CeltelTete)¢ rej
`Pharmaceutical
`-
`Excipients
`
`Fifth Edition |
`
`PGR2023-00043
`
`ogee C Rowe,Paul J Sheskey —
`1ere
`
`Edited by
`
`and Sian C Owen
`
`Accord Exhibit 1032
`Page 1 of 9
`PGR2023-00043
`
`

`

`Handbookof
`Pharmaceutical Excipients
`
`FIFTH EDITION
`
`Edited by
`
`Raymond C Rowe
`BPharm, PhD, DSc, FRPharmS, CChem,
`
`FRSC, CPhys, MinstP
`
`ChiefScientist
`
`Intelligensys Ltd
`Billingham, UK
`
`PaulJ Sheskey
`BSc, RPh
`
`Technical Services Leader
`
`The Dow Chemical Company
`Midland
`MI, USA
`
`Sian C Qwen
`BSc, MA
`
`DevelopmentEditor
`Royal Pharmaceutical Society of GreatBritain
`London, UK
`
`
`PP)
`
`Pharmaceutical Press
`
`london e Chicago
`
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`Page 2 of 9
`PGR2023-00043
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`

`

`NCE
`
`Published by the PharmaceuticalPress
`Publications division of the Royal Pharmaceutical Society of GreatBritain
`
`1 Lambeth High Street, London SE1 7JN, UK
`160 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
`
`(PP) 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. Nopart of this publication may be
`reproduced,stored in a retrieval system, or transmitted in any
`form or by any means, withoutthe 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 acceptany legal responsibility or
`liability for any errors or omissions that may be made.
`
`A catalogue record for this bookis available from the British Library
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients—Sth ed. / edited by Raymond C.
`Rowe,Paul J. Sheskey, Sian 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, RaymondC.Il. Sheskey, Paul J. III. Owen,Sian C.
`IV, American Pharmacists Association.
`
`RS201.E87H36 2006
`615'.19-de22
`
`2005028523
`
`Accord Exhibit 1032
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`PGR2023-00043
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`

`

`=
`
`INTENT
`
`Hypromellose
`
`
`
`1 Nonproprietary Names
`BP: Hypromellose
`JP: Hydroxypropylmethylcellulose
`PhEur: Hypromellosum
`USP: Hypromellose
`
`2 Synonyms
`hydroxypropyl methylcellulose;
`Benecel MHPC; E464;
`HPMC; Methocel; methylcellulose propylene glycol ether;
`methyl hydroxypropylcellulose; Metolose; Tylopur.
`
`3 Chemical Name and CASRegistry Number
`Cellulose hydroxypropyl methyl ether
`[9004-65-3]
`
`4 Empirical Formula and Molecular Weight
`The PhEur 2005 describes hypromellose as a partly O-
`methylated and O-(2-hydroxypropylated) cellulose. It is avail-
`able in several grades that vary in viscosity and extent of
`substitution. Grades may be distinguished by appending a
`numberindicative of the apparent viscosity, inmPas, of a 2%
`w/w aqueous solution at 20°C. Hypromellose defined in the
`USP 28 specifies the substitution type by appendinga four-digit
`numberto the nonproprietary name: e.g., hypromellose 1828.
`Thefirst two digits refer to the approximate percentage content
`of the methoxy group (OCH3). The second twodigits refer to
`the approximate percentage content of the hydroxypropoxy
`group (OCH,CH(OH)CHs), calculated on a dried basis. It
`contains methoxy and hydroxypropoxy groups conforming to
`the limits for the types of hypromellose stated in Table I.
`Molecular weight is approximately 10 000-1 500000. The JP
`2001 includes three separate monographs for hypromellose:
`hydroxypropylmethylcellulose 2208, 2906, and 2910, respec-
`tively.
`
`g
`
`.
