~JtbDth o~!
`
`SECOND EDITION
`
`A joint publication of the American Pharmaceutical Association
`and the Royal Pharmaceutical Society of Great Britain
`
`~.:
`
`~.
`
`II
`
`; ~A
`
`-.
`
`4~~%i~ ~
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`
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`AMERIC
`
`PHARMACEUTICAL ASSOCIATION
`
`Page 1 of 13
`
`KVK-TECH EXHIBIT 1028
`
`

`

`Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`American Pharmaceutical Association
`Washington
`
`1994
`
`The Pharmaceutical Press
`London
`
`Page 2 of 13
`
`

`

`© Copyright 1986, 1994 by the American Pharmaceutical Association, 2215 Constitution Avenue NW, Washington,
`DC 20037-2985, USA, and The Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High
`Street, London, SE1 7JN, England.
`
`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 9449492.
`
`International Standard Book Number (ISBN) in the UK: 0 85369 305 6
`International Standard Book Number (ISBN) in the USA: 0 91730 66 8
`
`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopy, recording, or any information storage or retrieval system, without prior written permission from
`the joint publishers.
`
`Typeset in Great Britain by Alden Multimedia, Northampton.
`Printed and bound in Great Britain by
`
`Page 3 of 13
`
`Page 3 of 13
`
`

`

`ethylcellulose films without the need for organic solvents. With
`coats of hydrated ethylcellulose, drug release is via diffusion.
`This can be a slow process unless a large surface area is utilized
`and aqueous ethylcellulose dispersions tend therefore to be
`used to coat granulesi~8’9~
`Ethylcellulose is also widely used in drug microencapsula
`tion,~°~4~ high viscosity grades usually being used. Release of
`a drug from an ethylcellulose microcapsule is a function of the
`microcapsule wall thicknessi’2~
`In tablet
`formulations, ethylcellulose may additionally be
`employed as a binder, the ethylcellulose being blended dry or
`wet-granulated with a solvent such as ethanol
`(95%).
`Ethylcellulose produces hard tablets, with low friability; they
`may however demonstrate poor dissolution.
`In topical formulations, ethylcellulose is used as a thickening
`agent
`in creams,
`lotions or gels, provided an appropriate
`solvent is used.
`Ethylcellulose is additionally used in cosmetics and food
`products.
`
`Concentration (%)
`10.0-20.0
`3.0-10.0
`1.0-3.0
`1.0-3.0
`
`free-flowing, white to light
`
`tan
`
`Use
`
`Microencapsulation
`Sustained release tablet coating
`Tablet coating
`Tablet granulation
`
`8. Description
`Ethylcellulose is a tasteless,
`colored powder.
`
`SEM: 1
`Excipient: Ethylcellulose
`Manufacturer: Hercules Ltd
`Lot No.: 57911
`Magnification: 60x
`voltage: 10 kV
`
`186 Ethylcellulose
`
`Ethylcelinlose
`
`1. Nonproprietary Names
`BP: Ethylcellulose
`PhEur: Ethylcellulosum
`USPNF: Ethylcellulose
`
`2. Synonyms
`Aquacoat; E462; Ethocel; Surelease.
`
`3. Chemical Names and CAS Registry Number
`Cellulose ethyl ether [9004-57-3]
`
`Molecular Weight
`4. Empirical Formula
`Ethylcellulose is an ethyl ether of cellulose, a long-chain
`polymer consisting of anhydroglucose units joined together by
`acetal
`linkages. Each anhydroglucose unit has three replace
`able hydroxyl groups which are substituted to the extent of
`2.25-2.60 ethoxyl groups (0C2H5) per unit, equivalent to an
`ethoxyl content of 44-51%.
`
`5. Structural Formula
`
`CH,OC~I5,
`
`L
`
`OC~H,
`
`—
`
`n
`
`Structure shown with complete ethoxyl substitution. See also
`Section 4.
`
`6. Functional Category
`Coating agent; tablet binder; viscosity-increasing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Ethylcellulose is widely used in oral and topical pharmaceu
`tical formulations.
`formulations is as a
`The main use of ethylcellulose in oral
`hydrophobic coating agent
`for
`tablets and granulesi~1~
`Ethylcellulose coatings are used to modify the release of a
`drug,~5~ to mask an unpleasant taste, or to improve the stability
`of a formulation, e.g. ethylcellulose dissolved in propan-2-ol is
`used to coat ascorbic acid granules to prevent oxidation.
`Modified release tablet
`formulations may also be produced
`using ethylcellulose as a matrix former.~6~
`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, tougher films. Ethylcellulose films may be modified,
`to alter their solubility, by the addition of hydroxypropyl
`methylcellulose~7~ or a plasticizer, see Section 19. An aqueous
`polymer dispersion (or
`latex) of ethylcellulose such as
`Aquacoat (FMC Corporation) may also be used to produce
`
`Page 4 of 13
`
`

