall be labeled in ac- (a) Requirements for certification—(1) cordance with the requirements of Standards of identity, strength, quality, § 432.5 of this chapter. and purity. Oxytetracycline hydro- (3) Requests for certification; samples. chloride-polymyxin B sulfate otic oint- In addition to complying with the re- ment is oxytetracycline hydrochloride quirements of § 431.1 of this chapter, and polymyxin B sulfate in a suitable each such request shall contain: and harmless ointment base. Each (i) Results of tests and assays on: gram of ointment contains oxytetra- (a) The tetracycline hydrochloride cycline hydrochloride equivalent to 5 used in making the batch for potency, milligrams of oxytetracycline and loss on drying, pH, absorptivity, crys- polymyxin B sulfate equivalent to tallinity, and identity. 10,000 units of polymyxin B. Its oxytet- (b) The batch for potency, sterility, racycline hydrochloride content is sat- and moisture. isfactory if it contains not less than 90 (ii) Samples required: percent and not more than 120 percent (a) The tetracycline hydrochloride of the number of milligrams of oxytet- used in making the batch: 10 packages, racycline that it is represented to con- each containing approximately 300 mil- tain. Its polymyxin B sulfate content is ligrams. satisfactory if it contains not less than (b) The batch: 90 percent and not more than 125 per- (1) For all tests except sterility: A cent of the number of units of poly- minimum of five immediate contain- myxin B that it is represented to con- ers. tain. Its moisture content is not more (2) For sterility testing: 20 immediate than 1 percent. The oxytetracycline containers, collected at regular inter- hydrochloride used conforms to the vals throughout each filling operation. standards prescribed by § 446.67(a)(1). (b) Tests and methods of assay—(1) Po- The polymyxin B sulfate used conforms tency. Proceed as directed in § 436.106 of to the standards prescribed by this chapter, preparing the sample for § 448.30(a)(1) of this chapter.
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(2) Labeling. It shall be labeled in ac- paring the sample for assay as follows: cordance with the requirements of Weigh accurately 0.5 to 1.0 gram of the § 432.5 of this chapter. ointment and place into a 15-milliliter (3) Requests for certification; samples. centrifuge tube. Add 10 milliliters of In addition to complying with the re- peroxide-free ether. Stir until contents quirements of § 431.1 of this chapter, are homogeneous and centrifuge for 10 each such request shall contain: minutes at 3,000 revolutions per (i) Results of tests and assays on: minute. Decant the supernatant ether. (a) The oxytetracycline hydro- Repeat washing and centrifugation chloride used in making the batch for steps once more. Add 10 milliliters of potency, loss on drying, pH, absorptiv- acetone, stir until contents are homo- ity, identity, and crystallinity. geneous, and centrifuge for 10 minutes (b) The polymyxin B sulfate used in at 3,000 revolutions per minute. Decant making the batch for potency, pH, loss the supernatant acetone. Repeat ace- on drying, residue on ignition, and tone wash and centrifugation once identity. more. Continue acetone washings until (c) The batch for oxytetracycline the yellow color in the residue dis- content, polymyxin B content, and appears. Add 3 to 4 drops of polysorbate moisture. 80 to the residue and mix well. Gently (ii) Samples required: wash the residue into a 100-milliliter (a) The oxytetracycline hydro- volumetric flask with 10 percent potas- chloride used in making the batch: 10 sium phosphate buffer, pH 6.0 (solution packages, each containing approxi- 6), and further dilute with solution 6 to mately 300 milligrams. the reference concentration of 10 units (b) The polymyxin B sulfate used in of polymyxin B per milliliter (esti- making the batch: 10 packages, each mated). containing approximately 300 milli- (2) Moisture. Proceed as directed in grams. § 436.201 of this chapter. (c) The batch: A minimum of six im- [43 FR 11171, Mar. 17, 1978, as amended at 50 mediate containers. FR 19920, May 13, 1985] (b) Tests and methods of assay—(1) Po- tency—(i) Oxytetracycline content. Pro- Subpart F—Dermatologic Dosage ceed as directed in § 436.106 of this chap- Forms ter, preparing the sample for assay as follows: Place an accurately weighed § 446.510 Chlortetracycline hydro- representative portion of the sample chloride ointment. into a separatory funnel containing ap- (a) Requirements for certification—(1) proximately 50 milliliters of peroxide- Standards of identity, strength, quality free ether. Shake the sample and ether