Handbook of Pharmaceutical Excipients
SIXTH EDITION
Edited by Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MlnstP Chief Scientist lntelligensys Ltd, Stokesley, North Yorkshire, UK
Paul J Sheskey BSc, RPh Application Development Leader The Dow Chemical Company, Midland, M( USA
Marian E Quinn BSc, MSc Development Editor Royal Pharmaceutical Society of Great Britain, London, UK
(l?P) London • Chicago Pharmaceutical Press Published by the Pharmaceutical Press An imprint of RPS Publishing
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© Pharmaceutical Press and American Pharmacists Association 2009
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First published 1986 Second edition published 1994 Third edition published 2000 Fourth edition published 2003 Fifth edition published 2006 Sixth edition published 2009
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ISBN 978 0 85369 792 3 (UK) ISBN 978 1 58 212 135 2 (USA)
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A ca talogue record for this book is available from the British Library Cellulose, Microcrystalline 129
14 Safety Sterotex K (Karlshamns Lipid Specialities), for example, is a Hydrogenated castor oil is used in oral and topical pharmaceutical mixture of hydrogenated castor oil and hydrogenated cottonseed formulations and is generally regarded as an essentially nontoxic oil. See Vegetable Oil, hydrogenated for further information. and nonirritant material. The EINECS number for hydrogenated castor oil is 232-292-2. Acute oral toxicity studies in animals have shown that hydrogenated castor oil is a relatively nontoxic material·. Irritation 19 Specific References tests with rabbits show that hydrogenated castor oil causes mild, transient irritation to the eye. 1 Kline CH. Thixcin R-thixotrope. Drug Cosmet Ind 1964; 95(6): 895- 897. LDso (rat, oral): > 10g/kg 2 Yonezawa Y et al. Release from or through a wax matrix system. III: Basic properties of release through the wax matrix layer. Chem Pharm 15 , Handling Precautions Bull (Tokyo) 2002; 50(6): 814-817. 3 Vergote GJ et al. An oral controlled release matrix pellet formulation Observe normal precautions appropriate to the circumstances and containing microcrystalline ketoprofen. Int J Phann 2002; 219: 81-87. quantity of material handled. 4 Danish FQ, Parrott EL. Effect of concentration and size of lubricant on flow rate of granules. J Pharm Sci 1971; 60: 752- 754. 16 Regulatory Status 5 Holzer AW, Sjogren]. Evaluation of some lubricants by the comparison Accepted in the USA as an indirect food additive. Included in the of friction coefficients and tablet properties. Acta Pharm Suec 1981; 18: 139-148. FDA Inactive Ingredients Database (oral capsules, tablets, and sublingual tablets). Included in nonparenteral medicines licensed in the UK. Included 20 General References in the Canadian List of Acceptable Non-medicinal Ingredients.
17 Related Substances 21 Author Castor oil; vegetable oil, hydrogenated. RT Guest. 18 Comments Various different grades of hydrogenated castor oil are commer 22 Date of Revision cially available, the composition of which may vary considerably. 11 February 2009.
Cellulose, Microcrystalline
1 Nonproprietary Names 5 Structural Formula BP: Microcrystalline Cellulose HO JP: Microcrystalline Cellulose PhEur: ,Cellulose, Microcrystalline '------0 USP-NF: Microcrystalline Cellulose
HO
,____ o 2 Synonyms Avicel PH; Cellets; Celex; cellulose gel; hellulosum microcristalli OH num; Celphere; Ceolus KG; crystalline cellulose; E460; Emcocel; Ethispheres; Fibrocel; MCC Sanaq; Pharmacel; Tabulose; Vivapur.
OH n/2
3 Chemical Name and CAS Registry Number Cellulose [9004-34-6]
4 Empirical Formula and Molecular Weight 6 Functional Category (C6H10Os),, ~ 36 000 Adsorbent; suspending agent; tablet and capsule diluent; tablet where n ~ 220. disintegrant.
···---- .. ~· -- ·------· ---~·~--·-· - --· 130 Cel lul ose, M ic rocrysta lli ne
, dv: Excipient: microcrystalline cellulose; manu facturer: JRS Pharma '" , Excipient: microcrystalline ce llulose (Avicel PH-I 05); LP; lot no. : 98662; magnification: 1OO x . manufacturer: FMC Biopolymer. magn ification: 500x ; voltage: 3 kV.
SEM 5: Excipient: microcrystalline cellulose (Avicel PH-200) ; manufacturer: FMC Biopolymer. magnification: 200x ; voltage: 3 kV.
!'!i~M 2: Excipient: microcrystalline cellulose (Avicel PH- I O 1); manufacturer: FMC Biopolymer. magnification: 200 x ; voltag e: 3 kV.
SEM 6: Excipient: microcrystalline cellulose {Avicel PH-302); manufacturer: FMC Biopolymer. magnification: 200x ; voltage: 3 kV.
SEM 3: Exci pient: microcrystalline cellulose (Avicel PH-I 02); manufacturer: FMC Biopolymer. magnification: 200x ; voltage: 3 kV.
7 Applications in Pharmaceutical Formulation or Technology Microcrystalline cellulose is widely used in pharmaceuticals, primarily as a binder/diluent in oral tablet and capsule formulations where it is used in both wet-granulation and direct-compression processesY- 7l In addition to its use as a binder/diluent, micro crystalline cellulose also has some lubricant( Bl and disintegrant properties that make it useful in tableting. ....
Cellulose, Microcrystalline 131
Microcrystalline cellulose is also used in cosmetics and food products; see Table I.
0) 8 Description __Q Microcrystalline cellulose is a purified, partially depolymerized .~ 0.0 l-'-"1-A,J--H+A-#11J\--J""-lnA-."r-f-+-l'---t-c-i=---I-H,,P'--I-I (!) cellulose that occurs as a white, odorless, tasteless, crystalline ""D powder composed of porous particles. It is commercially available ""D C in different particle sizes and moisture grades that have different ., , - .... ~ properties and applications. 2483 X ' 0 ' Table I: Uses of microcrystalline cellulose. 8 _,,·-- ' 2273 Use Concentration (%) 9 - 7. 0 ~~_,__----~-~~~_,__~----~~~_._...... - 0.2 Adsorbent 20- 90 1100 1300 1500 1700 1900 2100 2300 2500 Anti adherent 5-20 Wavelength/nm Capsule binder/diluenl 20- 90 Tablet disintegrant 5- 15 Tablet binder/diluent 20-90 Figure 1: Near-infrared spectrum of cellulose, microcrystalline measured ------··--·--·--·-----·------by reflectance.
3 1 1.420- 1.460 g/cm for Avicel PH-102.<1 ) 9 9 Pharmacopeial Specifications Flowability 1.41 g/s for Emcocel 90M_( ) See Table II. See also Section 18. Melting point Chars at 260-270°C. Moisture content Typically less than 5% w/w. However, different Tcibleli: Pharmacopeial specifications for microcrystalline cellulose. grades may contain varyinf amounts of water. Microcrystalline -- -- cellulose is hygroscopic .<1 2 See Table III. Test JP XV PhEur 6.3 USP32- NF27 1. ---· -···--·-·-·-- NIR spectra see Figure Identification + + + Particle size distribution Typical mean particle size is 20- 200 µm. Characters + + Different grades may have a different nominal mean particle size; pH 5.0-7.5 5.0-7.5 5.0-7.5 see Table Ill. Bulk density + + Solubility Slightly soluble in 5% w/v sodium hydroxide solution; Loss on drying ~:;7.0% ":;7.0% ,;; 7.0% practically insoluble in water, dilute acids, and most organic Residue on ignition ,;; 0.1 % ,;:; 0.1% solvents. Conductivii + + + Specific surfac e area Sulfated as ,;; 0.1 % 2 Ether-soluble substances ,;; 0.05% ,;; 0.05% ,;; 0.05% l.06-1.12 m /g for Avicel PH-101; Water-soluble substances + ,;; 0.25% ,;; 0.25% l.21- l.30m2/g for Avicel PH-102; Heavy metals ,;; JO ppm ,;; lOppm ,;; 0.001 % 0.78-1.18m2/g for Avicel PH-200. Microbial limits + + + Aerobic ,;; 103 cfu/g ,;; 103 cfu/g ,;; 103 cfu/g Molds and yeasts ,;; l02 cfu/g ,;; l 02 cfu/g ,;; 102 cfu/g 11 Stability and Storage Conditions Solubility + Microcrystalline cellulose is a stable though hygroscopic material. Particle size distribution - ---·------+ The bulk material should be stored in a well-closed container in a cool, dry place.
10 Typical Properties 12 Incompatibilities A ngle of repose Microcrystalline cellulose 1s incompatible with strong oxidizing 49° for Ceo/us KG; agents. 9 34.4° for Emcocel 90M _( ) Density (b ulk) 13 Method of Manufacture 3 0.337 g/cm ; Microcrystalline cellulose is manufactured by controlled hydrolysis 3 0.32g/cm for Avicel PH-101; (lOl with dilute mineral acid solutions of a-cellulose, obtained as a pulp 0.80 ± 5 g/cm3 for Cellets 100, 200, 350, 500, 700, 1000; from fibrous plant materials. Following hydrolysis, the hydro 3 9 cellulose is purified by filtration and the aqueous slurry is spray 0.29 g/cm for Emcocel 90M;( l dried to form dry, porous particles of a broad size distribution. 0.26-0.31 g/cm 3 for M CC Sanaq 101; 3 0.28-0.33 g/cm for MCC Sanaq 102; 14 Safety 3 0.29-0.36 g/cm for MCC Sanaq 200; Microcrystalline cellulose is widely used in oral pharmaceutical 3 0.34-0.45 g/cm for MCC Sanaq 301; formulations and food products and is generally regarded as a 0.35-0.46 g/cm3 for MCC Sanaq 302; relatively nontoxic and nonirritant material. 0.13-0.23 g/cm 3 for M CC Sanaq UL-002; Microcrystalline cellulose is not absorbed systemically fo ll owing 0.29 g/cm3 for Vivapur 101 . oral administration and thus has little toxic potential. Consumption Density (tapped) of large quantities of cellulose may have a laxative effect, although 3 this is unlikely to be a problem when cellulose is used as an excipient 0.478g/cm ; in pharmaceutical formulations. 3 0.45g/cm for Avice/ PH-101; Deliberate abuse of formulations containing cellulose, either by 3 9 0.35 g/cm for Erncocel 90M. ( I inhalation or br inj ec tion, has resulted in the fo rmation of cellul ose 3 3 Density (true) 1.512- 1.668 g/cm ; granulomas.<1 132 Cellu lose, Mic rocrys tallin e
Table Ill: Properties of selected commercially available grades of 16 Regulatory Status microcrystalline cellulose. GRAS lis ted. Acce pted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (inhalations; Grade Nominal Particle size analysis Moisture oral capsules, powders, suspensions, syrups, and tablets; topical and content (%) mean vaginal preparations). Included in nonparenteral medicines licensed particle size in the UK. Included in the Canadian List of Acceptable Non (11m) ·-· ··----- .. ----- Mesh size Amount medicinal Ingredients. retained (%)
Avice/ PH-IO 1 (a) 50 60 ,,:; 1.0 ,,:; 5.0 17 Related Substances 200 ,,:; 30.0 Microcrystalline cellulose and carrageenan; microcrystalline cellu Avice/ PH- I 02 (al 100 60 ,,:; 8.0 ,,:; 5.0 lose and carboxymethylcellulose sodium; microcrystalline cellulose 200 ;;, 45.0 and guar gum; powdered cellulose; silicified microcrystalline Avice/ PH-I 03 (a) 50 60 ,,:; 1.0 ,,:; 3.0 . 200 ,,:; 30.0 cellulose. Avicel PH- I 05 101 20 400 ,,:; 1.0 ,,:; 5.0 Microcrystalline cellulose and carrageenan Avice/ PH-112 (a) 100 60 ,,:; 8.0 ,,:; 1.5 Synonyms Lustre Clear. Avice/ PH-113 (al 50 60 ,,:; 1.0 ,,:; 1.5 Comments Lustre Clear (FMC Biopolymer) is an aqueous film 200 ,,:; 30.0 coating combining microcrystalline cellulose and carrageenan. Avice/ PH-200 (a) 180 60 ;;, 10.0 ,,:; 5 .0 100 ;;, 50.0 Microcrystalline cellulose and guar gum Avice/ PH-30 1 (a) 50 60 ,,:; 1.0 ,,:; 5.0 Synonyms Avicel CE -15. 200 ,,:; 30.0 Comments Avicel CE -15 (FMC Biopolymer) is a coprocessed Avice/ PH-302 (al 100 60 ,,:; 8.0 ,,:; 5.0 200 ;;, 45.0 mixture of microcrystalline cellulose and guar gum used in Ce/ex I OI (bl 75 60 ,,:; 1.0 ,,:; 5.0 chewable tablet fo rmula ti ons. 200 ;;, 30.0 Ceo/us KG-802 (cl 50 60 ,,:; 0.5 ,,:; 6.0 18 Comments 200 ,,:; 30.0 Em cocel 50M (di 50 60 ,,:; 0.25 ,,:; 5.0 Microcrystalline cellulose is one of the materials that have been 200 ,,:; 30.0 selected for harmonizati on by the Pharmacopeial Discussion Emcocel 90M (di 91 60 ,,:; 8.0 ,,:; 5.0 Group. For further information see the General Info rmation 200 ;;, 45.0 Chapter < 11 96> in the USP32- NF27, the General Chapter 5.8 MCC Sanaq 50 60 ,,:; 1.0 ,,:; 6.0 in PhEur 6.0, along with the 'State of Work' document on the PhEur 101 1•1 EDQM website, and also the General Information Chapter 8 in the 200 ,,:; 30.0 JPXV. MCC Sanaq 100 60 ,,:; 8.0 ,,:; 6.0 1 Several different grades of microcrysta lline cellulose are com 102 •1 5 16 mercially available that differ in their method of manufacture,!1 • > 200 ;;, 45.0 7 29 MCC Sanaq 180 60 ;;, 10.0 ,,:; 6.0 particle size, moisture, flow, and other physical properties .<1 - > 2001•1 The larger-particle-size grades generally provide better flow proper 100 ;;, 50.0 ties in pharmaceutical machinery. Low-moisture grades are used MCC Sanaq 50 60 ,,:; 1.0 ,,:; 6.0 with moisture-sensitive materials. Higher-density grades have 11 301 • improved flowability. 200 ;;, 30.0 Several coprocessed mi xtures of microcrystalline cellulose with MCC Sanaq 100 60 ,,:; 8.0 ,,:; 6.0 3021•) · other excipients such as carrageenan, carboxymethylcellulose 200 ;;, 45.0 sodium, and guar gum are commercially available; see Section 17. MCC Sanaq UL- 50 60 <0.5 ,,:; 6.0 Celphere (Asahi Kasei Corporation) is a pure spheronized 002!•) microcrystalline cellulose avail able in several different particle size 100 <5.0 ranges. Balocel Sanaq (Pharmatrans Sanaq AG) is an excipient used 200 <5.0-30.0 mainly in the production of pellets and granulates in direct Vivapur IO 1 !di 50 60 ,,:; 1.0 ,,:; 5.0 tableting, which contains lactose, microcrystalline cellulose, and 200 ,,:; 30.0 sodiµm carboxymethylcellulose. Vivapur 10 2 (dJ 90 60 ,,:; 8.0 ,,:; 5.0 200 ;;, 45.0 According to PhEur 6.3, microcrystalline cellulose has certain Vivapur 12 (di 160 38 ,,:; 1.0 ,,:; 5.0 functionality related characteristics that are recognised as being 94 ,,:; 50.0 relevant control parameters for one or more functions of the substance when used as an excipient. Non-mandatory testing Suppliers: procedures have been described for particle size distribution (2.9.31 (al FMC Biopolymer (bl International Specialty Products or 2.9.38) and powder fl ow (2.9.36). (cl Asahi Kasei Corporation A specification for microcrystalline cellulose is contained in the 130 (d) JRS Pharma Food Chemicals Codex (FCC). > The PubChem Compound ID (e) Pharmatrons Sanaq AG (CID) for microcrystalline cellulose is 14055602.
15 Handling Precautions 19 Specific References Observe normal precautions appropriate to the circumstances and 1 Enezian GM. [Direct compression of ta blets using microcrystalline quantity of material handled. Microcrystalline cellulose may be cellulose.] Pharm A cta He/v 1972; 47: 321-363[in French] . irritant to the eyes. Gloves, eye protection, and a dust mask a re 2 Lerk CF, Bolhuis GK. Comparative evaluation of excipients for direct recommended. In the UK, the workplace exposure limits -for compression I. Pharm .Weekb/ 1973; 108: 469-481. 3 3 Lerk CF et al. Comparative evaluation of excipients for direct cellulose have been set at 10 mr,m long-term (8 -hour TWA) for compression II. Pharm Weekbl 1974; 109: 945- 955. ~otal inhalable dust and 4 mg/m for respirable dust; the short-term 4 Lamberson RF, Raynor GE. Tableting properties of microcrystalline 3 4 limit for total inhalable dust has been set at 20 mg/m . (l J cellulose. M anuf Chem A erosol N ews 1976; 47(6): 55-61. Cellulose, Microcrystalline 133
5 Lerk CF et al. Effect of microcrystalline cellulose on liquid penetration 25 Hasegawa M. Direct compression: microcrystallinc ce llulose grade 12 in and disintegration of directly compressed tablets. J Pharm Sci 1979; versus classic grade 102. Pharm Technol 2002; 26(5): 50, 52, 54, 56, 68: 205-211. 58, 60. 6 Chilamkurti RN et al. Some studies on compression properties of tablet 26 Kothari SH et al. Comparative evaluations of powder and mechanical matrices using a computerized instrumented press. Drug Dev Ind properties of low crystallinity celluloses, microcrystalline celluloses, and Phann 1982; 8: 63-86. powdered celluloses. Int J Pharm 2002; 232: 69-80. 7 Wallace JW et al. Performance of pharmaceutical filler/binders as 27 Levis SR, Deasy PB. Production and evaluation of size-reduced grades related to methods of powder characterization. Pharm Technol 1983; of microcrystalline cellulose. int J Phann 2001; 213: 13-24. 7(9): 94-104. 28 Wu JS et al. A statistical design to eva luate the influence of 8 Omray A, Omray P. Evaluation of microcrystalline cellulose as a manufacturing factors on the material properties and functionalities glidant. Indian J Pharm Sci 1986; 48: 20-22. of microcrystalline cellulose. Eur J PharmSci 2001; 12: 417-425. 9 Celik M, Okutgen E. A feasibility study for the development of a 29 Suzuki T, Nakagami H. Effect of crystallinity of microcrystalline prospective compaction functionality test and the establishment of a cellulose on the compactability and dissolution of tablets. Eur J Pharm compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309- 2334. Biophann 1999; 47: 225-230. 10 Parker MD et al. Binder-substrate interactions in wet granulation 3: the 30 · Food Chemicals Codex, 6th edn. Bethesda, MD: United States effect of excipient source variation. Int J Pharm 1992; 80: 179-190. Pharmacopeia, 2008; 187. 11 Sun CC. True density of microcrystalline cel lulose. J Pharm Sci 2005; 94(10): 2132- 2134. 12 Callahan JC et al. Equilibrium moisture content of pharmaceutical 20 General References excipients. Drug Dev Ind Pharm 1982; 8: 355-369. Asahi Kasei Corporation. Ceo/us KG, Celphere. http://www.ceolus.com 13 Cooper CB et al. Cellulose granulomas in the lungs of a cocaine sniffer. (accessed 6 November 2008). Br Med J 1983; 286: 2021-2022. Doelker E. Comparative compaction properties of various microcrystalline 14 Health and Safety Executive. EH40/2005: Workplace Exposure Limits . cellulose types and generic products. Drug Dev Ind Pharm 1993; 19: Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ 2399-2471. coshh/tablel.pdf (accessed 5 February 2009). European Directorate for the Quality of Medicines and Healthcare 15 Jain JK et al. Preparation of microcrystallin e cellulose from cereal straw (EDQM). European Pharmacopoeia - State Of Work Of International and its evaluation as a tablet excipient. Indian J Pharm Sci 1983; 45: 83-85. Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.edq: m.eu/site/-6 14.html (accessed 5 February 2009). 16 Singla AK et al. Evaluation of microcrysta lline cellulose prepared from absorbent cotton as a direct compression ca rrier. Drug Dev Ind Pharm FMC Biopolymer. Problem Solver: Avicel PH, 2000. 1988; 14: 1131- 1136. International Specialty Products. Material Safety data sheet: Ce/ex 101, 17 Doelker E et al. Comparative tableting properties of sixteen micro 2003. crystalline celluloses. Drug Dev Ind Pharm 1987; 13: 1847-1875. JRS Pharma LP. Technical literature: Emcocel, 2003. 18 Bassam F et al. Effect of particle size and source on variability of Pharmatrans Sanaq AG. Product literature: Ce/lets. http://www.cellets.com Young's modulus of microcrystalline ce llulose powders. J Pharm (accessed 6 November 2008). Pharmacol 1988; 40: 68 P. Pharmatrans Sanaq AG. Product literature: MCC Sanaq. http://www.phar 19 Dittgen M et al. Microcrystalline cellulose in direct tabletting. Manu( matrans-sanaq.com/prod.html (accessed 6 November 2008). Chem 1993; 64(7): 17, 19, 21. Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. Boca 20 Landin M et al. Effect of country of origin on the properties of Raton, FL: CRC Press, 1992; 71-74. microcrystalline cellulose. Int J Pharm 1993; 91 : 123- 131. Staniforth JN et al. Effect of addition of water on the rheological and 21 Landin M et al. Effect of batch variation and source of pulp on the mechanical properties of microcrystalline celluloses. Int J Phann 1988; properties of microcrystal line cellulose. Int J Pharm 1993; 91: 133-141. 41: 231- 236. 22 Landin M et al. Influence of microcrysralline cellulose source and batch variation on tabletting behavior and stability of prcdnisone formula 21 Author tions. Int] Pharin 1993; 91: 143- 149. 23 Podczeck F, Revesz P. Evaluation of th e properties of microcrystalline A Guy. and microfine cellulose powders. /11t J Pham, 1993; 91: 183-193. 24 Rowe RC et al. The effect of batch and source variation on the 22 Date of Revision crystallinity of microcrystalline cellulose. /11t J Phann 1994; 101: 169- 172. 5 February 2009.
------·- ---·- ··-·-· Colloidal Silicon Dioxide 185
It has been shown that the increased force required to expel 18 Comments coconut oil from plastic syringes was due to uptake of the oil into A specification for coconut oil (unhydrogenated) is contained in the 3 the rubber plunger; this resulted in swelling of the rubber plunger Food Chemicals Codex (FCC)Y ) and an increased resistance to movement down the syringe barrel. (ll) 19 Specific References 1 Hung CF et al. The effect of oil components on the physicochemical 13 Method of Manufacture properties and drug delivery of emulsions: tocol emulsion versus lipid Coconut oil is the fixed oil obtained from the seeds of Cocos emulsion. Int J Pharm 2007; 335(1-2): 193-202. nucifera Linn. (Palmae). This oil is then refined to produce refined 2 Garti N, Arkad 0. Preparation of cloudy coconut oi l emulsions coconut oil, which is referred to in the coconut industry as RBD containing dispersed TiO2 using atomizer. J Dispersion Sci Technol (refined, bleached, and deodorized) coconut oil. 1986; 7(5): 513-523. 3 Fang JY et al. Lipid nano/submicron emulsions as delivery vehicles for topical flurbiprofen delivery. Drug De/iv 2004; 11(2): 97-105. 14 Safety 4 Nielsen HW et al. Intranasal administration of different liquid When administered orally, coconut oil is essentially nontoxic, formu lations of bumetanide to rabbits. Int J Pharm 2000; 204(1-2): although ingestion of large amounts may cause digestive or 35-41. gastrointestinal irritation or upset. Coconut oil can act as an 5 Tanabe K et al. Effect of different suppository bases on release of indomethacin. J Pharm Sci Technol Jpn 1984; 44: 115- 120. irritant when applied to the skin and when in contact with the eyes; 6 Broda H et al. Preparation and testing of suppositories with cep hradine it may be absorbed through the skin. Inhalati on of mist or vapor - evaluation of pharmaceutical availability and biological availability. may cause respiratory tract irritation. Farm Pol 1993; 49(11-12): 1-8. 7 Ogbolu DO et al. In vitro antimicrobial properties of of coconut oil on 15 Handling Precautions Candida species in Ibadan, Nigeria.] Med Food 2007; 10(2): 384-387. 8 Anonymous. Nitlotion. Pharm f 2000; 265: 345. Observe normal precautions appropriate to the circumstances and 9 Pajoumand A et al. Survival following severe aluminium phosphide quantity of the material handled. Coconut oil should be kept away poisoning. J Pharm Pract Res 2002; 32(4): 297-299. from heat and sources of ignition, and contact with oxidizing 10 Patel HR. Sales of coconut oil. Pharm J 1992; 249: 252. agents, acids, and alkalis should be avoided. 11 Todd RG, Wade A, eds. The Pharmaceutical Codex, 11th edn. London: If in the solid form, large spillages of coconut oil should be dealt Pharmaceutical Press, 1979; 214. with by shoveling the material into a waste disposal container. For 12 Dexter MB, Shott MJ . The eva luation of the force to expel oily injection liquid spillages, the oil should be absorbed with an inert material vehicles from syringes. J Pharm Pharmacol 1979; 31: 497-500. before removal for disposal. 13 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopiea, 2008; 222. 16 Regulatory Status 20 General References Included in the FDA Inactive Ingredients Database (oral capsules and tablets; topical creams, solutions, and ointments). Included in scalp ointments and therapeutic shampoos licensed i:n the UK. 21 Author 17 Related Substances CG Cable. Almond oil; canola oil; castor oil; castor oil, hydrogenated; corn oil; cottonseed oil; medium-chain triglycerides; olive oil; peanut oil; 22 Date of Revision sesame oil; soybean oil; sunflower oil. 27 February 2009.
Colloidal Silicon Dioxide
1 Nonproprietary Names 3 Chemical Name and CAS Registry Number BP: Colloidal Anhydrous Silica Silica (7631-86-9] JP: Light Anhydrous Silicic Acid PhEur: Silica, Colloidal Anhydrous 4 Empirical Formula and Molecular Weight
USP-NF: Colloidal Silicon Dioxide Si02 60.08
5 Structural Formula 2 Synonyms See Section 4. Aerosil; Cab-0-Sil; Cab-0-Sil M-SP; colloidal silica; fumed sili ca; fu med silicon dioxide; hochdisperses silicum dioxid; SAS; si lica 6 Functional Category colloidalis anhydrica; silica sol; silicic anhydride; silicon di oxide Adsorbent; anticaking age nt; emulsion stabilizer; glidant; suspend colloidal; silicon dioxide fumed; synthetic amorphous silica; ing agent; tablet disintegrant; thermal stabilizer; viscosity-increasing Wac ker HDK. agent.
It, ------.,.._.. .. _._ I
186 Collo idal Silicon Di oxide
7 Applications in Pharmaceutical Formulation or ~.; Exc ipient: colloidal silicon dioxide (Aerosil A-200); manufacturer: Technology Evoni k Degussa Corp. lot no.: 87A-1 (04 l 69C); magnification: 2400x ; voltage: 20 kV. Colloidal silicon dioxide is widely used in pharmaceuticals, cosmetics, and food products; see Table I. Its small particle size and large specific surface area give it desirable flow characteristics that are exploited to improve the flow properties of dry powders(l) 12 . in a number of processes such as tableting --4) and capsule filling. Colloidal silicon dioxide is also used to stabilize emulsions and as a thixotropic thickening and suspending agent in gels and semisolid preparations. (S) With other ingredients of similar refrac tive index, transparent gels may be formed. The degree of viscosity increase depends on the polarity of the liquid (polar liquids generally require a greater concentration of colloidal silicon dioxide than nonpolar liquids). Viscosity is largely independent of temperature. However, changes to the pH of a system may affect the viscosity; see Section 11. In aerosols, other than those for inhalation, co lloidal silicon dioxide is used to promote particulate suspension, eliminate hard settling, and minimize the clogging of spray nozzles. Colloidal silicon dioxide is also used as a tablet disintegrant and as an adsorbent dispersing agent for liquids in powders.( 61 Coll oidal silicon dioxide is frequently added to suppository fo rmulations containing lipophilic excipients to increase viscosity, prevent 7 81 sedimentation during molding, and decrease the releas e rate.( • Colloidal silicon dioxide is also used as an adsorbent during the 9 preparati on of wax microspheres / ) as a thickening agent for topical preparations;(lOJ and has been used to aid the fre eze-drying 9 Pharmacopeial Specifications of nanocapsules and nanosphere suspensions.(1 1 l See Table II. Sl'e also Section 18. Table I: Uses of colloidal silicon dioxide. Table II: Pharmacopeial specifications for colloidal si li con dioxide. Use Concentration (%) Test JP.XV PhEur 6.0 USP32-NF27 Aerosols 0.5-2.0 Emulsion stabilizer 1.0-5.0 Identification + + + Glidant 0. 1- 1.0 Characters + Suspending and thickening agent 2.0- 10.0 pH (4% w/v dispersion) 3.5-5.5 3.5-5.5 Arsenic .,:; 5ppm .,:; 8 µg/g Ch loride .,:; 0.011 % .,:; 250ppm 8 Description Heavy metals .,:; 40ppm .,:; 25ppm Colloidal silicon dioxide is a submicroscopic fumed silica with a Aluminum + particle size of about 15 nm. It is a light, loose, bluish-white-colored, Calcium + Iron .,:; 500ppm odorless, tasteless, amorphous powder. Loss on drying .,:; 7.0% .,:; 2.5% Loss on ignition .,:; 12.0% .,:; 5 .0% .,:; 2.0% Volum e test (5 g sample) ~ 70mL SEM 1: Excipient: colloidal silicon dioxide (Aerosil A-200); manufacturer: Assay (on ignited sample) ~ 98.0% 99.0-100.5% 99.0-100.5% Evonik Degussa Corp. lot no.: 87A-1 (04 l 69C); magnifi cation: 600x ; voltage: 20kV.
10 Typical Properties Acidity/alkalinity pH= 3.8-4.2 (4 % w/v aqueous dispersion) and 3. 5-4.0 (10 % w/v aqueous dispersion) for Cab-O-Sil M-SP Density (bulk) 0.029-0.042 g/cm3 Density (tapped) see Tables Ill, IV, and V. Melting point 1600°C 2 13 Moisture content see Figure 1Y • l Particle size distribution Primary particle size is 7- 16 nm. Aerosil forms loose agglomerates of 10-200 µm. See also Figure 2. Refractive index 1.46 Solubility Practically insoluble in organic solvents, water, and acids, except hydrofluoric acid; soluble in hot solutions of alkali hydroxide. Forms a colloidal dispersion with water. For Aerosil, solubility in water is 150 mg/L at 25°C (pH 7). Specific gravity 2.2 Specific surface area 100-400 m2/g depending on grade. See also Tables III, IV,and V. Several grades of colloidal silicon dioxide are commercially available, which are produced by modifying the manufactur ing process. The modifications do not affect the silica content, Colloidal Silicon Dioxide 187
80 Table Ill: Physical properties of Aerosil.
70 o Sorption Grade Specific surface area101 Density (tapped) (g/ cm3) • Desorption (m2 / g) 60 - 130 130 ± 25 0.05 ~ 130v 130 ± 25 0.1 2 ....Q) 200 200 ± 25 0.05 .2 50 200v 200 ± 25 0.12 ·a
