_)
`
`Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`... ·
`
`'.
`
`American Pharmaceutical Association
`Washington
`
`1994
`
`The Pharmaceutical Press
`·London
`
`Page 1 of 23
`
` Ex. 1003
`
`Mylan Ex. 1003
`IPR Petition - USP 6,335,031
`
`

`

`©Copyright 1986, 1994 by the American Pharmaceutical Association, 2215 Constitution Avenue NW, Washington,
`DC 20037-2985, USA, and The Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High
`Street, London, SEl 7JN, England.
`
`; --
`
`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 94--79492.
`
`International Standard Book Number {ISBN) in the UK: 0 85369 305 6
`International Standard Book Number {ISBN) in the USA: 0 91730 66 8
`
`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopy, recording, or any information storage or retrieval system, without prior written permission from
`the joint publishers.
`
`Typeset in Great Britain by Alden Multimedia, Northampton.
`Printed and bound in. Great Britain by
`
`Page 2 of 23
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` Ex. 1003
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`

`

`Contents
`
`Committees
`Contributors
`Additions to the Second Edition
`Preface
`Notice to Readers
`Selected Bibliography
`Abbreviations
`Units of Measurement
`
`Monographs
`Acacia
`Acesulfame Potassium
`Albumin
`Alcohol
`Alginic Acid
`Alpha Tocopherol
`Ascorbic Acid
`Ascorbyl Palmitate
`Aspartame
`Bentonite
`Benzalkonium Chloride
`Benzethonium Chloride
`Benzoic Acid
`Benzyl Alcohol
`Benzyl Benzoate
`Bronopol
`Butane
`Butylated Hydroxyanisole
`Butylated Hydroxytoluene
`Butylparaben
`Calcium Carbonate
`Dibasic Calcium Phosphate Dihydrate
`Tribasic Calcium Phosphate
`Calcium Stearate
`Calcium Sulfate
`Canola Oil
`Carbomer
`Carbon Dioxide
`Carboxymethylcellulose Calcium
`Carboxymethylcellulose Sodium
`J:iydrogenated Castor Oil
`Microcrystalline Cellulose
`Powdered Cellulose
`Cellulose Acetate Phthalate
`Cetostearyl Alcohol
`Cetrirnide
`Cetyl Alcohol
`Cetyl Esters Wax
`Chlorhexidine
`Chlorobutanol
`Chlorocresol
`Chlorodifluoroethane
`Chlorodifluoromethane
`Cholesterol
`Citric Acid Monohydrate
`Coloring Agents
`Com Oil
`Cottonseed Oil
`Cresol
`
`Croscarmellose Sodium
`Crospovidone
`Cyclodextrins
`Dextrates
`Dextrin
`Dextrose
`Dibuty1 Sebacate
`Dichlorodifluoromethane
`Dichlorotetrafluoroethane
`Diethanolamine
`Diethyl Phthalate
`Difluoroethane
`Dimethyl Ether
`Docusate Sodium
`Edetic Acid
`Ethyl Maltol
`Ethyl Oleate
`Ethyl Vanillin
`Ethylcellulose
`Ethylparaben
`Fructose
`Fumaric Acid
`Gelatin
`Liquid Glucose
`Glycerin
`Glyceryl Monoo1eate
`Glyceryl Monostearate
`Glyceryl Palmitostearate
`Glycofurol
`GuarGum
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`Hydroxypropyl Cellulose
`Hydroxypropyl Methylcellulose
`Hydroxypropyl Methylcellulose Phthalate
`Irnidurea
`!so butane
`Isopropyl Alcohol
`Isopropyl Myristate
`Isopropyl Palmitate
`Kaolin
`Lactic Acid
`Lactose
`Lanolin
`Lanolin Alcohols
`Hydrous Lanolin
`Lecithin
`Magnesium Aluminum Silicate
`Magnesium Carbonate
`Magnesium Oxide
`Magnesium Stearate
`Magnesium Trisilicate
`Ma1ic Acid
`Maltitol Solution
`Maltodextrin
`Maltol
`Mannitol
`Medium Chain Triglycerides
`Meglurnine
`Menthol
`Methylcellulose
`Methylparaben
`Mineral Oil
`Light Mineral Oil
`Mineral Oil and Lanolin Alcohols
`Monoethanolarnine
`
`vii
`viii
`ix
`xi
`xiii
`xiii
`xiv
`XV
`
`1
`3
`5
`7
`10
`12
`15
`19
`21
`24
`27
`30
`32
`35
`38
`40
`43
`45
`47
`49
`52
`56
`61
`63
`66
`69
`71
`74
`76
`78
`82
`84
`88
`91
`94
`96
`99
`104
`106
`111
`114
`117
`119
`121
`123
`126
`135
`137
`139
`
`Contents v
`
`141
`143
`145
`149
`151
`154
`158
`160
`163
`165
`167
`169
`171
`173
`176
`180
`182
`184
`186
`191
`194
`197
`199
`202
`204
`207
`209
`211
`213
`215
`217
`219
`223
`229
`233
`238
`240
`241
`243
`245
`247
`250
`252
`262
`264
`265
`267
`269
`274
`278
`280
`283
`285
`287
`289
`292
`294
`299
`302
`304
`306
`310
`314
`316
`318
`319
`
`Page 3 of 23
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`

