Handbook of
`,,
`PHARMACEUTICAL
`EXCIPIENTS
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`American Pharmaceutical Association
`Washington
`
`1994
`
`The Pharmaceutical Press
`London
`
`Exhibit 1033
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`© 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, I Lambeth High
`Street, London, SEI 7JN, England.
`
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`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 94-7949b
`
`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
`
`000002
`
`

`

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`Contents v
`
`0
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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
`Carbo mer
`Carbon Dioxide
`Carboxymethylcellulose Calcium
`Carboxymethylcellulose Sodium
`Hydrogenated Castor Oil
`Microcrystalline Cellulose
`Powdered Cellulose
`Cellulose Acetate Phthalate
`Cetostearyl Alcohol
`Cetrimide
`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
`Dibutyl 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 Monooleate
`Glyceryl Monostearate
`Glyceryl Palmitostearate
`Glycofurol
`Guar Gum
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`Hydroxypropyl Cellulose
`Hydroxypropyl Methylcellulose
`Hydroxypropyl Methylcellulose Phthalate
`Iinidurea
`Isobutane
`lsopropyl 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
`Malic Acid
`Maltitol Solution
`Maltodextrin
`Maltol
`Mannitol
`Medium Chain Triglycerides
`Meglumine
`Menthol
`Methylcellulose
`Methylparaben
`Mineral Oil
`Light Mineral Oil
`Mineral Oil and Lanolin Alcohols
`Monoethanolamine
`
`vii
`viii
`ix
`xi
`Xlll
`Xlll
`XIV
`xv
`
`I
`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
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`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
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`319
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`000003
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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. Individual~
`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.<5>
`
`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, Ind,
`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· di-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: C29H5002
`Molecular 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-a(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' -
`trimethyltridecyl)-6-chromanyl acetate; d-a-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.
`25:
`Specific rotation [a]0
`+ 0.25° (10% w/v solution in chloroform)
`Comments: unstable to alkalis.
`di-Alpha tocopheryl acetate: C31 H520 3
`Molecular weight: 472.73
`CAS number: [7695-91-2]
`Synonyms: ( ± )-3,4-dihydro-2,5, 7 ,8-tetramethyl-2-(4,8, l 2-tri(cid:173)
`methyl tri decy l)-2H- l -benzo py ran-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; a(cid:173)
`tocopheroli acetas; a/l-rac-a-tocopheryl acetate; dl-a-toco(cid:173)
`pheryl acetate; vitamin E.
`Appearance: a practically odorless, clear, yellow or greenish(cid:173)
`yellow viscous oil.
`Density: 0.953 g/cm3
`Melting point:-27.5°C
`20 = 1.4950-1.4972
`Refractive index: n0
`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: C33H540s
`Molecular weight: 530.8
`CAS number: [4345-03-3]
`Synonyms: ( + )-a-tocopherol hydrogen succinate; d-a-toco(cid:173)
`pheryl acid succinate; vitamin E.
`Appearance: a practically odorless white powder.
`Melting point: 76-77°C
`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.
`di-Alpha tocopheryl acid succinate: C33H540 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: C2sH4s02
`Molecular weight: 416.66
`CAS number: [148-03-8]
`Synonyms: cumotocopherol; ( ± )-3,4-dihydro-2,5,8-trimethyl-
`2-( 4,8, l 2-trimethyltridecyl)-2H-l-benzopyran-6-ol; 5,8-di(cid:173)
`methyltocol; neotocopherol; dl-,B-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 [ofo 20: + 6.37°
`
`000004
`
`

