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Contents[hide]

1 Introduction 2 Aspects of tablet coating 3 Basic principle of tablet coating 4 Type of tablet coating process

o 4.1 Sugar coating 4.1.1 Sealing/Water proofing 4.1.2 Subcoating 4.1.3 Grossing/ smoothing 4.1.4 Colour coating 4.1.5 Polishing

o 4.2 Film Coating 4.2.1 Process description 4.2.2 Process details 4.2.3 Basic process requirements for film coating 4.2.4 Coating formula optimization 4.2.5 Materials used in film coating

o 4.3 Enteric coating 4.3.1 = Enteric sugar coating 4.3.2 Enteric film coating 4.3.3 Controlled release coating

o 4.4 Specialized coating 4.4.1 Compressed coating 4.4.2 Electrostatic coating 4.4.3 Dip coating 4.4.4 Vacuum film coating

5 Equipments 6 Process parameters

o 6.1 Air capacity

o 6.2 Coating composition o 6.3 Tablet surface area o 6.4 Equipment efficiency

7 Key Phrases

Introduction(1-3,5)

Coated tablets are defined as “tablets covered with one or more layers of mixture of various substances such as natural or synthetic resins ,gums ,inactive and insoluble filler, sugar, plasticizer, polyhydric alcohol ,waxes ,authorized colouring material and some times flavoring material .

Coating may also contain active ingredient. Substances used for coating are usually applied as solution or suspension under conditions where vehicle evaporates.

Aspects of tablet coatingI. Therapy

i) Avoid irritation of oesophagus and stomach

ii) Avoid bad taste

iii) Avoid inactivation of drug in the stomach

iv) Improve drug effectiveness

v) Prolong dosing interval

vi) Improve dosing interval

vii) Improve patient compliance

II. Technology

i) Reduce influence of moisture

ii) Avoid dust formation

iii) Reduce influence of atmosphere

iv) Improve drug stability

v) Prolong shelve life

III. Marketing

i) Avoid bad taste

ii) Improve product identity

iii) Improve appearance and acceptability

Basic principle of tablet coatingThe principle of tablet coating is relatively simple. Tablet coating is the application of coating composition to moving bed of tablets with concurrent use of heated air to facilitate evaporation of solvent.

Basic principles involve

i) Insulation which influences the release pattern as little as possible and does not markedly change the appearance.

ii) Modified release with specific requirement and release mechanism adapted to body function in the digestive tract.

iii) Colour coating which provides insulation or is combined with modified release coating.

Type of tablet coating process

Sugar coating

(1,3,5)

Compressed tablets may be coated with coloured or uncoloured sugar layer. The coating is water soluble and quickly dissolves after swallowing. The sugarcoat protects the enclosed drug from the environment and provides a barrier to objectionable taste or order. The sugar coat also enhances the appearance of the compressed tablet and permit imprinting manufacturing’s information. Sugar coating provides a combination of insulation, taste masking, smoothing the tablet core, colouring and modified release. The disadvantages of sugar coating are the time and expertise required in the coating process and thus increases size, weight and shipping costs.

Sugar coating process involves five separate operations:

I. Sealing/Water proofing: provides a moisture barrier and harden the tablet surface.

II. Subcoating: causes a rapid buildup to round off the tablet edges.

III. Grossing/Smoothing: smoothes out the subcoated surface and increases the tablet size to predetermine dimension.

IV. Colouring: gives the tablet its colour and finished size.

V. Polishing: produces the characteristics gloss.

Sealing/Water proofing

Prior to applying any sugar/water syrup, the tablet cores must be sealed, thoroughly dried and free of all residual solvents.

The seal coat provides a moisture barrier and hardness the surface of the tablet in order to minimize attritional effects. Core tablets having very rapid disintegration rates conceivably could start the disintegration process during the initial phase of sugar coating. The sealants are generally water-insoluble polymers/film formers applied from an organic solvent solution. The quantities of material applied as a sealing coat will depend primarily on the tablet porosity, since highly porous tablets will tend to soak up the first application of solution, thus preventing it from spreading uniformly across the surface of every tablet in the batch. Hence, one or more further application of resin solution may be required to ensure that the tablet cores are sealed effectively.

