fluid
`
`Pharmac
`Assoc!
`
`(Ph
`
`MEDA_APTX03505655
`
`1
`
`CIP2110
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Third Edition
`
`Edited by
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes-Barre, Pennsylvania
`
`8
`
`American Pharmaceutical Association
`Washington, D.C.
`
`(PP)
`
`Pharmaceutical Pram
`London, United Kingdom
`
`MEDA_APTX03505656
`
`2
`
`

`

`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street, London SEI 7JN, UK
`wwwpharmpress .com
`
`' 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`
`First edition 1986
`Second edition 1994
`Third edition 2000
`
`Printed in the United States of America
`
`ISBN: 0-85369-381-1 (UK)
`ISBN: 0-917330-96-X (USA)
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients / edited by Arthur H. Kibbe.-3rd ed.
`p. cm.
`Includes bibliographical references and index.
`ISBN 0-917330-96-X
`1. Excipients--Handbooks, manuals, etc. 1. Kibbe, Arthur H. 11. American
`Pharmaceutical Association.
`[DNLM: I. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`615’. 19--dc2l
`
`A catalogue record for this book is available from the British Library.
`
`99-044554
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or
`by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or
`implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`Managing Editor: Melanie Segala
`Paul Gottehrer
`Copyeditor:
`Lillian Rodberg
`Indexer:
`Roy Barnhill
`Compositor:
`Tim Kaage
`Cover Designer:
`
`MEDA_APTX03505657
`
`3
`
`

`

`252 Hvdroxvp ropy l Met hvlcellu lose
`
`Hydroxypropyl
`Methylcellulose
`
`1. Nonproprietary Names
`
`BP: Hypromellose
`JP: Hydroxypropylmethylcellu lose
`PhEur: Methylhydroxypropylcellulosum
`USP: 1-lydroxypropyl methylcellulose
`
`2. Synonyms
`Benecel MHPC; Cellulose, hydroxypropyl methyl ether; E464;
`HPMC; Methocel; methylcellulose propylene glycol ether;
`methyl hydroxypropylcellulose; Mew/use; Pharrncicoar.
`
`3. Chemical Name and CAS Registry Number
`Cellulose, 2-Hydroxypropyl methyl ether [9004-65-3]
`
`4. Empirical Formula (cid:9) Molecular Weight
`The PhEur describes hydroxypropyl methylcellulose as a part-
`ly 0-methylated and 0-(2-hydroxypropylated) cellulose. It is
`available in several grades which vary in viscosity and extent
`of substitution. Grades may be distinguished by appending a
`number indicative of the apparent viscosity, in mPa s, of a
`2 17,o w/w aqueous solution at 20(cid:176)C, Hydroxypropyl methylcel-
`lulose defined in the USP specifies the substitution type by
`appending a four digit number to the nonproprietary name,
`e.g., hydroxypropyl rnethylcellulose 1828. The first two digits
`refer to the approximate percentage content of the mcthoxy
`group (OCH 3 ). The second two digits refer to the approximate
`percentage content of the hydroxypropoxy group
`(0CH2CH0I-IC11 3 ), calculated on a dried basis. Molecular
`weight is approximately 10 000-1 500 000.
`
`5. Structural Formula
`r (cid:9)
`
`CHOR (cid:9)
`
`OR (cid:9)
`
`__O
`Z, (cid:9)
`OR (cid:9)
`
`[ (cid:9)
`
`0
`CH7OR (cid:9)
`
`1
`
`j
`
`Where R is H, CH 3, or [CH 3CH(OH)CH2].
`
`6. Functional Category
`Coating agent; film-former; rate-controlling polymer for sus-
`tained release; stabilizing agent; suspending agent; tablet
`hinder; viscosity-increasing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Hydroxypropyl meihylcellulose is widely used in oral and top-
`ical pharmaceutical formulations.
`
`In oral products, hydroxypropyl methylcellulose is primarily
`used as a tablet binder,(cid:176) in film-coating,
`2 ’71 and as an ox-
`boded-release tablet matrix.18121 Concentrations of between
`2-5 17c w/w may be used as a binder in either wet- or dry-
`granulation processes. High viscosity grades may be used to
`retard the release of drugs from a matrix at levels 10-80%
`w/w in tablets and capsules.
