Critical Reports on Applied Chemistry Volume 6
`
`Materials Used in
`Pharmaceutical Formulation
`edited by A. T. Florence
`
`Published for the Society of Chemical Industry by
`Blackwell Scientific Publications
`Oxford London Edinburgh
`Boston Palo Alto Melbourne
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2042 - 1/39
`
`

`

`Critical Reports on Applied Chemistry: Editorial Committee
`C.A. Finch
`H.J. Cottrell
`I.D. Morton
`H. Egan
`K.R. Payne
`Chairman
`A.I. Bailey
`T. Galliard
`J.M. Sidwick
`N. Blakebrough
`C.R. Ganellin
`A.L. Waddams
`A.R. Burkin
`E.G. Hancock
`
`© 1984 by Society of Chemical Industry
`14-15 Belgrave Square, London, SWlX 8PS
`and published for them by
`Blackwell Scientific Publis;ations
`Osney Mead, Oxford, OX2 OEL
`8 John Street, London WClN 2ES
`9 Forrest Road, Edinburgh, EHl 2QH
`52 Beacon Street, Boston
`Massachusetts 02108, USA
`706 Cowper Street, Palo Alto,
`California 94301, USA
`99 Barry Street, Carlton,
`Victoria 3053, Australia.
`
`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,
`electronic, mechanical, photocopying,
`recording or otherwise
`without the prior permission of
`the copyright owner
`
`First published 1984
`
`Enset (Photosetting)
`Midsomer Norton, Bath.
`Printed in Great Britain by
`Butler & Tanner Ltd, Frame and London
`
`DISTRIBUTORS
`
`USA
`Blackwell Mosby Book Distributors
`11830 Westline Industrial Drive
`St Louis, Missouri 63141
`
`Canada
`Blackwell Mosby Book Distributors
`120 Melford Drive, Scarborough
`Ontario MlB 2X4
`Australia
`Blackwell Scientific Book Distributors
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`Victoria 3190
`
`British Library
`Cataloguing in Publication Data
`Materials used in pharmaceutical formulation.
`--(Critical reports on applied chemistry;
`v.6)
`l. Drugs-Vehicles
`II. Series
`I. Florence, A.T.
`615' .19
`RS201.V43
`
`ISBN 0-632-01257-9
`
`~ w I sc 0
`o
`NJ>
`/'1,.
`
`/...,,,;.,
`
`...
`
`;;.,
`t.'4
`~
`> _.
`
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`QUALICAPS EX. 2042 - 2/39
`
`

`

`Contents
`
`vii Editor's introduction
`A.T. Florence, Department of Pharmacy, University of Strathclyde,
`Glasgow Gl JXW
`
`1 Materials used in the film coating of oral dosage forms
`Raymond C. Rowe, /Cl plc, Pharmaceuticals Division, Macclesfield,
`Cheshire SKJO 2NA
`
`37 Tablet lubricants
`Peter York, Postgraduate School of Studies in Pharmacy, University of
`Bradford, Bradford, West Yorkshire BD71DP
`
`71 Polymeric materials used in drug delivery systems
`David A. Wood, Department of Pure and Applied Chemistry, University
`of Strathclyde, Glasgow GI IXL
`
`124 Properties of fatty alcohol mixed emulsifiers and emulsifying waxes
`Gillian Eccleston, Department of Pharmacy, University of Strathclyde,
`Glasgow Gl JXW
`
`157
`
`Index
`
`V
`
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`