`

`SEM: 2
`Excipient: Ethylcellulose
`Manufacturer: Hercules Ltd
`Lot No.: 57911
`Magnification: 600x
`Voltage: 10 kV
`
`SEM: 4
`Excipient: Ethylcellulose (Ethocel)
`Manufacturer: Dow Chemical Company
`Lot No.: 103051
`Magnification: 600x
`Voltage: 10 kV
`
`Ethylcellulose
`
`187
`
`SEM: 3
`Excipient: Ethylcellulose (Ethocel)
`Manufacturer: Dow Chemical Company
`Lot No.: 103051
`Magnification: 60x
`Voltage: 10 kV
`
`9. Pharmacopeial Specifications
`
`Test
`Identification
`pH (2% w/w suspension)
`Viscosity
`Loss on drying
`Residue on ignition
`Sulfated ash
`Arsenic
`Lead
`Heavy metals
`Acetaldehyde
`Chlorides
`Assay (of ethoxyl groups)
`
`PhEur 1993
`+
`5.0-7.5
`+
`~ 3.0%
`
`—
`
`~ 0.5%
`
`—
`
`—
`
`~ 20 ppm
`~ 100 ppm
`~ 0.05%
`
`—
`
`USPNF XVII
`+
`
`—
`
`+
`~ 3.0%
`~ 0.4%
`
`—
`
`~ 3 ppm
`~ 10 ppm
`~ 40 ppm
`
`—
`
`—
`
`44.0-51.0%
`
`10. Typical Properties
`Density (bulk): 0.4 gjcm3
`Glass transition temperature: 130-1 33°C~3~
`Hygroscopicity: ethylcellulose absorbs very little water at high
`relative humidities or during immersion; any absorbed water
`evaporates readily)~’5~ See also HPE Data.
`Solubility: practically insoluble in glycerin, propylene glycol
`and water. Ethylcellulose that contains less than 46.5% of
`ethoxyl groups is freely soluble in chloroform, methyl acetate,
`tetrahydrofuran, and in mixtures of aromatic hydrocarbons
`with ethanol (95%). Ethylcellulose that contains not less than
`46.5% of ethoxyl groups is freely soluble in chloroform,
`ethanol (95%), ethyl acetate, methanol and toluene.
`SpecifIc gravity: 1.12-1.15
`Viscosity: various grades of ethylcellulose are commercially
`available which differ in their ethoxyl content and degree of
`polymerization. They may be used to produce 5% w/v
`
`Page 5 of 13
`
`

`

`5
`
`4
`
`3
`
`2
`
`0U
`
`,
`CU
`‘U
`a)
`
`a,
`
`066
`
`.0
`
`0~a,
`Ca,
`C)
`a)a-
`
`—
`
`)
`
`10
`
`20
`
`40
`50
`30
`60
`70
`Percent Relative Humidity
`Fig. 1: Equilibrium moisture content of ethylcellulose.~’~
`
`80
`
`90
`
`100
`
`100
`
`80
`
`60
`
`40
`
`20
`
`1
`
`0,
`
`0
`
`0
`
`100
`
`200
`300
`Particle size (jim)
`Fig. 2: Particle size distribution of ethylcellulose.
`
`400
`
`50C
`
`13. Method of Manufacture
`Ethylcellulose is prepared from wood pulp by treatment witi
`alkali
`followed by ethylation of
`the alkali cellulose witi:
`chloroethane.
`
`14. Safety
`Ethylcellulose is widely used in oral and topical pharmaceu.
`tical formulations. It is also used in food products.
`Ethylcellulose is not metabolized following oral consumption
`and is therefore a noncaloric substance. It is generally regarded
`as a nontoxic, nonallergenic and nonirritant material. Since
`ethylcellulose is not metabolized it is not recommended for use
`in parenteral products; parenteral use may be harmful to the
`kidneys.
`
`188 Ethylcellulose
`
`solutions, in organic solvents, with viscosities of 6-110 mPa s
`(6-110 cP), see also Section 19. Specific ethylcellulose 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 stronger,
`tougher films. The viscosity of solutions increases with an
`increase in concentration of ethylcellulose, e.g. the viscosity at
`25°C of a 5% w/v solution of Ethocel
`in an 80/20 toluene/
`ethanol solvent blend is 4 mPa s (4 cP), whilst a 25% w/v
`solution in the same solvent mixture has a viscosity of 850
`mPas (850 cP). Solutions with a lower viscosity may be
`obtained by incorporating a higher percentage (up to 35%) of
`a low molecular weight aliphatic alcohol, such as methanol or
`ethanol, in a solvent mixture. The viscosity of such solutions
`depends almost entirely on the alcohol content and is
`independent of the other aromatic solvent.
`
`Average flow rate
`Moisture content
`
`Particle friability
`Particle size
`
`1.853%~
`
`(a)
`
`0.700% (a)
`1.020% (b)
`See Fig.
`I
`0.068% ~
`See Fig. 2. ~
`See Fig. 3. ~
`
`HPE Laboratory Project Data
`Method
`Lab #
`Results
`24
`1.66 g/s ~
`FLO-3
`MC-29
`23
`MC-20
`15
`23
`MC-29
`EMC-l
`15
`PF-1
`36
`PSD-6
`23
`PSD-6
`23
`SOL-6
`23
`Solubility
`Ethanol (95%) at 25°C
`Ethanol (95%) at 25°C
`Ethanol (95%) at 37°C
`Ethanol (95%) at 37°C
`Hexane at 25°C
`Hexane at 25°C
`Hexane at 37°C
`Hexane at 37°C
`Propylene glycol at 25°C
`Propylene glycol at 25°C
`Propylene glycol at 37°C
`Propylene glycol at 37°C
`Water at 25°C
`Water at 25°C
`Water at 37°C
`10 mg/mL (b)
`Water at 37°C
`Supplier:
`a. Hercules Ltd (Lot No.: 58587); b. Dow Chemical
`Company.
`
`53 mg/mL~
`< 2 mgjmL~
`25 mg/mL~
`< 1 mg/mL~
`
`15 mg/mL ~
`66 mg/mL ~
`25 mg/mL ~
`
`< 2 mg/mL ~
`< 6 mg/mL (a)
`< 6 mg/mL ~
`
`25 mg/mL ~
`25 mg/mL ~
`25 mg/mL ~
`< 1 mg/mL ~
`10 mg/mL (b)
`
`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, although it is more sensitive to acidic
`materials than cellulose esters.
`Ethylcellulose is subject
`to oxidative degradation in the
`presence of sunlight or UV light at elevated temperatures.
`This may be prevented by the use of an antioxidant and a
`compound with light absorption properties between 230-
`340 nm.
`The bulk material should be stored in a dry place, in a well-
`closed container at a temperature between 7-32°C.
`
`12. Incompatibilities
`Incompatible with paraffin wax and microcrystalline wax.
`
`Page 6 of 13
`
`

