Merck Exhibit 2201, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`

`Handbook of
`Pharmaceutical Excipients
`
`Merck Exhibit 2201, Page 2
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`

`

`Handbook of
`Pharmaceutical Excipients
`
`FOURTH EDITION
`
`Edited by
`
`Raymond C Rowe
`
`BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MlnstP
`
`Senior Principal Scientist
`
`AstraZeneca
`
`Macclesfield, UK
`
`Paul J Sheskey
`BSc, RPh
`
`Technical Service Leader
`
`Water Soluble Polymers R&D
`
`The Dow Chemical Company
`
`Midland
`
`MI, USA
`
`Paul J Weller
`BSc, MSc, CChem, MRSC
`
`Publisher - Science and Practice
`
`Royal Pharmaceutical Society of Great Britain
`
`London, UK
`
`London ¯ Chicago Pharmaceutical Press
`
`American
`Pharmaceutical
`Association
`
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`

`

`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 Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`
`© Pharmaceutical Press and American Pharmaceutical Association 2003
`
`(~P) is a trade mark of Pharmaceutical Press
`
`First edition published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`
`Text design by Barker Hilsdon, Lyme Regis
`Typeset by Bibliocraft Ltd, Dundee
`Printed in Great Britain by The Bath Press, Bath
`
`ISBN 0 85369 472 9 (UK)
`ISBN 1 58212 022 6 (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.- 4th ed. / edited by Raymond C.
`Rowe, Paul J. Sheskey, Paul J. Weller.
`p. ;cm.
`Includes bibliographical references and index.
`ISBN 1-58212-022-6 (atk. paper) -ISBN 0-85369-472-9 (alk. paper)
`1. Excipients-Handbooks, manuals, etc.
`[DNLM: 1. Excipients-Handbooks. QV 735 H236 2003] I. Rowe, Raymond
`C. II. Sheskey, Paul J. III. Weller, Paul J.
`
`RS201.E87H36 2003
`615’.19-dc21
`
`2003002641
`
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`

`

`Contents
`
`International Steering Committee
`Editorial Staff ix
`Contributors x
`About the Editors xiii
`New Monagraphs
`xiv
`Related Substances
`xv
`Preface xvii
`Acknowledgments
`Notice to Readers
`Bibliography ,xx
`Abbreviations xxi
`Units of Measurement
`
`xix
`xix
`
`xxii
`
`Monographs
`
`Acacia
`Acesulfame Potassium
`Acetic Acid, Glacial
`Acetyltributyl Citrate
`Acetyltriethyl Citrate
`Albumin
`Alcohol
`Alginic Acid
`Aliphatic Polyesters
`Alitame
`Almond Oil
`Alpha Tocopherol
`Ammonia Solution
`Ascorbic Acid
`Ascorbyl Palmitate
`Aspartame
`Attapulgite
`Bentonite
`Benzalkonium Chloride
`Benzethonium Chloride
`Benzoic Acid
`Benzyl Alcohol
`
`ix
`
`Benzyl Benzoate
`Bronopol
`Bulylated Hydroxyanisole
`Butylated Hydroxytoluene
`Butylparaben
`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
`Cetrimide
`Cetyl Alcohol
`Chitosan
`Chlorhexidine
`Chlorobutanol
`Chlorocresol
`Chlorodifluoroethane (HCFC)
`Chlorofluorocarbons (CFC)
`Chloroxylenol
`Cholesterol
`Citric Acid Monohydrate
`
`1
`3
`5
`7
`9
`11
`13
`16
`19
`23
`25
`27
`30
`32
`35
`37
`40
`42
`45
`48
`50
`53
`
`56
`58
`. 61
`63
`65
`68
`72
`74
`78
`8O
`83
`86
`89
`93
`95
`97
`101
`104
`106
`108
`112
`i15
`117
`120
`123
`125
`127
`130
`132
`136
`141
`144
`147
`149
`153
`155
`158
`
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`

`Contents
`
`Colloidal Silicon Dioxide
`Coloring Agents
`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
`Docusate Sodium
`Edetic Acid
`Ethyl Acetate
`Ethyl Maltol
`Ethyl Oleate
`Ethyl Vanillin
`Ethylcellulose
`Ethylene Glycol Palmitostearate
`Ethylparaben
`Fructose
`Fumaric Acid
`Gelatin
`Glucose, .Liquid
`Glycerin
`Glyceryl Behenate
`Glyceryl Monooleate
`Glyceryl Monostearate
`Glyceryl Palmitostearate
`Glycofurol
`Guar Gum
`Heptafluoropropane (HFC)
`Hexetidine
`
`161
`165
`174
`176