Common materials used as a sealant include Shellac, Zine, Cellulose acetate phthalate (CAP), Polyvinylacetate phthalate, Hyroxylpropylcellulose, Hyroxypropylmethylcellulose etc.

Subcoating

Subcoating is the actual start of the sugar coating process and provides the rapid buildup necessary to round up the tablet edge. It also acts as the foundation for the smoothing and colour coats.

Generally two methods are used for subcoating:

i)The application of gum based solution followed by dusting with powder and then drying. This routine is repeated until the desired shape is achieved.

ii)The application of a suspension of dry powder in gum/sucrose solution followed by drying.

Thus subcoating is a sandwich of alternate layer of gum and powder. It is necessary to remove the bulk o the water after each application of coating syrup.

TABLE.23. TYPICAL BINDER SOLUTION FORMULATION FOR SUBCOATING(1)

  %W/W %W/WGelatin 6 3.3Gum acacia (powdered) 8 8.7Sucrose (powdered) 45 55.3Distilled water to 100 to 100

TABLE.24. TYPICAL DUSTING POWDER FORMULATION FOR SUBCOATING(1)

  %W/W %W/WCalcium carbonate 40.0 -Titanium dioxide 5.0 1.0Talc, asbestos free 25.0 61.0Sucrose( powdered ) 28.0 38.6Gum acacia (powdered) 2.0 -

TABLE.25. TYPICAL SUSPENSION SUBCOATING FORMULATION(1)

  %W/WSucrose 40.0Calcium carbonate 20.0Talc, asbestos free 12.0Gum acacia(powdered) 2.0Titanium dioxide 1.0Distilled water 25.0

Grossing/ smoothing

The grossing/smoothing process is specifically for smoothing and filing the irregularity on the surface generated during subcoating. It also increases the tablet size to a predetermined dimension.

If the subcoating is rough with high amount of irregularities then the use of grossing syrup containing suspended solids will provide more rapid buildup and better filling qualities. Smoothing usually can be accomplished by the application of a simple syrup solution (approximately 60-70 % sugar solid). This syrup generally contains pigments, starch, gelatin, acacia or opacifier if required.

Small quantities of colour suspension can be applied to impart a tint of the desired colour when there are irregularities in coating.

Colour coating

This stage is often critical in the successful completion of a sugar coating process and involves the multiple application of syrup solution (60-70 % sugar solid) containing the requisite colouring matter. Mainly soluble dyes were used in the sugar coating to achieve the desired colour, since the soluble dye will migrate to the surface during drying. But now a days the insoluble certified lakes have virtually replaced the soluble dyes in pharmaceutical tablet coating. The most efficient process for colour coating involves the use of a predispersed opacified lake suspension.

Polishing

Sugar-coated tablets needs to be polished to achieve a final elegance. Polishing is achieved by applying the mixture of waxes like beeswax, carnubawax, candelila wax or hard paraffin wax to tablets in polishing pan.

Film Coating

Film coating is more favored over sugar coating.

TABLE.26. COMPARISON BETWEEN FILM COATING AND SUGAR COATING(1)

FEATURES FILM COATING SUGAR COATINGTablet:

Appearance

 

 

 

Weight increase because of coating material

 

Logo or ‘break lines’

 

Retain contour of original core.  Usually not as shiny as sugar coat type

 

 

2-3%

 

 

Possible

 

Rounded with high degree of polish

 

 

 

30-50%

 

 

Not possible

Process

Operator training required

 

 

Adaptability to GMP

 

Process stages

 

Functional coatings

 

Process tends itself to automation and easy training of operator

 

High

 

Usually single stage

 

Easily adaptable for controlled release

 

Considerable

 

 

 

Difficulty may arise

 

Multistage process

 

Not usually possible apart from enteric coating

Process description

(1)

Film coating is deposition of a thin film of polymer surrounding the tablet core. Conventional pan equipments may be used but now a day’s more sophisticated equipments are employed to have a high degree of automation and coating time. The polymer is solubilized into solvent. Other additives like plasticizers and pigments are added. Resulting solution is sprayed onto a rotated tablet bed. The drying conditions cause removal of the solvent, giving thin deposition of coating material around each tablet core.