`

`a)
`!~
`U,
`a)
`0
`
`0)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`0
`
`100
`
`300
`200
`Particle size (j.im)
`
`400
`
`500
`
`Fig. 3: Particle size distribution of ethylcellulose (Ethocel).
`
`The WHO has not specified an acceptable daily intake of
`ethylcellulose since the level of use in foods was not considered
`to be a hazard to health.~6~
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Dust may be irritant to the
`eyes and eye protection should therefore be worn. Excessive
`dust generation should be avoided to minimize the risk of
`explosions. Ethylcellulose is combustible.
`
`16. Regulatory Status
`GRAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Guide (oral
`capsules, suspensions and tablets,
`topical emulsions and
`vaginal preparations).
`Included in nonparenteral medicines
`licensed in the UK.
`
`17. Pharmacopelas
`Br, Eur, Mex and USPNF.
`
`18. Related Substances
`Methylcellulose.
`
`19. Comments
`Ethylcellulose is compatible with the following plasticizers:
`dibutyl phthalate; diethyl phthalate; dimethyl phthalate;
`benzyl benzoate; butyl and glycol esters of fatty acids; refined
`mineral oils; oleic acid; stearic acid; cetyl alcohol; stearyl
`alcohol; castor oil; corn oil; camphor and numerous other
`materials.
`Various grades of ethylcellulose are commercially available
`which differ in their ethoxyl content and physical properties,
`see Table I.
`
`Ethylcellulose
`
`189
`
`Table I: Comparison of different grades of ethylcellulose.
`
`Grade
`
`Mean particle
`Viscosity
`diameter (11m)
`(mPa ~)*
`160 (a)
`5.3
`Aqualon N7
`225 ~
`5.5
`Aqualon N10
`194 ~
`80.0
`Aqualon N100
`204 ~
`5.4
`Ethocel Std 4
`210 ~
`6.4
`Ethocel Std 7
`212 ~
`10.6
`Ethocel Std 10
`243 ~
`19.3
`Ethocel Std 20
`305 (b)
`47.6
`Ethocel Std 45
`280 ~
`95.9
`Ethocel Std 100
`262 (b)
`55.0
`Ethocel Med 50
`280 ~
`66,9
`Ethocel Med 70
`286 ~
`98.6
`Ethocel Med 100
`* Viscosities are for a 5% w/v solution at 25°C. Solvent is the supplier’s
`recommended blend of toluene/ethanol.
`Supplier: a. Aqualon Company; b. Dow Chemical Company.
`
`20. Specific References
`1. Donbrow M, Friedman M. Timed release from polymeric films
`containing drugs and kinetics of drug release. J Pharm Sci 1975;
`64: 76-80.
`2. Kent DJ, Rowe RC. Solubility studies on ethyl cellulose used in
`film coating. J Pharm Pharmacol 1978; 30: 808-810.
`3. Sakellariou P, Rowe RC, White EFT. The thermomechanical
`properties and glass transition temperatures of some cellulose
`derivatives used in film coating. mt J Pharmaceutics 1985; 27:
`267-277.
`4. Sarisuta N, Sirithunyalug J. Release rate of indomethacin from
`coated granules. Drug Dev md Pharm 1988; 14: 683-687.
`5. Porter SC. Controlled-release film coatings based on ethylcellu
`lose. Drug Dev md Pharm 1989; 15: 1495-1521.
`6. Upadrashta SM, Katikaneni PR, Hileman GA, Keshary PR.
`Direct compression controlled release tablets using ethylcellulose
`matrices. Drug Dev Ind Pharm 1993; 19: 449-460.
`7. Rowe RC. The prediction of compatibility/incompatibility in
`blends of ethyl cellulose with hydroxypropyl methylcellulose o
`hydroxypropyl cellulose using 2-dimensional solubility parameter
`maps. J Pharm Pharmacol 1986; 38: 214-215.
`8. Appel LE, Zentner GM. Release from osmotic tablets coated
`with modified Aquacoat lattices. Proceed Intern Symp Control
`Rel Bioact Mater 1990; 17: 335-336.
`9. Parikh NH, Porter SC, Rohera BD. Aqueous dispersion of
`ethylcellulose I: evaluation of coating process variables. Pharm
`Res 1993; 10: 525-534.
`Jalsenjak I, Nicolaidou CF, Nixon JR. The in vitro dissolution of
`phenobarbitone sodium from ethyl cellulose microcapsules. J
`Pharm Pharmacol 1976; 28: 912-914.
`11. Oya Alpar H, Walters V. The prolongation of the in vitro
`dissolution of a soluble drug (phenethicillin potassium) by
`microencapsulation with ethylcellulose.
`J Pharm Pharmacol
`1981; 33: 419-422.
`12. Benita S, Donbrow M. Effect of polyisobutylene on ethylcellu
`lose-walled microcapsules: wall structure and thickness of
`salicylamide and theophylline microcapsules. J Pharm Sci 1982;
`71: 205-210.
`13. Robinson DH. Ethyl cellulose-solvent phase relationships
`relevant
`to coacervation microencapsulation processes. Drug
`Dev md Pharm 1989; 15: 2597-2620.
`14. Tirkkonen 5, Paronen P. Enhancement of drug release from
`ethylcellulose microcapsules using solid sodium chloride in the
`wall. mt J Pharmaceutics 1992; 88: 39-5 1.
`
`10.
`
`Page 7 of 13
`
`