`178
`181
`184
`186
`191
`193
`195
`197
`200
`203
`205
`207
`209
`211
`213
`215
`217
`219
`222
`225
`229
`231
`233
`235
`237
`242
`244
`247
`250
`252
`255
`257
`260
`262
`264
`267
`269
`271
`274
`276
`
`Hydrocarbons (HC)
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`Hydroxyethylmethyl Cellulose
`Hydroxypropyl Cellulose
`Hydroxypropyl Cellulose, Low-substituted
`Hypromellose
`Hypromellose Phthalate
`Imidurea
`Isopropyl Alcohol
`Isopropyl Myristate
`Isopropyl Palmitate
`Kaolin
`Lactic Acid
`Lactitol
`Lactose
`Lanolin
`Lanolin, Hydrous
`Lanolin Alcohols
`Lecithin
`Magnesium Aluminum Silicate
`Magnesium Carbonate
`Magnesium Oxide
`Magnesium Silicate
`Magneswm 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
`
`278
`281
`283
`287
`289
`294
`297
`301
`306
`309
`312
`314
`316
`319
`321
`323
`333
`336
`338
`340
`343
`347
`350
`352
`354
`358
`360
`362
`364
`366
`369
`371
`373
`378
`381
`383
`386
`390
`395
`398
`400
`402
`4O4
`406
`
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`

`Nitrogen
`Nitrous Oxide
`Oleic Acid
`Olive Oil
`Paraffin
`Peanut Oil
`Petrolatum
`Petrolatum and Lanolin Alcohols
`Phenol
`Phenoxyethanol
`Phenylethyl Alcohol
`Phenylmercuric Acetate
`Phenylmercuric Borate
`Phenylmercuric Nitrate
`Phosphoric Acid
`Polacrilin Potassium
`Poloxamer
`Polydextrose
`Polyethylene Glycol
`Polyethylene Oxide
`Polymethacrylates
`Polyoxyethylene Alkyl Ethers
`Polyoxyethylene Castor Oil Derivatives
`Polyoxyethylene Sorbitan Fatty Acid Esters
`Polyoxyethylene Stearates
`Polyvinyl Acetate Phthalate
`Polyvinyl Alcohol
`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
`Saccharin
`Saccharin Sodium
`Sesame Oil
`
`Contents
`
`vii
`
`408
`410
`412
`414
`417
`419
`421
`424
`426
`429
`431
`433
`436
`438
`442
`444
`447
`451
`454
`460
`462
`469
`474
`479
`484
`488
`491
`493
`495
`497
`50O
`5O2
`504
`506
`508
`514
`516
`519
`521
`524
`526
`529
`532
`535
`
`Shellac
`Simethicone
`Sodium Alginate
`Sodium Ascorbate
`Sodium Benzoate
`Sodium Bicarbonate
`Sodium Chloride
`Sodium Citrate Dihydrate
`Sodium Cyclamate
`Sodium Hydroxide
`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)
`Sorbitol
`Soybean Oil
`Starch
`Starch, Pregelatinized
`Starch, Sterilizable Maize
`Stearic Acid
`Stearyl Alcohol
`Sucralose
`Sucrose
`Sugar, Compressible
`Sugar, Confectioner’s
`Sugar Spheres
`Sulfuric Acid
`Sunflower Oil
`Suppository Bases, Hard Fat
`Talc
`Tartaric Acid
`Tetrafluoroethane (HFC)
`Thimerosal
`Titanium Dioxide
`Tragacanth
`Trehalose
`Triacetin
`Tributyl Citrate
`Triethanolamine
`
`538
`541
`~543
`546
`549
`552
`556
`560
`563
`566
`568
`571 .
`574
`577
`579
`581
`585
`588
`591
`596
`6OO
`6O3
`609
`612
`615
`618
`620
`622
`626
`628
`630
`632
`634
`636
`641
`644
`646
`648
`651
`654
`657
`659
`661
`663
`
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`

`viii
`
`Contents
`
`Triethyl Citrate
`Vanillin
`Vegetable Oil, Hydrogenated
`Water
`Wax, Anionic Emulsifying
`Wax, Carnauba
`Wax, Cetyl Esters
`Wax, Microcrystalline
`Wax, Nonionic Emulsifying
`Wax, White
`
`665
`667
`669
`672
`677
`679
`681
`683
`685
`687
`
`......... j
`
`Wax, Yellow
`Xanthan Gum
`Xylitol
`Zein
`Zinc Stearate
`
`689
`691
`694
`698
`700
`
`Appendix I" Suppliers Directory 703
`Appendix Ih List of Excipient ’E’ Numbers 743
`Appendix IIh List of Excipient ’EINECS’ Numbers
`Appendix 1~6 List of Excipient Molecular Weights
`
`745 "
`747
`
`Index 751
`
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`

`8 Description
`Citric acid monohydrate occurs as colorless or translucent
`crystals, or as a white crystalline, efflorescent powder. It is
`odorless and has a strong acidic taste. The crystal structure is
`orthorhombic.