`

`Benzalkonium Chloride
`
`1. Nonproprietary Names
`BP: Benzalkonium chloride
`PhEur: Benzalkonii chloridum
`USPNF: Benzalkonium chloride
`
`2. Synonyms
`Alkylbenzyldimethylammonium chloride; alkyl dimethyl ben(cid:173)
`zyl ammonium chloride; BKC; Catigene DC JOO; Exameen
`3580; Hyamine 3500; Pentonium; Rocca!; Zephiran.
`
`3. Chemical Name and CAS Registry Number
`Alkyldimethyl(phenylmethyl)ammonium chloride
`[8001-54-5]
`
`4. Empirical Formula Molecular Weight
`The USPNF XVII describes benzalkonium chloride as a
`mixture of alkylbenzyldimethylammonium chlorides of the
`general formula [C6H5CH2N(CH3hR]Cl, where R represents a
`mixture of alkyls, including all or some of the group beginning
`with n-C8H 17 and extending through higher homologs, with n(cid:173)
`C12H25, n-Ct 4H29, and n-C 16H33 comprising the major portion.
`The average molecular weight ofbenzalkonium chloride is 360.
`
`5. Structural Formula
`
`,
`0-Cli,-~'....Rj Cl
`f
`R = mixture of alkyls: n-C8H 17 to n-C 18H 37; mainly n-C12H25
`(dodecyl), n-C 1JI29 (tetradecyl) and n-C 16H33 (hexadecyl).
`
`CH,
`
`CH1
`
`6. Functional Category
`Antimicrobial preservative; antiseptic; disinfectant; solubiliz(cid:173)
`ing agent; wetting agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Benzalkonium chloride is a quaternary ammonium compound
`used in pharmaceutical formulations as an antimicrobial
`preservative in applications similar to other cationic surfac(cid:173)
`tants, such as cetrimide.
`In ophthalmic preparations, benzalkonium chloride is one of
`the most widely used preservatives, at a concentration of 0.01-
`0.02 % w/v. Often it is used in combination with other
`preservatives or excipients, particularly 0.1 % w/v disodium
`edetate, to enhance its antimicrobial activity against strains of
`Pseudomonas.
`
`Benzalkonium Chloride 27
`
`In nasal and otic formulations a concentration of 0.002-0.02%
`is used, sometimes in combination with 0.002-0.005% w/v
`thimerosal. Benzalkonium chloride 0.01 % w/v is also
`employed as a preservative in small volume parenteral
`products.
`Benzalkonium chloride is additionally used as a preservative in
`cosmetics.
`
`8. Description
`Benzalkonium chloride occurs as a white or yellowish white
`amorphous powder, a thick gel, or gelatinous flakes. It is
`hygroscopic, soapy to the touch and has a mild aromatic odor
`and very bitter taste.
`
`9. Pbarmacopeial Specifications
`
`Test
`
`Identification
`Acidity or alkalinity
`Appearance of solution
`Water
`Residue on ignition
`Sulfated ash
`Water-insoluble matter
`Foreign amines
`Ratio of alkyl components
`Assay (dried basis)
`of n-C12H25
`of n-C14H29
`of 11-C12H2s & 11-C14H29
`for total alkyl content
`
`PhEur 1985
`+
`+
`+
`""' 10.0%
`
`""' 0.1%
`
`+
`
`95.0-104.0%
`
`USPNF XVII
`+
`
`""' 15.0%
`""'2.0%
`
`+
`+
`+
`
`;;;, 40.0%
`;;;, 20.0%
`;;;, 70.0%
`97.0-103.0%
`
`10. Typical Properties
`Acidity/alkalinity:
`pH = 5-8 for a 10% w/v aqueous solution.
`Antimicrobial activity : benzalkonium chloride solutions are
`active against a wide range of bacteria, yeasts and fungi.
`Activity is more marked against Gram-positive than Gram(cid:173)
`negative bacteria and minimal against bacterial endospores
`and acid fast bacteria. The antimicrobial activity of benzalk(cid:173)
`onium chloride is significantly dependent upon the alkyl
`composition of the homolog mixture.< 1l Benzalkonium
`chloride is ineffective against some Pseudomonas aeruginosa
`strains, Mycobacterium tuberculosis, Trichophyton interdigitale
`and T. rubrum. However, combined with disodium edetate
`(0.01-0.l % w/v), benzyl alcohol, phenylethanol or phenylpro(cid:173)
`panol, the activity against Pseudomonas aeruginosa is
`increased.<2l Antimicrobial activity may also be enhanced by
`the addition of phenylmercuric acetate,Ehenylmercuric borate,
`chlorhexidine, cetrimide or m-cresol. < .4J In the presence of
`citrate and phosphate buffers (but not borate), activity against
`Pseudomonas can be reduced. See also Sections 11 and 12.
`Benzalkonium chloride is relatively inactive against spores and
`molds, but is active against some viruses, including Hiv.<5l
`Inhibitory activity increases with pH although antimicrobial
`activity occurs between pH 4- 10. Typical minimum inhibitory
`concentrations (MICs) are shown in Table I .
`
`000005
`
`

