Tài liệu Pharmaceutical Coating Technology (Part 2) pptx

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2
Film-coating materials and their properties
John E.Hogan
SUMMARY
The chapter commences by reviewing the properties of the broad classes of materials used in film
coating, polymers, plasticizers, pigments and solvents (or vehicles).
An initial consideration of the polymers shows that while processing is most commonly performed
using these materials in solution, there are systems which utilize polymers in suspension in water. The
mechanism of coalescence and film formation for these types of materials are discussed.
The individual polymers are dealt with in some detail and an attempt is made to divide them into
functional and non-functional coating polymers. Functional polymers being defined as those which
modify the pharmaceutical function of the compressed tablet, for instance an enteric or modified releae
film. However, this distinction is sometimes blurred as one coating polymer can fall into both groups.
The essential polymer characteristics of solubility, solution viscosity, film permeability and mechanical
properties are described in terms of ultimate film requirements.
In the treatment and description of plasticizers, some prominence is given to their effect on the
mechanical properties of the film and its permeability characteristics, especially to water vapour. A
section is provided on the assessment of plasticizer activity on film-coating polymers.
The section on pigments describes how they function as opacifiers and also their ability to modify the
permeability of a film to gases.
In considering the solvents and vehicles used in film-coating techniques a discussion is provided of
the respective merits of aqueous and non-aqueous processing.
The chapter is concluded by some examples of formulae of film-coating systems which illustrate
several of the principles described previously.
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2.1 INTRODUCTION
A film coating is a thin polymer-based coat applied to a solid dosage form such as a tablet, granule or
other particle. The thickness of such a coating is usually between 20 and 100 µm. Under close
examination the film structure can be seen to be relatively non-homogeneous and quite distinct in
appearance, for example, from a film resulting from casting a polymer solution on a flat surface. This

non-homogeneous character results from the deliberate addition of insoluble ingredients such as
pigments and by virtue of the fact that the film itself is built up in an intermittent fashion during the
coating process. This is because most coating processes rely on a single tablet or granule passing
through a spray zone, after which the adherent material is dried before the next portion of coating is
received. This activity will of course be repeated many times until the coating is complete.
Film-coating formulations usually contain the following components:
However, while plasticizers have an established place in film-coating formulae they are by no means
universally used. Likewise, in clear coating, pigments and opacifiers are deliberately omitted.
Consideration must also be given to minor components in a film-coating formula such as flavours,
surfactants and waxes and, in rare instances, the film coat itself may contain active material.
2.2 POLYMERS
The vast majority of the polymers used in film coating are either cellulose derivatives, such as the
cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular
weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials.
The characteristics of the individual polymers and the essential properties of polymers used for film
coating will be covered in subsequent sections.
Frequently, the polymer is dissolved in an appropriate solvent either water or a non-aqueous solvent
for application of the coating to the solid dosage form. However, some of the water-insoluble polymers
are available in a form which renders them usable from aqueous systems. These materials find
considerable application in the area of modified release coatings. Basically there are two classes of such
material depending upon the method of preparation; true latexes and pseudolatexes.
2.2.1 True latexes
These are very fine dispersions of polymer in an aqueous phase and particle size is crucial in the
stability and use of these materials. They are characterized by a particle size range of between 10 and
1000 nm. Their tendency to sediment is counter-
• Polymer.
• Plasticizer.
• Pigment/opacifier.
• Vehicle.
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balanced by the Brownian movement of the particles aided by microconvection currents found in the
body of the liquid. The Stokes equation can be used to determine the greatest particle diameter that can
be tolerated in the system without sedimentation. At the other end of the size range the characteristic of
colloidal particles is approached where such dispersions are barely opaque to light and are almost clear.
One of the chief ways of producing latex dispersions is by emulsion polymerization. Characteristically
the process starts with the monomer which after purifica-tion is emulsified as the internal phase with a
suitable surfactant (Lehmann, 1972). Polymerization is activated by addition of an initiator. Commonly
the system is purged with nitrogen to remove atmospheric oxygen which would lead to side reactions.
As with any polymerization process, the initiator controls the rate and extent of the reaction. The
reaction is quenched when the particle size is in the range 50–200 nm. Using this process the following
acrylate polymers are produced: Eudragit L100–55 and NE30D (Lehmann, 1989a).
2.2.2 Psuedolatexes
Commercially there are two main products which fall into this category, both of them utilize
ethylcellulose as the film former but are manufactured in quite a different way and their method of
application also differs significantly. Characteristically pseudolatexes are manufactured starting with the
polymer itself and not the monomer. By a physical process the polymer particle size is reduced thereby
producing a dispersion in water; the characteristics of this dispersion need not differ significantly from a
true latex, including particle size considerations. The pseudolatex is also free of monomer residue and
traces of initiator, etc.
The earliest of the two ethylcellulose products (Aquacoat) is manufactured by dissolving
ethylcellulose in an organic solvent and emulsifying the solution in an aqueous continuous phase. The
organic solvent is eventually removed by vacuum distillation, leaving a fine dispersion of polymer
particles in water. Steuernagel (1989) has defined the composition of Aquacoat to have a solids content
of 30% w/w and a moisture content of 70%w/w, the solids being composed of ethylcellulose 87%, cetyl
alcohol 9% and sodium lauryl sulphate 4%. A food grade antifoam is also present. The cetyl alcohol and
sodium lauryl sulphate act as surfactants/stabi-lizers during the later stages of production.
The newer of the ethylcellulose products is Surelease. This is manufactured using a patented process
based on phase inversion technology (Warner, 1978). The ethylcellulose is heated in the presence of
dibutyl sebacate and oleic acid, and this mixture is then introduced into a quantity of ammoniated water.
The resulting phase inversion produces a fine dispersion of ethylcellulose particles in an aqueous