and purity. Chlortetracycline hydro- until homogeneous. Add 20 to 25 milli- chloride ointment contains chlortetra- liters of 0.1N hydrochloric acid and cycline hydrochloride and one or more shake well. Allow the layers to sepa- suitable and harmless preservatives in rate. Remove the acid layer and repeat a suitable and harmless ointment base. the extraction procedure with each of Each gram contains 30 milligrams of three more 20- to 25-milliliter quan- chlortetracycline hydrochloride. Its tities of 0.1N hydrochloric acid. Com- potency is satisfactory if it is not less bine the acid extractives in a suitable than 90 percent and not more than 125 volumetric flask and fill to volume percent of the number of milligrams of with 0.1N hydrochloric acid to obtain a chlortetracycline hydrochloride that it stock solution of convenient con- is represented to contain. Its moisture centration containing not less than 150 content is not more than 0.5 percent. micrograms of oxytetracycline per mil- The chlortetracycline hydrochloride liliter (estimated). Further dilute an used conforms to the standards pre- aliquot of the stock solution with ster- scribed by § 446.10(a)(1). ile distilled water to the reference con- (2) Labeling. In addition to the label- centration of 0.24 microgram of oxytet- ing requirements prescribed by racycline per milliliter (estimated). § 432.5(a)(3) of this chapter, each pack- (ii) Polymyxin B content. Proceed as age shall bear on its label or labeling, directed in § 436.105 of this chapter, pre- as hereinafter indicated, the following:
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(i) On the label of the immediate con- § 446.542 Meclocycline sulfosalicylate tainer and on the outside wrapper or cream. container, if any: (a) Requirements for certification—(1) (a) The batch mark. Standards of identity, strength, quality, (b) The name and quantity of each and purity. Meclocycline active ingredient contained in the sulfosalicylate cream contains drug. meclocycline sulfosalicylate in a suit- (ii) On the label of the immediate able and harmless cream base. Each container or other labeling attached to gram contains meclocycline or within the package, adequate direc- sulfosalicylate equivalent to 10 milli- tions under which the layman can use grams of meclocycline. Its potency is the drug safely and efficaciously. satisfactory if it is not less than 90 per- cent and not more than 125 percent of (3) Requests for certification; samples. the number of milligrams of In addition to complying with the re- meclocycline that it is represented to quirements of § 431.1 of this chapter, contain. The meclocycline each such request shall contain: sulfosalicylate used conforms to the (i) Results of tests and assays on: standards prescribed by § 446.42(a)(1). (a) The chlortetracycline hydro- (2) Labeling. It shall be labeled in ac- chloride used in making the batch for cordance with the requirements of potency, loss on drying, pH, crystallin- § 432.5 of this chapter. ity, and identity. (3) Requests for certification; samples. (b) The batch for potency and mois- In addition to complying with the re- ture. quirements of § 431.1 of this chapter, (ii) Samples required: each such request shall contain: (a) The chlortetracycline hydro- (i) Results of tests and assays on: chloride used in making the batch: 10 (a) The meclocycline sulfosalicylate packages, each containing approxi- used in making the batch for potency, mately 60 milligrams. moisture, pH, and crystallinity. (b) The batch for potency. (b) The batch: A minimum of five im- (ii) Samples required: mediate containers: (a) The meclocycline sulfosalicylate (b) Tests and methods of assay—(1) Po- used in making the batch: 10 packages, tency. Proceed as directed in § 436.106 of each containing approximately 300 mil- this chapter, preparing the sample for ligrams. assay as follows: Place an accurately (b) The batch: A minimum of five im- weighed representative portion of the mediate containers. sample into a separatory funnel con- (b) Tests and methods of assay; po- taining approximately 50 milliliters of tency. Use either of the following meth- peroxide-free ether. Shake the sample ods; however, the results obtained from and ether until homogeneous. Add 20 to the high-pressure liquid chroma- 25 milliliters of 0.01N hydrochloric acid tography method shall be conclusive. and shake well. Allow the layers to (1) Microbiological turbidimetric assay. separate. Remove the acid layer and re- Proceed as directed in § 436.106 of this peat the extraction procedure with chapter, preparing the sample for assay each of three more 20- to 25-milliliter as follows: Place an accurately weighed quantities of 0.01N hydrochloric acid. representative portion of the sample Combine the extractives in a suitable into a high-speed glass blender jar con- volumetric flask and dilute to volume taining sufficient 0.01N methanolic hy- with 0.01N hydrochloric acid. Further drochloric acid (solution 13) to obtain a dilute an aliquot with sterile distilled stock solution of convenient con- water to the reference concentration of centration. Blend for 3 to 5 minutes. 