`
`Structural Formula
`
`CH,OR
`
`OR
`
`1
`
`OR
`
`CH,OR
`
`where R is H, CH3, or CH3CH(OH)CH)
`
`Functional Category
`for
`rate-controlling polymer
`Coating agent;
`film-former;
`sustained release; stabilizing agent; suspending agent; tablet
`binder; viscosity-increasing agent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Hypromellose is widely used in oral, ophthalmic and topical
`pharmaceutical formulations.
`In oral products, hypromellose is primarily used as a tablet
`binder,” in film-coating,?-”) and as a matrix for use in
`extended-release
`tablet
`formulations.°“) Concentrations
`between 2% and 5% w/w may be used as a binderin either
`wet- or dry-granulation processes. High-viscosity grades may
`be usedto retard the release of drugs from a matrix at levels of
`10-80%w/w in tablets and capsules.
`Depending upon the viscosity grade, concentrations of
`2-20% wiw are used for film-forming solutions to film-coat
`tablets. Lower-viscosity grades are used in aqueousfilm-coating
`solutions, while higher-viscosity grades are used with organic
`solvents. Examples of film-coating materials that are commer-
`cially available include AnyCoat C, Spectracel, and Pharma-
`coat.
`Hypromellose is also used as a suspending and thickening
`agentin topical formulations. Compared with methylcellulose,
`hypromellose produces aqueous solutions of greater clarity,
`with fewer undispersedfibers present, and is therefore preferred
`in formulations for ophthalmic use. Hypromellose at concen-
`trations between 0.45-1.0% w/w maybe added as a thickening
`agent to vehicles for eye drops andartificial tear solutions.
`Hypromellose is also used as an emulsifier, suspending
`agent, andstabilizing agentin topical gels andointments. As a
`protective colloid, it can prevent droplets and particles from
`coalescing or agglomerating, thus inhibiting the formation of
`,,.sediments.
`In addition, hypromellose is used in the manufacture of
`capsules, as an adhesive in plastic bandages, and as a wetting
`agentfor hard contactlenses.It is also widely used in cosmetics
`and food products.
`
`8 Description
`Hypromellose is an odorless and tasteless, white or creamy-
`white fibrous or granular powder. See also Section 10.
`
`9 Pharmacopeial Specifications
`See Table I.
`
`‘Typical Properties
`10
`5.5-8.0 for a 1% w/w aqueous
`Acidity/alkalinity: pH =
`solution.
`Ash: 1.5-3.0%, depending upon the grade andviscosity.
`Autoignition temperature: 360°Cc
`Density (bulk): 0.341 g/cm?
`Density (tapped): 0,557 g/em?
`Density (true): 1.326 g/cm?
`Melting point: browns at 190-200°C; chars at 225—230°C.
`Glass transition temperature is 170-180°C.
`Moisture content: hypromellose absorbs moisture from the
`atmosphere; the amount of water absorbed depends upon
`the initial moisture content and the temperature andrelative
`humidity of the surroundingair. See Figure1.
`
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`

`348
`
`Hypromellose
`
`using organic solvents tend to be more viscous; increasing
`concentration also produces more viscous solutions; see
`Table II.
`
`Typical viscosity values for 2% (w/v) aqueous solutions of
`Table Il:
`Methocel (Dow Chemical Co.). Viscosities measured at 20°C.
`
`Methocel product
`
`Nominalviscosity
`USP 28
`designation (mPas)
`Methocel K100 Premium LVEP 2208
`100
`Methocel K4M Premium
`2208
`4000
`14 Safety
`Methocel KISM Premium
`2208
`15000
`Methocel KIO0M Premium
`2208
`100.000
`Hypromellose is widely used as an excipient in oral and topical
`Methocel EAM Premium
`2910
`4000
`pharmaceutical formulations. It
`is also used extensively in
`Methocel F50 Premium
`2906
`50
`cosmetics and food products.
