Handbook of
`Pharmaceutical
`Excipients
`Fifth Edition
`
`Edited by
`Raymond C Rowe, Paul J Sheskey
`and Siân C Owen
`
`Flat Line Capital Exhibit 1020
`Page 1
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 1
`
`

`

`Handbook of
`Pharmaceutical Excipients
`
`Flat Line Capital Exhibit 1020
`Page 2
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 2
`
`

`

`Flat Line Capital Exhibit 1020
`Page 3
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 3
`
`

`

`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
`
`Flat Line Capital Exhibit 1020
`Page 4
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 4
`
`

`

`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
`
`Flat Line Capital Exhibit 1020
`Page 5
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 5
`
`

`

`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
`
`Flat Line Capital Exhibit 1020
`Page 6
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 6
`
`

`

`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
`
`Flat Line Capital Exhibit 1020
`Page 7
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 7
`
`

`

`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
`
`Flat Line Capital Exhibit 1020
`Page 8
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 8
`
`

`

`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
`
`Flat Line Capital Exhibit 1020
`Page 9
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 9
`
`

`

`Citric Acid Monohydrate
`
`1 Nonproprietary Names
`BP: Citric acid monohydrate
`JP: Citric acid
`PhEur: Acidum citricum monohydricum
`USP: Citric acid
`
`2 Synonyms
`E330; 2-hydroxypropane-1,2,3-tricarboxylic acid monohy-
`drate.
`
`shown to improve the stability of spray-dried insulin powder in
`inhalation formulations.(5)
`In 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. Therapeu-
`tically, preparations containing citric acid have been used to
`dissolve renal calculi.
`
`Table I:
`
`Uses of citric acid monohydrate.
`
`Use
`
`Concentration (%)
`
`3 Chemical Name and CAS Registry Number
`2-Hydroxy-1,2,3-propanetricarboxylic
`acid monohydrate
`[5949-29-1]
`
`Buffer solutions
`Flavor enhancer for liquid formulations
`Sequestering agent
`
`0.1–2.0
`0.3–2.0
`0.3–2.0
`
`4 Empirical Formula and Molecular Weight
`C6H8O7 H2O
`210.14
`
`5 Structural Formula
`
`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
`Manufacturer: Pfizer Ltd.
`Magnification: 60
`
`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. It has also been used
`experimentally to adjust the pH of tablet matrices in enteric-
`coated formulations for colon-specific drug delivery.(1) Citric
`acid monohydrate is used in the preparation of effervescent
`granules, while anhydrous citric acid is widely used in the
`preparation of effervescent tablets.(2–4) Citric acid has also been
`
`Flat Line Capital Exhibit 1020
`Page 10
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 10
`
`

`

`186
`
`Citric Acid Monohydrate
`
`SEM: 2
`Excipient: Citric acid monohydrate
`Manufacturer: Pfizer Ltd.
`Magnification: 600
`
`9 Pharmacopeial Specifications
`See Table II.
`
`Pharmacopeial specifications for citric acid monohydrate
`Table II:
`(and anhydrous).
`
`Test
`
`PhEur 2005
`þ
`þ
`þ
`
`USP 28(a)
`þ
`—
`—
`
`48.8%
`40.5%
`—
`40.05%
`—
`—
`—
`þ
`—
`þ
`43 ppm
`40.001%
`—
`þ
`
`—
`þ
`
`599.5%
`
`99.5–101.0% 99.5–100.5%
`
`(a) Note that the JP 2001 and PhEur 2005 have separate monographs for the monohydrate and
`anhydrous material; the USP 28 has a single monograph for both materials.
`
`JP 2001
`þ
`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)
`
`7.5–9.0%
`—
`41.0%
`40.5%
`þ
`—
`40.1%
`—
`40.1%
`—
`þ
`—
`40.2 ppm
`—
`þ
`—
`4350 ppm
`—
`40.048% 4150 ppm
`41 ppm —
`410 ppm 410 ppm
`þ
`—
`þ
`þ
`þ
`
`—
`
`—
`
`—
`
`10 Typical Properties
`Acidity/alkalinity: pH = 2.2 (1% w/v aqueous solution)
`Dissociation constant:
`pKa1: 3.128 at 258C;
`pKa2: 4.761 at 258C;
`pKa3: 6.396 at 258C.
`Density: 1.542 g/cm3
`Heat of combustion: 1972 kJ/mol (471.4 kcal/mol)
`Heat of solution: 16.3 kJ/mol (3.9 kcal/mol) at 258C
`Hygroscopicity: at relative humidities less than about 65%,
`citric acid monohydrate effloresces at 258C, the anhydrous
`acid being formed at relative humidities less than about
`40%. At relative humidities 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: 1008C (softens at 758C)
`Particle size distribution: various grades of citric acid mono-
`hydrate with different particle sizes are commercially
`available.
`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 258C.
`See also Section 17.
`
`11 Stability and Storage Conditions
`Citric acid monohydrate loses water of crystallization in dry air
`or when heated to about 408C. It is slightly deliquescent in
`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.
`
`12 Incompatibilities
`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.(6)
`Citric acid and citrates also enhance intestinal aluminum
`absorption in renal patients, which may lead to increased,
`
`Flat Line Capital Exhibit 1020
`Page 11
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 11
`
`

