Handbook of
`Pharmaceutical
`Excipients
`Fifth Edition
`
`Edited by
`Raymond C Rowe, Paul J Sheskey
`and Siân C Owen
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0001
`
`

`

`Handbook of
`Pharmaceutical Excipients
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0002
`
`

`

`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0003
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0003
`
`

`

`Handbook of
`Pharmaceutical Excipients
`
`F I F T H E D I T I O N
`
`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
`
`Siaˆn C Owen
`BSc, MA
`
`Development Editor
`Royal Pharmaceutical Society of Great Britain
`London, UK
`
`London . Chicago
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0004
`
`

`

`Published by the Pharmaceutical Press
`Publications division of the Royal Pharmaceutical Society of Great Britain
`
`1 Lambeth High Street, London SE1 7JN, UK
`100 South Atkinson Road, Suite 206, Grayslake, IL 60030-7820, USA
`
`and the American Pharmacists Association
`2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA
`
`# Pharmaceutical Press and American Pharmacists Association 2006
`
`is a trademark of Pharmaceutical Press
`
`First published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`Fifth edition published 2006
`
`Printed in Great Britain by Butler & Tanner, Frome, Somerset
`Typeset by Data Standards Ltd, Frome, Somerset
`
`ISBN 0 85369 618 7 (UK)
`ISBN 1 58212 058 7 (USA)
`
`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 legal responsibility or
`liability for any errors or omissions that may be made.
`
`A catalogue record for this book is available from the British Library
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients.–5th ed. / edited by Raymond C.
`Rowe, Paul J. Sheskey, Siaˆ n C. Owen.
`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, Siaˆ n C.
`IV. American Pharmacists Association.
`
`RS201.E87H36 2006
`0
`.19–dc22
`615
`
`2005028523
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0005
`
`

`

`Contents
`
`International Steering Committee ix
`Editorial Staff
`ix
`x
`Contributors
`About the Editors
`New Monographs
`Related Substances
`Preface xvi
`xvii
`Arrangement
`Acknowledgments
`Notice to Readers
`Bibliography
`xx
`Abbreviations
`xx
`Units of Measurement
`
`xii
`xiii
`xiv
`
`xix
`xix
`
`xxii
`
`Monographs
`
`Acacia
`Acesulfame Potassium
`Acetic Acid, Glacial
`Acetone
`Acetyltributyl Citrate
`Acetyltriethyl Citrate
`Agar
`Albumin
`Alcohol
`Alginic Acid
`Aliphatic Polyesters
`Alitame
`Almond Oil
`Alpha Tocopherol
`Aluminum Hydroxide Adjuvant
`Aluminum Oxide
`Aluminum Phosphate Adjuvant
`Aluminum Stearate
`Ammonia Solution
`Ammonium Alginate
`Ascorbic Acid
`
`Ascorbyl Palmitate
`Aspartame
`Attapulgite
`Bentonite
`Benzalkonium Chloride
`Benzethonium Chloride
`Benzoic Acid
`Benzyl Alcohol
`Benzyl Benzoate
`Boric Acid
`Bronopol
`Butylated Hydroxyanisole
`Butylated Hydroxytoluene
`Butylparaben
`Calcium Alginate
`Calcium Carbonate
`Calcium Phosphate, Dibasic Anhydrous
`Calcium Phosphate, Dibasic Dihydrate
`Calcium Phosphate, Tribasic
`Calcium Stearate
`Calcium Sulfate
`Canola Oil
`Carbomer
`Carbon Dioxide
`Carboxymethylcellulose Calcium
`Carboxymethylcellulose Sodium
`Carrageenan
`Castor Oil
`Castor Oil, Hydrogenated
`Cellulose, Microcrystalline
`Cellulose, Powdered
`Cellulose, Silicified Microcrystalline
`Cellulose Acetate
`Cellulose Acetate Phthalate
`Ceratonia
`Cetostearyl Alcohol
`
`1
`4
`6
`8
`10
`12
`14
`16
`18
`21
`24
`28
`30
`32
`36
`38
`40
`42
`44
`46
`48
`
`51
`53
`56
`58
`61
`64
`66
`69
`72
`74
`76
`79
`81
`83
`86
`89
`93
`96
`100
`102
`105
`108
`111
`116
`118
`120
`124
`128
`130
`132
`136
`139
`142
`145
`148
`150
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0006
`
`