0.06 microgram of chlortetracycline hy- Further dilute an aliquot of the stock drochloride per milliliter (estimated). solution with distilled water to the ref- erence concentration of 0.06 microgram (2) Moisture. Proceed as directed in of meclocycline per milliliter (esti- § 436.201 of this chapter. mated). [43 FR 11172, Mar. 17, 1978, as amended at 50 (2) High-pressure liquid chroma- FR 19920, May 13, 1985] tography. Proceed as directed in
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§ 436.329 of this chapter, except, prepare ing by hand. Shake for 15 minutes on a the working standard and sample solu- wrist action shaker. Quantitatively tion and calculate the meclocycline transfer the contents of the centrifuge content as follows: tube into a 50-milliliter volumetric (i) Preparation of standard solution. flask. Rinse the centrifuge tube with Accurately weigh an amount of work- two 5-milliliter portions of methanol ing standard equivalent to approxi- and add to the flask. Dilute to volume mately 25 milligrams of meclocycline with methanol and mix. Transfer a por- into a 50-milliter volumetric flask. Dis- tion of the content of the volumetric solve and dilute to volume with meth- flask into an appropriate-sized cen- anol and mix. Transfer exactly 2.0 mil- trifuge tube. Centrifuge for 5 minutes liliters of this solution to a 100-milli- liter volumetric flask, dilute to volume at 2,000 revolutions per minute. Trans- with mobile phase, and mix. fer 5.0 milliliters of this solution into a (ii) Preparation of sample solution. Ac- 50-milliliter volumetric flask and di- curately weigh approximately 0.4 to 0.7 lute to volume with mobile phase and gram of sample into a 50-milliliter mix. Filter this solution through a 0.5 glass-stoppered centrifuge tube. Add 20 micrometer filter. Inject the filtrate milliliters of methanol and 20 milli- onto the column as described in liters of 0.025N sulfuric acid. Disperse § 436.329(e) of this chapter. the sample thoroughly by a combina- (iii) Calculations. Calculate the tion of ultrasonic/vortexing and shak- meclocycline content as follows:
A ×2 × milligrams of working standard × Potency Meclocycline content = of working standard in micrograms per milligram of cream in percent B ×100 × milligrams of sample
where: cycline content is satisfactory if it is A=Area or peak height of the sample peak not less than 90 percent and not more (at a retention time equal to that ob- than 120 percent of the number of milli- served for the standard); B=Area or peak height of the standard peak. grams of oxytetracycline that it is rep- resented to contain. Its polymyxin B [46 FR 3837, Jan. 16, 1981; 46 FR 21361, Apr. 10, sulfate content is satisfactory if it is 1981, as amended at 47 FR 22515, May 25, 1982; 50 FR 1504, Jan. 11, 1985] not less than 90 percent and not more than 125 percent of the number of units § 446.567 Oxytetracycline hydro- of polymyxin B that it is represented chloride dermatologic dosage to contain. Its moisture content is not forms. more than 1 percent. The oxytetra- cycline hydrochloride used conforms to § 446.567a [Reserved] the standards prescribed by § 446.567b Oxytetracycline hydro- § 446.67(a)(1). The polymyxin B sulfate chloride-polymyxin B sulfate topi- conforms to the standards prescribed cal ointment. by § 448.30(a)(1). (a) Requirements for certification—(1) (2) Labeling. In addition to the label- Standards of identity, strength, quality, ing requirements prescribed by and purity. Oxytetracycline hydro- § 432.5(a)(3) of this chapter, each pack- chloride-polymyxin B sulfate topical age shall bear on its label or labeling ointment is oxytetracycline hydro- as hereinafter indicated, the following: chloride and polymyxin B sulfate in a (i) On the label of the immediate con- suitable and harmless ointment base. tainer and on the outside wrapper or Each gram contains oxytetracycline container, if any: hydrochloride equivalent to 30 milli- (a) The batch mark. grams of oxytetracycline and poly- (b) The name and quantity of each myxin B sulfate equivalent to 10,000 active ingredient contained in the units of polymyxin B. Its oxytetra- drug.