Process details

(1)

Usually spray process is employed in preparation of film coated tablets. Accela cota is the prototype of perforated cylindrical drum providing high drying air capacity. Fluidized bed equipment has made considerable impact where tablets are moving in a stream of air passing through the perforated bottom of a cylindrical column. With a smaller cylindrical insert, the stream of cores is rising in the center of the device together with a spray mist applied in the middle of the bottom. For fluidized bed coating, very hard tablets (hardness > 20 N) have to be used.

Basic process requirements for film coating

(2)

The fundamental requirements are independent of the actual type of equipments being used and include adequate means of atomizing the spray liquid for application to the tablet core, adequate mixing and agitation of tablet bed, sufficient heat input in the form of drying air to provide the latent heat of evaporation of the solvent. This is particularly important with aqueous-based spraying and good exhaust facilities to remove dust and solvent laden air.

Development of film coating formulations (1)

If the following questions are answered concomitantly then one can go for film coating:

i) Is it necessary to mask objectionable taste, colour and odor?

ii) Is it necessary to control drug release?

iii) What tablets size, shape, or colour constrains must be placed on the developmental work?

Colour, shape and size of final coated tablet are important for marketing and these properties have a significant influence on the marketing strategies. An experienced formulator usually takes the pragmatic approach and develops a coating formulations modification of one that has performed well in the past. Spraying or casting films can preliminarily screen film formulations. Cast films cab is prepared by spreading the coating composition on teflon, glass or aluminum foil surface using a spreading bar to get a uniform film thickness. Sprayed films can be obtained by mounting a plastic-coated surface in a spray hood or coating pan.

Coating formula optimization

(1)

Basic formula is obtained from past experience or from various sources in the literature. Modifications are required to improve adhesion of the coating to the core, to decrease bridging of installations, to increase coating hardness, etc. Usually concentration of colorant and opaquant are fixed to get predetermined shade. Common modification is to alter polymer-to-plasticizer ratio or addition of different plasticizer/ polymer. Experimentation of this type can be best achieved by fractional factorial study.

Materials used in film coating

(1,13)

I.Film formers, which may be enteric or nonenteric

II.Solvents

III.Plasticizers

IV.Colourants

V.Opaquant-Extenders

VI. Miscellaneous coating solution components

I.Film formers (1)

Ideal requirements of film coating materials are summarized below:

i) Solubility in solvent of choice for coating preparation

ii) Solubility requirement for the intended use e.g. free water-solubility, slow water-solubility or pH -dependent solubility

iii) Capacity to produce an elegant looking product

iv) High stability against heat, light, moisture, air and the substrate being coated

v) No inherent colour, taste or odor

vi) High compatibility with other coating solution additives

vii) Nontoxic with no pharmacological activity

viii) High resistance to cracking

ix) Film former should not give bridging or filling of the debossed tablet

x) Compatible to printing procedure

Commonly used film formers are as follow

i.Hydroxy Propyl Methyl Cellulose (HPMC)

It is available in different viscosity grades. It is a polymer of choice for air suspension and pan spray coating systems because of solubility characteristic in gastric fluid, organic and aqueous solvent system. Advantages include: it does not affect tablet disintegration and drug availability, it is cheap, flexible, highly resistant to heat, light and moisture, it has no taste and odor, colour and other additives can be easily incorporated.