`SEM: 1
`Excipient: Citric acid monohydrate
`Mamtfacturer: Pfizer Ltd.
`Magnification: 60 ×
`
`SEM: 2
`Excipient: Citric acid monohydrate
`Manufacturer: Pfizer Ltd.
`Magnification: 600 x
`
`¸¸¸¸¸¸¸7¸
`
`i ~iiI
`
`ii 7
`
`~;i~iiiili ~ 7~
`
`1 Nonproprietary Names
`BP: Citric acid monohydrate
`JP: Citric acid
`PhEur: Acidum citricum monohydricum
`USP: Citric acid
`
`2 Synonyms
`2-Hydroxypropane-l,2,3-tricarboxytic acid monohydrate.
`
`3 Chemical Name and ¢AS Registry Number
`
`2-Hydroxy-l,2,3-propanetricarboxylic
`[5949-29-1]
`
`acid monohydrate
`
`4 Empirical Formula
`
`Molecular Weight
`
`C~HsO7.H20
`
`210.14
`
`5 Structural Formula
`
`¯ H20
`
`6 Functional Category
`Acidifying agent; antioxidant; buffering agent; chelating agent;
`flavor enhancer.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`
`Citric acid (as either the monohydrate or anhydrous material)
`is widely used in pharmaceutical formulations and food
`products, primarily to adjust the pH of solutions. Citric acid
`monohydrate is used in the preparation of effervescent gran-
`ules, while anhydrous citric acid is widely used in the prepara-
`tion of effervescent tablets.(>3)
`tn food products, citric acid is used as a flavor enhancer for
`its tart, acidic taste. Citric acid monohydrate is used as a
`sequestering agent and antioxidant synergist; see Table I. It is
`also a component of anticoagulant citrate solutions. Thera-
`peutically, preparations containing citric acid have been used
`to dissolve renal calculi.
`
`Table I:
`
`Uses of citric acid monohydrate.
`
`Use
`
`Concentration (%)
`
`Buffer solutions
`Flavor enhancer for liquid formulations
`Sequestering agent
`
`O. 1-2.0
`0.3-2.0
`0.3-2.0
`
`158
`
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`~i ili~iii~iiiiiii!~<
`
`9 Pharmacopeial Specifications
`
`See Table II.
`
`Table il: Pharmacopeial specifications for citric acid monohydrate
`(and anhydrous).
`
`Test
`
`JP 2001
`
`PhEur 2002 USP 25(°)
`
`+
`--
`-
`
`+
`4-
`+
`
`+
`--
`-
`
`-
`7.5-9.0%
`4 8.8%
`~< 1.0%
`40.5%
`40.5%
`-
`+
`-
`-
`40.1%
`40.05%
`-
`~<0.1%
`-
`-
`-
`+
`-
`40.2 ppm
`-
`+
`-
`+
`~< 350pprn -
`-
`4<.<0.048% 4150ppm
`+
`~< 1 ppm
`-
`4 3 ppm
`4 lOppm 410ppm
`~<0.001%
`+
`.
`--
`+
`+
`÷
`
`Identification
`Characters
`Appearance of solution
`Water
`(hydrous form)
`(anhydrous form)
`Bacterial endotoxins
`Residue on ignition
`Sulfated ash
`Calcium
`Aluminum
`Oxalate
`Oxalic acid
`Sulfate
`Arsenic
`Heavy metals
`Related substances
`Readily carbonizable
`substances
`Polycyclic aromatic
`hydrocarbon
`Organic volatile impurities -
`Assay (anhydrous basis) 999.5%
`
`+
`
`-
`
`-
`
`+
`--
`9~9.5-101.0% 99.5-100.5%
`
`Iol Note that the JP 2001 and PhEur 2002 have separate monographs for lhe monohydrate and
`
`anhydrous material; the USP 25 has a single monograph for both materials.