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(ii) On the label of the immediate ytetracycline per milliliter (esti- container or other labeling attached to mated). or within the package: Adequate direc- (ii) Polymyxin B content. Proceed as tions under which the layman can use directed in § 436.105 of this chapter, pre- the drug safely and efficaciously. paring the sample for assay as follows: (3) Requests for certification; samples. Weigh accurately 0.5 to 1 gram of the In addition to the requirements of ointment and place into a 15-milliliter § 431.1 of this chapter, each such re- centrifuge tube. Add 10 milliliters of quest shall contain: peroxide-free ether. Stir until contents (i) Results of tests and assays on: are homogeneous and centrifuge for 10 minutes at 3,000 revolutions per (a) The oxytetracycline hydro- minute. Decant the supernatant ether. chloride used in making the batch for Repeat washing and centrifugation potency, loss on drying, pH, absorptiv- steps once more. Add 10 milliliters of ity, identity, and crystallinity. acetone, stir until contents are homo- (b) The polymyxin B sulfate used in geneous, and centrifuge for 10 minutes making the batch for potency, loss on at 3,000 revolutions per minute. Decant drying, pH, residue on ignition, and the supernatant acetone. Repeat ace- identity. tone wash and centrifugation once (c) The batch for oxytetracycline more. Continue acetone washing until content, polymyxin B content, and the yellow color in the residue dis- moisture. appears. Add 3 to 4 drops of polysorbate (ii) Samples required: 80 to the residue and mix well. Gently (a) The oxytetracycline hydro- wash the residue into a 100-milliliter chloride used in making the batch: 10 volumetric flask with 10 percent potas- packages, each containing approxi- sium phosphate buffer, pH 6.0 (solution mately 300 milligrams. 6), and further dilute with solution 6 to (b) The polymyxin B sulfate used in the reference concentration of 10 units making the batch: 10 packages, each of polymyxin B per milliliter (esti- containing approximately 300 milli- mated). grams. (2) Moisture. Proceed as directed in (c) The batch: A minimum of six im- § 436.201 of this chapter. mediate containers. [43 FR 11172, Mar. 17, 1978, as amended at 50 (b) Tests and methods of assay—(1) Po- FR 19920, May 13, 1985] tency—(i) Oxytetracycline content. Pro- ceed as directed in § 436.106 of this chap- § 446.567c Oxytetracycline hydro- ter, preparing the sample for assay as chloride-polymyxin B sulfate topi- follows: Place an accurately weighed cal powder. representative portion of the sample (a) Requirements for certification—(1) into a separatory funnel containing ap- Standards of identity, strength, quality, proximately 50 milliliters of peroxide- and purity. Oxytetracycline hydro- free ether. Shake the ointment and chloride-polymyxin B sulfate topical ether until homogeneous. Add 20 to 25 powder is oxytetracycline hydro- milliliters of 0.1N hydrochloric acid chloride and polymyxin B sulfate with and shake well. Allow the layers to a suitable filler. Each gram contains 30 separate. Remove the acid layer and re- milligrams of oxytetracycline and peat the extraction procedure with 10,000 units of polymyxin B. Its oxytet- each of three more 20- to 25-milliliter racycline content is satisfactory if it is quantities of 0.1N hydrochloric acid. not less than 90 percent and not more Combine the acid extractives in a suit- than 120 percent of the number of milli- able volumetric flask and dilute to vol- grams of oxytetracycline that it is rep- ume with 0.1N hydrochloric acid to ob- resented to contain. Its polymyxin B tain a stock solution of convenient content is satisfactory if it is not less concentration containing not less than than 90 percent and not more than 120 150 micrograms of oxytetracycline per percent of the number of units of poly- milliliter (estimated). Further dilute myxin B that it is represented to con- an aliquot of the stock solution with tain. The loss on drying is not more sterile distilled water to the reference than 2.0 percent. The oxytetracycline concentration of 0.24 microgram of ox- hydrochloride used conforms to the
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standards prescribed by § 446.67. The tain a stock solution of convenient polymyxin B sulfate used conforms to concentration containing not less than the standards prescribed by 150 micrograms of oxytetracycline hy- § 448.30(a)(1) of this chapter. drochloride per milliliter (estimated). (2) Labeling. Each package shall bear Blend for 3 to 5 minutes. Remove an al- on its label or labeling, as hereinafter iquot of the stock solution and further indicated, the following: dilute with sterile distilled water to (i) On the label of the immediate con- the reference concentration of 0.24 tainer and on the outside wrapper or microgram of oxytetracycline per mil- container, if any: liliter (estimated). (a) The batch mark. (ii) Polymyxin content. Proceed as di- (b) The name and quantity of each rected in § 436.105 of this chapter, pre- active ingredient contained in the paring the sample for assay as follows: drug. Accurately weigh 