80 Table V: Physical properties of Wacker HOK.
101 ~ 70 Grade Specific surface area Density (tapped) lg/ cm 3) (m2 / g) Q) N 60 1 S13 125 ± 15 0.05 'iii.... Q) V15 150 ± 20 0.05 > 50 - 0 N20 200 ± 30 0.04 ..:c 130 300 ± 30 0.04 0) ,10 140 400 ± 40 0.04 ' specific gravity, refractive index, color, or amorphous form. 13 Method of Manufacture However, particle size, surface areas, and densities are Colloidal silicon dioxide is prepared by the flame hydrolysis of affected. The physical properties of three commercially chlorosilanes, such as silicon tetrachloride, at 1800°C using a available colloidal silicon dioxides, Aerosil (Evonik Degussa hydrogen-oxygen flame. Rapid cooling from the molten state Corp.), Cab-O-Sil (Cabot Corporation), and Wacker HDK during manufacture causes the product to remain amorphous. (Wacker-Chemie GmbH) a re shown in Tables III, IV and V, respectively. 14 Safety 11 Stability and Storage Conditions Colloidal silicon dioxide is widely used in oral and topical · Colloidal silicon dioxide is hygroscopic but adsorbs large quantities pharmaceutical products and is generally regarded as an essentially of water without liquefying. When used in aqueous systems at a pH nontoxic and nonirritant excipient. H owever, intraperitoneal and 0-7.5, colloidal silicon dioxide is effective in increasing the viscosity subcutaneous injection may produce local tissue reactions and/or of a system. H owever, at a pH greater than 7.5 the viscosity granulomas. Colloidal silicon dioxide should therefore not be increasing properties of colloidal silicon dioxide are reduced; and at administered parenterally. a pH grea ter than 10.7 this ability is lost entirely since the silicon 16 4 ) dioxide dissolves to form silicates.'1 ) Colloidal silicon dioxide LD 50 (rat, IV): 0.015 g/kg' powder should be stored in a well-closed container. LD50 (rat, oral): 3.16 g/kg l 88 Coll oidal Si li con Dioxide 15 Handling Precautions 5 Daniels R et al. The sta bility of drug absorbates on silica. Drug Dev Ind Pharm 1986; 12: 2127-2156. Observe normal precautions appropriate to the circumstances and 6 Sherriff M, Enever RP. Rheological and drug release properties of oil quantity of material handled. Eye protection and gloves are gels containing colloidal silicon dioxide. J Pharm Sci 1979; 68: 842- recommended. Considered a nuisance dust, preca utions should be 845. taken to avoid inhalation of coll oidal silicon dioxide. In the absence 7 Tukker JJ, De Blaey CJ. The addition of colloidal silicon dioxide to of suitable containment facilities, a dust mask should be worn when suspension suppositories II. The impact ori in vitro release and handling small quantities of material. For larger quantities, a dust bioavailability. Acta Pharm Technol 1984; 30: 155-160. 8 Realdon N et al. Effects of silicium dioxide on drug release from V respirator is recommended. Inhalation of colloidal silicon di oxide dust may ca use irritation suppositories. Drug Dev Ind Pharm 1997; 23: 1025-1041. to the respiratory tract but it is not associated with fibrosis of the 9 Mani N et al. Microencapsulation of a hydrophilic drug into a hydrophobic matrix using a salting-out procedure. II. Effects of lungs (silicosis), which can occur upon exposure to crystalline silica. adsorbents on microsphere properties. Drug Dev Ind Pharm 2004; 30(1): 83-93. 16 Regulatory Acceptance 10 Gallagher SJ et al. Effects of membrane type and liquid/liquid phase GRAS listed. Included in the FDA Inactive Ingredients Database boundary on in vitro release of ketoprofen from gel formulations. J Drug Target 2003; 11(6): 373-379. (oral capsules, suspensions, and tablets; transdermal, rectal, and 11 Schaffazick SR et al. Freeze-drying polymeric colloidal suspensions: vaginal preparations). Also approved by the FDA as a food additive nanocapsules, nanospheres and nanodispersion. A comparative study. and for food contact. Included in nonparenteral medicines licensed Eur J Pharm Biopharm 2003; 56(3): 501-505. in the UK. Included in the Canadian List of Acceptable Non 12 Ettlinger M et al. [Adsorption at the surface of fumed silica.] Arch medicinal Ingredients. Pharm 1987; 320: 1- 15[in German]. 13 Callahan JC et al. Equilibrium moisture content of pharmaceutical 17 Related Substances excipients. Drug Dev Ind Pharm 1982; 8: 355-369. 14 Ca bot Corporation. Technical literature: Cab-O-Sil fumed silicas, the Hydrophobic colloidal si lica. performance additives, 1995. 15 Johansen H, MIiler N. Solvent deposition of drugs on excipients II : 18 Comments interpretation of dissolution, adsorption and absorption characteristics of drugs. Arch Pharm Chem Sci Ed 1977; 5: 33-42. Colloidal silicon dioxide is one of the materials that have been 16 Lewis RJ, ed. Sax's Dangerous Properties of In dustrial Materials, 11th selected for harmonization by the Pharmacopeial Discussion edn. New York: Wiley, 2004; 3205. Group. For further information see the General In formation 17 Kienholz M. [The behaviour of bacteria in highly pure silicic acid.] Chapter < 11 96 > in the USP32-NF27, the General Chapter 5.8 Pharm Ind 1970; 32: 677- 679[in German]. in PhEur 6.0, along with the 'State of Work' document on the PhEur 18 WR Grace & Co. Technical literature: Sy/aid 244FP, 2002. EDQM website, and also the General Information Chapter 8 in the JPXV. 20 General References The PhEur 6.0 also contains a specification for hydrated Cabot Corporation. Technical literature PDSl 71: Cab-O-Sil M-5P, 2006. colloidal silicon dioxide. The incidence of microbial contamination Evonik Degu~sa Corp. Technical Bulletin Fine Particles No. 11 TB0011-1: 17 of colloidal silicon dioxide is low' l due to the high production Basic characteristics of Aerosil fumed silica, 2006. temperatures and inorganic precursor materials. Evonik Degussa Corp. Technical literature TI 1281-1: Aerosil colloidal Note that porous silica gel particles may also be used as a silicon dioxide for pharmaceuticals, 2006. · glidant, thickener, dispersant and to adsorb moisture, which may be European Directorate for the Quality of Medicines and Healthcare an advantage for some formulations. Syloid 244FP meets the USP (EDQM). European Pharmacopoeia - State Of Work Of International NF requirements for silicon dioxide, and Syloid 244 FP -BU meets Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.edq m.eu/site/-614.html (accessed 3 Fe bruary 2009). the PhEur and JP requirements for silicon dioxide. (JS) Meyer K, Zimmermann I. Effect of glidants in binary powder mixtures . Another CAS number that is used for colloidal silicon dioxide is Powder Technol 2004; 139: 40-54. 112945-52-5. Wacker-Chemie GmbH. Technical literature: Wacker HDK fumed silica, The EINECS number for colloidal silicon dioxide is 231-545-4. 1998. The PubChem Compound ID (CID) for colloidal silicon dioxide is Waddell WW. Silica amorphous.Kirk-Othmer Encyclopedia of Chemical 24261. Technology, 5th edn, vol. 22: New York: John Wiley & Sons, 2001; 380-406. 19 Specific References Wagner E, Brunner H. Aerosil: its preparation, properties and behaviour in organic liquids. Angew Chem 1960; 72: 744-750. York P. Application of powder fai lure testing equipment in assessing Yang KY et al. Effects of amorphoun ilicon dioxides on drug dissolution. J effect of glidants on flowability of cohesive pharmaceutical powders. J Pharm Sci 1979; 68: 560-565. Pharm Sci 1975; 64: 121 6- 1221. Zimmermann I et al. Nanomaterials as flow regulators in dry powders. Z 2 Lerk CF et al. Interaction of lubricants and colloidal silica during Phys Chem 2004; 218: 51-102. mixing with excipients I: its effect on tabletting. Pharm Acta I-lelv 1977; 52: 33-39. 3 Lerk CF, Bolhuis GK. Interaction of lubricants and colloid al silica 21 Author during mixing with excipients II: its effect on wettability and dissol ution KP Hapgood. velocity. Pharm A cta Helv 1977; 52: 39-44. 4 Jonat S et al. Influence of compacted hydrophobic and hydrophilic colloidal silicon dioxide on tabletting properties of pharmaceutical 22 Date of Revision excipients. Drug Dev Ind Pharm 2005; 31: 687-696. 3 February 2009. 208 Crospovidone 4 Shangraw R et al. A new era of tablet disintegrants. Pharm Technol 13 Ferrero C et al. Disintegrating efficiency of crosca nnellose sodium in a 1980; 4(10): 49- 57. direct compression formulation. Int J Pharm 1997; 147: 11-21. 5 Zhao N, Augsburger LL The influence of product brand-to-brand 14 FAO/WHO. Evaluation of certain food additives and contaminants. variability on superdisintegrant performance. A case study with Thirty-fifth report of the joint FAO/WHO expert committee on food croscarmellose sodium. Pharm Dev Technol 2006; 11(2): 179-185. additives. World Health Organ Tech Rep Ser 1990; No. 789. 6 Zhao N, Augsburger LI. The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorthiazide from directly compressed tablets. AAPS Pharm Sci 20 General References Tech 2005; 6(1): E120- E126. DMV-Frontera Excipients. Product literature: Primellose and Primojel, 7 Battu SK et al. Formulation and evaluation of rapidly disintegrating fenoverine tablets: effects of superdisintegrants. Drug Dev Ind Pharm August 2008. 2007; 33(11): 1225-1232. European Directorate for the Quality of Medicines and Healthcare 8 Gordon MS, Chowhan ZT. Effect of tablet solubility and hygroscopi (EDQM). European Pharmacopoeia - State Of Work Of International city on disintegrant efficiency in direct compression tablets in terms of Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edq dissolution. J Pharm Sci 1987;76: 907-909. m.eu/site/-614.html (accessed 6 February 2009). 9 Gordon MS, Chowhan ZT. The effect of aging on disintegrant FMC Biopolymer. Material Safety Datasheet: A c-Di-Sol, May 2008. efficiency in direct compression tablets with varied solubility and JRS Pharma. Product literature: Vivasol. http://www.jrspharma.de/Pharma/ hygroscopicity, in terms of dissolution. Drug Dev Ind Pharm 1990; 16: wEnglisch/produktinfo/productinfo_vivasol.shtml (accessed 6 February 43 7-447. 2009). 10 Johnson JR et al. Effect of formulation solubility and hygroscopicity on disintegrant efficiency in tablets prepared by wet granulation, in terms of dissolution. J Pharm Sci 1991; 80: 469--471. 21 Author 11 Gordon MS et al. Effect of the mode of super disintegrant incorporation RT Guest. on dissolution in wet granulated tablets. J Pharm Sci 1993; 82(2): 220- 226. 12 Khattab I et al. Effect of mode of incorporation of disintegrants on the 22 Date of Revision characteristics of fluid -bed wet-granulated tablets. J Pharm Pharmacol 1993; 45(8): 687- 691. 6 February 2009. t:Y. Crospovidone 1 Nonproprietary Names 7 Applications in Pharmaceutical Formulation or BP: Crospovidone Technology PhEur: Crospovidone Crospovidone is a water-insoluble tablet disintegrant and dissolu tion agent used at 2- 5% concentration in tablets prepared by direct USP-NF: Crospovidone compression or wet- and dry-granulation methodsY-6) It rapidly exhibits high capillary activity and pronounced hydration capacity, 2 Synonyms with little tendency to form gels. Studies suggest that the particle size Crospovidonum; Crospopharm; crosslinked povidone; E1202; of crospovidone strongly influences disintegration of analgesic Kollidon CL; Kollidon CL-M; Polyplasdone XL; Polyplasdone tablets.m Larger particles provide a faster disintegration than XL-1 O; polyvinylpolypyrrolidone; PVPP; 1-vinyl-2-pyrrolidinone smaller particles. Crospovidone can also be used as a solubility homopolymer. enhancer. With the technique of co-evaporation, crospovidone can be used to enhance the solubility of poorly soluble drugs. The drug is adsorbed on to crospovidone in the presence of a suitable solvent 3 Chemical Name and CAS Registry Number and the solvent is then evaporated. This technique results in faster 1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8] dissolution rate. 4 Empirical Formula and Molecular Weight 8 Description (C6H9NO)n > 1000000 Crospovidone is a white to creamy-white, finely divided, free The USP32- NF27 describes crospovidone as a water-insoluble flowing, practically tasteless, odorless or nearly odorless, hygro synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidinone. An scopic powder. exact determination of the molecular weight has not been established because of the insolubility of the material. 9 Pharmacopeial Specifications See Table I. See also Section 18. 5 Structural Formula 10 Typical Properties See Povidone. Acidity/alkalinity _pH= 5.0- 8.0 (1 % w/v aqueous slurry) Density l .22 g/cm 6 Functional Category Density (bulk) see Table II. Tablet disintegrant. Density (tapped) see Table II. Crospovidone 209 sEM l : Excipient: crospovido_n_e (~olyplasdone XL-IO); manufacturer: ISP 4.0 0.2 =Cl<'. 22 0 Corp.; lot no.: S8 103 1; magn1f1cahon: 400 x ; voltage: 10 kV...... _ 2312 ... r...... • .,,, 1668 f 2353 ' •.,..i,. "- "" ...... t 0) 0 > ·.:::: ...... _cZ Q) 0.0 u . u . '' ,.' 0) C ._ 0 ~ ' , • • '2' 148 2367 X 2262 0 .. -- ' . 0 ' ._ ' - ' 2282 0 ' -- 1-692 0 193 ~ - 5.0 -0. 2 1100 1300 1500 1700 1900 2 100 2300 2500 W avelength/nm Figure 1: Near-infrared spectrum of crospovidone measured by reflecta nce. Table Ill: Specific surface areas for commercial grades of crospovidone. 2 Commercial grade Surface area (m / g) Kollidon CL 1.0 Kollidon CL-M 3.0-6.0 Polyplasdone XL 0.6-0.8 Table I: Pharmacopeial specifications for crospovidone. Polyplasdone XL-10 1. 2-1.4 Test PhEur 6.3 USP32- NF27 Identification + + 12 Incompatibilities Characters + Crospovidone is compatible with most organic and inorganic pH (1 % suspension) 5.0- 8.0 Water ,;; 5.0% pharmaceutical ingredients. When exposed to a high water level, Residue on ignition ,;; 0.1 % ,;; 0.4% crospovidone may form molecular adducts with some materials; see Water-solu ble substances ,;; l .0% ,;; 1. 50% Povidone. Peroxides ,;; 400 ppm Heavy metals ,;; l Oppm ,;; 0.001 % 13 Method of Manufacture Vinylpyrroli dinone ,;; l Oppm .;; O 1% Loss on drying ,;; 5.0% Acetylene and formaldehyde are reacted in the presence of a highl y Nitrogen content (a nhydrous basis) 11.0- 12 .8% + active catalyst to form butynediol, which is hydrogenated to butanediol and then cyclodehydrogenated to form butyrolactone. Pyrrolidone is produced by reacting butyrolactone with ammonia. Table II: Density values of commercial grades of crospovidone. This is followed by a vinylation reaction in which pyrrolidone and acetylene are reacted under pressure. The monomer vinylpyrroli 3 3 Commercial grade Density (bulk) (g/ cm ) Density (tapped~{ cm ) done is then polymerized in solution, using a catalyst. Crospovidone Kollidon CL 0.3- 0 .4 0 .4-0.5 is prepared by a 'popcorn polymerization' process. Kollidon CL-M 0 .15-0.25 0.3- 0.5 Polyplasdone XL 0.2 13 0 .273 14 Safety ~}yplosdone XL-10 0.323 0.461 Crospovidone is used in oral pharmaceutical formulations and is generally regarded as a nontoxic and nonirritant material. Short Moisture content Maximum moisture sorption is approximately term animal toxicity studies have shown no adverse effects 60%. associated with crospovidone.(Sl However, owing to the lack of NIR spectra see Figure 1. available data, an acceptable daily intake in humans has nor been Particle size distribution Less than 400 µm for Polyplasdone X L; specified by the WHO.l8l less than 74 ~Lm for Polyplasdone X L-10. Approximately 50% greater than 50 µm and maximum of 3% greater than 250 µmin LD 50 (mouse, IP): 12 g/kg size for Kollidon CL. Minimum of 90% of particles are below 15 µm for Kollidon CL-M. The average particle size for 15 Handling Precautions Crospopharm type A is 100 µm and fo r Crospopharm type B Observe normal precautions appropriate to the circumstances and it is 30 µm. quantity of material handled. Eye protection, gloves, and a dust Solubility Practically insoluble in water and most common mask are recommended. organic solvents. Specific surface area see Table III. 16 Regulatory Status Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (IM injections, oral ca psules and 11 Stability and Storage Conditions tablets; topical, transdermal, and vaginal preparations). Included in Since crospovidone is hygroscopic, it should be stored in an airtight nonparenteral medicines licensed in the UK. Included in the conta iner in a cool, dry place. Canadian List of Acceptable Non-medicinal Ingredients. 210 Cyclodextrins 17 Related Substances 7 Schiermeier S, Schmidt PC. Fast dispersible ibu profen tablets. Eur J Pharm Sci 2002; 15(3): 295- 305. Copovidone; povidone. 8 FAO/WHO. Evaluation of certain foo d additives and contaminants. Twenty-seventh report of the joint FAO/WHO expert committee on 18 Comments foo d additives. World Health Organ Tech Rep Ser 1983; No. 696. Crospovidone is one of the materials that have been selected for 9 Thibert R, Hancock BC. Direct visualization of superdisintegrant harmonization by the Pharmacopeial Discussion Group. For further hydration using environmental scanning electron microscopy. J Pharm information see the General Information Chapter < 1196> in the Sci 1996; 85: 1255-1258. USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 10 Caraballo I et al. Influence of disintegrant on the drug percolation 'State of Work' document on the PhEur EDQM website, and also threshold in tablets. Drug Dev Ind Pharm 1997; 23(7): 665-669. the General Information Chapter 8 in the JP XV. 11 Yen SY et al. Investigation of dissolution enhancement of nifedipine by Crospovidone has been studied as a superdisintegrant. The deposition on superdisintegrants. Drug Dev Ind Pharm 1997; 23(3): 313-317. ability of the compound to swell has been examined directly using 9 12 Hirai N et al. Improvement of the agitation granulation method to scanning electron microscopy.( l The impact of crospovidone on prepare granules containing a high content of a very hygroscopic drug. J percolation has also been examined. (l O) The impact of crospovidone Pharm Pharmacol 2006; 56: 1437-1441. on dissolution of poorly soluble drugs in tablets has also been 13 Food Chemicals Codex, 6th ed n. Bethesda, MD: United States investigatedY l l Crospovidone has been shown to be effective with Pharmacopeia, 2008; 794. highly hygroscopic drugs. (lZJ It continues to be examined for its uses in a number of tablet formul ations. A specification for crospovidone is contained in the Food 20 General References 3 Chemicals Codex (FCC).'1 l Barabas ES; Adeyeye CM. Crospovidone. Brittain HG, ed. Analytical The PubChern Compound ID (CID) for crospovidone is 6917. Profiles of Drug Substances and Excipients., vol. 24: London: Academic Press, 1996; 87-163. 19 Specific References BASF. Technical literature: Insoluble Ko llidon grades, 1996. Ko rn blum SS, Stoopak SB. A new tablet disintegrating agent: cross European Directorate for the Quality of Med icines and Healthcare linked polyvinylpyrrolidone. J Pharm Sci 1973; 62: 43-49. (EDQM). European Pharmacopoeia - State Of Work Of International 2 Rudnic EM et al. Stud ies of the utility of cross linked polyvinylpoly Harmonisation. Pharmeuropa 2009; 21( 1): 142- 143. http://www.edq pyrrolidine as a tablet disintegrant. Drug Dev Ind Pharm 1980; 6: 291- m.eu/site/-614.html (accessed 3 February 2009). 309. ISP. Technical literature: Polyplasdone crospovidone NF, 1999. 3 Gordon MS, Chowhan ZT. Effect of tablet solubility and hygroscopi NP Pharm. Product data sheet: Crospopharm, 2008. city on disintegrant efficiency in direct compression tablets in terms of Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int J Pharm dissolu tion. J Phann Sci 1987; 76: 907-909. 1989; 50: 147- 153 . 4 Gordon MS et al. Effect of the mode of super disintegrant incorporation on dissol ution in wet granulated tablets. J Pharm Sci 1993; 82: 220- 226. 21 Author 5 Tagawa M et al. Effect of various disintegrants on drug release AH Kibbe. behavior from tablets. J Pharm Sci Tech Yakuzaigaku 2003; 63 (4): 238- 248. 6 Hipasawa N et al. Application of nilvadipine solid dispersion to tablet 22 Date of Revision formu lation and manufacturing using crospovidone and methylcellu lose on dispersion carriers. Chem Pharm Bu/12004; 52(2): 244-247. 3 February 2009 . . ·St; Cyclodextrins 1 Nonproprietary Names y-Cyclodextrin Cavamax W8 Pharma; cyclooctaamylose; cyclo BP: Alfadex Betadex maltooctaose. PhEur: Alfadex Betadex USP-NF: Alfa dex Betadex Ga mma Cyclodextrin 3 Chemical Name and CAS Registry Number 4 He L et al. A novel conrrolled porosity osmotic pump system for sodium 21 Author ferulate. Pharmazie 2006; 61(12): 1022-1027. RT Guest. 20 General References 22 Date of Revision Wilson AS. Plasticisers - Principles and Practice. London: Institute of Materials, 1995. 5 February 2009. Ex Dibutyl Sebacate 1 Nonproprietary Names Table I: Pharmacopeial specifications for dibutyl sebacote. USP-NF: Dibutyl Sebacate Test USP32- NF27 2 Synonyms Specific gravity 0.935-0.939 Refractive index 1 .429-1 .44 1 Bis(n-butyl)sebacate; butyl sebacate; DBS; decanedioic acid, dibutyl Acid value ,s;: 0.1 ester; dibutyl decanedioate; dibutyl 1,8-octanedicarboxylate; Koda Saponification value 352-360 flex DBS; Morflex DBS. Assay (of C1 aH3404) ;,: 92.0% 3 Chemical Name and CAS Registry Number 10 Typical Properties Decanedioic acid, di-n-butyl ester (109-43-3] Acid value 0.02 Boiling point 344-349°C; 180°C at 3 mmHg for Morflex DBS. 4 Empirical Formula and Molecular Weight Flash point 193°C; 178°C (OC) for Morflex DBS. C18H34O4 314.47 Melting point -10°C 5 The USP32-NF27 describes dibutyl sebacate as consisting of the Refractive index n t = 1.4401 esters of n-butyl alcohol and saturated dibasic acids, principally Solubility Soluble in ethanol (95% ), ether, isopropanol, mineral sebacic acid. · oil, and toluene; practically insoluble in water. Speci-fi.c gravity 0.937 at 20°c Vapor density (relative) 10.8 (air = 1) 5 Structural Formula Vapor pressure 0.4kPa (3mmHg) at 180°C 0 0 II II 11 Stability and Storage Conditions H,C- (CH2l,-O- C- (C H2)8 - - C- O- (CH2J,-CH3 Dibutyl sebacate should be stored in a closed container in a cool, dry location. Dibutyl sebacate is stable under the recommended storage conditions and as used in specified applicati ons under most 6 Functional Category conditions of use. As an ester, dibutyl sebacate may hydrolyze in the presence of water at high or low pH conditions. Pla sticizer. 12 Incompatibilities 7 Applications in Pharmaceutical Formulation or Dibutyl sebacate is incompatible with strong oxidizing materials Technology and strong alkalis. Dibutyl sebacate is used in oral pharmaceutical formulations as a 13 Method of Manufacture plasticizer for film coatings on tablets, beads, and granules, at 2 concentrations of 10- 30% by weight of polymer.(1, ) It is also used Dibutyl sebacate is manufactured by the esterification of n-butanol as a plasticizer in controlled-release tablets and microcapsule and sebacic acid in the presence of a suitable catalyst, and by the 4 distillation of sebacic acid with n-butanol in the presence of preparations. (3, I concentrated acid. Dibutyl sebacate is also used as a synthetic flavor and flavor 151 adjuvant in food products; for example, up to 5 ppm is used in ice 14 Safety cream and nonalcoholic beverages. Dibutyl sebacate is used in cosmetics, foods, and oral pharrnaceu- . tical formulations, and is generally regarded as a nontoxic and 8 Description nonirritant material. Following oral administration, dibutyl seba Dibutyl sebacate is a clear, colorless, oily liquid with a bland to cate is metabolized in the same way as fats. In humans, direct eye slight butyl odor. contact and prolonged or repeated contact with the skin may cause very mild irritation. Acute animal toxicity tests and long-term animal feeding studies have shown no serious adverse effects to be 9 Pharmacopeial Specifications associated with orally administered dibutyl se bacate. 16 See Table I. LD 50 (rat, oral): 16 g/kg ) _let,,,___ _ ~--~---"··- ---- ·-··-·------228 Diethanolamine 1 5 Handling Precautions 3 Lee BJ et al. Controlled release of dual drug loaded hydroxypropyl methylcellulose matrix tablet using drug containing polymeric coatings. Observe normal precautions appropriate to the circumstances and Int J Pharm 1999; 188: 71-80. quantity of material handled. It is recommended that eye protection 4 Zhang ZY et al. Microencapsulation and characterization of tramadol be used at all times. When heating this product, it is recommended resin complexes. J Control Release 2000; 66: 107-113. to have a well-ventilated area, and the use of a respirator is advised. 5 FAO/WHO. Fifty-ninth report of the Joint FAO/WHO Expert Committee on Food Additives. Dibutyl sebacate, 2002. 16 Regulatory Status 6 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 1165. Included in the FDA Inactive Ingredients Database (oral capsules, granules, film-coated, sustained action, and tablets). Included in the 20 General References C::anadian List of Acceptable Non-medicinal Ingredients. Appel LE, Zentner GM. Release from osmotic tablets coated with modified 17 Related Substances Aquacoat lattices. Proc Int Symp Control Rel Bioact Mater 1990; 17: 335- 336. Morflex Inc. Technical literature: Morflex DBS, March 2005. Ozturk AG et al. Mechanism of release from pellets coated with an 18 Comments ethylf:ellulose-based film. J Control Release 1990; 14: 203-213. Rowe RC. Materials used in the film coating of oral dosage forms. Florence As dibutyl sebacate is an emollient ester, the personal care grade is AT, ed. Materials Used in Pharmaceutical Formulation: Critical Reports recommended for use in cosmetics, hair products, lotions, and on Applied Chemistry., vol. 6: Oxford: Blackwell Scientific, 1984; 1- 36. creams. Wheatley TA, Steurnagel CR. Latex emulsions for controlled drug delivery. The EINECS number for dibutyl sebacate is 203-672-5. The McGinity JC, ed. Aqueous Polymeric Coatings for Pharmaceutical PubChem Compound ID (CID) for dibutyl sebacate is 7986. Dosage Forms, 2nd edn. New York: Marcel Dekker, 1996; 13-41. 19 Specific References 21 Author 1 Goodhart FW et al. An evaluation of aqueous film-forming dispersions T Farrell. for controlled release. Pharm Technol 1984; 8(4): 64, 66, 68, 70, 71. 2 Iyer U et al. Comparative evaluation of three organic so lvent and 22 Date of Revision dispersion-based ethylcellulose coating formulations. Pharm Technol 1990; 14(9): 68, 70, 72, 74, 76, 78, 80, 82, 84, 86. 14 January 2009. Diethanolamine 1 Nonproprietary Names 7 Applications in Pharmaceutical Formulation or USP-NF: Diethanolamine Technology Diethanolamine is primarily used in pharmaceutical formulations as a buffering agent, such as in the preparation of emulsions with fatty 2 Synonyms acids. In cosmetics and pharmaceuticals it is used as a pH adjuster Bis(hydroxyethyl)amine; DEA; diethylolamine; 2,2'-dihydroxy and dispersant. diethylamine; diolamine; 2 ,2' -iminodiethanol. Diethanolamine has also been used to form the soluble salts of active compounds, such as iodinated organic acids that are used as contrast media. As a stabilizing agent, diethanolamine prevents the 3 Chemical Name and CAS Registry Number discoloration of aqueous formulations containing hexamethylene 2,2' -Iminobisethanol [111 -42-2] tetramine-1,3-dichloropropene salts. Diethanolamine is also used in cosmetics. 4 Empirical Formula and Molecular Weight C H NO 105.14 4 11 2 8 Description The USP32-NF27 describes diethanolamine as a mixture of 5 Structural Formula ethanolamines consisting largely of diethanolamine. At about H room temperature it is a white, deliquescent solid. Above room temperature diethanolamine is a clear, viscous liquid with a mildly HO~N~OH ammoniacal odor. 6 Functional Category 9 Pharmacopeial Specifications Alkalizing agent; emulsifying agent. See Table I. ------·~''----,-··· 346 lsopropyl Alcohol Ndindayino F etal. Direct compression properties of melt-extruded isomalt. 21 Authors Int J Pharm 2002; 235(1-2): 149-157. B Fritzsching, 0 Luhn, A Schoch. Ndindayino F et al. Bioavailability of hydrochlorothiazide from isomalt based moulded tablets. Int J Pharm 2002; 246: 199-202. O'Brien Nabors L, ed. Alternative Sweeteners: An Overview, 3rd ed n. New 22 Date of Revision York: Marcel Dekker, 2001; 553. 16 January 2009. lsopropyl Alcohol 1 Nonproprietary Names 8 Description BP: Isopropyl Alcohol Isopropyl alcohol is a clear, colorless, mobile, volatile, flammable JP: Isopropanol liquid with a characteristic, spirituous odor resembling that of a mixture of ethanol and acetone; it has a slightly bitter taste. PhEur: Isopropyl Alcohol USP: Isopropyl Alcohol 9 Pharmacopeial Specifications See T1h k I. 2 Synonyms Alcohol isopropylicus; dimethyl carbinol; IPA; isopropanol; petro Table I: Phormacopeiol specifico tions for isopropyl alcohol. hol; 2-propanol; sec-propyl alcohol; rubbing alcohol. Test JP XV PhEur 6.0 USP 32 ·--·····- -·------" 3 Chemical Name and CAS Registry Number Identification + + + Appearance of + + Propan-2-ol [67-63-0] solution Absorbance + 4 Empirical Formula and Molecular Weight Characters + Specific gravity 0.785-0.788 0.785-0.789 0.783- 0.787 C3HsO 60.1 Refractive index l .376- 1 .379 1.376-1 .378 Acidity or alka li nity + + + 5 Structural Formula Water .,; 0.75% .,; 0.5% Nonvolatlle residue .,; 1.0mg .,; 20ppm .,; 0.005% Distillation range 81-83°C H3CYOH Benzene + Peroxides + Assay ;,99.0% CH 3 10 Typical Properties Antimicrobial activity Isopropyl alcohol is bactericidal; at con 6 Functional Category centrations greater than 70% v/v it is a more effective Disinfectant; solvent. antibacterial preservative than ethanol (95% ). The bactericidal effect of aqueous solutions increases steadily as the concentra 7 Applications in Pharmaceutical Formulation or tion approaches 100% v/v. Isopropyl alcohol is ineffective Technology against bacterial spores. Autoignition temperature 425°C Isopropyl alcohol (propan-2-ol) is used in cosmetics and pharma Boiling point 82.4°C ceutical formulations, primarily as a solvent in topical formula Dielectric constant D20 = 18.62 tionsYl It is not recommended for oral use owing to its toxicity; see Explosive limits 2.5-12.0% v/v in air Section 14. 'flammability Flammable. Although it is used in lotions, the marked degreasing properties Flash point 11.7°C (closed cup); 13°C (open cup). The water of isopropyl alcohol may limit its usefulness in preparations used azeotrope has a fl ash point of l6°C. repeatedly. Isopropyl alcohol is also used as a solvent both for tablet Freezing point - 89.5°C film-coating and for tablet granulation,(2l where the isopropyl Melting point - 88.S°C alcohol is subsequently removed by evaporation. It has also been Moisture content 0.1-13% w/w for commercial grades (13% w/w shown to significantly increase the skin permeability of nimesulide corresponds to the water azeotrope). from carbomer 934_(3l Refractive index Isopropyl alcohol has some antimicrobial activity (see Section nf)0 = 1.3776; 10) and a 70% v/v aqueous solution is used as a topical disinfectant. nf:/ = 1.3749. Therapeutically, isopropyl alcohol has been investigated for the Solubility Miscible with benzene, chloroform, ethanol (95%), 4 treatment of postoperative nausea or vomiting. ( ) ether, glycerin, and water. Soluble in acetone; insoluble in salt lsopropyl Al cohol 347 solutions. Forms an azeotrope with water, containing 87.4% LDso (rat, IV): 1.09 g/kg w/w isopropyl alcohol (boiling point 80.37°C). LD50 (rat, oral): 5.05 g/kg Specific gravity 0.786 Vapor density (relative) 2.07 (air= 1) 1 5 Handling Precautions Vapor pressure -, 133.3Pa (lmmHg) at - 26.1°C; Observe normal precautions appropriate to the circumstances and quantity of material handled. Isopropyl alcohol may be irritant to 4.32kPa (32.4mmHg) at 20°C; the skin, eyes, and mucous membranes upon inhalation. Eye 5.33kPa (40mmHg) at 23.8°C; protection and gloves are recommended. Isopropyl alcohol should 13.33 kPa (100 mrnHg) at 39.5°C. be handled in a well-ventilated environment. In the UK, the long Viscosity (dynamic) 2.43 mPa s (2.43 cP) at 20°C term (8-hour TWA) workplace exposure limit for isopropyl alcohol is 999 mg/m3 (400 ppm); the short-term (15-minute) workplace 3 11 Stability and Storage Conditions exposure limit is 1250 mg/m (500 ppm). (lO) OSHA standards state Isopropyl alcohol should be stored in an airtight container in a cool, that IPA 8-hour time weighted average airborne level in the dry place. workplace cannot exceed 400 ppm. Isopropyl alcohol is fl ammable and produces toxic fumes on combustion. 12 Incompatibilities 16 Regulatory Status Incompatible with oxidizing agents such as hydrogen peroxide and nitric acid, which cause decomposition. Isopropyl alcohol may be Included in the FDA Inactive Ingredients Database (oral capsules, salted out from aqueous mixtures by the addition of sodium tablets, and topical preparations). Included in nonparenteral chloride, sodium sulfate, and other salts, or by the addition of medicines licensed in the UK. Included in the Canadian List of sodium hydroxide. Acceptable Non-medicinal Ingredients. 13 Method of Manufacture 17 Related Substances Isopropyl alcohol may be prepared from propylene; by the Propan-"1-ol. catalytic reduction of acetone, or by fermentation of certain Propan- 1-ol carbohydrates. Empirical formula C3HsO Molecular weight 60.1 14 Safety CAS number [71-23-8] Isopropyl alcohol is widely used in cosmetics and topical Synonyms Propanol; n-propanol; propyl alcohol; propylic alco- pharmaceutical formulations. It is readily absorbed from the hol. gastrointestinal tract and may be slowly absorbed through intact Autoignition temperature 540°C Boiling point 97.2°C · skin. Prolonged direct exposure of isoproprl alcohol to the skin may 25 result in cardiac and neurological deficits. 5l In neonates, isopropyl Dielectric constant D = 22.20 alcohol has been reported to cause chemical burns following topical Explosive limits 2.15-13.15% v/v in air 6 7 application. ' • ' Flash point 15°C (closed cup) Isopropyl alcohol is metabolized more slowly than ethanol, Melting point -127°C primarily to acetone. Metabolites and unchanged isopropyl alcohol Refractive index n io = 1.3862 are mainly excreted in the urine. Solubility Miscible with ethanol (95 % ), ether, and water. Isopropyl alcohol is about twice as toxic as ethanol and should Specific gravity 0.8053 at 20°C therefore not be administered orally; isopropyl alcohol also has an Viscosity (dynamic) 2.3 mPa s (2.3 cP) at 20°C unpleasant taste. Symptoms of is opropyl alcohol toxicity are similar Comments Propan-1-ol is more toxic than isopropyl alcohol. In to those for ethanol except that isopropyl alc ohol has no initial the UK, the long-term (8-hour TWA) exposure limit for propan- 3 euphoric action, and gastritis and vomiting are more prominent; see 1-ol is 500 mg/m (200 ~pm); the short-term (1 5-minute) Alcohol. Delta osmolality may be useful as ra pid screen test to exposure limit is 625 mg/m (250 ppm). (JO) identify patients at risk of complications from ingestion of isopropyl alcohol.rs, The lethal oral dose is estimated to be about 120-250 mL 18 Comments although toxic symptoms may be produced by 20 mL. A specification for isopropyl alcohol is contained in the Food Adverse effects following parenteral administration of up to Chemicals Codex (FCC).'1 n 20 mL of isopropyl alcohol diluted with water have included only a The EINECS number for isopropyl alcohol is 200-661 -7. The ~ensation of heat and a slight lowering of blood pressure. However, PubChem Compound ID (CID) for isopropyl alcohol is 3776. 1sopropyl alcohol is not commonly used in parenteral products. Although inhalation can ca use irritation and coma, the inhala tion of isopropyl alcohol has been investigated in therapeutic 19 Specific References applications.'3' 1 Rafiee Tehrani H, Mehramizi A. In vitro release studies of piroxicam . Isopropyl alcohol is most frequently used in topical pharmaceu from oil-in-water creams and hydroalcoholic gel topical formulations. 9 Drug Dev Ind Pharm 2000; 26(4): 409--414. tical formulations where it may act as a local irritant.< > When applied to the eye it can ca use corneal burns and eye damage. 2 Ruckmani K et al. Eudragit matrices for sustained release of ketorolac tromethamine: formulation and kinetics of release. Boll Chim Form 9 LD50 (dog, oral): 4.80 g/kg' ' 2000; 139: 205-208. LD (mouse, oral): 3.6 g/kg 3 Guengoer S, Bergisadi N. Effect of penetration enhancers on in vitro 50 percutaneous penetration of nimesulide through rat skin. Pharmazie LD5o (mouse, IP): 4.48 g/kg 2004; 59: 39---41. LD50 (mouse, IV): 1.51 g/kg 4 Merritt BA et al. Isopropyl alcohol inhalation: alternative trea tment of LD (rabbit, oral): 6.41 g/kg postoperative nausea and vomiting. Nurs Res 2002; 51(2): 125 - 128. 50 5 Leeper SC et al. Topical absorption of isopropyl alcohol induced cardiac LD50 (rabbit, skin): 12.8 g/kg neurological deficits in an adult female with intact skin. Vet Hum LD50 (rat, IP): 2.74 g/kg Toxicol 2000; 42: 15- 17. -··------·------~--~ -~~-,-=->I ''""' ··-::>"· -'~- .. 348 ls o propyl Myristate 6 Schick JB, Milstein JM. Burn hazard of isopropyl alcohol in the 20 General References neonate. Pediatrics 1981; 68: 587-588. 7 Weintraub Z, Iancu TC. Isopropyl alcohol burns. Pediatrics 1982; 69: 506. 8 Monaghan MS et al. Use of delta osmolality to predict serum isopropanol and acetone concentrations. Pharmacotherapy 1993; 13(1): 60-63. 21 Author 9 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th CP McCoy. edn. New York: Wiley, 2004; 2148-2149. 10 Health and Safety Executive. EH40/2005: Workplace Exposure Limits. Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ coshh/ta ble 1. pdf (accessed 5 February 2009). 22 Date of Revision 11 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 511. 5 February 2009. 6_ : lsopropyl Myristate 1 Nonproprietary Names actives; it is also used cosmetically in stable mixtures of water and 2 BP: Isopropyl Myristate glycerol. t > Isopropyl myristate is used as a penetration enhancer for PhEur: Is opropyl Myristate transdermal formulations, and has been used in conjunction with USP-NF: Isopropyl Myristate therapeutic ultrasound and iontophoresis.'3> It has been used in a water-oil gel prolonged-release emulsion and in various microemul 2 Synonyms sions. Such microemulsions mar increase bioavailability in topical 4 Esto/ IPM; H al/Star IPM-NF; isopropyl ester of myristic acid; and transdermal applications.( Isopropyl myristate has also been used in microspheres, and significantli increased the release of drug Isopropylm yristat; isopropylis myristas; Kessco IPM 95; Lexol 5 IPM-NF; myristic acid isopropyl ester; Rita IPM; Stepan IPM; from etoposide-loaded microspheres. > Isopropyl myristate is used in soft adhesives for pressure Super Refined Crodamol IPM; Tegosoft M; tetradecanoic acid, 1- 6 methylethyl ester; Waglinol 601 4. sensitive adhesive tapes.( ) Table I: Uses of isopropyl myristote. 