Disadvantage includes: when it is used alone, the polymer has tendency to bridge or fill the debossed tablet surfaces. So mixture of HPMC and other polymers/ plasticizers is used.

ii.Methyl Hydroxy Ethyl Cellulose (MHEC)

It is available in wide variety of viscosity grades. It is not frequently used as HPMC because soluble in fewer organic solvents.

iii. Ethyl Cellulose (EC)

Depending on the degree of ethoxy substitution, different viscosity grades are available. It is completely insoluble in water and gastric fluids. Hence it is used in combination with water-soluble additives like HPMC and not alone. Unplasticized ethyl cellulose films are brittle and require film modifiers to obtain an acceptable film formulation. Aqua coat is aqueous polymeric dispersion utilizing ethyl cellulose. These pseudolatex systems contain high solids, low viscosity compositions that have coating properties quite different from regular ethyl cellulose solution.

iv.Hydroxy Propyl Cellulose (HPC)

It is soluble in water below 40oc (insoluble above 45 oC), gastric fluid and many polar organic solvents. HPC is extremely tacky as it dries from solution system. It is used for sub coat and not for colour or glass coat. It gives very flexible film.

v. Povidone

Degree of polymerization decides molecular weight of material. It is available in four viscosity grades i.e. K-15, K-30, K-60 and K-90. Average molecular weight of these grades is 10000, 40000, 160000 and 360000 respectively. K-30 is widely used as tablet binder and in tablet coating. It has excellent solubility in wide variety of organic solvents, water, gastric and intestinal fluids. Povidone can be cross-linked with other materials to produce films with enteric properties. It is used to improve dispersion of colourants in coating solution.

vi. Sodium carboxy methyl cellulose

It is available in medium, high and extra high viscosity grades. It is easily dispersed in water to form colloidal solutions but it is insoluble in most organic solvents and hence not a material of choice for coating solution based on organic solvents. Films prepared by it are brittle but adhere well to tablets. Partially dried films of are tacky. So coating compositions must be modified with additives.

viii. Polyethylene glycols (PEG)

Lower molecular weights PEG (200-600) are liquid at room temperature and are used as plasticizers. High molecular weights PEG (900-8000series) are white, waxy solids at room temperature. Combination of PEG waxes with CAP gives films that are soluble in gastric fluids.

ix. Acrylate polymers

E is freely soluble in gastricE is cationic co-polymer. Only Eudragit. EudragitIt is marketed under the name of Eudragit fluid up to pH 5 and expandable and permeable above pH 5. This material is available as organic solution (12.5% in RLisopropanol/acetone), solid material or 30% aqueous dispersion. Eudragit & RS are co-polymers with low content of quaternary ammonium groups. These are available only as organic solutions and solid materials. They produce films for delayed action (pH dependent).

II.Solvents (1)

Solvents are used to dissolve or disperse the polymers and other additives and convey them to substrate surface.

Ideal requirement are summarized below:

i) Should be either dissolve/disperse polymer system

ii) Should easily disperse other additives into solvent system

iii) Small concentration of polymers (2-10%) should not in an extremely viscous solution system creating processing problems

iv) Should be colourless, tasteless, odorless, inexpensive, inert, nontoxic and nonflammable

v) Rapid drying rate

vi) No environmental pollution

Mostly solvents are used either alone or in combination with water, ethanol, methanol, isopropanol, chloroform, acetone, methylene chloride, etc. Water is more used because no environmental and economic considerations. For drugs that readily hydrolyze in presence of water, non aqueous solvents are used.

III. Plasticizers (1)

As solvent is removed, most polymeric materials tend to pack together in 3-D honey comb arrangement. “Internal” or “External” plasticizing technique is used to modify quality of film. Combination of plasticizer may be used to get desired effect. Concentration of plasticizer is expressed in relation to the polymer being plasticized. Recommended levels of plasticizers range from 1-50 % by weight of the film former. Commonly used plasticizers are castor oil, PG, glycerin, lower molecular weight (200-400 series), PEG, surfactants, etc. For aqueous coating PEG and PG are more used while castor oil and spans are primarily used for organic-solvent based coating solution. External plasticizer should be soluble in the solvent system used for dissolving the film former and plasticizer. The plasticizer and the film former must be at least partially soluble or miscible in each other.