`

`vi Contents
`
`Nitrogen
`Nitrous Oxide
`Oleic Acid
`Paraffin
`Peanut Oil
`Petrolatwn
`Petrolatwn and Lanolin Alcohols
`Phenol
`Phenoxyethanol
`Phenylethyl Alcohol
`Phenylmercuric Acetate
`Phenylmercuric Borate
`Phenylmercuric Nitrate
`Polacrilin Potassiwn
`Poloxamer
`Polyethylene Glycol
`Polymethacrylates
`Polyoxyethylene Alkyl Ethers
`Polyoxyethylene Castor Oil Derivatives
`Polyoxyethylene Sorbitan Fatty Acid Esters
`·
`Polyoxyethylene Stearates
`Polyvinyl Alcohol
`Potassium Chloride
`Potassiwn Citrate
`Potassium Sorbate
`Povidone
`Propane
`Propyl Gallate
`Propylene Carbonate
`Propylene Glycol
`Propylene Glycol Alginate
`Propylparaben
`Saccharin
`Saccharin Sodiwn
`Sesame Oil
`Shellac
`Colloidal Silicon Dioxide
`Sodium Alginate
`Sodiwn Ascorbate
`Sodium Benzoate
`Sodiwn Bicarbonate
`Sodiwn Chloride
`Sodiwn Citrate Dihydrate
`Sodiwn Cyclamate
`Sodiwn Laury! Sulfate
`Sodiwn Metabisulfite
`
`321
`323
`325
`327
`329
`331
`334
`336
`338
`340
`342
`344
`346
`350
`352
`355
`362
`367
`371
`375
`379
`383
`385
`388
`390
`392
`400
`402
`405
`407
`409
`411
`415
`418
`420
`422
`424
`428
`431
`433
`436
`439
`443
`446
`448
`451
`
`Dibasic Sodiwn Phosphate
`Monobasic Sodiwn Phosphate
`Sodiwn Propionate
`Sodiwn Starch Glycolate
`Sodiwn Stearyl Fwnarate
`Sorbic Acid
`Sorbitan Esters (Sorbitan Fatty Acid Esters)
`Sorbitol
`Soybean Oil
`Starch
`Sterilizable Maize Starch
`Pregelatinized Starch
`Stearic Acid
`Stearyl Alcohol
`Sucrose
`Compressible Sugar
`Confectioner's Sugar
`Sugar Spheres
`Suppository Bases
`Talc
`Tartaric Acid
`Tetrafluoroethane
`Thimerosal
`Titanium Dioxide
`Tragacanth
`Triacetin
`T richloromonofluoromethane
`Triethanolamine
`Triethyl Citrate
`Vanillin
`Hydrogenated Vegetable Oil, Type I
`Water
`Anionic Emulsifying Wax
`Camauba Wax
`Microcrystalline Wax
`Nonionic Emulsifying Wax
`White Wax
`Yellow Wax
`Xanthan Gwn
`Xylitol
`Zein
`Zinc Stearate
`Appendix I: Suppliers' Directory
`Appendix II: HPE Laboratory Methods
`Index
`
`454
`457
`459
`462
`467
`470
`473
`477
`481
`483
`489
`491
`494
`498
`500
`506
`508
`510
`512
`519
`522
`524
`526
`529
`532
`534
`536
`538
`540
`542
`544
`546
`550
`552
`554
`556
`558
`560
`562
`564
`568
`569
`571
`625
`633
`
`Page 4 of 23
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` Ex. 1003
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`