`

`harmful serum aluminum levels. It has therefore been suggested
`that patients with renal failure taking aluminum compounds to
`control phosphate absorption should not be prescribed citric
`acid or citrate-containing products.(7)
`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 Regulatory 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 nonparenteral
`and parenteral medicines licensed in Japan and the UK.
`Included in the Canadian List of Acceptable Non-medicinal
`Ingredients.
`
`17 Related Substances
`Anhydrous citric acid; fumaric acid; malic acid; sodium citrate
`dihydrate; tartaric acid.
`
`Anhydrous citric acid
`Empirical formula: C6H8O7
`Molecular weight: 192.12
`CAS number: [77-92-9]
`Synonyms: acidum citricum anhydricum; citric acid; E330; 2-
`hydroxy-b-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
`holohedral.
`Dissociation constants:
`pKa1: 3.128 at 258C;
`pKa2: 4.761 at 258C;
`pKa3: 6.396 at 258C.
`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 258C. However, at relative humidities between 50% and
`75%, it absorbs significant amounts, with the monohydrate
`being formed at relative humidities approaching 75%. At
`relative humidities greater than 75% substantial amounts of
`water are absorbed by the monohydrate.
`Melting point: 1538C
`Solubility: soluble 1 in 1 part of ethanol (95%) and 1 in 1 of
`water; sparingly soluble in ether.
`Safety:
`LD50 (mouse, IP): 0.9 g/kg(8)
`
`Citric Acid Monohydrate
`
`187
`
`LD50 (mouse, IV): 0.04 g/kg
`LD50 (mouse, oral): 5.04 g/kg
`LD50 (mouse, SC): 2.7 g/kg
`LD50 (rabbit, IV): 0.33 g/kg
`LD50 (rat, IP): 0.88 g/kg
`LD50 (rat, oral): 3.0 g/kg
`LD50 (rat, SC): 5.5 g/kg
`Comments: the EINECS number for anhydrous citric acid is
`201-069-1.
`
`18 Comments
`A specification for citric acid monohydrate is contained in the
`Food Chemicals Codex (FCC).
`The EINECS number for citric acid monohydrate is 201-
`069-1.
`
`19 Specific References
`1 Nykaenen P, Sten T, Juerjenson H, Veski P, Marvola M. Citric acid
`as a pH-regulating additive in granules and the tablet matrix in
`enteric-coated formulations
`for colon-specific drug delivery.
`Pharmazie 2004; 59(4): 268–273.
`2 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.
`3 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.
`4 Nyka¨ nen P, Lempa¨ a¨ 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.
`5 Todo H, Okamoto H, Iida K, Danjo K. Improvement of stability
`and absorbability of dry insulin powder for inhalation by powder-
`combination technique. Int J Pharm 2004; 271(1–2): 41–52.
`6 Anonymous. Citric acid: tooth enamel destruction. Clin Alert
`1971; No. 151.
`7 Main I, Ward MK. Potentiation of aluminium absorption by
`effervescent analgesic tablets in a haemodialysis patient. Br Med J
`1992; 304: 1686.
`8 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,
`11th edn. New York: Wiley, 2004: 955.
`
`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 Authors
`GE Amidon.
`
`22 Date of Revision
`8 August 2005.
`
`Flat Line Capital Exhibit 1020
`Page 12
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 12
`
`

