Handbook ofPharmaceutical Excipients FIFTH EDITION Edited by Raymond C Rowe BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MInstP Chief Scientist Intelligensys Ltd Billingham, UK Paul J Sheskey BSc, RPh Technical Services Leader The Dow Chemical Company Midland MI, USA ˆ Sian C Owen BSc, MA Development Editor Royal Pharmaceutical Society of Great Britain London, UK London . Chicago
Published by the Pharmaceutical PressPublications division of the Royal Pharmaceutical Society of Great Britain1 Lambeth High Street, London SE1 7JN, UK100 South Atkinson Road, Suite 206, Grayslake, IL 60030-7820, USAand the American Pharmacists Association2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA# Pharmaceutical Press and American Pharmacists Association 2006 is a trademark of Pharmaceutical PressFirst published 1986Second edition published 1994Third edition published 2000Fourth edition published 2003Fifth edition published 2006Printed in Great Britain by Butler & Tanner, Frome, SomersetTypeset by Data Standards Ltd, Frome, SomersetISBN 0 85369 618 7 (UK)ISBN 1 58212 058 7 (USA)All rights reserved. No part of this publication may bereproduced, stored in a retrieval system, or transmitted in anyform or by any means, without the prior written permissionof the copyright holder. The publisher makes no representation, express or implied,with regard to the accuracy of the information contained inthis book and cannot accept any legal responsibility orliability for any errors or omissions that may be made.A catalogue record for this book is available from the British LibraryLibrary of Congress Cataloging-in-Publication DataHandbook of pharmaceutical excipients.–5th ed. / edited by Raymond C.Rowe, Paul J. Sheskey, Sian C. Owen. ˆ p. ; cm.Includes bibliographical references and index. ISBN 1-58212-058-7 (USA) – ISBN 0-85369-618-7 (UK)1. Excipients–Handbooks, manuals, etc. [DNLM: 1. Excipients–Handbooks. 2. Technology, Pharmaceutical–Handbooks.QV 735 H236 2006] I. Rowe, Raymond C. II. Sheskey, Paul J. III. Owen, Sian C. ˆIV. American Pharmacists Association.RS201.E87H36 20066150 .19–dc22 2005028523
International Steering CommitteeGregory E Amidon Stephen W Hoag Anthony Palmieri IIIPharmacia Corporation University of Maryland at Baltimore University of FloridaKalamazoo, MI, USA Baltimore, MD, USA Gainesville, FL, USAGraham Buckton Arthur H Kibbe Raymond C RoweUniversity of London Wilkes University Intelligensys LtdLondon, UK Wilkes-Barre, PA, USA Billingham, UKColin G Cable William J Lambert Shirish A ShahWestern General Hospital Eisai Inc Watson PharmaceuticalsEdinburgh, UK Research Triangle Park, NC, USA Corona, CA, USABrian A Carlin M Jayne Lawrence Bob SherwoodFMC Biopolymer King’s College, University of London JRS PharmaPrinceton, NJ, USA London, UK Patterson, NY, USAWalter Cook John MacLaine Paul J SheskeyAstraZeneca Boots Contract Manufacturing The Dow Chemical CoLoughborough, UK Nottingham, UK Midland, MI, USAHenk J de Jong Colin P McCoy Kamalinder K SinghServier International Research Institute Queens University Belfast SNDT Women’s UniversityCourbevoie, France Belfast, UK Mumbai, IndiaStephen Edge R Christian Moreton Paul J WellerDMV International Idenix Pharmaceuticals Royal Pharmaceutical Society of GreatVeghel, The Netherlands Cambridge, MA, USA Britain London, UKRoger T Guest Sandeep NemaGlaxoSmithKline Pfizer Inc Tim WoodWare, Hertfordshire, UK Chesterfield, MO, USA GlaxoSmithKline Ware, Hertfordshire, UKBruno Hancock Sian C Owen ˆPfizer Inc Royal Pharmaceutical Society of Great Mukund YelvigiGroton, CT, USA Britain Wyeth Research London, UK Pearl River, NY, USA Editorial StaffEditorial Staff of the Pharmaceutical Press:Laurent Y GalichetLouise ME McIndoeSian C Owen ˆPaul J Weller
ContributorsO AbuBaker R Chen B FritzschingPfizer Inc Pfizer Inc Palatinit GmbHAnn Arbor, MI, USA Groton, CT, USA Mannheim, GermanyKS Alexander JH Chu G FrunziUniversity of Toledo Pfizer Inc Bristol-Myers SquibbToledo, OH, USA Groton, CT, USA New Brunswick, NJ, USALV Allen JH Collett LY GalichetInternational Journal of Pharmaceutical University of Manchester Royal Pharmaceutical Society of Great Compounding Manchester, UK BritainEdmond, OK, USA London, UK JT ColvinGE Amidon Pfizer Inc SR GoskondaPharmacia Corporation Groton, CT, USA Sunnyvale, CA, USAKalamazoo, Michigan, USA W Cook JL GrayGP Andrews AstraZeneca The Queen’s University of BelfastThe Queen’s University of Belfast Loughborough, UK Belfast, UKBelfast, UK DQM Craig RT GuestNA Armstrong The University of East Anglia GlaxoSmithKlineHarpenden, Hertfordshire, UK Norwich, UK Ware, Hertfordshire, UKME Aulton TC Dahl RR GuptaDe Montford University Gilead Sciences SNDT Women’s UniversityLeicester, UK Foster City, CA, USA Mumbai, IndiaS Behn A Day VK GuptaAstraZeneca AstraZeneca Tyco HealthCare MallinckrodtMacclesfield, UK Loughborough, UK St Louis, MO, USAM Bond HJ de Jong G HaestDanisco Sweeteners Ltd Servier International Research Institute Cargill Cerestar BVBARedhill, Surrey, UK Courbevoie, France Mechelen, BelgiumCG Cable SP DenyerWestern General Hospital University of Cardiff BC HancockEdinburgh, UK Cardiff, UK Pfizer Inc Groton, CT, USAE Cahill X DuriezAstraZeneca Roquette Freres ` RJ HarwoodMacclesfield, UK Lestrem, France Bensalem, PA, USAW Camarco S Edge S HemISP Corp DMV International Purdue UniversityWayne, NJ, USA Veghel, The Netherlands West Lafayette, IN, USAWG Chambliss K Fowler L HendricksUniversity of Mississippi Schering-Plough Healthcare Products Rhodia IncUniversity, MS, USA Memphis, TN, USA Cranbury, NJ, USARK Chang SO Freers SE HepburnShire Laboratory Grain Processing Corporation Bristol Royal InfirmaryRockville, MD, USA Muscatine, IA, USA Bristol, UK