`

`12 Alpha Tocopherol
`
`Alpha Tocopherol
`
`1. Nonproprietary Names
`BP: Alpha tocopherol
`PhEur: a-Tocopherolum
`USP: Vitamin E
`See also Sections 3, 9 and 18.
`
`2. Synonyms
`( ± )-3,4-Dihydro-2,5, 7 ,8-tetramethyl-2-( 4,8, 12-trimethyltride(cid:173)
`cyl)-2H-l-benzopyran-6-ol; E307; synthetic alpha tocopherol;
`all-rae-a-tocopherol; dl-a-tocopherol; 5, 7 ,8-trimethyltocol.
`
`3. Chemical Name and CAS Registry Number
`( ± )-(2RS,4' RS,8' RS)-2,5, 7,8-Tetramethyl-2-(4',8',12'-trime(cid:173)
`thyltridecyl)-6-chromanol
`[10191-41-0]
`Note that alpha tocopherol has three chiral centres giving rise
`to eight isomeric forms. The naturally occurring form is known
`as d-alpha tocopherol or (2R,4' R,8' R)-alpha-tocopherol. The
`synthetic form, dl-alpha tocopherol or simply alpha tocopher(cid:173)
`ol, occurs as a racemic mixture containing equimolar
`quantities of all the isomers.
`Similar considerations apply to beta, delta and gamma
`tocopherol and tocopherol esters.
`See Section 18 for further information.
`
`4. Empirical Formula
`C29Hso02
`
`Molecular Weight
`430.69
`
`5. Structural Formula
`
`R2
`
`HO
`
`*
`CH,
`
`CH,
`
`CH3
`
`CH,
`
`R,
`Alpha tocopherol: R 1 = R2 = R3 = CH3.
`Beta tocopherol: R 1 = R3 = CH3; R2 = H.
`Delta tocopherol: R 1 = CH3; R2 = R3 = H.
`Gamma tocopherol: R 1 = R2 = CH3; R3 = H.
`* Indicates chiral centres.
`
`6. Functional Category
`Antioxidant; therapeutic agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Alpha tocopherol is primarily recognised as a source of
`vitamin E and the commercially available materials and
`specifications reflect this purpose. Whilst alpha tocopherol
`also exhibits antioxidant properties, the beta, delta and gamma
`tocopherols are considered to be more effective as anti(cid:173)
`oxidants.
`Of widespread regulatory acceptability, tocopherols are of
`value in oil or fat-based pharmaceutical products and are
`normally used in the concentration range of 0.001-0.05%.
`
`There is frequently an optimum concentration; thus the
`autoxidation of linoleic acid and methyl linolenate is reduced
`at low concentrations of alpha tocopherol but accelerated by
`higher concentrations. Antioxidant effectiveness can be
`increased by the addition of oil soluble synergists such as
`lecithin and ascorbyl palmitate.<!)
`
`8. Description
`Alpha tocopherol is a practically odorless, clear, colorless,
`yellow, yellowish-brown or greenish-yellow colored viscous oil.
`See also Section 18.
`
`9. Pharmacopeia! Specifications
`
`Test
`
`Identification
`Acidity
`Acid value
`Heavy metals
`Sulfated ash
`Assay
`
`PhEur 1990
`+
`
`,;;2
`,;; 20 ppm
`,;; 0.1%
`96.0-102.0%
`
`USPXXII
`+
`+
`
`96.0-102.0%
`
`Note that the USP XXII describes vitamin E as comprising d(cid:173)
`or dl-alpha tocopherol; d- or dl-alpha tocopheryl acetate; or d(cid:173)
`or dl-alpha tocopheryl acid succinate. However, the PhEur
`1990 and the BP 1993 describe alpha tocopherol and alpha
`tocopheryl acetate in separate monographs.
`The diversity of the tocopherols described in the various
`pharmacopeia! monographs makes a comparison of specifica(cid:173)
`tions difficult.
`
`10. Typical Properties
`Solubility: practically insoluble in water; freely soluble in
`acetone, ethanol, ether and vegetable oils.
`
`11. Stability and Storage Conditions
`Tocopherols are slowly oxidized by atmospheric oxygen and
`rapidly by ferric and silver salts. Oxidation products include
`tocopheroxide, tocopherylquinone and tocopherylhydroqui(cid:173)
`none, as well as dimers and trimers. Tocopherol esters are
`more stable to oxidation than the free tocopherols but are in
`consequence less effective antioxidants. See also Section 18.
`Tocopherols should be stored under an inert gas, in an airtight
`container in a cool, dry, place and protected from light.
`
`12. Incompatibilities
`Tocopherols are incompatible with peroxides and metal ions
`especially iron, copper and silver. Tocopherols may be
`absorbed into plastic."<2l
`
`13. Method of Manufacture
`Naturally occurring tocopherols are obtained by the extraction
`or molecular distillation of steam distillates of vegetable oils,
`e.g. alpha tocopherol occurs in concentrations of 0.1-0.3% in
`corn, rapeseed, soybean, sunflower and wheat germ oils.<3l
`Beta tocopherol and gamn1a tocopherol are usually found in
`natural sources along with alpha tocopherol. Racemic
`synthetic tocopherols may be prepared by the condensation
`of the appropriate methylated hydroquinone with racemic
`isophytoJ.('Il
`
`14. Safety
`Tocopherols (vitamin E) occur in many food substances that
`are consumed as part of the normal diet. The daily nutritional
`
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`

