Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Third Edition
`
`Edited by
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes-Barre,, Pennsylvania
`
`American Pharmaceutical Association
`Washington, D.C.
`
`London, United Kingdom
`
`Lupin Ex. 1045 (Page 1 of 18)
`
`

`

`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW. Washington, DC 20037-2985, USA
`www.aphanetoorg
`and the Pharmaceutical Press
`l Lambeth High Street, London SE1 7JN. UK
`www.pharmpress,corn
`
`© 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`
`First edition t986
`Second edition 1994
`Third edition 2000
`
`Printed in the United States of America
`
`ISBN: 0-85369-381-1 (UK)
`ISBN: 0-917330-96-X (USA~
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients / edited by Arthur H. Kibbe --3rd ed.
`p. ; crn.
`Includes bibliographical references and index
`ISBN 0-917330-96-X
`1. Excipients--Handbooks, manuals, etc. I. Kibbe, Arthur H. II. American
`Pharmaceutical Association.
`7DNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`RS201,E87 H36 2000
`615’.19--dc21
`
`A catalogue record for th~s book is available from the British Library~
`
`99-044554
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or
`by any means, without the prior written permission of the copyright holder: The publisher makes no representation, express or
`implied, with regard to the accuracy of the information contained in this book and cannot accept any le~aI responsibility or
`liability for any errors or omissions that may be made, ~
`
`Managing Editor: Melanie Segala
`Copyeditor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Desig~er:
`Tim Kaage
`
`Lupin Ex. 1045 (Page 2 of 18)
`
`

`

`Con ents
`
`COmmittees
`Co~:ributo~s
`Additions to the Third Edi.ticm
`Rela~ed Sutz~tat~ces
`p~@~ce
`Ack~mwledgmems
`N~tice to Readers
`Selected Bibliography
`Abbreviations
`Units q[ Measurement
`
`Monographs
`Acacia
`Acesulfame Potassium
`Albumin
`Alcohol
`Al~inic Acid
`Atipbatic Polyesters
`Alpha Tocopherol
`Ascorbic Acid
`Ascorbyl Palmitate
`Aspartame
`Bentonite
`Benzalkonium Chloride
`Benzethonium Chloride
`Benzoic Add
`Benzyl Alcohol
`BenzyI Benzoate
`
`Bu~y]med Hydroxyanisote
`Bmytated Hydroxytoluene
`Bu~ylparaben
`Calcium Carbonate
`Calcium Ptmsphate, Dibasic Anhydrous
`Calcium Phosplmte Dibasic Dihydr~te
`Calcium Phospha[e. Tribasic
`Calcium Ste~rate
`Calcium Sulfate
`Canola Oil
`Carbomer
`Carbon Dioxide
`Carboxymethylcellulose Calcmm
`Carboxymethyleellulose Sod]am
`Carrageen~n
`Castor Oil, Hydrogenated
`Cellulose Acetme
`Cellulose Acetate Phtl~ala~e
`Cellulose, Microcrystalline
`Cellulose, Powdered
`Cellulose, Siiicified Microcrystaillne
`Cetostearyl Alcohol
`Cetrimide
`Cetyl Alcohol
`Chlorfiexidine
`Ch]orobutanol
`Chlorocresol
`ChlorodJ.fluoroethane HCFC)
`Chtorofluorocarbons (CFC)
`
`Cholesterol
`Citric Acid Monohydrate
`Colloidal Silicon Dioxide
`Coloring Agents
`Corn Oil
`Cottonseed Oil
`Cresol
`Croscarmellose Sodiuin
`Crospovidone
`C yclodextrins
`Dextrates
`Dextrin
`Dextrose
`Dibutyl Sebacate
`Diethanolamine
`Diethyl Phthalate
`Difluoroethane (HFC)
`Dimethyl Ether
`Docusate Sodium
`Edetic Acid
`Ethylceltulose
`Ethyl Maltol
`Ethyl Oleate
`Etbylparaben
`Ethyl Vanillin
`Fructose
`Fumaric Acid
`Gelatin
`Glucose, Liquid
`Glycerin
`GlyceryI Monooleate
`G!yceryl Monostearate
`Glyceryl Palrnitostearate
`Glycofurol
`Guar Gum
`Heptafluoropropane (HFC)
`Hydrocarbons (HC)
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`Hydroxypropyl Cellulose
`Hydroxypropyl Cellulose, Low-substitnted
`Hydroxypropyl Methytcellulose
`Hydroxypropyl Methylcellulose Phlhatate
`Imidurea
`lsopropyl Alcohol
`Isopropyl Myristate
`Isopropyl Palmitate
`Kaolin
`Lactic Acid
`Lactitol
`Lactose
`Lanolin
`Lanoliu Alcohols
`Lanolin, Hydrous
`Lecithin
`Magnesium Aluminum Silicate
`Magnesimn Carbonate
`Magnesium Oxide
`Magnesium Stearate
`Magnesium Trisilicate
`
`ix
`
`xv
`xvii
`
`xix
`XX
`
`1
`3
`5
`7
`10
`13
`18
`2I
`25
`27
`30
`33
`36
`38
`41
`
`46
`49
`51
`53
`56
`6O
`63
`68
`70
`73
`77
`79
`83
`85
`87
`91
`94
`96
`99
`t02
`107
`110
`
`114
`117
`12t
`t26
`129
`132
`134
`
`138
`140
`143
`146
`!54
`156
`158
`t60
`163
`165
`169
`172
`175
`178
`180
`t82
`184
`186
`188
`191
`195
`201
`203
`205
`208
`210
`213
`215
`2!8
`220
`223
`225
`228
`230
`232
`234
`236
`238
`240
`244
`249
`252
`256
`26l
`263
`265
`267
`269
`272
`274
`276
`286
`288
`29O
`292
`295
`299
`303
`305
`309
`
`Lupin Ex. 1045 (Page 3 of 18)
`
`