3 Chemical Name and CAS Registry Number 1-Methylethyl tetradecanoate [110-27-0] Use Concentration (%) Detergent 0.003-0.03 4 Empirical Formula and Molecular Weight Otic suspension 0.024 Perfumes 0.5-2.0 C17H34O2 270.5 Microemulsions <50 Soap 0.03-0.3 5 Structural Formula Topical aerosols 2.0-98.0 Topical creams and lotions 1.0-10.0 8 Description Isopropyl myristate is a clear, colorless, practically odorless liquid of low viscosity that congeals at about 5°C. It consists of esters of propan-2-ol and saturated high molecular weight fatty acids, 6 Functional Category principally myristic acid. Emollient; oleaginous vehicle; skin penetrant; solvent. 9 Pharmacopeial Specifications 7 Applications in Pharmaceutical Formulation or See Table II. Technology Isopropyl myristate is a nongreasy emollient that is absorbed readily 10 Typical Properties by the skin. It is used as a component of semisolid bases and as a Boiling point 140.2°C at 266 Pa (2 mmHg) solvent for many substances applied topically. Applications in Flash point 153.5°C (closed cup) topical pharmaceutical and cosmetic formulations include bath oils; Freezing point ~s0 c make-up; hair and nail care products; creams; lotions; lip products; Solubility Soluble in acetone, chloroform, ethanol (95%), ethyl shaving products; skin lubricants; deodorants; otic suspensions; and acetate, fats, fatty alcohols, fixed oils, liquid hydrocarbons, vaginal creams; see Table I. For example, isopropyl myristate is a toluene, and waxes. Dissolves many waxes, cholesterol, or self-emulsifying component of a proposed cold cream formula,'1> lanolin. Practically insoluble in glycerin, glycols, and water. which is suitable for use as a vehicle for drugs or dermatological Viscosity (dynamic) 5-7 mPa s (5-7 cP) at 25°C lsopropyl Myristate 349 Table II: Pharmacopeial specifications for isopropyl myristale. 18 Comments Isopropyl myristate has been used in microemulsion templates to Test PhEur 6.0 USP32- NF27 produce nanoparticles as potential drug delivery vehicles for 11 12 Identification + + proteins and peptides. < , ) Characters + Isopropyl myristate 50% has been shown to be an effective 3 Appearance of solution + pediculicide for the control of head lice .<1 ) ::::, 0.853 Relative density 0.846-0.854 The EINECS number for isopropyl myristate is 203-751-4. The Refractive index l .434-1 .437 l .432-1 .436 Residue on ignition ~ 0.1 % ~ 0.1% PubChem Compound ID (CID) for isopropyl myristate is 8042. Acid value ~ 1.0 ~ l.O Saponification value 202-212 202-212 19 Specific References iodine value ~ 1.0 ~ 1.0 1 Jimenez SMM et al. Proposal and pharmacotechnical study of a modern Viscosity 5-6mPas Water ~ 0.1 % dermo-pharmaceutical formulation for cold cream. Boll Chim Farm Assay (as C17H340 2) ~ 90.0% ~ 90.0% 1996; 135: 364-373. 2 Ayannides CA, Ktistis G. Stabili ty estimation of emulsions of isopropyl myristate in mixtures of water and glycero l. J Cosmet Sci 2002; 53(3): 11 Stability and Storage Conditions 165-173. 3 Fang JY et al. Transdermal iontopheresis of sodium nonivaride acetate co Isopropyl myristate is resistant oxidation and hydrolysis, and III: combined effect of pretreatment by penetration enhancers. Int J does not become rancid. It should be stored in a well-closed Pharm 1997; 149: 183-195. container in a cool, dry place and protected from light. 4 Kogan A, Garti N. Microemulsions as transdermal delivery vehicles. Adv Colloid Interface Sci 2006; 123- 126: 369-385. 12 Incompatibilities 5 Schaefer MJ, Singh J. Effect of isopropyl myristic acid ester on the When isopropyl myristate comes into contact with rubber, there is a physical characteristics and in vitro release of etoposide from PLGA drop in viscosity with concomitant swelling and partial dissolution microspheres. AAPS Pharm Sci Tech 2000; 1(4): 32. of the rubber; contact with plastics, e.g. nylon and polyethylene, 6 Tokumura F et al. Properties of pressure-sensitive adhesive tapes with soft adhesives to human sk in and thei r mechanism. Skin Res Technol res ults in swelling. Isopropyl myristate is incompatible with hard 2007; 13(2): 211-216. paraffin, producing a granular mixture. It is also incompatible with 7 Stenback F, Shubik P. Lack of toxicity and carcinogenicity of some strong oxidizing agents. commonly used cutaneous agents. Toxicol Appl Pharmacol 1974; 30: 7-13. 13 Method of Manufacture 8 Opdyke DL. Monographs on fragrance raw materials. Fo od Cosmet Isopropyl myristate may be prepared either by the esterification of Toxicol 1976; 14(4): 307-338. myristic acid with propan-2-ol or by the reaction of myristoyl 9 Guillot JP et al. Safety evaluation of cosmetic raw materials. J Soc chloride and propan-2-ol with the aid of a suitable dehydrochlor Cosmet Chem 1977; 28: 377-393. inating agent. A high-purity material is also commercially available, 10 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 2164. produced by enzymatic esterification at low temperature. 11 Graf A et al. Protei n delivery using nanoparticles based on microemul sions with different structure types. Eur .I Pharm Sci 2008; 33(4-5): 14 Safety 43 4- 444. Isopropyl myristate is widely used in cosmetics and topical 12 Graf A et al. Microemulsions contai ning lecithin and sugar-based pharmaceutical formulations, and is generally regarded as a surfactant: nonparticle templates for delivery of proteins and peptides. 9 nontoxic and nonirritant material. (7- ) Int J Phann 2008; 350(1-2): 351- 360. 13 Kaul N et al. North American efficacy and safety of a novel pediculicide LDso (mouse, oral): 49.7 g/kg(l O) rinse, isopropyl myristate 50% (results). J Cutan Med Surg 2007; 11(5 ): LD 50 (rabbit, skin): 5 g/kg 161- 167. 15 Handling Precautions 20 General References Observe normal precautions appropriate to the circumstances and Fitzgerald JE et al. Cuta neous and parenteral studies with vehicles quantity of material handled. containing isopropyl myristate and peanut oil. Toxicol Appl Phannacol 1968; 13: 448-453. 16 Regulatory Status Nakhare S, Vyas SP. Prolonged release of rifampicin from internal phase of multiple w/o/w emulsion systems. Indian] Phann Sci 1995; 57: 71-77. Included in the FDA Inactive Ingredients Database (otic, topical, transdermal, and vaginal preparations). Used in nonparenteral 21 Author medicines licensed in the UK. Included in the Canadian List of Acce ptable Non-medicinal Ingredients. AK Taylor. 17 Related Substances 22 Date of Revision Isopropyl palmitate. 28 January 2009. h Lactose, Anhydrous 1 Nonproprietary Names See also Lactose, Inhalation; Lactose, Monohydrate; Lactose, BP: Anhydrous Lactose Spray-Dried. JP: Anhydrous Lactose 8 Description PhEur: Lactose, Anhydrous Anhydrous lactose occurs as white to off-white crystalline particles USP-NF: Anhydrous Lactose or powder. :Several different brands of anhydrous lactose are commercially available which contain anhydrous P-lactose and 2 Synonyms anhydrous a-lactose. Anhydrous lactose typically contains 70-80% Anhydrous 60M; Anhydrous Direct Tableting (DT); Anhydrous anhydrous P-lactose and 20-30% anhydrous a-lactose. DT High Velocity; Anhydrous Impalpable; Lactopress Anhydrous; Lactopress Anhydrous 250; lactosum anhydricum; lattosio; milk 9 Pharmacopeial Specifications sugar; SuperTab 21AN; SuperTab 22AN; saccharum lactis. See Table I. See also Section 18. 3 Chemical Name and CAS Registry Number 10 Typical Properties O-P-D-Galactopyranosyl-( 1 ---->4 )-P-D-glucopyranose [63-42-3) Brittle fracture index 0.0362 Bonding index 0.0049 (at compression pressure 177.8 MPa ) OH Anhydrous a-lactose ~ H ~O OH OH Anhydrous ~-lactose The PhEur 6.5 and USP32-NF27 describe anhydrous lactose as O SEM 2: Excipient: Super Tab 22AN; manufacturer: DMV-Fonterra P-o-galactopyranosyl-(l- ->4 )-P-o-glucopyranose; or a mixture of Excipients; magnification: 55 x ; voltage: 1.5 kV. O-P-D-galactopyranosyl-( 1- ->4 )-a-D-glucopyranose and O-P-D ~.--.'.""'.tr--;'."""'_.,.="'----~ galactopyranosyl-( 1--+ 4 )-P-D-glucopyranose. The JP XV describes anhydrous lactose as P-lactose or a mixture of P-lactose and a - lactose, and defines these as per the PhEur and USP- NF. 6 Functional Category Directly compressible tablet excipient; dry powder inhaler carrier; lyophilization aid; tablet and capsule diluent; tablet and capsule filler. 7 Applications in Pharmaceutical Formulation or Technology Anhydrous lactose is widely used in direct compression ta bleting applications, and as a tablet and capsule fill er and binder. Anhydrous lactose can be used with moisture-sensitive drugs due to its low moisture content. It may also be used in intravenous injections. 359 360 La ctose, Anhydrous 1.0 ~------, 0 .5 Table I: Pharmocopeiol specifications for lactose anhydrous. Test JP XV PhEur 6.5 USP32-NF27 Identi fica ti on + + + Ahpearance/color of solution + + + o? C oracters + ...... __ Optical rotation +54.4° lo + 54.4° to + 54.4° to 0) +55.9° + 55 .9° + 55.9° 0 Acid ity or a lka lini ty + + + Heavy meta ls ,;; 5ppm ,;; 5ppm ,;; 5 µg/g X \ '2 369 Protein and li ght absorbing + + 23 14 impu rities/subs tances 0 0 · 290 Absorbance 0 2264 2 10-220nm ..; 0 .25 ..; 0.25 ..; 0.25 ~ - l .2 .__..__...,__....__.___,__....__. ____ ....._..___.__...... __.__. -0. 2 270- 300nm ..; 0 .07 ..; 0.07 ..; 0.07 11 00 1300 1500 1700 1900 2 100 2300 2500 400nm ..; 0.04 ~ 0.04 ..; 0.04 Loss on drying ..; 0.5% + la) ..; 0 .5% W avelength / nm Water ..; 1.0% ,;; 1.0% ~ l .0% Residue on ig nition ..; 0. 1% ~ 0.1 % Figure 1: Near-infrared spectrum of lactose a nhydrous measured by Sulfa ted ash ..; 0.1 % reflecta nce. Microbial limit 2 Aerobic bacte ri a ..; l00 cfu/g l0 cfu/g ~ l00cfu/g Fungi ond rost ,;; 50cfu/g ~ 50cfu/g 12. At 80°C and 80% RH, tablets containing anhydrous lactose 12 Absence o Escherichia coli + + + have been shown to expand 1.2 times after one day. ) Absence of Salmonella + Lactose anhydrous should be stored in a well-closed container in +lo) Isomer rati o + + a cool, dry place. (al Not o mandatory fest. 12 Incompatibilities Density (tapped) 0.88 g/cm3 for SuperTab 21AN; 0. 78 g/cm3 for Lactose anhydrous is incompatible with strong oxidizers. When Super-Tab 22AN. mixtures containing a hydrophobic leukotriene antagonist and M elting point anhydrous lactose or lactose monohydrate were stored for six 223.0°C for anhydrous ex-lactose; weeks at 40°C and 75% RH, the mixture containing anhydrous lactose showed greater moisture uptake and drug degradation.13) 252.2°C for anhydrous ~-lactose; Studies have also shown that in blends of roxifiban acetate 232.0°C (typical) for commercial anhydrous lactose. (DMP-7 54) and lactose anhydrous, the presence of lactose NIR spectra see Figure 1. anhydrous accelerated the hydrolysis of the ester and amidine Particle size distribution see Table II. groups.14 ) Permanent deformation pressure 521.0 MPa (at compression Lactose anhydrous is a reducing sugar with the potential to pressure 177.8 MPai 1l interact with primary< 5l and secondary amines16l (Maillard reaction) Reduced modulus of elasticity 5315 (at compression pressure when stored under conditions of high humidity for extended 177.8 MPa)11 l periods. Solubility Soluble in water; sparingly soluble in ethanol (95%) and ether; 40 g/100 ml at 25°C for typical Sheffie ld Pharma See Lactose, Monohydrate. Ingredients products. Specific rotation [o:Jf,5 = 54.4° to 55.9° 13 Method of Manufacture Tensile strenr;;h 2.577 MPa (at compression press ure There are two anhydrous fo rms of lactose: ex-lactose and P-lactose. 177.8 MPa)1 l Methods for characterizing the mechanical The temperature of crystallization influences the ratio of o:- and ~ properties of compacts of pharmaceutical ingredients are specified lactose. The anhydrous forms that are commercially available may in the Handbook of Pharmaceutical Excipients, 3rd ednYl exhibit hygroscopicity at high relative humidities. Anhydrous lactose is produced by roller drying a solution of lactose above 93.5°C. The resulting product is then milled and sieved. Two 11 Stability and Storage Conditions anhydrous ex-lactoses can be prepared using special drying M old growth may occur under humid conditions (80% RH and techniques: one is unstable and hygroscopic; the other exhibits above). Lactose may develop a brown coloration on storage, the good compaction properties. 17) However, these materials are not reaction being accelerated by warm, damp conditions; see Section commercially available. ., Table II: Particle size distribution of selected commercially available anhydrous lactose. Supplier/ grade Percentage less than stated size ------<45µm <53µm < 150µm <250 µm DMV-Fonterra Excipients Super Tab 2 1AN ~ 20 40- 65 ;;. BO su erTab 22AN ~ 7 25-50 ;;. 65 Fries 10and Foods Domo Lactopress Anhydrous ..; 30 ;;. 80 Lactopress Anhydrous 250 ~ 20 40-65 ;;. 80 Lactose, Anhydrous 361 14 Safety monohydrate with tablets containing anhydrous lactose. Pharm Dev Technol 2001; 6(2): 159-166. Lactose is widely used in pharmaceutical formulations as a diluent 3 Jain R et al. Stability of a hydrophobic drug in presence of hydrous and and filler-binder in oral capsule and tablet formulations. It may also anhydrous lactose. Eur J Pharm Biopharm 1998; 46: 177-182. be used in intravenous injections. Adverse reactions to lactose are 4 Badawy SI et al. Effect of different acids on solid state stability of an largely due to lactose intolerance, which occurs in individuals with a ester prodrug of a Ilb/II!a glycoprotein receptor antagonist. Pharm Dev deficiency of the intestinal enzyme lactase, and is associated with Technol 1999;4: 325-331. oral ingestion of amounts well over those found in solid dosage 5 Castello RA, Mattocks AM. Discoloration of tablets containing amines forms. and lactose. J Pharm Sci 1962; 51: 106-108. See Lactose, Monohydrate. 6 Wirth DD et al. Maillard reaction of lactose and fluoxetine hydrochloride, a secondary amine.] PharmSci 1998; 87: 31-39. 15 Handling Precautions 7 Lerk CF et al. Increased binding capacity and flowability of alpha lactose monohydrate after dehydration. J Pharm Pharmacol 1983; Observe normal precautions appropriate to the circumstances and 35(11): 747- 748. quantity of materials handled. Excessive generation of dust, or 8 Heng PW et al. Investigation of the influence of mean HPMC particle inhalation of dust, should be avoided. size and number of polymer particles on the release of aspirin from swellable hydrophilic matrix tablets. J Control Release 2001; 76(1-2): 16 Regulatory Status 39-49. 9 Larhrib H et al. The use of different grades of lactose as a carrier for GRAS listed. Included in the FDA Inactive Ingredients Database aerosolized salbutamol sulphate. Int J Pharm 1999; 191(1): 1-14. (IM, IV: powder for injection solution; IV and sublingual prepara 10 Vanderbist Fetal. Optimization of a dry powder inhaler formulation of tions; oral: capsules and tablets; powder for inhalation; vaginal). nacystelyn, a new mucoactive agent. J Pharm Pharmacol 1999; 51 (11 ): Included in nonparenteral and parenteral medicines licensed in the 1229-1234. UK. Included in the Canadian List of Acceptable Non-medicinal 11 Cal S et al. Effects of hydration on the properties of a roller-dried ~ Ingredients. lactose for direct compression. Int J Pharm 1996; 129(1- 2): 253- 261. 12 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 522. 17 Related Substances Lactose, inhalation; lactose, monohydrate; lactose, spray-dried. 20 General References Bolhuis GK, Chowhan ZT. Materials for direct compaction. Alderborn G, 18 Comments Nystrom C, eds. Pharmaceutical Powder Compaction Technology. New Lactose anhydrous is one of the materials that have been selected for York: Marcel Dekker, 1996; 469-473. harmonization by the Pharmacopeial Discussion Group. For further Bolhuis GK, Armstrong NA. Excipients for direct compaction: an update. information see the General Information Chapter < 1196> in the Pharm Dev Technol 2006; 11: 111 ...:124. USP32-NF27, the General Chapter 5.8 in PhEur 6.5, along with the DMV-Fonterra Excipients. Technical literature: SuperTab 21AN, SuperTab 'State of Work' document on the PhEur EDQM website, and also 22AN, 2008. http://www.dmv-fonterra-excipients.com (accessed 27 the General Information Chapter 8 in the JP XV. February 2009). Lactose anhydrous has been used experimentally in hydrophilic European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia - State Of Work Of International matrix tablet formulations(S) and evaluated for dry powder 9 Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edq inhalation applications.( ,Io) Partial hydration of anhydrous lactose m.eu/site/-614.html (accessed 27 February 2009 ). increases the specific surface area and reduces the flow properties of 1 Friesland Foods Domo. Technical literature: Lactopress Anhydrous, powders but has no effect on compactibility.'1 ) A specification for Lactopress Anhydrous 250, 2008 . http://www.domo.nl/pharma 2 lactose is included in the Food Chemicals Codex (FCC(1 )); see (accessed 27 February 2009). Lactose, Monohydrate. Kirk JH et al. Lactose: a definite guide to polymorph determination. Int J The EINECS number for lactose anhydrous is 200-559-2. The Pharm 2007;334: 103-107. PubChem Compound ID (CID) for lactose anhydrous includes Sheffield Pharma Ingredients. Technical literature: Anhydrous Lactose, 6134 and 84571. 2008. http://www.sheffield-products.com/ (accessed 2 7 February 2009). 19 Specific References 21 Authors 1 Kibbe AH, ed. Handbook of Pharmaceu tical Excipients, 3rd edn. S Edge, AH Kibbe, J Shur. London and Washington, DC: Pharmaceutical Press and American Pharmaceutical Association, 2000; 641- 643. 22 Date of Revision 2 Du J, Hoag SW. The influence of excipienrs on the moisture sensitive drugs aspirin and niacinamide: comparison of tablets containing lactose 27 February 2009. - · ----.;:. ... .r ____ _ Lactose, Inhalation 1 Nonproprietary Names , : , ; : Excipient: Respitose SV003; manufacturer: DMV-Fonterra Excipients; magnification: 200x ; voltage: 5 kV. None adopted. 2 Synonyms Inhalac; inhalation lactose; Lactohale; Respitose. For grades, see Tables I and IL 3 Chemical Name and CAS Registry Number Inhalation lactose is lactose monohydrate, O-P-D-galactopyranosyl (l- t4 )-a-D-glucopyranose monohydrate [5989-81-1); [10039-26- 6]; [64044-51-5] (s ee Lactose, Monohydrate), mhydrous lactose, O-P-D-galactopyranosyl-(l- t4 )-P-D-glucopyranose [63 -42-3], or a mixture of O-P-D-galactopyranosyl-(l--t4 )-P-n-glucopyranose and O-P-D-galactopyranosyl-( 1---+ 4 )-a-D-glucopyranose (see Lactose, Anhydrous). CAS numbers for lactose monohydrate are [5989-81-1] (lactose monohydrate); [10039-26-6] (lactose monohydrate, cyclic); [64044-51 -5] (lactose monohydrate, open form). SEM 2: Excipient: Respitose MLOO 1; manufacturer: DMV-Fonterra 4 Empirical Formula and Molecular Weight Excipients; magnification: 1OOO x ; voltage: 5 kV. C12H 22 O11 342.30 (for anhydrous) C12H22O 11 -H 2 O 360.31 (for monohydrate) 5 Structural Formula See Lactose, Anhydrous; Lactose, Monohydrate. 6 Functional Category Diluent; dry powder inhaler carrier. 7 Applications in Pharmaceutical Formulation or Technology Inhalation lactose is widely used as a carrier, diluent, and flow aid in dry powder inhalation formulations. Inhalation lactose of suitable particle size can also be used to prepare soft pellets of dry powder inhaler formulations. See also Lactose, Anhydrous; Lactose, Monohydrate. 8 Description Lactose occurs as white to off-white crystalline particles or powder. 12 Incompatibilities It is odorless and slightly sweet-tasting. Lactose is a reducing sugar. Typical reactions include the Maillard 2 reaction with either primary(!) or secondary amines.( ) 9 Pharmacopeial Specifications See also Lactose, Anhydrous; Lactose, Monohydrate. See Lactose, Anhydrous; Lactose, Monohydrate. 13 Method of Manufacture 10 Typical Properties Inhalation lactose is manufactured by milling, sieving, air classify Density (bulk) see Table L ing, micronizing and/or blending pharmaceutical grade lactose, Density (tapped) see Table L typically in dedicated facilities. Although off-the-shelf grades are Loss on drying see Table L available, the manufacturing processes can be tailored to produce Particle size distribution see Table IL lactose with properties for a specific application. Surface area see Table I. 14 Safety 11 Stability and Storage Conditions Lactose is widely used in pharmaceutical formulations as a diluent Inhalation lactose should be stored in a well-closed container in a in oral capsule and tablet formulations, and has a history of being cool, dry place. used in dry powder inhaler formulations. 362 Lactose, Inhalation 363 Table I: Typical physical properti es of selected commercially available medicines licensed in the UK, which refer to lactose monohydrate in inhalation lactose. general. See also Lactose, Anhydrous; Lactose, Monohydrate. Supplier/ grade Surface Density Density Loss on area (bulk) (ta/cped) drying 3 3 17 Related Substances (m2/g) (g/cm ) (g cm ) (%) See Lactose, Anhydrous; Lactose, Monohydrate. DMV·Fonterra Excipients Respitose SV003 0.4 0.63 0.78 Respitose SVO 10 0.2 0.69 0.83 18 Comments Respitose MLO0 1 0.9 0.57 0.88 Lactose is one of a very small number of excipients that are used in Respitose ML006 1.6 0.43 0.75 marketed dry powder inhaler products. Specific grades of inhalation Ftesland Foods Domo L ctohale LH I 00 ,,; 0.2 lactose can be produced from the readily available wide range of Lactohale LH200 ,,; 0.2 pharmaceutical lactose grades using standard pharmaceutical Lactohale LH300 ,,; 0.5 manufacturing processes. Lactose is found in capsule, blister, and MeggleGmbH reservoir-based dry powder inhaler products. The relatively low lnhalac 70 0.60 0.66 mass per dose of lactose used means that, compared with lnhalac 120 0.68 0.78 conventional oral solid dosage forms, the levels of inhalation lnhalac 230 0.69 0.80 lactose ingested during inhalation are relatively small. Sheffield Pharma Ingredients In view of the importance of particle characteristics for powder Monohydrate Inhalation 40M 0.1 5 12 Monohydrate Inhalation B0M 0.1 blending and drug product performance( - l, it has been suggested Monohydrate Inhalation I 20M - 0.1 that pharmacopeial monograph acceptance criteria are not ade Monohydrate Inhalation 120MS 0.1 quate for controlling key physicochemical characteristics for Anhydrous Inhalation 120M 0.18 inhalation applications of this excipient. Accordingly, further Anhydrous Inhalation I 20MS 0.18 material controls may be required to ensure consistent drug product pharinaceutical performance, such as control of surface properties. The effect of modifying the surfaces of lactose particles by Table II: Typical particle size distribution of selected commercially particle smoothing, crystallization, and co-processing with other available inhalati on lactose. excipients on the aerosolization performance has been 113 191 reported. - . Supplier/ grade d10(µm) dso (µm) d90 (µm) See also Lactose, Anhydrous; Lactose, Monohydrate. DMV·Fonterra Excipients Respitose SV0031°I 30 60 100 19 Specific References 6 Respitose SV0 101 1 50 105 175 1 Castello RA, Mattocks AM. Discoloration of tablets containing amines Respitose MLO0 I ial 4 55 170 and lactose. J Phann Sci 1962; 51: 106-108. Respitose ML00616l 2 17 45 2 Wirth DD et al. Maillard reaction of lactose and flu oxetine Friesland Foods Domo hydrochloride, a secondary amine. J Phann Sci 1998; 87: 31- 39. Lactohale LH I 0ol6l 45- 65 125- 145 200- 250 3 Nowak-Wegrzyn A et al. Contamination of dry powder inhalers for Lactohale LH200l6l 5-15 50- 100 120-160 0 asthma with milk proteins containing lactose. J Allergy Clin lmm unol Lactohale LH300l 1 <5 ,,; 10 Meggle GmbH 2004; 113: 558-560. lnhalac 70 110 200 300 4 Morisset M et al. Allergy to cow milk proteins contaminating lactose, lnhalac 120 90 150 200 common excipient of dry powder inhalers for asthma. J Allergy Clin lnhalac 230 60 100 140 Immunol 2006; 117(Suppl. 1): 95. ··-----··-·-"- 5 Kawashima Y et al. Effect of surface morphology of carrier lactose on (a) Malvern (wet) laser diffraction. dry powder inhalation property of pralukast hydrate. Int J Pharm 1998; (b) Sympatec la ser diffraction. 172: 179- 188. 6 Steckel H et al. Functionality testing of inhalation grade lactose. Eur J Phann Biophann 2004; 57: 495-505 . Adverse reactions to lactose are large ly due to lactose intoler 7 Telko MJ, Hickey AJ . Dry powder inhaler formulation. Respir Care ance, which occurs in individuals with a deficiency of the enzyme 2005; 50: 1209-1227. lactase. Recently, the presence of milk proteins in lactose-containing 8 Jones MD, Price R. The influence of fine excipient particles on the dry powder inhalers, which can cause ana8hflaxis in cases of severe performance of carrier-based dry powder inhalation formulations. allergy to cow's milk, has been reported. ,4 Pharm Res 2006; 23: 1665- 1674. In view of the route of administration, inhalation lactose should 9 Hickey AJ et al. Physical characterization of component particles be tested to additional micobiological specifications, for example, included in dry powder inhalers. I. Strategy review and static endotoxins, as requested by the regulatory authorities. Inhalation characteristics. J Phann Sci 2007; 96: 1282-1301. 10 Hickey AJ et al. Physical characterization of component particles lactose is typically supplied with an increased range of micro included in dry powder inhalers. IL Dynamic characteristics. J Pharm biological tests. Sci 2007; 96: 1302-1319. See also Lactose, Anhydrous; Lactose, Monohydrate. 11 Shur J et al. The role of fines in the modification of the fluidizati on and dispersion mechanism within dry powder inhaler formulations. Phann Res 2008; 25: 1931- 1940. 1 5 Handling Precautions 12 Larhrib H et al. The use of different grades of lactose as a carrier fo r . Observe normal precautions appropriate to the circumstances and aerosolised salbutamol sulfa te. Int J Phann 1999; 191: 1- 14. quantity of the material being handled. Excessive generation of 13 Zeng XM et al. The influence of carrier morphology on drug delivery by dry powder inhalers. Int J Phann 2000; 200: 93- 106. dust, or inhalation of dust, should be avoided. 14 Zeng XM et al. The influence of crystallization conditions on the morphology of lactose intended for use as a carrier fo r dry powde r 16 Regulatory Status aeroso ls. J Pharm Pharmacol 2004; 52: 63 3-643. '1 5 Islam N et al. Lactose surface modification by decantatio n: Arc drng GRAS listed. Included in the FDA Inactive Ingredients Database fin e lactose ratios the key to better dispersion of salmeterol xinofate (inhalation preparations). Included in nonparenteral and parenteral from lactose interactive mixtures ? Phann Res 2004; 21: 492-499. 364 lactose, Mo no hydra te 16 Young PM et al. Characterisation of a surface modified dry powder EMEA. Committee for Medicinal Products for Human Use. Guidance on the inhalation carrier prepared by 'particle smoothing'. J Pharm Phannacol pharmaceutical quality of inhalation and nasal products. EMEA/CHMP/ 2002;54: 1339-1344. QWP/49313/2005 Corr. London; 12 June 2006. 17 EI-Sa bawi D et al. Novel temperature controlled surface di ssolution of Friesland Foods Domo. http://www.lactose.com/ (accessed 27 February excipient particles for carrier based dry powder inhaler formulations. 2009). D rug Dev Ind Pharm 2006; 32: 243-251. Ka erger JS et al. Carriers for DPis: formulation and regulatory challenges. 18 Kuman M et al. Application and mechanism of inhalation profile Pharm Tech Eur 2006; 18(10): 25-30. improvement of DPI formulations by mechanofusion with magnesium Kussendrager K et al. A new DSC method for the detection of very low stearate. Chem Pharm Bull (Tokyo) 2008; 56: 617-625. amorphous contents in lactose carriers for dry powder inhalers. Proc 19 Guchardi R et al. Influence of fine lactose and magnesium stearate on AAPS Ann11al M eeting, 2005. http://www.aapsj.org/abstracts/ low dose dry powder inhaler formulations. Int J Pharm 2008; 348: 10- AM_2005/AAPS2005-001716.pdf (accessed 27 February 2009). 17. Meggie GmbH. Technica l literature: Inhalac, 2008. http://www.meggle pharma.de (accessed 27 February 2009). 20 General References Sheffield Pharma Ingredients. Technical literature: Inhalation lactose, 2008. http://www.sheffield-products.com (accessed 27 February 2009). CDER. Guidance for industry: M etered dose inhaler (MDI) and dry powder inhaler (DPI) drug products (draft). Rockville, MD: United States Department of Health and Human Services, Food and Drug Adminis 21 Authors tration, Center for Drug Evaluation and Research; 1998. S Edge, JS Kaerger, J Shur. DMV-Fonterra Excipients. Technical literature: Respitose, 2008. http:// www.dmv-fonterra-excipients.com (accessed 27 February 2009). 22 Date of Revision Domo. Technical literature: Lactohale, 2008. http://www.domo.nl/pharma (accessed 27 February 2009). 27 February 2009. 8 Lactose, Monohydrate Nonproprietary Names 5 Structural Formula BP: Lactose PhEur: Lactose Monohydrate JP: Lactose Hydrate CH, OH l'~: USP-NF: Lactose Monohydrate ~ O~0~H ~ OH . H2O OH a-Lactose monohydrate 2 Synonyms The USP32-NF27 describes lactose monohydrate as a natural CapsuLac; GranuLac; Lactochem; lactosum monohydricum; disaccharide, obtained from milk, which consists of one galactose Monohydrate; Pharmatose; PrismaLac; SacheLac; SorboL(lc; and one glucose moiety. The PhEur 6.5 and JP XV describe lactose SpheroLac; SuperTab 30GR; Tablettose. monohydrate as the monohydrate of O-~-D-galactopyranosyl For grades, see Tables II and III. (l--+ 4)-a-o-glucopyranose. It is stated in the USP32-NF27 that lactose monohydrate may be modified as to its physical character istics, and may contain varying proportions of amorphous lactose. 6 Functional Category Dry powder inhaler carrier; lyophilization aid; tablet binder; tablet 3 Chemical Name and CAS Registry Number and capsule diluent; tablet and capsule filler. O-~-D-Galactopyranosyl-( 1--+4 )-a-o-glucopyranose monohy- drate [5989-81-1]; [10039-26-6]; [64044-51-5] 7 Applications in Pharmaceutical Formulation or CAS Registry numbers for lactose monohydrate are [5989-81- Technology 1] (lactose monohydrate), [10039-26-6] (lactose monohydrate, Lactose is widely used as a filler and diluent in tablets and capsules, cyclic), and [64044-51-5] (lactose monohydrate, open form). and to a more limited extent in lyophilized products and infant 9 formulas. (l- ! Lactose is also used as a diluent in dry-powder inhalation; seeLactose, Inhalation. Various lactose grades are commercially available that have different physical properties such as particle size distribution and flow characteristics. This permits the selection of the most suitable material for a particular 4 Empirical Formula and Molecular Weight application; for example, the particle size range selected for capsules C12H2201!'f-120 .1 60.3 1 is often dependent on the type of encapsulating machine used. La ctose, Mo nohydrate 365 Usually, fine grades of lactose are used in the preparation of tablets SEM 2: Excipient: Super Tab 30GR; manufacturer: DMV-Fo nterra by the wet-granulation method or when milling during processing is Excipients. carried out, since the fine size allows better mixing with other formulation ingredients and utilizes the binder more efficiently. Other applications of lactose include use in lyophilized products, where lactose is added to freeze-dried solutions to increase plug size and aid cohesion. Lactose is also used in combination with sucrose (approximately 1 : 3) to prepare sugar-coating solutions. It may also be used in intravenous injections. - Lactose is also used in the manufacture of dry powder formulations for use as aqueous film-coating solutions or suspen sions. Direct-compression grades of lactose monohydrate are available as granulated/agglomerated ct-lactose monohydrate, containing small amounts of anhydrous lactose. Direct-compression grades are often used to carry lower quantities of drug and this permits tablets to be made without SEM 3: Excipient: Lactochem Crystals; manufacturer: Friesland Foods granulation. Domo; magnification: 200x ; voltage: lOkV. Other directly compressible lactoses are spray-dried lactose and anhydrous lactose; see Lactose, Spray-Dried and Lactose, Anhy drous. 8 Description In the solid state, lactose appears as various isomeric forms, depending on the crystallization and drying conditions, i.e. ct lactose monohydrate, P-lactose anhydrous, and o:-lactose anhy drous. The stable crystalline forms of lactose are ct- lactose monohydrate, P-lactose anhydrous, and stable o:-lactose anhydrous. Lactose occurs as white to off-white crystalline particles or powder. Lactose is odorless and slightly sweet-tasting; ct-lactose is approximately 20% as sweet as sucrose, while P-lactose is 40% as sweet. 9 Pharmacopeial Specifications See Table I. See also Section 18. 10 Typical Properties SEM 4: Excipient: Lactochem Crystals; manufacturer: Friesland Foods Domo; magnification: 700 x ; voltage: 10 kV. Brittle fracture index 0.0749 (at compression pressure 189.5 MPa); 0.0883 (at compression pressure 191.0MPa). 001 Bonding index 0.0081 (at compression pressure 189.5 MPa); 0.0052 (at compression _pressure 191.0 MPa) .< toJ Density (true) 1.545 g/cm (ct-lactose monohydrate) Density (bulk) see Table II. SEM 1: Excipient: Pharmatose 125M; manufacturer: DMV-Fonterra Excipients; magnification: 1 OO x ; volta ge : 1.5 kV. Density (tapped) see Table II. Loss on drying Typically 0.2 % fo r Monohydrate 80M, Mono hydrate Impalpable; and 0.1-0.2% for Meggie products. Melting point 201-202°C (for dehydrated ct- lactose monohy drate) Moisture content Lactose monohydrate contains approximately 5% w/w water of crystallization and normall y has a range of 4.5-5.5 % w/w water content. See Table II. NIR spectra see Figure 1. ",, 366 Lactose, M o no hydrote Table I: Pharmacopeial specifications for lactose, monohydrote. Table II: Typical physical properties of selected commerc ially available lactose, monohydrate. Test JP XV PhEur 6.5 USP3 2-NF27 Supplier/ grade Density Density Water Identification + + + (bulk) (tafcped) content (%) Characters + 3 3 + (g/cm ) (g cm ) Appearance/color of + + + -----·-·-· ·- --~------·---·------solution DMV·Fonterra Excipients Acidt or alka li nity + + + Pharmatose SOM 0.70 0.82 Speci ic optical rotation +54.4° to +54.4° to +54.4° to Pharmatose 60M 0.80 0.98 +55.9° +55.9° +55.9° Pharmatose 70M 0.81 1.02 Protein and li ght- + + Pharmatose 80M 0.75 0.92 absorbing Pharmatose 90M 0.72 0.90 impurities/ Pharmatose 1OOM 0.73 0.88 substances Pharmatose 1 1OM 0.72 0.88 Absorbonce Pharmatose 125M 0.68 0.85 at 210- 220 nm ,,; 0 .25 ,:;; 0.25 ,s: 0.25 Pharmatose 130M 0.65 0.96 at 270- 300 nm ,,; 0.07 ,,; 0.07 ,s: 0.07 Pharmatose 150M 0.62 0.90 at 400nm ,s: 0.04 ,s: 0.04 ,:;; 0.04 Pharmatose 200M 0.57 0.84 Heavy metals ,,; 5ppm ,,; 5ppm ,,; 5 µg/g Pharmatose 350M 0.54 0.80 Water 4.5-5.5%101 4.5-5.5% 4.5-5.5% Pharmatose.450M 0.48 0.74 Su lfated ash ,s: 0.1 % SuperTab 30GR 0.53 0.66 Residue on ignition ,s: 0.1 % ,:;; 0.1 % Friesland Foods Domo Loss on drying ,s: 0.5%161 ,:;;'. 0.5%{c) Lactochem Coarse Crystals 0.75 0.88 Microbial limit Lactochem Crystals 0.74 0.86 Aerobic bacteria ,,; 100cfu/g 102 cfu/g ,:;; l00cfu/g Lactochem Fine Crystals 0.73 0.85 Fungi and rast ,,; 50cfu/g ,s: 50 cfu/g Lactochem Extra Fin e Crysta ls 0.73 0.86 Absence o + + + Lactochem Coarse Powder 0.71 0.95 Escherichia coli Lactochem Regular Powder 0.62 0.92 Absence of + Lactochem Powder 0.64 0.89 Salmonella Lactochem Fine Powder 0.61 0.84 Lactachem Extra Fine Powder 0.45 0.74 (a) 4.0- 5.5% far granulated powder. Lactochem Super Fine Powder 0.47 0.74 (b) For the granulated powder, not more than 1.0%. MeggleGmbH (c) Modified monohydrate form, not more than 1.0%. Capsulac 60 0.59 0.70 5.2 Granulac 70 0.72 0.90 5.2 Particle size distribution see Table III. Granulac 140 0.66 0.89 5.2 Permanent deformation pressure GranuLac 200 0.54 0.80 5.2 GranuLac 230 0.47 0.76 5.2 370.0 MPa (at compression pressure 189.5 MPa); Prismolac 40 0.47 0.54 5.2 10 485.0MPa (at compression pressure 191.0MPa).' l SacheLac 80 0.60 0.71 5.2 Reduced modulus of elasticity SorboLac 400 0.36 0.78 5.2 1472 (at compression pressure 189.5 MPa ); Spherolac 100 0.69 0.84 5.2 Tablettose 70 0.5 1 0.62 5.2 5155 (at compression pressure 191.0 MPa).0°> Tablettose 80 0.57 0.72 5.2 Solubility see Table IV. Tablettose 100 0.54 0.74 5.2 Specific rotation [a] ti0 = + 54.4° to +55.9° as a 10% w/v solution. Sheffield Pharma Ingredients Lactose exhibits mutarotation, and an equilibrium mixture Mon ohydrate 80M 0.66 0.92 4.8-5.2 containing 62% P-lactose and 38% a-lactose is obtained Monohydrate Impalpable 0.53 0.81 4.8-5.2 instantly on the addition of a trace of ammonia. Tensile strength 2.987 MPa (at compression pressure 189.5 MPa); 2.517 MPa (at compression pressure 191.0 MPa).11 0l storage, the reaction being accelerated by warm, damp conditions; Water content see Table IL see Section 12. The purities of different lactoses can vary and color evalu ation may be important, particularly if white tablets are being M ethods for characterizing the mechanical properties of fo rmulated. The color stabilities of various lactoses also differ. compacts of pharmaceutical ingredients are s~ecified in the Hand Solutions show mutarotation; see Section 10. book of Pharmaceutical Excipients, 3rd edn. 1 0> Lactose should be stored in a well-closed container in a cool, dry place. Table IV: Solubility of lactose. - -- . Solvent Solubility at 20UC unless otherwise stated 12 Incompatibilities Ch loroform Practically inso lu ble A Maillard-type condensation reaction is likely to occur between Ethanol Practically insoluble lactose and compounds with a primarr amine group to form brown, Ether Practically insoluble or yellow-brown-colored products. 111 The Maillard interaction has Water 1 in 5.24 also been shown to occur between lactose and secondary amine. 1 in 3.05 at 40°C However, the reaction sequence stops with the formation of the 1 in 2.30 at 50°C imine, and no yellow-brown coloration developsY2> l 1 in 1 .71 at 60°C Lactose is also incompatible with amino acids, amfetamines,113 1 in 0.96 at 80°C 4 and lisinopril.'1 ) 13 Method of Manufacture 11 Stability and Storage Conditions Lactose is a natural disaccharide consisting of galactose and Mold growth may occur under humid conditions (8 0% relative glucose, and is present in the milk of most mammals. Commercially, humidity and above). Lactose may develop a brown coloration on lactose is produced from the whey of cows' milk; whey being the Table Ill: Particle size distribution of selected commercially available lactose, monohydrote. ------···--·-- Supplier/ grade Typical particle size distribution (%) <10µm <32µm <45µm <63µm <75µm 368 Lac to se, Mo no hydrate ~ 1.0 pharmaceuticals seldom exceeds 2 g per day. It is unlikely that o2" 2243 2267 severe gastrointestinal symptoms can be attributed to the lactose in ...... ; 2303 2336 a conventional oral solid-dosage form, especially in adults who have 0) 1915 / / ' not previously been diagnosed as severely lactose-intolerant. __Q ' However, anecdotal reports of drug-induced diarrhea due to lactose ·.::> L. intolerance have been made following administration of pharma Cl) 0.0 -0 ceutical preparations containing lactose. -0 ., It has also been suggested that lactose intolerance may have a C role in irritable bowel syndrome, but this role is currently ~ ·,--' 2092 20 ' \~318/ unclear. ' ) X ...... ~ t 22782475 g0 ___ __ ,,, In the past, there have been concerns over the transmissible 2256 spongiform encephalopathies (TSE) contamination of animal 1934 ~ - 1 .2 ,.