`H A N D B 0 O K 0 F
`PHARMACEUTI
`
`
`EEEEEE
`
`American
`
`Page 1 of 15
`
`KVK-TECH EXHIBIT 1029
`
`

`

`
`
`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
`
`American Pharmaceutical Association
`Washington, D.C.
`
`(RP) ‘
`
`Pharmaceutical Press
`
`London, United Kingdom
`
`Page 2 of 15
`
`Page 2 of 15
`
`

`

`
`
`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 SE1 7JN, UK
`www.pharmpress.corn
`
`© 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)
`
`blication Data
`,
`/ edited by Arthur H. Kibbe.—-3rd ed.
`
`ress Catalo in -in-Pu
`f Co
`'
`“g
`g g
`Library 0
`Handbook of pharmaceutical excipients
`.
`p.
`; cm.
`Includes bibliographical references and index.
`ISBN 0—917330-96—X
`‘
`.
`1. Excipients——Handbooks, manuals, etc.
`1. Kibbe, Arthur H. II. American
`Pharmaceutical Association.
`[DNLM:
`l. Excipients-—Handbooks. QV 735 H236 2000] ,
`R8201.E87 H36 2000
`,
`615‘.19--dc21
`
`994344554
`
`A catalogue record for this book is available from the British Library.
`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
`Copyeditor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
`Page 3 of 15
`
`Page 3 of 15
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`

`

`hylcellulose
`
`nproprietary Names
`Ethylcellulose
`iir: Ethylcellulosum
`: Ethylcellulose
`
`
`
`
`ellulose ethyl ether [9004—57-3]
`
`4. Empirical Formula Molecular Weight
`Ethylcellulose with complete ethoxyl substitution (DS = 3) is:
`C12H2306(C12H2205)nc12H2305
`where n can vary to provide a wide variety of molecular
`weights. Ethylcellulose, an ethyl ether of cellulose, is a long-
`chain polymer of B—anhydroglucose units joined together by
`acetal linkages.
`
`5. Structural Formula
`
`The structures with complete ethoxyl substitution is given below.
`
`
`
`
`
`6. Functional Category
`
`flavoring fixative tablet binder;
`Coating agent;
`viscosityLincreasing agent.
`
`tablet filler;
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Ethylcellulose is widely used in oral and topical pharmaceu»
`tical formulations, see Table I.
`
`The main use of ethylcellulose in oral formulations is as a
`hydrophobic coating agent for tablets and granulesf”) Eth—
`ylcellulose coatings are used to modify the release of a
`drug,(7'9) to mask an unpleasant taste, or to improve the sta-
`bility of a formulation, as is the case where granules are coat—
`ed with ethylcellulose to inhibit oxidation. Modifiedvrelease
`tablet formulations may also be produced using ethylcellulose
`as a matrix formerflo‘m
`
`Ethylcellulose, dissolved in an organic solvent, or solvent
`mixture, can be used on its own to produce water—insoluble
`films. Higher viscosity ethylcellulose grades tend to produce
`stronger and more durable films. Ethylcellulose films may be
`
`Page4 of 15
`
`Ethylcellulose 195
`
`
`
`modified to alter their solubilityflm by the addition of hydroxypro-
`pyl ethylcelluloseu“) or a plasticizer,(15'16) see Section 19. An
`aqurgous polymer dispersion (or latex) of ethylcellulose such
`as Aquacoat (FMC Corp) or Surelease (Colorcon) may also
`be used to produce ethylcellulose films without the need for
`organic solvents. Drug release through ethylcellulose-coated
`dosage forms can be controlled by diffusion through the film
`coat This can be a slow process unless a large surface area
`(eg. pellets or granules vs. tablets) is utilized. In those in—
`stanties, aqueous ethyl'cellulose dispersions tend therefore to
`be (red to coat granules or pellets. Ethyleellulose-coated
`bea
`/granules have also demonstrated the ability to absorb
`pressure and hence protect the coating from fracture during
`compression.(17)
`
`High ViSCOSity grades 0f e'ihylcellulose are used in drug mi-
`croencapsulationfll8-20)
`
`Release of a drug from an ethylcellulose microcapsule is a
`function of the microcapsule wall thickness and surface area.
`In taflet formulations, ethylcellulose may additionally be em~
`d as a binder,
`the ethylcellulose being blended dry or
`wet-granulated with a solvent such as ethanol (95%). Ethyl—
`‘ose produces hard tablets with low friability; however,
`they may demonstrate poor dissolution.
`
`Ethylcellulose has also been used as an agent for delivering
`therapeutic agents from oral (e.g., dental) appliancespl)
`In topical formulations, ethylcellulose is used as a thickening agent
`l
`in creams, lotions, or gels, provided an appropriate solvent is used.
`Ethylolellulose is additionally used in cosmetics and food products.
`
`Table 1. Uses and typical concentrations of ethylcellulose.
`.__,____
`
` Use Concentration (%)
`Microe‘ncapsulation
`10.0—20.0
`Sustai ‘ed—release tablet coating
`31.3-20.0
`Tabletloating
`l.0~3.0
`1
`Tablet§ranulation
`1.0-3.0
`8. Delscription
`Ethylcellulose is a tasteless, free-flowing, white to light tan
`colored powder.
`
`9. PhIrmacopeial Specifications
`Test
`l,
`
`PhEur USP
`Identification
`+
`+
`Characters
`+
`—
`pH (2% w/w suspension)
`5.0—7.5
`—
`Viscosit
`+
`+
`Loss on drying
`S 3.0%
`S 3.0%
`Residue on ignition
`—
`S 0.4%
`Sulfatedéash
`g 0.5%
`.—
`Lead
`l
`m
`S 10 ppm
`Heavy rrietals
`S 20 ppm
`S 20 ttg/g
`Acetaldehyde
`S 100 ppm
`—
`Chlorides
`s 0.1%
`—
`Organic Volatile impurities
`—
`+
`44.0-51.0%
`44.0—51.0%
`Assay (of ethoxyl groups)
`
`Page 4 of 15
`
`