`

`vi Contents
`
`Malic Acid
`Maltitol
`Maltitol Solution
`Maltodextrin
`Maltol
`Maltose
`Mannitol
`Medium Chain Triglycerides
`Meglumine
`Meuthol
`Methylcellulose
`Methylparaben
`Mineral Oil
`Mineral Oil, Light
`Mineral Oil and Lanolin Alcohols
`Monoethanolamine
`Nitrogen
`Nitrous Oxide
`Oleic Acid
`Paraffin
`Peanut Oil
`Petrolatum
`Petrolatum and Lanolin Alcohols
`Phenol
`Phenoxyethanol
`Phenylethyl Alcohol
`Phenylmercuric Acetate
`Phenylmercuric Borate
`Phenylmereuric Nitrate
`POlacrilin POtassium
`Poloxamer
`Polydextrose
`Polyethylene Glycol
`Polyethylene Oxide
`PoIymethacrylates
`Polyoxyethylene Alkyl Ethers
`Polyoxyethylene Castor Oil Derivatives
`Polyoxyethylene Sorbitan Fatty Acid Esters
`Polyoxyethylene Stearates
`Polyvinyl Alcohol
`Potassium Chloride
`Potassium Citrate
`Potassium Sorbate
`Povidone
`Propylene Carbonate
`Propylm!e Glycol
`Propylene Glycol Alginate
`Propyl Gallate
`Propylparaben
`Saccharin
`Saccharin Sodium
`Sesame Oil
`Shellac
`Sodium Alginate
`
`31I
`313
`315
`317
`320
`322
`324
`329
`332
`334
`336
`340
`345
`347
`349
`350
`352
`354
`356
`358
`360
`362
`365
`367
`370
`372
`374
`377
`379
`383
`386
`389
`392
`399
`401
`407
`412
`416
`420
`424
`426
`429
`431
`433
`440
`442
`445
`447
`450
`454
`457
`460
`462
`465
`
`Sodium Ascorbate
`Sodium Benzoate
`Sodium Bicarbonate
`Sodium Chloride
`Sodium Citrate Dihydrate
`Sodium Cyclamate
`Sodium Lauryl Sulfate
`Sodium Metabisulfite
`Sodium Phosphate, Dibasic
`Sodium Phosphate, Monobasic
`Sodium Propionate
`Sodium Starch Glycolate
`Sodium Stearyl Fumarate
`Sorbic Acid
`Sorbitan Esters (Sorbitan Fatty Acid Esters)
`Sorbi tol
`Soybean Oil
`Starch
`Starch, Pregelatinized
`Starch, Sterilizable Maize
`Stearic Acid
`Stearyl Alcohol
`Sucrose
`Sugar, Compressible
`Sugar, Confectioner’s
`Sugar Spheres
`Suppository Bases, Hard Fat
`Talc
`Tartaric Acid
`Tetraftuoroethane (HFC)
`Thimerosal
`Titanium Dioxide
`Tragacanth
`Triacetin
`Triethanolamine
`Triethyl Citrate
`Vanillin
`Vegetable Oil, Hydrogenated, Type I
`Water
`Wax, Anionic Emulsifying
`Wax, Carnauba
`Wax, Cetyl Esters
`Wax, Microcrystalline
`Wax, Nonionic Emulsifying
`Wax, White
`Wax, Yellow
`Xanthan Gum
`Xylitol
`Zein
`Zinc Stearate
`
`Appendix 1: Suppliers’ Directory
`Appendix II: HPE Laboratory Methods
`index
`
`468
`471
`474
`478
`482
`485
`487
`490
`493
`496
`498
`50t
`505
`508
`5tl
`515
`519
`522
`528
`531
`534
`537
`539
`544
`546
`548
`550
`555
`558
`560
`562
`565
`568
`570
`572
`574
`576.
`578
`580
`585
`587
`589
`591
`593
`595
`597
`599
`602
`6O6
`608
`
`61l
`641
`645
`
`Lupin Ex. 1045 (Page 4 of 18)
`
`