1 gram of the powder (c) An expiration date that is 12 and place into a 50-milliliter centrifuge months after the month during which tube. Add 15 milliliters of acetone and the batch was certified, unless the use 1 drop of concentrated hydrochloric of a longer expiration period has been acid and stir well. Add 20 milliliters of approved in accordance with the provi- acetone and centrifuge for 10 minutes sions of § 432.5(a)(3) of this chapter. at 3,000 revolutions per minute. Decant (ii) On the label of the immediate the supernatant liquid and repeat the container or other labeling attached to acetone-acid extraction once more. or within the package, adequate direc- Dissolve and dilute the residue with tions for lay use of the drug. sufficient 10 percent potassium phos- (3) Requests for certification; samples. phate buffer, pH 6.0 (solution 6), to ob- In addition to the requirements of tain a stock solution of convenient § 431.1 of this chapter, each such re- concentration. Further dilute an ali- quest shall contain: quot of the stock solution with solu- (i) Results of tests and assays on: tion 6 to the reference concentration of (a) The oxytetracycline hydro- 10 units of polymyxin B per milliliter chloride used in making the batch for (estimated). potency, loss on drying, pH, absorptiv- ity, identity, and crystallinity. (2) Loss on drying. Proceed as directed (b) The polymyxin B sulfate used in in § 436.200(b) of this chapter. making the batch for potency, loss on [43 FR 11173, Mar. 17, 1978, as amended at 50 drying, pH, residue on ignition, and FR 19920, May 13, 1985] identity. (c) The batch for oxytetracycline § 446.581 Tetracycline hydrochloride content, polymyxin content, and loss dermatologic dosage forms. on drying. (ii) Samples required: §§ 446.581a—446.581b [Reserved] (a) The oxytetracycline hydro- chloride used in making the batch: 10 § 446.581c Tetracycline hydrochloride for topical solution. packages, each containing approxi- mately 300 milligrams. (a) Requirements for certification—(1) (b) The polymyxin B sulfate used in Standards of identity, strength, quality, making the batch: 10 packages, each and purity. Tetracycline hydrochloride containing approximately 300 milli- for topical solution is a dry mixture of grams. tetracycline hydrochloride, 4- (c) The batch: A minimum of six im- epitetracycline hydrochloride, and so- mediate containers. dium bisulfite packaged in combina- (b) Tests and methods of assay—(1) Po- tion with a suitable and harmless aque- tency—(i) Oxytetracycline content. Pro- ous vehicle. When reconstituted as di- ceed as directed in § 436.106 of this chap- rected in the labeling, each milliliter ter, preparing the sample for assay as contains 2.2 miligrams of tetracycline follows: Place an accurately weighed hydrochloride. The tetracycline hydro- representative portion of the sample chloride content of the reconstituted into a high-speed glass blender jar with solution is satisfactory if it contains sufficient 0.1N hydrochloric acid to ob- not less than 90 percent and not more
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than 130 percent of the number of milli- (b) Tests and methods of assay of the grams of tetracycline hydrochloride tetracycline hydrochloride for topical so- per milliliter that it is represented to lution—(1) Tetracycline hydrochloride contain. The 4-epitetracycline hydro- content and 4-epitetracycline hydro- chloride content is satisfactory if it chloride content. Proceed as directed in contains not less than 135 percent and § 436.340 of this chapter. not more than 165 percent of the (2) Loss on drying. Proceed as directed amount of tetracycline hydrochloride in § 436.200(a) of this chapter, except use in the reconstituted solution at the the contents of one immediate con- time of reconstitution. The loss on dry- tainer. ing of the dry mixture is not more than (3) pH. Proceed as directed in § 436.202 5.0 percent. When reconstituted as di- of this chapter, using the solution ob- rected in the labeling, its pH is not less tained when reconstituted as directed than 1.9 and not more than 3.5. The tet- in the labeling. racycline hydrochloride used conforms (c) Tests and methods of assay of the 4- to the standards prescribed by § 446.81a, epitetracycline hydrochloride used in except sterility, pyrogens, and hista- making the batch—(1) 4-epitetracycline mine. The 4-epitetracycline hydro- chloride used conforms to the following content and identity. Proceed as di- standards: It gives a positive identity rected in paragraph (b)(1) of this sec- test for 4-epitetracycline hydro- tion, except in lieu of § 446.581c(b)(1)(iv) chloride; its 4-epitetracycline content prepare the sample by weighing accu- ± is not less than 70 percent; its total rately 20 milligrams 5 milligrams of 4- anhydrotetracycline and 4- epitetracycline hydrochloride bulk epianhydrotetracycline content is not powder and transfer to a 25-milliliter more than 2.0 percent; its loss on dry- volumetric flask. Dissolve with 1.0 mil- ing is not more than 6.0 percent; its pH liliter of methyl alcohol and dilute to in an aqueous solution containing 10 volume with the buffer solution. Pipet