continuous phase. The dibutyl sebacate (fractionated coconut oil can also be used) is to be found in the
ethylcellulose fraction while the oleic acid and the ammonia together effectively stabilize the dispersed
phase in water. This siting of the dibutyl sebacate and oleic acid is important for the use of this material
as an effective coating agent. Both materials act as plasticizers and with the Surelease system are
physically situated where they are able to function most effectively, that is, in intimate contact with the
polymer. Surelease, unlike Aquacoat, does not require the
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further addition of plasticizer. Surelease also contains a quantity of fumed silica which acts as an
antitack agent during the coating process. Its total nominal solids content is 25% w/w.
Aqueous dispersions have significant advantages, enabling processing of water-insoluble polymers
from an aqueous media (see Chapter 14
).
2.2.3 Mechanism of film formation
Film formation from an aqueous polymeric dispersion is a complex matter and has been examined by
several authors (Bindschaedler
et al., 1983; Zhang et al., 1988, 1989). In the wet state the polymer is
present as a number of discrete particles, and these have to come together in close contact, deform,
coalesce and ultimately fuse together to form a discrete film. During processing, the substrate surface
will be wetted with the diluted dispersion. Under the prevailing processing conditions water will be lost
as water vapour and the polymer particles will increase in proximity to each other—a process which is
greatly aided by the capillary action of the film of water surrounding the particles. Complete
coalescence occurs when the adjacent particles are able to mutually diffuse into one another, as shown
in Fig. 2.1
.
Minimum film-forming temperature
(MFT)
This is the minimum temperature above which film formation will take place using individual defined
conditions. It is largely dependent on the glass transition temperature (
Tg) of the polymer, an attribute
which is capable of several definitions but can be considered as that temperature at which the hard

glassy form of an amorphous or largely amorphous polymer changes to a softer, more rubbery,
consistency. Lehmann (1992) states that the concept of MFT includes the plasticizing effect of water on
the film-forming process. With aqueous dispersions Lehmann recommends to keep the coating
temperature 10–20°C above the MFT to ensure that optimal conditions for film formation are achieved.
Examples of MFTs of Eudragit RL and RS aqueous dispersions are given by Lehmann (1989a).
2.3 POLYMERS FOR CONVENTIONAL FILM COATING
The term conventional film coating has been used here to describe film coatings applied for reasons of
improved product appearance, improved handling, and prevention of dusting, etc. This is to make a
distinction with functional film coats, which will be described in a later section, and where the purpose
of the coating is to confer a modified release aspect on the dosage form. An alternative term for
conventional film coating, therefore, would be non-functional film coating.
2.3.1 Cellulose ethers
The majority of the cellulose derivatives used in film coating are in fact ethers of cellulose. Broadly they
are manufactured by reacting cellulose in alkaline solution with, for example, methyl chloride, to obtain
methylcellulose. Hydroxypropoxyl substitution is obtained by similar reaction with propylene oxide.
The product is
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Fig. 2.1 Mechanism of film formation of aqueous polymer dispersions
thoroughly washed with hot water to remove impurities, dried and finally milled prior to packaging.
The structure of cellulose permits three hydroxyl groups per repeating anhydroglucose unit to be
replaced, in such a fashion. If all three hydroxyl groups are replaced the degree of substitution (DS) is
designated as 3, and so on for lower degrees of substitution. The term molar substitution (MS) covers
the situation where a side chain carries hydroxyl groups capable of substitution and takes into account
the total moles of a group whether on the backbone or side chain. Both DS and MS profoundly affect
the polymer properties with respect to solubility and thermal gel point.
The polymer chain length, together with the size and extent of branching, will of course determine the
viscosity of the polymer in solution. As a generality, film coating demands polymers at the lower end of
the viscosity scale.
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Individual cellulose ethers