`

`requirement has not been clearly defined but is estimated to be
`3-20 mg. Absorption from the gastrointestinal tract is
`dependent upon normal pancreatic function and the presence
`of bile. Tocopherols are widely distributed throughout the
`body with some ingested tocopherol metabolized in the liver;
`excretion of metabolites is via the urine or bile. Individuals
`with vitamin E deficiency are usually treated by oral
`administration of tocopherols although intramuscular and
`intravenous administration may sometimes be used.
`Tocopherols are well tolerated although large oral doses may
`cause diarrhea or other gastrointestinal disturbances. Topical
`application of tocopherols may cause contact dermatitis.
`The use of tocopherols as antioxidants in pharmaceuticals and
`food products is unlikely to pose any hazard to human health
`since the daily intake from such uses is small compared to the
`intake of naturally occurring tocopherols in the diet.
`The WHO has set an acceptable daily intake of tocopherol
`used as an antioxidant at 0.15-2 mg/kg body-weight.<S)
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances·
`and quantity of material handled. Gloves and eye protection
`are recommended.
`·
`
`16. Regulatory Status
`GRAS listed. Accepted in Europe as a food additive. Included
`in the FDA Inactive Ingredients Guide (oral capsules, tablets,
`and topical preparations). Included in nonparenteral medicines
`licensed in the UK.
`
`17. Pharmacopeias
`Aust, Br, Braz, Chin, Cz, Egypt, Eur, Fr, Ger, Gr, Hung, lnd,
`It, Jpn, Neth, Nord, Rom, Rus, Swiss, US and Yug. Also in
`BP Vet.
`Note that the nomenclature for tocopherols and tocopherol
`derivatives is confusing and many pharmacopeias do not
`specify clearly the isomer or form of the tocopherol.
`
`18. Related Substances
`d-Alpha tocopherol; d-alpha tocopheryl acetate; d/-alpha
`tocopheryl acetate; d-alpha tocopheryl acid succinate; d/(cid:173)
`alpha tocopheryl acid succinate; beta tocopherol; delta
`tocopherol; gamma tocopherol; tocopherols excipient.
`d-Alpha tocopherol: C29Hso02
`M o/ecular weight: 430.69
`CAS number: [59-02-9]
`Synonyms: natural alpha tocopherol; ( + )-(2R,4' R,8' R)-2,5, 7,8-
`tetramethyl-2-(4' ,8', 12'-trimethyltridecyl)-6-chromanol; d-o:(cid:173)
`tocopherol; vitamin E.
`Appearance: a practically odorless, clear, yellow or greenish(cid:173)
`yellow colored viscous oil.
`Solubility: practically insoluble in water; soluble in ethanol
`(95%). Miscible with acetone, chloroform, ether and vegetable
`oils.
`Comments: this is the naturally occurring form of alpha
`tocopherol.
`d-Alpha tocopheryl acetate: C31Hs203
`Molecular weight: 472.73
`CAS number: [58-95-7]
`Synonyms: ( + }-(2R,4' R,8' R}-2,5, 7 ,8-tetramethyl-2-( 4',8' ,12'(cid:173)
`trimethyltridecyl)-6-chromanyl acetate; d-o:-tocopheryl acet(cid:173)
`ate; vitamin E.
`Appearance: a practically odorless, clear, yellow or greenish(cid:173)
`yellow colored viscous oil which may solidify in the cold.
`
`Alpha Tocopherol 13
`
`Melting point: 28°C
`Solubility: practically insoluble in water; soluble in ethanol
`(95%). Miscible with acetone, chloroform, ether and vegetable
`oils.
`Specific rotation [o:]n25:
`+ 0.25° (10% w/v solution in chloroform)
`Comments: unstable to alkalis.
`d/-Alpha tocopheryl acetate: C31Hs203
`Molecular weight: 472.73
`CAS number: [7695-91-2]
`Synonyms: ( ± )-3,4-dihydro-2,5, 7 ,8-tetramethyl-2-( 4,8, 12-tri(cid:173)
`methyltridecyl)-2H-1-benzopyran-6-ol acetate; ( ± )(cid:173)
`(2RS,4' RS,8' RS}-2,5, 7 ,8-tetramethyl-2-(4' ,8', 12'-trimethyltri(cid:173)
`decyl)-6-chromanyl acetate; (±)-a-tocopherol acetate; o:(cid:173)
`tocopheroli acetas; a/1-rac-o:-tocopheryl acetate; d/-a-toco-
`. pheryl acetate; vitamin E.
`Appearance: a practically odorless, clear, yellow or greenish(cid:173)
`yellow viscous oil.
`Density: 0.953 gfcm3
`Melting point:-27.5°C
`Refractive index: nn20 = 1.4950-1.4972
`Solubility: practically insoluble in water; freely soluble in
`acetone, chloroform, ethanol, ether and vegetable oils; soluble
`in ethanol (95%}.
`Comments: unstable to alkali. However, unlike alpha toco(cid:173)
`pherol, the acetate is much less susceptible to the effects of air,
`light or ultraviolet light. Alpha tocopherol acetate concentrate,
`a powdered form of alpha tocopherol acetate, is described in
`some pharmacopeias, e.g. BP 1993. The concentrate may be
`prepared by either dispersing alpha tocopherol acetate in a
`suitable carrier such as acacia or gelatin, or by adsorbing alpha
`tocopherol acetate on silicic acid.
`d-Alpha tocopheryl acid succinate: C33Hs40 5
`Molecular weight: 530.8
`CAS number: [4345-03-3]
`Synonyms: (+)-a-tocopherol hydrogen succinate; d-a-toco~
`pheryl acid succinate; vitamin E.
`Appearance: a practically odorless white powder.
`. Melting point: 76-7rC
`Solubility: practically insoluble in water; slightly soluble in
`alkaline solutions; soluble in acetone, ethanol (95%), ether and
`vegetable oils; very soluble in chloroform.
`Comments: unstable to alkalis.
`d/-Alpha tocopheryl acid succinate: C33Hs40 5
`Molecular weight: 530.8
`CAS number: [17407-37-3]
`Synonyms: (±)-a-tocopherol hydrogen succinate; d/-a-toco(cid:173)
`pherol succinate; d/-a-tocopheryl acid succinate; vitamin E.
`Appearance: a practically odorless white crystalline powder.
`Solubility: practically insoluble in water; slightly soluble in
`alkaline solutions; soluble in acetone, ethanol (95%), ether and
`vegetable oils; very soluble in chloroform.
`Comments: unstable to alkalis.
`Beta tocopherol: C2s~02
`Molecular weight: 416.66
`CAS number: [148-03-8]
`Synonyms: cumotocopherol; ( ± )-3,4-dihydro-2,5,8-trimethyl-
`2-( 4,8, 12-trimethyltridecyl)-2H-1-benzopyran-6-ol; 5 ,8-di(cid:173)
`methyltocol; neotocopherol; d/-,8-tocopherol; vitamin E; p(cid:173)
`xylotocopherol.
`Appearance: a pale yellow colored viscous oil.
`Solubility: practically insoluble in water; freely soluble in
`acetone, chloroform, ethanol (95%}, ether and vegetable oils.
`Specific rotation [o:]n20: +6.37°
`
`Page 6 of 23
`
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`