Contributors xiNA Hodges MG Lee MP MullarneyUniversity of Brighton Medicines and Healthcare products Pfizer IncBrighton, UK Regulatory Agency Groton, CT, USA London, UKJT Irwin S MurdandePerrigo Corporation X Li Pfizer IncMI, USA University of the Pacific Groton, CT, USA Stockton, CA, USABR Jasti RA NashUniversity of the Pacific EB Lindblad St John’s UniversityStockton, CA, USA Brenntag Biosector Jamaica, NY, USA Frederikssund, DenmarkR Johnson S NemaAstraZeneca O Luhn Pfizer IncLoughborough, UK Palatinit GmbH Chesterfield, MO, USA Mannheim, GermanyDS Jones SC OwenThe Queen’s University of Belfast PE Luner Royal Pharmaceutical Society of GreatBelfast, UK Pfizer Inc Britain Groton, CT, USA London, UKAS KearneyGlaxoSmithKline HJ Mawhinney A PalmieriKing-of-Prussia, PA, USA The Queen’s University of Belfast University of FloridaSW Kennedy Belfast, UK Gainesville, FL, USAMorflex IncGreensboro, NC, USA CP McCoy D Parsons The Queen’s University of Belfast ConvaTec LtdVL Kett Belfast, UK Clwyd, UKThe Queen’s University of BelfastBelfast, UK OS McGarvey Y Peng The Queen’s University of Belfast University of TennesseeAH Kibbe Belfast, UK Memphis, TN, USAWilkes UniversityWilkes-Barre, PA, USA JW McGinity JD Pipkin University of Texas at Austin CyDex IncV King Austin, TX, USA Lenexa, KS, USARhodia IncCranbury, NJ, USA LME McIndoe D Pipkorn Royal Pharmaceutical Society of Great Pfizer IncPB Klepak Britain Ann Arbor, MI, USAReheis Inc London, UKBerkley Heights, NJ, USA JC Price LA Miller University of GeorgiaJJ Koleng Pfizer Inc Athens, GA, USAUniversity of Texas at Austin Groton, CT, USAAustin, TX, USA MA Repka RW Miller University of MississippiK Kussendrager Bristol-Myers Squibb University, MS, USADMV International New Brunswick, NJ, USAVeghel, The Netherlands B Sarsfield J-P Mittwollen Bristol-Myers SquibbWJ Lambert BASF Aktiengesellschaft New Brunswick, NJ, USAEisai Inc Ludwigshafen, GermanyResearch Triangle Park, NC, USA T Schmeller RC Moreton BASF AktiengesellschaftBA Langdon Idenix Pharmaceuticals Ludwigshafen, GermanyPfizer Inc Cambridge, MA, USAGroton, CT, USA A Schoch G Mosher Palatinit GmbHMJ Lawrence CyDex Inc Mannheim, GermanyKing’s College, University of London Lenexa, KS, USALondon, UK CJ Sciarra C Mroz Sciarra Laboratories IncJC Lee Colorcon Ltd Hicksville, NY, USACellegy Dartford, Kent, UKSan Jose, CA, USA ´
xii ContributorsJJ Sciarra JT Stewart KD VaughanSciarra Laboratories Inc University of Georgia Boots Healthcare InternationalHicksville, NY, USA Athens, GA, USA Nottingham, UK Y SunSA Shah H Wang University of TennesseeWatson Pharmaceuticals Pfizer Inc Memphis, TN, USACorona, CA, USA Groton, CT, USA AK TaylorRM Shanker Baton Rouge, LA, USA PJ WellerPfizer Inc Royal Pharmaceutical Society of GreatGroton, CT, USA MS Tesconi Britain Wyeth Research London, UK Pearl River, NY, USAPJ SheskeyThe Dow Chemical Co AJ Winfield D ThassuMidland, MI, USA Aberdeen, UK UCB Pharma Inc Rochester, NY, USAAJ Shukla AW WoodUniversity of Tennessee BF Truitt GlaxoSmithKlineMemphis, TN, USA Pfizer Inc Research Triangle Park, NC, USA Groton, CT, USAKK Singh M Yelvigi CK TyeSNDT Women’s University Wyeth Research Pfizer IncMumbai, India Pearl River, NY, USA Kalamazoo, MI, USAR Steer HM Unvala PM YoungAstraZeneca Bayer Corporation University of SydneyLoughborough, UK Myerstown, PA, USA Sydney, Australia About the EditorsRaymond C Rowe Committee since the third edition. He is a Technical Service Leader in the Water Soluble Polymers, Pharmaceutical R&DBPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MInstP Group at The Dow Chemical Company in Midland, Michigan,Raymond Rowe has been involved in the Handbook of USA. Paul received his BSc degree in pharmacy from FerrisPharmaceutical Excipients since the first edition was published State University. Previously, he has worked as a researchin 1986, initially as an author then as a Steering Committee pharmacist in the area of solid dosage form development at themember. In addition to his position as Chief Scientist at Perrigo Company and the Upjohn (Pharmacia) Company. PaulIntelligensys, UK, he is also Professor of Industrial Pharmaceu- has authored numerous journal articles in the area oftics at the School of Pharmacy, University of Bradford, UK. He pharmaceutical technology. He is a member of the AAPS,was formerly Senior Principal Scientist at AstraZeneca, UK. In Controlled Release Society, and the Institute for Briquetting and1998 he was awarded the Chiroscience Industrial Achievement Agglomeration.Award, and in 1999 he was the British PharmaceuticalConference Science Chairman. He has contributed to over ˆ Sian C Owen350 publications in the pharmaceutical sciences including a BSc, MAbook and eight patents. Sian Owen has been involved with the Handbook of ˆPaul J Sheskey Pharmaceutical Excipients since the fourth edition, as a contributor and Steering Committee member. Sian received ˆBSc, RPh her BSc degree in pharmacology from the University ofPaul Sheskey has been involved in the Handbook of Pharma- Sunderland, and her MA in biotechnological law and ethicsceutical Excipients as an author and member of the Steering from the University of Sheffield.