`

`190 Ethylcellulose
`
`15. Callahan IC, Cleary GW, Elefant M, Kaplan G, Kensler T, Nash
`RA. Equilibrium moisture content of pharmaceutical excipients.
`Drug Dev md Pharm 1982; 8: 355-369.
`16. FAO/WHO. Evaluation of certain food additives and contami
`nants:
`thirty-fifth report of
`the joint FAO/WHO expert
`committee on food additives. Tech Rep Ser WId Hith Org
`1990; No. 789.
`
`21. General References
`Aqualon Company. Technical literature: ethylcellulose, 1989.
`Dow Chemical Company. Technical literature: Ethocel, ethylcellulose
`in pharmaceutical applications, 1991.
`Doelker E. Cellulose derivatives. Adv Polymer Sci 1993; 107: 199-265.
`
`Iyer U, Hong W-H, Das N, Ghebre-Sellassie I. Comparative
`evaluation of three organic solvent and dispersion-based ethylcel
`lulose coating formulations. Pharmaceut Technol 1990; 14(9): 68,
`70, 72, 74, 76, 78, 80, 82, 84, 86.
`Rowe RC. Molecular weight studies on ethyl cellulose used in film
`coating. Acta Pharm Suec 1982; 19: 157-160.
`Rowe RC. Materials used in the film coating of oral dosage forms. In:
`Florence AT, editor. Critical reports on applied chemistry, volume
`6: materials used in pharmaceutical formulation. Oxford: Blackwell
`Scientific Publications, 1984: 1-36.
`
`22. Authors
`USA: TC Dahi.
`
`Page 8 of 13
`
`