`Materials used in the film coating of oral dosage forms
`
`Raymond C. Rowe
`
`1
`2
`2.1
`2.2
`2.3
`2.4
`
`2.5
`2.6
`
`3
`3.1
`3.2
`3.3
`3.4
`
`3.5
`3.6
`
`4
`4.1
`4.2
`
`4.3
`
`4.4
`
`Introduction, 2
`Polymers used in film coating, 3
`Water-soluble polymers, 6
`Water-insoluble polymers, 6
`pH-dependent soluble polymers, 7
`General properties of polymers, 8
`2.4.1 Viscosity and molecular weight, 8
`2.4.2 Effect of molecular weight on the mechanical properties of films, 11
`2.4.3 Refractive index, 11
`2.4.4 Softening (glass-transition) temperature, 11
`2.4.5 Surface activity, 12
`2.4.6 Stability to water and pH, 12
`2.4.7 Stability to heat and light, 12
`2.4.8 Biological stability, 13
`Analysis and specifications, 13
`Applications, 13
`
`Plasticizers used in film coating, 16
`Polyols, 16
`Organic esters, 17
`Vegetable oils and glycerides, 17
`General properties of plasticizers, 18
`3 .4 .1 Physical properties, 18
`3.4.2 Plasticizer compatibility, 18 ·
`3.4.3 Plasticizer efficiency, 20
`3.4.4 Plasticizer permanence, 21
`3 .4.5 The effect of plasticizers on thermal gelation, 22
`Analysis and specifications, 23
`Applications, 23
`3. 6 .1 Mechanical properties of plasticized films, 23
`3. 6. 2 Permeability of plasticizer films, 23
`
`Colourants used in film coating, 24
`Synthetic organic dyes and lakes, 24
`Inorganic pigments, 27
`4.2.1
`Iron oxides, 27
`4.2.2 Titanium dioxide, 28
`4.2.3 Calcium carbonate, 28
`4.2.4 Talc, 28
`Miscellaneous natural colourants, 28
`4.3.1 Cochineal and carmine, 29
`General properties of colourants, 29
`4.4.1 Particulate properties (particle size, shape and density), 29
`
`1
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`2
`
`Raymond C. Rowe
`
`4.4.2 Refractive index, 29
`4.4.3 Stability, 30
`Analysis and specifications, 30
`Applications, 31
`4.6.1 Optical effects in films, 31
`4.6.2 Mechanical properties of pigmented films, 33
`4.6.3 Permeability of pigmented films, 34
`
`Conclusion, 34
`
`References, 34
`
`4.5
`4.6
`
`5
`
`6
`
`Introduction
`1
`Film coating is a process which involves the deposition of a membrane-con(cid:173)
`sisting of polymer, plasticizer, colourant and possibly other additives-on to the
`surface of a pharmaceutical dosage form, typically a tablet or a granule. Over the
`past decade there has been a dramatic increase in the use of this process in the UK.
`An estimate of the growth can be obtained by studying the growth in the sales of
`low viscosity grades of hydroxypropylmethylcellulose, arguably the most com(cid:173)
`monly used film former for tablet film coating (Fig. 1) 1
`• Current UK sales of these
`grades of polymer are in excess of 30 tonnes per annum which if used to film coat a
`
`100
`
`80
`
`70
`
`60
`
`~
`co 90
`Q?
`0
`~
`~
`Q)
`V,
`.2
`..2
`ai
`~
`>,
`.c 50
`+-
`Q)
`E
`>, 40
`a.
`
`0 a. >, 30
`)( e
`"O
`>, 20
`.c
`0
`
`10
`
`V,
`Q)
`0
`Cf)
`
`l'
`
`·-·
`I
`•
`I
`•
`I
`•
`I
`·-·
`I
`•
`,/
`
`1970 1972 1974 1976 1978 1980 1982
`Year
`
`Fig. 1. Growth of tablet film coating in the UK as indicated by the growth of sales of low viscosity
`grades of hydroxypropylmethylcellulose.
`
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`