Related Substances xvMethylparaben potassium Saccharin ammoniumMethylparaben sodium Saccharin calciumN-Methylpyrrolidone Self-emulsifying glyceryl monostearateMicrocrystalline cellulose and carboxymethylcellulose sodium Shellolic acidMicrocrystalline cellulose and carrageenan Sodium bisulfiteMicrocrystalline cellulose and guar gum Sodium borate anhydrousModified lanolin Sodium edetateMonobasic potassium phosphate Sodium erythorbateMontmorillonite Sodium laurateMyristyl alcohol Sodium myristateNeotrehalose Sodium palmitateNormal magnesium carbonate Sodium sorbateOctyl gallate Sodium sulfite heptahydrateOleyl oleate Soft waterOlive-pomace oil Sorbitol solution 70%Palmitin Spermaceti waxPharmaceutical glaze Stearalkonium hectoritePhenoxypropanol Sterile water for inhalationPolacrilin Sterile water for injectionPoly(methyl methacrylate) Sterile water for irrigationPotassium bisulfite Sunset yellow FCFPotassium myristate Synthetic paraffinPotassium propionate DL-(Æ)-Tartaric acidPowdered fructose TartrazinePropan-1-ol Theobroma oil(S)-Propylene carbonate Tocopherols excipientPropylparaben potassium Tribasic sodium phosphatePropylparaben sodium Trimethyl-b-cyclodextrinPurified bentonite Trimethyltetradecylammonium bromidePurified stearic acid Trisodium edetateQuaternium 18-hectorite Virgin olive oilRapeseed oil Water for injectionRefined almond oil White petrolatumRefined olive-pomace oil Zinc propionate
PrefacePharmaceutical dosage forms contain both pharmacologically been more selective in including data relating to the physicalactive compounds and excipients added to aid the formulation properties of an excipient. However, comparative data thatand manufacture of the subsequent dosage form for adminis- show differences between either source or batch of a specifictration to patients. Indeed, the properties of the final dosage excipient have been retained as this was considered relevant toform (i.e. its bioavailability and stability) are, for the most part, the behavior of a material in practice. The Suppliers Directoryhighly dependent on the excipients chosen, their concentration (Appendix I) has also been completely updated with many moreand interaction with both the active compound and each other. international suppliers included.No longer can excipients be regarded simply as inert or inactive In a systematic and uniform manner, the Handbook ofingredients, and a detailed knowledge not only of the physical Pharmaceutical Excipients collects essential data on theand chemical properties but also of the safety, handling and physical properties of excipients such as: boiling point, bulkregulatory status of these materials is essential for formulators and tap density, compression characteristics, hygroscopicity,throughout the world. In addition, the growth of novel forms of flowability, melting point, moisture content, moisture-absorp-delivery has resulted in an increase in the number of the tion isotherms, particle size distribution, rheology, specificexcipients being used and suppliers of excipients have devel- surface area, and solubility. Scanning electron microphoto-oped novel excipient mixtures and new physical forms to graphs (SEMs) are also included for many of the excipients. Theimprove their properties. The Handbook of Pharmaceutical Handbook contains information from various internationalExcipients has been conceived as a systematic, comprehensive sources and personal observation and comments from mono-resource of information on all of these topics graph authors, steering committee members, and the editors. The first edition of the Handbook was published in 1986 and All of the monographs in the Handbook are thoroughlycontained 145 monographs. This was followed by the second cross-referenced and indexed so that excipients may beedition in 1994 containing 203 monographs, the third edition identified by either a chemical, a nonproprietary, or a tradein 2000 containing 210 monographs and the fourth edition in name. Most monographs list related substances to help the2003 containing 249 monographs. Since 2000, the data has formulator to develop a list of possible materials for use in aalso been available on CD-ROM, updated annually, and from new dosage form or product. Related substances are not2004 online. This new printed edition with its companion CD- directly substitutable for each other but, in general, they areROM, Pharmaceutical Excipients 5, contains 300 monographs excipients that have been used for similar purposes in variouscompiled by over 120 experts in pharmaceutical formulation or dosage forms.excipient manufacture from Australia, Europe, India and the The Handbook of Pharmaceutical Excipients is a compre-USA. All the monographs have been reviewed and revised in the hensive, uniform guide to the uses, properties, and safety oflight of current knowledge. There has been a greater emphasis pharmaceutical excipients, and is an essential reference sourceon including published data from primary sources although for those involved in the development, production, control, orsome data from laboratory projects included in previous regulation of pharmaceutical preparations. Since many phar-editions have been retained where relevant. Variations in test maceutical excipients are also used in other applications, themethodology can have significant effects on the data generated Handbook of Pharmaceutical Excipients will also be of value to(especially in the case of the compactability of an excipient), persons with an interest in the formulation or production ofand thus cause confusion. As a consequence, the editors have confectionery, cosmetics, and food products.