___.__.___.____._..___.__.___..____._.__.._._..__.___. -0. 2 derived products. However, in the light of current scientific 1100 1300 1500 1700 1900 2100 2300 2500 knowledge, and irrespective of geographical origin, milk and milk derivatives are reported as unlikely to present any risk of TSE Wavelength/ nm contaminati on; TSE risk is neglif ible if the calf rennet is produced in accordance with regulations. (2 t Figure 1: Near-infrared spectrum of lactose monohydrate measured by reflectance. LD 50 (rat, IP): > 10g/kg LD 50 (rat, oral): > 10 g/kg residual liquid of the milk following cheese and casein production. LD 5o (rat, SC) : > 5 g/kg Cows' milk contains 4.4-5.2% lactose; lactose constitutes 38% of the total solid content of milk. 15 Handling Precautions a-Lactose monohydrate is prepared by crystallization from Observe normal precautions appropriate to the circumstances and supersaturated solutions below 93.5°C. Various crystalline shapes quantity of material handled. Excessive generation of dust, or are prism, pyramidal, and tomahawk; these are dependent on the inhalation of dust, should be avoided. method of precipitation and crystallization. Direct compression grades of et-lactose monohydrate are prepared by granulation/ 16 Regula tory Status agglomeration and spray-drying. GRAS listed. Included in the FDA Inactive Ingredients Database 14 Safety (IM, IV, and SC: powder for injections; oral: capsules and tablets; inhalation preparations; vaginal preparations). Included in non Lactose is widely used in pharmaceutical formulations as a filler and parenteral and parenteral medicines licensed in the UK. Included in filler-binder in oral capsule and tablet formulations. It may also be the Canadian List of Acceptable Non-medicinal Ingredients. used in intravenous injections. Adverse reactions to lactose are largely attributed to lactose intolerance, which occurs in individuals 5 17 Related Substances with a deficiency of the intestinal enzyme lactaseY -ts) This results in lactose being undigested and may lead to cramps, diarrhea , Lactose, anhydrous; lactose, inhalation; lactose, monohydrate and distension, and flatulence. In lactose-tolerant individuals, lactase corn starch; lactose, monohydrate and microcrystalline cellulose; hydrolyzes lactose in the small intestine to glucose and galactose, lactose, monohydrate and povidone; lactose, monohydrate and which are then absorbed. Lactase levels are normally high at birth, powdered cellulose; lactose, spray-dried. and levels decline rapidly in early childhood. Malabsorption of lactose (hypolactasia) may occur at an early age (4-8 years) and 18 Comments varies among different ethnic groups. Lactose is excreted unchanged Lactose monohydrate is one of the materials that have been selected when administered intravenously. for harmonization by the Pharmacopeial Discussion Group. For The symptoms of lactose intolerance are caused by the osmotic further information see the General Information Chapter 1196 in effect of the unabsorbed lactose, which increases water and sodium the USP3 2-NF27, the General Chapter 5.8 in PhEur 6.0, along with levels in the lumen. Unabsorbed lactose, upon reaching the colon, the 'State of Work' document on the PhEur EDQM website, and can be fermented by colonic flora, which produces gas, causing abdominal distension and discomfort. A lactose tolerance test has also the General Information Chapter 8 in the JP XV. been developed based on the measurement of blood glucose level A number of different grades of lactose are commercially and the hydrogen level in the breath. However, its usefulness has available that vary in their physical properties, and many studies have been reported in the literature comparing the behavior of these been questioned as the test is based on a 50 g dose of lactose. 9 Approximately 10-20% of lactose-intolerant individuals, in two various materials in different formulations. (3';S, ) A number of co studies, showed clinical symptoms of intolerance after ingestion of processed excipients which contain lactose are available for direct 5 16 15 3-5 g of lactoseY • ) In one of the studies,! ) 75% of the subjects compression applications: co-processed lactose and starch (Starlac, 22 had symptoms with 12 g of lactose (equivalent to 250 mL of milk). Meggle/Roquette Freres), < l lactose and microcrystalline cellulose 16 23 In another,< ) eight out of 13 individuals developed diarrhea after (Microcelac, Meggle);< ) lactose and cellulose powder (Celli:l ctose, 24 25 the administration of 20 g of lactose, and nine out of 13 after the Meggle),' • ) lactose, Eovidone, and crospovidone (Ludipress, administration of 25 g. Ludipress LCE, BASF).< 6l Lower doses of lactose produce fewer adverse effects, and lactose Lactose may exhibit complex thermoanalytical transitions is better tolerated if taken with other foods. As a result, there is a because of its several crystalline, as well as amorphous, forms. significant population with lactose malabsorption who are still able Differential scanning calorimetry (DSC) can be used effectively to to ingest normal amounts of lactose, such as that in milk, without characterize the composition.<27- 29 ) For example, et-lactose becomes the development of adverse side effectsY 7l anhydrous at approximately 120°C. a -Lactose monohydrate may Most adults consume about 25 g of lactose per day (500 mL of also contain a small quantity of the ~-form. 8 19 milk) without symptomsY • ) When symptoms appear, they are A specification for lactose is included in the Food Chemicals 30 usually mild and dose-related. The dose of lactose in most Codex (FCq.< ) Lactose, M o nohydrate 369 The EINECS number for lactose is 200-559-2. The PubChem 23 Michael A et al. Comparative evaluation of co-processed lactose and compound ID (CID) for lactose monohydrate includes 62223 and microcrystalline cellulose with their physical mixtures in the formula 104938. tion of folic acid tablets. Pharm Dev Technol 2002; 7(1): 79-87. 24 Casalderrey M et al. A comparison of drug loading capacity of cellactose with two ad hoc processed lactose-cellulose direct compres 19 Specific References sion excipients. Chem Pharm Bull (Tokyo) 2004; 52(4): 398-401. 1 Alpar O et al. The compression properties of lactose. J Pharm 25 Arida AI, AI-Tabakha MM. Cellactose a co-processed excipient: a Pharmacol 1970; Dec(Suppl.}: 1S-7S. comparison study. Pharm Dev Technol 2008; 13: 165- 175. 2 Vromans H et al. Studies on the tableting properties of lactose: the effect 26 Heinz R et al. Formulation and development of tablets based on of initial particle size on binding properties and dehydration Ludipress and scale-up from laboratory to production scale. Drug Dev characteristics of ()(-lactose monohydrate. Rubinstein MH, ed. Pharma Ind Pharm 2000; 26: 513-521. ceutical Technology:Tableting Technology., vol. 1: Chichester: Ellis 27 Chidavaertzi OC et al. The use of thermal techniques to assess the Horwood, 198 7; 31-42. impact of feed concentration on the amorphous content and 3 Thwaites PM et al. An inves tigation of the effect of high speed mixing on the mechanical and physical properties of direct compression polymorphic forms present in spray dried lactose. Int J Pharm 1997; lactose. Drug Dev Ind Pharm 1991; 17: 503-517. 159: 67-74. 4 Riepma KA et al. The effect of moisture sorption on the strength and 28 Hill VL et al. Characterisation of spray-dried lactose using modulated internal surface area of lactose tablets. Int J Pharm 1992; 87: 149-159, differential scanning calorimetry. Int J Pharm 1998; 161: 95-107. 5 (:eli k M, Okutgen E. A feas ibility study for the development of a 29 Lerk CF et al. Alterations of ()(-lactose during differential scanning prospective compaction functionality test and the establishment of a calorimetry. J Phann Sci 1984; 73: 856-857. compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309-2334. 30 Food Chemicals Codex, 6th edn. Bethesda, MD: United States 6 Lerk CF. Consolidation and compaction of lactose. Drug Dev Ind Pharmacopeia, 2008: 522. Pharm 1993; 19: 2359-2398. 7 Otsuka M et al. Effect of humidity on solid-state isomerization of various kinds of lactose duri ng grinding. J Pharm Pharmacol 1993; 45: 20 General References 2-5. BASF. Technical literature: · Ludipress, Ludipress L CE, 2008. http:// 8 Paronen P. Behaviour of some direct compression adjuvants during the www.pharma-solutions.basf.com (accessed 10 March 2009). tabletting process. STP Pharma 1986; 2: 682-688. Bolhuis GK, Chowhan ZT. Materials for direct compaction. Alderborn G, 9 Zuurman K et al. The relationship between bulk density and Nystrom.C, eds. Pharmaceutical Powder Compaction Technology. New compactibility of lactose granulations. Int J Pharm 1994; 102: 1-9. York: Marcel Dekker, 1996; 459-469. 10 Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn. Bolhuis GK, Armstrong NA. Excipients for direct compaction: an update. London and Washington, DC: Pharmaceutical Press and American Pharm Dev Technol 2006; 11: 111- 124. Pharmaceutical Association, 2000; 641-643. DMV-Fonterra Excipients. Technical literature: Pharmatose, SuperTab 11 Castello RA, Mattocks AM. Discoloration of tablets containing amines 30GR, 2008. http://www.dmv-fonterra-excipients.com (accessed 10 and lactose. J Pharm Sci 1962; 51: 106-108. 12 Wirth DD et al. Maillard reaction of lactose and fluoxetine March 2009). hydrochloride, a secondary amine. J Pharm Sci 1998; 87: 31-39. European Directorate for the Quality of Medicines and Healthcare 13 Blaug SM, Huang W. Interaction of dextroamphetamine sulfate with (EDQM). European Pharmacopoeia - State Of Work Of International spray-dried lactose. J Pharm Sci 1972; 61: 1770- 1775. Harmonisation. Pharmeuropa 2009; 2 1(1): 142- 143.www.edqm.eu/ 14 Eyjolfsson R. Lisinopril-lactose incompatibility. Drug Dev Ind Pharm site/-61 4.html (accessed 10 March 2009). 1998; 24: 797- 798. Friesland Food Domo. Technical literature: Lactochem, 2008. http:// 15 Bedine MS, Bayless TM. Intolerance of small amounts of lactose by www.domo.nl/pharma (accessed 10 March 2009). individuals with low lactase levels. Gastroenterology 1973; 65: 735- Kirk JH et al. Lactose: a definite guid e to polymorph determination. Int J 743. Pharm 2007; 334: 103-107. 16 Gudmand-Hoyer E, Simony K. Individual sensitivity to lactose in Meggie GmbH. Technical literature: Lactose excipiellts, 2004. http:// lactose mala bso rption. Am] Dig Dis 1977; 22(3): 177- 181. www.meggle-pharma.de (accessed 10 March 2009). 17 Lorner M C et al. Review article: lactose intolerance in clinical practice - Rajah KK, Blenford DE, eds. The ALM Guide to Lactose Properties and myths and realities. Aliment Pharmacol Ther 2008; 27(2): 93-103. Uses. The Hague: Association of Lactose Manufacturers, 1998 . 18 Suarez FL, Savaiano Dennis A. Diet, genetics, and lactose intolerance. Roquette Freres. Technical literature: Starlac, 2008. http://www.roquette Food Technol 1997; 51(3): 74-76. pharma.com (accessed 10 March 2009). 19 Suarez FL et al. A comparison of symptoms after the consumption of Sheffield Pharma Ingredients. Technical literature: Excipients, 2008. http:// mil k or lactose-hydrolyzed milk by people with self-reported lactose www.sheffield-products.com (accessed 10 March 2009). intolerance. N Engl J Med 1995; 333: 1-4. 20 Spanier JA. A systemic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med 2003; 163(3): 265-274. 21 Authors 21 The European Agency for the Evaluation of Medicinal Products. Evaluation of Medicines for Human Use. London, 9 D ec 2002: EMEAI S Edge, AH Kibbe, J Shur. 410/01 Rev. 2. 22 Hauschild K, Picker-Freyer KM. Evaluation of a new coprocessed 22 Date of. Revision compound based on lactose and maize starch for tablet formulation. AAPS Pharm Sci Tech 2004; 6(2): e16. 10 March 2009. =----- ···--··------~------~~------·- ·------ 6l Lactose, Monohydrate and Corn Starch Nonproprietary Names 9 Pharmacopeial Specifications None adopted. Both lactose monohydrate and corn (maize) starch are listed as separate monographs in the JP, PhEur, and USP-NF, but the 2 Synonyms combination is not listed. See Lactose, Monohydrate, and Starch. See also Section 18. StarLac . 10 Typical Properties 3 Chemical Name and CAS Registry Number Angle of repose :( 29° for Star Lac See Section 8. Density (bulk) 0.57glcm3 for StarLac Density (tapped) 0.68 g/cm 3 fo r Star Lac 4 Empirical Formula and Molecular Weight Hausner ratio 1.19 for Star Lac See Section 8. Heavy metals 5 ppm for Star Lac Loss on drying :( 3.0% for Star Lac Microbial content Total viable aerobic count :( 100 cfu/g, molds 5 Structural Formula < 10cfu/g, yeasts < 10cfu/g (Escherichia co li and Salmonella See Section 8. species absent) for StarLac. Particle size distribution :( 15% < 32 µm, 35-65% <160 µm , 6 Functional Category ;?: 80% < 250 ~ltn for Star Lac. Sulfated ash :( 0.25 % for StarLac Directly compressible tablet excipient; disintegrant; tablet and Solubility Partially soluble in cold water for StarLac. caps ule diluent. 11 Stability and Storage Conditions 7 Applications in Pharmaceutical Formulation or Technology Store in well-closed conta iners under dry and odor-free conditions. Lactose monohydrate and corn starch can be used in tablets to improve compressi bility, flowability and disintegration proper- 12 Incompatibilities ties. (l) It is used in homeopathic and low-dose to mid-dose See Lactose, Monohydrate, and Starch. form ulations. 13 Method of Manufacture 8 Description Lactose monohydrate and corn starch is prepared by spray-drying a a-Lactose monohydrate and corn starch occurs as a white or almost mixture of the two ingredients. white odorless powder containing 82-88% of lactose monohydrate and 12- 18% of corn (maize) starch. It is a free-flowing powder 14 Safety owing to its spherical structure. See Lactose, Monohydrate, and Starch. 15 Handling Precautions :'.' M 1: Excipient: Starlac; manufacturer: Roquette/Meggle; magnification: 200x ; voltage: 2 kV. Observe normal precautions appropriate to the circumstances and quantity of material handled. 16 Regulatory Status Lactose monohydrate and corn starch is a mixture of two materials both of which are generally regarded as nontoxic: Lactose monohydrate GRAS listed. Included in the FDA Inactive Ingredients Database (IM, IV, and SC: powder for injections; oral: capsules and tablets; inhalation preparations; vaginal preparations). Included in nonparenteral and parenteral medi cines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. Starch GRAS listed. Included in the FDA Inactive Ingredients Database (buccal tablets, oral capsules, powders, suspensions and tablets; topical preparations; and vaginal tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 17 Related Substances Lactose, monohydrate; starch. 370 Lactose , Mono hydrate and Microcrystalli ne Cellulose 371 18 Comments 2 Hauschild K, Picker KM. Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formulation. AAPS J 2004; Lactose monohydrate and corn starch are two of the materials that 6(2) : 27-38. have been selected for harmonization by the Pharmacopeial 3 Roquette/Meggle. Technical data sheet. StarL ac additional information, Discussion Group. For further information see the General August 2007. Information Chapter < 1196> in the USP32-NF27, the General Chapter 5 .8 in PhEur 6.0, along with the 'State of Work' document 20 General References on the PhEur EDQM website, and also the General Information Deorkar N. High-functionality excipients: a review. Tablets and Capsules Chapter 8 in the JP XV. 2008: 22-26. http://www.tabletscapsules.com (accessed 3 March 2009). StarLac has been designed for direct compression, combining European Directorate for the Quality of Medicines and Healthca re good flowability and compressibility with fast disintegration (EDQM). European Pharmacopoeia - State Of Work Of International properties. Excipients or fo rmulations containing a variety of Harmonisation. Phanneuropa 2009; 21(1): 142- 143. http://www.edq drugs, namely ascorbic acid, paracetamol [acetaminophen] and m.eu/site/-614.html (accessed 3 February 2009). Gohel MC, Jogani PD. A review of co-processed directly compressible theophylline monohydrate show it to be superior to a simple excipients.J Pharm Pharm Sci 2005; 8(1): 76- 93 . mixture of its components in terms of flowability, tablet strength, Haeusler 0. A star is born. Pharmaceutical Formulation a11d Quality 2002; 1 2 friability and disintegration time. ' • ' Starch particles are embedded 54-57. in a matrix mainly consisting of crystalline lactose monohydrate, Meggie. Product literature: Lactose Excipients, September 2008 . and very low quantities of amorphous lactose are detectable. Its Nachaegari SK, Bansal AK. Coprocessed excipients for solid dosage forms. balanced elastic and brittle properties make it suitable for roller Pharm Tech 2004; (Jan): 52-64. Roquette. Technical datasheet: StarL ac - lactose-starch compound for direct compaction. Specific quantitative, analytical methods for the assay compression, October 2005. of starch and lactose in StarLac have been developed and 3 validated. ( l 21 Authors 19 Specific References ME Quinn, RC Rowe. 1 Wagner KG, Dressler JA. A corn starch/alpha-lactose monohydrate compound as a new directly compress ible excipient. Pharm Ind 2002; 22 Date of Revision 64( 9): 992-999. 3 March 2009. Lactose, Monohydrate and Microcrystalline Cellulose 1 Nonproprietary Names 8 Description None adopted. Lactose monohydrate and microcrystalline cellulose occurs as a white or almost white odorless powder co ntaining 73-77% of lactose monohydrate and 23-27% of microcrystalline ce llulose. 2 Synonyms MicroceLac 100. 9 Pharmacopeial Specifications Both lactose monohydrate and microcrystalline cellulose are listed 3 Chemical Name and CAS Registry Number as separate monographs in the JP, PhEur, and USP-NF, bur the See Section 8. combination is not listed. See Lactose, M onohydrate, and Cellulose, Microcrystalline. See also Section 18. 4 Empirical Formula and Molecular Weight 10 Typical Properties See Section 8. Acidity/alkalinity pH = 4.0-7.0 for MicroceLac 100 Angle of repose 34 ° for MicroceLac 100 3 S Structural Formula Density (bulk) 0.5 glcm for MicroceLac 100 Density (tapped) 0.61 g/cm3 for MicroceLac 100 See Section 8. Hausner ratio 1.16 for MicroceLac 1 00 Heavy metals ,;:; 5 ppm for MicroceLac 100 Loss on drying ,;:; 1.5% for Mi croceLac 100 . 6 Functional Category Microbial content Total viable aerobic count ,;:; l00 cfu/g, molds Tablet and capsule diluent. ,;:; 10 cfu/g, yeasts ,;:; 10 cfu/g (Escherichia coli and Sa lmonella species absent) for MicroceLac 100 Particle size distribution ,;:; 15 % < 32~tm, 45- 70% < 160~tm, 7 Applications in Pharmaceutical Formulation or ;;,: 90% <250 µm for MicroceLac 100 Technology Solubility Partially soluble in water fo r MicroceLac I 00 Lactose monohydrate and microcrystalline cellu lose can be used in Sulfated ash ,s; 0.1 % for MicroceLac 100 tablets fo r direct compression. Water content 4-6% for MicroceLac 100 It ... 372 Lactose , Monohydra te and Microcrystalline C ellulose · Excipient: Microcelac 100; manufacturer: Meggie; cines licensed in the UK. Included in the Canadian List of magnification: 200x ; voltage: 3 kV. Acceptable Non-medicinal Ingredients. Microcrystalline cellulose GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (inhalations; oral capsules, powders, suspensions, syrups, and tablets; topical and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 17 Related Substances Cellulose, microcrystalline; lactose, monohydrate. 18 Comments Lactose monohydrate and microcrystalline cellulose are two of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the USP32-NF27, the .}EM 2: Excipient: Microcelac 100; manufacturer: Meggie; General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' magnification: 500x ; voltage: 3 kV. document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV. ---- MicroceLac 100 has been designed for formulating high-dose small tablets with a poorly flowable active ingredient. It showed superior flow and binding properties compared to simple mixtures of its components. CJ •21 Differences between MicroceLac 100 and Cellactose 80 have recently been evaluated. (3 I · A specification for lactose and microcrystalline cellulose spheres 4 is contained in the Japanese Pharmaceutical Excipients (JPE);( l see Table I. Table I: JPE specification for lactose and microcrystalline cellulose spheres. Test JPE 2004 - Description + Identification + Heavy metals ,;:; 5ppm Arsenic ,;:; 2ppm Loss on drying ,;:;5 .0% Water ,;:; 9.0% 11 Stability and Storage Conditions Residue on ignition ,;:; 0.1% Store at room temperature in well-closed containers under dry and Assay (dried basis) odor-free conditions. Lactose 60-80% Microcrystalline cellulose 20-40% 12 Incompatibilities See Lactose, Monohydrate, and Cellulose, Microcrystalline. 19 Specific References 13 Method of Manufacture 1 Michael A et al. Comparative evaluation of co-processed lactose and Lactose monohydrate and microcrystalline cellulose is prepared by microcrystalline cellulose with their physical mixtures in the formula spray-drying a mixture of the two ingredients. tion of folic acid tablets. Pharm Dev Technol 2002; 7(1): 79- 87. 2 Goto K et al. Pharmaceutical evaluation of multipurpose excipients for direct compressed tablet manufacture: comparisons of the capabilities 14 Safety of multipurpose excipients with those in general use. Drug Dev Ind See Lactose, Monohydrate, and Cellulose, Microcrystalline. Pharm 1999; 25(8): 869- 878. 3 Muzikova J, Zvolankova J. A study of the properties of tablets from 1 S Handling Precautions coprocessed dry binders composed of alpha-lactose monohydrate and different types of cellulose. Ceska Slav Farm 2007; 56(6): 269-275. Observe normal precautions appropriate to the circumstances and 4 Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical quantity of material handled. Excipients 2004. Tokyo: Yakuji Nippo, 2004; 457-459. 16 Regulatory Status 20 General References Lactose monohydrate and microcrystalline cellulose is a mixture of Deorkar N. High-functionality excipients: a review. Tablets and Capsules two materials both of which are generally regarded as nontoxic: 2008: 22-26. http://www.tabletscapsules.com (accessed 3 March 2009). Lactose monohydrate GRAS listed. Included in the FDA Inactive European Directorate for the Quality of Medicines and Healthcare Ingredients Database (IM, IV, and SC: powder for injections; (EDQM). European Pharmacopoeia - State Of Work Of International oral: capsules and tablets; inhalation preparations; vaginal Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edq preparations). Included in nonparenteral and parenteral medi- m.eu/site/-614.html (accessed 3 February 2009). La ctose, M onohydrate and Povidone 373 Gohel MC, Jogani PD. A review of co-processed directly compress ible 21 Authors excipients. J Pharm Pharm Sci 2005; 8(1): 76-93. ME Quinn, RC Rowe. Meggie GmbH. Product literature: Lactose excipients, September 2008. Meggie GmbH. Product literature: MicroceLac 100, March 2006. Nachaegari SK, Bansal AK. Coprocessed excipients for solid dosage forms. 22 Date of Revision Pharm Tech 2004; 28: 52- 64. 3 March 2009. r Lactose, Monohydrate and Povidone Nonproprietary Names Particle size distribution ,;;;; 20% < 63 µm, 40-65% <200 µm, None adopted. ,:;;;20% <400 µm for Ludipress LCE Solubility Soluble in water for Ludipress LCE Water content ,;;;; 6.0% for Ludipress LCE 2 Synonyms Ludipress LCE. 11 Stability and Storage Conditions Store at room temperature iri tightly closed containers. 3 Chemical Name and CAS Registry Number See Section 8. 12 Incompatibilities See Lactose, Monohydrate, and Povidone. 4 Empirical Formula and Molecular Weight See Section 8. 13 Method of Manufacture Lactose monohydrate and povidone 1s manufactured by a s Structural Formula proprietary agglomeration process. See Section 8. 14 Safety 6 Functional Category See Lactose, Monohydrate, and Povidone. Tablet and capsule diluent. 1 5 Handling Precautions 7 Applications in Pharmaceutical Formulation or Observe normal precautions appropriate to the circumsta nces and Technology quantity of material handled. Lactose monohydrate and povidone can be used to formulate chewable tablets, lozenges, effervescent tablets, and controlled 16 Regulatory Status release tablets by direct compressionYl It is su itable for low-dose Lactose monohydrate and povidone is a mixture of two materials drugs. 12 ) both of which are generally regarded as nontoxic: Lactose monohydrate GRAS listed. Included in tl1e FDA Inactive 8 Description Ingredients Database (IM, IV, and SC: powder for injections; Lactose monohydrate and povidone occurs as white fre e-flowing oral: capsules and tablets; inhalation preparations; vaginal granules, odorless with a neutral taste, containing 96.5% ± 1.8% preparations). Included in nonparenteral and parenteral medi of lactose monohydrate and 3.5% ± 0.5% of povidone K30. cines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 9 Pharmacopeial Specifications Povidone Accepted fo r use in Europe as a food additive. Included in the FDA Inactive Ingredients Database (IM and IV in jections; Both lactose monohydrate and povidone are listed as separate ophthalmic preparations; oral capsules, drops, granules, suspen monographs in the JP, PhEur, and USP- NF, but the combination is sions, and tablets; sublingual tablets; topical and vaginal not listed. See Lactose, Monohydrate, and Povidone. See also preparations). Included in nonparenteral medicines licensed in Section 18. the UK. Included in the Canadian List of Acceptable Non medicinal Ingredients. 10 Typical Properties Angle of repose 29.5° for Ludip_ress LCE 17 Related Substances Density (bulk) 0.56 0. 6 glcm3 fo r Ludipress LCE ± Lactose, monohydrate; povidone. Hausner ratio 1.20 ± 0.10 for Ludipress LCE Heavy metals ,;;;; 10 ppm for Ludipress LCE Loss on drying 5.75% for Ludipress LCE 18 Comments Microbial content Mesophilic aerobes ,:;;; 1000cfu/g, yeasts and Lactose monohydrate and povidone are two of the materials that fungi ,:;;; l 00 cfu/g (Escherichia co li, Pseudomonas aeruginosa, have been selected fo r harmonization by the Pharmacopeial Staphylococcus aureus, and Salmonella species absent), other Discussion Group. For further information see the General Enterobacteriaceae ,:;;; 100 cfu/g) for Ludipress LCE Information Chapter < 11 96> in the USP32-NF27, the General ______..,. - · ,... . 37 4 lactose, Mo no hydrate and Powde red Cellul ose Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document 6 Baykara T et al. Comparing the compressibility of Ludipress with the on the PhEur EDQM website, and also the General Information other direct tabletin g agents by using acetaminophen as an active Chapter 8 in the JP XV. in gredient. Drug Deu Ind Pharm 1991; 17(1 7) : 2359- 2371. Ludipress LCE has been shown to have compression character 7 Schmidt PC, Rubensdorfer CJ. Evaluation of Ludipress as a multi 3 4 purpose excipients fo r direct compression. Part 2. Interactive blending istics superior to a simple physical mixture of its constituents.( , l and tableting with micronized glibenclamide. Drug D ev Ind Pha rrn Tablet strength has been shown to be independent of machine 1994; 20( 18): 2927- 2952 . 5 6 .speed( l and tablet geometry,(5l and does not increase on storage.( ) Disintegra tion time has been shown not to increase at high 20 General References compressi on forces.(?) Deorkar N. High-functionality excipients: a review. Tablets and Capsules 2008: 22- 26. http://www.tabletscapsules.com (accessed 3 March 2009). 19 Specific References Europea n Directorate for the Quality of Medicines and Healthcare 1 Kolter K, Fussnegger B. Development of tablet formulations using (EDQM). European Pharmacopoeia - State Of Work Of International Ludipress LCE as a direct compression excipient. BASF Product Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edq Literature, No. 1, November 1998. m.eu/site/-614.html (accessed 3 February 2009 ). 2 Kolter K et al. Ludipress LCE. A new direct compression excipient. Gobel MC, Jogani PD. A revi ew of co-processed directly compressible BASF Product Literature, No. 10, May 2003. excipients. J Phann Pharm Sci 2005; 8(1): 76- 93 . 3 Schmidt PC, Rubensdorfer CJ. Evaluation of Ludipress as a multi Nachaegari SK, Bansal AK. Coprocessed excipients fo r solid dosage forms. purpose excipients for direct compression. Part 1. Powder character Pharm Tech 2004; 28: 52- 64. istics and tableting properties. Drug Dev Ind Phann 1994; 20(18): BASF. Technical literature: Ludipress LCE, May 1999. 2899-2925. 4 Goto K et al. Pharmaceutical evaluation of multipurpose excipients for direct compressed tablet manufacture: comparisons of the capabilities 21 Authors of multipurpose excipients with those in general use. Drug Dev In d ME Quinn, RC Rowe. Phanll 1999; 25(8): 869-878. 5 H einz R et al. Formulation and development of tablets based on 22 Date of Revision Ludipress and scale-up for laboratory to production scale. Drug Dev Ind Pharm 2000; 26(5): 513- 521. 3 March 2009. Ex Lactose, Monohydrate and Powdered Cellulose Nonproprietary Names 8 Description None adopted. Lactose monohydrate and powdered cellulose occurs as a white or almost white odorless powder containing 73-77% of lactose monohydrate and 23- 27% of cellulose powder. 2 Synonyms Cellactose 80. 9 Pharmacopeial Specifications 3 Chemical Name and CAS Registry Number Both lactose monohydrate and powdered cellulose are listed as separate monographs in the JP, PhEur, and USP-NF, but the Sec Section 8. combination is not listed. See Lactose, Monohydrate, and Cellulose, Powdered. See also Section 18. 4 Empirical Formula and Molecular Weight See Section 8. 10 Typical Properties Acidity/alkalinity pH = 4.0-7.0 for Cellactose 80 5 Structural Formula Angle of repose 32- 35° for Cellactose 80 Density (bulk) 0.38 g/cm3 for Ce/lactose 80 See Section 8. Density (tapped) 0.5 glcm 3 for Ce/lactose 80 Hausner ratio 1.24 for Cellactose 80 6 Functional Category Heavy metals ,;;; 5 ppm for Cellactose 80 Loss on drying :;;; 3.5% for Cellactose 80 Tablet and capsule diluent. Microbial content Total viable aerobic count ,;;; 100 cfu/g, molds ~ 10 cfu/g, yeast ~ 10 cfu/g (Es cherichia coli and Salmonella species absent) for Cellactose 80 7 Applications in Pharmaceutical Formulation or Particle size distribution ,;;; 20% <32 µm , 35-65% < 160 µm , Technology ~ 80% < 250 µm for Cellactose 80 Lactose monohydrate and powdered cellulose can be used in tablets Sulfated ash ~ 0.2 % for ,Cellactose 80 for direct compression to improve compressibility and mouth Solubility Partially soluble in water for Cellactose 80 feel. (l) Water content 4- 7% for Cellactose 80 Lactose, Monohydrate and Powdered Cellulose 375 11 Stability and Storage Conditions Ce/lactose 80 has been designed especially for direct compres sion. It has been shown to be superior to a simple mixture of its Store at room temperature in well-closed containers under dry and 2 dor-free conditions. components in terms of dilution potential,< ) compressibility,(3) 0 4 5 6 7 tensile strength, <, ) lubricant susceptibility, <• ) and subsequent 8 tablet properties for a range of drugs.< ) 12 Incompatibilities Sec Lactose, Monohydrate, and Cellulose, Powdered. 19 Specific References 1 Nachaegari SK, Bansal AK. Coprocessed excipients for solid dosage 13 Method of Manufacture forms. Pharm Tech 2004; 28: 52-64. Lactose monohydrate and powdered cellulose is prepared by spray 2 Flores LE et al. Study of load capacity of Avicel PH-200 and Ce/lactose, drying a mixture of the two ingredients. two direct-compression excipients, using experimental design. Drug Dev Ind Pharm 2000; 26(4): 465-469. 3 Belda PM, Mielck JB. The tableting behavior of Cellactose compared 14 Safety with mixtures of celluloses with lactoses. Eur J Pharm Biopharm 1996; See Lactose, Monohydrate, and Cellulose, Powdered. 42(5): 325-330. 4 Muzikova J, Zvolankova J. A study of the properties of tablets from 15 Handling Precautions coprocessed dry binders composed of alpha-lactose monohydrate and different types of cellulose. Ceska Slov Farm 2007; 56(6): 269-275. Observe normal precautions appropriate to the circumstances and 5 Arida AI, Al-Tabakha MM. Ce/lactose a co-processed excipient: a quantity of material handled. comparison study. Pharm Dev Technol 2008; 13(2): 165-175. 6 Konkel P, Mielck JB. Associations of parameters characterizing the time 16 Regulatory Status course of the tabletting process on a reciprocating and on a rotary tabletting machine for high-speed production. Eur J Phann Biopharm Lactose monohydrate and powdered cellulose is a mixture of two 1998; 45(2): 137-148. materials both of which are generally regarded as nontoxic: 7 Flores LE et al. Lubricant susceptibility of Cellactose and Avicel PH- Lactose monohydrate GRAS listed. Included in the FDA Inactive 200: a quantitative relationship. Drug Dev Ind Phann 2000; 26(3): Ingredients Database (IM, IV, and SC: powder for injecti ons; 297-305. oral: capsules and tablets; inhalation preparations; vaginal 8 Casalderrey M et al. A comparison of drug loading capacity of preparations). Included in nonparenteral and parenteral medi cellactose with two ad hoc processed lactose-cellulose direct compres sion excipients. Chem Phann Bull (Tokyo) 2004; 52(4): 398-401. cines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. Powdered cellulose GRAS listed. Accepted for use as a food 20 General References additive in Europe (except for infant food in the UK). Included in Deorkar N. High-functionality excipients: a review. Tablets and Capsules nonparenteral medicines licensed in the UK. Included in the 2008: 22-26. http://www.tabletscapsules.com (accessed 3 March 2009). Canadian List of Acceptable Non-medicinal Ingredients. European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Phanneuropa 2009; 21(1): 142- 143. http://www.edq 17 Related Substances m.eu/site/-614.html (accessed 3 February 2009). Lactose, monohydrate; cellulose, powdered. Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Phann Sci 2005; 8(1): 76-93. Meggie. Product literature: Lactose e~cipients, September 2008. 18 Comments Meggie. Technical literature: Cellactose 80, August 2006. Lactose monohydrate and powdered cellulose are two of the materials that have been selected for harmonization by the 21 Authors Pharmacopeial Discussion Group. For further information see the ME Quinn, RC Rowe. General Information Chapter < 1196> in the US P32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General 22 Date of Revision Information Chapter 8 in the JP XV. 3 March 2009. ------.-._...,.,,c-> •. - -·-- -· · -··....- -· 6~ Lactose, Spray-Dried 1 Nonproprietary Names !EM l: Excipient: Super Tab 11 SD; manufacturer: DMV-Fanterra Exc ipients; magnification: 300x ; voltage: 5 kV. None adopted. 2 Synonyms FlowLac 90; FlowLac 100; Lactopress Spray-Dried; Lactopress Spray-Dried 250; NF Lactose-315; NF Lactose-316 Fast Flo; SuperTab llSD; SuperTab 14SD. 3 Chemical Name and CAS Registry Number Spray-dried lactose is a mixture of amorphous lactose, which is a 1 : 1 mixture of ci:-and-P-lactose, and O-P-D-galactopyranosyl (l--t4 )-ci:-D-glucopyranose monohydrate [5989-81-1]; [10039- 26-6]; [64044-51 -5]. CAS numbers for lactose monohydrate are [5 989-81 -1) (lactose monohydrate); (10039-26-6) (lactose monohydrate, cyclic); [64044-51-5 ) (l actose monohydrate, open form). 4 Empirical Formula and Molecular Weight C12 I-I22 0 11 342.30 (for amorphous) C12I-I22011" I-I20 360.31 (for monohydrate) !M '. :; Excipient: Lactopress Spray-Dried; manufacturer: Friesland Foods Domo; magnification: 500x ; voltage: 3 kV. 5 Structural Formula See Lactose, Anhydrous and Lactose, Monohydrate. 6 Functional Category Directly compressible tablet excipient; tablet and capsule diluent; tablet and capsule filler. 7 Applications in Pharmaceutical Formulation or Technology Spray-dried lactose is widely used as a binder, filler-binder, and flow aid in direct compression tableting. See also Lactose, Monohydrate; Lactose, Anhydrous. 8 Description Lactose occurs as white to off-white crystalline particles or powder. It is odorless and slightly sweet-tasting. Spray-dried direct compression grades of lactose are generally composed of 80-90% specially prepared pure ci:-lactose monohydrate along with 10-20% of amorphous lactose. 9 Pharmacopeial Specifications SEM 3: Excipient: NF lactose--316 Fast Flo; manufacturer: Sheffield See Section 18. See also Lactose, Monohydrate. Pharma Ingredients; magnification: 500x ; voltage: 3 kV. 10 Typical Properties Angle of repose 29° for Flow Lac 90; 28° for Flow Lac 100. Bonding index 0.0044 for NF Lactose-315 (at compression pressure 54.90 MPa}'1l Brittle fracture index 0.1671 for NF Lactose- 315 (at compres sion pressure 54.90 MPa)(lJ Density bulk see Table I. Loss on drying 0.3% for NF Lactose-315; 0.6% for NF Lactose- 316. Particle size distribution see Table II. Reduced modulus of elasticity 5648 for NF Lactose-315 (at compression pressure 54.90 MPa)(lJ Tensile strength 2.368 M Pa for NF Lactose- 315 (at compression pressure 54.90 MPa)( l ) Water content see Table I. 376 lactose, Spray-Dried 3 77 Table I: Typical physical properties of selected commercially availoble spray-dried lactose. 3 3 Supplier/ grade Density (bulk) (g/ cm ) Density (tapped) (g/cm ) Water content (%) DMV·Fonterra Excipients Super Tab 11 SD 0.60 0.71 SuperTab 14SD 0.62 0.72 MeggleGmbH Flowlac 90 0.57 0.67 Ffowlac 100 0.62 0.73 Sheffield Pharma Ingredients NF Laclose-3 15 0.67 0.78 4.8-5.2 NF Lactose-3 16 Fast Flo 0.58 0.67 4.8-5.2 Table II: Particle size distribution of selected commercially available spray-dried lactose. Supplier/ grade Percentage less than stated size <32µm <45~tm <75µm < 100µm <200µm < 250µm DMV·Fonterra Excipients Super Tab I I SD ~ 15 30-60 ~ 98 Super Tab I4SD ~ 15 30-60 ~ 98 Friesland Foods Domo laclopress Spray-Dried ~ 25 30- 60101 ~ 65 laclopress Spray-Dried 250 ~ 15 ~ 50 30-60 ~ 98 MeggleGmbH Flowlac 90 ~ 5 25- 40 ~ 85 Flowlac 100 ~ 10 20-45 ~ 80 Sheffield Pharma Ingredients NF Lactose-315 25- 45 40-701°1 NF lactose-3 16 Fast Flo 20-40 45-701°1 99.5- 100 (a) <106ttm. Methods for characterizing the mechanical properties of 1 5 Handling Precautions compacts of pharmaceutical ingredients are 5rrecified in the Hand Observe normal precautions appropriate to the circumstances and book of Pharmaceutical Excipients, 3rd edn. > quantity of material being handled. Excessive generation of dust, or inhalation of dust, should be avoided. 