`Materials used in the film coating of oral dosage forms
`
`3
`
`200 mg tablet with a film equivalent to a 2% weight gain, is equivalent to the
`production of 7 .5 thousand million tablets.
`The reasons for film coating are many and varied. They include 2 the following.
`(a) To improve product appearance, odour and taste and to aid swallowing.
`(b) To aid identification and hence decrease the risk of confusion, especially
`when patients have to take several preparations.
`( c) To protect the active ingredient against heat, light and moisture.
`( d) To separate incompatible active ingredients present in a preparation.
`( e) To prevent dust formation during subsequent packing on high speed packing
`lines.
`(f) To control the release of an active ingredient by use of either a coating with
`pH-dependent solubility or a coating that acts as a diffusion membrane.
`Compared to the conventional sugar coat, the film coat is relatively thin(cid:173)
`typically 10-100 µm. Although the technology involved in the application of such
`a thin coating is not new, having precedents in both the paints and adhesives
`technologies, problems do occur resulting in a variety of film defects (Table 1).
`These defects can be divided into two groups: those which can result in the loss of
`continuity of the film and thus affect the gastric resistance or diffusion rate of
`entero-soluble films or sustained release films respectively; and those which can
`affect the visual appearance of the coated tablet, resulting in some cases, e.g.
`bridging of the intagliations, in the loss of the advantage of using film-coated
`tablets to improve product identification.
`In this review the properties of the various constituents of the film-coating
`formulation, viz. polymers, plasticizers and colourants, are discussed with
`particular reference to their effect on the incidence of these film defects and other
`problems encountered during the film coating of tablets and other oral dosage
`forms. The review is not exhaustive in that it deals only with the cellulose ethers
`and plasticizers commonly used for these polymers. However, the trends reported
`are likely to be the same for all polymers and plasticizers used in film coating.
`
`2
`Polymers used in film coating
`Although many polymers are used in film coating, the most widely used in the UK
`are the cellulose derivatives, methylcellulose, hydroxypropylmethylcellulose,
`hydroxypropylcellulose, ethylcellulose, cellulose acetate phthalate and hydroxy(cid:173)
`propylmethylcellulose phthalate. All are derived from, and hence possess the
`polymeric backbone of, cellulose which contains a basic repeating structure of
`anhydroglucose units, each unit having three replaceable hydroxyl groups (Fig.
`2). The number of substituent groups of these hydroxyls can be designated either
`by a weight percentage or by the number of points where groups are attached-a
`concept known as degree of substitution (DS). If all three available positions on
`each anhydroglucose unit are substituted, the DS is designated as 3. In certain
`
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`

`4
`
`Raymond C. Rowe
`
`Table 1. Description and possible causes of some film defects seen on film coated tablets
`
`Defect
`
`Blistering
`
`Blushing
`
`Bridging
`( of the intagliations)
`
`Description
`
`Cause
`
`Film becomes detached from
`substrate forming a blister.
`
`Overheating during spraying or at
`end of coating run.
`
`Whitish specks or haziness
`in film (best seen with
`non-pigmented film).
`
`Film pulls out of intagliation
`forming a bridge across the
`edges of the mark.
`
`Precipitation of polymer due to
`high temperature or poor solvent.
`
`High internal stresses in film.
`
`Chipping
`
`Film becomes chipped and dented.
`
`Excessive attrition during coating
`process.
`
`Cracking
`
`Cratering
`
`Flaking
`
`Infilling
`( of the intagliations)
`
`Orange peel
`
`Film cracks or splits.
`
`High internal stresses in film.
`
`Volcanic-like craters in film
`exposing tablet surface.
`
`Film flakes off exposing the
`tablet surface.
`
`lntagliation filled with either
`particles of dried polymer or
`solidified foam.
`
`Surface appearance similar to
`that of an orange or lemon.
`
`Over-wetting and localized
`disintegration of tablet core.
`
`Associated with cracking and
`splitting.
`
`Over-drying of spray or excessive
`foaming of coating solution.
`
`Poor spreading of spray droplets
`associated with non-optimum spray
`atomization.
`
`Peeling
`
`Picking
`
`Pimpling
`
`Pitting
`
`Pulling out
`( of the intagliations)
`
`Splitting
`
`Film peels off exposing the
`tablet surface.
`
`Associated with cracking and
`splitting.
`
`Isolated areas of film pulled
`off the surface
`
`Over-wetting. Tablets stick
`together then part.
`
`As 'Orange peel'.
`
`Pits occur in tablet surface,
`but film surface not disrupted.
`
`Melting or dissolution of
`lubricants on tablet surface.
`
`As 'Bridging (of the intagliations)'
`
`Film splits usually around the
`edges of the tablet.
`
`High internal stresses in film.
`
`Wrinkling
`
`Film has a wrinkled appearance.
`
`Associated with 'Blistering'.
`
`circumstances the added substituent may also contain a hydroxyl group. If the
`hydroxyl group of the pendant chain is more reactive than the hydroxyl groups of
`the cellulose backbone, side chains may be formed ( a process known as 'chaining
`out'). A term molar substitution (MS) has been coined to describe the total
`number of moles of a group that has become attached to the cellulose backbone or
`
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`