ArrangementThe information consists of monographs that are divided into excipient along with the chemical name, e.g., Acacia [9000-22 sections to enable the reader to find the information of 01-5].interest easily. Although it was originally intended that eachmonograph contain only information about a single excipient, Sections 4 and 5, Empirical Formula and Molecular Weightit rapidly became clear that some substances or groups of and Structural Formula, are self-explanatory. Many excipientssubstances should be discussed together. This gave rise to such are not pure chemical substances, in which case their compo-monographs as ‘Coloring Agents’ and ‘Hydrocarbons’. In sition is described either here or in Section 8.addition, some materials have more than one monographdepending on the physical characteristics of the material, e.g. Section 6, Functional Category, lists the function(s) that anStarch versus Pregelatinized Starch. Regardless of the complex- excipient is generally thought to perform, e.g., diluent, emulsi-ity of the monograph they are all divided into 22 sections as fying agent, etc.follows: Section 7, Applications in Pharmaceutical Formulation or Tech- 1 Nonproprietary Names nology, describes the various applications of the excipient. 2 Synonyms 3 Chemical Name and CAS Registry Number Section 8, Description, includes details of the physical appear- 4 Empirical Formula and Molecular Weight ance of the excipient, e.g., white or yellow flakes, etc. 5 Structural Formula 6 Functional Category Section 9, Pharmacopeial Specifications, briefly presents the 7 Applications in Pharmaceutical Formulation or compendial standards for the excipient. Information included Technology is obtained from the British Pharmacopoeia (BP), European 8 Description Pharmacopeia (PhEur), Japanese Pharmacopeia (JP), and the 9 Pharmacopeial Specifications United States Pharmacopeia/National Formulary (USP/10 Typical Properties USPNF). Information from the JP, USP and USPNF are11 Stability and Storage Conditions included if the substance is in those compendia. Information12 Incompatibilities from the PhEur is also included. If the excipient is not in the13 Method of Manufacture PhEur but is included in the BP, information is included from14 Safety the BP. Pharmacopeias are continually updated with most15 Handling Precautions now being produced as annual editions. However, although16 Regulatory Status efforts were made to include up-to-date information at the17 Related Substances time of publication of this edition, the reader is advised to18 Comments consult the most current pharmacopeias or supplements.19 Specific References20 General References Section 10, Typical Properties, describes the physical proper-21 Authors ties of the excipient which are not shown in Section 9. All22 Date of Revision data are for measurements made at 208C unless otherwise indicated. Where the solubility of the excipient is described inDescriptions of the sections appear below with information words, the following terms describe the solubility ranges:from an example monograph if needed. Very soluble 1 part in less than 1Section 1, Nonproprietary Names, lists the excipient names Freely soluble 1 part in 1–10used in the current British Pharmacopoeia, European Pharma- Soluble 1 part in 10–30copeia, Japanese Pharmacopeia, and the United States Phar- Sparingly soluble 1 part in 30–100macopeia/National Formulary. Slightly soluble 1 part in 100–1000 Very slightly soluble 1 part in 1000–10 000Section 2, Synonyms, lists other names for the excipient, Practically insoluble 1 part in more than 10 000including trade names used by suppliers (shown in italics). or insolubleThe inclusion of one supplier’s trade name and the absence ofothers should in no way be interpreted as an endorsement of Where practical, data typical of the excipient or comparativeone supplier’s product over the other. The large number of data representative of different grades or sources of a materialsuppliers internationally makes it impossible to include all the are included, the data being obtained from either the primary ortrade names. the manufacturers’ literature. In previous editions of the Handbook a laboratory project was undertaken to determineSection 3, Chemical Name and CAS Registry Number, indi- data for a variety of excipients and in some instances this datacates the unique Chemical Abstract Services number for an has been retained. For a description of the specific methods
xviii Arrangementused to generate the data readers should consult the appro- current good manufacturing practice (GMP) and standardpriate previous edition(s) of the Handbook. chemical handling procedures is assumed.Section 11, Stability and Storage Conditions, describes the Section 16, Regulatory Status, describes the accepted uses inconditions under which the bulk material as received from foods and licensed pharmaceuticals where known. However,the supplier should be stored. In addition some monographs the status of excipients varies from one nation to another,report on storage and stability of the dosage forms that con- and appropriate regulatory bodies should be consulted fortain the excipient. guidance.Section 12, Incompatibilities, describes the reported incompat- Section 17, Related Substances, lists excipients similar to theibilities for the excipient either with other excipients or with excipient discussed in the monograph.active ingredients. If an incompatibility is not listed it doesnot mean it does not occur but simply that it has not been Section 18, Comments, includes additional information andreported or is not well known. Every formulation should be observations relevant to the excipient. Where appropriate, thetested for incompatibilities prior to use in a commercial pro- different grades of the excipient available are discussed. Com-duct. ments are the opinion of the listed author(s) unless referenced or indicated otherwise.Section 13, Method of Manufacture, describes the commonmethods of manufacture and additional processes that areused to give the excipient its physical characteristics. In some Section 19, Specific References, is a list of references citedcases the possibility of impurities will be indicated in the within the monograph.method of manufacture. Section 20, General References, lists references which haveSection 14, Safety, describes briefly the types of formulations general information about this type of excipient or the typesin which the excipient has been used and presents relevant of dosage forms made with these excipients.data concerning possible hazards and adverse reactions thathave been reported. Relevant animal toxicity data are also Section 21, Authors, lists the current authors of the mono-shown. graph in alphabetical order. Authors of previous versions of the monograph are shown in previous printed editions of theSection 15, Handling Precautions, indicates possible hazards text.associated with handling the excipient and makes recommen-dations for suitable containment and protection methods. A Section 22, Date of Revision, indicates the date on whichfamiliarity with current good laboratory practice (GLP) and changes were last made to the text of the monograph.