`

`UK Steering Committee vii
`
`UK Steering
`Committee
`
`Colin G Cable
`Royal Pharmaceutical Society of Great Britain
`Edinburgh, UK
`
`M Jayne Lawrence
`King’s College London
`London, UK
`
`Andy Dundon
`Glaxo Wellcome
`Ware~ UK
`
`Roger Guest
`SmithKline Beecham Pharmaceuticals
`Crawley, UK
`
`John E Hogan
`Pfizer Ltd
`Sandwich0 UK
`
`J Mike Newton
`School or" Pharmacy’, University of London
`Lo~don, UK
`
`Ray C Rowe
`Astra Zeneca Pharmaceuticals
`Macclesfield, UK
`
`A~nley Wade
`Bath, UK
`
`Paul J Weller
`Royal Pharmaceutical Society of Great Britain
`London, UK
`
`Lupin Ex. 1045 (Page 5 of 18)
`
`

`

`viii US Steering Committee
`
`US Steering
`Committee
`
`Gregory E Amidon
`Pharmacia & Upjohn, the,
`Kalamazoo, Michigan
`
`Walter G Chambliss
`Chambliss Technology Development and Transfer
`Germailtowil, Tennessee
`
`Albert HL Chow
`Chinese University of Hong Kong
`Shatin, NT Hong Kong
`
`Arthur H Kibbe
`Wilkes University
`Wilkes-Barre, Pennsylvania
`
`Ke~iKijima
`Japan Pharmaceutical Excipients Counci!
`Tokyo, Japan
`
`A Waseem Malick
`Hoffmann-LaRoche, Inc.
`Nutley, New Jersey
`
`Tsuneji Nagai
`Hoshi University
`Tokyo, Japan
`
`Anthony Palmieri III
`Pharmacia & Upjohn, Inc:
`Kalamazoo, Michigan
`
`Garnet E Peck
`Purdne University
`West Lafayette, Indiana
`
`Stuart C Porter
`Colorcon
`West Point, Pennsylvania
`
`George E Rder
`FMC Corporation (retired)
`Princeton, New Jersey
`
`Christopher T Rhodes
`University of Rhode Island
`Kingston, Rhode Island
`
`Paul J Sheskey
`The Dow Chemical Co.
`Midland, MichigaI~
`
`Bhogi B Sheth
`University of Tennessee
`Memphis, Tennessee
`
`Lupin Ex. 1045 (Page 6 of 18)
`
`

`

`Contributors
`
`Abbas Abdul,Rahman
`Organon, Inc.
`Wesl Orange, New Jersey
`
`Rohert Abramowitz
`Bristol-M yers Sq uibb
`New Brunswick. New Jersey
`
`Kenneth S Alexander
`University of Toledo
`Toledo, Ohio
`
`Loyd V Allen, Jr.
`International Journal of Phm’maceutical Compounding
`Edmond, Oklahoma
`
`Gregory E Amidon
`Pharmacm & Upjohn, Inc.
`Kalamazoo, Michigan
`
`N Anthony Armstrong
`Cardiff University
`Cardiff, UK
`
`Mike E Aulton
`De Monfford University
`Leicester. UK
`
`Martin W Beasley
`Applied Analytical Industries
`Wilmington, North Carolina
`
`Sheena Behn
`Astra Zeneca Pharmaceuticals
`Macc esfietd, UK
`
`Mike Booth
`Roquette (UK) Ltd.
`Tunbridge Wells, UK
`
`Eddie L Brunson
`Schering-Plough HeaithCare Products
`MemphiS, Tennessee
`
`John D Buehler
`Novartis USA
`East Hanover, New Jersey
`
`Colin G Cable
`Royal Pharmaceutical Society of Great Britain
`Edinbnrgh, UK
`
`Richard K Chang
`Schire C.o.
`Rockviile, Maryland
`
`Donald Chow
`University of Southern California
`Los Angeles, California
`
`JH Collett
`Manchester University
`Manchester, UK
`
`Vicki Conway
`Warner-Lambert Co
`Morris Plains, New Jersey
`
`Terrence C Dahl
`Gilead Sciences, Inc,
`Sunnyvale, California
`
`Yogesh Dandiker
`Roche PrOducts Ltd.
`Welwyn Gardens, UK
`
`Stefanos Daskalakis
`Smith-Kline Beecham
`Parsippany, New Jersey
`
`Andrew Day
`BoOts Contract Manufacturing
`Nottingham, UK
`
`Stephen Denyer
`University of Brighton
`Brighton, UK
`
`Xavier Duriez
`Roquette (UK) Ltd.
`Tunbridge Wells, UK
`
`Annette Ellison
`Boots Contract Manufacturing
`Nottingham, UK
`
`Anthony A Fazzi
`Wilkes University
`Wilkes’Barre, Pennsylvania
`
`Richard W Fengl
`Eastman Chemical Co,
`KingSport, Tennessee
`
`Kevin Fowler
`Schering,Plough HealthCare Products
`Memphis, Tennessee
`
`Susan O Freers
`Grain Processing Corp.
`Muscatine, Iowa
`
`Lupin Ex. 1045 (Page 7 of 18)
`
`