`

`6
`
`Raymond C. Rowe
`
`Each of the polymers listed possesses characteristic properties of aqueous or
`pH-dependent solubility depending on its type and degree of substitution. It is
`convenient, therefore, to consider these polymers in terms of their solubility.
`
`Water-soluble polymers
`2.1
`Of the three polymers; methylcellulose, hydroxypropylcellulose and hydroxy(cid:173)
`propylmethylcellulose (Table 2) in this group, the last is the most widely used in
`film coating. It is closely related to methylcellulose, the additional hydroxy(cid:173)
`propoxyl substitution giving the polymer superior organic compatibility. Good
`organic compatibility while maintaining good water solubility is also a feature of
`hydroxypropylcellulose, probably due to the formation of side chains during its
`manufacture. All three polymers have the appearance of white or off-white,
`odourless, tasteless powders. All are freely soluble in cold water but insoluble in
`hot water. The temperature at which they separate from their aqueous solution is
`called the gelation temperature, although hydroxypropylcellulose tends to
`precipitate as a highly swollen floe resulting in a decrease in viscosity, as opposed
`to the other polymers which tend to gel resulting in an increase in viscosity. The
`approximate 'gelation' temperatures for methylcellulose, hydroxypropylmethyl(cid:173)
`cellulose and hydroxypropylcellulose of the type used in film coating are 50°, 60°
`and 45°C respectively3 - 8 .
`
`Table 2. Water soluble polymers used in film coating"- 8
`
`Polymer
`
`Methoxyl
`substitution
`
`Hydroxypropoxyl substitution
`
`Methylcellulose
`Hydroxypropylmethylcellulose
`Hydroxypropylcellulose
`
`%w/w
`
`DS
`%w/w
`27.5-31.5 1.64-1.92
`28.0-30.0 1.67-1.81 7.0-12.0
`:s 80.5
`
`DS
`
`MS
`
`0.15-0.25 0.22-0.25
`:s 4.6
`
`Water-insoluble polymers
`2.2
`The most widely used water-insoluble cellulose ether used in film coating is
`ethylcellulose. It has a DS of between 2.17 and 2.62 corresponding to an ethoxyl
`content of between 44 and 51 % w/w. Distribution of the ethoxyl groups is
`reasonably uniform on both the primary and secondary hydroxyl of the
`anhydroglucose unit 9
`• Ethylcellulose is most soluble in solvents that have
`11
`-
`nearly the same cohesive energy density or solubility parameter as the material
`itself 12
`• The solubility parameter ranges vary with DS as shown in Table 3 13 •
`Although ethylcellulose is soluble in many solvents, in general hydrocarbon(cid:173)
`alcohol mixtures are better than single solvents. The amount of alcohol that is
`required to obtain minimum viscosity at a given concentration is proportional to
`
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`

`Materials used in the film coating of oral dosage forms
`
`7
`
`the number of hydroxyl groups that remain unsubstituted. Ethylcellulose with a
`DS of 2.17-2.35 (44.00-46.5% w/w ethoxyl content) dissolves in a 60: 40% w/w
`toluene-ethanol mixture, whereas that having a DS of 2.35-2.62 (46.5-51.0%
`w/w ethoxyl content) is most soluble in an 80: 20% w/w toluene-ethanol mixture.
`Ethylcellulose, as used in film coating, occurs both as a free-flowing white to
`light tan powder and as an aqueous suspension of approximately 30% w/w
`solids 14
`•
`
`Table 3. Solubility parameter ranges for ethylcellulo'!;e 13
`
`Solubility parameter range MPa V,
`
`Ethoxyl
`content
`%w/w
`
`DS
`
`Poorly hydrogen- Moderately hydrogen-
`bonded solvents
`bonded solvents
`
`Strongly hydrogen-
`bonded solvents
`
`2.28-2.38
`2.42-2.53
`> 2.53
`
`45.5-46.8
`47.5-49.0
`> 50.0
`
`0
`16.6-22.7
`17.4-19.4
`
`17.4-22.1
`15.1-22.1
`16.0-20.1
`
`19.4-23.3
`19.4-29.7
`19.4-23.3
`
`pH-dependent soluble polymers
`2.3
`The polymers in this group are either acetyl and/or phthalyl ( a- carboxybenzoyl)
`derivatives of cellulose or hydroxypropylmethylcellulose 15- 16 • They are insoluble
`at low pH but soluble at high pH, the specific pH at which they begin to dissolve
`being dependent on the degree of acetyl and phthalyl substitution (Table 4). The
`rate of dissolution of these materials in alkaline media, although dependent on the
`nature of the buffer ions present in solution, is relatively rapid 17
`• The solubility of
`the polymers in organic solvents depends on the degree and type of substitution
`(Table 5) 16
`• Alcohols are not good solvents for these polymers, nor are the
`chlorinated hydrocarbons but mixtures of these two are. All the polymers are
`white, tasteless, odourless powders or granules and all have a limit test for free
`
`Table 4. pH-dependent soluble polymers used in film coating 15
`
`•
`
`16
`
`Polymer
`
`Cellulose acetate
`phthalate (C.A.P.)
`
`Hydroxypropylmethyl
`cellulose phthalate
`(HP50)
`
`Hydroxypropylmethyl
`cellulose phthalate
`(HP55)
`
`% w/w Substitution
`Methoxyl Hydroxypropoxyl Acetyl
`
`Carboxybenzoyl
`
`pH
`for solubility
`
`10.0-23.5 30.0-36.0
`
`20.0-25.0 5.0-10.0
`
`20.0-24.0
`
`5.7
`
`5.0
`
`18.0-22.0 4.0- 9.0
`
`25.0-35.0
`
`5.5
`
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`