AcknowledgmentsA publication containing so much detail could not be produced thanks for their support over many years. Thanks are alsowithout the help of a large number of pharmaceutical scientists extended to excipient manufacturers and suppliers whobased world-wide. The voluntary support of over 120 authors provided helpful information on their products.has been acknowledged as in previous editions, but the current Thanks are also gratefully extended to the staff of theeditors would like to thank them all personally for their Pharmaceutical Press and American Pharmacists Associationcontribution. Grateful thanks also go to the members of the who were involved in the production of the Handbook: EricInternational Steering Committee who advised the editors and Connor, Tamsin Cousins, Simon Dunton, Laurent Galichet,publishers on all aspects of the Handbook project. Steering Julian Graubart, Louise McIndoe, Karl Parsons, Paul Weller,Committee members also diligently reviewed all of the and John Wilson. Once again, the diligent copy-editing andmonographs before their publication. Many authors and challenging questions asked by Len Cegielka helped the authorsSteering Committee members have been involved in previous and editors, we hope, to express their thoughts clearly,editions of the Handbook. For others, this was their first edition concisely, and accurately.although not, we hope, their last. Walter Chambliss and JohnHogan retired from the International Steering Committee Raymond C Rowe, Paul J Sheskey and Sian C Owen ˆduring the preparation of this edition and we extend our August 2005 Notice to ReadersThe Handbook of Pharmaceutical Excipients is a reference Suppliers Directory is not intended as an endorsement of thatwork containing a compilation of information on the uses and supplier or its products and, similarly, the unintentionalproperties of pharmaceutical excipients, and the reader is omission of a supplier or product from the directory is notassumed to possess the necessary knowledge to interpret the intended to reflect adversely on that supplier or its product.information that the Handbook contains. The Handbook of Although diligent effort was made to use as recentPharmaceutical Excipients has no official status and there is no compendial information as possible, compendia are frequentlyintent, implied or otherwise, that any of the information revised and the reader is urged to consult current compendia, orpresented should constitute standards for the substances. The supplements, for up-to-date information, particularly as effortsinclusion of an excipient, or a description of its use in a are currently in progress to harmonize standards for excipients.particular application, is not intended as an endorsement of Data presented for a particular excipient may not bethat excipient or application. Similarly, reports of incompat- representative of other batches or samples.ibilities or adverse reactions to an excipient, in a particular Relevant data and constructive criticism are welcome andapplication, may not necessarily prevent its use in other may be used to assist in the preparation of any future editionsapplications. Formulators should perform suitable experimen- or electronic versions of the Handbook. The reader is asked total studies to satisfy themselves and regulatory bodies that a send any comments to the Editor, Handbook of Pharmaceuticalformulation is efficacious and safe to use. Excipients, Royal Pharmaceutical Society of Great Britain, 1 While considerable efforts were made to ensure the accuracy Lambeth High Street, London SE1 7JN, UK, or Editor,of the information presented in the Handbook, neither the Handbook of Pharmaceutical Excipients, American Pharma-publishers nor the compilers can accept liability for any errors cists Association, 2215 Constitution Avenue, NW, Washington,or omissions. In particular, the inclusion of a supplier within the DC 20037-2985, USA.
BibliographyA selection of publications and websites which contain useful information on pharmaceutical excipients is listed below:Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd Japanese Pharmacopeia, 14th edn. and supplement. Tokyo: edn. Endicott, NY: Synapse Information Resources, 2002. Yakuji Nippo, 2001.Aulton ME, ed. Pharmaceutics: the Science of Dosage Form Kemper FH, Luepke N-P, Umbach W, eds. Blue List Cosmetic Design, 2nd edn. Edinburgh: Churchill Livingstone, 2002. Ingredients. Aulendorf, Germany: Editio Cantor, 2000.Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 4th edn. Lewis RJ, ed. Sax’s Dangerous Properties of Industrial New York: Marcel Dekker, 2002. Materials, 11th edn. New York: John Wiley, 2004.British Pharmacopoeia 2004. London: The Stationery Office, Lund W, ed. The Pharmaceutical Codex: Principles and 2004. Practice of Pharmaceutics, 12th edn. London: Pharmaceu-Bugay DE, Findlay WP. Pharmaceutical Excipients Character- tical Press, 1994. ization by IR, Raman, and NMR Spectroscopy. New York: National Library of Medicine. TOXNET. Marcel Dekker, 1999. http://toxnet.nlm.nih.gov (accessed 11 July 2005)European Pharmacopoeia, 5th edn. and supplements. Stras- O’Neil MJ, Smith A, Heckelman PE, eds.The Merck Index: an bourg: Council of Europe, 2005. Encyclopedia of Chemicals, Drugs, and Biologicals, 13thFlorence AT, Salole EG, eds. Formulation Factors in Adverse edn. Whitehouse Station, NJ: Merck, 2001. Reactions. London: Butterworth, 1990. Smolinske SC. Handbook of Food, Drug and CosmeticFood and Drug Administration. Inactive Ingredient Guide. Excipients. Boca Raton, FL: CRC Press, 1992. http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical (accessed 11 July 2005). Technology, 2nd edn. New York: Marcel Dekker, 2002.Food Chemicals Codex, 4th edn. Washington, DC: National Sweetman SC, ed. Martindale: the Complete Drug Reference, Academy Press, 1996. 34rd edn. London: Pharmaceutical Press, 2005.Health and Safety Executive. EH40/2002: Occupational United States Pharmacopeia 28 and National Formulary 23. Exposure Limits 2002. Sudbury: Health and Safety Execu- and supplement. Rockville, MD: United States Pharmaco- tive, 2001. peial Convention, 2005.Health Canada. Canadian List of Acceptable Non-medicinal University of the Sciences in Philadelphia. Remington: the Ingredients. http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/ Science and Practice of Pharmacy, 21st edn. Baltimore: nmi_list1_e.html (accessed 11 July 2005) Lippincott Williams and Wilkins, 2005.Hoepfner E, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of Weiner M, Bernstein IL. Adverse Reactions to Drug Formula- Excipients for Pharmaceuticals, Cosmetics and Related tion Agents: a Handbook of Excipients. New York: Marcel Areas. Aulendorf, Germany: Editio Cantor, 2002. Dekker, 1989.Japan Pharmaceutical Excipients Council. Japanese Pharma- Weiner ML, Kotkoskie LA, eds. Excipient Toxicity and Safety. ceutical Excipients 2004. Tokyo: Yakuji Nippo, 2004. New York: Marcel Dekker, 2000. AbbreviationsSome units, terms, and symbols are not included in this list as they are defined in the text. Common abbreviations have been omitted.The titles of journals are abbreviated according to the general style of the Index Medicus.% approximately. CFC chlorofluorocarbon.Ad Addendum. cm centimeter(s).ADI acceptable daily intake. cm2 square centimeter(s).approx approximately. cm3 cubic centimeter(s).atm atmosphere. cmc critical micelle concentration.BAN British Approved Name. CNS central nervous system.bp boiling point. cP centipoise(s).BP British Pharmacopoeia. cSt centistoke(s).BS British Standard (specification). CTFA Cosmetic, Toiletry, and Fragrance Association.BSI British Standards Institution. D&C designation applied in USA to dyes permitted for usecal calorie(s). in drugs and cosmetics.CAS Chemical Abstract Service. DoH Department of Health (UK).