`

`28 Benzalkonium Chloride
`
`Table I: Minimum inhibitory concentrations (MICs) of benzalkonium
`chloride.
`
`Microorganism
`
`MIC (µg/mL)
`
`Aerobacter oerogenes
`Clos1ridium histolyticum
`Clostridium oedema1iens
`Clostridium tetani
`Clostridium welchii
`Escherichia coli
`Pneumococcus II
`Proteus vulgaris
`Pseudomonas aeruginosa
`Salmonella enteritidis
`Salmonella paratyphi
`Salmonella typhosa
`Shigella dysenteriae
`Staphylococcus aureus
`Screptococcus pyrogenes
`Vibrio cholerae
`
`64
`5
`5
`5
`5
`16
`5
`64
`30
`30
`16
`4
`2
`l.25
`1.25
`2
`
`Density: ~ 0.98 g/cm3 at 20°C
`Melting point: ~ 40°C
`Partition coefficients: the octanol: water partition coefficient
`varies with the alkyl chain length of the homolog; 9.98 for C 12,
`32.9 for C 14 and 82.5 for C 16.
`Solubility: practically insoluble in ether; very soluble in
`acetone, ethanol (95%), methanol, propanol and water.
`Aqueous solutions of benzalkonium chloride foam when
`shaken, have a low surface tension and possess detergent and
`emulsifying properties.
`
`11. Stability and Storage Conditions
`Benzalkonium chloride is hygroscopic and may be affected by
`light, air and metals.
`Solutions are stable over a wide pH and temperature range and
`may be sterilized by autoclaving without loss of effectiveness.
`Solutions may be stored for prolonged periods at room
`temperature. Dilute solutions stored in polyvinyl chloride or
`polyurethane foam containers may lose antimicrobial activity.
`The bulk material should be stored in an airtight container,
`protected from light and contact with metals, in a cool, dry,
`place.
`
`12. Incompatibilities
`Incompatible with aluminum, anionic surfactants, citrates,
`cotton, fluorescein, hydrogen peroxide, hydroxypropyl
`methylcellulose,<6l iodides, kaolin, lanolin, nitrates, nonionic
`surfactants in high concentration, permanganates, protein,
`salicylates, silver salts, soaps, sulfonamides, tartrates, zinc
`oxide, zinc sulfate, some rubber mixes and some plastic mixes.
`
`13. Method of Manufacture
`Benzalkonium chloride is formed by the reaction of a solution
`of N-alkyl-N-methyl-benzamine with methyl chloride in an
`organic solvent suitable for precipitating the quaternary
`compound as it is formed.
`
`14. Safety
`Benzalkonium chloride is usually nonirritating, nonsensitizing
`and well tolerated in the dilutions normally employed on the
`skin and mucous membranes. However, benzalkonium
`
`chloride has been associated with adverse effects when used
`in some pharmaceutical formulations.(7)
`Ototoxicity can occur when benzalkonium chloride is applied
`to the ear<8l and prolonged contact with the skin can
`occasionally cause irritation and hypersensitivity. Benzalk(cid:173)
`onium chloride is also known to cause bronchoconstriction in
`some asthmatics when used in nebulizer solutions.<9- 13l
`Toxicity experiments with rabbits have shown benzalkonium
`chloride, in concentrations higher than that normally used as a
`preservative, to be harmful to the eye. However, the human
`eye appears to be less affected than the rabbit eye and many
`ophthalmic products have been formulated with benzalkonium
`chloride 0.01 % w/v as the preservative. Benzalkonium chloride
`is not suitable for use as a preservative in solutions used for
`storing and washing hydrophilic soft contact lenses, as the
`benzalkonium chloride can bind to the lenses and may later
`produce ocular toxicity when the lenses are worn.< 14l Solutions
`stronger than 0.03% w/v concentration entering the eye
`require prompt medical attention.
`Local irritation of the throat, esophagus, stomach and
`intestine can occur following contact with strong solutions
`( > 0.1 % w/v). The fatal oral dose of benzalkonium chloride in
`humans is estimated to be 1-3 g. Adverse effects following oral
`ingestion include vomiting, collapse and coma. Toxic doses
`lead to paralysis of the respiratory muscles, dyspnea and
`cyanosis.
`LD 50 (guinea pig, oral): 200 mg/kg< 15l
`LD50 (mouse, IP): 10 mg/kg
`LD50 (mouse, IV): 10 mg/kg
`LD 50 (mouse, oral): 175 mg/kg
`LD 50 (mouse, SC): 64 mg/kg
`LD 50 (rat, IP): 14.5 mg/kg
`LD50 (rat, IV): 13.9 mg/kg
`LD 50 (rat, oral): 240 mg/kg
`LD 50 (rat, SC): 400 mg/kg
`LD50 (rat, skin): 1.56 g/kg
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Benzalkonium chloride is
`irritant to the skin and eyes and repeated exposure to the skin
`may cause hypersensitivity. Concentrated benzalkonium
`chloride solutions accidentally spilled on the skin may
`produce corrosive skin lesions with deep necrosis and
`scarring, and should be washed immediately with water,
`followed by soap solutions applied freely. Gloves, eye
`protection and suitable protective clothing should be worn.
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (inhalations,
`IM injections, nasal, ophthalmic, otic and topical prepara(cid:173)
`tions). Included in nonparenteral medicines licensed in the
`UK.
`
`17. Pharmacopeias
`Aust, Br, Braz, Egypt, Eur, Fr, Gr, Hung, It, Jpn, Mex, Neth,
`Port, Swiss, Turk, Yug and USPNF. Also in BP Vet.
`
`18. Related Substances
`
`Benzethonium Chloride; Cetrimide.
`
`19. Comments
`
`000006
`
`