`

`vi
`
`Contents
`
`Cetrimide
`Cetyl Alcohol
`Cetylpyridinium Chloride
`Chitosan
`Chlorhexidine
`Chlorobutanol
`Chlorocresol
`Chlorodifluoroethane (HCFC)
`Chlorofluorocarbons (CFC)
`Chloroxylenol
`Cholesterol
`Citric Acid Monohydrate
`Colloidal Silicon Dioxide
`Coloring Agents
`Copovidone
`Corn Oil
`Cottonseed Oil
`Cresol
`Croscarmellose Sodium
`Crospovidone
`Cyclodextrins
`Cyclomethicone
`Denatonium Benzoate
`Dextrates
`Dextrin
`Dextrose
`Dibutyl Phthalate
`Dibutyl Sebacate
`Diethanolamine
`Diethyl Phthalate
`Difluoroethane (HFC)
`Dimethicone
`Dimethyl Ether
`Dimethyl Phthalate
`Dimethyl Sulfoxide
`Dimethylacetamide
`Disodium Edetate
`Docusate Sodium
`Edetic Acid
`Erythorbic Acid
`Erythritol
`Ethyl Acetate
`Ethyl Lactate
`Ethyl Maltol
`
`152
`155
`157
`159
`163
`168
`171
`174
`176
`180
`182
`185
`188
`192
`201
`204
`206
`208
`211
`214
`217
`222
`224
`226
`228
`231
`234
`236
`238
`240
`242
`244
`246
`248
`250
`253
`255
`257
`260
`264
`266
`268
`270
`272
`
`Ethyl Oleate
`Ethyl Vanillin
`Ethylcellulose
`Ethylene Glycol Palmitostearate
`Ethylene Vinyl Acetate
`Ethylparaben
`Fructose
`Fumaric Acid
`Gelatin
`Glucose, Liquid
`Glycerin
`Glyceryl Behenate
`Glyceryl Monooleate
`Glyceryl Monostearate
`Glyceryl Palmitostearate
`Glycofurol
`Guar Gum
`Hectorite
`Heptafluoropropane (HFC)
`Hexetidine
`Hydrocarbons (HC)
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`Hydroxyethylmethyl Cellulose
`Hydroxypropyl Cellulose
`Hydroxypropyl Cellulose, Low-substituted
`Hydroxypropyl Starch
`Hypromellose
`Hypromellose Acetate Succinate
`Hypromellose Phthalate
`Imidurea
`Inulin
`Iron Oxides
`Isomalt
`Isopropyl Alcohol
`Isopropyl Myristate
`Isopropyl Palmitate
`Kaolin
`Lactic Acid
`Lactitol
`Lactose, Anhydrous
`Lactose, Monohydrate
`Lactose, Spray-Dried
`Lanolin
`
`274
`276
`278
`283
`285
`287
`290
`293
`295
`299
`301
`304
`306
`308
`311
`313
`315
`318
`321
`323
`325
`328
`330
`334
`336
`341
`344
`346
`350
`354
`359
`362
`364
`366
`371
`374
`376
`378
`381
`383
`385
`389
`396
`399
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0007
`
`

`

`Lanolin Alcohols
`Lanolin, Hydrous
`Lauric Acid
`Lecithin
`Leucine
`Linoleic Acid
`Macrogol 15 Hydroxystearate
`Magnesium Aluminum Silicate
`Magnesium Carbonate
`Magnesium Oxide
`Magnesium Silicate
`Magnesium Stearate
`Magnesium Trisilicate
`Malic Acid
`Maltitol
`Maltitol Solution
`Maltodextrin
`Maltol
`Maltose
`Mannitol
`Medium-chain Triglycerides
`Meglumine
`Menthol
`Methylcellulose
`Methylparaben
`Mineral Oil
`Mineral Oil, Light
`Mineral Oil and Lanolin Alcohols
`Monoethanolamine
`Monosodium Glutamate
`Monothioglycerol
`Myristic Acid
`Neohesperidin Dihydrochalcone
`Nitrogen
`Nitrous Oxide
`Octyldodecanol
`Oleic Acid
`Oleyl Alcohol
`Olive Oil
`Palmitic Acid
`Paraffin
`Peanut Oil
`Pectin
`Petrolatum
`
`Contents
`
`vii
`
`402
`404
`406
`409
`412
`414
`416
`418
`422
`426
`428
`430
`434
`436
`438
`440
`442
`445
`447
`449
`454
`457
`459
`462
`466
`471
`474
`476
`478
`480
`482
`484
`486
`488
`490
`492
`494
`496
`498
`501
`503
`505
`507
`509
`
`Petrolatum and Lanolin Alcohols
`Phenol
`Phenoxyethanol
`Phenylethyl Alcohol
`Phenylmercuric Acetate
`Phenylmercuric Borate
`Phenylmercuric Nitrate
`Phosphoric Acid
`Polacrilin Potassium
`Poloxamer
`Polycarbophil
`Polydextrose
`Polyethylene Glycol
`Polyethylene Oxide
`Polymethacrylates
`Poly(methyl vinyl ether/maleic anhydride)
`Polyoxyethylene Alkyl Ethers
`Polyoxyethylene Castor Oil Derivatives
`Polyoxyethylene Sorbitan Fatty Acid Esters
`Polyoxyethylene Stearates
`Polyvinyl Acetate Phthalate
`Polyvinyl Alcohol
`Potassium Alginate
`Potassium Benzoate
`Potassium Bicarbonate
`Potassium Chloride
`Potassium Citrate
`Potassium Hydroxide
`Potassium Metabisulfite
`Potassium Sorbate
`Povidone
`Propionic Acid
`Propyl Gallate
`Propylene Carbonate
`Propylene Glycol
`Propylene Glycol Alginate
`Propylparaben
`2-Pyrrolidone
`Raffinose
`Saccharin
`Saccharin Sodium
`Saponite
`Sesame Oil
`Shellac
`
`512
`514
`517
`519
`521
`524
`526
`530
`532
`535
`539
`542
`545
`551
`553
`561
`564
`572
`580
`585
`589
`592
`594
`596
`598
`600
`603
`605
`607
`609
`611
`617
`619
`622
`624
`627
`629
`633
`635
`638
`641
`644
`646
`649
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0008
`
`