`8
`
`Raymond C. Rowe
`
`Table 5. Solubility of hydroxypropylmethycellulose phthalate and
`cellulose acetate phthalate in organic solvents 16
`
`Solvent
`
`HP 55 HP 50 C.A.P.
`
`Acetone
`Acetone
`Acetone: water (95: 5)
`Acetone: ethanol (1: 1)
`Acetone: isopropanol (1: 1)
`Acetone: dichloromethane (1: 1)
`Dichloromethane
`Dichloromethane: methanol (1: 1)
`Dichloromethane: ethanol (1: 1)
`Dichloromethane: isopropanol (1: 1)
`Ethyl acetate
`Ethyl acetate: methanol (1: 1)
`Ethyl acetate: ethanol (1: 1)
`Ethyl acetate: isopropanol (1: 1)
`Methanol
`Ethanol
`Isopropanol
`
`cs
`cs
`cs
`cs
`cs
`cs
`sl
`cs
`cS
`cs
`hS
`cs
`cS
`cs
`sl
`sI
`sI
`
`sI
`cS
`cS
`hS
`hS
`sI
`sl
`cs
`cs
`hS
`
`cs
`hS
`hS
`sI
`sl
`I
`
`cS
`cs
`cS
`cS
`cs
`cS
`sI
`cS
`cs
`cS
`I
`cS
`cs
`cS
`I
`I
`
`cS, Soluble clear solution.
`hS, Soluble hazy solution.
`sl, Swells but insoluble.
`I, Insoluble.
`
`acid; for hydroxypropylmethylcellulose phthalate the limit is 1 % but for cellulose
`acetate phthalate the limit is 6% 15
`16
`
`•
`
`•
`
`2.4
`
`General properties of polymers
`
`Viscosity and molecular weight. All the polymers used in film coating are
`2. 4.1
`controlled by means of an apparent viscosity representing the viscosity of a
`specified concentration of the polymer dissolved in a specified solvent at a speci(cid:173)
`fied temperature (Table 6). Since viscosity control is achieved by controlling the
`chain length (i.e. the degree of polymerization, DP, or number of anhydroglucose
`units) during the production process, the apparent viscosity (7/app.) can be
`regarded as an indirect measure of the molecular weight of the polymer. The
`relationship between the molecular weight and the apparent viscosity (measured
`in mPas) can be expressed in the form:
`
`Molecular weight = K ( 7/app.)°
`
`(1)
`
`where K and n are constants for each polymer determined by regression analysis
`and which depend on the method used to measure the molecular weight of the
`
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`