IV.Colourants (1)

Colourants can be used in solution form or in suspension form. To achieve proper distribution of suspended colourants in the coating solution requires the use of the powdered colourants (<10 microns). Most common colourants in use are certified FD & C or D & C colourants. These are synthetic dyes or lakes. Lakes are choice for sugar or film coating as they give reproducible results. Concentration of colourants in the coating solutions depends on the colour shade desired, the type of dye, and the concentration of opaquant-extenders. If very light shade is desired, concentration of less than 0.01 % may be adequate on the other hand, if a dark colour is desired a concentration of more than 2.0 % may be required. The inorganic materials (e.g. iron oxide) and the natural colouring materials (e.g. anthrocyanins, carotenoids, etc) are also used to prepare coating solution. Magenta red dye is non absorbable in biologic system and resistant to degradation in the gastro intestinal track. Opasray (complete film(opaque colour concentrate for film coating) and Opadry coating concentrate) are promoted as achieving less lot-to-lot colour variation.

V.Opaquant-Extenders (1)

These are very fine inorganic powder used to provide more pastel colours and increase film coverage. These inorganic materials provide white coat or mask colour of the tablet core. Colourants are very expensive and higher concentration is required. These inorganic materials are cheap. In presence of these inorganic materials, amount of colourants required decreases. Most commonly used materials are titanium dioxide, silicate (talc &aluminum silicates), carbonates (magnesium carbonates), oxides (magnesium oxide) & hydroxides (aluminum hydroxides). Pigments were investigated in the production of opaque films and it was found that they have good hiding power and film-coated tablets have highlighted intagliations.

VI. Miscellaneous coating solution component (1)

Flavors, sweeteners, surfactants, antioxidants, antimicrobials, etc. may be incorporated into the coating solution.

Enteric coating

(1, 2, 13)

This type of coating is used to protect tablet core from disintegration in the acid environment of the stomach for one or more of the following reasons:

i) To prevent degradation of acid sensitive API

ii) To prevent irritation of stomach by certain drugs like sodium salicylate

iii) Delivery of API into intestine

iv) To provide a delayed release component for repeat action tablet

Several kinds of enteric layer systems are now available

One layer system - The coating formulation is applied in one homogeneous layer, which can be whites-opaque or coloured. Benefit is only one application needed.

Two layer system - To prepare enteric tablets of high quality and pleasing appearance the enteric formulation is applied first, followed by coloured film. Both layers can be of enteric polymer or only the basic layer contains enteric polymer while top layer is fast disintegrating & water-soluble polymer

Ideal properties of enteric coating material are summarized as below

i) Resistance to gastric fluids

ii) Susceptible/permeable to intestinal fluid

iii) Compatibility with most coating solution components and the drug substrate

iv) Formation of continuous film

v) Nontoxic, cheap and ease of application

vi) Ability to be readily printed

Polymers used for enteric coating are as follow

i.Cellulose acetate phthalate (CAP)

It is widely used in industry. Aquateric is reconstituted colloidal dispersion of latex particles. It is composed of solid or semisolid polymer spheres of CAP ranging in size from 0.05 - 3 microns. Cellulose acetate trimellitate (CAT) developed as an ammoniated aqueous formulation showed faster dissolution than a similar formulation of CAP. Disadvantages include: It dissolves above pH 6 only, delays absorption of drugs, it is hygroscopic and permeable to moisture in comparison with other enteric polymer, it is susceptible to hydrolytic removal of phthalic and acetic acid changing film properties. CAP films are brittle and usually used with other hydrophobic film forming materials.

ii. Acrylate polymers

Eudragit®L & Eudragit®S are two forms of commercially available enteric acrylic resins. Both of them produce films resistant to gastric fluid. Eudragit®L & S are soluble in intestinal fluid at pH 6 & 7 respectively. Eudragit®L is available as an organic solution (Isopropanol), solid or aqueous dispersion. Eudragit®S is available only as an organic solution (Isopropanol) and solid.

iii Hydroxy propyl methyl cellulose phthalate

HPMCP 50, 55 & 55-s (also called HP-50, HP-55 & HP-55-s) is widely used. HP-55 is recommended for general enteric preparation while HP-50 & HP-55-s for special cases. These polymers dissolve at a pH 5-5.5.

iii. Polyvinyl acetate phthalate

It is similar to HP-55 in stability and pH dependent solubility.