`

`Thymol
`Titanium Dioxide
`Tragacanth
`Trehalose
`Triacetin
`Tributyl Citrate
`Triethanolamine
`Triethyl Citrate
`Vanillin
`Vegetable Oil, Hydrogenated
`Water
`Wax, Anionic Emulsifying
`Wax, Carnauba
`Wax, Cetyl Esters
`Wax, Microcrystalline
`Wax, Nonionic Emulsifying
`Wax, White
`Wax, Yellow
`Xanthan Gum
`Xylitol
`Zein
`Zinc Acetate
`Zinc Stearate
`
`780
`782
`785
`788
`790
`792
`794
`796
`798
`800
`802
`807
`809
`811
`813
`815
`817
`819
`821
`824
`828
`830
`832
`
`Appendix I: Suppliers’ Directory 835
`Appendix II: List of Excipient ‘E’ Numbers 882
`Appendix III: List of Excipient ‘EINECS’ Numbers 884
`Appendix IV: List of Excipient Molecular Weights 886
`Index 889
`
`viii
`
`Contents
`
`Simethicone
`Sodium Acetate
`Sodium Alginate
`Sodium Ascorbate
`Sodium Benzoate
`Sodium Bicarbonate
`Sodium Borate
`Sodium Chloride
`Sodium Citrate Dihydrate
`Sodium Cyclamate
`Sodium Hyaluronate
`Sodium Hydroxide
`Sodium Lactate
`Sodium Lauryl Sulfate
`Sodium Metabisulfite
`Sodium Phosphate, Dibasic
`Sodium Phosphate, Monobasic
`Sodium Propionate
`Sodium Starch Glycolate
`Sodium Stearyl Fumarate
`Sodium Sulfite
`Sorbic Acid
`Sorbitan Esters (Sorbitan Fatty Acid Esters)
`Sorbitol
`Soybean Oil
`Starch
`Starch, Pregelatinized
`Starch, Sterilizable Maize
`Stearic Acid
`Stearyl Alcohol
`Sucralose
`Sucrose
`Sugar, Compressible
`Sugar, Confectioner’s
`Sugar Spheres
`Sulfobutylether b-Cyclodextrin
`Sulfuric Acid
`Sunflower Oil
`Suppository Bases, Hard Fat
`Talc
`Tartaric Acid
`Tetrafluoroethane (HFC)
`Thaumatin
`Thimerosal
`
`652
`654
`656
`659
`662
`665
`669
`671
`675
`678
`681
`683
`685
`687
`690
`693
`696
`699
`701
`705
`708
`710
`713
`718
`722
`725
`731
`734
`737
`740
`742
`744
`748
`750
`752
`754
`758
`760
`762
`767
`770
`772
`775
`777
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0009
`
`

`

`International Steering Committee
`
`Gregory E Amidon
`Pharmacia Corporation
`Kalamazoo, MI, USA
`
`Graham Buckton
`University of London
`London, UK
`
`Colin G Cable
`Western General Hospital
`Edinburgh, UK
`
`Brian A Carlin
`FMC Biopolymer
`Princeton, NJ, USA
`
`Walter Cook
`AstraZeneca
`Loughborough, UK
`
`Stephen W Hoag
`University of Maryland at Baltimore
`Baltimore, MD, USA
`
`Anthony Palmieri III
`University of Florida
`Gainesville, FL, USA
`
`Arthur H Kibbe
`Wilkes University
`Wilkes-Barre, PA, USA
`
`Raymond C Rowe
`Intelligensys Ltd
`Billingham, UK
`
`William J Lambert
`Eisai Inc
`Research Triangle Park, NC, USA
`
`Shirish A Shah
`Watson Pharmaceuticals
`Corona, CA, USA
`
`M Jayne Lawrence
`King’s College, University of London
`London, UK
`
`Bob Sherwood
`JRS Pharma
`Patterson, NY, USA
`
`John MacLaine
`Boots Contract Manufacturing
`Nottingham, UK
`
`Paul J Sheskey
`The Dow Chemical Co
`Midland, MI, USA
`
`Kamalinder K Singh
`SNDT Women’s University
`Mumbai, India
`
`Paul J Weller
`Royal Pharmaceutical Society of Great
`Britain
`London, UK
`
`Tim Wood
`GlaxoSmithKline
`Ware, Hertfordshire, UK
`
`Mukund Yelvigi
`Wyeth Research
`Pearl River, NY, USA
`
`Henk J de Jong
`Servier International Research Institute
`Courbevoie, France
`
`Colin P McCoy
`Queens University Belfast
`Belfast, UK
`
`Stephen Edge
`DMV International
`Veghel, The Netherlands
`
`Roger T Guest
`GlaxoSmithKline
`Ware, Hertfordshire, UK
`
`Bruno Hancock
`Pfizer Inc
`Groton, CT, USA
`
`R Christian Moreton
`Idenix Pharmaceuticals
`Cambridge, MA, USA
`
`Sandeep Nema
`Pfizer Inc
`Chesterfield, MO, USA
`
`Siaˆ n C Owen
`Royal Pharmaceutical Society of Great
`Britain
`London, UK
`
`Editorial Staff
`
`Editorial Staff of the Pharmaceutical Press:
`
`Laurent Y Galichet
`Louise ME McIndoe
`Siaˆ n C Owen
`Paul J Weller
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0010
`
`