`

`14 Alpha Tocopherol
`
`Comments: less active biologically than alpha tocopherol.
`tocopherol and gamma
`Obtained along with alpha
`tocopherol from natural sources. Beta tocopherol is very
`stable to heat and alkalis and is slowly oxidized by
`atmospheric oxygen.
`Delta tocopherol: C27~02
`Molecular weight: 402.64
`CAS number: [119-13-1]
`Synonyms: ( ± )-3,4-dihydro-2,8-dimethyl-2-( 4,8,12-trimethyl(cid:173)
`tridecyl)-2H-1-benzopyran-6-ol; E309; 8-methyltocol; dl-6-
`tocopherol; vitamin E.
`Appearance: a pale yellow colored viscous oil.
`Solubility: practically insoluble in water; freely soluble in
`acetone, chloroform, ethanol (95%), ether and vegetable oils.
`Comments: occurs naturally as 30% of the tocopherol content
`of soybean oil. Delta tocopherol is said to be the most potent
`antioxidant of the tocopherols.
`Gamma tocopherol: C2s~s02
`Molecular weight: 416.66
`CAS number: [7616-22-0]
`Synonyms: ( ±)-3,4-dihydro-2, 7 ,8-trimethyl-2-( 4,8, 12-tri(cid:173)
`methyltridecyl)-2H-1-benzopyran-6-ol; 7,8-dimethyltocol;
`E308; dl-")'-tocopherol; vitamin E; o-xylotocopherol.
`Appearance: a pale yellow colored viscous oil.
`Melting point:-30°C
`Solubility: practically insoluble in water; freely soluble in
`acetone, chloroform, ethanol (95%), ether and vegetable oils.
`Specific rotation [a]0 20: -2.4° (in ethanol(95%))
`Comments: occurs in natural sources along with alpha and beta
`tocopherol. Gamma tocopherol is biologically less active than
`alpha tocopherol. Very stable to heat and alkalis; slowly
`oxidized by atmospheric oxygen and gradually darkens on
`exposure to light.
`Tocopherols excipient
`Synonyms: Embanox tocopherol.
`Appearance: a pale yellow colored viscous oil.
`Pharmacopeias: USPNF.
`
`Comments: tocopherols excipient is described in the USPNF
`XVII as a vegetable oil solution containing not less than 50.0%
`of total tocopherols, of which not less than 80.0% consists of
`varying amounts of alpha, beta, delta and gamma tocopherols.
`
`19. Comments
`Note that most commercially available tocopherols are used as
`sources of vitamin E rather than as antioxidants in
`pharmaceutical formulations.
`Various mixtures of tocopherols, and mixtures of tocopherols
`with other excipients are commercially available and indivi(cid:173)
`dual manufacturers should be consulted for specific informa(cid:173)
`tion on their products.
`
`20. Specific References
`1. Johnson DM, Gu LC. Autoxidation and antioxidants. In:
`Swarbrick J, Boylan JC, editors. Encyclopedia of pharmaceutical
`technology, volume 1. New York: Marcel Dekker, 1988: 415-450.
`2. Allwood MC. Compatibility and stability of TPN mixtures in big
`bags. J Clin Hosp Pharm 1984; 9: 181-198.
`3. Buck DF. Antioxidants. In: Smith J, editor. Food additive user's
`handbook. Blackie: Glasgow, 1991: 1-46.
`4. Rudy BC, Senkowski BZ. d/-Alpha-tocopheryl acetate. In: Florey
`K, editor. Analytical profiles of drug substances, volume 3. New
`York: Academic Press, 1974: 111-126.
`5. FAO{WHO. Evaluation of certain food additives and contami(cid:173)
`nants. Thirtieth report of the joint FAO[WHO expert committee
`on food additives. Tech Rep Ser Wld Hlth Org 1987; No. 751.
`
`21. General References
`US National Research Council Food and Nutrition Board. Recom(cid:173)
`mended dietary allowances, lOth edition. Washington DC:
`National Academy Press, 1989: 99-105.
`
`22. Authors
`UK: JA Stead.
`
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`