`
`10 Typical Properties
`Acidity/alkalinity: pH = 2.2 (1% w/v aqueous solution)
`Dissociation constant:
`pK~l: 3.128 at 25°C
`pK~2:4.761 at 25°C
`pKa3:6.396 at 25°C
`Density: 1.542 g/cm3
`Heat of combustion: - 1972 kJ/mot ( -471.4 kcal/mol)
`Heat of solution: -16.3 kJ/mol (-3.gkcal/mol) at 25°C
`Hygroscopicity: at relative humidities less than about 65%,
`citric acid monohydrate effloresces at 25°C, the anhydrous
`acid being formed at relative humidities less than about
`40%. At relative hmnidities between about 65% and 75%,
`citric acid monohydrate absorbs insignificant amounts of
`moisture, but under more humid conditions substantial
`amounts of water are absorbed.
`Melting point: ~ 100°C (softens at 75°C)
`Particle size distribution: various grades of citric acid mona-
`hydrate with different particle sizes are commercially avail-
`able.
`Solubility: soluble 1 in 1.5 parts of ethanol (95%) and 1 in less
`than 1 part of water; sparingly soluble in ether.
`Viscosity (dynamic): 6.5 mPa s (6.5 cP) for a 50% w/v aqueous
`solution at 25°C.
`See also Section 17.
`
`i i~iii~iii ii~
`
`5
`
`)i
`
`Citric Acid Monohydrate
`
`159
`
`moist air. Dilute aqueous solutions of citric acid may ferment
`on standing.
`The bulk monohydrate or anhydrous material should be
`stored in airtight containers in a cool, dry place.
`
`Citric acid is incompatible with potassium tartrate, alkali and
`alkaline earth carbonates and bicarbonates, acetates, and
`sulfides. Incompatibilities also include oxidizing agents,
`bases, reducing agents, and nitrates. It is potentially explosive
`in combination with metal nitrates. On storage, sucrose may
`crystallize from syrups in the presence of citric acid.
`
`13 Method of Manufacture
`Citric acid occurs naturally in a number of plant species and
`may be extracted from lemon juice, which contains 5-8 % citric
`acid, or pineapple waste. Anhydrous citric acid may also be
`produced industrially by mycological fermentation of crude
`sugar solutions such as molasses, using strains of Aspergillus
`niger: Citric acid is purified by recrystallization; the anhydrous
`form is obtained from a hot concentrated aqueous solution and
`the monohydrate from a cold concentrated aqueous solution.
`
`14 Safety
`Citric acid is found naturally in the body, mainly in the bones,
`and is commonly consumed as part of a normal diet. Orally
`ingested citric acid is absorbed and is generally regarded as a
`nontoxic material when used as an excipient. However,
`excessive or frequent consumption of citric acid has been
`associated with erosion of the teeth,t41
`Citric acid and citrates also enhance intestinal aluminum
`absorption in renal patients, which may lead to increased,
`harmful serum aluminum levels. It has therefore been sug-
`gested that patients with renal failure taking aluminum com-
`pounds to control phosphate absorption should not be
`prescribed citric acid or citrate-containing products.{s>
`See Section 17 for anhydrous citric acid animal toxicity
`data.
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Eye protection and gloves
`are recommended. Direct contact with eyes can cause serious
`damage. Citric acid should be handled in a well-ventilated
`environment or a dust mask should be worn.
`
`16 Regulatom! Status
`GRAS listed. The anhydrous form is accepted for use as a food
`additive in Europe. Included in the FDA Inactive Ingredients
`Guide (inhalations; IM, IV, and other injections; ophthalmic
`preparations; oral capsules, solutions, suspensions and tablets;
`topical and vaginal preparations). Included in nonparenterat
`and parenteral medicines licensed in Japan and the UK.
`
`| 7 Related Substances
`Anhydrous citric acid; sodium citrate dihydrate.
`
`1 1 Stability and Storage Conditions
`Citric acid monohydrate loses watm7 of c~ystallization in dry
`air or when heated to about 40°C. It is slightly deliquescent in
`
`Anhydrous citric acid
`Empirical formula: C6HsO7
`Molecular weight: 192.12
`
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`

`160
`
`Citric Acid Monohydrate
`
`18 Comments
`
`19 Specific References
`
`1 Anderson NR, Banker GS, Peck GE. Quantitative evaluation of
`pharmaceutical effervescent systems II: stability monitoring by
`reactivity and porosity measurements. J Pharm Sci 1982; 71(1): 7-13.
`2 Yanze FM, Duru C, Jacob M. A process to produce effervescent
`tablets: fluidized bed dryer melt granulation. Drug Dev Ind Pharm
`2000; 26(11): 1167-1176.