`

`196 EI/zylc'ellulm‘e
`
`SEM: 1
`
`Exclpiem: Elhy ellulose
`Mnnufnclurer: Hercules Ltd
`Lot No: 57911
`Magnfication: 60X
`Voltage:
`l() W
`
`SEM: 3
`Excipient: Elhylcelluluse lll cps llnc pmxder
`Manufacturer: DOW Chemical Co
`> gnific lion: 600><
`
`Voltage: 5 kV
`
`
`
`
`SEM: 2
`Excipicni: Elhylcelluluse l0 cpx 1321c pmxder
`Mnmlfncturer: Dov» Chemical Co
`Magnification: 60x
`Voltage: 5 kV
`
`SEM: 4
`Excipient: Ethylcellulnse IOU cps fine pa“ der
`Manufacturer: Dow Chemical Co
`MagnillCalinn: 600x
`Voltage: 5 kV
`
`
`
`Page 5 of 15
`
`Page 5 of 15
`
`

`

`Ef/Iylcellulose
`
`I97
`
`SEM: 5
`Excipiem: Ethylccllulose
`Manufacturer: Hercules Lul
`Lot No: 57911
`Magnification. 600><
`Voltage: 10 kV
`
`SEM: 6,,
`Excipiem:iEuiyiceliulosc lEI/im'cll
`': Dow Chemical Co
`Manufacuu
`
`LOI No: 103051
`Magnification: 600x
`Voltage:
`ll) RV
`
`
`
`
`
`
`
`Table II. Moisture content of ethylcellulose as a function of
`
`equilibrium relative humidity.
`
`Moisture %
`Equilibrium relative humidity
`
`l l
`0,3
`23
`0.60.9
`33
`43
`52
`64
`
`0.9
`1.3v 7
`'"
`
`33
`2-:
`75
`V
`s3
`.
`m
`93
`5.0
`g)
`l()()
`-
`
`V
`(D
`
`m(
`
`5
`
`*’
`
`.4
`
`3
`
`2
`
`fl
`
`SEoE E
`
`g
`é
`LU
`
`
`Table III. Particle size analysis of ethylcellulose.
`Ave. particle size
`Cumulative % frequency
`‘7: Wt.
`(1.1m)
`oversized
`retained
`(wt)
`
`1—19
`0
`0.00
`l37
`1.195
`1.20
`115
`3.983
`2.79
`90
`16.732
`12.75
`64
`37.648
`20.92
`
`69.64846 32.00
`
`
`Page 6 of 15
`
`
`
`
`
`
`l 8
`
`09O 100
`
`l
`
`l
`r
`l
`l
`70
`6
`50
`4O
`30
`Relative humidity %)
`
`0
`, O
`
`10
`
`l
`20
`
`Fig. ]: Equilibrium moisture content of ethylcellulose.
`
`Page 6 of 15
`
`