`Ascorbic Acid 15
`
`SEM:l
`Excipient: Ascorbic acid USP (rme powder)
`Manufacturer: P(JZer Ltd
`Lot No.: 9A-3/G92040-CO 146
`Magnification: 120x
`Voltage: 20 kV
`
`Ascorbic Acid
`
`1. Nonproprietary Names
`BP: Ascorbic acid
`PhEur: Acidum ascorbicum
`USP: Ascorbic acid
`
`2. Synonyms
`Cevitamic acid; C-97; 2,3-didehydro-L-threo-hexono-1 ,4-lac(cid:173)
`tone; E300; 3-oxo-L-gulofuranolactone, enol form; vitamin C.
`
`3. Chemical Name and CAS Registry Number
`L-( +)-Ascorbic acid [50-81-7]
`
`4. Empirical Formula
`C~s06
`
`· Molecular Weight
`176.13
`
`5. Structural Formula
`
`6. Functional Category
`Antioxidant; therapeutic agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Ascorbic acid is used as an antioxidant in aqueous
`pharmaceutical formulations at a concentration of 0.01-0.1%
`wjv. It is also widely used in foods as an antioxidant.
`
`SEM:l
`Excipient: Ascorbic acid USP (fine powder)
`Manufacturer: PrJZer Ltd
`Lot No.: 9A-3/G92040-CO 146
`Magnification: 600x
`Voltage: 20 kV
`
`8. Description
`Ascorbic acid occurs as a white to light yellow colored,
`nonhygroscopic, odorless, crystalline powder or colorless
`crystals with a sharp, acidic taste. It gradually darkens in
`color upon exposure to light.
`
`9. Pharmacopeia! Specifications
`
`Test
`Identification
`Specific rotation
`(10% wjv solution)
`Residue on ignition
`Sulfated ash
`Copper
`Heavy metals
`Iron
`Oxalic acid
`Appearance of
`solution
`Assay
`
`PbEur 1984
`
`USPXXU
`
`+
`+20.5" to +21.5"
`
`+
`+ 20.5" to + 21.5"
`
`:!6; 0.1%
`
`:!6; 0.002%
`
`~ 0.1%
`E; 5 ppm
`~ 10 ppm
`E; 2ppm
`+
`+
`
`99.0-100.5%
`
`99.0-100.5%
`
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`
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`

`16 Ascorbic Acid
`
`SEM:3
`Excipient: Ascorbic acid USP (granular)
`Manufacturer: PfJZer Ltd
`Lot No.: 9A-l/G01260-CO 140
`Magnification: 120x
`Voltage: 20 kV
`
`SEM:5
`Excipient: Ascorbic acid USP (fine granular)
`Manufacturer: Pfizer Ltd
`Lot No.: 9A-2/G01280-CO 148
`Magnification: 120x
`Voltage: 20 kV
`
`SEM:4
`Excipient: Ascorbic acid USP (granular)
`Manufacturer: PfJZer Ltd
`Lot No.: 9A-l/G01260-CO 140
`Magnification: 600x
`Voltage: 20 kV
`
`SEM:6
`Excipient: Ascorbic acid USP (fine granular)
`Manufacturer: Pfizer Ltd
`Lot No.: 9A-2/G01280-CO 148
`Magnification: 600x
`Voltage: 20 kV
`
`Page 9 of 23
`
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`
`