milligrams per milliliter is not less a 2.0-milliliter aliquot to a 10-milliliter than 2.3 and not more than 4.0. volumetric flask and dilute to volume (2) Labeling. It shall be labeled in ac- with the buffer solution. Place the col- cordance with the requirements of umn in a suitable support. Place a 100- § 432.5 of this chapter. milliliter graduate under the column. (3) Requests for certification; samples. Open the column stopcock, pipet 2.0 In addition to complying with the re- milliliters of solution from the 10-mil- quirements of § 431.1 of this chapter, liliter volumetric flask onto the col- each such request shall contain: umn packing and allow the sample to (i) Results of tests and assays on: permeate the column packing. Place a (a) The tetracycline hydrochloride solvent reservoir containing 20 milli- used in making the batch for potency, liters of benzene on top of the column loss on drying, pH, absorptivity, and and begin to collect the eluate (at flow crystallinity. rate of approximately 1 milliliter per (b) The 4-epitetracycline hydro- minute). When the benzene level chloride used in making the batch for reaches the top of the column packing, 4-epitetracycline content and identity, replace the empty solvent reservoir total anhydrotetracycline and 4- with a second solvent reservoir con- epianhydrotetracycline content, loss taining 60 milliliters of chloroform and on drying, and pH. continue elution. When the chloroform (c) The batch for tetracycline hydro- level reaches the top of the column chloride content, 4-epitetracycline hy- packing, replace second empty solvent drochloride content, loss on drying, reservoir with a third solvent reservoir and pH. containing 50-milliliters of the n-buta- (ii) Samples required: nol:chloroform mixture and replace the (a) The tetracycline hydrochloride 100-milliliter graduate with a 10-milli- used in making the batch: 10 packages, liter graduate. Collect 8.0 milliliters of each containing approximately 300 mil- eluate. Replace the 10-milliliter grad- ligrams. uate with a 50-milliliter low-actinic (b) The batch: A minimum of six im- volumetric flask and continue collect- mediate containers. ing the eluate containing the 4-
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epitetracycline fraction until the col- standards prescribed by § 446.81(a)(1), umn runs dry. Determine the absorb- except 4-epianhydrotetracycline con- ance of the 4-epitetracycline eluate as tent. described in paragraph (b)(1)(v) of this (2) Labeling. In addition to the label- section. ing requirements prescribed by Calculate the 4-epitetracycline hy- § 432.5(a)(3) of this chapter, each pack- drochloride content of the 4- age shall bear on its label or labeling epitetracycline hydrochloride bulk as hereinafter indicated, the following: powder as follows: (i) On the label of the immediate con- tainer and on the outside wrapper or Percent by weight A ×25 × 10 × 50 × 100 container, if any: 4-epitetracycline = (a) The batch mark. content a× W ×2 × 2 (b) The name and quantity of each active ingredient contained in the where: A=Absorbance at 366 nanometers of the drug. low-actinic 50-milliliter volumetric (ii) On the label of the immediate flask. container or other labeling attached to a=Previously established mean absorptiv- or inserted within the package: Ade- ity of the tetracycline hydrochloride quate directions under which the working standard eluates in liters/ layperson can use the drug safely and gram/centimeter with the calculation efficaciously. corrected for potency. W=Weight of 4-epitetracycline hydro- (3) Requests for certification; samples. chloride bulk powder in milligrams. In addition to complying with the re- quirements of § 431.1 of this chapter, The identity of the 4-epitetracycline each such request shall contain: hydrochloride is confirmed if the ab- (i) Results of tests and assays on: sorbance of the sample after column (a) The tetracycline hydrochloride elution is such that the 4- used in making the batch for potency, epitetracycline hydrochloride content loss on drying, pH, absorptivity, crys- is greater than 70 percent by weight. tallinity, and identity. (2) Total anhydrotetracycline and 4- (b) The batch for potency and mois- epianhydrotetracycline content. Proceed ture. as directed in § 436.309 of this chapter. (ii) Samples required: (3) Loss on drying. Proceed as directed (a) The tetracycline hydrochloride in § 436.200(a) of this chapter. used in making the batch: 10 packages, (4) pH. Proceed as directed in § 436.202 each containing approximately 300 mil- of this chapter, using a solution con- ligrams. taining 10 milligrams per milliliter. (b) The batch: A minimum of six im- [42 FR 59066, Nov. 15, 1977; 43 FR 3705, Jan. 27, mediate containers. 