`

`0
`()
`
`§"'
`::r,
`(l>
`
`~ p:, -(l>
`
`0..
`(l>
`C u,
`;;;-
`p:,
`::l.
`
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`Er -::r
`
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`o'
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`(Jq
`p:,
`0 u,
`0..
`!:?..
`0 ...,
`0 .....,
`
`(Jq
`
`290 mPas±20%
`
`190 mPas±20%
`
`240 mPas±20%
`
`50-90 mPas
`± 10% of nominal
`6-8.0 (for nominal 7)
`3-5.5 (for nominal 4)
`
`> 145 mPas
`±20% of nominal
`±20% of nominal
`
`20
`
`20
`
`20
`
`25
`
`25
`25
`
`25
`20
`20
`
`15
`
`15
`
`15
`
`15
`
`5
`5
`
`10
`2
`2
`
`Acetone
`
`Dichloromethane: methanol (1: 1)
`
`Dichlorornethane: methanol (1 : 1)
`
`HP55S
`
`HP55
`
`HP50
`
`1
`Water
`Anhydrous ethanol 249
`
`Toluene: ethanol (80: 20)
`Toluene: ethanol (60: 40)
`
`Hydroxypropylmethylcellulose
`
`phthalate
`
`Cellulose acetate phthalate
`
`Ethylcellulose
`Hydroxypropylcellulose
`Water
`Hydroxypropylmethylcellulose Water
`Methylcellulose
`Water
`
`(> 46.5% w/w ethoxyl)
`( < 46.5% w/w ethoxyl)
`
`Specification)
`
`(% w/w)
`Concentration Temperature
`
`(OC)
`
`Solvent
`
`Polymer
`
`by manufacturers to a specific grade of polymer
`Table 6. Apparent viscosity specifications for polymers used in film coating. The nominal viscosity represents that given
`
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`