`

`198 Ethylcellulose
`
`
`
`100
`
`
`
`O)O T
`
`l
`
`
`
`
`
`Weightoversize(%)
`
`.bo
`
`0
`
`l
`l
` L L l
`
`
`J
`l
`400
`500
`200
`300
`100
`0
`Particle size (um)
`
`
`
`Fig. 2: Particle size distribution of ethylcellulose.
`
` 100
`
`80*
`
`60“
`
`
`
`
`
`Weightoversize(%)
`
`
`
`0
`
` | J
`
`I
`1
`l
`l
`l
`l
`400
`500
`200
`300
`100
`O
`Particle size (um)
`
`
`
`Fig. 3: Particle size distribution of ethylcellulose (Ethocel).
`
`10. Typical Properties
`Density (bulk): 0.4 g/cm3
`Glass transition temperature: 129-13300”)
`Hygroscopicity: ethylcellulose absorbs very little water from
`humid air or during immersion, and that small amount
`evaporated readilyf”) The percent equilibrium moisture
`content as a function of relative humidity at 25°C for eth—
`ylcellulose, is shown in Table II. See also Fig. 1.(a)
`Particle size distribution: See Table Ill and Figs. 2 and 3.“”
`
`Page 7 of 15
`
`Table IV. Summary of ethylcellulose grades, suppliers, Viscosity, and
`particle size.
`Mean
`particle
`size
`(pm)
`204
`l60
`9
`210
`225
`5
`
`Supplier
`Dow Chemical
`Aqualon
`Dow Chemical
`Dow Chemical
`Aqualon
`Dow Chemical
`
`Solution
`viscosity
`(mPa 5)
`375.5
`5.6-8
`6.0—8.0
`6—8
`8—ll
`9.0—ll.0
`
`Grade
`Ethocel Std 4 Premium
`N—7
`Ethocel Std 7FP Premium
`Ethocel Std 7 Premium
`N-lO
`Ethocel Std lOFP Premium
`Ethocel Std IOP Premium
`9-11
`Dow Chemical
`N~l4
`12-16
`Aqualon
`Ethocel Std 20F Premium
`l8~22
`Dow Chemical
`N-22
`18-24
`Aqualon
`Ethocel Std 45F Premium
`DOW Chemical 4149
`N—SO
`Aqualon
`40‘52
`N_]OO
`Ethocel Std lOOFP Premium Aqualon
`80—105
`DOW Chemical
`90.0—1100
`Ethocel Std lOOP
`Dow Chemical
`907110
`'
`
`212
`——
`243
`—
`305
`~—
`194
`4O
`
`«
`
`Solubility: ethylcellulose is practically insoluble in glycerin,
`propylene glycol, and water. Ethylcellulose that contains
`less than 46.5% of ethoxyl groups is freely soluble in chlo—
`roform, methyl acetate,
`tetrahydrofuran, and in mixtures
`' of aromatic hydrocarbons with ethanol (95%). Ethylcellu—
`lose that contains not less than 46.5% of ethoxyl groups
`is freely soluble in chloroform, ethanol (95%), ethyl ace-
`_;
`tate, methanol, and toluene.
`.
`Specific gravity: 1.12-1.15 g/cm3
`Viscosity: the viscosity of ethylcellulose is measured typically
`at 25°C using 5% ethylcellulose dissolved in a solvent
`blend of 80% toluene/20% ethanol (w/w). Various viscosity
`grades of ethylcellulose are commercially available (see
`Table lV). They may be used to produce 5% solutions in
`: organic solvent blends with viscosities nominally ranging
`‘
`from 7 mPa s (7 CF) to 100 mPa s (100 cP). Specific eth—
`ylcellulose grades, or blends of different grades, may be
`' used to obtain solutions of a desired viscosity. Solutions
`, of higher viscosity tend to be composed of longer polymer
`chains and produce strong and durable films. The viscosity
`1 of an ethylcellulose solution increases with an increase in
`‘ ethyleellulose concentration, e.g.,
`the viscosity of a 5%
`w/v solution of Ethocel Standard 4 Premium is 4 mPa s
`(4 CF) and a 25% w/v solution of the same cthylcellulosc
`L
`‘ grade is 850 mPa s (850 cP). Solutions with a lower vis—
`cosity may be obtained by incorporating a higher percent—
`‘ age (30~40%) of a low molecular weight aliphatic alcohol,
`such as ethanol, butanol,
`isopropanol, or n-butanol with
`toluene. The viscosity of such solutions depends almost
`entirely on the alcohol content and is independent of toluene
`In addition, nonpharmaceutical grades of ethylcellulose which
`differ in their ethoxyl content and degree of polymerization
`are also available.
`‘31 Handbook of Pharmaceutical Excipients, First Edition.
`
`11. Stability and Storage Conditions
`Ethylcellulose is a stable, slightly hygroscopic material. it is
`chemically resistant to alkalis, both dilute and concentrated,
`and to salt solutions. It is, however, more sensitive to acidic
`
`materials than cellulose esters.I,
`
`Page 7 of 15
`
`