`
`Depending upon the viscosity grade, concentrations between
`2-20% w/w are used as film-forming solutions to film-coat
`tablets. Lower viscosity grades are used in aqueous film-coat-
`ing solutions while higher viscosity grades are used with or-
`ganic solvents.
`
`Hydroxypropyl methylcellulose is also used as a suspending
`and thickening agent in topical formulations, particularly oph-
`thalmic preparations. Compared with methylcellulose,
`hydroxypropyl methylcellulose produces solutions of greater
`clarity, with fewer undispersed fibers present, and is therefore
`preferred in formulations for ophthalmic use. Concentrations
`of between 0.45-1.0 17c w/w may be added as a thickening
`agent to vehicles for eye drops and artificial tear solutions.
`
`Hydroxypropyl methylcellulose is also used as an emulsifier,
`suspending agent, and stabilizing agent in topical gels and
`ointments. As a protective colloid, it can prevent droplets and
`particles from coalescing or agglomerating, thus inhibiting the
`formation of sediments.
`
`In addition, hydroxypropyl methyleellulose is used in the
`manufacture of capsules, as an adhesive in plastic bandages
`and as a wetting agent for hard contact lenses. It is also widely
`used in cosmetics and food products.
`
`8. Description
`
`Hydroxypropyl niethylcellulose is an odorless and tasteless,
`white or creamy-while colored fibrous or granular powder.
`
`9. Pharmacopeial Specifications
`
`Test
`
`JP
`
`PhEur
`
`USP
`
`+
`+
`5.0-8.0
`+
`
`5.0%
`
`-
`-
`
`+
`-
`–
`5.5-8.0 -
`+
`+
`
`10.0%
`
`5.0%
`
`1.5%
`8 3.0%
`-
`8 5.0%
`-
`1.0% -
`8 0.5% -
`8 20 ppm 5 0,001%
`
`ldeetilication
`Appearance of solution
`pH (1% w/w solution)
`Apparent viscosity
`Loss on drying
`Residue on ignition
`For viscosity grade > 50 mPa a
`1.5%
`For viscosity grade 8 50 mPu s 8 1.5 010
`For type 1828 of all viscosities 8 1.5%
`Sulfated ash
`Chlorides
`Heavy metals
`Methoxy content
`Type 1828
`Type 2208
`Type 2906
`Type 2910
`Hydroxypropoxy contest
`Type 1828
`Type 2208
`Type 2906
`Type 2910
`
`-
`
`19.0-24.0%
`27.0-30.0% -
`28.0-30.0% -
`
`-
`-
`4.0-12.0% -
`4.0-7.517c -
`7.0-110%
`
`16.5-20.0%
`19.0-24.0%
`27.0-30.0%
`28.0-30.0%
`
`23.0-32.0%
`4.0-110%
`4.0-7.517o
`7.0-12.017c
`
`MEDA_APTX03505658
`
`4
`
`

`

`Hydroxypropyl IvIethylcellulose 253
`
`SEM: I
`Excipient: [-lydroxypropyl meth y[cellulose
`Manufacturer: Dow Chemical Co
`Lot No.: ME200I2NII
`Magnification: 600x
`Voitnee; 5kv
`
`SEM: 2
`Excipient: 1’lydroxypropyl methylcellulose
`Manufacturer: Dow Chemical Co
`Lot No.: ME200I2NI1
`Magnification: 60x
`Voltage: 5kV
`
`10. Typical Properties
`Acidity/alkalinity:
`pH = 5.5-8.0 for a 1% w/w aqueous solution.
`Ash: 1.5-3.0%, depending upon the grade.
`Auioignition temperature: 360(cid:176)C
`Density (bulk): 0.341 g/cm 3
`Densits’ (lapped): 0.557 g/cm 3
`Density (true): 1.326 glcm 3
`Melting point: browns at 190-200(cid:176)C; chars at 225-230 (cid:176) C.
`Glass transition temperature is 170-180(cid:176)C.
`Moisture content: hydroxypropyl methylcellulose absorbs
`moisture from the atmosphere, the amount of water
`absorbed depending upon the initial moisture content and
`the temperature and relative humidity of the surrounding
`air. See Fig. 1.
`Particle size distribution: See Table [.