`

`x Contribitlors
`
`Gerard Frunzi
`Bristol-Myers Products
`Hillside, New Jersey
`
`Dawn L Gabriel
`Warner-Lambert Co.
`Morris Plains, New Jersey
`
`Sanjay R Goskonda
`Oread
`Palo Alto, California
`
`Michael J Groves
`University of Illinois
`Chicago, Illinois
`
`Richard Harwood
`Consultant
`Bensalem, Pennsylvania
`
`Ken Herbert
`La Gap Pharmaceuticals
`Bordon, UK
`
`Norman A Hodges
`University of Brighton
`Brighton, UK
`
`john E Hogan
`Pfizer Lid
`Sandwich, UK
`
`Harvey A Jacobs
`Wilkes University
`Wilkes,Barre, Pennsylvania
`
`T Robert Ju
`Pharmacia & Upjolm, Inc.
`Kalamazoo, Michigan
`
`Thomas N Julian
`Parke-Davis
`Annandale, New JerSey
`
`Albert S Kearney
`Smith-Kline Beecham
`King-of-Prussia, Pennsylvania
`
`Sam W Kennedy
`Morflex, Inc.
`Greensboro, North Carolina
`
`Arthur H Kibbe
`Wilkes University
`Wilkes-Barre, Pennsylvania
`
`Norman H Kobayashi
`Agouron Pharmaceuticals
`La Jolla, California
`
`John Koleng
`University of Texas at Anstin
`Austin, Texas
`
`M Jayne Lawrence
`King’s College London
`London, UK
`
`Jung-Chung Lee
`Cellegy
`San Jose, California
`
`M Gerard Lee
`Medicines Cona!ol Agency
`London, UK
`
`XlaoRng Li
`University of the Pacific
`Stockton, California
`
`Nicholas G Lordi
`Rntgers University
`Piscataway, New Jersey
`
`Paul E Luner
`University of Iowa
`Iowa Cityi Iowa
`
`A Waseem Malick
`Hoffmann-LaRoche, Inc.
`Nntley, New Jersey
`
`James W McGinity
`University of Texas at Austin
`Austin, Texas
`
`Elaine Morefield
`Whitehall Robbins
`Eads, Tennessee
`
`R Chris Moreton
`Penwest Pharmaceuticals Group
`Patterson, New York
`
`Michael Mulski
`Warner-Lambert Co.
`Morris Plains, New Jersey
`
`Robert A Nash
`St. John’s University
`Jamaica, New York
`
`Denise OD noghue
`~ o
`BristobMyers Squibb
`New Brunswick, New Jersey
`
`Anthony Palmieri III
`Pharmacia & Upjohn, Inc,
`Kalamazoo, Michigan
`
`David Parsons
`ConvaTec Ltd,
`Clwyd, UK
`
`H Popli
`University of Delhi
`Delhi, India
`
`Lupin Ex. 1045 (Page 8 of 18)
`
`

`

`James C Price
`University of Georgia
`Athens. Georgia
`
`George E Reier
`FMC Corporation (Retired)
`Philadelphia. Pennsylvania
`
`William J Reilly, Jr.
`Consultant
`Philadelphia. Pennsylvania
`
`Michael A Repka
`University of Texas ar Austin
`Austin, Texas
`
`Martin M Rieger
`M & A Rieger Associates
`Morris Plains, New Jersey
`
`Geoff Rowley
`University of Sunderland
`Sunderland. UK
`
`Gail Russell
`Boots Healthcare International
`Nottingham. UK
`
`Beth A Sarsfield
`Bristol-Myers Products
`Somerset, New Jersey
`
`Robert L Schmitt
`Union Carbide
`Bound Brook, New Jersey
`
`Christopher J Sciarra
`Sciarra Aeromed Development
`Locust Valley, New York
`
`John J Sciarra
`Sciarra Aeromed Development
`Locust Valley, New York
`
`Eli Shelter
`University of Colorado
`Denver, Colorado
`
`Atul J Shukla
`University of Tennessee
`Memphis, Tennessee
`
`Denis Simon
`Roquette (UK) Ltd,
`Tunbridge Wells, UK
`
`,~ohn A Stead
`Hoechst Marion Roussel Ltd.
`Swindon, UK
`
`James T Stewart
`University of Georgia
`Athens, Georgia
`
`Yichun Sun
`University of Tennessee
`Memphis, Tennessee
`
`Anne K Taylor
`
`Consultant and TechnicaI Writer
`Baton Rouge, Louisiana
`
`David Thurgood
`
`Boots Healthcare International
`Nottingham, UK
`
`Hoshang M Unvala
`Bayer Corp.
`Myerstown, Pennsylvania
`
`Ravindra C Vasavada
`University of the Pacific
`Stockton, California
`
`Ken D Vaughan
`
`Boots Healthcare International
`Nottingham, UK
`
`Paul J Weller
`Royal Pharmaceutical Society of Great Britain
`London, UK
`
`Thomas A Wheatley
`
`FMC Corporation (retired)
`Philadelphia, Pennsylvania
`
`Mick J Wilkin
`Boots Contract Manufacturing
`Nottingham, UK
`
`Arthur J Winfield
`University of Aberdeen
`Aberdeen, UK
`
`A Wayne Wood
`
`Glaxo Wellcome, Inc.
`Research Triangle Park, North Carolina
`
`Andrew Yu
`
`Food and Drug Administration
`Rockville, Maryland
`
`Cheng D Yu
`
`Bristol-Myers Squibb
`New Brunswick, New Jersey
`
`Lupin Ex. 1045 (Page 9 of 18)
`
`