= Enteric sugar coating

(2)

Here the sealing coat is tailored to include one of the enteric polymers in sufficient quantity to pass the enteric test for disintegration. The sub coating and subsequent coating steps are then as for conventional sugar coating.

Enteric film coating

(2)

Enteric polymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has to be used to ensure an efficient enteric effect. Enteric coating can be combined with polysaccharides, which are enzyme degraded in colon e.g. Cyclodextrin & galactomannan.

Controlled release coating

(2)

Polymers like modified acrylates, water insoluble cellulose (ethyl cellulose), etc. used for control release coating.

Specialized coating

(1)

Compressed coating

This type of coating requires a specialization tablet machine. Compression coating is not widely used but it has advantages in some cases in which the tablet core cannot tolerate organic solvent

or water and yet needs to be coated for taste masking or to provide delayed or enteric properties to the finished product and also to avoid incompatibility by separating incompatible ingredients.

Electrostatic coating

Electrostatic coating is an efficient method of applying coating to conductive substrates. A strong electrostatic charge is applied to the substrate. The coating material containing conductive ionic species of opposite charge is sprayed onto the charged substrate. Complete and uniform coating of corners and adaptability of this method to such relatively nonconductive substrate as pharmaceutical is limited.

Dip coating

Coating is applied to the tablet cores by dipping them into the coating liquid. The wet tablets are dried in a conventional manner in coating pan. Alternative dipping and drying steps may be repeated several times to obtain the desired coating. This process lacks the speed, versatility, and reliability of spray-coating techniques. Specialized equipment has been developed to dip-coat tablets, but no commercial pharmaceutical application has been obtained.

Vacuum film coating

Vacuum film coating is a new coating procedure that employs a specially designed baffled pan. The pan is hot water jacketed, and it can be sealed to achieve a vacuum system. The tablets are placed in the sealed pan, and the air in the pan is displaced by nitrogen before the desired vacuum level is obtained. The coating solution is then applied with airless spray system. The evaporation is caused by the heated pan, and the vapour is removed by the vacuum system. Because there is no high-velocity heated air, the energy requirement is low and coating efficiency is high. Organic solvent can be effectively used with this coating system with minimum environmental or safety concerns.

EquipmentsThree general types of equipments are available

1.Standard coating pan

e.g., Pellegrin pan system

Immersion sword system

Immersion tube system

2.Perforated pan system e.g.,Accela cota system

Hicoater system

Glattcoater system

Driacoated system

3.Fluidized bed coater

THREE MATHODS:

a. top spray b. bottom spray c. tangential spray

IMPORTANT PROCESSING PARAMETERS FOR FLUIDIZED BED COATER: A. inlet & bed temprature B. relative humidity C. atomization air pressure D. liquid spray rate E. droplet size F. drying time

Process parameters

Air capacity

This value represents the quantity of water or solvent that can be removed during the coating process which depends on the quantity of air flowing through the tablet bed, temperature of the air and quantity of water that the inlet air contains.

Coating composition

The coating contains the ingredients that are to be applied on the tablet surface and solvents which act as carrier for the ingredients.

Tablet surface area

It plays an important role for uniform coating. The total surface area for unit weight decreases significantly from smaller to larger tablets. Application of a film with the same thickness requires less coating composition. In the coating process only a portion of the total surface is coated. Continuous partial coating and recycling eventually results in fully coated tablets.

Equipment efficiency

Tablet coaters use the expression “coating efficiency” a value obtained by dividing the net increase in coated tablet weight by the total nonvolatile coating weight applied to the tablet. Ideally 90-95 % of the applied film coating should be on the tablet surface. Coating efficiency for conventional sugar coating is much less and 60% would be acceptable. The significant difference in coating efficiency between film and sugar coating relates to the quantity of coating material that collects on the wall.

Key Phrases

The sugar coating involves several steps like, sealing, subcoating, colour coating and printing.

Sugar coating process yields elegant and highly glossed tablet.