`

`Ethylcellulose
`
`199
`
`19. Comments
`
`Ethylcellulose is compatible with the following plasticizers:
`dibutyl phthalate; diethyl phthalate; dibutyl sebacate; triethyl
`citrate; tributyl citrate; acetylated monoglyceride; acetyl tribu—
`tyl citrate; triacetin; dimethyl phthalate; benzyl benzoate; bu—
`tyl and glycol esters of fatty acids; refined mineral oils; oleic
`acid; stearic acid; ethyl alcohol; stearyl alcohol; castor oil;
`corn oil; camphor.
`
`ER)
`
`(.1)
`
`5.
`
`20. Specific References
`l. Ozturk A, et a1. Mechanism of release from pellets coated
`withtan ethyl cellulose-based film. J Controlled Release
`1990, 14 (3): 203—213.
`Narisawa S, et a1. Porosity—controlled ethyl cellulose film
`coating.
`IV. Evaluation of mechanical strength of porous
`ethyl cellulose film. Chem Pharm Bull 1994; 42(7):
`1491:1495.
`Bodtneier R and Paeratakul O. The effect of curing on drug
`release and morphological properties of ethyl cellulose
`pseudolatex-coated beads. Drug Dev Ind Pharm 1994; 20(9):
`1517-1533.
`4. Dressman J, et a1. Circumvention of pH—dependent release
`from ethyl cellulose—coated pellets. JControlled Release
`1995; 36(3): 251-260.
`Iyer U, et al. Comparative evaluation of three organic solvent
`and dispersion-based ethyl cellulose coating formulations.
`Pharmaceut Technol 1990; 14(9): 68—86.
`6. Sarisuta N, Sirithunyalug J. Release rate of indomethacin
`from coated granules. Drug Dev Ind Pharm 1988: 14:
`683-687.
`7. Porter SC. Controlled—release film coatings based on ethyl—
`cellulose. Drug Dev Ind Pharm 1989; 15(10): 1495—1521.
`8. Goracinova K, et al. Preparation, physical characterization,
`mechanisms of drug/polymer interactions, and stability stud-
`ies of controlled—release solid dispersion granules containing
`weak. base as active substance. Drug Dev Ind Pharm 1996:
`22(3): 255-262.
`_
`9. Lin S, et al. Studies on microencapsulation._l4. Theophylllne
`bioavailability after single oral—administration of sustained—I
`release microcapsules. Cur Ther Res Clin Exp 1987; 41(4)
`564—573.
`.
`.
`10. Pollock D and Sheskey P. Opportunities in direct—compres
`sion controlled—release tablets. Pharmaceuz‘ Technol 1996;
`20(9): 1207130.
`,
`ll. Klinger (3, Ct al. FOl'l'lluliillOn of controlled release matrix“
`by granulation with a polymer disperston. Drug Dev Ind
`Pharm 1990; 16(9): 1473-1490.
`12. Katilcaneni P, et al. Ethyl cellulose matrix controlled-release
`tablets of a water-soluble drug. Int J. Pharmaceutics 1995;
`123: 1199-125.
`13. Kent D, etal. Solubility studies on ethyl cellulose used in
`film coating. J Pharm Pharmacol 1978; 30: 808—810.
`14. Rowe R. The prediction of compatibility/incompatibility in
`blends of ethyl cellulose with hydroxypropyl methylcellulose
`or hydroxypropyl cellulose using 2-dimensional solubility
`parameter maps. J Pharm Pharmacol 1986; 38: 214—215.
`15. Saettone M, et al. Effect of different polymer—plasticizer
`combinations on ‘in vitro’ release of theophylline from
`coated pellets. Int J Pharmaceutics 1995; 126: 83-88.
`16. Beck M, Tomka I. On the equation of state of plasticized
`ethyl‘cellulose of varying degrees of substititution. Macro-
`moledules 1996; 29(27): 8759—8766.
`17. Celilq M. Compaction of Multiparticulate Oral Dosage
`Forms. In: Ghebre-Sellassie I, editor. Multiparticulate Oral
`Drug Delivery, New York, Marcel Dekkcr Inc., 1994;
`181—215.
`
`Ethylcellulose is subject to oxidative degradation in the pres—
`ence of sunlight or UV light at elevated temperatures. This
`may be prevented by the use of an antioxidant and chemical
`additives which absorb light in the 230—340 nm range.
`Ethylcellulose should be stored at a temperature not exceeding
`QODF (32°C) in a dry area away from all sources of heat. Do
`not store next to peroxides or other oxidizing agents.
`
`12. Incompatibilities
`Incompatible with paraffin wax and microcrystalline wax.
`
`13. Method of Manufacture
`
`Ethylcellulose is prepared by treating purified cellulose
`(sourced from chemical—grade cotton linters and wood pulp)
`with an alkaline solution followed by ethylation of the alkali
`cellulose with chloroethane:
`
`RONa + C2H5Cl —-> ROC2H5 + NaCl
`
`where R represents the cellulose radical. The manner in which
`the ethyl group is added to cellulose can be described as the
`Degree of Substitution (DS) The DS designates the average
`number of hydroxyl positions on the anhydroglucose unit that
`have been reacted with ethyl chloride. Since each anhydro—
`glucose unit of the cellulose molecule has three hydroxyl
`groups, the maximum value for DS is three.
`
`14. Safety
`Ethylcellulose is widely used in oral and topical pharmaceu—
`tical formulations. It is also used in food products. Ethylcele
`lulose is not metabolized following oral consumption and is
`therefore a noncaloric substance. It is generally regarded as
`a nontoxic, nonallergenic, and nonirritating material. Ethyl—
`cellulose is not metabolized and therefore is not recommended
`for parenteral products; parenteral use may be harmful to the
`kidneys.
`hazard,
`(24)
`Since ethylcellulose is not considered to be a health
`the WHO has not specified an acceptable daily intake.
`
`15. Handling Precautions
`It is important to prevent fine (Just clouds or Clhylcullulosc
`from reaching potentially explosive levels in the air. Ethyl—
`cellulose is combustible. Ethylcellulosc powder my be an ir—
`ritant to the eyes and therefore eye protection should be worn.
`
`16. Regulatory Status
`Ethylcellulose is GRAS listed and is included in the FDA
`Inactive Ingredients Guide (oral capsules, suspensions and
`tablets, topical emulsions, and vaginal preparations).
`
`17. Pharmacopeias
`Eur, Int, and US.
`
`18. Related Substances
`
`Ethylcellulose is commercially available as a powder and as
`an aqueous colloidal dispersion or ethylcellulose aqueous dis—
`persion. Other related water-insoluble cellulosic polymers in—
`clude cellulose acetate butyrate, cellulose acetate, and
`cellulose nitrate. Methylcellulose is the closest chemically re~
`lated substance.
`
`Page 8 of 15
`
`Page 8 of 15
`
`