Abbreviations xxiDSC differential scanning calorimetry. mg milligram(s).EC European Community. MIC minimum inhibitory concentration.e.g. exemplit gratia, ‘for example’. min minute(s) or minimum.EINECS European Inventory of Existing Commercial mL milliliter(s). Chemical Substances. mm millimeter(s).et al et alii, ‘and others’. mM millimolar.EU European Union. mm2 square millimeter(s).FAO Food and Agriculture Organization of the United mm3 cubic millimeter(s). Nations. mmHg millimeter(s) of mercury.FAO/ Food and Agriculture Organization of the United mmol millimole(s).WHO Nations and the World Health Organization. mN millinewton(s).FCC Food Chemicals Codex. mol mole(s).FDA Food and Drug Administration of the USA. mp melting point.FD&C designation applied in USA to dyes permitted for use mPa millipascal(s). in foods, drugs, and cosmetics. MPa megapascal(s).FFBE Flat face beveled edge. mg microgram(s).g gram(s). mm micrometer(s).GMP Good Manufacturing Practice. N newton(s) or normal (concentration).GRAS generally recognized as safe by the Food and Drug nm nanometer(s). Administration of the USA. o/w oil-in-water.HC hydrocarbon. o/w/o oil-in-water-in-oil.HCFC hydrochlorofluorocarbon. Pa pascal(s).HFC hydrofluorocarbon. pH the negative logarithm of the hydrogen ionHIV human immunodeficiency virus. concentration.HLB hydrophilic–lipophilic balance. PhEur European Pharmacopeia.HSE Health and Safety Executive (UK). pKa the negative logarithm of the dissociation constant.i.e. id est, ‘that is’. pph parts per hundred.IM intramuscular. ppm parts per million.INN International Nonproprietary Name. psia pounds per square inch absolute.IP intraperitoneal. RDA recommended dietary allowance (USA).ISO International Organization for Standardization. rpm revolutions per minute.IU International Units. s second(s).IV intravenous. SC subcutaneous.J joule(s). SEM scanning electron microscopy or scanning electronJP Japanese Pharmacopeia. microphotograph.JPE Japanese Pharmaceutical Excipients SI ¨ Statutory Instrument or SystUme Internationalkcal kilocalorie(s). d’Unites (International System of Units).kg kilogram(s). TPN total parental nutrition.kJ kilojoule(s). TWA time weighted average.kPa kilopascal(s). UK United Kingdom.L liter(s). US or United States of America.LAL Limulus amoebocyte lysate. USALC50 a concentration in air lethal to 50% of the specified USAN United States Adopted Name. animals on inhalation. USP The United States Pharmacopeia.LD50 a dose lethal to 50% of the specified animals or USPNF The United States Pharmacopeia National microorganisms. Formulary.LdLo lowest lethal dose for the specified animals or UV ultraviolet. microorganisms. v/v volume in volume.m meter(s). v/w volume in weight.m2 square meter(s). WHO World Health Organization.m3 cubic meter(s). w/o water-in-oil.M molar. w/o/w water-in-oil-in-water.max maximum. w/v weight in volume.MCA Medicines Control Agency (UK). w/w weight in weight.
Units of MeasurementThe information below shows imperial to SI unit conversions 1 millimeter of mercury (mmHg) = 133.322 pascals (Pa)for the units of measurement most commonly used in the 1 pound per square inch (psi) = 6894.76 pascals (Pa)Handbook. SI units are used throughout with, where appro-priate, imperial units reported in parentheses. Surface tension 1 dyne per centimeter (dyne/cm) = 1 millinewton per meterArea (mN/m)1 square inch (in2) = 6.4516 Â 10–4 square meter (m2)1 square foot (ft2) = 9.29030 Â 10–2 square meter (m2)1 square yard (yd2) = 8.36127 Â 10–1 square meter (m2) Temperature Celsius (8C) = (1.8 Â 8C) þ 32 Fahrenheit (8F)Density Fahrenheit (8F) = (0.556 Â 8F) –17.8 Celsius (8C)1 pound per cubic foot (lb/ft3) = 16.0185 kilograms per cubicmeter (kg/m3) Viscosity (dynamic) 1 centipoise (cP) = 1 millipascal second (mPa s)Energy 1 poise (P) = 0.1 pascal second (Pa s)1 kilocalorie (kcal) = 4.1840 Â 103 joules (J)Force Viscosity (kinematic)1 dyne (dynes) = 1 Â 10–5 newton (N) 1 centistoke (cSt) = 1 square millimeter per second (mm2/s)Length Volume1 angstrom (a) = 10–10 meter (m) ˜ 1 cubic inch (in3) = 1.63871 Â 10–5 cubic meter (m3)1 inch (in) = 2.54 Â 10–2 meter (m) 1 cubic foot (ft3) = 2.83168 Â 10–2 cubic meter (m3)1 foot (ft) = 3.048 Â 10–1 meter (m) 1 cubic yard (yd3) = 7.64555 Â 10–1 cubic meter (m3)1 yard (yd) = 9.144 Â 10–1 meter (m) 1 pint (UK) = 5.68261 Â 10–4 cubic meter (m3) 1 pint (US) = 4.73176 Â 10–4 cubic meter (m3)Pressure 1 gallon (UK) = 4.54609 Â 10–3 cubic meter (m3)1 atmosphere (atm) = 0.101325 megapascal (MPa) 1 gallon (US) = 3.78541 Â 10–3 cubic meter (m3)
Acacia1 Nonproprietary Names 8 DescriptionBP: Acacia Acacia is available as white or yellowish-white thin flakes,JP: Acacia spheroidal tears, granules, powder, or spray-dried powder. It isPhEur: Acaciae gummi odorless and has a bland taste.USPNF: Acacia 9 Pharmacopeial Specifications2 Synonyms The PhEur 2005 provides monographs on acacia and spray-Acacia gum; arabic gum; E414; gum acacia; gummi africanum; dried acacia, while the USPNF 23 describes acacia in a singlegum arabic; gummi arabicum; gummi mimosae; talha gum. monograph that encompasses tears, flakes, granules, powder, and spray-dried powder. The JP 2001 also has monographs on acacia and powdered acacia. See Table II.3 Chemical Name and CAS Registry Number Table II: Pharmacopeial specifications for acacia.Acacia [9000-01-5] Test JP 2001 PhEur 2005 USPNF 