`

`xii Addition,s to the Third Edidon
`
`Additions to the Third
`Edition
`
`Aliphatic Polyesters
`Calcium Phosphate, Dibasic Anhydrous
`Cellulose Acetate
`Heptafluoropropane
`Hydroxypropyl Cellulose, Low-substituted
`Lactitol
`Maltitol
`Maltose
`Polydextrose
`Polyethylene Oxide
`
`Lupin Ex. 1045 (Page 10 of 18)
`
`

`

`:elated Substances
`
`Acetyltributyl Citrate
`Acetyltriethyl Citrate
`Aleuritic Acid
`d-Alpha Tocopherol
`d-Alpha Tocopheryl Acetate
`d/-Alpha Tocopheryl Acetate
`d-Alpha Tocopheryl Acid Succinate
`all-Alpha Tocopheryl Acid Succinate
`Amylopectin
`o~-Amylose
`Anhydrous Citric Acid
`Anhydrous Sodium Citrate
`Anhydrous Sodium Propionate
`Bacteriostatic Water for Injection
`Bentonite Magma
`Beta-Carotene
`Beta-Tocopherol
`Butylparaben Sodimn
`Calcium Alginate
`Calcium Ascorbate
`Calcium Cyclamate
`Calcium Propionate
`Calcium Silicate
`Calcium Sorbate
`Calcium Sulfate Hemihydrate
`Carbon Dioxide-Free Water
`Carboxymethylcellulose Sodium 12
`Castor Oil
`Cationic Emulsifying Wax
`Chlorhexidine Acetate
`Chlorhexidine Gluconate
`Chlorhexidine Hydrochloride
`Chlorodifluoromethane
`Chlorophenoxyethanol
`Chloroxylenol
`Corn Syrup Solids
`m-Cresol
`o-Cresol
`p-Cresol
`Cyclamic Acid
`Dehydrated Alcohol
`Delta-Tocopherol
`Denatured Alcohol
`Dextrose Anhydrous
`Diazolidinyl Urea
`Dibasic Sodium Phosphate
`Dibutyl Phthalate
`Dilute Alcohol
`Dilute Hydrochloric Acid
`Dimethyl-[3-Cyclodextrin
`Dimethyl Phthalate
`Dipotassium Edetate
`Disodium Edetate
`Docusate Calcium
`Docusate Potassium
`Dodecyl Gallate
`Dodecyltrimethylammonmm Bromide
`Edetate Calcium Disodium
`Egtumine
`
`Ethyl Gallate
`Ethylparaben Potassium
`Ethylparaben Sodium
`Frt~ctose Liquid
`Fructose Milled
`Fructose Pyrogen-Free
`Gamma-Tocopherol
`Glyceryl Behenate
`Hard Water
`Hexadecyltrimethylammonium Bromide
`High Fructose Syrup
`Hydrogenated Vegetable Oil, Type II
`2.Hydroxyethyl-13-Cyclodextrin
`2_Hydroxypropyl-~-Cyclodextrin
`Indigo Carmine
`Invert Sugar
`Iron Oxides
`Liquified Phenol
`Magnesium Carbonate Anhydrous
`Magnesium Carbonate Hydroxide
`Magnesium Lauryl Sulfate
`Magnesium Silicate
`Magnesium T:risiiicate Anhydrous
`D-Malic Acid
`~Malic Acid
`d-Mentho!
`/+Menthol
`Methyl Methacrylate
`Methyl Oleate
`Methylparaben Potassium
`Methylparaben Sodium
`Microcrystalline Cellulose and Cm.boxymethylcellulose Sodium
`Monobasic Potassium Phosphate
`Montmorillonite
`Normal Magnesium Carbonate
`Octyl Gallate
`Palmitic Acid
`Pharmaceutical Glaze
`Phenoxy propanol
`Polaerilin
`Po!y (Methyl Methacrylate)
`Potassium Alginate
`Potassium Benzoate
`Potassium Bicarbonate
`Potassium Bisulfite
`Potassium Citrate Anhydrous
`Potassium Metabisuifite
`Potassium Propionate
`Powdered Fructose
`Propan- 1-ol
`Propionic Acid
`(S)-Propylene Carbonate
`Propylparaben Potassium
`Propylparaben Sodium
`Purified Stearic Acid
`RapeSeed Oil
`Saccharin Ammonium
`Saccharin Calcium
`Sapoaite
`
`II I I n n n n n n r n n r I I I I ’ I ’ I ’ I ’ I ........................... I" "’ " " ’" ,,,"’"’,,,,,, "’"’""i’i’i’i’i’i’i’?i
`
`Lupin Ex. 1045 (Page 11 of 18)
`
`