Newer techniques utilize spraying systems and varying degree of automation to improve coating efficiency and product uniformity.

Film coating is deposition of a thin film of polymer surrounding the tablet core.

Film coating is more favored than sugar coating because weight increase is 2-3%, single stage process, easily adaptable to controlled release, it retains colour of original core, high adaptability to GMP, automation is possible, etc.

Accela cota and fluidized bed equipments are widely used for film coating.

Basic formula is obtained from past experience or from literature and modifications are made accordingly. Common modifications are to alter polymer-to-plasticizer ratio or addition of different plasticizer/polymer. Experimentation of this type can be best achieved by fractional factorial study.

Materials used in film coating include film formers, solvents, plasticizers, colourants, opaquant-extenders, surfactant, anti oxidant, etc.

Widely used film formers are Hydroxy Propyl Methyl Cellulose (HPMC),Methyl Hydroxy Ethyl Cellulose (MHEC), Ethyl Cellulose (four grades available i.e. K-15, K-30, K-60and K-90), Sodium carboxy methyl(EC), Hydroxy Propyl Cellulose (HPC), Povidone cellulose, Polyethylene glycols (PEG) and Acrylate polymers (Eudragit®, Eudragit®RL, Eudragit®RS, Eudragit®E) are used for film coating. Eudragit®L & S are used for enteric coating. Eudragit®RL, Eudragit®RS, Eudragit®S are available as organic solution and solid while Eudragit®L and Eudragit®E are available as organic, solid or aqueous dispersion.

Quality of film can be modified by plasticizer. Commonly used plasticizers include PG, glycerin, low molecular weight PEG, castor oils, etc. Castor oil and spans are more used for organic-solvent based coating solution while PE and PEG are used for aqueous coating.

FD & C or D & C certified colourants are used. Lakes are choice for film coating as they give reproducible results. Opaspray® (opaque colour concentrate for film coating) and Opadry® (complete film coating concentrate) are promoted as achieving less lot-to-lot variation.

Colourants are expensive and higher concentration is required. So materials like titanium dioxides, silicates, and carbonates are used to provide more pastel colours and increase film coverage.

Enteric Coating:

Enteric coating is used to protect tablet core from disintegration in the acid environment of stomach to prevent degradation of acid sensitive API, prevent irritation to stomach by certain drugs, delivery of API into intestine, to provide a delayed release components for repeat action, etc.

Several kinds of enteric layer systems are available like one layer system and two-layer system. Polymers used for enteric coating are cellulose Acetate Phthalate (CAP), Acrylates (Eudragit®L and Eudragit®S, Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP50, HPMCP55 & HPMCP 55s) and polyvinyl acetate phthalate

Enteric sugar coating:

Here sealing coat is modified to comprise one of the enteric polymers in sufficient quantity to pass the enteric test for disintegration. The sub coating and subsequent coating steps are then as for conventional sugar coating.

Enteric polymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has to be used to ensure an efficient enteric effect.

Enteric coating can be combined with polysaccharides, which are enzymatically degraded in colon. For example, Cyclodextrin & Galactomannan.

Controlled release coating:

Polymers like modified acrylates, ethyl cellulose, etc are used for the same.

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Film-coating materials and their properties Fold Table of ContentsSUMMARY2.1 INTRODUCTION2.2 POLYMERS2.2.1 True latexes2.2.2 Psuedolatexes2.2.3 Mechanism of film formation2.3 POLYMERS FOR CONVENTIONAL FILM COATING2.3.2 Acrylic polymers2.4 POLYMERS FOR MODIFIED RELEASE APPLICATION2.4.1 Methacrylate ester copolymers2.4.2 Ethylcellulose (EC)2.5 ENTERIC POLYMERS2.5.1 Cellulose acetate phthalate (CAP)2.5.2 Polyvinyl acetate phthalate (PVAP)2.5.3 Shellac2.5.4 Methacrylic acid copolymers2.5.5 Cellulose acetate trimellitate (CAT)2.5.6 Hydroxypropyl methylcellulose phthalate (HPMCP)2.6 POLYMER CHARACTERISTICS2.6.1 Solubility2.6.2 Viscosity