Various groups are capable of substitution into the cellulose structure, as shown in Fig. 2.2.
Hydroxypropyl methylcellulose (HPMC)
Substituent groups: —CH
3
, —CH
2
—CH(OH)—CH
3
This polymer provides the mainstay of coating with the cellulose ethers and its usage dates back to
the early days of film coating. It is soluble in both aqueous media and the organic solvent systems
normally used for film coating. HPMC provides aqueously soluble films which can be coloured by the
use of pigments or used in the absence of pigments to form clear films. The polymer affords relatively
easy processing due to its non-tacky nature. A typical low-viscosity polymer can be sprayed from an
aqueous solution containing around 10–
15%w/w polymer solids. From the regulatory aspect, in addition
to its use in pharmaceutical products, HPMC has a long history of safe use as a thickener and emulsifier
in the food industry.
Table 2.2
shows that the USP and JP recognize definite substitution types in separate monographs.
The first two digits of the four-digit designation specify the nominal percentage of methoxyl groups
while the final two specify the nominal
Fig. 2.2 The structure of a substituted cellulose. (R can be represented as –H or, as in the
text, under individual polymers.)
Table 2.1
Substitution data of some cellulose ethers (after Rowe, 1984c)
Polymer Methoxyl substitution Hydroxypropoxyl substitution
%w/w DS %w/w DS MS
Methylcellulose 27.5–31.5 1.64–1.92 — — —
Hydroxypropyl methylcellulose 28.0–30.0 1.67–1.81 7.0–12.0 0.15–0.25 0.22–0.25
Hydroxypropyl cellulose — —

≤
80.5
—
≤
4.6
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percentage of hydroxypropoxyl groups. The EP has no specified ranges for substitution. Significant
differences exist between the USP and EP monographs. These relate to tighter requirements for ash,
chloride for the EP which also possesses tests on solution colour, clarity and pH. Methodology
differences also exist, particularly with regard to solution viscosity. The JP has a very low limit on
chloride content.
Methylcellulose (MC)
Substituent group: —CH
3
This polymer is used rarely in film coating possibly because of the lack of commercial availability of
low viscosity material meeting the appropriate compendial requirements. As a distinction from the USP
and the JP the EP has no required limits on the content of methoxyl substitution. However, the USP and
JP have slightly different limits, which are 27.5–31.5% against 26.0–33.0% respectively.
Hydroxyethyl cellulose (HEC)
Substituent group: —CH(OH)—CH
3
This water-soluble cellulose ether is generally insoluble in organic solvents. The USNF is the sole
pharmacopoeial specification; there is no requirement on the quantity of hydroxyethyl groups to be
present. The USNF allows the presence of additives to promote dispersion of the powder in water and to
prevent caking on storage.
Hydroxypropyl cellulose (HPC)
Substituent group: —CH
2
—CH(OH)—CH
3

HPC has the property of being soluble in both aqueous and alcoholic media. Its films unfortunately
tend to be rather tacky, which possess restraints on rapid coating; HPC films also suffer from being
weak. Currently this polymer is very often used in combination with other polymers to provide
additional adhesion to the substrate. The EB/BP has no requirements on hydroxypropoxyl content. The
USNF states this must be less than 80.5% while the JP has two monographs differing in substitution
requirements. The monograph most closely corresponding to the USNF material has a substitution
specification of 53.4–77.5%. The other monograph relates to material of much lower substitution
content and is used for purposes other than film coating, e.g. direct compression.
2.3.2 Acrylic polymers
These comprise a group of synthetic polymers with diverse functionalities.
Table 2.2
Compendial designations of HPMC typess in the USP and JP
2910 2208 2906
1828
a
% Methoxyl 7–12 4–12 4–7.5 16–20
% Hydroxypropoxyl 28–20 19–24 27–30 23–32
a
Monograph only in the USP.
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Methacrylate aminoester copolymer
This polymer is basically insoluble in water but dissolves in acidic media below pH 4. In neutral or
alkaline environments, its films achieve solubility by swelling and increased permeability to aqueous
media. Formulations intended for conventional film coating can be further modified to enhance swelling
and permeability by the incorporation of materials such as water soluble cellulose ethers, and starches in
order to ensure complete disintegration/dissolution of the film.
This material is supplied in both powder form or as a concentrated solution in isopropanol/acetone,
which can be further diluted with solvents such as ethanol, methanol, acetone and methylene chloride.
Talc, magnesium stearate or similar materials are useful additions to the coating formula as they assist in
decreasing the sticky or tacky nature of the polymer. In general, the polymer does not require the

addition of a plasticizer.
2.4 POLYMERS FOR MODIFIED RELEASE APPLICATION
Despite the considerable difference in application between a polymer intended for a simple conventional
(non-functional) coating and one intended to confer a modified release performance on the dosage form,
the categorizing of the polymers themselves into these divisions is not such an exact process. Several
examples exist of polymers fulfilling both needs, hence there is a considerable overlap of use. However,
the divisions used here represent perhaps the majority practice.
Table 2.3
Methacrylate aminoester copolymers (after Lehmann & Dreher, 1981)
Scientific name
n
1
:n
2
:n
3
MW USNF
designation
Eudragit
type
Marketed form
Poly(butylmethacrylate), (2-
dimethylaminoethyl) methacrylate,
methylmethacrylate
1:2:1 150
000
None E12.5 12.5% solution in
isopropanol/ acetone
R=—CH2—CH
2