`
`Methocel ETOM Premium CR=2906 10000
`Hypromellose is generally regarded as a nontoxic and
`Methocel E3 Premium LV
`2906
`3
`nonirritant material, although excessive oral consumption may
`Methocel E5 Premium LY
`2906
`5
`have a laxative effect.“*) The WHO has not specified an
`Methocel E6 Premium LV
`2906
`6
`acceptable daily intake for hypromellose since the levels
`Methocel E15 Premium LY
`2906
`15
`consumed were not considered to represent a hazard to
`Methocel E50 Premium LV
`2906
`50
`health.)
`Melolose 60SH
`2910
`50, 4000, 10000
`LDso (mouse,IP): 5 g/kg't®
`Metolose 65SH
`2906
`50, 400, 1500, 4000
`LDso(rat, IP): 5.2 g/kg
`Metolose 90SH
`2208
`100, 400, 4000, 15000
`
`13. Methed of Manufacture
`
`A purified form ofcellulose, obtained from cotton linters or
`wood pulp,
`is reacted with sodium hydroxide solution to
`produce a swollen alkali cellulose that is chemically more
`reactive than untreated cellulose. The alkali cellulose is then
`treated with chloromethane and propylene oxide to produce
`methyl hydroxypropy! ethers of cellulose. The fibrous reaction
`productis then purified and groundtoa fine, uniform powder
`or granules.
`
`TIT
`
`To prepare an aqueoussolution, it is recommended that
`hypromelloseis dispersed and thoroughly hydrated in about
`20-30% of the required amountof water. The water should
`be vigorously stirred and heated to-80-90°C,
`then the
`remaining hypromellose should be added. Sufficient cold
`water should then beadded to produce the required volume.
`When a water-miscible organic solvent such as ethanol
`(95%), glycol, or mixtures of ethanol and dichloromethane
`are used, the hypromellose shouldfirst be dispersed into the
`organic solvent, at a ratio of 5-8 parts of solvent to 1 partof
`hypromellose. Cold water is then added to produce the
`required volume.
`a7
`
`is
`
`Stability and Storage Conditions
`11
`Hypromellose powder is a stable material, although it
`hygroscopic after drying.
`Solutions are stable at pH 3-11. Increasing temperature
`reduces the viscosity of solutions. Hypromellose undergoes a
`reversible sol-gel transformation upon heating and cooling,
`respectively. The gel point is 50-90°C, depending upon the
`grade and concentration of material.
`Aqueous solutions are comparatively enzyme-resistant
`providing goodviscosity stability during long-term storage."13)
`However, aqueous solutions are liable to microbial spoilage
`and should be preserved with an antimicrobial preservative:
`when hypromellose is used as a viscosity-increasing agent in
`ophthalmic solutions,
`.benzalkonium chloride is commonly
`used as the preservative. Aqueous solutions may also be
`sterilized by autoclaving;
`the coagulated polymer must be
`redispersed on cooling by shaking.
`Hypromellose powder should be stored in a well-closed
`container, in a cool, dry place.
`
`Incompatibilities
`12
`Hypromellose is incompatible with some oxidizing agents.
`Since it
`is nonionic, hypromellose will not complex with
`metallic salts or ionic organics to form insoluble precipitates.
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Hypromellose dust may be
`irritant
`to the eyes and eye protection is recommended.
`Excessive dust generation should be avoided to minimize the
`risks of explosion. Hypromellose is combustible.
`
`oe
`
`16 Regulatory Status
`GRASlisted. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Guide (ophthalmic
`preparations; oral capsules, suspensions, syrups, and tablets;
`topical and vaginal preparations). Included in nonparenteral
`medicines licensed in the UK. Included in the CanadianList of
`Acceptable Non-medicinalIngredients.
`
`17 Related Substances
`
`Hydroxyethy! cellulose; hydroxyethylmethyl cellulose; hydr-
`oxypropylcellulose; hypromellose phthalate; methylcellulose.