1978, as amended at 48 FR 51291, Nov. 8, 1983; (b) Tests and methods of assay—(1) Po- 50 FR 19920, May 13, 1985] tency. Proceed as directed in § 436.106 of this chapter, preparing the sample for § 446.581d Tetracycline hydrochloride assay as follows: Place an accurately ointment. weighed representative portion of the (a) Requirements for certification—(1) sample into a separatory funnel con- Standards of identity, strength, quality, taining approximately 50 milliliters of and purity. Tetracycline hydrochloride peroxide-free ether. Shake the sample ointment contains tetracycline hydro- and ether until homogeneous. Add 20 to chloride in a suitable and harmless 25 milliliters of 0.1N hydrochloric acid ointment base. Each gram contains 30 and shake well. Allow the layers to milligrams of tetracycline hydro- separate. Remove the acid layer and re- chloride. Its potency is satisfactory if peat the extraction procedure with it contains not less than 90 percent and each of three more 20- to 25-milliliter not more than 125 percent of the num- quantities of 0.1N hydrochloric acid. ber of milligrams of tetracycline hy- Combine the acid extractives in a suit- drochloride that it is represented to able volumetric flask and fill to vol- contain. Its moisture content is not ume with 0.1N hydrochloric acid to ob- more than 1 percent. The tetracycline tain a stock solution of convenient hydrochloride used conforms to the concentration containing not less than
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150 micrograms of tetracycline hydro- potency, loss on drying, pH, absorptiv- chloride per milliliter (estimated). Fur- ity, identity, and crystallinity. ther dilute an aliquot of the stock solu- (b) The polymyxin B sulfate used in tion with sterile distilled water to the making the batch for potency, loss on reference concentration of 0.24 drying, pH, residue on ignition, and microgram of tetracycline hydro- identity. chloride per milliliter (estimated). (c) The batch for oxytetracycline (2) Moisture. Proceed as directed in content, polymyxin B content, and loss § 436.201 of this chapter. on drying. [43 FR 11174, Mar. 17, 1978 as amended at 44 (ii) Samples required: FR 30333, May 25, 1979. Redesignated at 45 FR (a) The oxytetracycline hydro- 16472, Mar. 14, 1980, and amended at 50 FR 19920, May 13, 1985] chloride used in making the batch: 10 packages, each containing approxi- Subpart G—Vaginal Dosage mately 300 milligrams. Forms (b) The polymyxin B sulfate used in making the batch: 10 packages, each § 446.667 Oxytetracycline hydro- containing approximately 300 milli- chloride-polymyxin B sulfate vagi- grams. nal tablets. (c) The batch: A minimum of 30 tab- (a) Requirements for certification—(1) lets. Standards of identity, strength, quality, (b) Tests and methods of assay—(1) Po- and purity. Oxytetracycline hydro- tency—(i) Oxytetracycline content. Pro- chloride-polymyxin B sulfate vaginal ceed as directed in § 436.106 of this chap- tablets are tablets composed of oxytet- ter, preparing the sample for assay as racycline hydrochloride and polymyxin follows: Place a representative number B sulfate with one or more suitable of tablets into a high-speed glass blend- diluents, binders, lubricants, and pre- er jar containing sufficient 0.1N hydro- servatives. Each tablet contains oxy- chloric acid to obtain a stock solution tetracycline hydrochloride equivalent of convenient concentration containing to 100 milligrams of oxytetracycline not less than 150 micrograms of oxytet- and polymyxin B sulfate equivalent to racycline per milliliter (estimated). 100,000 units of polymyxin B. Its oxy- Blend for 3 to 5 minutes. Remove an al- tetracycline content is satisfactory if iquot of the stock solution and further it is not less than 90 percent and not dilute with sterile distilled water to more than 120 percent of the number of the reference concentration of 0.24 milligrams of oxytetracycline that it is microgram of oxytetracycline per mil- represented to contain. Its polymyxin liliter (estimated). B content is satisfactory if it is not (ii) Polymyxin B content. Proceed as less than 90 percent and not more than directed in § 436.105 of this chapter, pre- 120 percent of the number of units of paring the sample for assay as follows: polymyxin B that it is represented to Grind a representative number of tab- contain. The loss on drying is not more than 3.0 percent. The oxytetracycline lets into a fine powder and place this hydrochloride used conforms to the powder, accurately weighed, into a fil- standards prescribed by § 446.67(a)(1). ter funnel with a solvent-resistant The polymyxin B sulfate used conforms membrane filter of 1.0 micrometer po- to the standards prescribed by rosity. Wash the powder with five 20- § 448.30(a)(1) of this chapter. milliliter portions of acetone or until (2) Labeling. It shall be labeled in ac- the yellow color has disappeared. Re- cordance with the requirements of move the filter and soak in 400 milli- § 432.5 of this chapter. liters of 10 percent potassium phos- (3) Requests for certification; samples. phate buffer, pH 6.0 (solution 6), and In addition to complying with the re- blend. Quantitatively transfer to a 500- quirements of § 431.1 of this chapter, milliliter volumetric flask and adjust each such request shall contain: to volume with solution 6. Further di- (i) Results of tests and assays on: lute an aliquot with solution 6 to the (a) The oxytetracycline hydro- reference concentration of 10 units of chloride used in making the batch for polymyxin B per milliliter (estimated).