`

`Hydrochloric Acid
`
`1 Nonproprietary Names
`BP: Hydrochloric acid
`JP: Hydrochloric acid
`PhEur: Acidum hydrochloridum concentratum
`USPNF: Hydrochloric acid
`
`2 Synonyms
`Chlorohydric acid; concentrated hydrochloric acid; E507.
`
`3 Chemical Name and CAS Registry Number
`Hydrochloric acid [7647-01-0]
`
`4 Empirical Formula and Molecular Weight
`HCl
`36.46
`
`5 Structural Formula
`HCl
`
`6 Functional Category
`Acidifying agent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Hydrochloric acid is widely used as an acidifying agent, in a
`variety of pharmaceutical and food preparations (see Section
`16). It may also be used to prepare dilute hydrochloric acid,
`which in addition to its use as an excipient has some therapeutic
`use, intravenously in the management of metabolic alkalosis,
`and orally for the treatment of achlorhydria. See Section 17.
`
`8 Description
`Hydrochloric acid occurs as a clear, colorless, fuming aqueous
`solution of hydrogen chloride, with a pungent odor.
`The JP 2001 specifies that hydrochloric acid contains
`35.0–38.0% w/w of HCl;
`the PhEur 2005 specifies that
`hydrochloric acid contains 35.0–39.0% w/w of HCl; and the
`USPNF 23 specifies
`that hydrochloric
`acid contains
`36.5–38.0% w/w of HCl. See also Section 9.
`
`9 Pharmacopeial Specifications
`See Table I.
`
`Table I:
`
`Pharmacopeial specifications for hydrochloric acid.
`
`Test
`
`USPNF 23
`PhEur 2005
`JP 2001
`þ
`þ
`þ
`Identification
`þ
`þ
`—
`Characters
`þ
`—
`Appearance of solution —
`40.008%
`41.0 mg
`—
`Residue on ignition
`40.01%
`—
`Residue on evaporation —
`þ
`þ
`—
`Bromide or iodide
`þ
`þ
`—
`Free bromine
`þ
`þ
`44 ppm
`Free chlorine
`þ
`þ
`420 ppm
`Sulfate
`þ
`þ
`—
`Sulfite
`41 ppm
`—
`—
`Arsenic
`45 ppm
`42 ppm
`45 ppm
`Heavy metals
`40.04 ppm —
`—
`Mercury
`Assay (of HCl)
`35.0–38.0% 35.0–39.0% 36.5–38.0%
`
`10 Typical Properties
`Acidity/alkalinity: pH = 0.1 (10% v/v aqueous solution)
`Boiling point: 1108C (constant boiling mixture of 20.24% w/w
`HCl)
`Density: 1.18 g/cm3 at 208C
`Freezing point: 248C
`20 = 1.342 (10% v/v aqueous solution)
`Refractive index: nD
`Solubility: miscible with water; soluble in diethyl ether, ethanol
`(95%), and methanol.
`
`11 Stability and Storage Conditions
`Hydrochloric acid should be stored in a well-closed, glass or
`other inert container at a temperature below 308C. Storage in
`close proximity to concentrated alkalis, metals, and cyanides
`should be avoided.
`
`12 Incompatibilities
`Hydrochloric acid reacts violently with alkalis, with the
`evolution of a large amount of heat. Hydrochloric acid also
`reacts with many metals, liberating hydrogen.
`
`13 Method of Manufacture
`Hydrochloric acid is an aqueous solution of hydrogen chloride
`gas produced by a number of methods including: the reaction of
`sodium chloride and sulfuric acid; the constituent elements; as a
`by-product from the electrolysis of sodium hydroxide; and as a
`by-product during the chlorination of hydrocarbons.
`
`14 Safety
`When used diluted, at low concentration, hydrochloric acid is
`not usually associated with any adverse effects. However, the
`concentrated solution is corrosive and can cause severe damage
`on contact with the eyes and skin, or if ingested.
`LD50 (mouse, IP): 1.4 g/kg(1)
`LD50 (rabbit, oral): 0.9 g/kg
`
`Flat Line Capital Exhibit 1020
`Page 13
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 13
`
`