`

`xiv Rek~ted Substances
`
`Self-emulsifyil~g Glyceryl Monosleara~e
`SheHolic Acid
`Sodium Bisulfite
`Sodium Edetate
`Sodium S~rbate
`Sodium Sulfite
`Soft Water
`Sorbito! SoIution 70%
`Spermaceti Wax
`Sterile Water for Inhalation
`S~erile Wa~er for Iiljection
`Sterile Water for Irrigation
`Sugartab
`Sunset Yellow FCF
`
`Syn:thefic Pa~;afl] n
`D-(-),-Tavtaric Acl.d
`Dk-(_+)-Tartaric Acid
`Tartrazine
`Theobroma Oil
`Tocopherols Excipients
`Tribasic Sodium Phosphate
`Tvibutyt Citrate
`Trimethy!-~-Cyclodextrin
`T~’imethyltetradecyl am moniu m Bromide
`Trisodium Edetate
`Water for Injection
`Wh ile Petrolatum
`Zinc Propionate
`
`Lupin Ex. 1045 (Page 12 of 18)
`
`

`

`Preface
`
`Pharmaceutical dosage forms contain both active ingredients
`and inactive materials called excq~lents, The behavior of the
`dosa~e form is dependent on process variables and the inter-
`relationship between the various excipien~s and their ~mpact
`on the active ingredient. Suppliers of ezcipients have devel-
`oped nox, el excipiem mixtures and new physical forms of ex-
`mpients, which give them ~mproved characteristics, In addition,
`~he fi~ternational nature of the pharmaceutical iudustry and its
`suppliers demands that formulators throughout the world have
`as m.uch inl’orma~{on as possible about the chemical and phys-
`ical nature of excipients and combinations of excipients, For-
`mulators are also concerned about the efteel of the finished
`product on the patient fi is intended m treat. Therefore, they
`are concerned about ~eneral and specific toxic effects of the
`excipients, allergic reactions to excipien~s, disease-specific i~-
`tolerance to excip~ems and interactions between the excipient
`and the acuve ingredient, In addition, l:ormutators need to be
`aware of the potential environmental impac~ of the use of
`c~p~ents. Lasfl3. the effect of regulatory change associated with
`harmonization is also a concern of the professional formulator.
`
`The Ha,.tdl~oo!~ qf Phart~,aceutical E.rcipie~ts is a joint publics-
`:ion of the American Pharmaceutical Association and the Royal
`Pharmaceutical Society of Great Britain. The Ha~zdbook
`P!~ar~ac’eutica! Exc@ze~tts, originally published in 1986, was
`the first English-language publication to comprehensively and
`systematically describe the chemical and physical properties of
`pharmaceutical excipients. The first edition contained !45 mono-
`graphs, and the second contained 203. The presen~ edition con-
`rains 210 monographs authored by experts in phm-maceutical
`formulation or excipiem manufacture from around. ~l~e world.
`This edition also contains the results of extensive laboratory
`testing carried out over the last two years m laboratories in
`Grea* Brilain and the United States, Some data developed by
`the first edition’s laboratory project are retained, h is clem-ly
`noted as such in the monographs. The new data generated for
`this ectitio~ should help the formulator in the selection of ap-
`proprmte excipiems for various dosage forms. A major devel-
`opment since the publication of the last edition of the Ha~Mboo~
`has been the trend towards global pharmaceutical harmonization.
`To reflect this. where appropriate more detailed informauon on
`excipients ttsed in Japan has been included in this edition. Ad-
`dflionally the index has been revised and expanded and the sup-
`pliers’ directory has been completely ul?dated.
`
`The Handbook q[ Pharmaceutical Excipier~ts collects in a sys--
`tematic and uni%rm manner esseutial data on the physical prop-
`erties of e~cipients such as: boiliug point, btdk and tap density,
`compte ssion characteristics, hygroscol?ic~Y, flowabi!ity, melting