`

`20. Specific References
`I. Euerby MR. High performance liquid chromatography of
`benzalkonium chlorides -
`variation in commercial prepara(cid:173)
`tions. J Clin Hosp Pharm 1985; 10: 73-77.
`2. Richards RME, McBride RJ. Enhancement of benzalkonium
`chloride and chlorhexidine acetate activity against Pseudomonas
`aeruginosa by aromatic alcohols. J Pharm Sci 1973; 62: 2035-
`2037.
`3. Hugbo PG. Additivity and synergism in vitro as displayed by
`mixtures of some commonly employed antibacterial preserva(cid:173)
`tives. Can J Pharm Sci 1976; 11: 17-20.
`4. McCarthy TJ, Myburgh JA, Butler N. Further studies on the
`influence of formulation on preservative activity. Cosmet Toilet
`1977; 92(3): 33-36.
`5. Chermann JC, Barre-Sinoussi F, Henin Y, Marechal V. HIV
`inactivation by a spermicide containing benzalkonium. AIDS
`Forsch 1987; 2: 85-86.
`6. Richards RME. Effect of hypromellose on the antibacterial
`activity of benzalkonium chloride. J Phann Pharmacol 1976; 28:
`264.
`7. Smolinske SC. Handbook of food, drug, and cosmetic excipients.
`Boca Raton, FL: CRC Press Inc, 1992: 31-39.
`8. Honigman JL. Disinfectant ototoxicity Detter]. Pharm J 1975;
`215: 523.
`9. Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor
`properties of preservatives in ipratropium bromide (Atrovent)
`nebuliser solution. Br Med J 1987; 294: 1197-ll98.
`10. Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The
`contribution of histamine release to bronchoconstriction pro(cid:173)
`voked by inhaled benzalkonium chloride in asthma. Br J Clin
`Pharmacol 1988; 25 : 157-163.
`11. Miszkiel KA, Beasley R, Holgate ST. The influence of
`ipratropium bromide and sodium cromoglycate on benzalko(cid:173)
`nium chloride-induced bronchoconstriction in asthma. Br J Clin
`Pharmacol 1988; 26: 295-301.
`12. Worthington I. Bronchoconstriction due to benzalkonium
`chloride in nebulizer solutions. Can J Hosp Phann 1989; 42:
`165-166.
`13. Boucher M, Roy MT, Henderson J. Possible association of
`
`Benzalkonium Chloride 29
`
`benzalkonium chloride in nebulizer solutions with respiratory
`arrest. Ann Pharmacother 1992; 26: 772-774.
`14. Gasset AR. Benzalkonium chloride toxicity to the human cornea.
`Am J Ophthalmol 1977; 84: 169-171.
`15. Sweet DV, editor. Registry of toxic effects of chemical
`substances. Cincinnati: US Department of Health, 1987.
`
`21. General References
`Cowen RA, Steiger B. Why a preservative system must be tailored to a
`specific product. Cosmet Toilet 1977; 92(3): 15-20.
`El-Fa!aha BMA, Rogers DT, Furr JR, Russell AD. Surface changes in
`Pseudomonas aeruginosa exposed to chlorhexidine diacetate and
`benzalkoniurn chloride. Int J Pharmaceutics 1985; 23: 239-243.
`El-Falaha BMA, Russell AD, Furr JR, Rogers DT. Activity of
`benzalkonium chloride and chlorhexidine diacetate against wild(cid:173)
`type and envelope mutants of Escherichia coli and Pseudomonas
`aeruginosa. Int J Pharmaceutics 1985; 23: 239-243.
`Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation of
`preservative efficacy III: the determination of antimicrobial
`characteristics of benzalkoniurn chloride. Int J Pharmaceutics
`1988; 46: 141-147.
`Lien EJ, Perrin JH. Effect of chain length on critical rnicelle formation
`and protein binding of quaternary ammonium compounds. J Med
`Chem 1976; 19: 849-850.
`Martin AR. Anti-infective agents. Jn: Doerge RF, editor. Wilson and
`Gisvold's textbook of organic, medicinal and pharmaceutical
`chemistry. Philadelphia: J.B. Lippincott Company, 1982: 141-142.
`Pense AM, Vauthier C, Puisieux F, Benoit JP. Microencapsulation of
`benzalkonium chloride. Int J Pharmaceutics 1992; 81: 111-117.
`Prince HN, Nonemaker WS, Norgard RC, Prince DL. Drug resistance
`studies with topical antiseptics. J Pharm Sci 1978; 67: 1629-1631.
`Wallhausser KH . Benzalkonium chloride. Jn: Kabara JJ, editor.
`Cosmetic and drug preservation principles and practice. New York:
`Marcel Dekker Inc, 1984: 731-734.
`
`22. Authors
`USA: NM Vemuri.
`
`000007
`
`