`Solubility: soluble in cold water, forming a viscous colloidal solu-
`tion; practically insoluble in chloroform, ethanol (95%), and
`ether, but soluble in mixtures of ethanol and dichloromethane,
`mixtures of methanol and dichioromethane, and mixtures of
`water and alcohol. Certain grades of hydroxypropyl methyl-
`cellulose are soluble in aqueous acetone solutions, mixtures
`of dichloromethane and propan-2-ol, and other organic sol-
`vents. See also Section 11.
`Specific gravity: 1.26
`Viscosity (dynamic): a wide range of viscosity types are com-
`mercially available. Aqueous solutions are most commonly
`prepared although hydroxypropyl methylcellulose may also
`be dissolved in aqueous alcohols such as ethanol and pro-
`pan-2-ol provided the alcohol content is less than 50%
`w/w. Dichloromethane and ethanol mixtures may also be
`used to prepare viscous hydroxypropyl methylcellulose
`solutions. Solutions prepared using organic solvents tend
`to be more viscous; increasing concentration also produces
`more viscous solutions, see Table II.
`To prepare an aqueous solution, it is recommended that hy-
`droxypropyl methylcellulose is dispersed and thoroughly hy-
`
`Table I: Typical particle size distribution for hydroxypropyl
`methyl cellulose.
`
`Average
`particle size
`(tim)
`
`Cumulative
`frequency
`oversize (%)
`
`Weight
`retained
`(%)
`
`Lot LCI50I2NII (cid:9)
`
`Lot LA29012NO2 (cid:9)
`
`250
`200
`137
`115
`90
`64
`pan
`250
`200
`137
`115
`90
`64
`pan
`
`5.6
`18.8
`26.6
`35.4
`54.4
`85.8
`100
`2.8
`15.6
`20.6
`26.4
`42.8
`68
`100
`
`5.60
`13.20
`7,8
`8.8
`19.0
`31.4
`14.0
`2.8
`12.8
`5.0
`5.8
`16.4
`25.2
`33
`
`Note: Using an ATM Sonic Softener.
`
`drated in about 20-30% of the required amount of water. The
`water should be vigorously stirred and heated to 80-90(cid:176)C then
`the remaining hydroxypropyl methylcellulose added. Cold wa-
`ter should then be added to produce the required volume.
`
`When a water-miscible organic solvent such as ethanol, gly-
`col, or mixtures of ethanol and dichioromethane is used, the
`hydroxypropyl methylcellulose should first be dispersed into
`the organic solvent, at a ratio of 5-8 parts of solvent to I part
`of hydroxypropyl methylcellulose. Cold water is then added
`to produce the required volume.
`
`11. Stability and Storage Conditions
`
`Hydroxypropyl methylcellulose powder is a stable material
`although it is hygroscopic after drying.
`
`MEDA_APTX03505659
`
`5
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`254 T-{ydroxypropyl Meihylcellulose
`
`40
`
`30
`
`20
`
`U,
`0
`E 20
`E
`
`4:
`(cid:149)5 10
`uJ
`
`0 10 20 30 40 50 60 70 80 90 100
`Relative humidity (%)
`
`Fig. 1: Absorption desorption isotherm for hydroxypropyl
`methylcellulose.
`(cid:149) : sorption
`(cid:149) desorption
`
`Table II: Typical viscosity values for 2% (w/v) aqueous solutions of
`Methocel (Dow Chemical Co.) Viscosities measured at 20(cid:176)C.
`
`Methocel grade
`
`K100LVP (1 )
`K4MP)a)
`1
`K15MP(cid:176)
`K100MP(a)
`E4MP(U)
`E1OMP CRt(cid:176)
`E3 PREM.LV
`ES PREM.LV
`E6 PREM.LV
`E15 PREM.LV
`E50 PREM.LV
`K3 PREM.LV
`
`Nominal
`
`100
`4000
`15000
`100 000
`4000
`10000
`
`Viscosity (mPa s)
`
`80-120
`3000-5600
`12 000-21 000
`80 000-120 000
`3500-5600
`8000-13 000
`2.4-3.6
`4-6
`5-7
`12-18
`40-60
`14-3.6
`
`(a) Dow Chemical Company.