234 Empirical Formula and Molecular Weight Identification þ þ þ Characters þ þ þAcacia is a complex, loose aggregate of sugars and hemi- Microbial limit — 4104/g þcelluloses with a molecular weight of approximately Water 417.0% 415.0% 415.0%240 000–580 000. The aggregate consists essentially of an 415.0%(a) 410.0%(b) —arabic acid nucleus to which are connected calcium, mag- Total ash 44.0% 44.0% 44.0%nesium, and potassium along with the sugars arabinose, Acid-insoluble ash 40.5% — 40.5%galactose, and rhamnose. Insoluble residue 40.2% 40.5% 450 mg Arsenic — — 43 ppm5 Structural Formula Lead — — 40.001% Heavy metals — — 40.004%See Section 4. Starch, dextrin, and agar þ þ þ Tannin-bearing gums þ þ þ Tragacanth — þ —6 Functional Category Sterculia gum — þ —Emulsifying agent; stabilizing agent; suspending agent; tablet Glucose and fructose — þ —binder; viscosity-increasing agent. Solubility and reaction — — þ Organic volatile impurities — — þ (a) Powdered acacia.7 Applications in Pharmaceutical Formulation (b) Spray-dried acacia. or TechnologyAcacia is mainly used in oral and topical pharmaceuticalformulations as a suspending and emulsifying agent, often in 10 Typical Propertiescombination with tragacanth. It is also used in the preparation Acidity/alkalinity: pH = 4.5–5.0 (5% w/v aqueous solution)of pastilles and lozenges, and as a tablet binder, although if used Acid value: 2.5incautiously it can produce tablets with a prolonged disin- Hygroscopicity: at relative humidities of 25–65%, the equili-tegration time. Acacia has also been evaluated as a bioad- brium moisture content of powdered acacia at 258C ishesive;(1) and has been used in novel tablet formulations,(2) and 8–13% w/w, but at relative humidities above about 70% itmodified release tablets.(3) See Table I. absorbs substantial amounts of water. Acacia is also used in cosmetics, confectionery, food Solubility: soluble 1 in 20 of glycerin, 1 in 20 of propyleneproducts, and spray-dried flavors.(4) glycol, 1 in 2.7 of water; practically insoluble in ethanol See also Section 18. (95%). In water, acacia dissolves very slowly, although almost completely after two hours, in twice the mass ofTable I: Uses of acacia. water leaving only a very small residue of powder. The solution is colorless or yellowish, viscous, adhesive, andUse Concentration (%) translucent. Spray-dried acacia dissolves more rapidly, inEmulsifying agent 10–20 about 20 minutes.Pastille base 10–30 Specific gravity: 1.35–1.49Suspending agent 5–10 Viscosity (dynamic): 100 mPa s (100 cP) for a 30% w/v aqueousTablet binder 1–5 solution at 208C. The viscosity of aqueous acacia solutions varies depending upon the source of the material, processing,
2 Acacia storage conditions, pH, and the presence of salts. Viscosity LD50 (rat, oral): >16 g/kg increases slowly up to about 25% w/v concentration and exhibits Newtonian behavior. Above this concentration, viscosity increases rapidly (non-Newtonian rheology). 15 Handling Precautions Increasing temperature or prolonged heating of solutions results in a decrease of viscosity owing to depolymerization Observe normal precautions appropriate to the circumstances or particle agglomeration. See also Section 12. and quantity of material handled. Acacia can be irritant to the eyes and skin and upon inhalation. Gloves, eye protection, and a dust respirator are recommended.11 Stability and Storage ConditionsAqueous solutions are subject to bacterial or enzymatic 16 Regulatory Statusdegradation but may be preserved by initially boiling thesolution for a short time to inactivate any enzymes present; GRAS listed. Accepted for use in Europe as a food additive.microwave irradiation can also be used.(5) Aqueous solutions Included in the FDA Inactive Ingredients Guide (oral prepara-may also be preserved by the addition of an antimicrobial tions and buccal or sublingual tablets). Included in thepreservative such as 0.1% w/v benzoic acid, 0.1% w/v sodium Canadian List of Acceptable Non-medicinal Ingredients.benzoate, or a mixture of 0.17% w/v methylparaben and Included in nonparenteral medicines licensed in the UK.0.03% propylparaben. Powdered acacia should be stored in anairtight container in a cool, dry place. 17 Related Substances12 Incompatibilities Ceratonia; guar gum; tragacanth.Acacia is incompatible with a number of substances includingamidopyrine, apomorphine, cresol, ethanol (95%), ferric salts, 18 Commentsmorphine, phenol, physostigmine, tannins, thymol, and vanil-lin. Concentrated aqueous solutions are used to prepare pastilles An oxidizing enzyme present in acacia may affect prepara- since on drying they form solid rubbery or glasslike massestions containing easily oxidizable substances. However, the depending upon the concentration used. Foreign policy changesenzyme may be inactivated by heating at 1008C for a short and politically unstable conditions in Sudan, which is thetime; see Section 11. principal supplier of acacia, has created a need to find a suitable Many salts reduce the viscosity of aqueous acacia solutions, replacement.(10) Poloxamer 188 (12–15% w/w) can be used towhile trivalent salts may initiate coagulation. Aqueous solu- make an oil/water emulsion with similar rheological character-tions carry a negative charge and will form coacervates with istics to acacia. Other natural by-products of foods can also begelatin and other substances. In the preparation of emulsions, used.