`

`10. Typical Properties
`Acidity/ alkalinity:
`pH = 2.1-2.6 (5% wfv aqueous solution)
`Density (bulk):
`0.7-0.9 g/cm3 for crystalline material;
`0.5-0.7 gfcm3 for powder.
`Density {particle): 1.65 gfcm3
`Density (tapfed):
`1.0-1.2 g/cm for crystalline material;
`0.9-1.1 g/cm3 for powder.
`Dissociation constant:
`Pl<.at = 4.17;
`pl<.a2 = 11.57
`Melting point: 19o•c (with decomposition)
`Moisture content: 0.1% wfw
`Particle size distribution: various grades of ascorbic acid with
`different particle size distributions are commercially available.
`See Fig. 1.
`Solubility:
`
`Solvent
`Chloroform
`Ethanol
`Ethanol (95%)
`Ether
`Fixed oils
`Glycerin
`Propylene glycol
`Water
`
`Solubility at 20°C
`practically insoluble
`1 in 50
`1 in 25
`practically insoluble
`practically insoluble
`1 in 100
`I in 20
`1 in 3.5
`
`25
`
`20
`
`15
`
`10
`
`5
`
`-c
`CJ ... Cl) c.
`
`CD
`
`en
`en
`IV
`::E
`
`0 ~----------~~-----~~~--------------------~
`100
`200
`300
`500
`0
`400
`
`Particle size distribution (pm)
`Fig. 1: Particle size distribution of ascorbic acid.
`
`11. Stability and Storage Conditions
`In powder form, ascorbic acid is relatively stable in air. In the
`absence of oxygen and other oxidizing agents it is also heat
`stable. Ascorbic acid is unstable m solution, especially alkaline
`solution, readily undergoing oxidation on exposure to the
`air.<1•2> The oxidation process is accelerated by light and heat
`. and is catalyzed by traces of copper and iron. Aseorbic acid
`solutions exhibit maximum stability at about pH 5.4. Solutions .
`may be sterilized by ftltration.
`
`Ascorbic Acid 17
`
`The bulk material should be stored in a well-closed
`nonmetallic container, protected from light, in a cool, dry,
`place.
`
`12. Incompatibilities
`Incompatible with alkalis, heavy metal ions, especially copper
`and iron, oxidizing materials, methenamine, phenylephrine
`hydrochloride, pyrilamine maleate, salicylamide, sodium
`nitrite, sodium salicylate and theobromine salicylate.<3>
`
`13. Method of Manufacture
`Ascorbic acid is prepared synthetically or extracted from
`various vegetable sources in which it occurs naturally, such as
`rose hips, blackcurrants, the juice of citrus fruits and the ripe
`fruit of Capsicum annuum L. A common synthetic procedure
`involves the hydrogenation ofo-glucose too-sorbitol, followed
`by oxidation using Acetobacter suboxydans to form L-sorbose.
`A carboxyl group is then added at C1 by air oxidation of the
`diacetone derivative of L-sorbose and the resulting diacetone-
`2-keto-t-gulonic acid converted to L-ascorbic acid by heating
`with hydrochloric acid.
`
`14. Safety
`Ascorbic acid is an essential part of the human diet with 40 mg
`the recommended daily dose in the UK<4> and 60 mg in the
`USA.<S) However, these figures are controversial with some
`advocating doses of 150 mg or 250 mg daily. Megadoses of
`10 g daily have also been suggested to prevent illness.<6.7)
`The body can absorb about 500 mg of ascorbic acid daily with
`any excess immediately excreted by the kidneys. Large doses
`may cause diarrhea or other gastrointestinal disturbances.
`Damage to the teeth has also been reported.<8> However, at the
`levels employed as an antioxidant in foods and pharmaceu(cid:173)
`ticals no adverse effects have been reported. The WHO has set
`an acceptable daily intake of ascorbic acid, potassium
`ascorbate and sodium ascorbate, as antioxidants in food, at
`up to 15 mgfkg body-weight in addition to that naturally
`present in food.{9>
`LDso (mouse, IP): 0.64 g/kg<10>
`LDso (mouse, IV): 0.52 g/kg
`LDso (mouse, oral): 3.37 g/kg
`LD50 (rat, oral): 11.9 g/kg
`
`15. Handling Precautions
`May be harmful if ingested in large quantities and may be
`irritating to the eyes. Observe normal precautions appropriate
`to the circumstances and quantity of material handled. 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 (inhalations, injections, ·
`oral capsules, suspensions and tablets). Included in medicines
`licensed in the UK.
`
`17. Pharmacopeias
`Aust, Br, Braz, Chin, Cz, Egypt, Bur, Fr, Ger, Gr, Hung, lnd,
`Int, It, Jpn, Mex, Neth, Nord, Port, Rom, Rus, Swiss, Turk,
`US and Yug. Also in BP Vet.
`
`18. Related Substances
`Ascorbyl Palmitate; Sodium Ascorbate.
`
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`

`18 Ascorbic Acid
`
`19. Comments
`
`20. Specific References
`1. Hajratwala BR. Stability of ascorbic acid. STP Pharma 1985; 1:
`281-286.
`2. Touitou E, Gilhar D, Alhaique F, Memoli A, Riccieri FM,
`Santucci E. Ascorbic acid in aqueous solution: bathochromic
`shift in dilution and degradation. Int J Pharmaceutics 1992; 78:
`85-87.
`3. Botha SA, LOtter AP, du Preez JL. DSC screening for drug-drug
`interactions in polypbarmaceuticals intended for the alleviation
`of the symptoms of colds and flu. Drug Dev Ind Pharm 1987; 13:
`345-354.
`4. Department of Health. Dietary reference values for food energy_
`and nutrients for the United Kihgdom: report of the panel on
`dietary reference values of the committee on medical aspects of
`food policy. Report on health and social subjects 41. London:
`HMSO, 1991.
`5. Subcommittee on the tenth edition of the RDAs, Food and
`Nutrition Board, Commission on Life Sciences, National
`Research Council. Recommended dietary allowances, 1Oth
`edition. Washington, DC: National Academy Press, 1989.
`6. Ovesen L. Vitamin therapy in the absence of obvious deficiency:
`what is the evidence? Drugs 1984; 27: 148-170.
`7. Bates CJ. Is there a maximum safe dose of vitamin C (ascorbic
`acid)? Br Med J 1992; 305: 32.
`8. Giunta JL. Dental erosion resulting from chewable vitamin C
`tablets. JAm DentAssoc 1983; 107: 253-256.
`9. FAO{WHO. Toxicological evaluation of certain food additives
`with a review of general principles and of specifications.
`
`Seventeenth report of the joint FAO{WHO expert committee
`on food additives. Tech Rep Ser Wld Hlth Org 1974; No. 539.
`10. Sweet DV, editor. Registry of toxic effects of chemical
`substances. Cincinnati: US Department of Health, 1987.
`
`21. General References
`· Abramovici B, Molard F, Seguin B, Gromenil JC. Comparative study
`of the tabletability of different grades of vitamin C [in French]. STP
`Pharma 1987; 3: 16-22.
`Allwood MC. Factors influencing the stability of ascorbic acid in total
`parenteral nutrition infusions. J Clin Hosp Pharm 1984; 9: 75-85.
`Bhagavan HN, Wolkoff Bl. Correlation between the disintegration
`time and the bioavailability of vitamin C tablets. Pharm Res 1993;
`10: 239-242.
`Davies MB, Austin J, Partridge DA. Vitamin C- its chemistry and
`biochemistry. London: Royal Society of Chemistry, 1991.
`Martin J, editor. Handbook of pharmacy health education. London:
`The Pharmaceutical Press, 1991: 11-47.
`Saleh SI, Stamm A. Contribution to the preparation of a directly
`compressible L-ascorbic acid granular form: comparison of
`granules prepared by three granulation methods and evaluation
`of their corresponding tablets. STP Pharm.a.1988; 4: 182-187.
`Seta Y, Higuchi F, Otsuka T, Kawahara Y, Nishimura K, Okada R,
`Koike H. Preparation and pharmacological evaluation of Capto(cid:173)
`pril sustained-release dosage forms using oily semisolid matrix. Int
`J Pharmaceutics 1988; 41: 255-262.
`
`22. Authors
`USA: A Abdul-Rahman.
`
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`