`

`Contributors
`
`O AbuBaker
`Pfizer Inc
`Ann Arbor, MI, USA
`
`KS Alexander
`University of Toledo
`Toledo, OH, USA
`
`LV Allen
`International Journal of Pharmaceutical
`Compounding
`Edmond, OK, USA
`
`GE Amidon
`Pharmacia Corporation
`Kalamazoo, Michigan, USA
`
`GP Andrews
`The Queen’s University of Belfast
`Belfast, UK
`
`NA Armstrong
`Harpenden, Hertfordshire, UK
`
`ME Aulton
`De Montford University
`Leicester, UK
`
`S Behn
`AstraZeneca
`Macclesfield, UK
`
`M Bond
`Danisco Sweeteners Ltd
`Redhill, Surrey, UK
`
`CG Cable
`Western General Hospital
`Edinburgh, UK
`
`E Cahill
`AstraZeneca
`Macclesfield, UK
`
`W Camarco
`ISP Corp
`Wayne, NJ, USA
`
`WG Chambliss
`University of Mississippi
`University, MS, USA
`
`RK Chang
`Shire Laboratory
`Rockville, MD, USA
`
`R Chen
`Pfizer Inc
`Groton, CT, USA
`
`JH Chu
`Pfizer Inc
`Groton, CT, USA
`
`JH Collett
`University of Manchester
`Manchester, UK
`
`JT Colvin
`Pfizer Inc
`Groton, CT, USA
`
`W Cook
`AstraZeneca
`Loughborough, UK
`
`DQM Craig
`The University of East Anglia
`Norwich, UK
`
`TC Dahl
`Gilead Sciences
`Foster City, CA, USA
`
`A Day
`AstraZeneca
`Loughborough, UK
`
`B Fritzsching
`Palatinit GmbH
`Mannheim, Germany
`
`G Frunzi
`Bristol-Myers Squibb
`New Brunswick, NJ, USA
`
`LY Galichet
`Royal Pharmaceutical Society of Great
`Britain
`London, UK
`
`SR Goskonda
`Sunnyvale, CA, USA
`
`JL Gray
`The Queen’s University of Belfast
`Belfast, UK
`
`RT Guest
`GlaxoSmithKline
`Ware, Hertfordshire, UK
`
`RR Gupta
`SNDT Women’s University
`Mumbai, India
`
`VK Gupta
`Tyco HealthCare Mallinckrodt
`St Louis, MO, USA
`
`HJ de Jong
`Servier International Research Institute
`Courbevoie, France
`
`SP Denyer
`University of Cardiff
`Cardiff, UK
`
`X Duriez
`Roquette Fre`res
`Lestrem, France
`
`S Edge
`DMV International
`Veghel, The Netherlands
`
`G Haest
`Cargill Cerestar BVBA
`Mechelen, Belgium
`
`BC Hancock
`Pfizer Inc
`Groton, CT, USA
`
`RJ Harwood
`Bensalem, PA, USA
`
`S Hem
`Purdue University
`West Lafayette, IN, USA
`
`K Fowler
`Schering-Plough Healthcare Products
`Memphis, TN, USA
`
`L Hendricks
`Rhodia Inc
`Cranbury, NJ, USA
`
`SO Freers
`Grain Processing Corporation
`Muscatine, IA, USA
`
`SE Hepburn
`Bristol Royal Infirmary
`Bristol, UK
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0011
`
`