`

`200 Ethylcellulose
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`Robinson DH. Ethyl cellulose-solvent phase relationships
`relevant to coacervation microeneapsulation processes. Drug
`Dev Ind Pharm 1989; 15: 2597-2620.
`Lavasanifar A, et a1. Microencapsulation of theophylline
`using ethyl cellulose: In vitro drug release and kinetic mod—
`eling. J Microencapsulazion 1997; 14(1): 91-100.
`Moldenhauer M, Nairn J. The control of ethyl cellulose
`microencapsulation using solubility parameters. J Controlled
`Release 1992; 22(3): 205-218.
`Friedman M, et al. Inhibition of plaque formation by a sus—
`tained release delivery system for cetylpyridinium chloride.
`Int J Pharmaceutics 1988; 44: 243—247.
`Sakellariou P, Rowe RC, White EFT. The thermomechanical
`properties and glass transition temperatures of some cellulose
`derivatives used in film coating. Int J Pharmaceutics 1985;
`27: 267-277.
`
`i 24. FAQ/WHO. Evaluation of certain food additives and contaminants:
`thirty-fifth report of the joint FAQ/WHO expert committee on food
`additives. Tech Rep Ser Wld Hlth Org 1990', No. 789.
`
`‘21. General References
`Dow Chemical Company. Technical literature: Ethocel, FP Poly—
`mers Product Specification Sheet, 1996.
`Dow Chemical Company. Technical literature: Ethocel Premium
`Polymers for Pharmaceutical Applications. 1996.
`European Pharmacopoeia, Council of Europe, 3rd edition, Sup-
`plement 1999, Strassbourg, 1999; 8480-8481.
`Hercules Incorporated. Technical literature: Aqualon Ethylcellu-
`lose (EC), 1996.
`’
`:Majewicz T, Podlas T. Cellulose others: In: Kroschwitz J., editor
`Encyclopedia of Chemical Technology. New York, NY, John
`Wiley & Sons. Inc, 1993; 541563.
`
`Callahan JC, Cleary GW, Elefant M, Kaplan G, Kensler T,
`Nash RA. Equilibrium moisture content of pharmaceutical
`excipients. Drug Dev Ind Pharm 1982; 8: 355—369.
`
`122. Authors
`:TC Dahl.
`
`Page 9 of 15
`
`Page 9 of 15
`
`

`

`
`
`Polymethacrylates
`
`For Eudmgit NE 30 D:
`
`R], R3‘= H, CH3
`R2, R4I= CH3, CQHS
`
`Polymethacrylazes 401
`
`For Eudragiz L 30 D—55 and L 100-55, Eastacryl 30D, Kol-
`licoat MAE 30 D and MAE 30 DP
`
`R1, R3,: H, CH3
`R2 = H
`R4 = CH3, CZHS
`
`6. Functional Category
`
`Film former; tablet binder; tablet diluent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Polymethacrylates are primarily used in oral capsule and tab-
`let formulations as film—coating agents.i1'15) Depending on the
`type of polymer used, films of different solubility character-
`istics canébe produced, see Table III.
`
`Eudragit E is used as a plain or insulating film former; it is
`soluble in gastric fluid below pH 5. In contrast, Eudragil L
`and S types are used as enteric coating agents since they are
`resistant to gastric fluid. Different types are available which
`are soluble at different pH values, e.g., Eudragit L 100 is
`soluble at > pH 6, Eudragit S 100 is soluble at > pH 7.
`Eudragit KL, RS, and NE 30 D are used to form water~insol-
`uble film coats for sustained—release products. Eudragit RL
`films are more permeable than those of Eudragit RS, and by
`mixing the two types together films of varying permeability
`can be obtained.
`
`Eudragit L 30 D55 is used as an enteric coating film former
`for solid—dosage forms. The coating is resistant to gastric JUICE
`but readily dissolves at a pH above 5.5.
`Eudragit L [00-55 is an alternative to Eudragir L 30 D—55.
`It is commercially available as a redlspersrble powder.
`Eastacryl 30D, Kallicoat MAE 30 D, and Kollicoat MAE 30
`DP, are aqueous dispersions of methacryhc acrd/ethyl acrylate
`copolymers. They are also used as enteric coatings for solid—
`dosage forms.
`
`Polymethacrylates are also used as binders in both aqueous
`and organic wet—granulation processes. Larger quantities
`(5-20%) of dry polymer are used to control the release of an
`active substance from a tablet matrix. Solid polymers may be
`used in direct-compression processes in quantities of lO-50%.
`Polymethacrylate polymers may additionally be used to form
`the matrix layers of transdermal delivery systems and have
`also been used to prepare novel gel formulations for rectal
`administrationf”)
`See also Section 19.
`
`8. Description
`Polymethacrylates are synthetic cationic and anionic polymers
`of dimethylaminoethylmethacrylates, methacrylic acid, and
`methacrylic acid esters in varying ratios. Several different
`types are commercially available and may be obtained as the
`dry powder, an aqueous dispersion, or as an organic solution.
`A (60:40) lmixture of acetone and propan—Q—ol
`is most come
`monly user'i as the organic solvent. See Tables I and II.
`
`1. Nonproprietary Names
`
`USP: Ammonio methacrylate copolymer
`USP: Methacrylic acid copolymer
`Note that
`two separate monographs applicable to poly—
`methacrylates are contained in the USP; see Section 9.
`
`2. Synonyms
`
`Eastacryl 300; Eudmgit; Kallicoat MAE 30 D; Kallicoat
`MAE 30 DP; polymeric methacrylates,
`
`3. Chemical Name and CAS Registry Number
`See Table l.
`
`4. Empirical Formula and Molecular Weight
`
`The USP describes methacrylic acid copolymer as a fully po—
`lymerized copolymer of methacrylic acid and an acrylic or
`methacrylic ester. Three types, Type A, Type B, and Type C,
`are defined in the monograph. They vary in their methacrylic
`acid content and solution viscosity. Type C may contain suit-
`able surface-active agents. Two additional polymers, Type A
`(Eudragir RL) and Type B (Eudragit RS), also referred to as
`ammonio methacrylate copolymers, consisting of fully poly—
`merized copolymers of acrylic and methacrylic acid esters
`with a low content of quaternary ammonium groups, are also
`described in the USP. See Section 9.
`
`Typically, the molecular weight of the polymer is 2100 000.
`
`5. Structural Formula
`
`1'23
`1,11
`1'23
`$1
`------- c —— CHZ— C — CH2—- c — CH2——- Cl —— Griz-«~-
`l
`l
`I
`c=o
`C=O
`C=O
`$=0
`I
`.L
`A
`o
`o
`I
`I
`r
`l
`R2
`R4
`R2
`R,i
`
`For Eudmgit E:
`R1, R3 = CH3
`R2 = CHZCH2N(CH3)2
`R4 = CH3, C4H9
`For Eudragz't L and S:
`R, R3 = CH3
`R2 = H
`R4 = CH3
`For Eudragit RL and RS:
`R1 = H, CH3
`R2 = CH3, Csz
`R3 = CH3
`R4 = CHQCH2N(CH3)3*CI'
`
`Page100f15
`
`Page 10 of 15
`
`