`

`

`Materials used in the film coating of oral dosage forms
`
`11
`
`Table 7. Constants for the Mark-Houwink equation for some of the polymers
`24
`used in film coating 22-
`
`Polymer
`
`Solvent
`
`Temperature K
`(xl0-5dJg-') a
`(°C)
`
`Methylcellulose
`Hydroxypropylcellulose
`Ethylcellulose
`
`Water
`Ethanol
`Chloroform
`Benzene
`
`25
`25
`25
`25
`
`316
`2.6
`11.8
`29.2
`
`0.55
`0.92
`0.89
`0.81
`
`of K and a for some of the polymers used in film coating are given in Table 722
`- 24 .
`It is interesting to note that recent work on ethylcellulose has shown that the
`molecular weights calculated for commercial samples of polymer using the Mark(cid:173)
`Houwink constants determined for fractionated samples were very close to the
`peak molecular weights of the same samples using gel permeation chromat(cid:173)
`ography20.
`
`Effect of molecular weight on mechanical properties of films. All the
`2.4.2
`polymers used in film coating produce relatively strong flexible films. The
`mechanical properties of these films are dependent on the molecular weight of the
`pol)4Iller used to prepare them. The dependence of the mechanical properties of
`• At
`polymers on their molecular weight is qualitatively the same for all polymers 25
`low molecular weights they are relatively weak, but as the molecular weight
`increases their strength also increases proportionately until at some critical
`molecular weight there is no further increase. This inflection in the curve should
`occur at a DP of 200-250, corresponding to a molecular weight of 4-5 x 104 for the
`cellulose derivatives. In practice it has been found that for the commercial
`film-coating polymers the inflection occurs somewhat higher at a molecular weight
`• 20. It is thought that this discrepancy is due to the presence of very
`of 7-8 x 104 19
`low molecular weight components ( < 5 x 103
`) within the molecular weight
`distribution, which are known to have a deleterious effect on the mechanical
`properties of polymers disproportionate to their concentration on a weight
`basis 19
`20
`
`•
`
`•
`
`Refractive index. The refractive index of a polymer film former is of
`2.4.3
`fundamental importance in determining the appearance of film coatings
`containing pigments (see Section 4.6.1). Films prepared from the cellulose ethers
`are isotropic. The refractive indices of methylcellulose, hydroxypropylcellulose,
`hydroxypropylmethylcellulose and ethylcellulose are 1.50, 1.56, 1.49 and 1.47
`respectively 26
`•
`
`2.4.4
`
`Softening (glass-transition) temperature. The softening temperature is
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`12
`
`Raymond C. Rowe
`
`the temperature at which a film strip laid on a heated metal bar begins to soften. It
`is closely related to the more fundamental property of glass-transition tempera(cid:173)
`ture and is of importance to the formulator since it gives an indication of the
`degree of tackiness likely to be encountered with film coatings either during
`high-temperature drying or during the heat sealing process for strip or blister
`packing. The high thermal softening point or glass-transition temperature of
`hydroxypropylcellulose, hydroxypropylmethylcellulose
`and
`ethylcellulose
`(120°, 180° and 140°C respectively) 1
`9 make them ide~l polymers in this respect.
`-
`With ethylcellulose the softening temperature is related to the degree of
`substitution, a minimum occurring at a DS of2.5 (48.5% ethoxyl content) 9
`• The
`degree of lowering of the softening or glass-transition temperature on the addition
`of plasticizers to polymer film formers is an indication of their efficiency (see
`Section 3.4.3).
`
`Surf ace activity. The surface activity of polymer solutions is important in
`2. 4. 5
`determining the degree of wetting of the substrate and hence spreading of the
`spray droplet during film coating. When coating with organic solvents, wetting is
`not a problem, but with aqueous solutions it is an important factor to be con(cid:173)
`sidered. All the water-soluble polymers have some surface activity lowering the
`surface tension of water to approximately 50 mN m -i depending on concentration
`and temperature3- 8 •
`
`Stability to water and pH. All the water-soluble polymers absorb
`2.4.6
`moisture from the air. At any given relative humidity the equilibrium moisture
`content is methylcellulose > hydroxypropylmethylcellulose > hydroxypropyl(cid:173)
`cellulose3-8. As all are non-ionic polymers, the viscosity of their aqueous solution
`is unaffected over the pH range 2-11. For optimum stability the pH of the solution
`should be held between 6 and 8. Acid hydrolysis can lead to an increase in the
`number of reducing end groups due to chain scission.
`Ethylcellulose is the most stable of the cellulose derivatives. It is resistant to
`alkalis, both dilute and concentrated, but is sensitive to acids. It takes up very little
`water from moist air or during immersion, and this evaporates readily leaving the
`ethylcellulose unchanged 9
`•
`Cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate are
`both resistant to acids below pH 5 but soluble at higher pH. In the presence of
`moisture, e.g. during adverse storage conditions, cellulose acetate phthalate is
`known to hydrolyse with the elimination of free acid and subsequent loss in
`efficiency as an enteric coating agent 15• 16•
`
`Stability to heat and light. In the dry state all the polymers and the films
`2. 4. 7
`produced from them are stable to the temperatures currently used during stability
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`Materials used in the film coating of oral dosage forms
`
`13
`
`i.e. below 50°C, and have good light stability. Ethylcellulose,
`testing,
`methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose are
`stable up to their softening temperatures.
`
`Biological stability. In the dry state or as films all the polymers show good
`2.4.8
`resistance to degradation by moulds and bacteria. Aqueous solutions of methyl(cid:173)
`cellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose do not
`readily support the growth of micro-organisms but are not bacteriostatic. If
`contamination does occur degradation and loss of viscosity can resuit3- 8 .
`
`Analysis and specifications
`2.5
`Analytical methods for all the polymers invariably include the determination of:
`( a)
`the degree of substitution-usually expressed as a weight percentage;
`(b)
`the apparent viscosity;
`( c)
`the moisture content or loss on drying;
`(d)
`the ash content or residue on ignition.
`Other methods for specific polymers include the determination of:
`(a)
`the pH of an aqueous solution-applicable to the water soluble polymers
`only;
`(b)
`limits for arsenic and heavy metal contamination-applicable to the water
`soluble polymers and hydroxypropylmethylcellulosephthalate;
`(c)
`the free acid content-applicable to cellulose acetate phthalate and
`hydroxypropylmethylcellulose phthalate only.
`Ethylcellulose and methylcellulose may also be identified by their IR absorption
`9
`spectra 4
`•
`•
`
`Applications
`2.6
`The wide range of properties illustrated above makes these polymers ideal for the
`film coating of solid dosage forms. For water soluble coatings applied primarily to
`improve product odour, taste, appearance and to prevent dust formation during
`high speed packaging, the water-soluble polymers alone or as mixtures are ideal
`candidates. These may be applied in aqueous solution eliminating the use of toxic
`and flammable organic solvents, and they produce tough flexible films stable to
`the majority of environmental changes likely to be encountered during the life of
`the product. They also dissolve readily without significantly affecting the dis(cid:173)
`solution of the active ingredient. Hydroxypropylmethylcellulose is the preferred
`polymer because of its higher water solubility and higher thermal gelation
`point 27•
`• Ethylcellulose is ideal for the manufacture of films for sustained release
`28
`dosage forms. In many cases it needs to be formulated with a water-soluble
`polymer (the water-soluble cellulose ethers are ideal for this purpose) to obtain
`the correct diffusion rate of the active ingredient 29 . Again the films produced are
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`Materials used in the film coating of oral dosage forms
`
`15
`
`Table 8. Dissolution of a model drug from granules coated with two
`molecular weight grades of hydroxypropylmethylcellulose
`phthalate (HP55)-dissolution medium simulated gastric juice pH
`1.5
`
`Coating weight
`(% w/w)
`
`Sample (2)
`Sample (1)
`(M.Wt 19.68 x 104)
`(M.Wt7.95Xl0 4)
`% drug released after (h)
`3.0
`1.5
`
`3.0
`
`1.5
`
`5
`7.5
`10.0
`12.5
`15.0
`
`11.5
`8.6
`5.7
`3.5
`
`23.5
`18.8
`13.5
`8.3
`
`12.8
`5.1
`2.3
`0.6
`0.2
`
`24.9
`11.8
`6.7
`2.8
`0.6
`
`more resistant to cracking than films prepared from lower molecular weight
`grades, is in the solution of the film defects cracking or edge splitting and peeling
`(Table 1). Figure 4 shows the effect of the molecular weight of hydroxypropyl(cid:173)
`methylcellulose on the tensile strength of free films and the incidence of both edge
`splitting (measured by visual examination) and micro-cracks (measured by a
`• 30· 31. It can be seen that there is an inverse
`mercury porosimetry technique) 18
`relationship between the incidence of these two defects and the tensile strength,
`and that the molecular weight at which the incidence of the two defects is
`negligible is the same as that at which there is no further increase in tensile
`strength. Similar results on the effect of the molecular weight of hydroxy(cid:173)
`propylmethylcellulose phthalate (HP55) is shown in Table 821. It can be seen that
`the higher molecular weight grade of the polymer is between 1.5 and 1. 7 times
`more effective than the lower molecular weight grade in preventing the release of
`a model drug from a granule formulation previously known to be prone to film
`cracking on coating.
`The availability of a large number of molecular weight grades of these
`polymers also allows the formulator to blend different grades and thus modify
`further the properties of the films produced. Blending may be carried out using
`the formula:
`Niog1) 1, + (100- N) log772
`log 7Js =
`100
`
`(3)
`
`where 7Js is the apparent viscosity sought, 7J I and 772 are the apparent viscosities of
`the first and second components of the blend, and N is the weight percentage of
`the first component. Recently it has been shown that the incidence of edge
`splitting and peeling on film-coated tablets could be significantly reduced when
`blends of low and high molecular weight grades of hydroxypropylmethylcellulose
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`