`

`NA Hodges
`University of Brighton
`Brighton, UK
`
`JT Irwin
`Perrigo Corporation
`MI, USA
`
`BR Jasti
`University of the Pacific
`Stockton, CA, USA
`
`R Johnson
`AstraZeneca
`Loughborough, UK
`
`DS Jones
`The Queen’s University of Belfast
`Belfast, UK
`
`AS Kearney
`GlaxoSmithKline
`King-of-Prussia, PA, USA
`
`SW Kennedy
`Morflex Inc
`Greensboro, NC, USA
`
`VL Kett
`The Queen’s University of Belfast
`Belfast, UK
`
`AH Kibbe
`Wilkes University
`Wilkes-Barre, PA, USA
`
`V King
`Rhodia Inc
`Cranbury, NJ, USA
`
`PB Klepak
`Reheis Inc
`Berkley Heights, NJ, USA
`
`JJ Koleng
`University of Texas at Austin
`Austin, TX, USA
`
`K Kussendrager
`DMV International
`Veghel, The Netherlands
`
`WJ Lambert
`Eisai Inc
`Research Triangle Park, NC, USA
`
`BA Langdon
`Pfizer Inc
`Groton, CT, USA
`
`MJ Lawrence
`King’s College, University of London
`London, UK
`
`JC Lee
`Cellegy
`San Jose´, CA, USA
`
`MG Lee
`Medicines and Healthcare products
`Regulatory Agency
`London, UK
`
`X Li
`University of the Pacific
`Stockton, CA, USA
`
`EB Lindblad
`Brenntag Biosector
`Frederikssund, Denmark
`
`O Luhn
`Palatinit GmbH
`Mannheim, Germany
`
`PE Luner
`Pfizer Inc
`Groton, CT, USA
`
`HJ Mawhinney
`The Queen’s University of Belfast
`Belfast, UK
`
`CP McCoy
`The Queen’s University of Belfast
`Belfast, UK
`
`OS McGarvey
`The Queen’s University of Belfast
`Belfast, UK
`
`JW McGinity
`University of Texas at Austin
`Austin, TX, USA
`
`LME McIndoe
`Royal Pharmaceutical Society of Great
`Britain
`London, UK
`
`LA Miller
`Pfizer Inc
`Groton, CT, USA
`
`RW Miller
`Bristol-Myers Squibb
`New Brunswick, NJ, USA
`
`J-P Mittwollen
`BASF Aktiengesellschaft
`Ludwigshafen, Germany
`
`RC Moreton
`Idenix Pharmaceuticals
`Cambridge, MA, USA
`
`G Mosher
`CyDex Inc
`Lenexa, KS, USA
`
`C Mroz
`Colorcon Ltd
`Dartford, Kent, UK
`
`Contributors
`
`xi
`
`MP Mullarney
`Pfizer Inc
`Groton, CT, USA
`
`S Murdande
`Pfizer Inc
`Groton, CT, USA
`
`RA Nash
`St John’s University
`Jamaica, NY, USA
`
`S Nema
`Pfizer Inc
`Chesterfield, MO, USA
`
`SC Owen
`Royal Pharmaceutical Society of Great
`Britain
`London, UK
`
`A Palmieri
`University of Florida
`Gainesville, FL, USA
`
`D Parsons
`ConvaTec Ltd
`Clwyd, UK
`
`Y Peng
`University of Tennessee
`Memphis, TN, USA
`
`JD Pipkin
`CyDex Inc
`Lenexa, KS, USA
`
`D Pipkorn
`Pfizer Inc
`Ann Arbor, MI, USA
`
`JC Price
`University of Georgia
`Athens, GA, USA
`
`MA Repka
`University of Mississippi
`University, MS, USA
`
`B Sarsfield
`Bristol-Myers Squibb
`New Brunswick, NJ, USA
`
`T Schmeller
`BASF Aktiengesellschaft
`Ludwigshafen, Germany
`
`A Schoch
`Palatinit GmbH
`Mannheim, Germany
`
`CJ Sciarra
`Sciarra Laboratories Inc
`Hicksville, NY, USA
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0012
`
`

`

`xii
`
`Contributors
`
`JJ Sciarra
`Sciarra Laboratories Inc
`Hicksville, NY, USA
`
`SA Shah
`Watson Pharmaceuticals
`Corona, CA, USA
`
`RM Shanker
`Pfizer Inc
`Groton, CT, USA
`
`PJ Sheskey
`The Dow Chemical Co
`Midland, MI, USA
`
`AJ Shukla
`University of Tennessee
`Memphis, TN, USA
`
`KK Singh
`SNDT Women’s University
`Mumbai, India
`
`R Steer
`AstraZeneca
`Loughborough, UK
`
`JT Stewart
`University of Georgia
`Athens, GA, USA
`
`Y Sun
`University of Tennessee
`Memphis, TN, USA
`
`AK Taylor
`Baton Rouge, LA, USA
`
`MS Tesconi
`Wyeth Research
`Pearl River, NY, USA
`
`D Thassu
`UCB Pharma Inc
`Rochester, NY, USA
`
`BF Truitt
`Pfizer Inc
`Groton, CT, USA
`
`CK Tye
`Pfizer Inc
`Kalamazoo, MI, USA
`
`HM Unvala
`Bayer Corporation
`Myerstown, PA, USA
`
`KD Vaughan
`Boots Healthcare International
`Nottingham, UK
`
`H Wang
`Pfizer Inc
`Groton, CT, USA
`
`PJ Weller
`Royal Pharmaceutical Society of Great
`Britain
`London, UK
`
`AJ Winfield
`Aberdeen, UK
`
`AW Wood
`GlaxoSmithKline
`Research Triangle Park, NC, USA
`
`M Yelvigi
`Wyeth Research
`Pearl River, NY, USA
`
`PM Young
`University of Sydney
`Sydney, Australia
`
`About the Editors
`
`Raymond C Rowe
`BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MInstP
`Raymond Rowe has been involved in the Handbook of
`Pharmaceutical Excipients since the first edition was published
`in 1986, initially as an author then as a Steering Committee
`member. In addition to his position as Chief Scientist at
`Intelligensys, UK, he is also Professor of Industrial Pharmaceu-
`tics at the School of Pharmacy, University of Bradford, UK. He
`was formerly Senior Principal Scientist at AstraZeneca, UK. In
`1998 he was awarded the Chiroscience Industrial Achievement
`Award, and in 1999 he was the British Pharmaceutical
`Conference Science Chairman. He has contributed to over
`350 publications in the pharmaceutical sciences including a
`book and eight patents.
`
`Paul J Sheskey
`BSc, RPh
`Paul Sheskey has been involved in the Handbook of Pharma-
`ceutical Excipients as an author and member of the Steering
`
`Committee since the third edition. He is a Technical Service
`Leader in the Water Soluble Polymers, Pharmaceutical R&D
`Group at The Dow Chemical Company in Midland, Michigan,
`USA. Paul received his BSc degree in pharmacy from Ferris
`State University. Previously, he has worked as a research
`pharmacist in the area of solid dosage form development at the
`Perrigo Company and the Upjohn (Pharmacia) Company. Paul
`has authored numerous
`journal articles
`in the area of
`pharmaceutical technology. He is a member of the AAPS,
`Controlled Release Society, and the Institute for Briquetting and
`Agglomeration.
`
`Siaˆn C Owen
`BSc, MA
`Siaˆ n Owen has been involved with the Handbook of
`Pharmaceutical Excipients since the fourth edition, as a
`contributor and Steering Committee member. Siaˆ n received
`her BSc degree in pharmacology from the University of
`Sunderland, and her MA in biotechnological law and ethics
`from the University of Sheffield.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0013
`
`