`point, moisture content, moisture-abso~tion isotherms, particle
`size distribution, theology, specific surface area. and solubility.
`Scanning electron rmcrophotographs {SEMsl are also included
`for many of the excipients, The Ha~Mboolc coati, ins information
`from various internationa! sources, but also includes laboratory
`data determined specifically for the Ha~Mbook and personal ob-
`servauoll and comnlonts from the monograph author, steerlng
`committee members, slid the editor. It also contains information
`on the safe use and potential toxicity of the materials.
`All of the monographs in the Ha~u]boolc are thoroughly cross-
`referenced and indexed so that excipients may be identified
`by either a chemical, nonpropr~etary, or trade name. Most
`
`monographs list related substance{ s) to help the formulator
`develop a list of possible materials for use in a new dosage
`form or product. Related substances are not directly substi-
`tutable for each other but are excipients that have been used
`for similar purposes in various dosage forms.
`
`The Ha~dbool~ q[" P!~armaceutical E,vC’il)ie~ts ~s a comprehen-
`sive. uniform guide to the uses, propemes, and saiEty of phar-
`maceutical excipients and is an essential reference source for
`those involved in the development, production, control or reg-
`nlation of pharmaceutical preparauons. Since many pharma-
`ceutical excipients are also used in other applications, the
`Handbook ql Pt~arr~,aceutical Exci;~ienrs will also be of value
`to persons with an interest in the forn-mlation or production
`of confectionery, cosmeuc, and food products.
`
`Arrangement
`
`The Handbook consists of monographs that are divided into 22
`sections to make it easy for the reader to go directly to the
`information of interest. Although ~t was originally intended that
`each monograph contain only information about a single excip-
`ient., it rapidly became clear that some substances or groups of
`substances must be diseassed together. This gave rise to such
`monographs as ’Coloring Agents’ and ’Hydrocarbons.’ In addi-
`tion. some materials have more than one monograph dependiug
`on the physical characterisncs of the material due mainly to ~ts
`preparation. A good example of this is the various starch mono-
`graphs, particularly Starch vs, Pregelatinized Starch. Regardless
`of the complexity of the monograph they are all divided in 22
`secdons as follows:
`
`1. Nonproprietary Names
`2. S) nonyms
`3. Chemical Name and CAS Registry Number
`4. Empirical Formula and Molecular Weight
`5. Structural Formula
`6. Functional Category
`7. Applications in Pharmaceutical Formulation or Technology
`8. Description
`9. Pharmacopeial Specifications
`10. Typical Properties
`I l, Stability and Storage Conditions
`12. Incompatibilities
`13. Method of Manufacture
`14. Safety
`15. Handling Precautions
`16. Regulatory Status
`l 7. Pharmacopmas
`18. Related Substances
`19. Comments
`20. Specific References
`2l, General References
`22. Authors
`
`To make ~t easy for the first time nser, descriptions of the
`sections appear below with information from an example
`monograph if needed
`
`Section 1. Nonproprietary Names, lists the exmpmnt names
`used in the current British Pharmacopoeia. Enropean Pharma-
`copem. Japanese Pharmacopeia. and the United States Phar-
`macopeia. For nonpharmacopeiat excipients the appropriate
`approved name. e.g., USAN or INN is indicated.
`Section 2, Synonyms, lists other names for the excipient, in-
`cluding trade names used by suppliers; trade names are listed
`in italics. The inclusion of one supplier’s trade name and the
`absence of others shonld in no way be interpreted as an
`
`Lupin Ex. 1045 (Page 13 of 18)
`
`