`Ascorbyl Palmitate
`
`1. Nonproprietary Names
`BP: Ascorbyl palmitate
`PhEur: Ascorbylis palmitas
`USPNF: Ascorbyl palmitate
`
`2. Synonyms
`L-Ascorbic acid 6-palm.itate; E304; 3-oxo-L-gulofuranolactone
`6-palm.itate; vitamin C palmitate.
`
`3. Chemical Name and CAS Registry Number
`L-Ascorbic acid 6-hexadecanoate [137-66-6]
`
`4. Empirical Formula Molecular Weight
`C22H3s01
`414.54
`
`5. Structural Formula
`
`H-C-OH
`
`0
`
`HO
`
`OH
`
`6. Functional Category
`Antioxidant.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Ascorbyl palmitate is primarily used either alone or in
`combination with alpha tocopherol as a stabilizer for oils in
`oral pharmaceutical formulations and food products. It may
`also be used in oral and topical preparations as an antioxidant
`for drugs unstable to oxygen. The combination of ascorbyl
`palmitate with alpha tocopherol shows marked synergism,
`which increases the effect of the components and allows the
`amount used to be reduced.
`The solubility of ascorbyl palmitate in alcohol permits it to be
`used in nonaqueous and aqueous systems and emulsions.
`
`8. Description
`Ascorbyl palmitate is a practically odorless, white to yellowish
`powder.
`
`Ascorbyl Palmitate 19
`
`9. Pharmacopeia} Specifications
`
`Test
`
`PhEur 1993
`
`USPNFXVII
`
`Identification
`Appearance of solution
`Melting range
`Specific rotation
`(10% wfv in methanol)
`Loss on drying
`Residue on ignition
`Sulfated ash
`Heavy metals
`Assay (dried basis)
`
`+
`+
`
`+
`
`+21° to +24°
`
`107-ll7°C
`+21° to +24°
`
`~ 1.0%
`
`~ 0.1%
`~ 10 ppm
`98.0-100.5%
`
`~ 2.0%
`~ 0.1%
`
`~ 0.001%
`95.0-100.5%
`
`10. Typical Properties
`Solubility:
`
`Solvent
`
`Acetone
`Chloroform
`
`Ethanol
`
`Ethanol (95%)
`Ethanol (50%)
`Ether
`Methanol
`
`Olive oil
`Peanut oil
`Propan-2-ol
`
`Sunflower oil
`Water
`
`Solubility at
`Unless otherwise stated
`
`1 in 15
`1 in 3300
`1 in 11 at 60°C
`lin8
`1 in 1.7 at 70°C
`1 in 9.3
`1 in 2500
`1 in 132
`1 in 5.5
`1 in 1.7 at 60°C
`1 in 3300
`1 in 3300
`1 in 20
`1 in 5 at 70°C
`1 in 3300
`practically insoluble
`1 in 500 at 70°C
`1 in 100 at 100°C
`
`11. Stability and Storage Conditions
`Ascorbyl palmitate is stable in the dry state, but is gradually
`oxidized and becomes discolored when exposed to light and
`high humidity. In an unopened container, stored in a cool
`place, it has a shelf life of at least twelve months. During
`processing, temperatures greater than 65°C should be avoided.
`The bulk material should be stored in an airtight container, in
`a cool, dry place.
`
`12. Incompatibilities
`Incompatibilities are known with oxidizing agents, e.g. in
`solution oxidation is catalyzed by trace metal ions such as
`Cu2+ and Fe3 +.
`
`13. Method of Manufacture
`Ascorbyl palmitate is prepared synthetically by the reaction of
`ascorbic acid with sulfuric acid followed by reesterification
`with palmitic acid.
`
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`20