`3 Nyk~inen P, Lemp~i~i S, Aaltonen M-L, et al. Citric acid as
`excipient in multiple-unit enteric-coated tablets for targeting drugs
`on the colon. Int J Pharm 2001; 229(1-2): 155-162.
`4 Anonymous. Citric acid: tooth enamel destruction. Clin Alert
`1971; No. 151.
`5 Main I, Ward MK. Potentiation of aluminium absorption by
`effervescent analgesic tablets in a haemodialysis patient. Br Med J
`1992; 304(6843): 1686.
`6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,
`10th edn. New York: Wiley, 2000: 959.
`
`CAS number: [77-92-9]
`Synonyms: acidum citricum anhydricum; citric acid; E330; 2-
`hydroxy-[3-1,2,3-propanetricarboxylic acid; 2-hydroxypro- --
`pane 1,2,3-tricarboxylic acid.
`Appearance: odorless or almost odorless, colorless crystals or a
`white crystalline powder. Crystal structure is monoclinic
`holohedra.
`Dissociation constants:
`pKal: 3.128 at 25°C
`pKa2:4.761 at 25°C
`pKa3:6.396 at 25°C
`Density: 1.665 g/cm3
`Heat of combustion: -1985 kJ/mol (-474.5 kcal/mol)
`Hygroscopicity: at relative humidities between about 25-50%,
`anhydrous citric acid absorbs insignificant amounts of
`water at 25°C. However, at relative humidities between
`50% and 75%, it absorbs significant amounts, with the
`monohydrate being formed at relative humidities approach-
`ing 75%. At relative humidities greater than 75% substan-
`tial amounts of water are absorbed by the monohydrate.
`Melting point: 153°C
`Solubility: soluble 1 in 1 part of ethanol (98%) and 1 in 1 of
`water; sparingly soluble in ether.
`Safety:
`LD50 (mouse, IP): 0.9 g/kg(6)
`LD50 (mouse, IV): 0.04 g/kg
`LD50 (mouse, oral): 5.04 g/kg
`LDs0 (mouse, SC): 2.7g/kg
`LDs0 (rabbit, IV): 0.33g/kg
`LD50 (rat, IP): 0.88 g/kg
`LDs0 (rat, oral): 3.0 g/kg
`LDs0 (rat, SC): 5.5 g/kg
`Comments: the EINECS number for anydrous citric acid is
`201-069-1.
`
`20 General References
`
`Cho MJ, Scieszka JF, Burton PS. Citric acid as an adjuvant for
`transepithelial transport. Int J Pharm 1989; 52: 79-81.
`Timko RJ, Lordi NG. Thermal characterization of citric acid solid
`dispersions with benzoic acid and phenobarbital. J Pharm Sci
`1979; 68: 601-605.
`
`21 Author
`
`GE Amidon.
`
`22 Date of Revision
`
`8 October 2002.
`
`Merck Exhibit 2201, Page 11
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`IPR2020-00040
`
`

`

`Fumari¢ Acid
`
`| Nonproprietary Names
`
`USPNF: Fumaric acid
`
`2 Synonyms
`
`8 Description
`Fumaric acid occurs as white, odorless or nearly odorless,
`granules or as a crystalline powder that is virtually nonhygro-
`scopic.
`
`Allomaleic acid; allomalenic acid; boletic acid; butenedioic
`acid; E297; 1,2-ethenedicarboxylic acid; lichenic acid; trans-
`butenedioic acid; NSC-2752; trans-l,2-ethylenedicarboxylic
`acid; U-1149; USAF EK-P-583.
`
`9 Pharmacopeial Specifications
`
`See Table I.
`
`3 Chemical Name and CAS Registry Number
`
`Table I:
`
`Pharmacopeial specifications for fumaric acid.
`
`(E)-2-Butenedioic acid [110-17-8]
`
`Test
`
`4 Empirical Formula
`
`Molecular Weight
`
`C4H404
`
`116.07
`
`5 Structural Formula
`
`Identification
`Water
`Residue on ignition
`Heavy metals
`MaIeic acid
`Organic volatile impurities
`Assay (dried basis)
`
`USPNF 20
`
`+
`~<0.5%
`~<0.1%
`~<0.001%
`~<0.1%
`+
`99.5-100.5%
`
`10 Typical Properties
`
`Acidity/alkalinity:
`pH = 2.45 (saturated aqueous solution at 20 °C)
`pH = 2.58 (0.1% w/v aqueous solution at 25 °C)
`pH = 2.25 (0.3% w/v aqueous solution at 25 °C)
`pH = 2.15 (0.5% w/v aqueous solution at 25 °C)
`Density: 1.635 g/cm3 at 20 °C
`Density (bulk): 0.77 g/cm3
`Density (tapped): 0.93 g/cm3
`Dissociation constant:
`pKal = 3.03 at 25 °C;
`pK,~2 = 4.54 at 25 °C
`Melting point: 287 °C (closed capillary, rapid heating); partial
`carbonization and formation of mateic anhydride occur at
`230 °C (open vessel); sublimes at 200 °C.