`
`18 - Comments
`
`Powdered or granular, surface-treated grades of hypromellose
`are also available that are dispersible in cold water. These are
`not recommendedfororal use. A specification for hypromellose
`is contained in the Food Chemicals Codex (FCC).
`
`Specific References
`19
`1 Chowhan ZT. Role of binders in moisture-induced hardness
`increase in compressed tablets andits effect on in vitro disintegra-
`tion and dissolution. J Pharm Sci 1980; 69: 1-4.
`2 Rowe RC. The adhesion offilm coatings to tablet surfaces — the
`effect of some direct compression excipients and lubricants. |
`Pharm Pharmacol 1977; 29: 723-726.
`3. Rowe RC. The molecular weight and molecular weight distribu-
`tion of hydroxypropyl methylcellulose used in the film coating of
`tablets. | Pharm Pharmacol 1980; 32: 116-119.
`
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`

`4 Banker G, Peck G, Jan S, Pirakitikulr P. Evaluation of hydroxy-
`propylcellulose and hydroxypropyl methyl cellulose as aqueous
`based film coatings. Drug Dev Ind Pharm 1981; 7: 693-716.
`5 Okhamafe AO, York P, Moisture permeation mechanism of some
`aqueous-basedfilm coats. J Pharm Pharmacol 1982; 34 (Suppl.):
`53P.
`6 Alderman DA, Schulz GJ. Method of making a granular, cold
`water dispersible coating composition for tablets. United States
`Patent No. 4,816,298; 1989.
`7 Patell MK. Taste masking pharmaceutical agents. United_States
`Patent No. 4,916,161; 1990.
`8 Hardy JG, Kennerley JW, Taylor MJ, et al. Release rates from
`sustained-release buccal tablets in man. J Pharm Pharmacol 1982;
`34 (Suppl.): 91P.
`9 Hogan JE. Hydroxypropylmethylcellulose sustained release tech-
`nology. Drug Dev Ind Pharm 1989; 15: 975-999.
`10 Shah AC, Britten NJ, Olanoff LS, Badalamenti JN. Gel-matrix
`systems exhibiting bimodal controlled release for oral delivery. J
`Control Release 1989; 9: 169-175.
`11 Wilson HC, Cuff GW. Sustained release of isomazole from matrix
`tablets administered to dogs. J Pharm Sci 1989; 78: 582-584.
`12 Dahl TC, Calderwood T, Bormeth A,
`e¢ al.
`Influence of
`physicochemical properties of hydroxypropyl methylcellulose on
`naproxenrelease from sustained release matrix tablets. J Control
`Release 1990; 14: 1-10.
`13 Banker G, Peck G, Williams E, et al. Microbiological considera-
`tions of polymersolutions used in aqueousfilm coating. Drug Dev
`Ind Pharm 1982; 8: 41-51.
`14 Anonymous. Final report on the safety assessment of hydroxy-
`ethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxy-
`propyl! methylcellulose and cellulose gum.J Am Coll Toxicol 1986;
`5(3): 1-60.
`15 FAO/WHO. Evaluation of certain food additives and contami-
`nants. Thirty-fifth report of the joint FAO/WHO expert committee
`on food additives. World Health Organ Tech Rep Ser 1990; No.
`789.
`16 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,
`11th edn. New York: Wiley, 2004: 2054.
`
`Hypromellose
`
`349
`
`Li CL, Martini LG, Ford JL, Roberts M. The use of hypromellose in
`oral drug delivery. J] Pharm Pharmacol 2005; 57: 533-546.
`Malamataris S, Karidas T, Goidas P. Effect of particle size and sorbed
`moisture on the compression behavior of some hydroxypropyl
`methylcellulose (HPMC) polymers. Int J Pharm 1994; 103: 205-
`215.
`Papadimitriou E, Buckton G, Efentakis M. Probing the mechanisms of
`swelling of hydroxypropy!methylcellulose matrices. Int J Pharm
`1993; 98: 57-62,
`Influence of hydroxypropyl
`Parab PV, Nayak MP, Ritschel WA.