`

`402 Polymethacrylates
`
`———+—
`Table 1: Chemical name and CAS Registry Number of polymethacrylates.
`Chemical name
`Trade name
`Company name
`CAS number
`
`Poly(butyl methacrylate, (2-dimethyl aminoethyl)
`Eudrégiz E 100
`Rohm GmbH
`[24938»16—7|
`methacrylate, methyl methacrylate) 1:221
`Eudrqgir E 12.5
`Rohm GmbH
`Poly(ethy1 acrylate, methyl methacrylate) 2:1
`Eudragit NE 30 D
`Rohm GmbH
`[9010-882]
`(formerly Eudragit 30 D)
`Poly(methacrylic acid, methyl methacrylate) 1:1
`Eudragit L 100
`Rohm GmbH
`[25806-15—1]
`Eudragi! L 12.5
`Rohm GmbH
`Eudragit L 12.5 P
`Rohm GmbH
`Eudragit L 30 D—55
`Rohm GmbH
`Eudragit L 100-55
`Rohm GmbH
`Easta‘cryl 30D
`Eastman Chemical
`Kollz‘toar MAE 30 D
`BASF Fine Chemicals
`Kalli’coat MAE 30 DP
`BASF Fine Chemicals
`Eudragit S 100
`Rohm GmbH
`Eudragit S 12.5
`Rohm GmbH
`Eudragit S 12.5 P
`Rohrn GmbH
`Eudragir RL 100
`Eudrpgit RL P0
`Eudragzt RL 30 D
`Eudragit RL 12.5
`Eudraaiz RS 100
`‘
`s
`.
`Rohm GmbH
`E d a 7 RS PO
`Poly(ethy1 acrylate. methyl methacrylate, tximethylammomoet
`Rohm GmbH
`E:d::§1t RS 30 D
`methacrylate chloride) 1:2:0.l
`Rohm GmbH
`Eudragir RS 12.5
`
`
`[25212—88—81
`[25212~88-8]
`[25212-88—8]
`
`[25086-154]
`
`[33434244]
`
`[33434'24’1]
`
`Rohm GmbH
`Rohm GmbH
`Rohm GmbH
`
`Poly(methacrylic acid, ethyl acrylate) 1:1
`
`Poly(methacrylic acid, methyl methacrylate) 1:2
`
`Poly(ethyl acrylate, methyl methacrylate. trimethylammonioethy
`methacrylate chloride) 1:2:O.2
`
`h 1
`)
`
`Table II: Solubility of commercially available polymethacrylates in various solvents.
`Type
`Solvent
`1N NaOH Petroleum ether Walel'
`1N HCl
`Acetone and Dichloromethane Ethyl acetate
`alcohols“)
`
`Eudragit, Rdhm GmbH
`Eudragit E 12.5
`Eudragit E 100
`Eudragit L 12.5 P
`Eudragit L 12.5
`Eudragit L [00—55
`Eudragit L 100
`Eudragiz L 30 D—551‘” M“)
`Eudragil S 12.5 P
`Eudragit S 12.5
`Eudragit S 100
`Eudragit KL 12.5
`Eudragit RL 100
`Eudragir RL P0
`Eudragit RL 30 D
`Eudragl't RS 12.5
`Eudragit RS 100
`Eudmgit RS PO
`M“)
`Eudragit RS 30 D
`Eastacryl, Eastman Chemical Company
`_
`Mid)
`._
`_
`-—
`Ml“)
`Eastacryl 30D”)
`Kallicoat, BASF Fine Chemicals
`._
`MM)
`_.
`_~
`‘
`——
`Ml“)
`Kollicoat MAE 30 Dib’
`
`-
`_
`—
`Ml“)
`Kullicoat MAE 30 DP“)
`Mid)
`_._
`
`
`mezzwmzmzzlwwzzmz
`
`(E)
`
`ammzzwwzrzzlrrzzmz
`
`3mmgzmmi“zzl”“zzmz
`
`ll
`
`““11““Ilmzzlmwzzll
`
`HHHrUHHHrgl—«wgvggwy—awrgHz
`
`l—lh—dl—UV-UHI
`
`23gZ““§§”“§H“‘jm
`
`Where: S = soluble; M = miscible; I : insoluble or immiscible; P = precipitates.
`“‘1 Alcohols including ethanol, methanol and propan-2~ol.
`(”1 Supplied as a milky-white colored aqueous dispersion.
`(C) A 1:5 mixture forms a clear, viscous, solution.
`W A 1:2 mixture forms a clear or slightly opalescent, viscous liquid.
`‘6) A 1 part of both Eudragit RL 30 D and Eudmgit RS 30 D dissolve completely in 5 parts acetone, ethanol or propan-Z—ol to form a clear or slightly turbid
`solution. However, when mixed in a ratio of 1:5 with methanol, Eudragil RL 30 D dissolves completely, whereas Eudragiz RS 30 D only partially.
`
`Page 11 of15
`
`Page 11 of 15
`
`