`

`used to absorb wound exudate or transepidermal water and
`sweat.
`Carboxymethylcellulose sodium is also used in cosmetics,
`toiletries<6l and food products.
`
`Use
`
`Emulsifying agent
`Gel-forming agent
`Injections
`Oral solutions
`Tablet binder
`
`Concentration(%)
`
`0.25-J.O
`4.0-6 .0
`0.05-0.75
`0.1-1.0
`1.0-6.0
`
`8. Description
`Carboxymethylcellulose sodium occurs as a white to almost
`white colored, odorless, granular powder. See also Section 19.
`
`9. Pbarmacopeial Specifications
`
`Test
`
`Identification
`pH (I% w/v solution)
`Appearance of solution
`Viscosity
`Loss on drying
`Heavy metals
`Chloride
`Sodium glycolate
`Sulfated ash
`Assay (of sodium)
`
`PhEur 1986
`
`+
`6.0-8.0
`+
`+
`,,;; 10.0%
`,,;; 20 ppm
`,,;; 0.25%
`,,;; 0.4%
`20.0-33.3%
`6.5-10.8%
`
`USP XXII
`(Suppl 8)
`+
`6.5-8.5
`
`+
`,,;; 10.0%
`,,;; 0.004%
`
`6.5-9.5%
`
`SEM: 1
`Excipient: Carboxymethylcellulose sodium
`Manufacturer: Buckeye Cellulose Corp
`Lot No.: 9247 AP
`Magnification: l20x
`Voltage: JO kV
`
`78 Carboxymethylcellulose Sodium
`
`Carboxymethylcellulose
`Sodium
`
`1. Nonproprietary Names
`BP: Carmellose sodium
`PhEur: Carboxymethylcellulosum natricum
`USP: Carboxymethylcellulose sodium
`
`2. Synonyms
`Akucell; Blanose; Ceko/; cellulose gum; CMC sodium;
`Courlose; E466; Nymcel; SCMC; sodium carboxymethylcellu(cid:173)
`lose; sodium cellulose glycolate; sodium CMC; Tylose CB.
`
`3. Chemical Name and CAS Registry Number
`Cellulose, carboxymethyl ether, sodium salt [9004-32-4]
`
`4. Empirical Formula Molecular Weight
`The USP XXII describes carboxymethylcellulose sodium as
`the sodium salt of a polycarboxymethyl ether of cellulose.
`Typical molecular weight is 90 000-700 000.
`
`5. Structural Formula
`
`CH20CH2C00Na
`
`OH
`
`0
`
`0
`
`OH
`
`CH,OCH,COONa
`
`Structure shown with a degree of substitution (DS) of 1.0.
`
`6. Functional Category
`Coating agent; tablet and capsule disintegrant; tablet binder;
`stabilizing agent; suspending agent; viscosity-increasing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Carboxymethylcellulose sodium is widely used in oral and
`topical pharmaceutical formulations primarily for its viscosity(cid:173)
`increasing properties. Viscous aqueous solutions are used to
`suspend powders intended for either topical application or oral
`and parenteral administration.< 1> Carboxymethylcellulose
`sodium may also be used as a tablet binder and disinte(cid:173)
`grant,<Z-4) and to stabilize ernulsions.<5>
`Higher concentrations, usually 4-6%, of the medium viscosity
`grade is used to produce gels which can be used as the base for
`applications and pastes; glycerin is often included in such gels
`to prevent drying out. Carboxyrnethylcellulose sodium is
`additionally one of the main ingredients of self adhesive
`ostomy, wound care and dermatological patches where it is
`
`000008
`
`