`methylcellulose and of manufacturing technique on im vitro
`performance ofselected antacids. Drug Dev Ind Pharm 1985; 11:
`169-185.
`Radebaugh GW, Murtha JL, Julian TN, Bondi JN. Methods for
`evaluating the puncture and shear properties of pharmaceutical
`polymeric films. Int J Pharm 1988; 45: 39-46.
`Rowe RC.Materials used in the film coating of oral dosage forms. In:
`Florence AT, ed. Critical Reports on Applied Chemistry, vol. 6.
`Oxford: Blackwell Scientific, 1984: 1-36.
`Sako K, Sawada T, NakashimaH,etal. Influence of water solublefillers
`in hydroxypropylmethylcellulose matrices on ix vitro and in vivo
`drug release. ] Control Release 2002; 81: 165-172.
`' Sebert P, Andrianoff N, Rollet M. Effect of gammairradiation on
`hydroxypropylmethylcellulose powders: consequences on physical,
`theological and pharmacotechnical properties. Int ] Pharm 1993;
`99: 37-42.
`Shin-Etsu Chemical Co. Ltd. Metolose. http:/fwww.metolose.jp/e/
`pharmaceutical/metolose.shtml (accessed 25 August 2005). _.
`Shin-Etsu Chemical Co. Ltd. Technicalliterature: Pharmacoat hydro-
`xypropyl methylcellulose, 1990.
`Wan LSC, Heng PWS, Wong LEThe effect of hydroxypropylmethyl-
`cellulose on water penetration into a matrix system. Int J] Pharm
`1991; 73: 111-116.
`
`21 Authors
`
`RJ Harwood.
`
`20 General References
`
`Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199-265,
`Dow Chemical Company.
`‘Technical
`literature: Methocel cellulose
`ethers in aqueous systems for tablet coating, 2000.
`
`» 22 Date of Revision
`
`17 August 2005.
`
`mmr’
`
`INTENT
`
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`

`

`Talc
`
`
`
`1 Nonproprietary Names
`BP;Purified talc
`JP: Talc
`PhEur: Talcum
`USP: Talc
`
`8 Description
`Talc is a very fine, white to grayish-white, odorless, impalpable,
`unctuous,crystalline powder. It adheres readily to the skin and
`is soft to the touch and free from grittiness.
`
`CRNPT
`
`2 Synonyms
`Altale; E553b; hydrous magnesium calcium silicate; hydrous
`magnesium silicate; Luzenac Pharma; magnesium hydrogen
`metasilicate; Magsil Osmanthus; Magsil Star; powderedtalc;
`purified French chalk; Purtalc; soapstone;steatite; Superiore.
`
`3 Chemical Name and CAS Registry Number
`Tale [14807-96-6]
`
`4 Empirical Formula and Molecular Weight
`Talc is a purified, hydrated, magnesiumsilicate, approximating
`to the formula Mg¢(SizOs5)4(OH)4.
`It may contain small,
`variable amounts of aluminum silicate and iron.
`
`Structural Formula
`5
`See Section 4.
`
`Functional Category
`6
`Anticaking agent; glidant; tablet and capsule diluent; tablet and: «
`capsule lubricant.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Talc was once widely usedin oral solid dosage formulations as
`a lubricant anddiluent, see Table I,*~*) although todayit is less
`commonly used. However, it is widely used as a dissolution
`retardant
`in the development of controlled-release pro-
`ducts.Talc is also used as a lubricant in tablet formula-
`tions;in a novel powder coating for extended-release
`pellets;®) and as an adsorbant.”)
`In topical preparations, talc is used as a dusting powder,
`although it should not be used to dust surgical gloves; see
`Section 14. Talc is a natural material;
`it may therefore
`frequently contain microorganisms and should besterilized
`when used as a dusting powder; see Section 11.