`

`362 Polymethacrylates
`
`Polymethacrylates
`
`6. Functional Category
`Film-former; tablet binder; tablet diluent.
`
`1. Nonproprietary Names
`USPNF: Ammonio methacrylate copolymer
`USPNF: Methacrylic acid copolymer
`Note that two separate monographs applicable to polymetha
`crylates are contained in the USPNF, see Section 9.
`
`2. Synonyms
`Eudragit; polymeric methacrylates.
`
`3. Chemical Name and CAS Registry Number
`See Table I.
`
`4. Empirical Formula
`Molecular Weight
`The USPNF XVII describes methacrylic acid copolymer as a
`fully polymerized copolymer of methacrylic acid and an acrylic
`or methacrylic ester. Three types, type A (Eudragit L), type B
`(Eudragit 5), and type C (Eudragit L 30 D-55), are defined
`which vary in their methacrylic acid content and solution
`viscosity. Two additional polymers, type A (Eudragil RL) and
`type B (Eudragit RS), also referred to as ammonio methacry
`late copolymers, consisting of fully polymerized copolymers of
`acrylic acid and methacrylic acid esters with a low content of
`quaternary ammonium groups, are also described in the
`USPNF XVII. See Section 9.
`Typically, the molecular weight of the polymer is ~ 100 000.
`
`5. Structural Formula
`
`C—CH2—C—CH~—C—CH2—C—CH
`
`R3
`
`c=o
`I
`I
`
`0
`
`R2
`
`c~~o
`
`0
`
`R4
`
`c—o
`
`0
`
`I
`
`c=o
`I
`I
`
`0
`
`R4
`
`For Eudragit E:
`R1, R3 = CH3
`R2 = CH2CH2N(CH3)2
`R4 = CH3, C4H9
`For Eudragit L and 5:
`R1, R3 = CH3
`= H
`= CH3
`For Eudragit RL and RS:
`R1 = H, CH3
`R2 = CH3, C2H5
`R3
`CH3
`R4
`CH2CH2N(CH3)3 ÷ Cl
`For Eudragit NE 30 D:
`R1, R3 = H, CH3
`R2, R4 = CH3, C2H5
`For Eudragit L 30 D-55 and L 100-55:
`R1, R3 = H, CH3
`= H
`= CH3, C2H5
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Polymethacrylates are primarily used in oral capsule and tablet
`formulations as film coating agents.~’’°~ Depending on the
`type of polymer used, films of different solubility character
`istics can be 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, Eudragit 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 5 100 is soluble at > pH 7.
`Eudragit RL, RS and NE 30 D are used to form water-
`insoluble 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 100-55 is a redispersible powder
`and is an alternative to Eudragit L 30 D-55 for aqueous enteric
`coating.
`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 10-50%.
`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
`administration.~’ 1)
`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) mixture of acetone and propan-2-ol
`is most
`commonly used as the organic solvent. See Tables I and II.
`Eudragit E is cationic polymer based on dimethylaminoethyl
`methacrylate and other neutral methacrylic acid esters. It is
`soluble in gastric fluid as well as in weakly acidic buffer
`solutions (up to approximately pH 5). Eudragit E is available
`as a 12.5% ready-to-use solution in propan-2-ol/acetone
`(60:40). It is light yellow in color with the characteristic odor
`of the solvents. Solvent-free granules contain ~ 98% dried
`weight content of Eudragit E.
`Eudragit L and 5, also referred to as methacylic acid
`copolymers in the USPNF monograph, are anionic copoly
`merization products of methacrylic acid and methyl metha
`crylate. The ratio of free carboxyl groups to the ester
`is
`approximately 1:1 in Eudragit L and approximately 1:2 in
`Eudragit S. Both polymers are readily soluble in neutral
`to
`weakly alkaline conditions (pH 6-7) and form salts with
`alkalis, thus affording film coats which are resistant to gastric
`media but soluble in intestinal fluid. They are available as a
`12.5% solution in propan-2-ol without plasticizer (Eudragit L
`12.5 and S 12.5); and as a 12.5% ready-to-use solution in
`propan-2-ol with 1.25% dibutyl phthalate as plasticizer
`(Eudragit L 12.5 P and S 12.5 F). Solutions are colorless,
`with the characteristic odor of the solvent. Eudragit L-100 and
`
`Page 9 of 13
`
`