`

`SEM:2
`Excipient: Carboxymethylcellulose sodium
`Manufacturer: Huckeye Cellulose Corp
`Lot No.: 9247 AP
`Magnification: 600x
`Voltage: 10 kV
`
`SEM:4
`Excipient: Carboxymethykellulose sodium
`Manufacturer: Hercules Ltd
`Lot No.: 21 A-1 (44390)
`Magnification: 600x
`Voltage: 20 kV
`
`Carboxyme1hyLce!/ulose Sodium 79
`
`SEM:3
`Excipient: Carboxymethylcellulose sodium
`Manufacturer: Hercules Ltd
`Lot No.: 21 A-1 (44390)
`Magnification: 120x
`Voltage: 20 kV
`
`10. Typical Properties
`Densily (bulk): 0.75 g/cm3
`Dissociation constant: pK3 = 4.30
`Melting point: browns at approximately 227°C, chars at
`approximately 252°C.
`Moisture content: typically, contains less than 10% of water.
`However, carboxymetbylcellulose sodium is hygroscopic and
`absorbs significant amounts of water at temperatures up to
`37°C at relative humidities of about 80%. See also HPE Data
`and Section 11.
`SoLubi!it]: practically insoluble in acetone, ethanol, ether and
`toluene. Easily dispersed in water at all temperatures, forming
`clear, colloidal solutions. The aqueous solubility varies with
`the degree of substitution (DS). See Section 19.
`Viscosity: various grades of carboxymethylcellulose sodium
`are commercially available which have differing aqueous
`viscosities; aqueous 1 % w/v solutions with viscosities of
`5-4000 mPa s (5-4000 cP) may be obtained. An increase in
`concentration results in an increase in aqueous solution
`viscosity.<6l Viscosities of various grades of carboxymethyl(cid:173)
`cellulose sodium are shown in Table I. See also Section 11 .
`
`Table I: Viscosity of aqueous carboxymethylcellulose sodium solutions at
`25°C.
`
`Grade
`
`Concentration
`(% w/v)
`
`Low viscosity
`Medium viscosity
`High viscosity
`
`4
`2
`I
`
`Viscosity
`(mPa s)
`
`50-200
`400-800
`1500-3000
`
`000009
`
`