`Talc is additionally used to clarify liquids andis also used in
`cosmetics and food products, mainly for its lubricant proper-
`ties.
`
`Table |:
`
`Uses oftale.
`
`
`
` Use Concentration (%)
`
`Dusting powder
`Glidantandtablet lubricant
`Tablet and capsule diluent
`
`90.0-99.0
`1.0-10.0
`5.0-30.0
`
`SEM: 1
`Excipient: Tale (Purtalc)
`Manufacturer: Charles B Chrystal Co., Inc.
`Lot No.; 1102A-2
`Magnification: 1200x
`
`
`
`Voltage: 10kV
`
`9 Pharmacopeial Specifications
`See TableII.
`
`10 Typical Properties
`Acidity/alkalinity: pH = 7-10 for a 20% w/v aqueous
`dispersion.
`Hardness (Mohs): 1.0-1.5
`Moisture content: talc absorbs insignificant amounts of water
`at 25°C and relative humidities up to about 90%.
`Particle size distribution: varies with the source and grade of
`material. Two typical grades are >99% through a 74 um
`(#200 mesh) or >99% through a 44 jum (#325 mesh).
`Refractive index: a? = 1.54-1.59
`Solubility: practically insoluble in dilute acids and alkalis,
`organic solvents, and water.
`Specific gravity: 2.7-2.8
`Specific surface area: 2.41-2.42 m’/g
`
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`

`Table Il:©Pharmacopeial specificationsfortalc.
`ever, intranasal or intravenous abuse of products containing
`talc can cause granulomas in body tissues, particularly the
`
`
`JP 2001Test PhEur 2005 USP 28
`lungs.{'@1®) Contamination of wounds or body cavities with
`talc may also cause granulomas;therefore, it should not be used
`to dust surgical gloves. Inhalation of talc causesirritation and
`may cause severe respiratory distress in infants;") see also
`Section 15.
`Although tale has been extensively investigated for its
`carcinogenic potential, and it has been suggestedthat there is an
`increased risk of ovarian cancer in women using talc,
`the
`evidence is inconclusive.'2°?" However,
`talc contaminated
`with asbestos has been proved to be carcinogenic in humans,
`and asbestos-free grades should therefore be used in pharma-
`ceutical products.)
`Also, long-term toxic effects of talc contaminated with large
`quantities of hexachlorophéne caused serious irreversible
`neurotoxicity in infants accidentally exposed to the sub-
`stance.'*2)
`
`768
`
`Tale
`
`Identification
`Characters
`Acid-soluble substances
`Acidity oralkalinity
`Production
`:
`
`+
`-
`<2.0%
`—
`_
`—
`<0.1%
`—
`=
`
`+
`+
`+
`+
`—
`—2.0%
`+
`—
`+
`=
`70-90
`—
`<0.2%
`=
`<2.0%
`-
`<0.9%
`=
`<0.25%
`-
`<10ppm —
`-
`17,0-19.5
` —
`_
`<5.0% <7.0%
`<6.5%
`_
`+
`<500/g
`—
`<107/g
`—
`-
`_
` <107/g
`~
`<4.0mg —
`<2.0%
`
`Water-soluble substances
`Aluminum
`Calcium
`Iron
`Lead
`Magnesium
`Loss on ignition
`Microbial contamination
`Aerobic bacteria
`Fungi
`Acid and alkali-soluble
`substances
`+
`=
`+
`Water-soluble iron
`<3 ppm
`<4ppm —
`Arsenic
`<0.004%
`=
`=
`Heavy metals
`
`Lead <0.001% =_ —
`
`
`
`Stabilityand Storage Conditions
`Talc is a stable material and maybesterilized by heating at
`160°C for not less than 1 hour. It may also besterilized by
`exposure to ethylene oxide or gammairradiation.
`Talc should be stored in a well-closed containerin a cool,
`dry place.
`,
`
`Incompatibilities
`Incompatible with quaternary ammonium compounds.