`

`Table I: Chemical name and CAS registry number of polymethacrylates.
`
`Chemical name
`Poly(butyl methacrylate, (2-dimethyl aminoethyl)
`methacrylate, methyl methacrylate) 1:2:1
`Poly(ethyl acrylate, methyl methacrylate) 2:1
`
`Poly(methacrylic acid, methyl methacrylate) 1:1
`
`Poly(methacrylic acid, ethyl acrylate) 1:1
`
`Poly(methacrylic acid, methyl methacrylate) 1:2
`
`Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl
`methacrylate chloride) 1:2:0.2
`
`Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl
`methacrylate chloride) 1:2:0.1
`
`Eudragit 5-100 are white free flowing powders with at least
`95% of dry polymers.
`Eudragit RL and Eudragit RS, also referred to as ammonio
`methacrylate copolymers in the USPNF monograph, are
`copolymers synthesized from acrylic acid and methacrylic
`acid esters with Eudragit RL (type A) having 10% of
`functional quaternary ammonium groups and Eudragit RS
`(type B) having 5% of functional quaternary ammonium
`groups. The ammonium groups are present as salts and give
`rise to pH-independent permeability of the polymers. Both
`polymers are water-insoluble, and films prepared from
`Eudragit RL are freely permeable to water, whereas,
`films
`prepared from Eudragit RS are only slightly permeable to
`water. They are available as 12.5% ready-to-use solutions in
`propan-2-ol/acetone (60:40). Solutions are colorless or slightly
`yellow in color, and may be clear or slightly turbid; they have
`an odor characteristic of the solvents. Solvent-free granules
`(Eudragit RL 100 and Eudragit RS 100) contain ~ 97% of the
`dried weight content of the polymer.
`Eudragit RL P0 and Eudragit RS P0 are fine, white powders
`with a slight amine-like odor. They are characteristically the
`same polymers as Eudragit RL and RS. They contain ~ 97%
`of dry polymer.
`Eudragit RL 30 D and Eudragit RS 30 D are aqueous
`dispersions of copolymers of acrylic acid and methacrylic acid
`esters with a low content of quaternary ammonium groups.
`The dispersions contain 30% polymer. The quaternary groups
`occur as salts and are responsible for the permeability of films
`made from these polymers. Films prepared from Eudragit RL
`30 D are readily permeable to water and to dissolved active
`substances, whereas films prepared from Eudragit RS 30 D are
`less permeable to water. Film coatings prepared from both
`polymers give pH-independent
`release of active substance.
`Plasticizers are usually added to. improve film properties.
`Eudragit NE 30 D is an aqueous dispersion of a neutral
`copolymer consisting of polymethacrylic acid esters. The
`dispersions are milky-white liquids of low viscosity and have
`a weak aromatic odor. Films prepared from the lacquer swell
`in water,
`to which they become permeable. Thus,
`films
`produced are insoluble in water, but give pH-independent
`drug release.
`
`Polymethacrylates
`
`363
`
`Trade name
`Eudragit E 100
`Eudragit E 12.5
`Eudragit NE 30 D
`(formerly Eudragit 30 D)
`Eudragit L 100
`Eudragit L 12.5
`Eudragit L 12.5 P
`Eudragit L 30 D-55
`Eudragit L 100-55
`Eudragit S 100
`Eudragit S 12.5
`Eudragit S 12.5 P
`Eudragit RL 100
`Eudragit RL P0
`Eudragit RL 30 D
`Eudragil RL 12.5
`Eudragit RS 100
`Eudragit RS P0
`Eudragit RS 30 D
`Eudragit RS 12.5
`
`CAS number
`
`[24938-16-7]
`
`[9010-88-2]
`
`[25806-15-1]
`
`[25212-88-8]
`
`[25086-1 5-1]
`
`[33434-24-1]
`
`[33434-24-1]
`
`Eudragit L 30 D-55 is an aqueous dispersion of an anionic
`copolymer based on methacrylic acid and acrylic acid ethyl
`ester. The polymer corresponds to USPNF methacrylic acid
`copolymer, type C. The ratio of free carboxyl groups to ester
`groups is 1:1. Films dissolve above pH 5.5 forming salts with
`alkalis, thus affording coatings which are insoluble in gastric
`media, but soluble in the small intestine.
`Eudragit L 100-55 (prepared by spray-drying Eudragit L 30 D
`55) is a white,
`free-flowing powder which is redispersible in
`water to form a latex which has properties similar to Eudragit
`L 30 D-55.
`
`9. Pharmacopeial Specifications
`Specifications for methacrylic acid copolymers (Eudragit L, S
`and L 30 D-55).
`
`Test
`Identification
`Viscosity
`Type A
`Type B
`Type C
`Loss on drying
`Type A
`Type B
`Type C
`Residue on ignition
`TypeA
`TypeB
`Type C
`Arsenic
`Heavy metals
`Monomers
`Assay of methacrylic acid
`units (dried basis)
`Type A
`Type B
`Type C
`
`USPNF XVII (Suppl 6)
`
`+
`
`50-200 mPa s
`50-200 mPa s
`100-200 mPa s
`
`~ 5.0%
`~ 5.0%
`~ 3.0%
`
`~ 0.4%
`~ 2 ppm
`~ 0.002%
`~ 0.3%
`
`46.0-50.6%
`27.6-30.7%
`46.0-50.6%
`
`Page 10 of 13
`
`