`

`15 Handling Precautions
`Caution should be exercised when handling hydrochloric acid
`and suitable protection against inhalation and spillage should
`be taken. Eye protection, gloves,
`face mask, apron, and
`respirator are recommended, depending on the circumstances
`and quantity of hydrochloric acid handled. Spillages should be
`diluted with copious amounts of water and run to waste.
`Splashes on the skin and eyes should be treated by immediate
`and prolonged washing with large amounts of water and
`medical attention should be sought. Fumes can cause irritation
`to the eyes, nose, and respiratory system; prolonged exposure
`to fumes may damage the lungs. In the UK, the recommended
`short-term exposure limit
`for hydrogen chloride gas and
`aerosol mists is 8 mg/m3 (5 ppm). The long-term exposure limit
`(8-hour TWA) is 2 mg/m3 (1 ppm).(2)
`
`16 Regulatory Status
`GRAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Guide (dental
`solutions; epidural
`injections,
`IM,
`IV, and SC injections,
`inhalations, ophthalmic preparations, oral solutions, nasal,
`otic, rectal, and topical preparations). Included in parenteral
`and nonparenteral medicines licensed in the UK. Included in the
`Canadian List of Acceptable Non-medicinal Ingredients.
`
`17 Related Substances
`Dilute hydrochloric acid.
`
`Hydrochloric Acid
`
`329
`
`prepared by mixing 274 g of hydrochloric acid with 726 g of
`water. The USPNF 23 specifies 9.5–10.5% w/v of HCl,
`prepared by mixing 226 mL of hydrochloric acid with
`sufficient water to make 1000 mL.
`
`18 Comments
`In pharmaceutical formulations, dilute hydrochloric acid is
`usually used as an acidifying agent in preference to hydro-
`chloric acid. Hydrochloric acid is also used therapeutically as
`an escharotic.(3) The PhEur 2005 also contains a specification
`for hydrochloric acid, dilute; see Section 17.
`A specification for hydrochloric acid is contained in the
`Food Chemicals Codex (FCC).
`The EINECS number for hydrochloric acid is 231-595-7.
`
`19 Specific References
`1 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,
`11th edn. New York: Wiley, 2004: 1980.
`2 Health and Safety Executive. EH40/2002: Occupational Exposure
`Limits 2002. Sudbury: Health and Safety Executive, 2002.
`3 Sweetman S, ed. Martindale: The Complete Drug Reference, 34th
`edn. London: Pharmaceutical Press, 2005: 1699.
`
`20 General References
`Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical
`Excipients Directory 1996. Tokyo: Yakuji Nippo, 1996: 228.
`
`Dilute hydrochloric acid
`Synonyms: acidum hydrochloridum dilutum; diluted hydro-
`chloric acid.
`Density: 1.05 g/cm3 at 208C
`Comments: the JP 2001 and PhEur 2005 specify that dilute
`hydrochloric acid contains 9.5–10.5% w/w of HCl and is
`
`21 Authors
`SC Owen.
`
`22 Date of Revision
`12 August 2005.
`
`Flat Line Capital Exhibit 1020
`Page 14
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 14
`
`

`

`Sodium Benzoate
`
`1 Nonproprietary Names
`BP: Sodium benzoate
`JP: Sodium benzoate
`PhEur: Natrii benzoas
`USPNF : Sodium benzoate
`
`SEM: 1
`Excipient: Sodium benzoate
`Manufacturer: Bush Boake Allen Corp.
`Magnification: 60
`
`2 Synonyms
`Benzoic acid sodium salt; benzoate of soda; E211; natrium
`benzoicum; sobenate; sodii benzoas; sodium benzoic acid.
`
`3 Chemical Name and CAS Registry Number
`Sodium benzoate [532-32-1]
`
`4 Empirical Formula and Molecular Weight
`C7H5NaO2
`144.11
`
`5 Structural Formula
`
`6 Functional Category
`Antimicrobial preservative; tablet and capsule lubricant.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Sodium benzoate is used primarily as an antimicrobial
`preservative in cosmetics, foods, and pharmaceuticals. It is
`used in concentrations of 0.02–0.5% in oral medicines, 0.5% in
`parenteral products, and 0.1–0.5% in cosmetics. The useful-
`ness of sodium benzoate as a preservative is limited by its
`effectiveness over a narrow pH range; see Section 10.
`Sodium benzoate is used in preference to benzoic acid in
`some circumstances, owing to its greater solubility. However, in
`some applications it may impart an unpleasant flavor to a
`product. Sodium benzoate has also been used as a tablet
`lubricant(1) at 2–5% w/w concentrations. Solutions of sodium
`benzoate have also been administered, orally or intravenously,
`in order to determine liver function.
`
`SEM: 2
`Excipient: Sodium benzoate
`Manufacturer: Bush Boake Allen Corp.
`Magnification: 2400
`
`8 Description
`Sodium benzoate occurs as a white granular or crystalline,
`slightly hygroscopic powder. It is odorless, or with faint odor of
`benzoin and has an unpleasant sweet and saline taste.
`
`9 Pharmacopeial Specifications
`See Table I.
`
`Flat Line Capital Exhibit 1020
`Page 15
`
`KVK-Tech, Flat Line Capital Exhibit 1020
`Page 15
`
`