(11) Acacia is also used in the food industry as ansolutions of acacia are incompatible with soaps. emulsifier, stabilizer, and thickener. A specification for acacia is contained in the Food Chemicals Codex (FCC). The EINECS number for acacia is 232-519-5.13 Method of ManufactureAcacia is the dried gummy exudate obtained from the stemsand branches of Acacia senegal (Linne) Willdenow or other ´ 19 Specific Referencesrelated species of Acacia (Fam. Leguminosae) that grow mainly 1 Attama AA, Adiknu MV, Okoli ND. Studies on bioadhesivein the Sudan and Senegal regions of Africa. granules. STP Pharma Sci 2003; 13(3): 177–181. The bark of the tree is incised and the exudate allowed to dry 2 Streubel A, Siepmann J, Bodmeier R. Floating matrix tablets basedon the bark. The dried exudate is then collected, processed to on low density foam powder. Eur J Pharm Sci 2003; 18: 37–45.remove bark, sand, and other particulate matter, and graded. 3 Bahardwaj TR, Kanwar M, Lai R, Gupta A. Natural gums andVarious acacia grades differing in particle size and other modified natural gums as sustained-release carriers. Drug Dev Indphysical properties are thus obtained. A spray-dried powder is Pharm 2000; 26(10): 1025–1038.also commercially available. 4 Buffo R, Reineccius G. Optimization of gum acacia/modified starch/maltodextrin blends for spray drying of flavors. Perfumer & Flavorist 2000; 25: 45–54.14 Safety 5 Richards RME, Al Shawa R. Investigation of the effect of microwave irradiation on acacia powder. J Pharm PharmacolAcacia is used in cosmetics, foods, and oral and topical 1980; 32: 45P.pharmaceutical formulations. Although it is generally regarded 6 Maytum CK, Magath TB. Sensitivity to acacia. J Am Med Assocas an essentially nontoxic material, there have been a limited 1932; 99: 2251.number of reports of hypersensitivity to acacia after inhalation 7 Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipi-or ingestion.(6,7) Severe anaphylactic reactions have occurred ents. Boca Raton, FL: CRC Press, 1992: 7–11. 8 FAO/WHO. Evaluation of certain food additives and contami-following the parenteral administration of acacia and it is now nants. Thirty-fifth report of the joint FAO/WHO expert committeeno longer used for this purpose.(6) on food additives. World Health Organ Tech Rep Ser 1990; No. The WHO has not set an acceptable daily intake for acacia 789.as a food additive because the levels necessary to achieve a 9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,desired effect were not considered to represent a hazard to 11th edn. New York: Wiley, 2004: 289.health.(8) 10 Scheindlin S. Acacia – a remarkable excipient: the past, present, and future of gum arabic. JAMA 2001; 41(5): 669–671. LD50 (hamster, oral): >18 g/kg(9) 11 I-Achi A, Greenwood R, Akin-Isijola A. Experimenting with a new LD50 (mouse, oral): >16 g/kg emulsifying agent (tahini) in mineral oil. Int J Pharm Compound LD50 (rabbit, oral): 8.0 g/kg 2000; 4(4): 315–317.
Acacia 320 General References 21 AuthorsAnderson DMW, Dea ICM. Recent advances in the chemistry of acacia AH Kibbe. gums. J Soc Cosmet Chem 1971; 22: 61–76.Anderson DM, Douglas DM, Morrison NA, Wang WP. Specifications for gum arabic (Acacia Senegal): analytical data for samples collected between 1904 and 1989. Food Add Contam 1990; 7: 303–321.Aspinal GO. Gums and mucilages. Adv Carbohydr Chem Biochem 22 Date of Revision 1969; 24: 333–379.Whistler RL. Industrial Gums. New York: Academic Press, 1959. 20 August 2005.
Acesulfame Potassium1 Nonproprietary Names Table I: Pharmacopeial specifications for acesulfame potassium.PhEur: Acesulfamum kalicum Test PhEur 2005 Characters þ2 Synonyms Identification þAcesulfame K; E950; 6-methyl-3,4-dihydro-1,2,3-oxathiazin- Appearance of solution þ4(3H)-one 2,2-dioxide potassium salt; Sunett; Sweet One. Acidity or alkalinity þ Acetylacetamide þ Impurity B and related substances 420 ppm3 Chemical Name and CAS Registry Number Fluorides 43 ppm6-Methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium Heavy metals 45 ppm Loss on drying 41.0%salt [55589-62-3] Assay 99.0–101.0%4 Empirical Formula and Molecular WeightC4H4KNO4S 201.24 SEM: 1 Excipient: Acesulfame potassium Magnification: 150Â5 Structural Formula Voltage: 5 kV6 Functional CategorySweetening agent.7 Applications in Pharmaceutical Formulation or TechnologyAcesulfame potassium is used as an intense sweetening agent incosmetics, foods, beverage products, table-top sweeteners,vitamin and pharmaceutical preparations, including powdermixes, tablets, and liquid products. It is widely used as a sugarsubstitute in compounded formulations,(1) and as a toothpastesweetener.(2) The approximate sweetening power is 180–200 times that 10 Typical Propertiesof sucrose. It enhances flavor systems and can be used to mask Bonding index: 0.007some unpleasant taste characteristics. Brittle fracture index: 0.08(3) Flowability: 19% (Carr compressibility index)(3)8 Description Density (bulk): 1.04 g/cm3(3) Density (tapped): 1.28 g/cm3(3)Acesulfame potassium occurs as a colorless to white-colored, Elastic modulus: 4000 MPa(3)odorless, crystalline powder with an intensely sweet taste. Melting point: 2508C Solubility: see Table II. Specific volume: 0.538 cm3/g(4)9 Pharmacopeial Specifications Tensile strength: 0.5 MPa(3)See Table I. Viscoelastic index: 2.6(3)