—N(CH
3
)
2
None E100 Granulate
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2.4.1 Methacrylate ester copolymers
Structurally these polymers bear a resemblance to the methacrylic acid copolymers but are totally
esterified with no free carboxylic acid groups. Thus these materals are neutral in character and are
insoluble over the entire physiological pH range. However they do possess the ability to swell and
become permeable to water and dissolved substances so that they find application in the coating of
modified release dosage forms. The two polymers Eudragit RS and RL, can be mixed and blended to
achieve a desired release profile. The addition of hydrophilic materials such as the soluble cellulose
ethers, polyethylene glycol (PEG), etc., will also enable modifications to be achieved with the final
formulation. The polymer Eudragit RL is strongly permeable and thus only slightly retardant. Its films
are therefore also indicated for use in quickly disintegrating coatings. The polymers themselves have
solubility characteristics similar to the methacrylic acid copolymers.
For aqueous spraying a latex form of each polymer is available. In addition the polymer Eudragit
NE30D has been made for this purpose. This materal is also used as an immediate-release non-
functional coating in film coat formulations where relatively large quantities of water-soluble materials
are added to ensure efficient disruption of the coat.
2.4.2 Ethylcellulose (EC)
Substituent group (Fig. 2.2): —CH
2
—CH
3
Ethylcellulose is a cellulose ether produced by the reaction of ethyl chloride with the appropriate
alkaline solution of cellulose. Apart from its extensive use in controlled release coatings, ethylcellulose
has found a use in organic solvent-based coatings in a mixture with other cellulosic polymers, notably
HPMC. The ethylcellulose component optimizes film toughness in that surface marking due to handling

is minimized. Ethylcellulose also conveys additional gloss and shine to the tablet surface.
In many ways ethylcellulose is an ideal polymer for modified release coatings. It is odourless,
tasteless and it exhibits a high degree of stability not only under physiological conditions but also under
normal storage conditions, being stable to light and heat at least up to its softening point of
c. 135°C
(Rowe, 1985). Commercially, ethylcellulose is available in a wide range of viscosity and substitution
types giving a good range of possibilities for the formulator. It also possesses good solubility in
common solvents used for film coating but this feature is nowadays of lesser importance with the advent
of water-dispersible presentations of ethylcellulose which have been especially designed for modified
release coatings. The polymer is not usually used on its own but normally in combination with
secondary polymers such as HPMC or polyethylene glycols which convey a more hydrophilic nature to
the film by altering its structure by virtue of pores and channels through which drug solution can more
easily diffuse. Only the USNF contains a monograph, an ethoxy group content of between 44.0 and
51.0% is specified. The USNF also contains a monograph ‘Ethylcellulose Aqueous Dispersion’ which
defines one type of such material which finds a use in aqueous processing. The monograph permits the
presence of cetyl alcohol and sodium lauryl sulphate which are necessary to stabilize the dispersion.
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2.5 ENTERIC POLYMERS
As will be seen later, enteric polymers are designed to resist the acidic nature of the stomach contents,
yet dissolve readily in the duodenum.
2.5.1 Cellulose acetate phthalate (CAP)
Substituent groups (Fig. 2.2): —CO—CH
3
, —CO—C
6
H
4
—COOH
This is the oldest and most widely used synthetic enteric coating polymer patented as an enteric agent
by Eastman Kodak in 1940. It is manufactured by reacting a partial acetate ester of cellulose with

phthalic anhydride. In the resulting polymer, of the free hydroxyl groups contributed by each glucose
unit of the cellulose chain, approximately half are acylated and one-quarter esterified with one of the
two carboxylic acid groups of the phthalate moiety. The second carboxylic acid group being free to form
salts and thus serves as the basis of its enteric character.
Table 2.4
Methacrylate ester copolymers (after Lehmann & Dreher, 1981)
Scientific name
n
1
:n
2
:n
3
MW USNF
designation
a
Eudragit
type
Marketed form
Poly(ethylacrylate, methylmethacrylate 2:1 800
000
None NE30D 30% aqueous
dispersion
Poly(ethylacrylate, methylmethacrylate)
trimethylammonioethylmethacrylate chloride
1:2:0.2 150
000
Type A RL12.5 12.5% solution in
isopropanol/acetone
RL100 Granulate