`

`
`
`3 id units
`°
`
`te copolymers
`
`Polymethacrylates 403
`
`
`
`1:1. Films prepared from the copolymers dissolve above pH
`iragit E is cationic polymer based on dimethylaminoethyl
`5.5 forming salts with alkalis, thus affording coatings which are
`thacrylate and other neutral methacrylic acid esters. It is
`insoluble in gastrli: media, but soluble in the small intestine.
`0
`uble in gastric fluid as well as in weakly acidic buffer
`llicoat MAE 30 D, and Kollicoat MAE 30
`Eastacryl 30D
`utions (up to approximately pH 5). Eudragit E is available
`DP are also aq eous dispersions of the anionic copolymer
`a 125% ready—to-use solut10n' in propan-Z-ol/acetone
`based on methac ylic acid and ethyl acrylate. The copolymer
`MO)‘ It ‘3 llght yellow m 001” With the characteristic odor
`also corresponds to USPNF methacrylic acid copolymer, Type
`the solvents. Solvent—free granules contain 298% dried
`C. The ratio of free-carboxyl groups to ester groups is 1:1.
`lght content Of Eudragrt E'
`Films prepared iFrom the copolymers dissolve above pH 5.5
`dragit L and S, also referred to as methacylic acid copol-
`forming salts w th alkalis, thus affording coatings which are
`ters in the USP monograph, are anionic copolymerization
`insoluble in gastric media, but soluble in the small intestine.
`oducts of methacrylic acid and methyl methacrylate. The
`Eudragit L 10055 (prepared by spray-drying Eudragit L 30
`:10 of free carboxyl groups to the ester is approximately 1:1
`D-55) is a white, free-flowing powder which is redispersible
`Eudragtt L and approxu'nately 1’2 1“ Eudrlagzt 5' Both poly—
`in water to form a latex which has properties similar to
`ers are readlly 5011MB in neutral to weak y alkaline condi-
`:7
`Eudragit L 30 13—55.
`)ns (pH_ 6—7) and form salts wrth alkalis, thus affording film
`2
`rats Wthh are resrstant to gastrlc media but soluble in 1n-
`E
`.
`_
`.
`stinal fluid. They are available as a 12.5% solution in pro-
`.:
`9- Pharmacoperal Spec1ficatlons
`m-2-ol without plasticizer (Eudragit L 12.5 and S 12.5); and
`:5
`Specifications 1‘ r methacrylic acid copolymers (Eudragit L,
`i a 125% ready—to—use solution in propan—Z—ol With 125%
`31
`S, L 30 D—55, gastacryl 30D, Kollicoat MAE 30 D, and Kol—
`.butyl phthalate as plasticizer (Eudragit L 12.5 P and S 12.5
`g
`licoat MAE 30 DP).
`). Solutions are colorless, with the characteristic odor of the
`%
`)lvcnt. Eudragit L—100 and Eudragit S-100 are white free—
`owing powders with at least 95% of dry polymers. / ~
`'udragit RL and Eudragit RS, also referred to as ammoni-
`Test
`USP
`methacrylate copolymers in the USP monograph, are copol-
`Identification
`+
`.1
`mers synthesized from acrylic acid and methacrylic acid
`Viscosity
`sters with Eudragit RL (type A) having 10% of functional qua-
`Type A
`50-200 mPa s
`;
`emary ammonium groups and Eudragit RS (type B) having 5%
`Type B
`50-200 mPa s
`i
`if functional quaternary ammonium groups. The ammonium
`Type c
`100-200 mPa s
`‘
`groups are present as salts and give rise to pH—independent
`Loss on drying
`)ermeability of the polymers. Both polymers are water—insol-
`Type A
`g 5.0%
`ible, and films prepared from Eudragit RL are freely perme-
`Type B
`55.0%
`ible to water, whereas, films prepared from Eudragit RS are
`Type C
`s 5.0%
`)nly slightly permeable to water. They are available as 12.5%
`Residue on ignit on
`ready-to-use solutions in plOpan-Z-ol/acetone (60:40). Solu—
`TypeA
`30.1%
`.
`tions are colorless or slightly yellow in color, and may be
`TypeB
`i083;
`clear or slightly turbid; they have an odor characteristic of
`Type C
`2 2.
`cm
`the solvents. Solvent-free granules (Eudragit RL 100 and
`Arsenic
`208827
`‘
`Eudragit RS 100) contain 2 97% of the dried weight content
`Heavy metals
`20-37 0
`1,
`h .
`of the polymer.
`Monomefrs
`' '
`a
`Eudragit RL PO and Eudragit RS P0 are finej white powders WI
`“(5331; gift” ‘6
`a slight amine—like odor. They are characteristically the same poly—
`Type A
`;
`46.0-50.6%
`mers as Eudragit RL and RS. They contain 2 97% of dry Polymef-
`Type B
`27.6—30.7%
`46.0—50.6’70
`Eudragit RL 30 D and Eudragit RS 30 D are aqueous disper—
`Type C
`.
`sions of copolymers of acrylic acid and methacrylic acrd es—
`ters with a low content of quaternary ammonium groups. The
`.
`dispersions contain 30% polymer. The quaternary groups 00—
`Specifications for ammonio methacryla
`l
`(Eudragit RD and RS).
`bility 0f films
`cur as salts and are responsible for the permea
`made from these polymers. Films prepared from Eudragit RL
`dissolved active /USP
`30 D are readily permeable to water and to
`substances, whereas films prepared from Eudragit RS 30 D
`Te“
`are less permeable to water. Film coatings prepared from both
`Identification
`polymers give pH-independent release of active substance.
`Viscosity
`Plast1c12ers are usually added to improve film propertles.
`Types A am B
`Eudragit NE 30 D is an aqueous dispersion of a neutral co-
`Loss on dryin‘
`polymer consisting of polymethacrylic acid esters. The dis-
`TypesA an B
`persions are milky-white liquids of low viscosity and have a weak
`Residue on ig ition
`aromatic odor. Films prepared from the lacquer swell in water,
`Types A an B
`to which they become permeable. Thus, films produced are in-
`Arsenic
`soluble in water, but give pH-independent drug release.
`Heavy metals 1
`_
`,
`.
`.
`Ezrdragit L 30 D—55,
`is an aqueous dispersion of an anionic
`Monomers
`,
`:spolymer based on methacrylic acid and ethyl acrylate. The
`Assay 0f ammrmo methacrylate ““5 (dned has“)
`Type A
`;:polymer corresponds to USP methacrylic acid copolymer,
`Type C. The ratio of free—carboxyl groups to ester groups is
`Type B
`i
`
`+
`S 15 mPa s
`33.0%
`S 0.1%
`s 2 ppm
`g 0.002%
`5 (“5%
`BBS-11.96%
`4.48-6.77%
`
`Page120f15
`
`Page 12 of 15
`
`