`

`New Monographs
`
`The following new monographs have been added to the Handbook of Pharmaceutical Excipients, 5th edition.
`
`Acetone
`Agar
`Aluminum Hydroxide Adjuvant
`Aluminum Oxide
`Aluminum Phosphate Adjuvant
`Ammonium Alginate
`Aluminum Stearate
`Boric Acid
`Calcium Alginate
`Cetylpyridinium Chloride
`Copovidone
`Dimethylacetamide
`Disodium Edetate
`Erythorbic Acid
`Erythritol
`Ethyl Lactate
`Ethylene Vinyl Acetate
`Hectorite
`Hydroxypropyl Starch
`Hypromellose Acetate Succinate
`Inulin
`Iron Oxides
`Isomalt
`Lactose, Anhydrous
`Lactose, Monohydrate
`Lactose, Spray-Dried
`
`Lauric Acid
`Leucine
`Linoleic Acid
`Macrogol 15 Hydroxystearate
`Myristic Acid
`Neohesperidin Dihydrochalcone
`Octyldodecanol
`Oleyl Alcohol
`Palmitic Acid
`Pectin
`Polycarbophil
`Poly(methylvinyl ether/maleic anhydride)
`Potassium Alginate
`2-Pyrrolidone
`Raffinose
`Saponite
`Sodium Acetate
`Sodium Borate
`Sodium Hyaluronate
`Sodium Lactate
`Sodium Sulfite
`Sulfobutylether b-Cyclodextrin
`Thaumatin
`Thymol
`Zinc Acetate
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0014
`
`

`

`Related Substances
`
`Acetic acid
`Activated attapulgite
`Aleuritic acid
`d-Alpha tocopherol
`d-Alpha tocopheryl acetate
`dl-Alpha tocopheryl acetate
`d-Alpha tocopheryl acid succinate
`dl-Alpha tocopheryl acid succinate
`Aluminum distearate
`Aluminum monostearate
`Amylopectin
`a-Amylose
`Anhydrous citric acid
`Anhydrous sodium citrate
`Anhydrous sodium propionate
`Artificial vinegar
`Bacteriostatic water for injection
`Bentonite magma
`Beta tocopherol
`Beta-carotene
`n-Butyl lactate
`Butylparaben sodium
`Calcium ascorbate
`Calcium cyclamate
`Calcium polycarbophil
`Calcium propionate
`Calcium silicate
`Calcium sorbate
`Calcium sulfate hemihydrate
`Capric acid
`Carbon dioxide-free water
`Cationic emulsifying wax
`Ceratonia extract
`Cetylpyridinium bromide
`Chlorhexidine acetate
`Chlorhexidine gluconate
`Chlorhexidine hydrochloride
`Chlorodifluoromethane
`Chlorophenoxyethanol
`Corn syrup solids
`m-Cresol
`o-Cresol
`p-Cresol
`Crude olive-pomace oil
`Cyclamic acid
`De-aerated water
`Dehydrated alcohol
`Delta tocopherol
`Denatured alcohol
`Dextrose anhydrous
`Diazolidinyl urea
`Dibasic potassium phosphate
`Diethylene glycol monopalmitostearate
`Dilute acetic acid
`Dilute alcohol
`
`Dilute ammonia solution
`Dilute hydrochloric acid
`Dilute phosphoric acid
`Dilute sulfuric acid
`Dimethyl-b-cyclodextrin
`Dioctyl phthalate
`Dipotassium edetate
`Docusate calcium
`Docusate potassium
`Dodecyl gallate
`Dodecyltrimethylammonium bromide
`Edetate calcium disodium
`Eglumine
`Ethyl gallate
`Ethylene glycol monopalmitate
`Ethylene glycol monostearate
`Ethyl linoleate
`Ethylparaben potassium
`Ethylparaben sodium
`Extra virgin olive oil
`Fine virgin olive oil
`Fuming sulfuric acid
`Gamma tocopherol
`Hard water
`Hesperidin
`Hexadecyltrimethylammonium bromide
`High-fructose syrup
`Hyaluronic acid
`Hydrogenated lanolin
`Hydrogenated vegetable oil, type II
`2-Hydroxyethyl-b-cyclodextrin
`2-Hydroxypropyl-b-cyclodextrin
`3-Hydroxypropyl-b-cyclodextrin
`Indigo carmine
`Invert sugar
`Isotrehalose
`Lampante virgin olive oil
`Lanolin alcohols ointment
`DL-Leucine
`Liquefied phenol
`Liquid fructose
`Magnesium carbonate anhydrous
`Magnesium carbonate hydroxide
`Magnesium lauryl sulfate
`Magnesium metasilicate
`Magnesium orthosilicate
`Magnesium trisilicate anhydrous
`D-Malic acid
`L-Malic acid
`d-Menthol
`l-Menthol
`Methyl lactate
`Methyl linoleate
`Methyl methacrylate
`Methyl oleate
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0015
`
`