11 Stability and Storage Conditions Spray-dried lactose should be stored in a well-closed container in a 16 Regulatory Status cool, dry place. See Lactose, Monohydrate. 12 Incompatibilities 17 Related Substances Lactose is a reducing sugar. The amorphous lactose, which is the Lactose, anhydrous; lactose, inhalation; lactose, monohydrate. most reactive form of lactose present in spray-dried lactose, will interact more readily than conventional crystalline gradesYl Typical reactions include the M aillard reaction with either 18 Comments 131 14 primary or secondary > amines. Spray-dried lactose was one of the first direct-compression See Lactose, Anhydrous and Lactose, Monohydrate. excipients. Spray-dried lactose typically comprises lactose mono hydrate and amorphous lactose (see Section 8); see Lactose, 13 Method of Manufacture Monohydrate for the relevant pharmacopeial information. It has been shown that during the spray-drying process the A suspension of ix-lactose monohydrate crystals in a lactose solution 6 effects of nozzle orifice diameter and atomization air flow control is atomized and dried in a spray drier. 15• ) Approximately 10-20% the droplet size during atomization; however, it has also been of the total amount of lactose is in solution and the remaining demonstrated that increasing feed concentration results in increased 80-90% is present in the crystalline form. The spray-drying process shell thickness of hollow particles that are formed. IS) The physical predominantly produces spherical particles. The compactibility of properties of spray-dried lactose produced from alcoholic media are the material and its flow characteristics are a function of the directly affected by the ethanol-to-water ratio in the feed solution. primary particle size of the lactose monohydrate and the amount of Lactose spray-dried from pure ethanol was shown to be 100% amorphous lactose. I?) crystalline, whereas lactose spray-dried from pure water was 100% amorphous. Furthermore, the surface area of the spraJ;-dried lactose. 14 Safety 1 increased as a function of amorphous content. > Spray-dried 10 Lactose is widely used in pharmaceutical formulations as a diluent lactoses exhibit good fl ow properties.< > in oral capsule and ta blet formulations. It may also be used in Polyethylene glycol (PEG) 4000, when spray-dried with lactose, intravenous injections. has been shown to accelerate the rate and extent of crystallization of Adverse reactions to lactose are largely due to lactose intoler lactose_(lll It has also been shown that spray-dried lactose ance, which occurs in individuals with a defi ciency of the enzyme composite particles containing an ion complex of chitosan are 2 lactase. su itable for the dry-coating of tablets_l1 ) Spray-dried lactose and See Lactose, Monohydrate. crystallized spray-dried lactose have been evaluated for dry powder ------·------,- 378 La no lin 13 14 inhalation application.! , l Amorphous sriray-dried lactose has 15 Berggren J et al. Compression behaviour and tablet-forming ability of also been studied in composites with pyp_(J l spray-dried amorphous composite particles. Eur J Pharm Sci 2004; 22: See also Lactose, Anhyd rous, Lactose, Inhalation and Lactose, 191-200. Monohydrate. 20 General References 19 Specific References Bo lhuis GK, Armstrong NA. Excipients for direct compaction: an update. 1 Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn. Pharm Dev Technol 2006; 11: 111-124. London and Washington, DC: Pharmaceutical Press and American Bolhuis GK, Chowhan ZT. Materials for direct compaction. Alderborn G, Pharmaceutical Association, 2000; 641-643. Nystrom C, eds. Pharmaceutical Powder Compaction Technology. New 2 Blaug SM, Huang W. Interaction of dextro amphetamine sulfate with York: Marcel Dekker, 1996; 473-476. spray-dried lactose. J Pharm Sci 1972; 61: 1770-1775. 3 Castello RA, Mattocks AM. Discoloration of tablets containing amines Bolhuis G et al. New developments in spray-dried lactose. Pharm Tech 2004; and lactose. J Pharm Sci 1962; 51: 106-108. June: 26-31. 4 Wirth DD et al. Maillard reaction of lactose and fluoxetine DMV-Fonterra Excipients. Technical literature: SuperTab 11SD, SuperTab hydrochloride: a secondary amine. J Pharm Sci 1998; 87: 31- 39. 14SD, 2008. http://www.dmv-fonterra-excipients.com (accessed 27 5 Hutton JT et al. Lactose product and method. United States Patent No. February 2009). 3,639,170; 1972. Friesland Foods Domo. Technical literature: Lactopress Sp ray-Dried, 6 Vromans H et al. Spray-dried lactose and process for preparing the Lactopress Spray-Dried 250, 2008. http://www.domo.nl/pharma same. United States Patent No. 4,802,926; 1989. (accessed 27 February 2009 ). 7 Vromans H et al. Studies on tableting properties of lactose. VII. The Fell JT, Newton JM. The characterization of the form of lactose in spray effect of variations in prima ry particle size and percentage of dried lactose. Pharm Acta Helv 1970; 45: 520-522. amorphous lactose in spray dried lactose products. Int J Phann 1987; Fell JT, Newton JM. The production and properties of spray-dried lactose, 35(1-2): 29-37. part 1: the construction of an experimental spray drier and the 8 Elversson J et al. Droplet and particle size relationship and shell production of spray-dried lactose under various conditions of operation. thickness of inhalable lactose particles during spray drying. J Phann Sci Pharm Acta Helv 1971; 46: 226- 235. 2003; 92(4): 900-910. Fell JT, Newton JM. The production and properties of spray-dried lactose, 9 Harjunen PI et al. Effects of ethanol to wa ter ratio in feed solution on part 2: the physical properties of samples of spray-dried lactose produced the crystallinity of spray dried lactose. Drug Dev illd Pharm 2002; on an experimental drier. Pharm Acta Helv 1971; 46: 425-430. 28(8): 949-955. Meggie GmbH. Technical literature: Flow Lac 90, FlowLac 100, 2008. 10 Bhattachar SN et al. Evaluation of the vibratory feeder method for assessment of powder flow properties. Int I Phann 2004; 269: 385- http://www.meggle-pharma. de (accessed 27 February 2009). 392. Price R, Young PM. Visualisation of the crystallisation of lactose from the 11 Corrigan DO et al. The effects of spray drying solutions of polyethylene amorphous state. J Pharm Sci 2004; 93: 155- 164. glycol (PEG) and lactose/PEG on their physicochemical properties. Int J Sheffield Pharma Ingredients. Technical literature: NF Lactose-3 15, NF Pharm 2002; 235(1- 2): 193-205. Lactose-3 16 Fast Flo, 2008. http://www.sheffield-products.com 12 Takeuchi H et al. Spray dried lactose composite particles containing an (accessed 27 February 2009). ion complex of alginate- chitosa n for designing a dry coated ta blet having a time controlled releasing function. Pharm Res 2000; 17: 94- 99. 21 Authors 13 Kawashima Y et al. Effect of surface morphology of ca rrier lactose on S Edge, AH Kibbe, J Shur. dry powder inhalation property of pra nlukast hydrate. Int J Pharm 1998; 172: 179-188. 14 Harjunen P et al. Lactose modifications enhance its drug performance in 22 Date of Revision the novel multiple dose Taifun (R) DPI. Eur J Pharm Sci 2002; 16(4- 5): 313- 32 1. 2 7 February 2009. (y Lanolin 1 Nonproprietary Names 4 Empirical Formula and Molecular Weight BP: Wool Fat The USP 32 describes lanolin as the purified wax-like substance JP: Purified Lanolin obtained from the wool of the sheep, Ovis aries Linne (Fam. Bovidae), that has been cleaned, decolorized, and deodorized. PhEur: Wool Fat It contains not more than 0.25% w/w of water and may contain up to USP: Lanolin 0.02 % w/w of a suitable antioxidant; the PhEur 6.0 specifies up to 200 ppm of butylated hydroxytoluene as an antioxidant. See also Section 18. 2 Synonyms Adeps lanae; cera Janae; E913; lanolina; lanolin anhydrous; S Structural Formula Protalan anhydrous; purified lanolin; refined wool fat. See Section4. 3 Chemical Name and CAS Registry Number 6 Functional Category Anhydrous lanolin [8006-54-0) Emulsifying agent; ointment base. - - - - - . - - - -~------ Magnesium Stearate Nonproprietary Names SEM 1: Excipient: magnesium stearate; magnification: 600x . BP: Magnesium Stearate JP: Magnesium Stearate PhEur: Magnesium Stearate USP-NF: Magnesium Stearate 2 Synonyms Dibasic magnesium stearate; magnesium distearate; magnesii stearas; magnesium octadecanoate; octadecanoic acid, magnesium salt; stearic acid, magnesium salt; Synpro 90. 3 Chemical Name and CAS Registry Number Octadecanoic acid magnesium salt [557-04-0] 4 Empirical Formula and Molecular Weight C.,6H70MgO4 591.24 The USP32- NF27 describes magnesium stearate as a compound of magnesium with a mixture of solid organic acids that consists chiefly of variable proportions of magnesium stearate and magnesium palmitate (C32H62MgO4 ). The PhEur 6.5 describes magnesium stearate as :1 mixture of solid organic acids consisting mainly of variable proportions of magnesium stearate and SEM 2: Excipient: magnesium stearate; magnification: 2400x _ magnesium palmitate obtained from sources of vegetable or animal ongm. 5 Structural Formula [CH3(CH2)16COO]iMg 6 Functional Category Tablet and capsule lubricant. 7 Applications in Pharmaceutical Formulation or Technology Magnesium stearate is widely used in cosmetics, foods, and pharmaceutical formulations. It is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5 .0% w/w. It is also used in barrier creams. See also Section 18. 8 Description Magnesium stearate is a very fine, light white, precipitated or milled, impalpable powder of low bulk density, having a faint odor of stearic acid and a characteristic taste. The powder is greasy to the touch and readily adheres to the skin. 9 Pharmacopeial Specifications See Table I. See also Section 18. 126-130°C (high purity magnesium stearate). NIR spectra see Figure 1. 10 Typical Properties Solubilit:y Practically insoluble in ethanol, ethanol (95%), ethe~ and water; slightly soluble in warm benzene and warm ethano Crystalline forms High-purity magnesium stearate has been (95%). isolated as a trihydrate, a dihydrate, and an anhydrate. 2 Specific surface area 1.6-14.8 m /g Densit:y (bulk) 0.159g/cm3 Densit:y (tapped) 0.286 g/cm3 Densit:y (true) 1.092 g/cm3 Flash point 250°C Flowabilit:y Poorly flowing, cohesive powder. 11 Stability and Storage Conditions Melting range Magnesium stearate is stable and should be stored in a well-closed 117- 150°C (commercial samples); container in a cool, dry place. 404 Magnes ium Stearate 405 1.5 0.2 Table I: Pharmacopeial specifications for magnesium stearate. cZ 2325 '-.._ 2295 2363 JP XV PhEur 6.5 USP32-NF27 1747 '- Test CT) lckrrlification + + + 0 characters + 0.0 -,_~ 12 14 cZ Microbial li mits I '-.._ + + 3 + Q) Aerobic microbes ~ lOOOcfu/g ~ 10 cfu/g ~ lOOOcfu/g u 1764 I 2 I CT) Fungi and yeasts ~ 500cfu/g ~ 10 cfu/g ~ 500cfu/g u 1730 I C Acidity or alka linity ~ I ..2 + + + ~ /1 ., Acid va lue of the fat ty 195-210 I J\ ~ / 235 1 X -...... _... acid I "''...,' 0 I\ ", ,, I freez ing point ;;, 53°C 0 I \ ..__ / ...... Nickel ~ 5ppm 0 _t -- 23 11 Cadmium ~ 3ppm ~ - 3.0 - 0.2 Specific surfa ce area + 11 00 1300 1500 1700 1900 2100 2300 2500 ~ 6.0% ~ 6.0% ~ 6.0% Loss on dryi ng W avelength /nm Chl oride ~ 0.1% ,s; 0. 1% ~ 0. 1% Sulfate ~ 1.0% ,s; l .0% ,s; l .0% Lead ~ l Oppm ,s; 0.001 % Figure 1: Near-in frared spectrum of magnesium stearate measured by Heavy meta ls ~ 20ppm re fl ectance. Rel ative stea ri c/palmitic + + + content tions; intravitreal implants and injections). Included in nonpar Assay (dried, as Mg) 4.0-5.0% 4.0-5.0% 4.0-5.0% enteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. Listed on the US TSCA 12 Incompatibilities inventory. Incompatible with strong acids, alkalis, and im n salts. Avoid mixing with strong oxidizing materials. Magnes ium stearate cannot be used 17 Related Substances in prod ucts containing aspirin, some vitamins, and most alkaloidal Calcium stearate; magnesium aluminum silicate; stearic acid; zinc salts. stearate. 13 Method of Manufacture 18 Comments Magnesium stearate is prepared either by the interaction of aqueous Magnesium stearate is one of the materials that have been selected so lutions of magnesium chloride with sodium stearate or by the for harmonization by the Pharmacopeial Discussion Group. For interaction of magnesium oxide, hydroxide, or carbonate with further info rmation see the General Information Chapter <1196> stearic acid at elevated temperatures. in the USP3 2-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, 14 Safety and also the General In fo rmation Chapter 8 in the JP XV. Magnesium stearate is hydrophobic and may retard the Magnesium stearate is widely used as a pharmaceutical excipient dissolution of a drug from a solid dosage fo rm; the lowest possible and is generally regarded as being nontoxic fo llowing oral concentration is therefore used in such formulations_(5-l0) Capsule administration. However, oral consumption of large quantities dissolution is also sensi ti ve to both the amount of magnesium may produce a laxative effect or mucosa! irritation. stearate in the fo rmulation and the mixing time; higher levels of No toxicity information is available relating to normal routes of magnesium stearate and long mixing times can result in the occupational exposure. Limits for heavy metals in magnesium fo rmation of hydrophobic g owder beds that do not disperse after stearate have been evaluated in terms of magnesium stearate worst 1 12 the capsule shell dissolves .< • ) case da ily intake and heavy metal composition. 7 39 41 42 4 461 consist of mixtures of crystalline fo rms.P • • • ' 4- Because of 8 Chowhan ZT et al. Tablet-to-tablet dissolution variability and its the possibility of conversion of crystalline forms during heating, relationship to the homogeneity of a water-soluble drug. Drug Dev Ind consideration should be given to the pretreatment conditions Pharm 1982; 8: 145- 168 . employed when determining physical 1,roperties of magnesium 9 Lerk CF et al. Interaction of tablet disintegrants and magnesium 4 4 stearate during mixing II : effect on dissolution rate. Pharm Acta Helv stearate powders such as surface area.( , Sl 1982; 57: 282-286. Physical properties of magnes ium stearate can vary among 461 10 Hussain MSH et al. Effect of commercial and high purity magnesium ba tches fr om different manufacturers' because the solid-state stearates on in-vitro disso lution of paracetamol DC tablets. Int J Pharm characteristics of the powder are influenced by manufacturing 1992; 78: 203-207. 361 variables. ' Variations in the physical properties of different lots of 11 Samyn JC, Jung WY. In vitro dissolution from several experimental magnesium stearate from the same vendor have also been capsule formulations. J Pharm Sci 1970; 59: 169-175. 46 observed.' ) Presumably because of these variations, it has not 12 Murthy KS, Samyn JC. Effect of shear mixing on in vitro drug release of been possible to conclusively correlate the dissolution rate retarda capsule formulations contai ning lubricants. J Pharm Sci 1977; 66: 49 tion with observed lubricity. ( ) 1215-1219. However, various physical properties of different batches of 13 Ragnarsson G et al. The influence of mi xing time and colloidal silica on magnesium stearate, such as specific surface area, particle size, the lubricating properties of magnesium stearate. Int J Pharm 1979; 3: 127-131. crystalline structure, moisture content, and fatt acid comriosition, 45 46 14 Bolhuis GK et al. Mixing action and eva luation of tablet lubricants in have been correlated with lubricant efficacy.'37, 41t, , ,50- 5 l Due to direct compression. Drug Deu Ind Phann 1980; 6: 573-589. variations in the specific surface area, the labeling states that specific 15 Bossert J, Stamm A. Effect of mixing on the lubrication of crystalline surface area and the method specified for its determination should lactose by magnesium stearate. Drug Dev Ind Pharm 1980; 6: 573-589. be listed on the label. Reduction in dissolution caused by the effects 16 Bolhuis GK et al. Interaction of ta blet disintegrants and magnesium of magnesium stearate in some cases can be overcome by including a stearate during mixing I: effect on ta blet dis integration. J Pharm Sci 56 highly swelling disintegrant in the formulation. ( ) 198 1; 70: 1328- 1330. The impact of magnesium stea rate levels on tablet compaction 17 Sheikh-Salem M, Fell JT. The influence of magnesi um stearate on time properties and performance of roller compacted granulations has dependent strength changes in tablets. Drug Dev Ind Pharm 1981; 7: 7 59 been examinedY - l In other compaction studies performed with 669- 674. granules, magnesium stearate has been shown to exert an influence 18 Stewart PJ. Influence of magnesium stearate on the homogeneity of a prednisone gran ule ordered mix. Drug Dev Ind Pharm 1981; 7: 485- on granule relaxation and may help to prevent capping. (GO) 495. There is evidence to suggest that the hydrophobic nature of 19 Jarosz PJ, Parrott EL. Effect of tablet lubricants on axial and radial magnesium stearate can vary from batch to batch owing to the work of fai lure. Drug Dev In d Phann 1982; 8: 445- 453. presence of water-sol uble, surface-active impurities such as sodium 20 Mitrevej KT, Augsburger LL. Adhesion of tablets in a rotary ta blet press stearate. Batches containing very low concentrations of these II: effects of blending time, running time, and lubricant concentration. impurities have been shown to retard the dissolution of a drug to Drug Dev Ind Pharm 1982; 8: 237-282. a greater extent than when using batches that contain higher levels 21 Khan KA et al. The effect of mixing time of magnesium stearate on the 4 9 of impurities . ( l One study related lubricity to the fatty acid tableting properties of dried microcrystalline cellulose. Phann Acta composition (stearate : palmitate) of lubricant lots for tablet Helv 1983; 58: 109-111. formulations based on compaction data and tablet material 22 Johansson ME. Investigations of the mixing time dependence of the propertiesY4 l However, other studies have indicated that fatty lubricating properties of granular and powdered magnesium stearate. Acta Phann Suec 1985; 22: 343- 350. acid composition has no influence on lubricant activity(37l and high 23 Johansson ME. Influence of the granulation technique and starting purity magnesium stearate was as effective a lubricant as the material properties on the lubricating effect of granular magnesium commercial material.(JOJ Moisture sorption at different relative stearate. J Pharm Pharmacol 1985; 37: 68 1-685. humidities can result in morphological changes in the magnesium 61 62 24 Chowhan ZT, Chi LI-I. Drug- excipient interactions resulting from stearate. ' • ) powder mixing III: solid state properties and their effect on drug Magnesium stearate has been investi~ated for use in inhalation dissolution. J Pharm Sci 1986; 75: 534-541. powders to control their performance. (6 l 25 Chowhan ZT, Chi LH. Drug-excipient interactions resulting from A specification for ma~nesium stearate is included in the Food powder mixing IV: role of lubricants and their effect on in vitro Chemicals Codex (FCC). ( 4l The EINECS number for magnesium dissolution. J Pharm Sci 1986; 75: 542- 545. stearate is 209-150-3. 26 Johansson ME, Nicklasson M. Influence of mixing time, particle size and colloidal silica on the surface coverage and lubrication of magnesium stearate. Rubinstein MH, ed. Pharmaceutical Technology: 19 Specific References Tableting Technology. Chichester: Ellis Horwood, 1987; 43- 50. 1 Chowhan ZT. Harmonization of excipient standards. Weiner ML, 27 Wang LH, Chowhan ZT. Drug-excipient interactions resulting from Kotkoskie LA, eds. Excipient Toxicity and Safety. New York: Marcel powder mixing V: role of sodium lauryl sulfa te. Int J Pharm 1990; 60: Dekker, 2000; 321-354. 61-78. 2 Anonymous. Final report of the safety assessment of lithium stearate, 28 Muzikova J, Horacek J. 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Effect of moisture and magnesium stearate concentra 57 Wurster DE et al. The influence of magnesium stearate on the hiestand tion on flow properties of cohesive granular materials. Int J Pharm tableting indices and other related mechanical properties of maltodex 2007; 336(2): 338-345. trins. Pharm Dev Technol 2005; 10(4): 461--466. 35 Muller BW. The pseudo-polymorphism of magnesium stearate. Zbl 58 Likitlersuang S et al. The effect of binary mixture composition and Pharm 1977; 116(12): 1261-1266. magnesium stearate concentration on the hiestand tableting indices and 36 Miller TA, York P. Physical and chemical characteristics of some high other related mechanical properties . Pharm Dev Technol 2007; 12(5): purity magnesium stearate and palmitate powders. Int J Pharm 1985; 533-541. 23: 55-67. 59 He X et al. Mechanistic study of the effect of roller compaction and 37 Ertel KD, CarstensenJT. Chemical, physical, and lubricant properties of lubricant on tablet mechanical strength. J Pharm Sci 2007; 96(5): magnesium stearate. Pharm Sci 1988; 77: 625-629. J 1342-1355. 38 Ertel KD, Carstensen JT. An examination of the physical properties of 60 Ebba F et al. Stress relaxation studies of granules as a function of pure magnesium stearate. Int J Pharm 1988; 42: 171- 180. different lubricants. Eur Pharm Biopharm 2001; 52(2): 211-220. 39 Wada Y, Matsubara T. Pseudo-polymorphism and crystalline transition J of magnesium stearate. Thermochim Acta 1992; 196: 63- 84. 61 Swaminathan V, Kildisig DO. An examination of the moisture sorption 40 Sharpe SA et al. Physical characterization of the polymorphic variations characteristics of commercial magnesium stearate. AAPS Pharm Sci of magensium stearate and magnesium palmitate hydrate species. Struct Tech 2001; 2(4): 28. Chem 1997; 8(1): 73- 84. 62 Bracconi P et al. Structural properties of magnesium stearate 41 Leinonen UI et al. Physical and lubrication properties of magnesium pseudopolymorphs: effect of temperature. Int J Pharm 2003; stearate. J Pharm Sci 1992; 81(12): 1194-1198. 262(1-2): 109-124. 42 Muller BW. Polymorphism of magnesium stearate and the influence of 63 Guchardi R et al. Influence of fine lactose and magnesium stearate on the crystal structure on the lubricating behavior of excipients. Acta low dose dry powder inhaler formulations. Int J Pharm 2008; 348( 1-2): Pharm Suec 1981; 18: 74- 75. 10-17. 43 Okoye P, Wu S.H. Lubrication of direct-compressible blends with 64 Food Chemicals Codex, 6th edn. Bethesda, MD: United States magnesium stearate monohydrate and dihydrate. Pharm Technol 2007; Pharmacopeia, 2008; 568. 31(9): 11 6-129. 44 Brittain HG. Raw materials. Drug Dev Ind Pharm 1989; 15(13): 2083- 2103. 20 General References 45 Dansereau R, Peck GE. The effect of the variability in the physical and Bohidar NR et al. Selecting key pharmaceutical formulation factors by chemical properties of magnesium stearate on the properties of regression anaysis. Drug Dev Ind Pharm 1979; 5: 175-216. compressed tablets. Drug Dev Ind Pharm 1987; 13: 975-999. Butcher AE, Jones TM. Some physical characteristics of magnesium stearate. 46 Barra J, Somma R. Influence of the physicochemical variability of J Pharm Pharmacol 1972; 24: 1P-9P. magnesium stearate on its lubricant properties: possible solutions. Drug European Directorate for the Quality of Medicines and Healthcare Dev Ind Pharm 1996; 22(11): 1105- 1120. (EDQM). European Pharmacopoeia - State Of Work Of International 47 Phadke DS, Collier JL. Effect of degassing temperature on the specific Harmoaisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edq surface area and other physical properties of magnesium stearate. Drug m.eu/site/-614.html (accessed 3 February 2009). Dev Ind Pharm 1994; 20(5): 853- 858. Ford JL, Rubinstein MH. An investigation into some pharmaceutical 48 Koivisto M et al. Effect of temperature and humidity on vegetable grade interactions by differential scanning calorimetry. Drug Dev Ind Pharm magnesium stearate. Powder Technol 2004; 147(1- 3): 79- 85. 1981; 7: 675-682. 49 Billany MR, Richards JH. Batch variation of magnesium stearate and its Johansson ME. Granular magnesium stearate as a lubricant in tablet effect on the dissolution rate of salicylic acid from solid dosage forms. Drug Dev Ind Phann 1982; 8: 497- 511. formulations. Int J Pharm 1984; 2 1: 307- 315. 50 Frattini C, Simioni L. Should magnesium stearate be assessed in the Jones TM. The effect of glidant addition on the flowability of bulk formulation of solid dosage forms by weight or by surface area ? Drug particulate solids. J Soc Cosmet Chem 1970; 21: 483-500. Dev Ind Pharm 1984; 10: 1117- 1130. · Pilpel N. Metal stearates in pharmaceuticals and cosmetics. Manuf Chem 51 Bos CE et al. Lubricant sensitivity in relation to bulk density for Aerosol N ews 1971; 42(10): 37--40. granulations based on starch or cellulose. lnt J Pharm 1991; 67: 39- 49. York P. Tablet lubricants. Florence AT, ed. Materials Us ed in Pharmaceutical 52 Phadke DS, Eichorst JL. Evaluation of particle size distribution and Formulation. London: Society of Chemical Industry, 1984; 37-70. specific surface area of magnesium stearate. Drug D_ev Ind Pharm 1991; Zanowiak P. Lubrication in solid dosage form design and manufacture. 17: 901-906. Swarbick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Teclmol 53 Steffens KJ, Koglin J. The magnesium steara te problem. Manuf Chem ogy., vol. 9: New York: Marcel Dekker, 1990; 87-112. 1993; 64(12): 16-19. 54 Marwaha SB, Rubinstein MH. Structure-lubricity evaluation of 21 Authors magnesium stearate. Int J Pharm 1988; 43(3): 249- 255. 55 Rao KP et al. Impact of solid-state properties on lubrication efficacy of LV Allen Jr, PE Luner. magnesium stearate. Pharm Dev Technol 2005; 10(3): 423--437. 56 Desai DS et al. Physical interactions of magnesium stearate with starch 22 Date of Revision derived disintegrants and their effects on capsule and tablet dissolution. Int J Pharm 1993; 91(2- 3): 21 7- 226. 3 February 2009. ______. ,.,.-~ae~~----·------ 424 M a nnitol gloves, and a dust respirator are recommended. When heated to 19 Specific References decomposition, maltose emits acrid smoke and irritating fumes. 1 SP! Pharma Group. Technica l literature: Advantose 100 maltose, 2004. 2 Bowe KE et al. Crystalline maltose: a direct compression pharmaceu tical excipi ent. Pharm Technol Eur 1998; 10(5): 40. 16 Regulatory Status 3 Mulderrig KB. Placebo eva luation of selected sugar-based excipients in In the USA, maltose is considered as a fo od by the FDA and is pharmaceutical and nutraceutical tableting. Pharm. Technol 2000; .th erefore not subject to food additive and GRAS regulations. 24(5): 34, 36, 38 , 40, 42, 44 . Included in the FDA Inactive Ingredients Database (oral solutions). 4 Palevsky PM et al. Maltose-induced hyponatremia. Ann Intern Med 1993; 118(7): 526-528. Included in the Canadian List of Acceptable Non-medicinal 5 Mundt S, Wedzicha BL. Role of glucose in the Maillard browning of Ingredients. Included in parenteral products available in a number maltose and glycine: a radiochemical approach. J Agric Fo od Chem of countries worldwide. 2005;53: 6798-6803. 6 Lewis RJ, ed . Sax's Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 2275. 17 Related Substances 7 Japan Pharmaceutical Excipients Council. Japan Pharmaceutical Glucose, liquid. Excipients, 2004. Tokyo, Yakuji Nippo: 2004; 51 6-518. 20 General References 18 Comments Crystalline maltose, e.g. Advantose 100 (SPI Pharma Group), is spray-dried to produce spherical particles with good flow proper 21 Author ties. The material is also nonhygroscopic and is highly compressible. A specification for maltose syrup powder is contained in the CK Tye. Japanese Pharmaceutical Excipients (JPE).(7) The EINECS number fo r maltose is 200-716-5. The PubChem Compound ID (CID) for 22 Date of Revision ma ltose includes 6255 and 23724983. 19 February 2009. E.t Mannitol Nonproprietary Names 6 Functional Category BP: M annitol Diluent; plasticizer; sweetening agent; tablet and capsule diluent; JP: D-Mannitol therapeutic agent; tonicity agent. PhEur: Mannitol USP: Mannitol 7 Applications in Pharmaceutical Formulation or Technology 2 Synonyms Mannitol is widely used in pharmaceutical formulations and food Cordycepic acid; c •· PharmMannidex; E421; Emprove; manna products. In pharmace utical preparations it is primarily used as a sugar; D-mannite; mannite; mannitolum; Mannogem; Pearlitol. diluent (10- 90 % w/w) in tablet formulations, where it is of particular value since it is not hygroscopic and may thus be used 2 with moisture-sensitive active ingredientsY• ) 3 Chemical Name and CAS Registry Number Mannitol may be used in direct-compression tablet applica tions,,3,4l for which the granular and spray-dried forms are D-Mannitol (6 9-65-8] 5 availa ble, or in wet granulations.< ,6l Granulations containing mannitol have the advantage of being dried easily. Specific tablet 4 Empirical Formula and Molecular Weight applications include antacid preparations, glyceryl trinitrate tablets, and vitamin prepara tions. Mannitol is commonly used as an C6H14O6 182.17 excipient in the manufacture of chewable tablet formulations because of its negative heat of solution, sweetness, and 'mouth 6 7 5 Structural Formula feel'.' ' ) In lyophilized preparations, mannitol (20-90% w/w) has been OH OH included as a carrier to produce a stiff, homogeneous cake that 8 10 improves the appearance of the lyophilized plug in a vial.( - l A pyrogen-free form is available specifically for this use. HO Mannitol has also been used to prevent thickening in aqueous OH antacid suspensions of aluminum hydroxide ( < 7% w/v). It has been suggested as a plas ticizer in soft-gelatin capsules, as a component of 11 sustained-release tablet formulations,' ) and as a carrier in dry 12 13 OH OH powder inhalers.' , ) It is also used as a diluent in rapidly Mannitol 425 4 5 dispersing oral dosage forms_(l ,l l It is used in food applications as SEM 3: Excipient: niannitol powder; manufacturer: SPI Polyols Inc.; lot no: a bulking agent. 3140GB; magnification: 1OO x . Therapeutically, mannitol administered parenterally is used as an osmotic diuretic, as a diagnostic agent for kidney function, as an adjunct in the treatment of acute renal failure, and as an agent to reduce intracranial pressure, treat cerebral edema, and reduce intraocular pressure. Given orally, mannitol is not absorbed significantly from the gastrointestinal tract, but in large doses it can cause osmotic diarrhea; see Section 14. 8 Description Mannitol is D-mannitol. It is a hexahydric alcohol related to mannose and is isomeric with sorbitol. Mannitol occurs as a white, odorless, crystalline powder, or free flowing granules. It has a sweet taste, approximately as sweet as glucose and half as sweet as sucrose, and imparts a cooling sensation in the mouth. Microscopically, it appears as orthorhom bic needles when crystallized from alcohol. Mannitol shows 6 polymorphism. (l ) SEM 4: Excipient: mannitol granular; manufacturer: SPI Polyols Inc.; lot no: 2034F8; magnification: 1OO x . 9 Pharmacopeial Specifications See Table I. See also Section 18. SEM 1: Excipient: mannitol; manufacturer: Merck; magnification: 50x ; voltage: 3.5 kV. 10 Typical Properties Compressibility see Figure 1. Density (bulk) 0.430 g/cm3 for powder; SEM 2: Excipient: mannitol; manufacturer: Merck; magnification: 500x ; 0.7 g/cm3 for granules. voltage: 3.5 kV. Density (tapped) 0.734 g/cm3 for powder; 0.8 g/cm3 for granules. Density (true) 1.514 g/cm3 Dissociation constant pKa = 13.5 at l 8°C Flash point < 150°C Flowability Powder is cohesive, granules are free flowing. Heat of combustion 16.57 kJ/g (3. 96 kcal/g) Heat of solution - 120.9 Jig (- 28 .9 cal/g) at 25°C Melting point 166-168°C Moisture content see Figure 2. NIR spectra see Figure 3. Osmolarity A 5.07% w/v aqueous solution is isoosmotic with serum. Particle size distribution Pearlitol 300 DC: maximum of 0.1 % greater than 500 µm and minimum of 90 % greater than 200 ~tm in size; 426 Mannitol 100 Table I: Pharmacopeial specifications for mannitol. £.::- 90 - Test JP XV PhEur 6.4 USP 32 --·--·-- '\{° Iden tification + + + 80 ,l u Characters + z Appearance of _c Li.'/ + + 70 - /,lj µ solution CT,) C Melting range 166-169°C 165- 170°C 164-169°C Q) l= 60 - Specific rototion + 137° to + 145° + 23° to +25° + 137° to + 145° V) 1 ,I Conductivity ~ 20µS-cm- 0) l 50 Acidity C I\ )(/ + + _c Loss on drying ~ 0.3% ~ 0.5% ~ 0.3% V) ~ 0.007% ~ 0.007% 2 40 Chloride u Sulfate ~ 0.01 % ~ 0.01 % Q) Arsenic ~ 1.3 ppm ~ 1 ppm 30 0 PeaniloJ 300DC ....0 Lead ~ 0.5 ppm I lJ Pe.arlitol 400DC ~ 20 Nickel + ~ 1 ppm £> eorlito.J 500DC Heavy metals ~ 5ppm Reducing sugars + ~ 0.2% + 10 Residue on ~ 0.10% ignition 00 10 20 40 50 60 70 80 90 100 Related + 30 substances Compression force (kN) Bacterial ~ 4 IU/glbJ endotoxinsl0 l ~ 2.5IU/g!cJ figul·,. I; Compress ion characteri stics of granular mannitol (Pearlitol, Roquette Freres). . Microbial ~ lOOcfu/g contamination Tablet diameter: 20 mm. Lubricant: magnesium stearate 0.7% w/w for Assay (dried ;;, 98.0% 98 .0- 102.0% 96.0- 101.5% Pearlitol 400 DC and Pea rlitol 500 DC; magnesium stearole 1% w/w for bas is) Pearlitol 300 DC. (al Test applied only ii the mon nitol is ta be used in the manufacture of parenteral dosage forms. , 12 ,------, (bl For parenteral preparations having a concentration of l 00 g/L or less of mannitol. (cl For parental preparations having a concentration of more than l 00 g/L of monnitol. • Sorption equilibrium moisture 10 + Desorption equi librium moisture Pear/ital 400 D C: maximum of 20 % greater than 500 µm and ~ 8 - minimum of 85% greater than 100 µmin size; c Pear/ital 500 D C: maximum of 0.5% greater than 841 µm and 2 C minimum of 90% greater than 150 µmin size. 0 u 6 Average particle diameter is 250 µm for Pearlitol 300 DC, Q) L... 360 ~Lm for Pearlitol 400 D C and 520 µm for Pearlitol 500 .2 7 V) DCY l See also Figure 4. ·o 4 Refractive index n5° = 1.333 ~ Solubility see Table IL Specific surface area 0.37-0.39 m2/g 2 - Table II: Solubility of mannitol. ------..--- Solvent Solu bility at 20°C 33 43 52 57 67 75 100 Alkalis Soluble Relative humidity (%) Ethan ol (95%) 1 in 83 Ether Practically insoluble Glycerin 1 in 18 Figure 2: Sorption-desorption isotherm for mannitol. Propan-2-ol 1 in 100 Water 1 in 5 .5 12 Incompatibilities Mannitol solutions, 20% w/v or stronger, may be salted out by potassium chloride or sodium chlorid e.T1 91 Precipitation has been 11 Stability and Storage Conditions reported to occur when a 25% w/v mannitol solution was allowed 20 Mannitol is stable in the dry state and in aqueous solutions. to contact plastic.< J Sodium cephapirin at 2 mg/mL and 30 mg/mL Solutions may be sterilized by filtration or by autoclaving and if concentration is incompatible with 20% w/v aqueous mannitol necessary may be autoclaved repeatedly with no adverse physical or solution. Mannitol is incompatible with xylitol infusion and may chemical effects. !lBJ In solution, mannitol is not attacked by cold, form complexes with some metals such as aluminum, copper, and dilute acids or alkalis, nor by atmospheric oxygen in the absence of iron. Reducing sugar impurities in mannitol have been implicated in catalys ts. Mannitol does not undergo Maillard reactions. the oxidative degradation of a peptide in a lyophilized forma The bulk material should be stored in a well-closed container in a tion.<21l Mannitol was found to reduce the oral bioavailability of cool, dry place. cimetidine compared to sucrose. 122l Mannitol 427 ~ 1.5 ...------.0.6 An acceptable daily intake of mannitol has not been specified by o2" 2245 the WHO since the amount consumed as a sweetening agent was '-- 26 not considered to represent a hazard to health. ( ) 0) _Q 27 LD5o (mouse, IP): 14 g/kg( ) 1674 "i:> LD 5o (mouse, IV): 7.47 g/kg ~ 0.0 !Ll'.l,...ltlj,,.JM-1-.t-lH ff.-+-tl.f-rnrllfl~ I-J-'l,,Jl,ol.....lH-l-ltf\l LD 5o (mouse, oral): 22 g/kg 0) -0 0 LDso (rat, IV): 9.69 g/kg C: ~ LD 50 (rat, oral): 13.5 g/kg X 0 • ' 0 ' 15 Handling Precautions 0 .• ,,...... _.. , 2082 226 1 Observe normal precautions appropriate to the circumstances and ~ - 1.5 .__....._...... __.__._...... _..__._.__....._...... _.__.__,_____. - 0 .2 1100 1300 1500 1700 1900 2100 2300 2500 quantity of material handled. Mannitol may be irritant to the eyes; eye protection is recommended. Wavelength/nm 16 Regulatory Status Figure 3: Near-infrared spectrum of mannitol measured by reflectance. 100 ~------~ GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (IP, IM, IV, and SC injections; infusions; buccal, oral and sublingual tablets, powders and capsules; ophthalmic preparations; topical solutions). 80 - \ Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Mon-medicinal ~ Ingredients. (I) .!::! 60 - 17 Related Substances V) I I) Sorbitol. ~ 111_1 jJ 0 .1:0) 40 18 Comments Mannitol is one of the materials that have been selected for ~ harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter < 1196> in the 20 It USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State of Work' document on the PhEur 'EDQM website, and also 1) the General Information Chapter 8 in the JP XV. Mannitol is an isomer of sorbitol, the difference between the two 40 80 100 160 200 polyols occurring in the planar orientation of the OH group on the Particle diameter (f.lm) second carbon atom. Each isomer is characterized by its own individual set of properties, the most important difference being the response to moisture. Sorbitol is hygroscopic, while mannitol resists , igure 4: Particle size distribution of mannitol powder. moisture sorption, even at high relative humidities. Granular mannitol flows well and imparts improved fl ow 13 Method of Manufacture properties to other materials. However, it usually cannot be used Mannitol may be extracted from the dried sap of manna and other with concentrations of other materials exceeding 25% by weight. natural sources by means of hot alcohol or other selective so lvents. Recommended levels of lubricant are 1 % w/w calcium stearate or It is commercially produced by the catalytic or electrolytic reduction 1-2% w/w magnesium stearate. Suitable binders for preparing of monosaccharides such as mannose and glucose. granulations of powdered mannitol are gelatin, methylcellulose 400, starch paste, povidone, and sorbitol. Usually, 3-6 times as much magnesium stearate or 1.5-3 times as much calcium stearate 14 Safety is needed fo r lubrication of mannitol granulations than is needed fo r Mannitol is a naturally occurring sugar alcohol fo un~ in animals other excipients. and plants; it is present in small quantities in almost all vegetables. A study has examined the influence of common excipients such Laxative effects may occur if mannitol is consumed orally in large as sucrose and trehalose, on the crystallization of rnannitol in freeze 3 2 quantitiesY ) If it is used in foods as a bodying agent and daily drying. ( S) ingestion of over 20 g is foreseeable, the product label should bear Mannitol has been reported to sublime at 130°CY91 the statement 'excessive consumption may have .a laxative effect'. Ludiflash (BASF) is a coprocessed excipient used as a tablet fill er, After intravenous injection, mannitol is not metabolized to any binder, and disintegrant, and contains mainly mannitol, and also appreciable extent and is minimally reabsorbed by the renal tubule, crospovidone and polyvinyl acetate. 