`
`13 Method of Manufacture
`
`Talc is a naturally occurring hydropolysilicate mineral foundin
`manyparts of the world including Australia, China,Italy, India,
`France, and the USA."
`The purity of talc varies depending on the country oforigin.
`For example, Italian types are reported to contain calcium
`silicate as the contaminant; Indian types contain aluminum and
`iron oxides; French types contain aluminum oxide; and
`American types contain calcium carbonate (California), iron
`oxide (Montana), aluminum andiron oxides (North Carolina),
`or aluminum oxide (Alabama).'
`Naturally occurring talc is mined and pulverized before
`being subjected to flotation processes to remove various
`impurities such as asbestos (tremolite); carbon; dolomite; iron
`oxide; and various other magnesium and carbonate minerals.
`Following this process, the talc is finely powdered,treated with
`dilute hydrochloric acid, washed with water, and then dried.
`The processing variables of agglomerated talc strongly influ-
`ence its physical characteristics.19-15)
`
`14 Safety
`Talc is used mainly in tablet and capsule formulations. Talc is
`not absorbed systemically following oral
`ingestion and is
`therefore regarded as an essentially nontoxic material. How-
`
`iar
`
`NTENI
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled.Talc is irritant if inhaled and
`prolonged excessive exposure may cause pneumoconiosis.
`In the UK,
`the occupational exposure limit for tale is
`1mg/m? of respirable dust long-term (8-hour TWA).4) Eye
`protection, gloves, and a respirator are recommended.
`
`16 Regulatory Status
`Accepted for use as a food additive in Europe. Included in the
`FDA Inactive Ingredients Guide (buccal tablets; oral capsules
`and tablets;
`rectal and topical preparations).
`Included in
`nonparenteral medicines licensed in the UK. Included in the
`Canadian List of Acceptable Non-medicinal Ingredients.
`
`, ‘217 Related Substances
`Bentonite; magnesium aluminum silicate; magnesium silicate;
`magnesium trisilicate.
`
`18 Comments
`
`Various different grades of talc are commercially available that
`vary in their chemical composition depending upontheir source
`and methodof preparation.'115.26)
`’
`Talc derived from deposits that are known to contain
`associated asbestosis not suitable for pharmaceutical use. Tests
`for amphiboles and serpentines should be carried out to ensure
`that the product is free of asbestos. A specification for talc is
`contained in the Food Chemicals Codex (FCC).
`The EINECS numberfortalc is 238-877-9.
`
`Specific References
`19
`1 Dawoodbhai S, Rhodes CT. Pharmaceutical and cosmetic uses of
`talc. Drug Dev Ind Pharm 1990; 16: 2409-2429.
`2 DawoodbhaiS, Suryanarayan ER, Woodruff CW. Optimization of
`tablet formulations containing talc. Drug Dev Ind Pharm 1991;
`17: 1343-1371.
`.
`3 Wang DP, Yang MC, Wong CY. Formulation developmentoforal
`controlled release pellets of diclofenac sodium. Drug Dev Ind
`Pharm 1997; 23: 1013-1017.
`Fassihi RA, McPhillips AM, Uraizee SA, Sakr AM.Potential use of
`magnesium stearate and talc as dissolution retardants in the
`development of controlled release drug delivery systems. Pharm
`Ind 1994; 56: 579-583.
`
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`Fassihi R, Fabian J, Sakr AM. Application of response surface
`methodology to design optimization in formulation of a typical
`controlled release system. Drugs Made Ger 1996; 39(Oct-Dec):
`122-126.
`Schultz P, Tho I, Kleinebudde P. New multiparticulate delayed
`release system. Part 2. Coating formulation and properties of free
`films. J Control Release 1997; 47:.191-199.
`Oetari RA, Yuwano T, Fudhdi A. Formulation of PGV-O a new
`antiinflammatory agent as a tablet dosage form. Indonesian J
`Pharm 2003; 14(4): 160-168.