`

`Related Substances
`
`xv
`
`Methylparaben potassium
`Methylparaben sodium
`N-Methylpyrrolidone
`Microcrystalline cellulose and carboxymethylcellulose sodium
`Microcrystalline cellulose and carrageenan
`Microcrystalline cellulose and guar gum
`Modified lanolin
`Monobasic potassium phosphate
`Montmorillonite
`Myristyl alcohol
`Neotrehalose
`Normal magnesium carbonate
`Octyl gallate
`Oleyl oleate
`Olive-pomace oil
`Palmitin
`Pharmaceutical glaze
`Phenoxypropanol
`Polacrilin
`Poly(methyl methacrylate)
`Potassium bisulfite
`Potassium myristate
`Potassium propionate
`Powdered fructose
`Propan-1-ol
`(S)-Propylene carbonate
`Propylparaben potassium
`Propylparaben sodium
`Purified bentonite
`Purified stearic acid
`Quaternium 18-hectorite
`Rapeseed oil
`Refined almond oil
`Refined olive-pomace oil
`
`Saccharin ammonium
`Saccharin calcium
`Self-emulsifying glyceryl monostearate
`Shellolic acid
`Sodium bisulfite
`Sodium borate anhydrous
`Sodium edetate
`Sodium erythorbate
`Sodium laurate
`Sodium myristate
`Sodium palmitate
`Sodium sorbate
`Sodium sulfite heptahydrate
`Soft water
`Sorbitol solution 70%
`Spermaceti wax
`Stearalkonium hectorite
`Sterile water for inhalation
`Sterile water for injection
`Sterile water for irrigation
`Sunset yellow FCF
`Synthetic paraffin
`DL-()-Tartaric acid
`Tartrazine
`Theobroma oil
`Tocopherols excipient
`Tribasic sodium phosphate
`Trimethyl-b-cyclodextrin
`Trimethyltetradecylammonium bromide
`Trisodium edetate
`Virgin olive oil
`Water for injection
`White petrolatum
`Zinc propionate
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0016
`
`