24 about 80% of a dose being excreted in the urine in 3 hours.( ) A specification for mannitol is contained in the Food Chemicals 3 A number of adverse reactions to mannitol have been reported, Codex (FCC).( 0) primarily following the therapeutic use of 20% w/v aqueous The EINECS number for mannitol is 200-711 -8 . The PubChem 25 intravenous infusions.( ) The quantity of mannitol used as an · Compound ID (CID) for mannitol includes 6251 and 453. excipient is considerably less than that used therapeutically and is consequently associated with a lower incidence of adverse reactions. 19 Specific References However, allergic, hypersensitive-type reactions may occur when 1 Allen LV. Fea tured exc ipient: capsule and tablet diluents. Int J Pharrn mannitol is used as an excipient. Compound 2000; 4(4): 306- 310324- 325. ------.------ 428 Mannitol 2 Yoshinari T et al. Improved compaction properties of rnannitol after a 21 Dubost DC et al. Characterization of a solid state reaction product frn1n moisture induced polymorphic transition. Int J Pharm 2003; 258(1-2): a lyophilized formulation of a cyclic heptapeptide. A novel example 1;f 121-131. an excipient-induced oxidation. Phann Res 1996; 13: 1811-1814. 3 Debord B et al. Study of different crystalline forms of mannitol: 22 Adkin DA et al. The effect of mannitol on the ora l bioavailability ,,f comparative behaviour under compression. Drug Dev Ind Pharm 1987; cimetidine. J Phann Sci 1995; 84: 1405-1409. 13: 1533-1546. 23 Anonymous. Flatulence, diarrhoea, and polyol sweeteners. Lan,~t 4 Molokhia AM et al. Aging of tablets prepared by direct compression of 1983; ii: 1321. bases with different moisture content. Drug Dev Ind Pharm 1987; 13: 24 Porter GA et al. Mannitol hemodilution-perfusion: the kinetics of 1933-1946. mannitol distribution and excretion during cardiopulmonary bypass_J 5 Mendes RW et al. Wet granulation: a comparison of Manni-Tab and Surg Res 1967; 7: 447-456. mannitol. Drug Cosmet Ind 1978; 122(3 ): 36, 38, 40, 44, 87-88. 25 McNeill IY. Hypersensitivity reaction to mannitol. Drug Inte/1 Cli,1 6 Bouffard J et al. Influence of processing variables and physicochemical Pharm 1985; 19: 552- 553. properties on the granulation mechanisms of mannitol in a fluid bed top 26 FAO/WHO. Evaluation of certain food additives and contaminanis_ spray granulator. Drug Dev Ind Pharm 2005; 31: 923-933. Thirtieth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1987; No. 751. 7 Daoust RG, Lynch MJ. Mannitol in chewable tablets. Drug Cosmet Ind 2 7 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, l I 1963; 93(1): 26-2888, 92, 128-129. th edn. New York: Wiley, 2004; 1944-1945. 8 Cavatur RK et al. Crystallization behavior of mannitol in fro zen 28 Schneid S et al. Influence of common excipients on the crystall i 11~ aqueous solutions. Pharm Res 2002; 19: 894-900. modification of freeze-dried mannitol. Pharmaceutical Technology 9 Liao XM et al. Influence of processing conditions on the physical state 2008; 32: 178-184. of mannitol - implications in freeze drying. Pharm Res 2007; 24: 370- 29 Weast RC, ed. Handbook of Chemistry and Physics, 60th edn. Boe, 376. Raton: CRC Press, 1979; c-369. 10 Pyne A et al. Crystallization of mannitol below Tg' during freeze-drying 30 Food Chemicals Codex, 6th edn. Bethesda, MD: United Sta ~ in binary and ternary aqueous systems. Pharm Res 2002; 19: 901-908. Pharmacopeia, 2008; 583. 11 Parah PV et al. Sustained release from Precirol (glycerol palmito stearate) matrix. Effect of mannitol and hydroxypropyl methylccllulose on the release of theophylline. Drug Dev Ind Pharm 1986; 12: 1309- 20 General References 1327. Armstrong NA. Tablet manufacture. Diluents. Swarbrick J, Boylan JC, eds. 12 Tee SK et al. Use of different sugars as fine and coarse carriers for Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3: Ne \' aerosolised salbutamol sulphate. Int J Pharm 2000; 208: 111-123. York: Marcel Dekke1; 2002; 2713-2732. 13 Steckel H, Bolzen N. Alternative sugars as potential carri ers for dry BASF. Product literature: Ludiflash, 2004. http://www.pharma-solutions.• powder inhalers. Int J Pharm 2004; 270(1-2): 297- 306. basf.com (accessed 3 February 2009). 14 Lee KJ et al. Evaluation of critical formulation factors in the Bolhuis GK, Armstrong NA. Excipients for direct compression - an update. development of a rapidly dispersing captopril oral dosage form . Drug Phann Tech Technol 2006; 11: 111-124. Dev Ind Pharm 2003; 29(9): 967- 979. European Directorate for the Quality of Medicines and Healthcal1! 15 Seager H. Drug development products and the Zydis fast dissolving (EDQM). European Pharmacopoeia - State Of Work Of Internation~l dosage form . J Pharm Pharmacol 1998; 50: 375-382. Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.ed.:i· 16 Bauer H et al. Investigations on polymorphism of mannitol/sorbitol m.eu/site/-614.html (accessed 3 February 2009). mixtures after spray drying using differential scanning calorimetry, x Pikal MJ. Freeze drying. Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 2: New York: Marcel Dekke r, ray diffraction and near infrared spectroscopy. Pharm Ind 2000; 62(3): 2002; 1299-1326. 23 1-235. 17 Roquette Freres. Technical literature: Pearlitol, 2004. 18 Murty -BSR, Kapoor JN. Properties of mannitol injection (25% ) after 21 Author repeated autoclavings. Am J Hosp Pharm 1975; 32: 826- 827, NA Armstrong. 19 Jacobs J. Factors influencing drug stability in intravenous infusions. J Hosp Pharm 1969; 27: 341-347. 20 Epperson E. Mannitol crystallization in plastic containers [l etter]. Am J 22 Date of Revision Hosp Pharm 1978; 35: 1337. 3 February 2009. 6.c Polymethacrylates 1 Nonproprietary Names mass of about 150 000. The ratio of (2-dimethylaminoethyl) BP: Ammonio Methacrylate Copolymer (Type A) methacrylate groups to butyl methyacrylate and methyl methacry Ammonio Methacrylate Copolymer (Type B) late groups is about 2: 1: 1. The PhEur 6.0 describes ammonio Basic Butylated Methacrylate Copolymer methyacrylate copolymer as a poly(ethyl propenoate-co-methyl 2- Methacrylic Acid-Ethyl Acrylate Copolymer (1: 1) methylpropenoate-co-2-(trimethylammonio)ethyl 2-methylpro Methacrylic Acid-Ethyl Acrylate Copolymer (1: 1) penoate) chloride having a mean relative molecular mass of about Dispersion 30 per cent 150 000. The ratio of ethyl propenoate to methyl 2-methylpro Methacrylic Acid-Methyl Methacrylate Copolymer (1: 1) penoate to 2-(trimethylammonio)ethyl 2-methylpropenoate . is Methacrylic Acid-Methyl Methacrylate Copolymer (1: 2) about 1: 2: 0.2 for Type A and 1: 2: 0.1 for Type B. Polyacrylate Polyacrylate Dispersion (30 per cent) dispersion (30 per cent) is described in the PhEur 6.3 as a dispersion in water of a copolymer of ethyl acrylate and methyl methacrylate PhEur: Ammonio Methacrylate Copolymer (Type A) having a mean relative molecular mass of about 800 000. It may Ammonio Methacrylate Copolymer (Type B) contain a suitable emulsifier. Basic Butylated Methacrylate Copolymer The USP32-NF27 describes methacrylic acid copolymer as a Methacrylic Acid- Ethyl Acrylate Copolymer (1: 1) fully polymerized copolymer of methacrylic acid and an acrylic or Methacrylic Acid-Ethyl Acrylate Copolymer (1: 1) methacrylic ester. Three types of copolymers, namely Type A, Type Dispersion 30 per cent B, and Type C, are defined in the monograph. They vary in their Methacrylic Acid-Methyl Methacrylate Copolymer (1: 1) methacrylic acid content and solution viscosity. Type C may contain Methacrylic Acid-Methyl Methacrylate Copolymer (1: 2) suitable surface-active agents. Ammonio methacrylate copolymers Polyacrylate Dispersion 30 per cent Type A and Type B, consisting of fully polymerized copolymers of USP-NF: Amino Methacrylate Copolymer acrylic and methacrylic acid esters with a low content of quaternary Ammonio Methacrylate Copolymer ammonium groups, are also described in the USP32-NF27. They Ammonio Methacrylate Copolymer Dispersion vary in their ammonio methacrylate units. The USP32-NF27 also Ethyl Acrylate and Methyl Methacrylate Copolymer describes amino methacrylate copolymer as a fully polymerized Dispersion copolymer of 2-dimethylaminoethyl methacrylate, butyl methacry Methacrylic Acid Copolymer late and methyl methacrylate. See Sections 9 and 18. Further Methacrylic Acid Copolymer Dispersion monographs for aqueous dispersions of Type C methacrylic acid Note that six separate monographs applicable to polymethacrylates copolymer, ammonio methacrylate copolymer, and also ethyl are contained in the USP32-NF27. Several different types of acrylate and methyl methacrylate copolymer are also defined; see material are defined in the same monographs. The PhEur (6.0, 6.2, Section 9. and 6.3) contains eight separate monographs applicable to Typically, the molecular weight of the polymer is ;:;, 100 000. polymethacrylates. See also Section 9. S Structural Formula 2 Synonyms Acryl-EZE; acidi methacrylici et ethylis acrylatis polymerisatum; R1 R3 R1 R3 acidi methacrylici et methylis methacrylatis polymerisatum; ammo I I I I nio methacrylatis copolymerum; copolymerum methacrylatis buty - -1--c-cH, - C- CH, - C-CH,- C-CH,-+-- lati basicum; Eastacryl; Eudragit; Kollicoat MAE; polyacrylatis I I I I dispersio 30 per centum; polymeric methacrylates. See also Table I. c= o c= o c= o c= o I I I I 0 0 0 0 3 Chemical Name and CAS Registry Number See Table I. l, l. l, l. n 4 Empirical Formula and Molecular Weight For Eudragit E: R1,R3 =CH The PhEur 6.2 describes methacrylic acid-ethyl acrylate copolymer 3 R2 = CH2CH2N(CH3)i (1 : 1) as a copolymer of methacrylic acid and ethyl acrylate having a R4 = CH3, C4H9 mean relative molecular mass of about 250 000. The ratio of For Eudragit L and Eudragit S: carboxylic groups to ester groups is about 1 : 1. It may contain 3 suitable surfactants such as sodium dodecyl sulfate or polysorbate R1,R =CH3 R2 =H 80. An aqueous 30% w/v dispersion of this material is also defined 4 in a separate monograph. Methacrylic acid-methyl methacrylate R = CH3 copolymer (1: 1) is described in the PhEur 6.0 as a copolymer of For Eudragit PS: R1 = H methacrylic acid and methyl methacrylate having a mean relative 2 molecular mass of about 135 000. The ratio of carboxylic acid to R =H,CH3 3 ester groups is about 1 : 1. A further monograph in the PhEur 6.0 R = CH3 4 describes methacrylic acid- methyl methacrylate copolymer (1: 2), R = CH3 where the ratio of carboxylic acid to ester groups is about 1 : 2. The For Eudragit RL and Eudragit RS: 1 PhEur 6.0 describes basic butylated methyacrylate copolymer as a R = H, CH3 copolymer of (2-dimethylaminoethyl) methacrylate, butyl methya R 2 = CH3, C2Hs 3 crylate, and methyl methacrylate having a mean relative molecular R = CH3 525 526 Po lymethacry lates Table I: Chemical name and CAS Registry Number of polymethacrylates. Chemical name Trade name Company name CAS number -- --- ·--·-·--·------. Poly(butyl methacrylate, (2-d imethylaminoethyl) methacrylate, methyl methacrylate) 1 : 2 : 1 Eudrogit E I 00 Evonik Industries [24938-J~j Eudragit E 12.5 Evonik Industries Eudrogit E PO Evonik Industries Poly(ethyl acrylate, methyl methacrylate) 2: 1 Eudragit NE 30 D Evonik Industries [9010-88-2] Eudragit NE 40 D Evonik Industries Eudragit NM 30 D Evonik Industries Poly(methacrylic acid, methyl methacrylate) 1 : 1 Eudragil L I 00 Evonik Industries [25806-15-1] Eudragit L 12.5 Evonik Industries Eudragit L 12.5 P Evonik Industries Poly(methacrylic acid, ethyl acrylate) 1 : 1 Acryl-EZE Colorcon [25212-88-8] Acryl-EZE 93A Colorcon Ac;r,.,'-EZE MP Colorcon Eu ragit L 30 0-55 Evonik Industries Eudragit L I 00-55 Evonik Industries Eastocryl 300 Eastman Chem ical Kollicoot MAE BASF Fine 30 DP Chemicals Kollicoot MAE BASF Fine IO0P Chemicals Poly(methacrylic acid, methyl methacrylate) 1 : 2 Eudragit S I 00 Evonik Industries [25086-15-1] Eudrogit S 12.5 Evonik Industries Eudrogit S 12.5 P Evonik Industries Poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7: 3: 1 Eudrogit FS 300 Evonik Industries [26936-24-3] Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2: 0.2 Eudrogit RL I 00 Evonik Industries [33434-24- 1] Eudrogit RL PO Evonik Industries Eudrogit RL 30 D Evonik Industries Eudrogit RL 12.5 Evonik Industries Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 : 2: 0. 1 Eudrogit RS I 00 Evonik Industries [33434-24-1] Eudrogit RS PO Evonik Industries Eudrogit RS 30 D Evonik Industries Eudrogit RS 12.5 Evonik Industries 4 R = CH2CH2N(CH3)J +ci- functional ionic groups. They swell in aqueous media independently For Eudragit NE 30 D and Eudragit NE 40 D: of pH without dissolving. R1, R3 = H, CH3 Eudragit L 30 D-55 is used as an enteric coating film former for R2, R4 = CH3, C2Hs solid-dosage form~. The coating is resistant to gastric juice but For Acryl-EZE and A cryl-EZE MP; Eudragit L 30 D-55 and dissolves readily at above pH 5.5. Eudragit L 100-55, Eastacryl 30 D, Kollicoat MAE 100 P, and Eudragit L 100-55 is an alternative to Eudragit L 30 D-55. It is Kollicoat MAE 30 DP: commercially available as a redispersible powder. 1 1 R. , R. = H, CH3 Kollicoat MAE 100 P, Acryl-EZE and Acryl-EZE MP are also R2 = H commercially available as redispersible powder forms, which are R 4 = CH3, C2Hs designed for enteric coating of tablets or beads. Eastacryl 30 D and Kollicoat MAE 30 DP are aqueous 6 Functional Category dispersions of methacrylic acid-ethyl acrylate copolymers. They are also used as enteric coatings for solidcdosage forms. Film-forming agent; tablet binder; tablet diluent. Polymethacrylates are also used as binders in both aqueous and organic wet-granulation processes. Larger quantities (5-20%) of 7 Applications in Pharmaceutical Formulation or dry polymer are used to control the release of an active substance Technology from a tablet matrix. Solid polymers may be used in direct Polymethacrylates are primarily used in oral capsule and tablet compression processes in quantities of 10-50%. 2 1 formulations as film-coating agentsY- ) Depending on the type of Polymethacrylate polymers may additionally be used to form the matrix layers of transdermal delivery systems and have also been polymer used, films of different solubility characteristics can be 21 produced; see Table II. used to prepare novel gel formulations for rectal administration.12 Eudragit E is used as a plain or insulating film former. It is See also Section 18. soluble in gastric fluid below pH 5. In contrast, Eudragit L, Sand FS types are used as enteric coating agents because they are resistant 8 Description to gastric fluid. Different types of enteric coatings are soluble at Polymethacrylates are synthetic cationic and anionic polymers of different pH values: e.g. Eudragit L is soluble at pH > 6 whereas dimethylaminoethyl methacrylates, methacrylic acid, and Eudragit S and FS are soluble at pH > 7. The S grade is generally methacrylic acid esters in varying ratios. Several different types used for coating tablets, while the flexible FS 30 D dispersion is are commercially av ailable and may be obtained as the dry powder, preferred for coating particles. as an aqueous dispersion, or as an organic solution. A (60: 40) Eudragit RL, RS, NE 30 D, NE 40 D, and NM 30 Dare used to mixture of acetone and propan-2-ol is most commonly used as the form water-insoluble film coats for sustained-release products. organic solvent. See Tables I and Ill. Eudragit RL films are more permeable than those of Eudragit RS, Eudragit E is a cationic polymer based on dimethylaminoethyl and films of varying permeability can be obtained by mixing the two methacrylate and other neutral methacrylic acid esters. It is soluble types together. The neutral Eudragit NE/NM grades do not have in gastric fluid as well as in weakly acidic buffer solutions (up to pH Po lymeth acryl ates 527 Table II: Summary of properties and uses of commercially available polymethacrylates. Grade Supply form Polymer dry weight Recommended solvents Solubility/ permeability Applications content or diluents Eudragit E 12.5 Organic solution 12.5% Acetone, alcohols Soluble in gastric fluid to Film coating ILH 5 Eudragit E 100 Granules .98% Acetone, alcohols So uble in gastric fluid to Film coating H 5 ' Eudragit E PO Powder 98% Acetone, alcohols Soluble in gastric fluid to Film coating ILH 5 Eudragif L 12.5 P Organic solution 12.5% Acetone, alcohols So uble in intestinal fluid En teric coatings from pH 6 Eudragit L 12.5 Organic solution 12.5% Acetone, alcohols Soluble in intestinal flu id Enteric coatings from pH 6 Eudragit L 100 Powder 95% Acetone, alcohols Soluble in intestinal flu id Enteric coatings from pH 6 Eudragit L 100-55 Powder 95% Acetone, alcohols Soluble in intesti na l fluid Enteric coatings from p H 5 .5 Eudragif L 30 D-55 Aqueous dispersion 30% Water Soluble in intestinal fluid Enteric coatings from pH 5.5 Eudragif S 12.5 P Organic solution 12.5% Acetone, alcohols Soluble in intestinal fluid Enteric coatings from pH 7 Eudragif S 12.5 O rganic solu tion 12.5% Acetone, a lcohols Soluble in intestinal fluid Enteric coatings from pH 7 Eudrag if S 100 Powder 95% Acetone, alcohols Soluble in intestina l fluid En teric coatings from pH 7 Eudragit FS 30 D Aqueous dispersion 30% Water Soluble in intestinal fluid Enteric coatings from pH 7 Eudragit RL 12.5 Organic solution 12.5% Acetone, a lcohols High permeabili ty Susta ined release Eudragif RL 100 Granules 9 7% Acetone, alcohols High permeability Sustained relea se Eudragif RL PO Powder 97% Acetone, alcohols High permeability Sustained release Eudragit RL 30 D Aqueous dispersion 30% Water High permeability Susla ined release Eudragit RS 12.5 Organic solution 12.5% Acetone, alcohols l ow permeability Sustained release Eudragif RS 100 Granules 97% Acetone, alcohols low permeability Sustained release Eudragit RS PO Pow der 97% Acetone, a lcohols low permeability Sustained release Eudragit RS 30 D Aqueous dispersion 30% Water l ow permeability Sustained release Eudragit NE 30 D Aqueous dispersion 30% Water Swellable, permeable Sustained release, tablet matrix Eudragit NE 40 D Aqueous dispersion 40% Water Swellable, permeable Sustained release, tablet matrix Eudragit NM 30 D Aqueous dispersion 30% Water Swellable, permea ble Sustained release, tablet matri x Eostacry/30 D Aqueous dispersion 30% Water Soluble in intestinal fluid Enteric coatings from pH 5.5 Kollicoat MAE 30 DP Aqueous dispersion 30% Water Soluble in intestina l fluid Enter ic coating s from pH 5 .5 Kollicoaf MAE 100 P Powder 95% Acetone, a lcohols Soluble in intes tinal fluid Enteric coating s from pH 5.5 Acryl-EZE Powder 95% Acetone, alcohols Soluble in intestinal fl uid Enteri c coating s from pH 5.5 Acryl-EZE 93 A Powder 95% Acetone, alcohols Soluble in intestina l fluid Enter ic coatings from pH 5.5 Acryl-EZE MP Powder 95% Acetone, alcohols Soluble in intestinal fluid Enteric coatings from pH 5.5 Note: Recommended plasticizers for the above polymers include di butyl phtha late, polyethylene glycols, tri ethyl citrate, tria cetin, and l ,2-propylene glycol. Th e recommended concentration of th e plasticizer is approximately l 0-25% plasti cizer (based on the dry polymer weight). A plasticizer is not necessary with Eudragit E 12. 5, Eudragit E I 00 and Eudragit NE 30 D. ~ 5). Eudragit E is availa ble as a 12.5% ready-to-use solution in ready-to-use solution in propan-2-ol with 1.25 % dibutyl phthalate propan-2-ol-acetone (60 : 40). It is light yellow in color with the as plasticizer (Eudragit L 12.5 P and S 12.5 P). Solutions are characteristic odor of the solvents. Solvent-free granules contain colorless, with the characteristic odor of the solvent. Eudragit L - ~98% dried weight content of Eudragit E. Eudragit E PO is a white 100 and Eudragit S-100 are white free-fl owing powders with at free-flowing powder with at least 95% of dry polymer. least 95% of dry polymers. Eudragit L and S, also referred to as methacrylic acid Eudragit FS 30 D is the aqueous dispersion of an anionic copolymers in the USP32-NF27 monograph, are anionic copoly copolymer based on methyl acrylate, methyl meth acrylate, and merization products of methacrylic acid and methyl methacrylate. methacrylic acid. The ratio of free carboxyl groups to es ter groups is The rati o of free carboxyl groups to the es ter is approximately 1: 1 approximately 1: 10. It is a highl y fl exible polymer, designed fo r use in Eudragit L (Type A) and approximately 1: 2 in Eudragit S (Type in enteric-coated solid-dosage forms, and dissolves in aqueous B). Both polymers are readily soluble in neutral to weakly alkaline systems at pH > 7. conditions (pH 6-7) and form salts with alkalis, thus affording film Eudragit RL and Eudragit RS, also referred to as ammonia coats that are resistant to gastric media but soluble in intestinal methacrylate copolymers in the USP32- NF27 monograph, are fluid. They are available as a 12.5% solution in propan-2-ol copolymers synthesized fr om acrylic acid and methacrylic acid without plasticizer (Eudragit L 12.5 and S 12.5); and as a 12.5 % esters, with Eudragit RL (Type A) having 10 % of fun cti onal ------ 528 Polyme thacry la tes Table Ill: Solubility of C?mmerciany available polymethacrylates in various solvents. Grade Solvent Acetone and Dichloromethane Ethyl 1 N HCI 1 N NaOH Petroleum Water alcohols la) acetate ether ------·------·--·------·-· . Eudragit E 12.5 M M M M M Eudragit E 100 s s s I I Eudragit L 12.5 P M M M M p p Eudragit L 12.5 M M M M p p Eudragit L 100-55 s I I s I I Eudragit L 100 s I I s I I Eudragit L 30 D-551bl Mic! M M Eudragit 5 12.5 P M M M M p p Eudragit 5 12.5 M M M M p p Eudragit 5 100 s I I s I I Eudragit RL 12.5 M M M p M Eudragit RL 100 s s s I I Eudragit RL PO s s s I I Eudragit RL 30 D161 Mic! M M I M Eudragit RS 12 .5 M M M p M Eudragit RS 100 s s s I I Eudragit RS PO s s s I I I Eudragit RS 30 olbJ Mic! M M I I M Eastacryl 30 ol b) MicJ M M Kol/icoat MAE 30 op.bl Mlcl M M Kollicoat MAE 100 P MlcJ M M Acryl-EZE s s I ~'!yl-EZE MP s s I (o) Alco hols including ethanol (95%), methanol, ond propon-2-ol. (b) Supplied os o mi lky-white aqueous dispersion. (c) A l : 5 mi xture forms o clear, viscous, solution. S = soluble; M = miscible; I = insoluble or immiscible; P = precipitates. l port of Eudrogit RL 30 Dor of Eudragit RS 30 D dissolves completely in 5 ports acetone, ethanol (95%), or propon-2-ol lo form a clear or slightly turbid solution. However, when mixed in o ratio of 1 : 5 with methanol, Eudragif RL 30 D dissolves completely, whereas Eudragit RS 30 D dissolves only partially. quaternary ammonium groups and Eudragit RS (Type B) having produced are insoluble in water, but give pH-independent drug 5% of functional quaternary ammonium groups. The ammonium release. groups are present as salts and give rise to pH-independent Eudragit NM 30 D is an aqueous dispersion of a neutral permea bility of the polymers. Both polymers are water-insoluble, copolymer based on ethyl acrylate and methyl methacrylate, and is and films prepared from Eudragit RL are freely permeable to water, of identical monomer composition to Eudragit NE 30 D. whereas, films prepared from Eudragit RS are only slightly Eudragit L 30 D-55 is an aqueous dispersion of an anionic permeable to water. They are available as 12.5% ready-to-use copolymer based on methacrylic acid and ethyl acrylate. The solutions in propan-2-ol-acetone (60: 40). Solutions are colorless copolymer corresponds to USP32-NF2 7 methacrylic acid copoly or slightly yellow in color, and may be clear or slightly turbid; they mer, Type C. The ratio of free-carboxyl groups to ester groups is have an odor characteristic of the solvents. Solvent-free granules 1: 1. Films prepared from the copolymers dissolve above pH 5.5, (Eudragit RL 100 and Eudragit RS 100) contain :;,,: 97% of the forming salts with alkalis, thus affording coatings that are insoluble dried weight content of the polymer. in gastric media but soluble in the small intestine. Eudragit RL PO and Eudragit RS PO are fine, white powders Eastacryl 30D and Kollicoat MAE 30 DP are also aqueous with a slight amine-like odor. They are characteristically the same dispersions of the anionic copolymer based on methacrylic acid and polymers as Eudragit RL and RS. They contain :;,,: 97% of dry ethyl acrylate. The copolymer also corresponds to USP32- NF27 polymer. methacrylic acid copolymer, Type C. The ratio of free-carboxyl Eudragit RL 30 D and Eudragit RS 30 D are aqueous groups to ester groups is 1 : 1. Films prepared from the copolymers dispersions of copolymers of acrylic acid and methacrylic acid dissolve above pH 5.5, forming salts with alkalis, thus affording esters with a low content of quaternary ammonium groups. The coatings that are insoluble in gastric media but soluble in the small dispersions contain 30% polymer. The quaternary groups occur as intestine. salts and are responsible for the permeability of films made from Eudragit L 100-55 (prepared by spray-drying Eudragit L 30 D- these polymers. Films prepared from Eudragit RL 30 Dare readily 55) is a white, free-flowing powder that is redispersible in water to permeable to water and to dissolved active substances, whereas form a latex that has properties similar to those of Eudragit L 30 D- films prepared from Eudragit RS 30 Dare less permeable to water. 55. Film coatings prepared from both polymers give pH-independent Acryl-EZE and Acryl-EZE MP are also commercially available release of active substance. Plasticizers are usually added to improve as redispersible powder forms, which are designed for enteric film properties. coating of tablets and beads, respectively. Eudragit NE 30 D and Eudragit NE 40 D are aqueous dispersions of a neutral copolymer consisting of polymethacrylic 9 Pharmacopeial Specifications acid esters. The dispersions are milky-white liquids of low viscosity Specifications for polymethacrylates from PhEur 6.0, 6.2, and 6.3 and have a weak aromatic odor. Films prepared from the lacquer are shown in Table IV, and those from the USP32-NF27 in Table V. swell in water, to which they become permeable. Thus, films See also Section 18. Table IV: Specifications from PhEur 6.0, 6.2, and 6.3. ------Test Ammonia methacrylate Methacrylic acid-ethyl Methacrylic acid-ethyl Methacrylic acid- methyl Methacrylic acid-methyl Basic butylated Polyacrylate dispersion copolymer10l (PhEur 6.0) acrylate copolymer acrylate copolymer methacrylate copolymer methac1ate copolymer methacrylate 30% 191 (PhEur 6.3) (1 : l Jib! (PhEur 6.2) (1: 1) dispersion 30%(cl (1 : lJ 1dJ (PhEur 6.0) (1 : 2J!el PhEur 6.0) copolymer1~ (PhEur 6.3) (PhEur 6.0) Identifica ti on + + + + + + + Characters + + + + + + + Appearance of o film + - + + + + + Relative density 1.037- 1.047 Apparent viscosity ,;;1 5mPas ,_ ,;; 15 mPa s 50- 200mPas 50- 200mPas 3-6 mPas ,;;50 mPa s Absorbance at 420 nm ,;; 0.3 Particulate matter - - ,;;1 .0% - ,;;0.5% Limit of monomers ,;; 0.3% ,;; l00ppm Ethyl acrylate and ,;; l00ppm ,;;0.1 % ,;; 0.1% - - methacrylic acid Methyl methacrylate and ,;; 50ppm ,;; 0.1 % ,;;0.1% methacrylic acid Residue on evaporation - - 28.5- 31.5% - - - 28.5- 31 .5% Loss on drying ,;; 3.0% ,;;5.0% ,;; 5.0% ,;;5.0% ,;; 2.0% Methanol + - - - - Heavy metals ,s;20ppm ,;; 20ppm ,;; 20ppm Su lfated ash - + ,;; 0.2% ,;; 0.1% ,;;0.1 % ,;;0.1% ,;;0.4% Type A - 0.4% - - - - Type B - 0.5- 3.0% - - - - Microbial contamination - - ,;; 103 cfu/ g ,;; 103 cfu/g Assay Ammonia methacrylate Methacrylic acid Methacrylic acid Methacrylic acid Methacrylic acid Dimethylaminoethyl Residue on units units units units units units evaporation + + 46.0- 50.6% 46.0-50.6% 27.6- 30.7% 20.8-25.5% 28.5%- 31 .5% Type A 8.9- 12.3% 46.0- 50.6% Type B 4.5- 7.0% 43.0- 48.0% (a) Corresponds lo Eudragil RL/RS. (b) Corresponds 10 Eudragit L100.55 . (c) Corresponds 1o Eudragit L 30 0-55. (d) Corresponds lo Eudragit L. (e) Corresponds to Eudragit S. (f) Corresponds to Eudragit E. ,., (g) Corresponds to Eudragit NE 30 D. "0 --< 3 (D 5'- 0 n -< 0 u,ro (JI "',0 u, Table V: Specifications from USP32-NF27. w 0 Test Amino methacrylate Ammonio methacrylate Ammonio methacrylate Ethyl acrylate and methyl Methacrylic acid Methacrylic acid c copolymer 101 copolymerlbJ copolymer dispersion1 (al Corresponds to Eudrogit E 100. (b) Corresponds to Eudrogit RL and RS. (c) Corresponds to Eudragit RL 30 D and RS 30 D. (d) Corresponds to Eudragit NE 30 D. (e) Corresponds to Eudragit L, Sand L100-55 . (f) Corresponds to Eudrogit L 30 0-55. (g) Calculated based on undried dispersion basis. Po lymethacrylates 531 10 Typical Properties l.5.------, 1. 2 1649 Acid value ,··---- 1_331 I 300-330 for Eudragit L 12.5, L 12.5 P, L 100, L 30 D-55, L 0) ,,, 100-55, Eastacryl 30 D, Kollicoat MAE 100 P, and Kollicoat 0 1224 :, r:R'J / MAE30 DP; ·;::> i:iZ 180-200 for Eudragit S 12.5, S 12.5 P, and S 100. ~ 0.O1-'-t--+t-f--1~1-1\fv--"'-V-:t-JhrRN"+Hf-lF-+M''-+.;;wA...,,,.-J ---- - Alkali value 7J 0) 162-198 for Eudragit E 12.5 and E 100; C .2. ~ I I 2136 23.9-32.3 for Eudragit RL 12.5, RL 100, and RL PO; X I 1953 27.5-31.7 for Eudragit RL 30 D; 0 I 0 1187 19 10 12.1-18.3 for Eudragit RS 12.5, RS 100, and RS PO; 0 1678 .- -1.5 ..._.._...__.___,___._.___.._...__.___,___,__.___..____, 0. l 16.5-22.3 for Eudragit RS 30 D. 11 00 1300 1500 1700 1900 2100 2300 2500 Density (bulk) 0.390 g/cm3 Density (tapped) 0.424 g/cm 3 Wavelength/nm Density (true) 0.811-0.821 g/cm 3 for Eudragit E; Figure 1: N ear-infrared spectrum of polymethacrylates (Eudragit E 100) measured by refl ectance. 0.83-0.85 g/cm3 for Eudragit L, S 12.5 and 12.5 P; ~ 5.0 0.2 1.058-1.068 g/cm 3 for Eudragit FS 30 D; ciZ" '--. 23 16 0.831-0.852g/cm3 for Eudragit L, S 100; 0) l.062-l.072g/cm3 for Eudragit L 30 D-55; 22 16 -2 165 1 3 1711 0.821-0.841g/cm for Eudragit L 100-55; 1931 ' 3 -~ IY. 0.816-0.836g/cm for Eudragit RL and RS 12.5; (I) , _ 7J 3 0. 0 · 0.816- 0.836 g/crn for Eudragit RL and RS PO; 7J U) 3 C 0 1.047-1.057 g/cm for Eudragit RL and RS 30 D; ~ 118/ 1.037-1.047 g/cm3 for Eudragit NE 30 D; X 1910 , , - I \ ' ~ 12136 1.062- 1.072 g/cm 3 fo r Eastacryl 30 D; 0 ,\ , ... , ~- --- 0 I\ ,-,, I 1729 , 3 0 I '--.._I ,.._ _ _... l 680 2282' 1.062-1.072 g/cm for Kollicoat MAE 100 P and Kollicoat 0 224 ~ MAE 30 DP. .- - 5. 0 ..._..___.__~_._~~------..__...__...___.___.__. - 0 .2 NIR spectra see Figures 1, 2, 3, 4, 5, 6, and 7. 1100 1300 1500 1700 1900 2100 2300 2500 Refractive index Wavelength/ nm nt0 = 1.38-1.385 for Eudragit E; Figure 2: Near-infrared spectrum of polymethacrylates (Eudragil E PO) 0 = nt 1.39- 1.395 for Eudragit Land S; measured by re flectance. nt0 = 1.387-1.392 for Eudragit L 100-55; ~ 1.0 ~------~ 0.5 nt0 = 1.38- 1.385 for Eudragit RL and RS. ciZ" Solubility see Table III. '--. Viscosity (dynamic) 0) 0 3-12 mPa s for Eudragit E; ;;;; 50mPas fo r Eudragit NE 30 D; . ~ 0 ,0 l¼-rP-""'-1,j -h,,_;:,.-q ....___a-:: (I) 50-200 mPa s for Eudragit L and S; -cJ 11 74 2440 rn -cJ I ) ;;;; 20 111Pa s for Eudragit PS 30 D; C 2282 ;;;; 15mPas for Eudragit L 30 D-55; ~ X 100-200mPas for Eudragit L 100-55; 0 r, ;;;; 15 mPa s for Eudragit RL and RS; 8 / .,_ __, 2250 ;;;; 200 111Pa s for Eudragit RL and RS 30 D; .-- 1.5 .__,__,___.___.___.___,___,___,__--'--'----'-----'---'--' 0.2 1500 1700 1900 2100 2300 2500 ;;;; 15 mPa s for Kollicoat MAE 100 P and Kollicoat MAE 30 DP; 1100 1300 145 mPas for Eastacryl 30D. Wavelength/ nm Figure 3: Near-infrared spectrum of polymethacrylates (Eudragit L 100) measured by reflectance. 11 Stability and Storage Conditions Dry powder polymer forms are stable at temperatures less than 12 Incompatibilities 30°C. Above this temperature, powders tend to form clumps, Incompatibilities occur with certain polymethacrylate dispersions although this does not affect the quality of the substance and the depending upon the ionic and physical properties of the polymer clumps can be readily broken up. Dry powders are stable for at least and solvent. For example, coagulation may be ca used by soluble 3 years if stored in a tightly closed container at less than 30°C. electrolytes, pH changes, some organic solvents, and extremes of Dispersions are sensitive to extreme temperatures and phase temperature; see Table II. For example, dispersions of Eudragit L 30 separation occurs below 0°C. Dispersions should therefore be D, RL 30 D, L 100-55, and RS 30 D are incompatible with stored at temperatures betwee n 5 and 25°C and are stable for at magnesium stearate. Eastacryl 30 D, Ko llicoat MAE 100 P, and least 18 months after shipping fr om the manufacturer's warehouse Ko llicoat MAE 30 DP are also incompatible with magnesium if stored in a tightly closed container at the above conditions. stearate. ------c---··········------ 5 3 2 Polymeth acrylates 0.7 1.2 .------.0.6 &""" 22 71 2320 2267 ...... __ 1646 2425 ' 22 13 : ' 2317 0) 0) _Q ..Q 0.0 > 0 .0 l-¼--P----'--lt>A--#'"-..J...\¾r4P"'+ --F:::>..£-\ll-l--'--4--ll+~H-F-l ·>;::: ·;::: Q) Q) -0 1178 -0 I 21 36 ; 1907; -0 1909 ' . 24ot I -~ -0 228 12441 ~ C 1678 .. , ,'. / .. , 2442 C 1677,,__ '··' £::!... . \ .. : "' ..... ,' £::!... : . X . ·' X ' 0 ,. 0 , ' ' 0 , . ' 0 p I: 2251 0 . ' 2255 0 ,' \ ...... ' ~ - 1 .5 .___,___.__,___,_..___.__,____._..__...__.____..___,..__. -0. 2 ~ - 2. 0 ,...__.__.__..__...__...__...,___,___,___,__...... _...... __,____._....,, 0 2 1100 1300 1500 1700 1900 2100 2300 2500 1100 1300 1500 1700 1900 2100 2300 250-0 . Wavelength/nm Wavelength/nm Figure 4: Near-infrared spectrum of polymethocrylates (Eudragit RL PO) Figure 7: Near-infrared spectrum of polymethacrylates (Eudragit S 100) measured by reflectance. measured by reflectance. 1.5 .------~ 1. 2 1645 ...... __&""" 14 Safety 1328 ...... - ' Polymethacrylate copolymers are widely used as film-coating 0) 31 _Q .--, 1883 1. t·· materials in oral pharmaceutical formulations. They are also used 12 17 ' ' ,' ' •2084 in topica l formulations and are generally regarded as nontoxic and > l ' \ ' ...... ,,'/ ·;::: nonirritant materials. Q) -0 0.0 Based on relevant chronic oral toxicity studies in rats and -0 conventionally ca lculated with a safety factor of 100, a daily intake C £::!... ,, of 2- 200 mg/kg body-weight depending on the grade of Eudragit 2 111 2 136 may be regarded as essentially safe in humans. X .' . 1950 ' . 1907 See also Section 15. 0 ' . I '\ 0 1663 1675 0 1178 ~ - 1. 5 '----'---'--'-----'--....L..-'--'-----'----'------'------'---"'--'---' 82 15 Handling Precautions 1100 1300 1500 1700 1900 2100 2300 250 . Observe normal precautions appropriate to the circumstances and Wavelength/ nm quantity of material handled. Additional measures should be taken when handling organic solutions of polymethacrylates. Eye protec tflur . ,i: Near-infrared spectrum of polymethacrylates (Eudragit RS 100) tion, gloves, and a dust mask or respirator are recommended. meas ured by reflectance. Polymethacrylates should be handled in a well-ventilated environ ~ 0.7 ...------, 0.4 ment and measures should be taken to prevent dust formation. &""" 227 1 2320 Acute and chronic adverse effects have been observed in workers '--- 1M6 U~ handling the related substances methyl methacrylate and poly 3 (methyl methacrylate) (PMMA).'2 l In the UK, the workplace exposure limit for methyl methacrylate has been set at 208 mg/m 3 3 I (50 ppm) long-term (8 -hour TWA), and 416 mg/m (100 ppm) J 24 < l short-term. r I 240~ I 0) See also Section 17. ~ 1908 ,1,./ 2442 _Q \ / \ ,. I \ 1\ ' , l '- --. 12 136 11678 -.. - - 16 Regulatory Status X ,. , .... \ I 0 I \ I °' / Included in the FDA Inactive Ingredients Database (oral capsules 0 I '- ..., _I ' ~.. ..., and ta blets) . Included in nonparenteral medicines licensed in the 0 2255 ~ - l .5 .__..___.__.___.___._..__...___....,__.____..__..__...._..,____, -0. 2 UK. Included in the Canadian List of Acceptable Non-medicinal 1100 1300 1500 1700 1900 2100 2300 2500 Ingredients. Wavelength/ nm 17 Related Substances Figure 6: Near-infrared spectrum of polymethacrylates (Eudragit RS PO) Methyl methacrylate; poly(methyl methacrylate). measured by reflectance. Methyl methacrylate Empirical fonnula C5Hs02 Interactions between polymethacrylates and some drugs can Molecular weight 100.13 occur, although solid polymethacrylates and organic solutions are CAS number (80-62-6] generally more compatible than aqueous dispersions. Synonyms Methacrylic acid, methyl ester; methyl 2-methacrylate; methyl 2-methylpropenoate; MME. Safety LD50 (dog, SC): 4.5 g/kg 13 Method of Manufacture LDso (mouse, IP): 1 g/kg Prepared by the polymerization of acrylic and methacrylic acids or LD so (mouse, oral): 5 .2 g/kg their esters, e.g. butyl ester or dimethylaminoethyl ester. LD 50 (mouse, SC): 6.3 g/kg Polymethacrylates 533 LD (rat, IP): 1.33 g/kg 11 Ibekwe VC et al. A comparative in vitro assessment of the drug release 50 performance of pH-responsive polymers for ileo-colonic delivery. Int J LD5o (rat, SC): 7.5 g/kg Pharm 2006; 308(1- 2): 52-60. Comments Methyl methacrylate forms the basis of acrylic bone 12 Kidokoro M et al. Properties of tablets containing granulations of cements used in orthopedic surgery. ibuprofen and an acrylic copolymer prepared by thermal processes. Poly(methyl methacrylate) Pharm Dev Technol 2001; 6(2): 263-275. (CsHs02)n 13 Lorenzo-Lamosa M et al. Development of a microencapsulated form of Empirical formula cefuroxime axetil using pH-sensitive acrylic polymers. J Microencapsul Synonyms Methyl methacrylate polymer; PMMA. 1997; 14(5): 607-616. Comments Poly(methyl methacrylate) has been used as a material 14 Nisar ur R et al. Drug-polymer mixed coating: a new approach for for intraocular lenses, for denture bases, and as a cement for controlling drug release rates in pellets. Pharm Dev Technol 2006; dental prostheses. 11(1): 71- 77. 