`Boiling point: 290 °C (sealed tube)
`Solubility: see Table II.
`
`! I Stability and Storage Conditions
`Fumaric acid is stable although it is subject to degradation by
`both aerobic and anaerobic microorganisms. When heated in
`sealed vessels with water at 150-170 °C it forms (±)-malic
`acid.
`The bulk material should be stored in a welt-closed con-
`tainer in a cool, dry place.
`
`12 incompatibilities
`Fumaric acid undergoes reactions typical of an organic acid.
`
`6 Functional Category
`Acidulant; antioxidant; flavoring agent; therapeutic agent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Fumaric acid is used primarily in liquid pharmaceutical pre-
`parations as an acidulant and flavoring agent. Fumaric acid
`may be included as the acid part of effervescent tablet for-
`mulations, although this use is limited as the compound has an
`extremely low solubility in water. It is also used as a chelating
`agent which exhibits synergism when used in combination
`with other true antioxidants.
`In the design of novel pelletized formulations manufactured
`by extrusion-spheronization, fumaric acid was used to aid
`spheronization, favoring the production of fine pellets,ilt It
`has also been investigated as an alternative filler to lactose in
`pellets.(2)
`Fumaric acid has been investigated as a lubricant for
`effervescent tablets(3) and copolymers of fumaric acid and
`sebacic acid have been investigated as bioadhesive micro-
`spheres.(4)
`Fumaric acid is also used as a food additive at concentra-
`tions up to 3600ppm, and as a therapeutic agent in the
`treatment of psoriasis and other skin disorders.(s)
`
`250
`
`Merck Exhibit 2201, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Table I1: Solubility of fumaric acid.
`
`Solvent
`
`Acetone
`Benzene
`Carbon tetrachtoride
`Chloroform
`Ethanol
`Ethanol (95%)
`Ether
`
`Olive oil
`Propylene glycol
`Water
`
`Solubility at 20 C
`unless otherwise stated
`
`1 in 58 at 30°C
`Very slightly soluble
`Very slightly soluble
`Very slightly soluble
`1 in 28
`1 in 17at30°C
`Slightly soluble
`1 in t39 at 25~C
`Very slightly soluble
`1 in 33
`1 in 200
`1 in 432 at0°C
`1 in 303 at t0~C
`t in 159at25~C
`1 in 94 at 40°C
`1 in 42 at 60°C
`1 in t0atl00°C
`
`13 Method of Manufacture
`Commercially, fumaric acid may be prepared from glucose by
`the action of fungi such as Rhizopus nigricans, as a by-product
`in the manufacture of maleic and phthalic anhydrides, and by
`the isomerization of maleic acid using heat or a catalyst.
`On the laboratory scale, fumaric acid can be prepared by
`the oxidation of furfural with sodium chlorate in the presence
`of vanadium pentoxide.
`
`] 4 Safety
`Fumaric acid is used in oral pharmaceutical formulations and
`food products and is generally regarded as a relatively nontoxic
`and nonirritant material. However, acute renal failure and
`other adverse reactions have occurred following the topical
`and systemic therapeutic use of fumaric acid and fumaric acid
`derivatives in the treatment of psoriasis or other skin disor-
`ders.(s) Other adverse effects of oral therapy have included
`disturbances of liver function, gastrointestinal effects, and
`flushing.(s)
`The WHO has stated that the establishment of an estimated
`acceptable daily intake of fumaric acid or its salts was
`unnecessary since it is a normal constituent of body tissues.(6)
`
`¸¸¸¸4
`
`i!ii!~i!~i!i~i!;ili
`
`Fumaric Acid
`
`251
`
`be handled in a well-ventilated environment. Gloves and eye
`protection are recommended.
`
`16 Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included
`in the FDA Inactive Ingredients Guide (capsules, tablets, and
`oral liquids).
`
`17 Related Substances
`Citric acid monohydrate; malic acid; tartaric acid.
`
`18 Comments
`The EINECS number for fumaric acid is 203-743-0.