`

`Table I:
`
`Pharmacopeial specifications for sodium benzoate.
`
`Test
`
`PhEur 2005
`JP 2001
`þ
`þ
`Identification
`þ
`þ
`Characters
`þ
`þ
`Acidity or alkalinity
`þ
`Appearance of solution þ
`42 ppm —
`Arsenic
`þ
`4200 ppm
`Chloride
`420 ppm 410 ppm
`Heavy metals
`Organic volatile
`—
`—
`impurities
`Loss on drying
`Phthalic acid
`Sulfate
`Total chlorine
`Assay (dried basis)
`
`USPNF 23
`þ
`—
`þ
`—
`—
`—
`40.001%
`þ
`
`41.5%
`42.0%
`41.5%
`þ
`—
`—
`40.120% —
`—
`4300 ppm
`—
`—
`599.0%
`99.0–100.5% 99.0–100.5%
`
`10 Typical Properties
`Acidity/alkalinity: pH = 8.0 (saturated aqueous solution at
`258C). It is relatively inactive above approximately pH 5.
`Antimicrobial activity: sodium benzoate has both bacteriostatic
`and antifungal properties attributed to undissociated
`benzoic acid, hence preservative efficacy is best seen in
`acidic solutions (pH 2–5). In alkaline conditions it is almost
`without effect.
`Density: 1.497–1.527 g/cm3 at 248C
`Freezing point depression: 0.248C (1.0% w/v)
`Osmolarity: a 2.25% w/v aqueous solution is iso-osmotic with
`serum.
`Partition coefficients:
`Vegetable oil : water = 3–6
`Solubility: see Table II.
`
`Table II:
`
`Solubility for sodium benzoate.
`
`Solvent
`
`Ethanol (95%)
`Ethanol (90%)
`Water
`
`Solubility at 208C
`unless otherwise stated
`
`1 in 75
`1 in 50
`1 in 1.8
`1 in 1.4 at 1008C
`
`11 Stability and Storage Conditions
`Aqueous
`solutions may be sterilized by autoclaving or
`filtration.
`The bulk material should be stored in a well-closed
`container, in a cool, dry place.
`
`12 Incompatibilities
`Incompatible with quaternary compounds, gelatin, ferric salts,
`calcium salts, and salts of heavy metals, including silver, lead,
`and mercury. Preservative activity may be reduced by interac-
`tions with kaolin(2) or nonionic surfactants.
`
`13 Method of Manufacture
`Prepared by the treatment of benzoic acid with either sodium
`carbonate or sodium bicarbonate.
`
`Sodium Benzoate
`
`663
`
`14 Safety
`Ingested sodium benzoate is conjugated with glycine in the liver
`to yield hippuric acid, which is excreted in the urine. Symptoms
`of systemic benzoate toxicity resemble those of salicylates.(3)
`Whereas oral administration of the free-acid form may cause
`severe gastric irritation, benzoate salts are well tolerated in
`large quantities: e.g. 6 g of sodium benzoate in 200 mL of water
`is administered orally as a liver function test.
`Clinical data have indicated that sodium benzoate can
`produce nonimmunological contact uricartia and nonimmuno-
`immediate contact reactions.(4) However,
`logical
`it is also
`recognized that these reactions are strictly cutaneous, and can
`therefore be used safely at concentrations up to 5%. However,
`this nonimmunological phenomenon should be considered
`when designing formulations for infants and children.
`Other adverse effects include anaphylaxis(5–7) and urticarial
`reactions, although a controlled study has shown that the
`incidence of urticaria in patients given benzoic acid is no greater
`than that with a lactose placebo.(8)
`It has been recommended that caffeine and sodium benzoate
`injection should not be used in neonates;(9) however, sodium
`benzoate has been used by others in the treatment of some
`neonatal metabolic disorders.(10) It has been suggested that
`there is a general adverse effect of benzoate preservatives on the
`behavior of 3-year-old children, which is detectable by parents,
`but not by a simple clinical assessment.(11)
`total benzoates,
`The WHO acceptable daily intake of
`calculated as benzoic acid, has been estimated at up to
`5 mg/kg of body-weight.(12,13)
`LD50 (mouse, IM): 2.3 g/kg(13,14)
`LD50 (mouse, IV): 1.4 g/kg
`LD50 (mouse, oral): 1.6 g/kg
`LD50 (rabbit, oral): 2.0 g/kg
`LD50 (rat, IV): 1.7 mg/kg
`LD50 (rat, oral): 4.1 g/kg
`See also Benzoic Acid.
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Sodium benzoate may be
`irritant to the eyes and skin. Eye protection and rubber or
`plastic gloves are recommended.
`
`16 Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included in
`the FDA Inactive Ingredients Guide (dental preparations; IM
`and IV injections; oral capsules, solutions and tablets; rectal;
`and topical preparations). Included in nonparenteral medicines
`licensed in the UK. Included in the Canadian List of Acceptable
`Non-medicinal Ingredients.
`
`17 Related Substances
`Benzoic acid; potassium benzoate.
`
`18 Comments
`Sodium benzoate has been used as an