`Pearnchob N, Bodmeier R. Dry powder coating of pellets with
`micronized Eudragil (R) RS for extended drug release. Pharm Res
`2003; 20(12); 1970-1976.
`:
`Mani N, Suh HR, Jun HW. Microencapsulation of a hydrophilic
`drug into a hydrophobic matrix using a salting-out procedure:II.
`Effects of adsorbents on microsphere properties. Drug Dev Ind
`Pharm 2004; 30(1): 83-93.
`Bubik JS. Preparation ofsterile talc for treatment of pleural
`effusion[letter]. Am J Hosp Pharm 1992; 49: 562-563.
`Grexa RW, Parmentier CJ. Cosmetic talc properties and specifica-
`tions. Cosmet Toilet 1979; 94(2): 29-33.
`Hoepfner EM, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of
`Excipients for Pharmaceuticals, Cosmetics and Related Areas, Sth
`edn, vol. II. Aulendorf: Editio Cantor Verlag, 2002: 1556-1559.
`Lin K, Peck GE. Development of agglomerated talc. Part 1.
`Evaluation offluidized bed granulation parameters on the physical
`properties of agglomerated talc, Drug Dev Ind Pharm 1995; 21:
`447-460.
`Lin K, Peck GE. Development of agglomerated talc. Part 2.
`Optimization of the processing parameters for the preparation of
`granulated talc. Drug Dev Ind Pharm 1995; 21: 159-173.
`Lin K, Peck GE. Development of agglomerated talc. Part 3.
`Comparisons of the physical properties of the agglomerated talc
`prepared by three different processing methods. Drug Dev Ind
`Pharm 1996; 22: 383-392.
`Schwartz IS, Bosken C. Pulmonary vasculartalc granulomatosis.
`J Am MedAssoc 1986; 256: 2584.
`Johnson DC, Petru A, Azimi PH.: Foreign body pulmonary
`granulomas in an abuser of nasally inhaled drugs. Pediatrics
`1991; 88: 159-161.
`
`11
`
`12.
`
`13
`
`14
`
`1s
`
`16
`
`17
`
`Tale
`
`769
`
`18 Sparrow SA, Hallam LA.Talc granulomas[letter]. Br Med J 1991;
`303: 58.
`19 Pairaudeau PW, Wilson RG, Hall MA, Milne M.Inhalation of
`baby powder: an unappreciated hazard. Br Med J 1991; 302:
`1200-1201.
`20 Longo DL, Young RC. Cosmetic talc and ovarian cancer. Lancet
`1979; ii: 349-351.
`21 Phillipson IM.Talc quality [letter]. Lancet 1980;i: 48.
`22 International Agency for Research on Cancer/World Health
`Organization. Silica and Some Silicates: IARC Monographs on
`the Evaluation of the Carcinogenic Risk of Chemicals to Humans.
`Geneva: WHO,1987: 42.
`23 Anonymous. Long-term sequelae of hexachlorophene poisoning.
`Prescrire Int 1992; 1: 168.
`24 Health andSafety Executive. EH40/2002: Occupational Exposure
`Limits 2002. Sudbury: Health and Safety Executive, 2002.
`25 Phadke DS, Keeney MP, Norris DA. Evaluation of batch-to-batch
`and manufacturer-to-manufacturer variability in the physical
`properties of talc and stearic acid. Drug Dev Ind Pharm 1994;
`20: 859-871.
`26 Lin K, Peck GE. Characterization of talc samples from different
`sources. Drug Dev Ind Pharm 1994; 20: 2993-3003.
`
`20 General References
`
`Gold G, Campbell JA. Effects of selected USP talcs on acetylsalicylic
`acid stability in tablets. J Pharm Sci 1964; 53: 52-54.
`
`21 Authors
`AH Kibbe.
`
`22 Date of Revision
`
`17 August 2005.
`
`nL
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