`
`19 Specific References
`1 Law MFL, Deasy PB. Effect of common classes of excipients on
`extrusion-spheronization. J Microencapsul 1997; 14(5): 647-657.
`2 Bianchini R, Bruni G, Gazzaniga A, Vecchio C. Influence of
`extrusion-spheronization processing on the physical properties of
`d-indobufen pellets containing pH adjusters. Drug Dev Ind Pharm
`1992; 18(14): 1485-1503.
`3 R6scheisen G, Schmidt PC. The combination of factorial design
`and simplex method in the optimization of lubricants for
`effervescent tablets. EurJ Pharm Biopharm 1995; 41(5): 302-308.
`4 Chickering DE, Mathiowitz E. Bioadhesive microspheres: I. A
`novel electrobalance-based method to study adhesive interactions
`between individual microspheres and intestinal mucosa. J Control
`Release 1995; 34: 251-262.
`5 Sweetman SC, ed. Martindale: The Complete Drug Reference,
`33rd edn. London: Pharmaceutical Press, 2002: 1114.
`6 FAO/WHO. Evaluation of certain food additives and contami-
`nants. Thirty-fifth report of the joint FAOPvViHO expert commit-
`tee on food additives. World Health Organ Tech Rep Ser 1990;
`No. 789.
`7 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,
`1Oth edn. New York: Wiley, 2000: 1838.
`
`20 General References
`
`Malic and fumaric acids. Manuf Chem Aerosol News 1964; 35(12):
`56-59.
`Robinson WD, Mount RA. In: Kirk-Othmer Encyclopedia of
`Chemical Technology, voh 14; 3rd edn. New York: Wiley-
`Interscience, 1981: 770-793.
`
`LDso (mouse, IP): 0.1 g/kg(vt
`LDso (rat, oral): 9.3 g/kg
`
`15 Handling Precautions
`
`21 Author
`
`SC Owen.
`
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Fumaric acid may be
`irritating to the skin, eyes, and respiratory system and should
`
`22 Dote of Revision
`
`21 May 2002.
`
`Merck Exhibit 2201, Page 13
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Sulfuric Acid
`
`1 Nonproprietary Names
`
`BP: Sulphuric acid
`PhEur: Acidum sulfuricum
`USPNF: Sulfuric acid
`
`2 Synonyms
`
`E513; hydrogen sulfate; oil of vitriol.
`
`3 Chemical Name and CAS Registry Number
`
`Sulfuric acid [7664-93-9].
`
`4 Empirical Formula
`
`Molecular Weight
`
`H2SO4
`
`98.08
`
`5 Structural Formula
`
`H2SO4
`
`6 Functional Category
`
`Acidifying agent..
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`
`Sulfuric acid is used as an acidifying agent in a variety of
`pharmaceutical and food preparations. It may also be used ro
`prepare dilute sulfuric acid, which, in addition to its use as an
`excipient, has some therapeutic use for the treatment of gastric
`hypoacidity, as an astringent in diarrhea, or to sumulate
`appente. Sulfuric acid has been used in parenteral, oral,
`topical, and ophthalmic pharmaceutical formulations.
`
`8 Description
`Sulfuric acid occurs as a clear, colorless, odorless, oily liquid. It
`is very corrosive and has a great affinity for water.
`The USPNF 20 specifies that sulfuric acid contains not less
`than 95% and not more than 98%, by weight, of H2SO4; the
`remainder is water. See also Section 9.
`
`9 Pharmacopeial Specifications
`See Table I.
`
`632
`
`Table I: Pharmacopeial specifications for sulfuric acid.
`
`Test
`
`PhEur 2002
`
`USPNF 20
`
`Identification
`+
`Residue on ignition
`-
`Chloride
`~ 50 ppm
`Arsenic
`~ 1 ppm
`Heavy metals
`~5ppm
`Weight per mL
`~ 1.84
`Iron
`~ 25 ppm
`+
`Nitrate
`Reducing substances -
`Assay (of H2SO4)
`95.0-100.5%
`
`+
`~0.005%
`.< 0.005%
`~ 1 ppm
`~<5 ppm
`-
`-
`-
`+
`95.0-98.0%
`
`10 Typical Properties
`
`Boiling point:
`~290°C for H2SO4 (95%-98% w/w)
`330°C for H2SO4 (100% w/w)
`Density: ~ 1.84 g/cm3 at 20°C
`Dissociation constant:
`pK~l = -3.00
`pKa2 = 1.99
`Freezing point:
`10°C for H2SO4 (100% w/w)
`3°C for H2SO4 (98% w/w)
`-32°C for H2SO4 (93% w/w)
`Solubility: miscible with ~thanol and water.