R=CH
2
—CH
2
—N
+
(CH
3
)
3
Cl
−
RL30D 30% aqueous
dispersion
Poly(ethylacrylate, methylmethacrylate)
trimethylammonioethylmethacrylate chloride
1:2:0.1 150
000
Type B RS12.5 12.5% solution in
isopropanol/acetone
RS100 Granulate
R=CH2—CH
2
—N
+
(CH3)3Cl
−
RS30D 30% aqueous
dispersion
a

Ammoniomethacrylate co-polymer
Page 16
CAP is a white free-flowing powder usually with a slightly odour of acetic acid. Among the
pharmacopoeias it is found in the EP, JP and USNF. The USNF and JP impose specifications for the
percentage content of the substituent groups. The JP has requirements for the content of acetyl and
phthalyl to be respectively 17–22 and 30–40% while the USNF requires 21.5–26 and 30–36%
respectively. The JP is alone in not specifying any viscosity control on a standard solution. All three
pharmacopoeias require a maximum limit on the quantity of free acid (JP specifies phthalic acid) and
loss on drying (EP specifies water content). The last two parameters are important as CAP is somewhat
prone to hydrolysis.
Of the generally accepted solvents used for tablet coating, CAP is insoluble in water, alcohols and
chlorinated hydrocarbons. In the following solvents or solvent mixtures (data from the
Handbook of
Pharmaceutical Excipients, 1986) it possesses greater than 10% solubility:
acetone
A pseudolatex version of CAP is available (Aquateric) as a dry powder for reconstitution in water and
offers the convenience of aqueous-based processing.
Owing to their chemical constitution, most of the phthalate-based enteric coating agents are to a
greater or lesser degree unstable. This important aspect is dealt with in more detail in Chapter 14
, along
with the implications this has on the use of the materal in practice.
2.5.2 Polyvinyl acetate phthalate (PVAP)
PVAP was first patented by the Charles E. Frost Company of Canada and was subsequently investigated
by Millar (1957) who studied the effect that the phthalyl content of the polymer had upon the pH of
disintegration of tablets coated with the material. He found the optimal phthalyl content to be between
60 and 70%. However, given the characteristics of the polymer commercially available nowadays, this
range has been revised and now forms part of the USNF monograph. It is manufactured by reacting
polyvinyl alcohol with acetic acid and phthalic anhydride.
The USNF contains a monograph specifying a total phthalate content of between 55 and 62%. The
polymer characteristics are further controlled by imposition of a viscosity specification. The extent of

hydrolysis, while much less likely than CAP for instance, is controlled with a limit on free phthalic acid
and other free acids. As the final separation process is from water, a limit of 5% of water is specified.
Polyvinyl acetate phthalate possesses the following solubility characteristics, with the extent of
solubility given in parentheses:
methanol (50%)
methanol/methylene chloride (30%)
ethyl acetate:isopropanol 1:1
acetone:ethanol 1:1
acetone:methanol 1:1 and 1:3
acetone:methylene chloride 1:3
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ethanol 95% (25%)
ethanol/water 85:15 (30%)
An aqueous dispersible form (Sureteric) is available for water-based spraying.
2.5.3 Shellac
This is a purified resinous secretion of the insect Laccifer lacca, indigenous to India and other parts of
the Far East. Shellacs can be modified to suit specialized needs. For instance, bleached shellac is
produced by dissolving crude shellac in warm soda solution followed by bleaching with hypochlorite.
Various grades of dewaxed material can be produced by removing some or all of the approximately 5%
of wax in the final shellac.
Shellac is insoluble in water but shows solubility in aqueous alkalis; it is moder-
ately soluble in warm
ethanol.
Over the years, shellac has been used for a variety of applications, which have included.
For all these applications, shellac suffers from the general drawback that it is a material of natural
origin and consequently suffers from occasional supply problems and quality variation. As will be
described later, there are also stability problems associated with increased disintegration and dissolution
times on storage.
2.5.4 Methacrylic acid copolymers
Because these polymers possess free carboxylic acid groups they find use as enteric-coating materials,