15 Rahman N, Yuen K. Eudragit NE40-drug mixed coating system for 18 Comments controlling drug release of core pellets. Drug Dev Ind Pharm 2005; 31(4-5): 339- 347. A number of different polymethacrylates are commercially available 16 Rao VM et al. Design of pH-independent controlled release matrix that have different applications and properties; see Table II. tablets for acidic drugs. Int J Pharm 2003; 252(1- 2 ): 81- 86. For spray coating, polymer solutions and dispersions should be 17 Saravanan M et al. The effect of tablet formulation and hardness on in diluted with suitable solvents. Some products need the addition of a vitro release of cephalexin from Eudragit LlO0 based extended release plasticizer such as dibutyl sebacate, dibutyl phthalate, glyceryl tablets. Biol Pharm Bull 2002; 25(4): 541-545. triacetate, or polyethylene glycol. Different types of plasticizer may 18 Signorino C et al. The use of acrylic resins for improved aqueous enteric be mixed to optimize the polymer properties for special require coating. Pharm Technol Excipients Solid Dosage Forms 2004; (Suppl.): ments. 32- 39. The Japanese Pharmaceutica l Excipients (JPE) 2004 includes 19 Sohi H et al. Taste masking technologies in oral pharmaceuticals: recent specifications for aminoalkyl methacrylate copolymer RS, ami developments and approaches. Drug Dev Ind Pharm 2004; 30(5): 429- noalkyl methacrylate copolymer E, dried methacrylic acid copoly 448. mer LD, ethyl acrylate and methyl methacrylate copolymer 20 Zheng W et al. Influence of hydroxyethylceHulose on the drug release dispersion, methacrylii:: acid copolymer L, methacrylic acid copo properties of theophylline pellets coated with Eudragit RS 30 D. Eur j Pharm Biopharm 2005; 59(1): 147- 154. lymer S, and methacrylic acid copolymer LD. 21 Zhu Y et al. Influence of thermal processing on the properties of chlorpheniramine maleate tablets containing an acrylic polymer. Pharm 19 Specific References Dev Technol 2002; 7(4): 481--489. 1 Akhgari A et al. Combination of time-dependent and pH-dependent 22 Umejima H et al. Preparation and evaluation of Eudragit gels VI: in vivo polymethacrylates as a single coating formulation for colonic delivery evaluation of Eudispert rectal hydrogel and xerogel containing of indomethacin pellets. Int J Pharm 2006; 320(1-2): 137-142. salicylamide. J Pharm Sci 1993; 82: 195- 199. 2 Arno EA et al. Eudragit NE30D based metformin/gliclazide extended 23 Routledge R. Possible hazard of contact lens manufacture [letter]. Br release tablets: formulation, characterisation and in vitro release Med J 1973; 1: 487--488. studies. Chem Pharm Bull (Tokyo) 2002; 50(11): 1495-1498. 24 Health and Safety Executive. EH40/2005: Workplace Exposure Limits. 3 Ceballos A et al. Influence of formulation and process variables on in Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ vitro release of theophylline from directly-compressed Eudragit matrix coshh/tablel.pdf (accessed 5 February 2009). tablets. Farmaco 2005; 60(11-12): 913- 8. 4 Cerea M et al. A novel powder coating process for attaining taste 20 General References masking and moisture protective films applied to tablets. Int J Pharm 2004; 279(1-2): 127-139. Evonik Industries . Eudragit. http://www.pharma-polymers.com/pharmapo 5 Cheng G et al. Time- and pH-dependent colon-specific drug delivery for lymers/en/eudragit/ (accessed 4 March 2009). orally administered diclofenac sodium and 5-aminosa licylic acid. World Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Exci ]Gastroenterol2004; 10(12): 1769-1774. pients 2004. Tokyo: Yakuji Nippo, 2004. 6 Cole ET et al. Enteric coated HPMC capsules designed to achieve McGinity JW. Aqueous Polymeric Coatings for Pharmaceutical Dosage intestinal targeting. Int J Phann 2002; 231(1): 83-95. Forms, 2nd edn. New York: Marcel Dekker, 1997. 7 Dittgen M et al. Acrylic polymers: a review of pharmaceutical Petereit HU et al. Eudragit Application Guidelines, 10th edn. Darmst,1dr, applications. STP Pharma Sciences 1997; 7(6): 403--43 7. Germany: Evonik Industries AG, 2008 . 8 Felton L, McGinity J. Enteric film coating of soft gelatin capsules. Drug De/iv Technol 2003; 3(6): 46-51. 21 Authors 9 Gao Y et al. Preparation of roxithromycin-polymeric microspheres by the emulsion solvent diffusion method for taste masking. Int J Pharm RK Chang, Y Peng, N Trivedi, AJ Shukla. 2006; 318(1-2): 62-69. 10 Hamed E, Sakr A. Effect of curing conditions and plasticizer level on the 22 Date of Revision release of highly lipophilic drug from coated mu!tiparticulate drug delivery system. Pharm Dev Technol 2003; 8(4): 397- 407. 4 March 2009. Povido ne 581 7 Fo od Chemicals Codex, 6th edn. Bethesda, MD: United States 21 Authors Pharmacopeia, 2008; 818. ME Quinn, PJ Sheskey. 20 General References Smolinske SC, ed. Handbook of Food, Drug, and Cosmetic Excipients. Boca Raton, FL: CRC Press, 1992; 363-367. Sofas ]N, Busta FF. Sorbates. Branen AL, Davidson PM, eds. Antimicrobials in Foods. New York: Marcel Dekker, 1983; 141-175. Walker R. Toxicology ofsoi:bic acid and sorbates. Food Add Contam 1990; 22 Date of Revision 7(5): 671-676. ------~ 17 February 2009. Povidone 1 Nonproprietary Names Table I: Approximate molecular weights for different grades of BP: Povidone povidone. JP: Povidone K-value Approximate molecular weight PhEur: Povidone 12 2500 USP: Povidone 15 8000 17 10000 25 30000 30 50000 60 400000 2 Synonyms 90 1000000 120 3000000 E1 201; Kollidon; Plasdone; poly[l-(2-oxo-1-pyrrolidinyl)ethyle~e]; polyvidone; polyvinylpyrrolidone; povidonum; Povipharm; PVP; 1- vinyl-2-pyrrolidinone polymer. See also Section 8. 5 Structural Formula 3 Chemical Name and CAS Registry Number 1-Ethenyl-2-pyrrolidinone homopolymer (9003-39-8] 4 Empirical Formula and Molecular Weight n (C6H 9NO)n 2500-3 000 000 The USP 32 describes povidone as a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing 6 Functional Category degree of polymerization of which results in polymers of va rious Disintegrant; dissolution enhancer; suspending agent; tablet binder. molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, in the 7 Applications in Pharmaceutical Formulation or range 10-120. The K-value is calculated using Fikentscher's Technology equation:(l) Although povidone is used in a variety of pharmaceutical 1 formulations; it is primarily used in solid-dosage forms. In tableting, log z= c --75k- l+k [ 1 + 1.5kc povidone solutions are used as binders in wet-granulation 3 processes.(2, ) Povidone is also added to powder blends in the dry where z is the relative viscosity of the solution of concentration c form and granulated in situ by the addition of water, alcohol, or 3 (in % w/v) , and k is the K-value ; 10- • Alternati vely, the K-value hydroalcoholic solutions. Povidone is used as a solubilizer in oral and parenteral formulations, and has been shown to enhance may be determined from the following equation: · 4 6 dissolution of poorly soluble drugs from solid-dosage forms . ( - ) 300c log z (c + 1.5c log d + 1.5 K-va lue = Povidone solutions may also be used as coating agents or as binders O.lSc + 0.003c2 when coating active pharmaceutical ingredients on a support such as sugar beads. where z is the re lative viscosity of the solution of concentrati on c Povidone is additionally used as a suspending, stabilizing, or (in % w/v). Approximate molecular weights for different viscosity-increasing agent in a number of topical and oral povidone grades are shown in Table I. suspensions and solutions. The solubility of a number of poorly 582 Povidone soluble active drugs may be increased by mixing with povidone. See · Excipient: povidone K-15 (Plosdone K- 15); manufacturer: ISP; lot Table II. no.: 82A-1; magnification: 600 x; voltage: 5 kV. Special grades of pyrogen-fre e povidone are available and have been used in parenteral formulations; see Section 14. _.!able II: Uses of povid<:me. Use Concentration (%) Carrier for drugs 10-25 Dispersing agent Up to 5 Eye drops 2- 10 Suspending agent Up to 5 Tablet binder, tablet diluent, or 0.5-5 coating agent 8 Description Povidone occurs as a fine, white to creamy-white colored, odorless or almost odorless, hygroscopic powder. Povidones with K-values equal to or lower than 30 are manufactured by spray-drying and occur as spheres. Povidone K-90 and higher K-value povidones are manufactured by drum drying and occur as plates. SEM 3: Excipient: povidone K-26/28 (Plosdone K-26/28); manufacturer: 9 Pharmacopeial Specifications ISP; lot no.: 82A-2; magnification: 60 x; voltage: 5 kV. See Table III. See also Section 18. 10 Typical Properties Acidity/alkalinity pH = 3.0-7.0 (5% w/v aqueous solution); pH = 4.0-7.0 (5 % w/v aqueous solution) for Povipharm K90. Density (bulk) 0.29-0.39 g/cm 3 for Plasdone. Density (tapped) 0.39-0.54 g/cm3 for Plasdone. Density (true) 1.180g/cm3 Flowability 20g/s for povidone K-15; 16 g/s for povidone K-29/32. Melting point Softens at 150°C. Moisture content Povidone is very hygroscopic, significant amounts of moisture being absorbed at low relative humidities. See Figures 1 and 2. NIR spectra see Figure 3 . . SEM 1: Excipient: povidone K-15 (Plosdone K-15); manufacturer: ISP; lot no.: 82A-1; magnification: 60x ; voltage: 5 kV. Particle size distribution Kollidon 25/30: 90% >50 µm, 50% > 100 µm, 5% > 200 µm; Kollidon 90: 90% >200 µm, 95 % > 250 ~lm.m Solubility Freely soluble in acids, chloroform, ethanol (95%), ketones, methanol, and water; practically insoluble in ether, hydrocarbons, and mineral oil. In water, the concentration of a solution is limited only by the viscosity of the resulting solution, which is a function of the K-value. Viscosity (dynamic) The viscosity of aqueous povidone solution} depends on both the concentration and the molecular weight 0 the polymer employed. See Tables IV and v.m 11 Stability and Storage Conditions Povidone darkens to· some extent on heating at 150°C, with a reduction in aqueous solubility. It is stable to a short cycle of heat exposure around 110-130°C; steam sterilization of an aqueous solution , does not alter its properties. Aqueous solutions are Povidone 583 SEM 4: Excipient: povidone K-26/28 (Plasdone K-26/28); manufacturer: 5EM 6: Excipient: povidone K-30 (Plasdone K-30); manufacturer: ISP; lot ISP; lot no.: 82A-2; magnification: 600x ; voltage: 10 kV. na.: 82A-4; magnification: 600x ; voltage: 10 kV. .. M 5: Excipient: povidone K-30 (Plasdone K-30); manufacturer: ISP; lot SEM 7: Excipient: povidone K-29 /32 (Plasdone K-29 /32); manufacturer: no.: 82A-4; magnification: 60 x ; voltage: l O kV. ISP; lot no .: 82A-3; magnification: 60x ; voltage: 5 kV. ~ susceptible to mold growth and consequently require the addition of 13 Method of Manufacture suitable preservatives. Povidone is manufactured by the Reppe process. Acetylene and Povidone may be stored under ordinary conditions without formaldehyde are reacted in the presence of a highly active copper undergoing decomposition or degradation. However, since the acetylide catalyst to form butynediol, which is hydrogenated to powder is hygroscopic, it should be stored in an airtight container in butanediol and then cyclodehydrogenated to form butyrolactone. a cool, dry place. Pyrrolidone is produced by reacting butyrolactone with ammonia. This is fo llowed by a vinylation reaction in which pyrrolidone and acetylene are reacted under pressure. The monomer, vinylpyrroli done, is then polymerized in the presence of a combination of 12 Incompatibilities catalysts to produce povidone. Povidone is compatible in solution with a wide range of inorganic salts, natural and synthetic resins, and other chemicals. It fo rms molecular adducts in solution with sulfathiazole, sodium sa licylate, 14 Safety sa licylic acid, phenoharbital, tannin, and other compounds; see Povidone has been used in pharmaceutical formulations for many Section 18. The efficacy of some preservatives, e.g. thimerosal, may years, being first used in the 1940s as a plasma expander, although it be adversely affected by the formation of complexes with povidone. has now been superseded for this purpose by dextran. 18 l ------>=------·------ 584 Povidone , , , .. : Exc ipien t: povidone K-29/32 (Plasdone K-29 /32); man ufacture r: 50 ....------, ISP; lot no.: 82A-3; magnification: 600x ; voltage: l 0 kV. ~ Lu 40 0 ~ N -0 30 - Q) '- .2 /) ·o Hgure 1: Sorption- desorption isotherm of povidone K-15 (P/asdone K- 15, ISP). Table Ill: Pharmacopeial specifications for povidone. 50 .------, Test JP XV PhEur 6.5 USP 32 identification ~ + + + 40 Characters + u pH 3.0-7.0 0 + + ~ K ~ 30 3.0-5.0 3.0- 5 .0 N K > 30 4 .0-7.0 4 .0-7.0 0 30 Appearance of solution + + Q) '- Viscosity + .2 Water ~ 5 .0% ~ 5.0% ~ 5.0% (a) Expressed as acetaldehyde. (b) Expressed as hydrogen peroxide. Figure 2: Sorption- desorption isotherm of povidone K-29 /32 (Plasdone K-29/32, ISP) . Table IV: Dynamic viscosity of 10% w/v aqueous povidone (Kollidon) solutions at 20°C. 171 Table V: Dynamic viscosity of 5% w/v Bovidone (Kollidon) solutions in ethanol (95%) and propan-2-ol at 25°C. I Grade Dynamic viscosity (mPa s) Grade Dynamic viscosity (mPa s) K- 11/14 1.3-2.3 K-16/18 1.5-3.5 Ethanol (95%) Propan-2-ol K-24/27 3.5- 5.5 K-28/32 5.5-8.5 K-12PF 1.4 2.7 K-85/95 300-700 K-17PF 1.9 3.1 K,25 2.7 4.7 K-30 3.4 5.8 K-90 53.0 90.0 Povidone is widely used as an excipient, particularly in oral tablets and solutions. When consumed orally, povidone may be regarded as essentially nontoxic since it is not absorbed from the Reports of adverse reactions to povidone primarily conce~n thf gastrointestinal tract or mucous membranes. 181 Povidone addition formation of subcutaneous granulomas at the injection site 0 ally has no irritant effect on the skin and causes no sensitization. intramuscular injections formulated with povidone.191Evidenc e also Povidone 585 2 Becker D et al. Effectiveness of binders in wet granulation: comparison using model formulations of different tabletability. Drug Dev Ind 1669 2239 :" \, Pharm 1997; 23(8): 791-808. 0) ,, ...... /· - 3 Stubberud L et al. Water-solid interactions. Part 3. Effect of glass 0 2353 transition temperature, Tg and processing on tensile strength of compacts of_ lactose and lactose/polyvinyl pyrrolidone. Pharm Dev -~ Technol 1996; 1(2 ): 195-204. ~ 0. 0 l-"l-c-F-""""1'1hA~-Hi-cAHIN-+/>;J'--""'--f-11"4-ltHt\Jf+-I 4 Iwata M, Ueda H. Dissolution properties of glibenclamide in 0) u q combinations with polyvinylpyrrolidone. Drug Dev Ind Phann 1996; C 22: 11 61- 11 65. ~ 1172 2148 5 Lu WG et al. Development of nifedipine (NE) pellets with a high X , ' . 1734 ,, ,' : bioavailability. Chin Phann J Z hongguo Ya oxue Zazhi 1995; 30: 24- 0 "...... , _, I '' ' 2261 2282 26. 0 l .~ .. ,. r 0 1692 1932 6 Chowdary KP, Ramesh KV. Microencapsulation of solid dispersions of ~ - 1.0 ~~~~-~-~~-~~~-~~- 0. 2 nifedipine - novel approach for controlling drug release. Indian D rugs 1100 1300 1500 1700 1900 2100 2300 2500 1995; 32(Oct): 477-483. Wavelength/nm 7 BASF Corporation. Technical literature: Soluble Kollidon Grades, Soluble Polyvinylpyrrolidone for the Pharmaceutical Industry, 1997. Figure 3: Near-infrared spectrum of povidone measured by reflectance. 8 Wessel W et al. Polyvinylpyrrolidone (PVP), its diagnostic, therapeutic and technical application and consequences thereof. Arzneimittel forschung 1971; 2 1: 1468-1482. exists that povidone may accumulate in the organs of the body 9 Hizawa K et al. Subcutaneous pseudosarcomatous polyvinylpyrroli following intramuscular injection. (to) done granuloma. Am J Surg Pathol 1984; 8: 393-398. A temporary acceptable daily intake for povidone has been set 10 Christensen M et al. Storage of polyvinylpyrrolidone (PVP) in tissues 1 by the WHO at up to 25 mg/kg body-weight.'1 ' following long-term treatment with a PVP containing vasopressin Acta Med Scand 204: 12 preparation. 1978; 295- 298. LD 50 (mouse, IP): 12 g/kg( l 11 FAO/WHO. Evaluation of certain food additives and contaminants . Twenty-seventh report of the joint FAO/WHO expert committee on 15 Handling Precautions foo d additives. World Health Organ Tech Rep Ser 1983; No. 696. 12 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th Observe normal precautions appropriate to the circumstances and edn. New York: Wiley, 2004; 3016- 3017. quantity of material h:wdled. Eye protection, gloves, and a dust 13 Food Chemicals Codex, 6th edn. Bethesda, MD: United States mask are recommended. Pharmacopeia, 2008; 795. 16 Regulatory Status 20 General References Accepted for use in Europe as a food additive. Included in the FDA Adeyeye CM, Barabas E. Povidone. Brittain HG, ed. Analytical Profiles of Inactive Ingredients Database (IM and IV injections; ophthalmic Drug Substances and Excipients., vol. 22: London: Academic Press, preparations; oral capsules, drops, granules, suspensions, and 1993;555-685. tablets; sublingual tablets; topical and vaginal preparations). European Directorate for the Quality of Medicines and Healthcare Included in nonparenteral medicines licensed in the UK. Included (EDQM). European Pharmacopoeia - State Of Work Of International in the Canadian List of Acceptable Non-medicinal Ingredients. Harmonisation. Pharmeuropa 2009; 21(1): 142- 143. http://www.edq m.eu/site/-6 14.html (accessed 3 February 2009). Genovesi A et al. Binder evaluation in tab letting. Manuf Chem 2004; 175 (6 ): 17 Related Substances 29-30. \ Crospovidone. Horn D, Ditter W. Chromatographic study of interactions between polyvinylpyrrolidone and drugs. J Pharm Sci 1982; 71: 1021- 1026. 18 Comments Hsiao CH et al. Fluorescent probe study of sulfonamide binding to povidone. J Pharm Sci 1977; 66: 1157- 1159. Povidone is one of the materials that have been selected for ISP. Technical literature: Plasdone povidone USP, 1999. harmonization by the Pharmacopeial Discussion Group. For further Jager KF, Bauer KH. Polymer blends from PVP as a means to optimize information see the General Information Chapter < 11 96> in the properties of fluidized bed granulates and tablets, Acta Phann Technol USP32- NF27, the General Chapter 5.8 in PhEur 6.0, along with the 1984; 30(1): 85- 92. 'State of Work' document on the PhEur EDQM website, and also NP Pharm. Product data sheet: Povipharm, 2008. the General Information Chapter 8 in the JP XV. Plaizier-Vercammen JA, DeNeve RE. Interaction of povidone with aromatic The molecular adduct formation properties of povidone may be compounds III: thermodynamics of the binding equilibria and interaction used advantageously in solutions, slow-release solid-dosage forms, . forces in buffer solutions at varying pH values and varying dielectric and parenteral formulations. Perhaps the best-known example of constant. J Pharm Sci 1982; 71: 552-556. povidone complex formation is povidone- iodine, which is used as a Robinson BV et al. PVP: A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone (Povidone). Chelsea, MI: Lewis Publishers, 1990. topical disinfectant. Shefter E, Cheng KC. Drug- polyvinylpyrrolidone (PVP) dispersions. A For accurate standardization of solutions, the water content of differential scanning calorimetric study. Int J Phann 1980; 6: 179-182. the solid povidone must be determined before use and taken into Smolinske SC. Handbook of Fo od, Drug, and Cosmetic Excipients. Boca account for any calculations. Many excipients such as povidone Raton, FL: CRC Press, 1992; 303- 305. may contain peroxides as trace contaminants. These can lead to Wasylaschuk WR et al. Evaluation of hydroperoxides in common degradation of ari active pharmaceutical ingredient that is sensitive pharmaceutical excipients. J Pharm Sci 2007; 96: 106-116. to oxidation. A specification for povidone is contained in the Food Chemicals 21 Author Codex (FCq.<13l AH Kibbe. 19 Specific References 22 Date of Revision 1 Fikentscher H, Herrle K. Polyviny lpyrro lidone. M odern Plastics 1945; 23 (3): 157- 161212, 214,216, 218. 3 February 2009. ------· ------Sodium Starch Glycolate 663 The therapeutic use of sodium propionate in topical antifungal 5 Health and Safety Executive. EH40/2005: Workplace Exposure Limits. preparations has largely been superseded by a new generation of Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/ antifungal drugs. coshh/tablel.pdf (accessed 5 February 2009). A specification for sodium propionate is contained in the Food 6 Food Chemicals Codex, 6th edn. Bethesda, MD: United States 6 Pharmacopeia, 2008; 906. Chemicals Codex (FCC).( > The EINECS number for sodium propionate is 205-290-4. The PubChem Compound ID (CID) for sodium propionate is 20 General References 23663426. Doores S. Organic acids. Branen AL, Davidson PM, eds. Antimicrobials in Foods. New York: Marcel Dekker, 1983; 85-87. 19 Specific References Furia TE, ed. CR C Handbook of Food Additives. Cleveland, OH: CRC Press, 1972; 13 7-141. 1 Bishop Y, ed. The · Veterinary Formulary, 6th edn. London: Pharmaceutical Press, 2005; 419-420. 2 Heseltine WW. A note on sodium propionate. J Pharm Pharmacol 21 Author 1952; 4: 120- 122. T Sakurai. 3 Graham WD et al. Chronic toxicity of bread additives to rats. J Pharm Pharmacol 1954; 6: 534-545. 22 Date of Revision 4 Lewis RJ, ed. Sax's Dangerous Properties of Industrial M aterials, 11th edn. New York: Wiley, 2004; 3276. 5 February 2009. ~ Sodium Starch Glycolate Nonproprietary Names 5 Structural Formula BP: Sodium Starch Glycolate PhEur: Sodium Starch Glycolate USP-NF: Sodium Starch Glycolate 2 Synonyms 0 0 Carboxymethyl starch, sodium salt; carboxymethylamylum natri OH OH OH cum; Ex plosol; Explotab; Glycolys; Primojel; starch carboxymethyl ether, sodium salt; Tabla; Vivastar P. n 3 Chemical Name and CAS Registry Number 6 Functional Category Sodium carboxymethyl starch [9063-38-1] Tablet and capsule disintegrant. 7 Applications in Pharmaceutical Formulation or 4 Empirical Formula and Molecular Weight Technology The USP32-NF27 describes two types of sodium starch glycolate, Sodium starch glycolate is widely used in oral pharmaceuticals as a 1 6 7 Type A .and Type B, and states that sodium starch glycolate is the disintegrant in capsule' - > and tablet formulations.( - lO) It is sodium salt of a carboxymethyl ether of starch or of a crosslinked commonly· used in tablets prepared by either direct-compres 4 16 carboxymethyl ether of starch. sion(ll-lJ) or wet-granulation processes.'1 - > The usual concen The PhEur 6.0 describes three types of material: Type A and Type tration employed in a formulation is between 2% and 8%, with the B are described as the sodium salt of a crosslinked partly O optimum concentration about 4%, although in many cases 2% is carboxymethylated potato starch. Type C is described as the sodium sufficient. Disintegration occurs by ra~id uptake of water followed 7 2 salt of a · partly O-carboxymethylated starch, crosslinked by by rapid and enormous swelling. (l - > · physical dehydration. Types A, B, and C are differentiated by their Although the effectiveness of many disintegrants is affected by pH, sodium, and sodium chloride content. the presence of hydrophobic excipients such as lubricants, the The PhEur and USP-NF monographs have been harmonized for disintegrant efficiency of sodium starch glycolate is unimpaired. Type A and Type B variants. Increas ing _the tablet compression pressure also appears to have no 10 12 Sodium starch glycolate may be characterized by the degree of effect on d1smtegrat1on tune. ( - Y substitution and crosslinking. The molecular weight is typically 5 x Sodium starch glycolate has also been investigated for use as a 5 6 1 10 -1 X 10 • suspending vehicle.'2 > 664 Sodiu m Starch G lycolate 8 Description 0. 756 g/cm3 for Gly colys; Sodium starch glycolate is a white or almost white free-flowing very 0.81 g/cm' for Primojel; hygroscopic powder. The PhEur 6.0 states that when examined 0.67 g/cm3 for Tabla. under a microscope it is seen to consist of: granules, irregularly Density (tapped) shaped, ovoid or pear-shaped, 30-100 ~1111 in size, or rounded, 0.945 g/cm3 for Glycolys; 10- 35 ~1m in size; compound granules consisting of 2-4 compo 0.98 g/cm 3 for Primojel; nents occur occasionally; the granules have an eccentric hilum and 3 clearly visible concentric striations. Between crossed nicol prisms, 0.83 g/cm for Tab la. Density (true) the granules show a distinct black cross intersecting at the hilum; 3 small crystals are visible at the surface of the granules. The granules 1.56 g/cm for Primojel; show considerable swelling in contact with water. 1.49 g/cm 3 for Tabla. Melting point Does not melt, but chars at approximately 200°C. 9 Pha rmacopeial Specifications NIR spectra see Figure 1. Particle size distribution 100% of particles less than 106 µmin See Table I. See also Section 18. size. Average particle size (d 50) is 38 µm and 42 µm for Primoje/ by microscopy and sieving, respectively. 10 Typical Properties Solubility Practically insoluble in methylene chloride. It gives a Acidity/alkalinity See Section 9. translucent suspension in water. Density (bulk) Specific surface area 0.24 m2/f for Glycolys; Sf!M 1: Excipient: sodium starch glycolate (Explotab); manufacturer: JRS 0.185 m lg for Primojel; Pharma; magnification: 300x ; voltage: 5 kV. 0.335 m2/g for Tabla. T SEM 3 : Excipient: sodium starch glycolate (Primoiet manufacturer: DMV Fonterra Excipients; magnification: 200x ; voltage: 1.5 kV. ~EM 4: Excipient: sodium starch glycolate (Vivastar f1); manufacturer: JRS Excipient: sodium starch glycolate (G/yco/ys}; manufacturer: - :;~ 2: Pharma; magnification: 300x ; voltage: 5 kV. Ro qu ettes Frere s. Sod ium Starch G lycolate 665 :::=: 3.0 .------=,~--, 0.5 Table I: Pharmacopeial specifications for sod ium starch glycolate. o<: 1406 1888 -·n39 '-.. 2011 Test PhEur 6.0 USP32-NF27 0) Identification + + ...Q Characters + > Appearance of solution + -~ 0.0 1-"..-+V-+t-+-.f-\c-r---Hl\---+-t---t~-r"hrff-lltt-----11-1 pH + + -0 Type A 5.5-7.5 5.5-7.5 -0 0) C Type B 3.0-5.0 3.0-5.b 1201 ..2 ~ 2325 Type C 5.5-7.5 X Heavy metals ~ 20ppm ~ 0.002% 0 , ' Iron ~ 20ppm ~ 0.002% 0 '• / ·- . , .1433 1923 Loss on drying + ~ 10% 0 2282 Type A ~ 10.0% ~ -4. 0 ,.._..,___._ ...... __.___..___.,__..,__....___.__ ...... __._L...... I - 0. 2 Type B ~ 10.0% 1100 1300 1500 1700 1900 2100 2300 2500 TypeC ~ 7.0% Microbial limits +la) +la) Wavelength/ nm Sodium chloride + ~ 7.0% Type A ~ 7.0% Figure 1: Near-infrared spectrum of sodium starch glycolote measured Type B ,;:; 7.0% by reflectance. Type C ~ l.0% Sodium glycolote + ~ 2.0% Type A ~ 2.0% 15 Hcmdling Precautions Type B ~ 2.0% Observe normal precautions appropriate to the circumstances and TypeC ~ 2.0% quantity of material handled. Sodium starch glycolate may be Assay (of No) + + Type A 2.8-4.2% 2.8-4.2% irritant to the eyes; eye protection and gloves are recommended. A Type B 2.0-3.4% 2.0-3.4% dust mask or respirator is recommended for processes that generate Type C 2.8-5.0% a large quantity of dust. (a) Complies with tests for Salmonella and Escherichia coli. 16 Regulatory Acceptance Swelling capacity In water, sodium starch glycolate swells to up to Included in the FDA Inactive Ingredients Database (oral capsules 300 times its volume. and tablets). Included in nonparenteral medicines licensed in the Viscosity (dynamic) ,;;; 200 mPa s (200 cP) for a 4% w/v aqueous UK. Included in the Canadian List of Acceptable Non-medicinal dispersion; viscosity is 4.26 mPa s for a 2 % w/v aqueous 'Ingredients. dispersion (depending on source and grade). 17 Related Substances 11 Stability and Storage Conditions Prege'fatinized starch; starch. Tablets prefared with sodium starch glycolate have good storage 2 24 properties .< - > Sodium starch glycolate is stable although very 18 Comments hygroscopic, and should be stored in a well-closed container in order to protect it from wide variations of humidity and Sodium starch glycolate is one of the materials that have 'been temperature, which may cause caking. selected for harmonization by the Pharmacopeial Discussion The physical properties of sodium starch glycolate remain Group. For further information see the General Information unchanged for up to 3 years if it is stored at moderate temperatures Chapter <1196> in the USP32-NF27, the General Chapter 5 .8 and humidity. in PhEur 6.0, along with the 'State of Work' document on the PhEur EDQM website, and also the General Info rmation Chapter 8 in the 12 Incompatibilities JP XV. 1251 The physical properties of sodium starch glycolate, and hence its Sodium starch glycolate is incompatible with ascorbic acid. effectiveness as a disintegrant, are affected by the de~ree of 27 2 crosslinkage, extent of carboxyrriethylation, and purity.< • 1 13 Method of Manufacture Sodium starch glycolate has been reported to interact with 129 301 Sodium starch glycolate is a substituted derivative of potato starch. glycopeptide antibiotics, • basic drugs, and increase the photo Typically, commercial products are also crosslinked using either stability 'of norfloxacin. 1311 The solubility of the formulation matrix sodium trimetaphosphate (Types A and B) or dehydration (Type and mode of incorporation in wet granulation can affect the C).(26) disintegration time; djsintegration times can be slower in tablets Starch is carboxymethylated by reacting it with sodium containing high levels of soluble excipients.<3 21 chloroacetate in an alkaline, nonaqueous medium, typically Commercially, sodium starch glycolate is available in a number denatured ethanol or methanol, followed by neutralization with of speciality grades, e.g. low pH (Explotab L ow pH, Glycolys Low citric ac id, acetic acid, or some other acid. Vivastar P is pH); low viscosity (Explotab CLV, Glycolys LV); low solvent manufactured in methanolic medium, and Explotab in ethanolic (Vivastar PSF); and low moisture Glycolys LM. medium. A specification for sodium starch glycolare is included in the 33 Japanese Pharmaceutical Excipients (JPE) .< > 14 Safety Sodium starch glycolate is widely used in oral pharmaceutical 19 Specific References formulations and is generally regarded as a nontoxic and Newton JM, Razzo FN. Interaction of formulation factors and nonirritant material. However, oral inges tion of large quantities dissolution fluid and the in vitro release of drug from hard gelatin may be harmful. capsules. J Pharm Pharmacol 1975; 27: 78 P. 666 Sodium Starch G lycolate 2 Stewart AG et al. The release of a model low-dose drug (riboflavine) tion of the symptoms of colds and flu. III. Drug Dev Ind Phann. 1987, from hard gelatin capsule formulations. J Pharm Pharmacol 1979; 31: 13(7): 1197-1215. · ' 1-6. 26 Bolhuis GK et al. On the similarity of sodium starch glycolate from 3 Chowhan ZT, Chi L-H. Drug-excipient interactions resulting from different sources. Drug Dev Ind Pharm 1986; 12(4): 621-630. powder mixing III: solid state properties and their effect on drug 27 Rudnic EM et al. Effect of molecular structure variation on the dissolution. J Pharm Sci 1986; 75: 534-541. disintegrant action of sodium starch glycolate. J Pharm Sci 1985; 74: 4 Botzolakis JE, Augsburger LL. Disintegrating agents in hard gelatin 647-650. capsules part 1: mechanism of action. Drug Dev Ind Pharm 1988; 28 Bolhuis GK et al. Effect of variation of degree of substitution 14(1): 29-41. .· crosslinking and purity on the disintegrant efficiency of sodium starch 5 Hannula A-M et al. Release of ibuprofen from hard gelatin capsule glycolate. Acta Pharm Technol 1984; 30: 24- 32. formulations: effect of modern disintegrants. Acta Pharm Fenn 1989; 29 Claudius JS, Nea u SH. Kinetic and equilibrium characterization of 98: 189- 196. interactions between glycopeptide antibiotics and sodium carboxy 6 Marvola M et al. Effect of sodium bicarbonate and sodium starch methyl starch. Int J Pharm 1996; 144: 71- 79. glycolate on the in vivo disintegration of hard gelatin capsules - a 30 Claudius JS, Neau SH. The solution stability of vancomycin in the radiological study in the dog. Acta Pharm Nord 1989; 1: 355- 362. presence and absence of sodium carboxymethyl starch. Int J Pharm 7 Khan KA, Rooke DJ. Effect of disintegrant type upon the relationship 1998; 168: 41-48. between compressional pressure and dissolution efficiency. J Pharm 31 Cord oba-Borrego M et al. Validation of a high performance liquid Pharmacol1976;28: 633-636. chromatographic method for the determination of norfloxacin and its 8 Rubinstein MH, Price EJ. In vivo evaluation of the effect of five applicati on to stability studies {photostability study of norfl oxacin). J disintegrants on the bioavailability of frusemide from 40 mg tablets. J Pharm Biomed Anal 1999; 18: 919-926. Pharm Pharmacol 1977; 29: SP. 32 Gordon MS et al. Effect of the mode of super disintegrant incorporation 9 Caramella C et al. The influence of disintegrants on the characteristics on dissolution in wet granulated tablets. J Pharm Sci 1993; 82: 220- of coated acetylsalicylic acid tablets. Farmaco (Prat) 1978; 33: 498- 226. 507. 33 Japanese Pharmaceutical Excipients Council. Japanese Pharmaceutical 10 Gebre Mariam T et al. Evaluation of the disintegration efficiency of a Excipients 2004. Tokyo: Yakuji Nippo, 2004; 77~. sodium starch glycolate prepared from enset starch in compressed tablets. Eur J Pharm Biopharm 1996; 42(2): 124-132. :t 1 Cid E, Jaminet F. [Influence of adjuvants on the dissolution rate and 20 General References stability of acetylsalicylic acid in compressed tablets.] J Phann Belg Augsburger LL et al. Superdisintegrants: characterisation and function. 1971; 26: 38-48[in French]. Swarbrick J, ed. Encyclopedia of Pharmaceutical Technology, 3rd edn. 12 Gordon MS, Chowhan ZT. Effect of tablet so lubility and hygroscopi London: lnforma Healthcare, 2007; 2553-2567. city on disintegrant efficiency in direct compression tablets in terms of Blanver. Technical literature: Tabla, Explosol, 2008. dissolution. J Pharm Sci 1987; 76: 907-909. DMV-Fonterra Excipients. Technical-literature: Primojel, 2008. 13 Cordoba-Diaz M et al. Influence of pharmacotechnical des ign on the European Directorate for the Quality of Medicines and Healthcare interaction and availability of norfloxacin in directly compressed tablets (EDQM). European Pharmacopoeia - State Of Work Of International with certain antacids. Drug Dev Ind Pharm 2000; 26: 159- 166. Harmonisa tion. '.Pharmeuropa 2009; 21(1): 142-143. http://www.edq 14 Sekulovic D et al. The investigation of the influence of Explotab on the m.eu/site/-6 14.html (accessed 3 February 2009). disintegration of tablets. Pharmazie 1986; 41: 153- 154. Edge S et al. Chemical characterisation of sodium starch glycolate particles. 15 Bolhius GK et al. Improvement of dissolution of poorly soluble drugs by Int J Pharm 2002; 240: 67-78. solid deposition on a super disintegrant. Part 2. Choice of super Edge S et al. Powder compaction properties of sodium starch glycolate disintegrants and effect of granulation. Eur J Pharm Sci 1997; 5(2): 63- disintegrants. Drug Dev Ind Pharm 2002; 28(8): 989-999. 69 . JRS Pharma. Technical literature: Explotab, Vivastar P, 2004. 16 Gordon MS et al. Effect of the mode of super disinregrant incorpora tion Khan KA, Rhodes CT. Further studies of the effect of compaction pressure on dissolution in wet granulated tablets. J Phann Sci 1993; 82: 220- on the dissolution efficiency of direct compression systems. Pharm Acta 226. Helv 1974; 49: 258- 261. 17 Khan KA, Rhodes CT. Disintegration properties of calcium phosphate Mantovani F et al. A combination of vapor sorptlon and dynamic laser light dibasic dihyd rate tablets. J Pharm Sci 1975; 64: 166- 168. scattering methods for the determination of the Flory parameter chi and 18 Khan KA, Rhodes CT. Water-sorption properties of tablet disintegrants. the crosslink density of a powdered polymeric gel. Fluid Phase Equilib J Pharm Sci 1975; 64: 447- 451. 2000; 167(1): 63- 81. 19 Wan LSC, Prasad KPP. Uptake of water by excipients in ta blets. Tut J Mendell E. An eva luation of carboxymethyl starch as a· tablet disintegrant. Pharm 1989; 50: 147-153. Pharm Acta Helv 1974; 49: 248-250. 20 Thibert R, Hancock BC. Direct visualiza tion of superdisintegra nt Roquette Freres. Technical literature: Glycolys, 2008. hydration using environmental scanning electron microscopy. J Pharm Shah U, Augsburger L. Multiple sources of sodium starch glycolate NF: Sci 1996; 85: 1255- 1258. evaluation of functional equivalence and development of standard 21 Danckwerts MP et al. Pharmaceutical formulation of a fi xed-dose anti performance tests. Pharm Dev Tech 2002; 7(3): 345-359. tuberculosis combination. Int J Tuberc Lung D 2003; 7: 289-297. Young PM et al. Interaction of moisture with sodium starch glycolate. 22 Horhota ST et al. Effect of storage at specified temperature and Pharm Dev Tech 2007; 12: 211-216. humidity on properties of three directly compressible tablet fo rmula Young PM et al. The effect of moisture on the compressibility and tions. J Pharm Sci 1976; 65: 1746- 1749. compactability of sodium starch glycolates. Pharm Dev Tech 2007; 12: 23 Sheen P-C, Kim S-I. Comparative study of disintegrating agents in 217- 222. tiaramide hydrochloride tablets. Drug Dev Ind Pharm 1989; 15(3): 401-414. 24 Gord on MS, Chowhan ZT. The effect of aging on disintegrant 21 Author efficiency in direct compression tablets with va ried solubility and PM Young. hygroscopicity, in terms of dissolution. Drug Dev Ind Pharm 1990; 16(3): 437-447. 22 Date of Revision 25 Botha SA et al. DSC screening fo r drug-excipient and excipient excipient interactions in polypharmaceuticals intended fo r the allevia - 3 February 2009. ______rfl 728 Tal c Synonyms Jyxo-2-Hexulose 3 FAO/WHO. Joint FAO/WHO Expert Committee on Food Additives. Chemica l and Technical Assessment, 2003: 61. L·Tagatose 4 Freimund S et al. Convenient chemo-enzymatic synthesis of D-tagatose. Empirical formula C6H12 0 6 J Carbohydr Chem 1996; 15(1): 115-120. CAS number [17598-82-2] 5 Que L, Gray GR. 13C Nuclear magnetic resonance spectra and the Melting point 134-135°C tautomeric equilibria of ketohexoses in solution. Biochemistry 1974; 6 Specific rotation cxf) = + 1 ° (2 % aqueous solution) 13(1): 146-153. Comments Sweetening agent for pharmaceutical and personal aid products. 20 General References 18 Comments The EINECS number for tagatose is 201-772-3. The PubChem Compound ID (CID) for tagatose is 92092. 21 Author 19 Specific References GE Amidon. 1 Levin GV. Tagatose, the new GRAS sweetener and health product. J M ed Food 2002; 5: 23-36. 22 Date of Revision 2 Lu Y. Humectancies of d-tagatose and d-sorbitol. Int J Cosmet Sci 2001; 23: 175-181. 