`

`364 Polymethacrylates
`
`Specifications for ammonio methacrylate copolymers (Eu
`dragit RL and RSI.
`
`USPNF XVII (Suppl 4)
`+
`
`Test
`Identification
`Viscosity
`TypesAandB
`Loss on drying
`Types A and B
`Residue on ignition
`~ 0.1%
`Types A and B
`~ 2 ppm
`Arsenic
`~ 0.002%
`Heavy metals
`~ 0.3%
`Monomers
`Assay of ammonio methacrylate
`units (dried basis)
`Type A
`Type B
`
`~ l5mPas
`
`~ 3.0%
`
`8.85-11.96%
`4.48-6.77%
`
`Alkali value:
`162-198 for Eudragit E 12.5 and E 100;
`23.9-32.3 for Eudragit RL 12.5, RL 100, and .RL P0;
`27.5-3 1.7 for Eudragit RL 30 D;
`12.1-18.3 for Eudragit RS 12.5, RS 100, and PS P0;
`16.5-22.3 for Eudragit PS 30 D.
`Density:
`0.81-0.82 g/cm3 for Eudragit E;
`0.83-0.85 gJcm3 for Eudragit L, S 12.5 and 12.5 F;
`0.83-0.85 g/cm3 for Eudragit L, S 100;
`1.06-1.07 g/cm3 for Eudragit L 30 D-55;
`0.82-0.84 g/cm3 for Eudragit L 100-55;
`0.815-0.835 g/cm3 for Eudragit RL and RS 12.5;
`0.8 15-0.835 g/cm3 for Eudragit RL and RS P0;
`1.045-1.055 g/cm3 for Eudragit RL and RS 30 D.
`Refractive index:
`= 1.38-1.385 for Eudragit E;
`= 1.39-1.395 for Eudragit L and 5;
`1.387-1.392 for Eudragit L 100-55;
`= 1.38-1.385 for Eudragit RL and RS.
`Solubility: see Table II.
`Viscosity (dynamic):
`3-12 mPa s for Eudragit E;
`50-200 mPa s for Eudragit L and 5;
`~ 50 mPa s for Eudragit L 30 D-55;
`100-200 mPa s for Eudragit L 100-55;
`~ 15 mPa s for Eudragit RL and PS;
`~ 200 mPa s for Eudragit RL and PS D.
`
`nn
`
`10. Typical Properties
`Acid value: 315 for Eudragit L 12.5, L 12.5 P, L 100, L 30 D-55,
`and L 100-55; 180-200 for Eudragit S 12.5, S 12.5 F, and S 100.
`
`Table IT: Solubility of commercially available polymethacrylates (Eudragit, Röhm Pharma GmbH) in various solutions.
`
`Type
`
`Eudragit E 12.5
`Eudragit E 100
`Eudragit L 12.5 P
`Eudragit L 12.5
`Eudragit L 100-55
`Eudragit L 100
`Eudragit L 30 D-S5~
`Eudragit S 12.5 P
`Eudragit S 12.5
`Eudragit S 100
`Eudragit RL 12.5
`Eudragit RL 100
`Eudragit RL PU
`Eudragit RL 30 D
`Eudragit RS 12.5
`Eudragit RS 100
`Eudragit PS P0
`Eudragit RS 30 D
`
`Acetone and
`a1cohols~
`M
`S
`M
`M
`S
`S
`M(+
`M
`M
`S
`M
`S
`S
`M~
`M
`5
`S
`~
`
`Dichioromethane
`
`Solvent
`Ethyl acetate
`
`iN HO
`
`iN NaOH
`
`Petroleum ether
`
`Water
`
`M
`S
`M
`M
`I
`I
`
`—
`
`M
`M
`I
`M
`S
`S
`M
`M
`5
`
`M
`
`M
`S
`M
`M
`I
`I
`
`—
`
`M
`M
`I
`M
`S
`S
`M
`M
`S
`
`M
`
`M
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`—
`
`M
`M
`S
`S
`M@)
`M
`M
`S
`
`—
`
`—
`
`I
`I
`
`—
`
`—
`
`I
`
`M
`I
`P
`P
`I
`I
`
`—
`
`P
`P
`I
`P
`I
`I
`I
`P
`I
`
`I
`
`—
`
`I
`P
`P
`I
`I
`M
`P
`P
`I
`M
`I
`I
`M
`M
`I
`
`M
`
`Where: S = soluble;
`M = miscible;
`I = insoluble or immiscible;
`P = precipitates.
`Note: a. Alcohols including ethanol, methanol and propan-2-ol.
`b. Supplied as a milky-white colored aqueous dispersion.
`c. A 1:5 mixture forms a clear, viscous, solution.
`d. A 1:2 mixture forms a clear or slightly opalescent, viscous liquid.
`e. A 1 part of both Eudragit RL 30 D and Eudragit P530 D dissolve completely in 5 parts acetone, ethanol or propan-2-ol to form a clear or slightly
`turbid solution. However, when mixed in a ratio of 1:5 with methanol, Eudragit RL 30 D dissolves completely, whereas Eudragit PS 30 D only
`partially.
`
`Page 11 of 13
`
`