forming salts with alkalis and having an appreciable solubility at pH in excess of 5.5
Of the two organic solvent soluble polymers, Eudragit S100 has a lower degree of substitution with
carboxyl groups and consequently dissolves at higher pH than Eudragit L100. Used in combination,
these materials are capable of providing films with a useful range of pH over which solubility will
occur.
All the polymers shown in Table 2.5
are recommended to be used with plasticizers. Pigments and
opacifiers are useful additions as they counteract the sticky nature of the polymers. A feature of these
polymers is their ability to bind large quantities of pigments—approximately two or three times the
quantity of polymer used. Polyethylene glycols are frequently added as they provide a measure of gloss
to the final product. They also assist in stabilizing the water-dispersible form, Eudragit L30D. Pigment
and other additions to the water-dispersible forms Eudragit, L30D and L100–55, should be performed
according to the manufacturer’s recommendations to prevent coagulation of the coating dispersion.
• A seal coat for tablet cores prior to sugar coating.
• An enteric-coating material. This application is really of historic interest only as shellac has a
relatively high apparent p
K
a
of between 6.9 and 7.5 and leads to poor solubility of the film in the
duodenum (Chambliss, 1983).
• A modified release coating.
Page 18
These polymers comply with the USNF requirements for methacrylic acid copolymer as outlined in
Table 2.5
. Both Eudragit L100 and S100 are available in powder form and for convenience purposes
they are also available as concentrates in organic solvent solution, which are capable of further dilution
in the common processing solvents used in organic solvent-based film coating. As previously indicated,
two further commercial forms are available, first, a 30% aqueous dispersion, Eudragit L30D, and,
secondly, a water-dispersible powder, Eudragit L100–55.
The Eudragit acrylate polymers can be described using a generic type nomenclature as given below.

Reference can also be made to the corresponding parts of Tables 2.3
, 2.4 and 2.5.
Monomers
Copolymers
Table 2.5
Methacrylic acid copolymers (after Lehmann & Dreher, 1981)

Scientific name
n
1
:n
2
MW
R
1
R
2
USNF
designation
a
Eudragit
type
Marketed form
Polymethylacrylate,
ethylacrylate)
1:1 250
000
H
C
2

H
5
Type C L30D 30% aqueous
dispersion
L100–55 Powder
Poly(methacrylic acid,
methylmethacrylate)
1:1 135
000
CH
3
CH
3
Type A L12.5 12.5% solution in
isopropanol
L100 Powder
Poly(methacrylic acid,
methylmethacrylate)
1:2 135
000
CH
3
CH
3
Type B S12.5 12.5% solution in
isopropanol
S100 Powder
a
Methacrylic acid copolymer
MMA methylmethacrylate

MA methacrylic acid
EA ethylacrylate
TAMCl trimethylammonioethylmethacrylate chloride
poly(MA-EA) 1:1 copolymer of MA and EA in a molar ratio of 1:1 (Eudragit L30D, Eudragit
L100–55)
poly(MA-MMA)
1:1
copolymer of MA and MMA in a molar ratio of 1:1 (Eudragit L100)

Page 19
2.5.5 Cellulose acetate trimellitate (CAT)
Substituent groups (Fig. 2.2): —CO—CH
3
, CO—C
6
H
3
—(COOH)
2
Chemically this polymer bears a strong resemblance to cellulose acetate phthalate but possesses an
additional carboxylic acid group on the aromatic ring. Manufacturer’s quoted typical values for
timellityl and acetyl percentages are 29 and 22% respectively. The useful property of this polymer is its
ability to start to dissolve at the relatively low pH of 5.5 (Anon., 1988) which would help ensure
efficient dissolution of the coated dosage form in the upper small intestine.
As yet, CAT does not appear in any pharmacopoeia but is the subject of a US FDA Drug Master File.
The solubility of CAT in organic solvents is similar to that for CAP. For aqueous processing, the
manufacturers recommend the use of ammoniacal solutions of CAT in water, and fully enteric results
are claimed. The recommended plasticizers for aqueous use are triacetin, acetylated monoglyceride or
diethyl phthalate.
2.5.6 Hydroxypropyl methylcellulose phthalate (HPMCP)

Substituent groups: —CH
3
, —CH
2
CH(OH)CH
3
, —CO—C
6
H
4
—COOH
HPMCP is prepared by treating hydroxypropyl methylcellulose with phthalic acid. The degree of
substitution of the three possible substituents determines the polymer characteristics, in particular the
pH of dissolution.
HPMCP may be plasticized with diethylphthalate, acetylated monoglyceride or triacetin.
Mechanically it is a more flexible polymer and on a weight basis will not require as much plasticizer as
CAP or CAT.
HPMCP is a white powder or granular material; monographs can be found in both the USNF and JP.
Both pharmacopoeias describe two substitution types, namely HPMCP 200731 and 220824. The six-
digit nomenclature refers to the percentages of the respective Substituent methoxyl, hydroxypropoxyl
and carboxy-benzoyl groups. For example, HPMCP 200731 has a nominal methoxyl content of 20%
and so on for the other two substituents. Substitution requirements are the same in both pharmacopoeias.
Commercial designations such as ‘50’ or ‘55’ refer to the pH (×10) of the aqueous buffer solubility.
Fine particle size grades designated with a suffix ‘F’ are intended for suspension in aqueous systems,
with suitable plasticizers prior to spray application.
HPMCP is insoluble in water but soluble in aqueous alkalis and acetone/water 95:5 mixtures. The
following summarizes the solubility of HPMCP in common non-aqueous processing solvents:
poly(MA-MMA) 1:2 copolymer of MA and MMA in a molar ratio of 1:2 (Eudragit S100)
poly(EA-MMA-TAMCl)
1:2:0.1