28 February 2009. Talc 1 Nonproprietary Names Talc is also used as a lubricant in tablet formulations;'7' in a novel BP: Purified Talc powder coating for extended-release pellets;(B) and as an adsor bant. (9 ) JP: Talc In topical preparations, talc is used as a dusting powder, PhEur: Talc although it should not be used to dust surgical gloves; see Section USP: Talc 14. Talc is a natural material; it may therefore frequently contain microorganisms and should be sterilized when used as a dusting 2 Synonyms powder; see Section 11 . Altaic; E553b; hydrous magnesium calcium silicate; hydrous Talc is additionally used to clarify liquids and is also used in magnesium silicate; Imperial; Luzenac Pharma; magnesium hydro cosmetics and food products, mainly for its lubricant properties. gen metasilicate; Magsil Osmanthus; Magsil Star; powdered talc; purified French chalk; Purtalc; soapstone; steatite; Superiore; Table I: Uses of talc. talcum. Use Concentration (%) 3 Chemical Name and CAS Registry Number Dusti ng powder 90.0-99.0 Glidant and tablet lubricant 1.Q:.-10.0 Talc [14807-96-6] Tablet and capsule diluent 5.0-30.0 4 Empirical Formula and Molecular Weight Talc is a purified, hydrated, magnesium silicate, approximating to 8 Description the formula Mg (Si 0 ) (0Hk It may contain small, variable 6 2 5 4 Talc is a very fine, white to grayish-white, odorless, impalpable, amounts of aluminum silicate and iron. unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and free from grittiness. 5 Structural Formula See Section 4. 9 Pharmacopeial Specifications See Table II. See also Section 18. 6 Functional Category Anticaking agent; glidant; tablet and capsule diluent; tablet and 10 Typical Properties capsule lubricant. Acidity/alkalinity pH= 7-10 for a 20% w/v aqueous dispersion. Hardness (Mohs) 1.0-1.5 7 Applications in Pharmaceutical Formulation or Moisture content Talc absorbs insignificant amounts of water at Technology 25.°C and relative humidities up to about 90%. Talc was once widely used in oral solid dosage formulations as a NIR spectra see Figure 1. 3 lubricant and diluent, see Table I, (l- ) although today it is less Particle size distribution Varies with the source and grade of commonly used. However, it is widely used as a dissolution material. Two typical grades are ;,: 99% through a 74 µm (#200 4 6 retardant in the development of controlled-release products.( - ) mesh) or ;,: 99% through a 44 µm _(#325 mesh) . Talc 729 SEM 1: Excipient: talc (Purtalc); manufacturer: Charles B Chrystal Co., Table II: Pharmacopeial spec ifications for talc. Inc.; lot no.: l 102A-2; magnification: 1200x ; voltage: lOkV. Test JPXV PhEur 6.3 USP 32 Identification + + + Characters + + Acid-soluble substances ~ 2.0% ,;:; 2.0% Acidity or alkalinity + + Production + pH Water-soluble substances ~ 0.2% ,;:; 0.1 % Aluminum ~2.0% 2.0% Calcium ~ 0 .9% 0.9% Iron. ~ 0 .25% 0.25% Lead ~ lOppm ,;:; 0.001% Magnesium 17.0-19.5% 17.0- 19.5% Loss on ignition ,;:; 5.0% ~ 7.0% ,;:;7.0% Microbial contamination + ~ 500cfu/g Aerobic bacteria ,;:; l02 cfu/g l 02 du/glaf 103 cfu/glbJ Fungi ~ 102 cfu/g 50cfu/gTa) 102cfu/g161 Acid and alkali-soluble ,;:; 4.0mg ,;:; 2.0% substances Water-soluble iron + Arsenic ,;:; 4ppm ,;:; 3 ppm Heavy metals ,;:; 0.004% Absence of asbestos SEM 2: Excipient: talc; magnification: l 000 x; voltage: 3 kV. + (a) If intended for topical administration. t! (b) If intended for oral administration. 3.0 .------, 0. 2 o2" "-. 0) 1379 _Q 1405 ·.:> 0.0 Q) ""'O ""'O 0) C _Q ~ ,,, 1392 X ,, 0 ,, 0 ,, 0 - ... 4 ...... ,;' ...... - - ...... 23 12 - 5.0 ,_...__...,__._____.____._..._...__.....__._____.____._.___.___. -0. 2 1100 1300 1500 1700 1900 2100 2300 2500 . Wavelength/nm Figure 1: Near-infrared spectrum of talc measured by reflectance. 11 Stability and Storage Conditions Talc is a stable material and may be sterilized by heating at 160°C for not less than 1 hour. It may also be sterilized by exposure to ethylene oxide or gamma irradiation.!1 °1 Talc should be stored in a well-closed container in a cool, dry place. 12 Incompatibilities Incompatible with quaternary ammonium compounds. 13 Method of Manufacture Talc is a naturally occurring hydropolysilicate mineral found in many parts of the world including Australia, China, Italy, India, France, and the USA. 1111 Refractive index n5° = 1.54- 1.59 The purity of talc varies depending on the country of origin. For Solubility Practically insoluble in dilute acids and alkalis, organic example, Italian types are reported to contain calcium silicate as the solvents, and water. contaminant; Indian types contain aluminum and iron oxides; Specific gravity 2.7- 2.8 French types contain aluminum oxide; and American types contain Specific surface area 2.41- 2.42 m 2/g calcium carbonate (California), iron oxide (Montana), aluminum 730 Talc and iron oxides (North Carolina), or aluminum oxide (Ala The EINECS number for talc is 238-877-9. The PubChem bama).'12> Compound ID (CID) for talc includes 26924, 443754 and Naturally occurring talc is mined and pulverized before being 16211421. subjected to flotation processes to remove various impurities such as asbestos (tremolite); carbon; dolomite; iron oxide; and various 19 Specific References other magnesium and carbonate minerals. Following this process, 1 Dawoodbhai S, Rhodes CT. Pharmaceutical and cosmetic uses of talc. the talc is fin ely powdered, treated with dilute hydrochloric acid, Drug Dev Ind Phann 1990; 16: 2409-2429. washed with water, and then dried. The processing variables of 2 Dawoodbhai S et al. Optimization of tablet formulations containing agglomerated talc strongly influence its physical characteris- talc. Drug Dev Ind Phann 1991; 17: 1343-1371. tics.<1 3- 15> · 3 Wang DP et al. Formulation development of oral controlled release pellets of diclofenac sodium. Drug Dev Ind Phann 1997; 23: 1013- 14 Safety 1017. 4 Fassihi RA et al. Potential use of magnesium stearate and talc as Talc is used mainly in tablet and capsule formulations. Talc is not dissolution retardants in the development of controlled release drug absorbed systemically following oral ingestion and is therefore delivery systems. Pharm Ind 1994; 56: 579-583. regarded as an essentially nontoxic material. However, intranasal or 5 Fassihi R et al. Application of response surface methodology to design intravenous abuse of products containing talc can ca use granulo optimization in formulation of a typical controlled release system. 6 18 mas in body tissues, particularly the lungs.'1 - ) Contamination of Drugs Made Ger 1996; 39(Oct-Dec ): 122-126. wounds or body cavities with talc may also cause granulomas; · 6 Schultz P et al. New multiparticulate delayed release system. Part 2. therefore, it should not be used to dust surgical gloves. Inhalation of Coating fo rmulation and properties of free films. J Control Release talc causes irritation and may cause severe respiratory distress in 1997;47: 191- 199. 7 Oetari RA et al. Formulation of PGV-O a new antiinflammatory agent infants;09) see also Section 15. as a tablet dosage form. Indonesian J Pharm 2003; 14(4): 160-168. Although talc has been extensively investigated for its carcino 8 Pearnchob N, Bodmeier R. Dry powder coating of pellets with genic potential, and it has been suggested that there is an increased micronized Eudragil (R) RS for extended drug release. Pharm Res risk of ovarian cancer in women using talc, the evidence is 20 21 2003; 20(12): 1970-1976. inconclusive. ' • ) However, talc contaminated with asbestos has 9 Mani N et al. Microencapsulation of a hydrophilic drug into a been proved to be carcinogenic in humans, and as bestos-free grades hydrophobic matrix using a salting-out procedure: II. Effects of should therefore be used in pharmaceutical produccs.'22 > adsorbents on microsphere properties. Drug Dev Ind Pharm 2004; Also, long-term toxic effects of talc contaminated with large 30(1): 83- 93. quantities of hexachlorophene caused serious irreversible neuro 10 Bubik JS. Preparation of sterile talc for treatment of pleural effusion toxicity in infants accidentally exposed to the substance.<23> [letter]. Am J Hosp Pharm 1992; 49: 562-563. 11 Grexa RW, Parmentier CJ. Cosmetic talc properties and specifications. Cosmet Toilet 1979; 94(2): 29-33. 1 5 Handling Precautions 12 H oepfner EM et al, ed. Fiedler Encyclopedia of Excipients fo r Observe normal precautions appropriate to the circumstances and Pharmaceuticals, Cosmetics and Related Areas, 5th edn, vol. II: quantity of material handled. Talc is irritant if inhaled and Aulendorf: Editio Cantor Verlag, 2002; 1556-1559. prolonged excessive exposure may cause pneumoconiosis. 13 Lin K, Peck GE. Development of agglomerated talc. Part 1. Evaluation of fluidized bed granulation parameters on the physical properties of In the UK, the workplace exposure limit for talc is 1 mg/m3 of 24 agglomerated talc. Drug Dev Ind Pharm 1995; 21: 447-460. respirable dust long-term (8 -hour TWA).' >Ey e protection, gloves, 14 Lin K, Peck GE. Development of agglomerated talc. Part 2. Optimiza and a respirator are recommended. tion of the processing parameters for the preparation of granulated talc. Drug Dev Ind Pharm 1995; 21: 159-173. 16 Regulatory Status 15 Lin K, Peck GE. Development of agglomerated talc. Part 3. Comparisons of the physical properties of the agglomerated talc Accepted for use as a food additive in Europe. Included in the FDA prepared by three different processing methods. Drug Dev Ind Pharm Inactive Ingredients Database (buccal tablets; oral capsules and 1996; 22: 383-392. tablets; rectal and topical preparations). Included in nonparenteral 16 Schwartz IS, Bosken C. Pulmonary vascular talc granulomatosis. J Am medicines licensed in the UK. Included in the Canadian List of Med Assoc 1986; 256: 2584. Acceptable Non-medicinal Ingredients. 17 Johnson DC et al. Foreign body pulmonary granulomas in an abuser of nasally inhaled drugs. Pediatrics 1991; 88: 159- 161. 17 Related Substances 18 Sparrow SA, H allam LA. Talc granulomas [letter). Br Med] 1991; 303: 58. Bentonite; magnesi um aluminum silicate; magnesium silicate; 19 Pairaudeau PW et al. Inhalation of baby powder: an unappreciated magnesium trisilicate. hazard. Br Med] 1991; 302: 1200- 1201. 20 Longo DL, Young RC. Cosmetic talc and ovarian cancer. Lancet 1979; 18 Comments ii: 349- 351. 21 Phillipson IM. Talc quality [letter). Lancet 1980; i: 48. Talc is one of the materials that have been selected for harmoniza 22 International Agency for Research on Cancer/World Health Organizaf tion by the Pharmacopeial Discussion Group. For further informa tion. Silica and Some Silicates: !ARC Monographs on the Evaluation° tion see the General Information Chapter < 11 96 > in the USP32- th e Carcinogenic Risk of Chemicals to Humans. Geneva: WHO, 1987: NF27, the General Chapter 5.8 in PhEur 6.0, along with the 'State 42. of Work' document on the PhEur EDQM website, and also the 23 Anonymous. Long-term sequelae of hexachlorophene poisoning, General Information Chapter 8 in the JP XV. Prescrire Int 1992; 1: 168. Various grades of talc are commercially available that vary in 24 Health and Safety Executive. EH40/2005: Workplace Ex posure LirniW their chemical composition depending upon their source and Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.u method of preparation.<1 1·25·26> coshh/ta hlel.pdf (accessed 3 February 2009). 25 Phadke DS et al. Evaluation of batch-to-batch and manufacturer-to Talc derived from deposits that are known to contain associated manufa cturer variability in the physical properties of talc and steanc as bestos is not suitable for pharmace utica l use. Tests for amphiboles acid. Drug Dev Ind Pharm 1994; 20: 859- 871. and serpentines should be carried out to ensure that the product is 26 Lin K, Peck GE. Characterization of talc samples from different sources . free of as bestos. Drug Dev fod Phann 1994; 20: 2993- 3003. A specifica tion for talc is contained in the Food Chemicals 27 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Codex (FCC).< 27> Pharmacopeia, 2008; 943. Tartaric Acid 731 20 General References 21 Author European Directorate for the Quality of Medicines and Healthcare AH Kibbe. (EDQM). European Pharmacopoeia - State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.edq m.eu/site/-614.html (accessed 3 February 2009). Gold G, Campbell JA. Effects of selected USP talcs on acetylsalicylic acid stability in tablets. J Pharm Sci 1964; 53: 52-54. Leterne P et al. Influence of the morphogranulometry and hydrophobicity of 22 Date of Revision talc on its antisticking power in the production of tablets. Int J Pharm 2005;289: 109-115. 3 February 2009. & Tartaric Acid 1 Nonproprietary Names 8 Description BP: Tartaric Acid Tartaric acid occurs as colorless monoclinic crystals, or a white or JP: Tartaric Acid almost white crystalline powder. It is odorless, with an extremely PhEur: Tartaric Acid tart taste. USP-NF: Tartaric Acid 2 Synonyms 9 Pharmacopeial Specifications Acid um tartaricum; L-(+ )-2,3-dihydroxybutanedioic acid; (2R,3R)- See Table I. 2,3-dihydroxybutane-1,4-dioic acid; 2,3-dihydroxysuccinic acid; E334; d-tartaric acid; L-( + )-tartaric acid. Table I: Pharmacopeial specifications for tartaric acid. Test JPXV PhEur 6.0 USP32-NF27 3 Chemical Name and CAS Registry Number Identification [R-(R * ,R *))-2,3-Dihydroxybutanedioic acid (8 7-69-4] + + + Characters + Appearance of solution + 4 Empirical Formula and Molecular Weight Specific rotation + 12.0° to + 12.0° 10 + 12.8° + 13.0° C4H60 6 150.09 Loss on drying ~ 0.5% ~ 0.2% ~ 0.5% Sulfated ash .;;0.1% 5 Structural Formula Residue on igni tion ~ 0.05% ~ 0 .1 % Chloride ~ JOO ppm Oxalic acid ~ 350ppm Oxalate + + Sulfate ~ 0.048% ~ 150ppm + Calcium + ~ 200ppm Heavy meta ls ~ lOppm ~ l Oppm ~ 0.001 % Arsenic ~ l ppm -- Assay !dried basis) ;,, 99.7% 99.5-101.0% 99.7- 100.5% 6 Functional Category Acidifying agent; flavoring agent; sequestering agent. 10 Typical Properties Acidity/alkalinity pH= 2.2 (1.5% w/v aqueous solution) 7 Applications in Pharmaceutical Formulation or Density l.76 g/cm Technology Dissociation constant Tartaric acid is used in beverages, confectionery, food products, and pK. 1 = 2.93 at 25°C; pharmaceutical formulations as an acidulant. It may also be used as pK.2 = 4.23 at 25°C. a sequestering agent and as an antioxidant synergist. In pharma Heat of combustion 1151 kJ/mol (275. 1 kcal/mo!) ceutical formulations, it is widely used in combination with Melting point 168-170°C bicarbonates, as the acid component of effervescent granules, NIR spectra see Figure l. powders, and tablets. Osmolarity A 3.9% w/v aqueous solution 1s isoosmotic with Tartaric acid is also used to form molec ular compounds (salts serum. and cocrystals) with active pharmaceutical ingredients to improve So lubility see Table II. physicochemical properties such as dissolution rate and solubi Specifi c heat 1.20 JI§ (0.28 8 cal/g) at 20°C. lityY •2) Specific rotation [a] 0°=+12.0° (20% w/v aqueous solution). _L______--- w ~ Water 1 Nonproprietary Names purified water, water for injection (WFI), sterile water for injection BP: Purified Water bacteriostatic water for injection; sterile water for irrigation, 0 ; sterile water for inhalation. Validation is required for all systems JP: Purified Water producing the water indicated, with the exception of potable water. PhEur: Water, Purified The chemical composition of potable water is variable, and the USP: Purified Water nature and concentrations of the impurities in it depend upon the See also Sections 8 and 17. source from which it is drawn. Water classified as potable water for applications such as some initial rinsing and API manufacturing 2 Synonyms operations, must meet the US Environmental Protection Agency's ble Aqua; aqua purificata; hydrogen oxide. National Primary Drinking Water Regulations, or compara regulations of the EU or Japan. For most pharmaceutical applica tions, potable water is purified by distillation, ion exchange 3 Chemical Name and CAS 'Registry Number treatment, reverse osmosis (RO), or some other suitable process Water [7732-18-5] to produce 'purified water'. For certain applications, water with pharmacopeial specifications differing from those of purified water 4 Empirical Formula and Molecular Weight should be used, e.g. WFI; see Sections 9 and 18. H2O 18.02 Water is a clear, colorless, odorless, and tasteless liquid. 5 Structural Formula See Section 4. 9 Pharmacopeial Specifications See Table IL See also Section 17. 6 Functional Category Solvent. 7 Applications in Pharmaceutical Formulation or 10 Typical Properties Technology Boiling point l 00°C Water is widely used as a raw material, ingredient and solvent in the Critical pressure 22.l MPa (218.3 atm) processing, formulation and manufacture of pharmaceutical Critical temperature 374.2°C products, active pharmaceutical ingredients ·(API) and intermedi Dielectric constant D 25 = 78.54 ates, and analytical reagents. Specific gi'ades of water are used for Dipole moment particular applications in concentrations up to 100%; see Table I. 1.76 in benzene at 25°C; 1. 86 in dioxane at 25°C. Table I: Typical applications of specific grades of water. Ionization constant 1.008 x 10- 14 at 25°C. Latent heat of fusion 6 kJ/mol (1.436 kcal/mo!) Type Use Latent heat of vaporization 40.7 kJ/mol (9.71 7 kcal/mo!) Bacteriostatic water for in jection Diluent for ophthalmic and multi ple Melting point 0°C dose injecti ons. Refractive index ni0 = 1.3330 Potable water Public supply suitable for drinkin g, So lubility Miscible with most polar solvents. the purity of which is unlikely to be Specific gravity 0.9971 at 25°C. suitable for use in the manufacture of pharmaceuticals. Specific heat (liquid) 4.1 84 J/g/°C (1.00 cal/gl°C) at 14°C. Purified water Vehicle and solvent for the Surface tension 71.97 mN/m (71.97 dynes/cm) at 25°C. manufacture of drug products and Vapor pressure 3.17 kPa (23.76 mmHg) at 25°C. pharmaceutical preparations; not Viscosity (dynamic) 0.89 mPa s (0. 89 cP) at 25°C. suitable for use in the manufacture of parenteral products. Sterile water for inhalation Diluent for inhalation therapy products. 11 Stability and Storage Conditions Sterile water for injection Diluent for injections. Sterile water for irrigation Diluent for internal irrigation therapy Water is chemicall y stable in all physical states (ice, liquid, and products, vapor). Water leaving the pharmaceutical purification system and Water for injections in bulk Water for the bulk preparation of entering the storage tank must meet specific requirements. The go~! medicines for paren teral when designing and operating the storage and distribution system is admi nistrati on. to keep the water from exceeding allowable limits during storage·. In particular, the storage and distribution system must ensure that water is protected against ionic and organic contamination, which 8 Description would lead to an increase in conductivity and total organic carbon, The term 'water' is used to describe potable water that is fres hl y respectively. The system must also be protected against physical drawn direct from the public supply and is suita ble fo r drinking. entry of foreign particles and microorganisms so that microbial Water used in the pharmaceutical industry and re lated disciplines is growth is prevented or minimized. Water for specific pu rposes classified as either drinking (potable) water, purified water, sterile should be stored in appropriate containers; see Table Ill. 766 Table 11, Phmmocopeiol specificotioos of=•>< foe diff Identification Product ion - - + - + Characters - + ..... ·- · + ------+ Appearance of solution - + ------+ Odor a nd ta ste - + ------+ pH ------5 .0-7.0 4.5-7.0 Acid or a lkali - + + ------+ - - + + Cadmi um Chloride - + - + - - + - - - - - + - + + Cya nide Copper Sulfate - + + - - + - - - - + - + + Ammon ium ,;; 0.05 mg/ l ,;; 0.05mg/ l - ,;; 0 .2 ppm - - + - - - - + - - ,;; 0.2ppm ,;; 0 .05 mg/ l Iron Calcium - - + - + + ------+ lead Magnesium - - + ------+ Alum inum - - ,;; ]0ppb - - ,;; l0ppb ------,;;l 0ppb ,;;] 0ppb Nitrate - - ,;; 0.2 ppm - - <; 0.2 ppm ------,;; 0.2 ppm <; 0.2 ppm + Nitrogen from nitrate - + ------+ -- - + Nitrogen from nitrite - + - - - - - + -- - + Carbon dioxide - - - - + + Heavy metals - + <; 0.1 ppm ------+ - - - + Oxidizable su bstances - - + + -- + - + + + - - - + Potassium - + ------+ - - - + permanganate- re ducing substances Residue-on evaporation - ;!f l .O mg - :!f 0.001 % - - - - - + - - • ~ l.Omg Total organic carbon - - + - + ,;;0.5 mg / l - - - - +!bl + ,;; 0.5 mg/l Tota l hardness ------Conductivity - - + - - + - - ,;; 25 µS/cm for ,;;25 µS / cm for · ,;; 25 µS/cm - + + ,;; 25 µS / cm for containers containers for containers containers ,;; l0ml, ,;; l 0ml, ,;; l0ml, ,;; l 0ml, ,;; 5 µS / cm ,;; 5 µS / cm ,;5 µS / cm for ,;; 5 µS / cm for containe rs for containers containers for containers ;, 10ml ;, 10 ml ;, 10ml ;, 10 ml Anionic surfactants Antimicrobial agents ------+ Sterility ------+ + + + + T - - + + Extracta ble volume ------+ Particulate matter - - - - - + + - - - - + Microbial contamination - - - ~ 102 du/ ml Bacterial endotoxins - - ,;; 0.25 1U/ml - - ,;0.25 1U/ml ,;0.25EU/ ml <0.5 EU/ ml <0.5 ~U/ ml ,;; 0.25 EU/ ml - ,;; 0.25EU/ml ,;0.25 EU/ ml ,;; 0.25tU/ ml <0.251U/ ml (a) For water for injection preserved in containers and sterilized, the JP XV provides separate tests for ocid or alkali, chloride, ammon ium, ond residue on evaporation within the monograph. (b) For woter for injection prepared by reverse osmosis-ultrofiltrotion. ~ 0 co ""0,. "" 768 W a te r Table Ill: Storage requirements for differen t grades of water. exchange, RO or any other suitable method that complies with ---- regulations on water intended for human consumption laid down 10 Type Storage requirements J by the competent authority. The USP 32 and the JP XV permit the use of RO in additioq to distillation and ultrafiltration. In the past Bacteriostatic water for injection Preserve in single-dose and multiple dose containers, preferably of 10-15 years, RO has become the most common way to produce Type I or Type II glass, not larger pharmaceutical purified water, either as a final treatment step or as a than 30 ml in size. pretreatment step for the distillation stills. Potable water Preserve in tightly sealed containers. Distillation Distillation is a process that involves the evaporation Purified water Preserve in tightly sealed containers. of water followed by the condensation of the resulting steam. If it is stored in bulk, the conditions While expensive, it allows removal of almost all organic and of storage should be designed to inorganic impurities and achieves very high quality water. It is limit the growth of microorganisms also considered the safest method to avoid microbial and and avoid any other contamination. endotoxin contamination. To improve energy efficiency, distilla Sterile water for inhalation Preserve in single-dose containers, tion is usually conducted in multiple-effects stills designed to preferably of Type I or Type II recover most of the energy spent on evaporating the water. A glass. typical design consists of an evaporator, vapor separator, and Sterile water for injection Preserve in -~ingle-dose containers, compressor. The distilland (raw feed water) is heated in the preferably of Type I or Type II evaporator to boiling and the vapor produced is separated from glass, not more than 1000 ml in entrained distilland in the separator. The vapor then enters a size. Water for injection Preserve in tightly sealed containers. compressor where the temperature of the vapors is raised to Water for injections in bulk Collect and store in conditions 107°C. Superheated vapors are then condensed on the outer designed to prevent growth of surface of the tubes of the evaporator containing cool distilland microorganisms and avoid any circulating within. other contamination. Vapor compression stills of various sizes are commercially available and can be used to produce water of high purity when (a) To prevent evaporation and to maintain quality. properly constructed. A high-quality distillate, such as WFI, can be obtained if the water is first deionized. The best stills are constructed from types 304 or 31 6 stainless steel and coated with 12 Incompatibilities pure tin, or are made from chemical-resistant glass. In pharmaceutical formulations, water can react with drugs and Deionization An ionic exchange process is bas~d on the ability of other excipients that are susceptible to hydrolysis (decomposition in certain synthetic resins to selectively adsorb either cations or the presence of water or moisture) at ambient and elevated anions, and to release (exchange) other ions based on their temperatures. relative activity. Cationic and anionic ion exchange resins are Water can react vi olently with alkali metals and rapidly with used to purify potable water by removing any dissolved ions. alkaline metals and their oxides, such as calcium oxide and Dissolved gases are also removed, while chlorine, in the magnesium oxide. Water also reacts with anhydrous salts to form concentrations generally found in potable water, is destroyed hydrates of various compositions, and with certain organic by the resin itself. Some organics and colloidal particles are materials and calcium carbide. removed by adsorption and filtration. Resin beds may, however, foster microbial life and produce pyrogenic effluent unless 13 Method of Manufacture adequate precautions are taken to prevent contamination. Unlike other excipients, water is not purchased fr om outside Another disadvantage is the type of chemicals required for resin suppliers but is manufactured in-house by pharmaceutical compa regeneration. A continuous deionizacion system, which repre nies. As naturally occurring water has a variety of contaminants, sents a combination of ion exchange and membrane separation many treatment processes have been developed to remove these. A technologies, uses an electrical current to continuously regener typical pharmaceutical water purification system contains several ate the ion exchange resin simultaneously with the water unit 'operations designed to remove various components. The treatment process, eliminating the need to handle powerful selection of the most appropriate system and its overall design are chemicals. Ion exchange units are normally used today to treat crucial factors in ensuring that water of the correct quality is raw feed water prior to distillation or RO processing. 21 produced. 11 • Reverse osmosis Water is forced through a semipermeable To produce potable or drinking water, insoluble matter is first membrane in the opposite direction to norm,al osmotic diffusion. removed fr om a water supply by coagulation, settling (clarifica Typically, membranes range between 1-10 A and reject not only tion), and filtering processes. Pathogenic microorganisms present organic compounds, bacteria and viruses, but also 90-99 % of are then destroyed by aeration, chlorination, or some other means. all ions. It is common to use double-pass RO systems with two Water may also be rendered free of viable pathogenic microorgan filtration stages connected in series . Such systems meet require isms by active boiling for 15-20 minutes. Activated carbon filters ments for USP purified water and WFI. However, EU regulations are employed to remove chlorine and many dissolved organic do not allow RO to be used as a final treatment step for the materials found in water, although they may become a breeding production of WFI. ground for microorganisms. The palatability of the water is Membrane filtration Membrane filters are surface-type filters, improved by aeration and charcoal filtration. which stop particles larger than the pore size at the upstream Purified water suitable for use in pharmaceutical formulations is surface of the polymeric membrane. Microfiltration uses usually prepared by purifying potable water by one of several membranes with pores in the 0.1- 1.0 µm range, which can fil ter 3 processes, such as distillation, deionization, or R0.11 , -s> out particles of dust, activated carbon, ion exchange resin fin es, The quality attributes of WFI are stricter than those for purified and most microorganisms. Ultrafiltration uses membra nes that water. Consequently, the preparation methods typically vary in the reject not only solid particles but also dissolved matter with a last stage to ensure good control of WFI quality. Methods for the high molecular weight. The 'molecular weight cut-off' point of production of WFI arc th e subject of current debate. The PhEur 6.3 such membranes varies in the range 10 000- 100 000 Da, and indicates that only distillation would give assurance of consistent bacteria, endotoxins, colloidal contaminants, and large orga nic supply of the appropriate quality, but permits distillation, ion molecules can be removed. Water 769 14 Safety Sterile w ater for irrigation Water is the base for many biological life forms, and its safety in Comments The USP 32 describes sterile water for irrigation as pharmaceutical formulations is un~uestioned provided it meets WFI sterilized and suitably packaged. It contains no antimicro standards of quality for potability( l and microbial content; see bial agents or other substances. Sections 9 and 18. Plain water is considered slightly more toxic Water for injection (WFI) upon injection into laboratory animals than physiological salt Comments The USP 32 describes WFI as water purified by solutions such as normal saline or Ringer's solution. distillation or RO. It contains no added substances. The PhEur Ingestion of excessive quantities of water can lead to water 6.3 title is 'water for injections' and comprises two parts: 'water intoxication, with disturbances of the electrolyte balance. for injections in bulk' and 'sterilized water for injection'. The WFI should be free from pyrogens. · PhEur 6.3 states that water for injections is produced by LDso (mouse, IP): 25 g/kg(lO) distillation. 18 Comments 15 Handling Precautions In most pharmacopeias, the term 'water' now refers to purified or Observe normal precautions appropriate to the circumstances and distilled water. quantity of material handled. · Without further purification, 'water' may be unsuitable for certain pharmaceutical applications; for example, the presence of calcium in water affects the viscosity and gel strength of algins and 16 Regulatory Status pectin dispersions, while the use of potable water affects the clarity Included in nonparenteral and parenteral medicines licensed in the and quality of cough mixtures, and the stability of antibiotic liquid UK and USA. preparations. Water commonly contains ·. salts of aluminum, calcium, iron, magnesium, potassium, sodium, and zinc. Toxic substances such as 17 Related Substances arsenic, barium, cadmium, chromium, cyanide, lead, mercury, and Bacteriostatic water for inj ection; carbon dioxide-free water; de selenium may constitute a danger to health if present in excessive aerated water; hard water; soft water; sterile water for inhalation; amounts. Ingestion of water containing high amounts of calcium sterile water for injection; sterile water for irrigation; water for and nitrate is also contraindicated. National standards generally injection (WFI). specify the maximum limits for these inorganic substances in Bacteriostatic water for injection potable water. Limits have also been placed on microorganisms, Comments The USP 32 describes bacteriostatic water for injection detergents, phenolics, chlorinated phenolics, and other organic as sterile water for injection that contains one or more suitable substances. The WHO(ll) and national bodies have issued guide lines for water quality, although many countries have their own antimicrobial agents. 2 standards for water quality embodied in specific legislation.'1 ) See Carbon dioxide-free w ater Table IV. Comments Purified water that has been boiled vigorously for 5 minutes and allowed to cool while protecting it from absorption of atmospheric carbon dioxide. Table IV: Limits for inorganic substances in potable water (mg/L). De-aerated water Contominant UK (mg/L) WHO (mg/L) ---- Comments Purified water that has been boiled vigorously for 5 Aluminum 0.2 0.2 minutes and cooled to reduce the air (oxygen) content. Ammonium 0.5 Hard water Antimony 0.01 Arsenic 0.05 0.05 Comments Water containing the equivalent of not less than Barium 1.0 No limit 120 mg/L and not more than 180 mg/L of calcium carbonate. Beryllium No limit Soft water Boron 2.0 Cadmium 0.005 0.005 Water containing the equivalent of not more than Comments Calcium 250 60 mg/L of calcium carbonate. Chloride 400 250 Sterile water for inhalation Chromium 0.05 0.05 3.0 1.0 Comments The USP 32 describes sterile water for inhalation as Copper Cyanide 0.05 0.1 -~----..-..l WFI sterilized and suitably packaged. It contains no antimicro Fluoride 1.5 1.5 bial agents or other added substances, except where used in Iron 0.2 0.3 humidifiers or other similar devices, and where liable to Lead 0.05 0.05 contamination over a period of time. Magnesium 50 Manganese 0.05 0.1 Sterile water for injection Mercury 0.001 0.001 Comments The USP 32 describes sterile water for injection as WFI Nickel 0.05 No limit sterilized and suitably packaged. It contains no antimicrobial Nitrate (as N) 10 agents or other substances. Nitrate (as N03) 50 Sterile water for injection in containers is one of the materials Nitrite (as N02) 0.1 Phosphorus 2.2 that have been selected for harmonization by the Pharmacopeial Potassium 12 Discussion Group. For further information see the General Selenium 0.01 0.01 Information Chapter < 1196> in the USP32-NF27, the General Silver 0.01 No limit Chapter 5.8 in PhEur 6.0, along with the 'State of Work' Sodium 150 200 document on the PhEur EDQM website, and also the General Sulfate 250 400 Zinc 5.0 5.0 Information Chapter 8 in the JPX V. ------~---- 770 Wax, Anionic Emul sifying Control of microbiological contamination is critical for waters 5 Cross J. Steam sterilisa ble ultrafiltration membranes, Manuf Chern used in preparation of pharmaceuticals, as proliferation of 1989; 60( 3): 25-27. microorganisms can potentially occur during all stages of manu 6 Horry JM, Cross JR. Purifying water for ophthalmic and injectable facture, storage, or distribution. Suitable control is achieved by preparations. Pharm ] 1989; 242: 169- 171, ensuring that the water system is well designed and well maintained. 7 Smith VC. Pure water. Manuf Chem 1990; 61(3): 22-24. Purified water that is produced, stored, and circulated at ambient 8 Burrows WD, Nelson JH. IV fluidmakers: preparation of sterile water temperatures is susceptible to the establishment of biofilms; for inj ection in a fi eld setting. J Parenter Sci Technol 1993; 47(3): 124- therefore, frequent monitoring, high usage, correct flow rate, and 129. 9 Walker A. Drinking wa ter - doubts about quality. Br Med] 1992; 304: appropriate sanitization are all factors that require consideration to 13 175- 178 . ensure that water is satisfactory.< ) 10 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th Monitoring of the whole system is essential in order to edn. New York: Wiley, 2004; 3692. demonstrate that correct microbiological quality is achieved. For . 11 World Health Organiza tion. Guidelines for Drinking-water Quality, WFI, the recommended methodology is membrane filtration'. vol. 1: Recommendations. Geneva: WHO, 1984. (0.45 µm) as a large sample size (100-300 mL) is required. For 12 Statutory Instrument 114 7. The water supply (water quality) regula purified water, membrane filtration or plate count methods are tions 1989. London: HMSO, 1989. http://www. opsi.gov.uk/ (accessed typically used depending on the quality requirements of the system. 27 February 2009 ). It is important to set appropriate target, alert, and action limits to 13 Riedewald F. Biofilms in pharmaceutica l waters. Pharm Eng 1997; serve as an indication of action required to bring the quality of Nov/Dec: 8- 18. · water back under control. It is recognized that limits are not 14 Food and Drug Administration. Guide to Inspections of High Purity intended as pass/fail criteria for water or product batches; however Water Systems. Washington, DC: FDA, 1993 . http://www.fda.gov/ora/ 4 an investigation regarding the implications should be conducted. (l l inspect_ref/igs/high.html (accessed 27 February 2009). Va lidation is conducted to provide a high level of assurance that the water production and distribution system will consistently 20 General References produce water conforming to a defined quality specification. The validation process serves to qualify the design (DQ), installation Collentro WV, ed. Pharmaceutical Water: System Design, Operation and Validation. Buffalo Grove, IL: interpharm Press, 1999. (IQ), operation (OQ), and performance (PQ) of the system. The Europea n Directorate for the Quality of Medicines and Healthca re extent of monitoring data required should be defined, with (ED QM). Europea n Pharmacopoeia - State Of Work Of International consideration given to whether validation to FDA guidelines is 14 Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.edq required.< ) It is also important to have an ongoing control m.eu/site/-614.html (accessed 27 February 2009 ). program with respect to maintenance, and periodic reviews of the Rossler R. Water and air, two important media in the manufacture of sterile performance of the water system. pharmaceuticals, with regard to the GMP. Drµgs Made Ger 1976; 19: The PubChem Compound ID (CID) for water is 962. 130- 136. . Santoro M, Maini C. Which water fo r pharmaceutical use? Eur J Parenter 19 Specific References Pharm Sci 2003; 8: 15- 20. 1 Thomas WH, Harvey H. Achieving purity in pharmaceutical water. Manuf Chem Aerosol N ews 1976; 47(10): 32, 36, 39, 40. 21 Authors 2 McWilliam AJ. High purity water distribution systems. Pharm Eng 1995; Sept/Oct: 54-71. D Dubash, U Shah. 3 Honeyman T. Purified water for pharmaceuticals. Manuf Chem 198 7; 58(3): 53, 54, 57, 59. 22 Date of Revision 4 Cross J. Trea ting waters for the pharmaceutical industry. Manuf Chem 1988; 59(3): 34- 35. 27 February 2. UWJ. & Wax, Anionic Emulsifying 1 Nonproprietary Names 4 Empirical Formula a nd Molecular Weight BP: Emulsifying Wax The PhEur 6.2 specifies that cetostearyl alcohol (type A), emulsify PhEur: Cetostearyl Alcohol (Type A), Emulsifying ing contains a minimum of 80% cetostearyl alcohol and 7% sodium cetostearyl sulfate. Cetostearyl alcohol (type B), emulsifying PhEur: Cetostearyl Alcohol (Type B), Emulsifying contains a minimum of 80% cetostearyl alcohol and 7% sodium lauryl sulfate. A suitable buffer can be added to both. The BP 2009 describes anionic emulsifying wax as containing 2 Synony ms cetostearyl alcohol, purified water, and either sodium lauryl sulfa te or a sodium salt of a similar sulfated higher primary aliphatic Collone HV; Crodex A; Cyclonette Wax; Lanette SX; Lanette W. alcohol. See also Section 18. The BP 2009 specifies that the formula of anionic emulsifying wax 1s: Ce tostearyl alcohol 90g 3 Chemical Name and CAS Registry Number Sodium lauryl sulfate lOg Anionic emulsifying wax [8014-38-8] Purified water 4 ml