`Vapor density: 3.4 (air = 1.0)
`Vapor pressure: < 0.3 mmHg at 20°C
`
`1 1 Stability and Storage Conditions
`
`Sulfuric acid is stable but very corrosive and hygroscopic. It
`will draw moisture from the atmosphere. Sulfuric acid should
`be stored in a tightly closed container in an explosion proof
`area. Containers should be stored out of direct sunlight and
`away from heat. Avoid heat and moisture. Isolate from
`incompatible materials. See also Section 12.
`
`12
`
`Incompatibilities
`
`Avoid storage in close proximity to water, most common
`metals, organic materials, strong reducing agents, combusti-
`ble materials, strong bases, carbonates, sulfides, cyanides,
`strong oxidizing agents, and carbides.
`Sulfuric acid is a powerful oxidizer and may ignite or
`explode on contact with many materials.
`It can react violently with the evolution of a large amount of
`heat. Oxides of sulfur and hydrogen can be generated during
`reactions.
`Great care must be exercised when mixing with other
`liquids.
`
`13 Method of Manufacture
`
`Sulfuric acid may be prepared industrially by either the contact
`process or the chamber process.(~’2)
`
`Merck Exhibit 2201, Page 14
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`Contact Process
`2SO2 +02 -’2SO3
`$03 +H20 -+ H2SO4
`
`Chamber Process
`2NO + 02 --* 2NO2
`NO2 + SO2 + H20 --* H2SO4 + NO
`
`14 Safety
`
`Sulfuric acid is widely used in a variety of pharmaceutical
`formulations. Although concentrated sulfuric acid is very
`corrosive, it is normally used well diluted in formulations.
`Concentrated sulfuric acid will react violently with water and
`much heat is generated. When diluting sulfuric acid, the acid
`should always be added to the other liquid with great caution.
`The concentrated solution is extremely corrosive and can
`cause severe damage or necrosis on contact with the eyes and
`skin. Ingestion may cause severe injury or death. Inhalation of
`concentrated vapors can cause serious lung damage.
`
`LDso (rat, oral): 2.14 g/kg13)
`
`Su furic Acid
`
`633
`
`17 Related Substances
`Dilute sulfuric acid; fuming sulfuric acid.
`
`Dilute sulfuric acid
`Density: 1.062-1.072 g/cm3
`Comments: prepared by adding 104 g of sulfuric acid to 896 g
`of purified water with constant stirring and cooling. Dilute
`sulfuric acid contains between 9.5% and 10.5% w/w of
`H2SO4.
`
`Fuming sulfuric acid
`Synonyms: oleum.
`Comments: fuming sulfuric acid consists of H2SO4 with free
`sulfur trioxide (SO3). It is prepared by adding sulfur
`trioxide to sulfuric acid. Available in grades containing up
`to about 80% free SO3.
`Fuming sulfuric acid is a colorless or slightly colored, viscous
`liquid that emits choking fumes of sulfur trioxide. It is
`extremely corrosive and should be handled with great
`care and stored in tightly closed glass-stoppered bottles.
`
`15 Handling Precautions
`
`18 Comments
`
`Caution should be exercised when handling sulfuric acid and
`suitable protection against inhalation and spillage should be
`made. Respiratory protection may not be required where
`adequate ventilation exists. Eye protection (safety goggles
`and face shield), rubber gloves, and apron are recommended,
`depending on the circumstances and quantity of sulfuric acid
`handled. Do not dilute spills of concentrated acid with water
`since an exothermic reaction will occur. Spills should be
`neutralized with soda ash or lime. Splashes on the skin and
`eyes should be treated by immediate and prolonged washing
`with large amounts of water followed by the application of
`sodium bicarbonate and medical attention should be sought.
`Fumes can cause irritation or permanent damage to the
`eyes, nose, and respiratory system; prolonged exposure to
`fumes may damage the lungs.
`In the UK, the long-term exposure limit (8-hour TWA) for
`-
`3 (4)
`sulfuric acid is i mg/m .
`
`The EINECS number for sulfuric acid is 231-639-5.
`
`19 Specific References
`
`1 Druecker WW, West JR. The Manufacture of Sulfuric Acid. New
`York: Reinhold, 1959: 515.
`2 Nickless G, ed. Inorganic Sulphur Chemistry. New York: Elsevier,
`1968: 535-561.
`3 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,
`10th edn. New York: Wiley, 2000: 3330-3331.
`4 Health and Safety Executive. EH40/2002: Occupational E