`

`Table 111: Summary of properties and uses of commercially available polymethacrylates.
`Type
`Supply form
`Polymer dry
`Recommended
`Solubility
`Applications
`weight content
`solvents or diluents
`
`Eudragit. Riihm GmbH
`Eudragir E 125
`
`
`
`12.5%
`
`98%
`
`12.5%
`
`12.5%
`
`95%
`95%
`30%
`12.5%
`12.5%
`95%
`12.5%
`97%
`l
`97%
`’
`i
`30%
`l
`12.5% *
`97%
`.
`97%
`‘
`30%
`‘
`30% or 40%
`
`404 Polymethacrylates
`
`Eudragit E 100
`
`Eudragit L 12.5 P
`
`Eudragit L 12.5
`
`Eudragit L 100
`Eudragit L 100-55
`Eudmgit L 30 D-55
`Eudragit S 12.5 P
`Eudmgit S 12.5
`.
`Eudragzt S 100
`Eudragit RL 12.5
`.
`Eudraglt RL 100
`Eudmgit RL P0
`Eudragit RL 30 D
`Eudragit RS 12.5
`Eudragit RS 100
`Eudragiz RS PO
`Eudragit RS 30 D
`Eudragit NE 30 D
`
`Organic
`solution
`Granules
`
`Organic
`solution
`Organic
`solution
`Powder
`Powder
`Aqueous
`dispersion
`Orsgjlnuigon
`Organic
`solution
`Powder
`Organic
`Griillulteizn
`Powder
`Aqueous
`dispersion
`Organic
`solution
`Granules
`Powder
`Aqueous
`dispersion
`Aqueous
`dispersion
`
`Acetone, alcohols
`to pH 5
`Acetone, alcohols
`
`Acetone, alcohols
`
`Acetone. alcohols
`
`Acetone, alcohols
`Acetone, alcohols
`Water
`Acetone, alcohols
`Acetone. alcohols
`Acetone, alcohols
`Acetone, alcohols
`Acetone, alcohols
`Acetone, alcohols
`W ter
`a
`Acetone. alcohols
`Acetone, alcohols
`Acetone, alcohols
`Water
`Water
`
`Soluble in gastric fluid
`
`