copolymer of EA, MMA and TAMCl in a molar ratio of 1:2:0.1 (Eudragit
RS30D, Eudragit RS100)
poly(EA-MMA-TAMCl)
1:2:0.2
copolymer of EA, MMA and TAMCl in a molar ratio of 1:2:0.2 (Eudragit
RL30D Eudragit RL100)
Page 20
2.6 POLYMER CHARACTERISTICS
2.6.1 Solubility
Inspection of the solubility characteristics of the film-coating polymers show that the following have a
good solubility in water: HPMC, HPC, MC, PVP, PEG plus gastrointestinal fluids and the common
organic solvents used in coating.
Acrylic polymers used for conventional film coating include methacrylate amino ester copolymers.
These bcome water soluble by swelling, increasing permeability in aqueous media. The polymer in its
unmodified form is however soluble only in organic solvents.
Where it is proposed to use an aqueous solvent for film coating it is necessary to consider, first, the
need to minimize contact between the tablet core and water and, secondly, the need to achieve a
reasonable process time. Both can be achieved by using the highest possible polymer concentration (i.e.
the lowest possible water content). The limiting factor here is one of coating suspension viscosity.
2.6.2 Viscosity
HPMC coating polymers, for example, are available in a number of viscosity designations defined as the
nominal viscosity of a 2%w/w aqueous solution at 20°C. Thus a 5mPa s grade will have a nominal
viscosity of 5 mPa s in 2% aqueous solution in water at 20°C and similarly with 6 mPa s, 15 mPa s and
50 mPa s grades. Commercial nomenclature for these grades may still describe them as ‘5 cP’ etc.
Commercial designations such as E5 (Methocel) or 606 (Pharmacoat) also correspond with the viscosity
designation, such that for example Methocel E5 has a nominal viscosity of 5mPa s under the previously
described standard conditions. While Pharmacoat 606 would have a nominal viscosity of 6 mPa s under
the same conditions.
Considering the final polymer solution to be sprayed, a normal HPMC-based system would have a
viscosity of approximately 500 mPa s. Inspection of Fig. 2.3

shows that if, for instance, a 5 mPa s grade
is used (E5) a solids concentration of about 15%w/w can be achieved. This has the advantage over, for
example, a coating solution prepared from a 50 mPa s grade (E50) where only a 5%w/w solids
concentration could be achieved. The lower viscosity grade polymer permits a higher solids
concentration to be used, with consequent reduction in solvent content of the solution. The practical
advantage to be gained is that the lower the solvent content of the solution, the shorter will be the
processing time as less solvent has to be removed
HP55 HP50
Acetone/methanol 1:1 + +
Acetone/ethanol 1:1 + *
Methylene chloride/ethanol 1:1 + +
+=soluble, clear solution
*=slightly soluble, cloudy solution
(data from the
Handbook of Pharmaceutical Excipients, 1986)
Page 21
Fig. 2.3 Comparison of solution viscosity of three commercially available HPMC grades.
during the coating procedure. This beneficial interaction between polymer viscosity and possible coating
solids is self-limiting in that very low viscosity polymers will suffer from poor film strength due to low
molecular weight composition. Delporte (1980) has examined polymer solution viscosities in the 250–
300 mPa s range and has concluded that 5 mPa s HPMC is preferable to the use of 15 mPa s material.
Page 22
Furthermore, Delporte advocated the use of elevated temperature coating media in order to additionally
increase solids loadings via a decrease in viscosity.
2.6.2 Permeability
One of the reasons for coating tablets is to provide a protection from the elements of the atmosphere
such that a shelf-life advantage for the product may be gained.
With the continuing change from sugar- to film-based coating has come associated problems of
stability due to sugar-coating techniques providing a better moisture barrier than that offered by simple
non-functional cellulosics or acrylics. Usually the moisture permeability of a simple film may be