`

`Preface
`
`Pharmaceutical dosage forms contain both pharmacologically
`active compounds and excipients added to aid the formulation
`and manufacture of the subsequent dosage form for adminis-
`tration to patients. Indeed, the properties of the final dosage
`form (i.e. its bioavailability and stability) are, for the most part,
`highly dependent on the excipients chosen, their concentration
`and interaction with both the active compound and each other.
`No longer can excipients be regarded simply as inert or inactive
`ingredients, and a detailed knowledge not only of the physical
`and chemical properties but also of the safety, handling and
`regulatory status of these materials is essential for formulators
`throughout the world. In addition, the growth of novel forms of
`delivery has resulted in an increase in the number of the
`excipients being used and suppliers of excipients have devel-
`oped novel excipient mixtures and new physical forms to
`improve their properties. The Handbook of Pharmaceutical
`Excipients has been conceived as a systematic, comprehensive
`resource of information on all of these topics
`The first edition of the Handbook was published in 1986 and
`contained 145 monographs. This was followed by the second
`edition in 1994 containing 203 monographs, the third edition
`in 2000 containing 210 monographs and the fourth edition in
`2003 containing 249 monographs. Since 2000, the data has
`also been available on CD-ROM, updated annually, and from
`2004 online. This new printed edition with its companion CD-
`ROM, Pharmaceutical Excipients 5, contains 300 monographs
`compiled by over 120 experts in pharmaceutical formulation or
`excipient manufacture from Australia, Europe, India and the
`USA. All the monographs have been reviewed and revised in the
`light of current knowledge. There has been a greater emphasis
`on including published data from primary sources although
`some data from laboratory projects included in previous
`editions have been retained where relevant. Variations in test
`methodology can have significant effects on the data generated
`(especially in the case of the compactability of an excipient),
`and thus cause confusion. As a consequence, the editors have
`
`been more selective in including data relating to the physical
`properties of an excipient. However, comparative data that
`show differences between either source or batch of a specific
`excipient have been retained as this was considered relevant to
`the behavior of a material in practice. The Suppliers Directory
`(Appendix I) has also been completely updated with many more
`international suppliers included.
`In a systematic and uniform manner, the Handbook of
`Pharmaceutical Excipients collects essential data on the
`physical properties of excipients such as: boiling point, bulk
`and tap density, compression characteristics, hygroscopicity,
`flowability, melting point, moisture content, moisture-absorp-
`tion isotherms, particle size distribution, rheology, specific
`surface area, and solubility. Scanning electron microphoto-
`graphs (SEMs) are also included for many of the excipients. The
`Handbook contains information from various international
`sources and personal observation and comments from mono-
`graph authors, steering committee members, and the editors.
`All of the monographs in the Handbook are thoroughly
`cross-referenced and indexed so that excipients may be
`identified by either a chemical, a nonproprietary, or a trade
`name. Most monographs list related substances to help the
`formulator to develop a list of possible materials for use in a
`new dosage form or product. Related substances are not
`directly substitutable for each other but, in general, they are
`excipients that have been used for similar purposes in various
`dosage forms.
`The Handbook of Pharmaceutical Excipients is a compre-
`hensive, uniform guide to the uses, properties, and safety of
`pharmaceutical excipients, and is an essential reference source
`for those involved in the development, production, control, or
`regulation of pharmaceutical preparations. Since many phar-
`maceutical excipients are also used in other applications, the
`Handbook of Pharmaceutical Excipients will also be of value to
`persons with an interest in the formulation or production of
`confectionery, cosmetics, and food products.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1013-0017
`
`

`

`Arrangement
`
`The information consists of monographs that are divided into
`22 sections to enable the reader to find the information of
`interest easily. Although it was originally intended that each
`monograph contain only information about a single excipient,
`it rapidly became clear that some substances or groups of
`substances should be discussed together. This gave rise to such
`monographs as ‘Coloring Agents’ and ‘Hydrocarbons’. In
`addition, some materials have more than one monograph
`depending on the physical characteristics of the material, e.g.
`Starch versus Pregelatinized Starch. Regardless of the complex-
`ity of the monograph they are all divided into 22 sections as
`follows:
`
`1 Nonproprietary Names
`2 Synonyms
`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
`11 Stability and Storage Conditions
`12 Incompatibilities
`13 Method of Manufacture
`14 Safety
`15 Handling Precautions
`16 Regulatory Status
`17 Related Substances
`18 Comments
`19 Specific References
`20 General References
`21 Authors
`22 Date of Revision
`
`Descriptions of the sections appear below with information
`from an example monograph if needed.
`
`Section 1, Nonproprietary Names, lists the excipient names
`used in the current British Pharmacopoeia, European Pharma-
`copeia, Japanese Pharmacopeia, and the United States Phar-
`macopeia/National Formulary.
`
`lists other names for the excipient,
`Section 2, Synonyms,
`including trade names used by suppliers (shown in italics).
`The inclusion of one supplier’s trade name and the absence of
`others should in no way be interpreted as an endorsement of
`one supplier’s product over the other. The large number of
`suppliers internationally makes it impossible to include all the
`trade names.
`
`Section 3, Chemical Name and CAS Registry Number, indi-
`cates the unique Chemical Abstract Services number for an
`
`excipient 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 excipients
`are not pure chemical substances, in which case their compo-
`sition is described either here or in Section 8.
`
`Section 6, Functional Category, lists the function(s) that an
`excipient is generally thought to perform, e.g., diluent, emulsi-
`fying agent, etc.
`
`Section 7, Applications in Pharmaceutical Formulation or Tech-
`nology, describes the various applications of the excipient.
`
`Section 8, Description, includes details of the physical appear-
`ance of the excipient, e.g., white or yellow flakes, etc.
`
`Section 9, Pharmacopeial Specifications, briefly presents the
`compendial standards for the excipient. Information included
`is obtained from the British Pharmacopoeia (BP), European
`Pharmacopeia (PhEur), Japanese Pharmacopeia (JP), and the
`United States Pharmacopeia/National Formulary
`(USP/
`USPNF).
`Information from the JP, USP and USPNF are
`included if the substance is in those compendia. Information
`from the PhEur is also included. If the excipient is not in the
`PhEur but is included in the BP, information is included from
`the BP. Pharmacopeias are continually updated with most
`now being produced as annual editions. However, although
`efforts were made to include up-to-date information at the
`time of publication of this edition, the reader is advised to
`consult the most current pharmacopeias or supplements.
`
`Section 10, Typical Properties, describes the physical proper-
`ties of the excipient which are not shown in Section 9. All
`data are for measurements made at 208C 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
`
`1 part in less than 1
`1 part in 1–10
`1 part in 10–30
`1 part in 30–100
`1 part in 100–1000
`1 part in 1000–10 000
`1 part in more than 10 000
`
`Where practical, data typical of the excipient or comparative
`data representative