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(2) Loss on drying. Proceed as directed polymyxin B sulfate hydrocortisone oph- in § 436.200(b) of this chapter. thalmic ointment. 448.321 Colistin sulfate for ophthalmic solu- [43 FR 11174, Mar. 17, 1978, as amended at 50 tion. FR 19920, May 13, 1985] 448.330 Polymyxin B sulfate-trimethoprim hemisulfate ophthalmic solution. Subpart H—Rectal Dosage Forms [Reserved] Subpart E—Otic Dosage Forms 448.421 Colistin sulfate-neomycin sulfate- Subpart I [Reserved] thonzonium bromide-hydrocortisone ace- tate otic suspension. Subpart J—Certain Other Dosage 448.430 Polymyxin B sulfate-hydrocortisone Forms [Reserved] otic solution. Subpart F—Dermatologic Dosage Forms PART 448—PEPTIDE ANTIBIOTIC DRUGS 448.510 Bacitracin dermatologic dosage forms. 448.510a Bacitracin ointment. Subpart A—Bulk Drugs 448.510b—448.510c [Reserved] Sec. 448.510d Bacitracin-neomycin sulfate oint- 448.10 Bacitracin. ment. 448.10a Sterile bacitracin. 448.510e Bacitracin–neomycin sulfate-poly- 448.13 Bacitracin zinc. myxin B sulfate ointment. 448.13a Sterile bacitracin zinc. 448.510f Bacitracin-polymyxin B sulfate top- 448.15a Sterile capreomycin sulfate. ical aerosol. 448.20a Sterile colistimethate sodium. 448.513 Bacitracin zinc dermatologic dosage 448.21 Colistin sulfate. forms. 448.23 Cyclosporine. 448.513a Bacitracin zinc-polymyxin B sul- 448.25 Gramicidin. fate ointment. 448.30 Polymyxin B sulfate. 448.513b Bacitracin zinc-neomycin sulfate 448.30a Sterile polymyxin B sulfate. ointment. 448.75 Tyrothricin. 448.513c Bacitracin zinc-neomycin sulfate- polymyxin B sulfate ointment; baci- Subpart B—Oral Dosage Forms tracin zinc-neomycin sulfate-polymyxin B sulfate hydrocortisone ointment. 448.121 Colistin sulfate for oral suspension. 448.123 Cyclosporine oral dosage forms. 448.513d Bacitracin zinc-polymyxin B sul- 448.123a Cyclosporine oral solution. fate topical powder. 448.123b Cyclosporine capsules. 448.513e Bacitracin zinc-polymyxin B sul- fate topical aerosol. Subpart C—Injectable Dosage Forms 448.513f Bacitracin zinc ointment. 448.210 Sterile bacitracin. Subpart G—Vaginal Dosage Forms 448.215 Sterile capreomycin sulfate. [Reserved] 448.220 Colistimethate sodium injectable dosage forms. Subparts H–I [Reserved] 448.220a Sterile colistimethate sodium. 448.223 Cyclosporine for infusion. Subpart J—Certain Other Dosage Forms 448.230 Sterile polymyxin B sulfate. 448.910 Bacitracin for prescription Subpart D—Ophthalmic Dosage Forms compounding. 448.310 Bacitracin ophthalmic dosage forms. 448.913 Bacitracin zinc for prescription compounding. 448.310a [Reserved] 448.310b Bacitracin-neomycin sulfate-poly- 448.930 Polymyxin B sulfate in certain other myxin B sulfate ophthalmic ointment. dosage forms. 448.310c Bacitracin ophthalmic ointment. 448.930a Polymyxin B sulfate for prescrip- 448.313 Bacitracin zinc ophthalmic dosage tion compounding. forms. 448.930b Sterile polymyxin B sulfate-benz- 448.313a Bacitracin zinc-polymyxin B sul- alkonium chloride urethral lubricant. fate ophthalmic ointment. AUTHORITY: 21 U.S.C. 357. 448.313b Bacitracin zinc-neomycin sulfate- polymyxin B sulfate ophthalmic oint- SOURCE: 39 FR 19115, May 30, 1974, unless ment; bacitracin zinc-neomycin sulfate- otherwise noted.
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