`

`Polymethacrylates
`
`365
`
`11. Stability and Storage Conditions
`Dry powder polymer forms are stable at temperatures less than
`30°C. Above this temperature, powders tend to form clumps
`although this does not affect the quality of the substance and
`the clumps can be readily broken up. Dry powders are stable
`for at least two years if stored in a tightly closed container at
`less than 30°C.
`Dispersions are sensitive to extreme temperatures and phase
`separation occurs below 0°C. Dispersions should therefore be
`stored at temperatures between 5-25°C and are stable for at
`least one year after shipping from the manufacturer’s
`warehouse if stored in a tightly closed container at the above
`conditions.
`
`12. Incompatibilities
`Incompatibilities occur with certain polymethacrylate disper
`sions depending upon the ionic and physical properties of the
`polymer and solvent. For example, coagulation may be caused
`by soluble electrolytes, pH changes, some organic solvents and
`extremes of temperature, see Table II. Dispersions of Eudragit
`
`L 30 D, RL 30 D, L 100-55 and RS 30 D are also incompatible
`with magnesium stearate.
`Interactions between polymethacrylates and some drugs can
`occur although solid polymethacrylates and organic solutions
`are generally more compatible than aqueous dispersions.
`
`13. Method of Manufacture
`Prepared by the polymerization of acrylic and methacrylic
`acids or their esters, e.g. butyl ester or dimethylaminoethyl
`ester.
`
`14. Safety
`Polymethacrylate copolymers are widely used as film coating
`materials in oral pharmaceutical formulations. They are also
`used to a lesser extent in topical formulations and are generally
`regarded as nontoxic and nonirritant materials.
`A daily intake of 2 mg/kg body-weight of Eudragit (equivalent
`to approximately 150 mg for an average adult) may be
`regarded as essentially safe in humans.
`See also Section 15.
`
`Table III: Summary of properties and uses of commercially available polymethacrylates (Eudragit, Röhm Pharma GmbH).
`
`Solubility
`
`Applications
`
`Type
`
`Supply form
`
`Eudragit E 12.5
`
`Eudragit E 100
`
`Eudragit L 12.5 P
`
`Eudragit L 12.5
`
`Eudragit L 100
`
`Eudragit L 100-55
`
`Organic
`solution
`Granules
`
`Organic
`solution
`Organic
`solution
`Powder
`
`Powder
`
`Polymer dry
`weight content
`12.5%
`
`Recommended
`solvents or diluents
`Acetone, alcohols
`
`98%
`
`12.5%
`
`12.5%
`
`95%
`
`95%
`
`Acetone, alcohols
`
`Acetone, alcohols
`
`Acetone, alcohols
`
`Acetone, alcohols
`
`Acetone, alcohols
`
`Soluble in gastric fluid
`to pH 5
`Soluble in gastric fluid
`to pH 5
`Soluble in intestinal
`fluid from pH 6
`Soluble in intestinal
`fluid from pH 6
`Soluble in intestinal
`fluid from pH 6
`Soluble in intestinal
`fluid from pH 5.5
`Soluble in intestinal
`fluid from pH 5.5
`Soluble in intestinal
`fluid from pH 7
`Soluble in intestinal
`fluid from pH 7
`Soluble in intestinal
`from pH 7
`High permeability
`
`High permeability
`High permeability
`High permeability
`
`Film coating
`
`Film coating
`
`Enteric coatings
`
`Enteric coatings
`
`Enteric coatings
`
`Enteric coatings
`
`Enteric coatings
`
`Enteric coatings
`
`Enteric coatings
`
`Enteric coatings
`
`Sustained release
`
`Sustained release
`Sustained release
`Sustained release
`
`Water
`
`Acetone, alcohols
`
`Acetone, alcohols
`
`Acetone, alcohols
`
`Acetone, alcohols
`
`Acetone, alcohols
`Acetone, alcohols
`Water
`
`Acetone, alcohols
`
`Low permeability
`
`Sustained release
`
`Acetone, alcohols
`Acetone, alcohols
`Water
`
`Low permeability
`Low permeability
`Low permeability
`
`Sustained release
`Sustained release
`Sustained release
`
`30% or 40%
`
`Water
`
`Swellable, permeable
`
`Eudragit L 30 D-55
`
`Eudragit S 12.5 P
`
`Eudragit S 12.5
`
`Eudragit S 100
`
`Eudragit EL 12.5
`
`Eudragit EL 100
`Eudragit RL P0
`Eudragit EL 30 D
`
`Eudragit RS 12.5
`
`Eudragit RS 100
`Eudragit ES P0
`Eudragit ES 30 D
`
`Eudragit NE 30 D
`
`30%
`
`12.5%
`
`12.5%
`
`95%
`
`12.5%
`
`97%
`97%
`30%
`
`12.5%
`
`97%
`97%
`30%
`
`Aqueous
`dispersion
`Organic
`solution
`Organic
`solution
`Powder
`fluid
`Organic
`solution
`Granules
`Powder
`Aqueous
`dispersion
`Organic
`solution
`Granules
`Powder
`Aqueous
`dispersion
`Sustained release,
`Aqueous
`tablet matrix
`dispersion
`Note: Recommended plasticizers for the above types of Eudragit polymers include dibutyl phthalate, polyethylene glycols and triethyl citrate.
`Approximately 20% plasticizer is required for Eudragit EL 30 D and Eudragit RS 30 D. A plasticizer is not necessary with Eudragit E 12.5, Eudragit
`E 100 and Eudragit NE 30 D.
`
`Page 12 of 13
`
`

`

`366 Polymethacrylates
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Additional measures should
`be taken when handling organic solutions of polymethacry
`lates. Eye protection, gloves and a dust mask or respirator are
`recommended. Polymethacrylates should be handled in a well-
`ventilated environment and measures taken to prevent dust
`formation.
`Acute and chronic adverse effects have been observed in
`workers handling the related substances methyl methacrylate
`and poly(methyl methacrylate) (PMMA).°2”3~ In the UK, the
`occupational ex~osure limit for methyl methacrylate has been
`set at 410 mg/rn (100 ppm) long-term (8-hour TWA), and 510
`mg/rn3 (125 ppm) short-term.t1~~
`See also Section 18.
`
`16. Regulatory Status
`Includ