`
`Solutions are stable between pH 3-11. Increasing temperature
`reduces the viscosity of solutions. Hydroxypropyl methylcel-
`lulose undergoes a reversible sol to gel transformation upon
`heating and cooling respectively. The gel point is 50-90(cid:176)C,
`depending upon the grade and concentration of material.
`
`Aqueous solutions are comparatively enzyme-resistant, pro-
`viding good viscosity stability during long-term storage. 13
`However, aqueous solutions are liable to microbial spoilage
`and should be preserved with an antimicrobial preservative.
`When used as a viscosity-increasing agent in ophthalmic solutions,
`benzalkonium chloride is commonly used for this purpose. Aqueous
`solutions may also be sterilized by autoclaving; the coagulated poly-
`mer must be redispersed on cooling by shaking.
`
`Hydroxypropyl methylcellulose powder should be stored in a
`well-closed container, in a cool, dry, place.
`
`12. Incompatibilities
`
`Hydroxypropyl methylcellulose is incompatible with some ox-
`idizing agents. Since it is nonionic, hydroxypropyl methylcel-
`lulose will not complex with metallic salts or ionic organics
`to form insoluble precipitates.
`
`13. Method of Manufacture
`A purified form of cellulose, obtained from cotton linters or
`wood pulp, is reacted with sodium hydroxide solution to pro-
`duce a swollen alkali cellulose which is chemically more re-
`active than untreated cellulose. The alkali cellulose is then
`treated with chiorometharie and propylene oxide to produce
`methylhydroxypropyl ethers of cellulose. The fibrous reaction
`product is then purified and ground to a fine uniform powder
`or granules.
`
`I:
`
`14. Safety
`Hydroxypropyl methylcellulose is widely used as an excipient
`in oral and topical pharmaceutical formulations. It is also used
`extensively in cosmetics and food products.
`Hydroxypropyl mcthylcellulose is generally regarded as a
`nontoxic and nonirritant material although excessive oral con-
`sumption may have a laxative effect. 1141 The WHO has not
`specified an acceptable daily intake for hydroxypropyl meth-
`ylcellulose since the levels consumed were not considered to
`represent a hazard to health.
`151
`LD 5 (mouse, IP): 5 g/kg (16)
`LD 5 (rat, EP): 5.2 g/kg
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Hydroxypropyl methylcel-
`lulose dust may be irritant to the eyes and eye protection is
`recommended. Excessive dust generation should be avoided
`to minimize the risks of explosions. Hydroxypropyl methyl-
`cellulose is combustible.
`
`16. Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included
`in the FDA Inactive Ingredients Guide (ophthalmic prepara-
`tions, oral capsules, suspensions, syrups and tablets, topical
`and vaginal preparations). Included in nonparenteral medi-
`cines licensed in the UK.
`
`17. Pharmacopeias
`China, Eur, mt. Jpn, P01, and US.
`
`18. Related Substances
`Hydroxyethyl cellulose; hydroxypropyl cellulose; hydroxypro-
`pyl methylcellulose phthalate; methylcellulose.
`
`19. Comments
`Powdered or granular, surface-treated grades of hydroxypro-
`pyl methylcellulose are also available which are dispersible
`in cold water. These are not recommended for oral use.
`
`20. Specific References
`Chowhan ZT. Role of binders in moisture-induced hardness
`increase in compressed tablets and its effect on in vitro dis-
`integration and dissolution. J Pharm Sci 1980; 69: 1-4.
`2. Rowe RC. The adhesion of film coatings to tablet surfaces
`- the effect of some direct compression excipients and lubri-
`cants. J Pharm Pharmacol 1977; 29: 723-726,
`Rowe RC. The molecular weight and molecular weight dis-
`tribution of hydroxypropyl methylcellulose used in the tilifl
`coating of tablets. J Pharrn Pharmacol 1980; 32: 116-119.
`
`MEDA_APTX03505660
`
`6
`
`

`

`4. Banker G, Peck 0, Jan S, Pirakitikulr P. Evaluation of
`hydroxypropyl cellulose and hydroxypropyl methyl cellulose
`as aqueous based film coatings. Drug Dcv Ind Pharm 1981;
`7: 693-716.
`5, Okhamafe AO, York P. Moisture permeation mechanism of
`some aqueous-based film coats. I Pharni Phormocol 1982:
`34(Suppl); 53P.