decreased by the incorporation of water-insoluble polymers, however disintegration and dissolution
characteristics of the dosage form must be carefully checked.
Permeability effects can be assessed practically by a technique of sealing a sample of cast film over a
small container of desiccant or saturated salt solution, the permeability to water vapour being followed
by successive weighings to determine respectively weight gain or weight loss (Hawes, 1978). In
addition to being tedious to perform, the results are only comparable when performed under identical
conditions. Using similar techniques Higuchi & Aguiar (1959) demonstrated that water vapour
permeability of a polymer is dependent on the relative polarity of the polymer. Both Hawes (1978) and
Delporte (1980) have seen little difference in water vapour permeability between two commercial
grades of HPMC (E5 and E15) which differ only in molecular weight. Okhamafe & York (1983) have
used an alternative method of assessing water vapour permeability, and that is a sorption-desorption
technique to evaluate the performance of two film-forming polymers, HPMC (606) and polyvinyl
alcohol (PVA). Addition of PVA to the HPMC was seen to enhance very effectively the moisture barrier
effect of the HPMC. The authors ascribe this behaviour to the possible potentiation of the crystallinity of
the HPMC by the PVA.
Sometimes permeability of other atmospheric gases is of concern, particularly that of oxygen. This
area has been studied by Prater
et al. (1982) who examined the permeability of oxygen through films of
HPMC. These workers used a specially constructed cell which held a 21 mm diameter sample of the
film. The passage of gas into the acceptor portion of the cell was monitored by using a mass
spectrometer detection system. Earlier, Munden
et al. (1964) had also determined oxygen permeability
through free films of HPMC. They concluded that there was an inverse relationship between oxygen
permeation and water vapour transmission. These results were obtained using a technique of sealing the
films across a container of alkaline pyrogallol and measuring the consequent solution darkening. As
Prater
et al. (1982) point out, this method is not only tedious but water vapour from the pyrogallol is
capable of plasticizing the film and modifying the result.
2.6.4 Mechanical properties
Some of the film mechanical properties of concern are:

• tensile strength
• modulus of elasticity
Page 23
To perform any function a film coat must be mechanically adequate so that in use it does not crack,
split or generally fail. Also, during the rigours of the coating process itself the film is often relied upon
for the provision of some mechanical strength to protect the tablet core from undue attrition.
These attributes may be conveniently measured by tensile tests on isolated films although other
techniques such as indentation tests have a part to play. Much discussion has also taken place in the
literature on the merits and validity of examining isolated films as opposed to examination of a film
produced under the actual conditions of coating. Both arguments have been reviewed by Aulton (1982).
Suffice it to say that much useful data can be obtained relatively easily from isolated films which, in
practice, has demonstrated the validity of such techniques.
A typical stress-strain curve for a coating polymer is shown in Fig. 2.4
. From this, several definitions
become apparent:
Fig. 2.4 Typical stress-strain curve for a coating polymer (after Aulton et al., 1982).
• work of failure
• strain.
• Tensile strength: The most important parameter here is the ultimate tensile strength, which is the
maximum stress applied at the point at which the film breaks.
Page 24
Table 2.6
gives a comparison of some simple mechanical properties of a selection of film coating
materials. All these properties of a polymer film are related to its molecular weight which, in turn,
affects the viscosity of the polymer in solution. In general, apart from the acrylics, the different types of
individual polymers are available in various commercial viscosity designations. These designations rely
on the description of a standard solution in a specified solvent, as previously indicated.
The relationship between molecular weight and apparent viscosity of a polymer in solution can be
summarized as follows:
MWT=

K(η
app
)
k
(2.1)
where K and k are constants and η
app
is the apparent viscosity. This equation, although useful, is
empirical as the necessarily high concentrations needed for viscosity determination mean that significant
molecular interaction will be taking place. Other equations can be used which take into account this
interaction (Okhamafe & York, 1987).
Some techniques used for molecular weight determination rely on molecular mass for the result (
M
w
)
while others provide data based on molecular numbers (
M
n
). An approximate index of molecular weight
distribution can be obtained by dividing M
w
by M
n
—the higher the value, the wider the distribution.
It should be realized that polymer manufacturers achieve the correct viscosity for the specification by
blending different polymer batches together. It therefore follows that different batches of the same
viscosity grade of polymer may have substantially different ranges of molecular weights. Rowe (1980)
quotes examples (Fig. 2.5
) of how polymer grades of differing apparent viscosity have very similar peak
molecular weights; the viscosity difference being accounted for by the fact that the higher viscosity

grades possess rather more of a very high molecular weight fraction.
The effect of molecular weight on polymer mechanical properties is a well-under-stood phenomenon
in polymer science and is not confined to tablet-coating polymers. Generally, as molecular weight
increases so does the strength of the film. Ultimately a limiting value is reached, and Rowe (1980) has
quoted this molecular weight value as 7–8×10
4
for the commonly used tablet-coating polymers. In
addition, increases in polymer molecular weight result in the polymer film becoming successively more
rigid owing to associated increases in the modulus of elasticity.
• Tensile strain at break: A measure of how far the sample elongates prior to break.
• Modulus (elastic modulus): This is applied stress divided by the corresponding strain in the
region of linear elastic deformation. It can be regarded as an index of stiffness and rigidity of a
film.
• Work of failure: This is numerically equivalent to the area under the curve and equates to the
work done in breaking the film. It is an index of the toughness of a film and is a better measure of
the film’s ability to withstand a mechanical challenge than is a simple consideration of tensile
strength.