`

`80 Carboxymethylcellulose Sodium
`
`HPE Laboratory Project Data
`
`Method
`
`MC-10
`MC-7
`EMC-I
`
`Lab#
`
`Results
`
`10
`5
`10
`
`8.5%
`6.5%
`See Fig. l.
`
`Moisture content
`Moisture content
`Moisture content
`
`Supplier: Hercules Ltd (Lot #76493).
`
`50
`
`40
`
`(.)
`
`N
`
`0 .,.,
`co
`~ 30
`=>
`'iii
`·5
`E
`E
`=>
`
`20 g
`·5
`CT w
`-;f!.
`0
`
`10
`
`0
`I
`I
`A
`rt
`1-. if
`_ / ~
`~ u
`
`II'"'\
`
`~
`
`(y u
`
`The bulk material should be stored in a well-closed container
`in a cool, dry, place.
`
`12. Incompatibilities
`Carboxymethylcellulose sodium is incompatible with strongly
`acidic solutions and with the soluble salts of iron and some
`other metals, such as aluminum, mercury and zinc; it is also
`incompatible with xanthan gum. Precipitation can occur al
`pH < 2 and when mixed with ethanol (95%).
`Carboxymethylcellulose sodium also forms complex coacer(cid:173)
`vates with gelatin and pectin. It additionally forms a complex
`with collagen and is capable of precipitating certain positively
`charged proteins.
`
`13. Method of Manufacture
`Alkali cellulose is prepared by steeping cellulose obtained from
`wood pulp or cotton fibres in sodium hydroxide solution. The
`alkali cellulose is then reacted with sodium monochloroacetate
`to produce carboxymethylcellulose sodium. Sodium chloride
`and sodium glycolate are obtained as by-products of this
`etherification.
`
`14. Safety
`Carboxymethylcellulose sodium is used in oral, topical and
`some parenteral formulations. It is also widely used in
`cosmetics, toiletries and food products and is generally
`regarded as a nontoxic and nonirritant material. However,
`oral consumption of large amounts of carboxymethylcellulose
`sodium can have a laxative effect; therapeutically 4-10 g, in
`daily divided doses, of the medium and high viscosity grades of
`carboxymethylcellulose sodium have been used a bulk
`laxatives.
`The WHO has not specified an acceptable daily intake for
`carboxymethylcellulose sodium as a food additive since the
`levels necessary to achieve a desired effect were not considered
`to be a hazard to health_C9l
`In animal studies, subcutaneous administration of carboxy(cid:173)
`methylcellulose sodium has been found to cause inflammation
`and in some cases of repeated injection fibrosarcomas have
`been found at the injection site.cior
`Hypersensitivity and anaphylactic reactions have occurred in
`cattle and horses which have been attributed to carboxy(cid:173)
`methylcellulose sodium in parenteral formulations such as
`12
`vaccines and penicillins.(J 1
`•
`)
`LD 50 (guinea pig, oral): 16 g/kg< 13l
`LD50 (mouse, oral): > 27 gfkg
`LD 50 (rabbit, oral): > 27 g/kg
`LD 50 (rat, oral): 27 g/kg
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Carboxymethylcellulose
`sodium may be irritant to the eyes. Eye protection is
`recommended.
`
`16. Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included
`in the FDA Inactive Ingredients Guide (dental preparations,
`inhalations, intra-articular, intrabursal, intradermal, intrale(cid:173)
`sional, IM, intrasynovial and SC injections, oral capsules,
`drops, solutions, suspensions, syrups and tablets, topical and
`vaginal preparations). Included in nonparenteral medicines
`licensed in the UK.
`
`0
`
`1 0
`
`20
`
`70
`60
`50
`40
`30
`% Relative humidity
`
`80
`
`90 100
`
`Fig. 1: Equilibrium moisture content of carboxymethylcellulose
`sodium.
`
`11. Stability and Storage Conditions
`Carboxymethylcellulose sodium is a stable, though hygro(cid:173)
`scopic material. Under high humidity conditions carboxy(cid:173)
`methylcellulose sodium can absorb a large quantity ( > 50%)
`of water. In tablets, this has been associated with a decrease in
`tablet hardness and an increase in disintegration timeOl
`Aqueous solutions are stable between pH 2-10; below pH 2
`precipitation can occur while above pH 10 solution viscosity
`rapidly decreases. Generally, solutions exhibit maximum
`viscosity and stability at pH 7-9.
`Carboxymethylcellulose sodium may be sterilized in the dry
`state by maintaining it at a temperature of 160°C for 1 hour.
`However, this process results in a significa