`6. Alderman DA, Schulz GJ. Method of making a granular, cold
`water dispersible coating composition for tablets. US Patent
`4816298, 1989.
`7. Patell MK. Taste masking pharmaceutical agents. US Patent
`4916161, 1990,
`S. Hardy JG, Kennerley JW, Taylor MJ. Wilson CD, Davis SS.
`Release rates from sustained-release buccal tablets in man.
`I Pharm Pharmacol 1982; 34(Suppl): 91 P.
`9. Hogan JE. Hydroxypropylmethylcellulose sustained release
`technology. Drug Dcv !isd Phar,n 1989: 15: 975-999.
`10. Shah AC, Britten NJ, Olanoff LS, Badalamenti JN. Gel-
`matrix systems exhibiting bimodal controlled release for oral
`delivery. I Controlled Release 1989: 9: 169-175.
`11. Wilson HC, Cuff GW. Sustained release of isomazole from
`matrix tablets administered to dogs. I Pharin Sci 1989; 78:
`582-584.
`12. Dahl TC, Calderwood T, Bormeth A, Trimble K, Piepmeier
`E. Influence of physicochemical properties of hydroxypropyl
`methylcellulose on naproxen release from sustained release
`matrix tablets. I Controlled Release 1990; 14: 1-10.
`13, Banker 0, Peck 0, Williams E, Taylor D, Pirakitikulr P.
`Microbiological considerations of polymer solutions used in
`aqueous film coating. Drug Dcv Ind Pharin 1982; 8: 41-51.
`14. Final report on the safety assessment of hydroxyethylcellu-
`lose, hydroxypropylcellulose, methylcellulose, hydroxypro-
`pyl rnethylcellulose and cellulose gum. I Am Coil Toxicoi
`1986; 5(3): 1-60.
`15. FAQ/WHO. Evaluation of certain food additives and contam-
`inants: thirty-fifth report of the joint FAD/WHO expert com-
`mittee on food additives. Tech Rep Set- Wld Hith Org 1990;
`No. 789.
`
`Hydroxypropvl Meihvlcellulose 255
`
`16. Sweet DV. editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati, US Department of Health, 1987.
`
`21. General References
`Dociker E. Cellulose derivatives. 4dv Polymer Sd 1993; 107:
`199-265.
`Dow Chemical Company. Technical literature: Metlzocel. 1993.
`Malamataris S, Karidas T, Goidas P. Effect of particle size and
`sorbed moisture on the compression behavior of some hydrox-
`ypropyl methylcellulose (HPMC) polymers. lot I Pharmaceu-
`tics 1994; 103: 205-215.
`Papadimitriou E, Buckton 0, Eferitakis M. Probing the mecha-
`nisms of swelling of hydroxyp ropy lmethylcellulose matrices.
`tnt I Pharmaceutics 1993; 98: 57-62.
`Parab PV, Nayak MP, Ritschel WA. influence of hydroxypropyl
`methylcellulose and of manufacturing technique on
`in vitro
`performance of selected antacids. Drug Dcv Ind Pharm 1985;
`11: 169-185.
`Radebaugh GW, Murtha JL, Julian TN, Bondi iN. Methods for
`evaluating the puncture and shear properties of pharmaceutical
`polymeric films. mt i Pharmaceutics 1988; 45: 39-46.
`Rowe RC. Materials used in the film coating of oral dosage forms.
`In: Florence AT, editor. Critical Reports on Applied Chemistry,
`volume 6. Oxford, Blackwell Scientific Publications, 1984;
`1-36.
`Sebert P. Andrianoff N, Rollet M. Effect of gamma irradiation
`on hydroxypropylmethylcellulose powders: consequences on
`physical, rheological and pharmacotechnical properties. lot I
`Pharmaceutics 1993; 99: 37-42.
`Shin-Etsu Chemical Co Ltd. Technical literature: Metolose, 1977.
`Shin-Etsu Chemical Co Ltd. Technical literature: Phormacoar
`hydroxypropyl inethylcellulose, 1990.
`Wan LSC, Heng PWS, Wong LF. The effect of hydroxypropylm-
`ethylcellulose on water penetration into a matrix system.
`tnt
`I Pharmaceutics 1991; 73: 111-116.
`
`22. Authors
`RI Harwood.
`
`MEDA_APTX03505661
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