`16
`
`Raymond C. Rowe
`
`were used instead of the commerciaHy available grades of the same molecular
`weight and apparent viscosity. It was concluded that this effect was due to the
`presence, in the blends, of an increased proportion of a very high molecular
`weight component (> 5 x 105
`) in the molecular weight distribution which was
`thought to increase the toughness of the polymer film 30
`
`•
`
`Plasticizers used in film coating
`3
`Plasticizers may be defined as relatively low molecular weight substances of low
`volatility which, when added to a polymer, changes its physical properties in such
`a manner that the finished product is in a more useful form. More specifically, a
`plasticizer imparts flexibility to a polymer. At the molecular level it is thought that
`to be effective, a plasticizer must interpose itself between the polymer chains and
`interact with the forces which hold the chains together thereby extending and
`softening the polymer matrix. The most effective plasticizers generally closely
`resemble in structure the polymers they plasticize. Thus, the water-soluble
`cellulose ethers containing a large proportion of hydroxyl groups are best
`plasticized by hydroxyl-containing materials such as the polyols, glycerol,
`propylene glycol and polyethylene glycols. On the other hand, the less polar
`cellulose esters, cellulose acetate phthalate and hydroxypropylmethylcellulose
`phthalate are best plasticized by the organic esters, especially those of citric and
`phthalic acids.
`Plasticizers commonly used in tablet film coating can be conveniently divided
`into three groups: the polyols, the organic esters and the vegetable oils and
`glycerides.
`
`Polyols
`3.1
`Included in this group are glycerol, propylene glycol and the polyethylene glycols
`of molecular weight 200-6000. All are used as plasticizers for the water soluble
`cellulose ethers. All are miscible or freely soluble in water and, with the exception
`of the higher molecular weight polyethylene glycols, all are hygroscopic.
`
`Table 9. Comparative hygroscopicity figures
`for glycerol and the polyethylene glycols 32
`• 33
`
`Plasticizer
`
`Comparative
`hygroscopicity
`
`Glycerol
`Polyethylene glycol 200
`Polyethylene glycol 300
`Polyethylene glycol 400
`Po