`

`endorsement of one supp!ier’s product over the other. The
`large number of suppliers internationally makes it impossihIe
`to include all the trade names.
`
`Section 3, Chemical Name and CAS Registry Number, indi-
`cates the unique Chemical Abstract Services number for an ex-
`cipient along with the chemical name, e.g., Acacia [9000-01-5].
`
`Sections 4 and 5, Empirical Formula and Molecular Weight
`and Structural Formula, are self-explanatory. Many excipi-
`ents are not pure chemical substances, in which case their
`composition is desc:ribed either here or in Section 8,
`
`Section 6, Functional Category, lists the functlon(s) that an
`excipient is generally thought to perform, e.g., diluent, emul-
`sifying agent, etc.
`
`Section 7, Applications in Pharmaceutical Formulation or
`Technology, describes the various applications o[ the excipicnt.
`
`Section 8, Description, includes details of the physical ap-
`pearance of the excipient, e.g., white or yellow flakes~ etc.
`
`Section 9, Pharmacopeial Specifications, briefly presents the
`compendial standards [or the excipient, Information included is
`obtained fi:orn the British Pharmacopoeia (BP), European Phar-
`macopeia (PhEm’), Japanese Pharmacopeia (JP), and the United
`States Pharmacopeia/National Formulary (USP). Information
`from the JP m~d USP are included if Ihe substance is in those
`compendia. Lnformation fi;om the PhEur is also included. If the
`excipient is not in the PhEur but is included in the BP, ilffon~nation
`is included from the BR The pharmacopeias m:e continually up-
`dated and revisions or supplements am published. It was neces-
`sary to select a point in time and use that as our reference when
`selecting the information to be included i~ this section. Therefore
`the information is fiom the following volumes:
`
`BP - 1998 Edition
`JP - Thirteenth Edition 1996
`PhEur -Third Edition plus supplements to 1999
`USP - USP 24 NF 19 2000 Edition
`
`Since the USP and NF were combined into a single reference
`many years ago it was felt that a single abbreviation would
`be sufficient, Therefore throughout the Handbook whenever
`the USP abbreviation is used it refers to this combined text,
`
`Section 10, Typical Properties, describes the physical prop-
`erties of the excipient which are not shown in Section 9. All
`data are for measurements made at 20°C unless otherwise
`indicated. Where the solubility of the excipient is described
`in words, the following terms describe the solubility ranges:
`
`Very soluble
`Freely soluble
`Soluble
`Sparingly soluble
`Slightly soluble
`Very slightly soluble
`Practically insoluble
`or insoluble
`
`part in less than 1
`part in 1-10
`part in 10-30
`part in 30-100
`part in 100-1000
`part in. 1000-10 000
`part in more than 10 000
`
`Experimental data were determined specifically for the Hand-
`book and are included in this section. Data from the HPE
`Laboratory Project in support of the third edition are clearly
`marked as such. The methods that were used to collect that
`dala ,’ire included in Appendix II: HPE Laboratory Meth-
`ods~ Data from the HPE Laboratory Project performed for the
`first edition m’e either replaced hy the new data or referenced
`as such iu each monograph: The reader is referred to the ear-
`lier editions of this book for the metlmds used.
`
`Section 1 t, StabiliU, and Storage Conditions, describes the con-
`ditions under which the Ixdk material as received from the sup-
`plier should be stored. In addition some monographs report on
`storage and stability of the dosage forms that contain the excip-
`lent,
`
`Section !2, Incompatibilities, describes the reported incompati-
`bilities for the excipient either with other excipients or with active
`ingredients. If aa incompatibility is not listed it does not mean it
`does not occur but simply that it has not been reported or is not
`well knowm Every formulation should be tested for incompati-
`bilities prior to use in a commercial product.
`
`Section 13, Method. of Manufacture, describes the common
`inetliods of niauafacture and additional processes that are used
`to give the excipient its physical Characteristics, Iil some cases
`the possibility of impurities will be indicated in the method
`of manufacture.
`
`Section 14, Safety, describes briefly the types of formulations in
`which the excipient has been used and presents relevant data con-
`cerning possible hazards and adverse reactions that have been re-
`ported. Relevant animal toxicity data are also shown.
`
`Section 15, Handling Preeautions~ indicates possible hazards
`associated with handling the excipient and makes recommen-
`dations for suitable containment and protective methods. A
`familiarity with current good laboratory practice (GLP) and
`current: good manufacturing practice (GMP) and standard
`chemical handling procedures is assumed.
`
`Section I6, Regulatory Status, describes the accepted uses
`in foods and licensed pharmaceuticals where known. The sta-
`tus of excipients varies fi,om one nation to another, even in
`this time of harmonization. Dependence on this reference in
`place of checking with the regulatory body in the nation in
`which the product is to be Sold is unwise.
`
`Section !7~ Pharmacopeias, lists the pharmacopeias in which
`the e~cipient is listed. If the excipient is listed in the European
`Pharmacopeia (PhEur), conntries that are party to the PhEur
`are not listed: only "Ettr" is. The following countries are party
`to the PhEur: Austria, Belgium, Bosnia-Herzegovina, Croatia,
`Cyprus, Czech Republic, Denmark, Finland, France, Germany,
`Greece, Iceland, Ireland, Italy, Luxembourg, the Netherlands,
`Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, Swit-
`zerland, Turkey, the United Kingdom of Great Britain and
`Northern h’eland, and the former Yugoslav Republic of Mace-
`donia. The information from the four major pharmacopeias is
`listed in Section 9.
`
`Section 18, Related Substances, lists the excipients similar
`to the excipient discussed in the monograph. The reader
`should look at the monographs for the related substance for
`comparative inforination,
`
`Section 19~ Comments, includes additional information and
`observations relevant to the excipient. Where appropriate, the
`different grades of the excipient available are discussed. Com-
`ments are the opinion of the listed author(s) unless referenced
`or indicated otherwise.
`
`Section 20, Specific References, is a list of references cited
`within the monograph.
`
`Section 2t, General References, lists references whicti have
`general information about ttiis type of exCipient or the types
`of dosage forms made with these exclpients.
`
`Section 22, Authors, lists in alphabetical order the current authors
`of the monograph. Authors of previous editions cma be found in
`the earlier editions.
`
`Lupin Ex. 1045 (Page 14 of 18)
`
`

`

`Acknowledgments
`
`This editio~, of the Handbook of Pharmaceutical Excipiems
`is the result of the efforts of many individuals and corpora-
`lions. The publication of the Handbook continues to depend
`on the support of hundreds of scientists throughout the world
`who act as authors or members of the HPE Laboratory Projec~
`and the members of the two steering committees. The mem-
`bers of the US and UK steering committees rewewed all the
`monographs and contributed to their overall quality. Without
`the energettc and enthusiastic efforI by these two steering
`committees this book would be impossible to produce. Spe-
`cifically I would like to thank the chair of the UK steering
`committee Paul We tier from the Royal Pharmaceutical Society
`of Great Britain staff who was the co-editor of the second
`edition. His work on that edition and his advice on every
`aspect of this editior~ made nay job much easier. In addition.
`this edition had extenswe laboratory work done by the HPE
`Laboratory Project headed by Anthony Palmieri III. It is