new page

2.6.2 Permeability2.6.4 Mechanical properties2.7 PLASTICIZERS2.7.1 Classification2.7.2 Compatibility and permanence2.7.3 Effect of plasticizers on the mechanical properties of the film2.7.4 Effect of plasticizers on permeability of film coatings2.7.5 Measurement and characterization of plasticizer activity2.8 COLOURANTS/OPACIFIERS2.8.1 Classification2.8.2 Regulatory aspects and specifications2.8.3 Advantages of pigments over dyes2.8.4 Effects of pigments on film-coating systems2.9 SOLVENTS/VEHICLES2.10 AUXILIARY SUBSTANCES IN THE FILM-COATING FORMULAE2.11 THE CHOICE BETWEEN AQUEOUS AND ORGANIC SOLVENT-BASEDREFERENCESSUMMARY

The chapter commences by reviewing the properties of the broad classes of materials used in filmcoating, polymers, plasticizers, pigments and solvents (or vehicles).An initial consideration of the polymers shows that while processing is most commonly performedusing these materials in solution, there are systems which utilize polymers in suspension in water. Themechanism 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 intofunctional and non-functional coating polymers. Functional polymers being defined as those whichmodify the pharmaceutical function of the compressed tablet, for instance an enteric or modified releaefilm. 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 mechanicalproperties are described in terms of ultimate film requirements.In the treatment and description of plasticizers, some prominence is given to their effect on themechanical properties of the film and its permeability characteristics, especially to water vapour. Asection 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 ofthe respective merits of aqueous and non-aqueous processing.The chapter is concluded by some examples of formulae of film-coating systems which illustrateseveral of the principles described previously.

2.1 INTRODUCTION

A film coating is a thin polymer-based coat applied to a solid dosage form such as a tablet, granule orother particle. The thickness of such a coating is usually between 20 and 100 μm. Under closeexamination the film structure can be seen to be relatively non-homogeneous and quite distinct inappearance, for example, from a film resulting from casting a polymer solution on a flat surface. Thisnon-homogeneous character results from the deliberate addition of insoluble ingredients such aspigments and by virtue of the fact that the film itself is built up in an intermittent fashion during thecoating process. This is because most coating processes rely on a single tablet or granule passingthrough a spray zone, after which the adherent material is dried before the next portion of coating isreceived. 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 meansuniversally 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 thecellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecularweight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials.The characteristics of the individual polymers and the essential properties of polymers used for filmcoating 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 polymersare available in a form which renders them usable from aqueous systems. These materials findconsiderable application in the area of modified release coatings. Basically there are two classes of suchmaterial 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 thestability and use of these materials. They are characterized by a particle size range of between 10 and1000 nm. Their tendency to sediment is counter-• Polymer.• Plasticizer.• Pigment/opacifier.• Vehicle.balanced by the Brownian movement of the particles aided by microconvection currents found in thebody of the liquid. The Stokes equation can be used to determine the greatest particle diameter that canbe tolerated in the system without sedimentation. At the other end of the size range the characteristic ofcolloidal 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. Characteristicallythe process starts with the monomer which after purifica-tion is emulsified as the internal phase with asuitable surfactant (Lehmann, 1972). Polymerization is activated by addition of an initiator. Commonlythe 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. Thereaction is quenched when the particle size is in the range 50–200 nm. Using this process the followingacrylate 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 utilizeethylcellulose as the film former but are manufactured in quite a different way and their method

ofapplication also differs significantly. Characteristically pseudolatexes are manufactured starting with thepolymer itself and not the monomer. By a physical process the polymer particle size is reduced therebyproducing a dispersion in water; the characteristics of this dispersion need not differ significantly from atrue latex, including particle size considerations. The pseudolatex is also free of monomer residue andtraces of initiator, etc.The earliest of the two ethylcellulose products (Aquacoat) is manufactured by dissolvingethylcellulose in an organic solvent and emulsifying the solution in an aqueous continuous phase. Theorganic solvent is eventually removed by vacuum distillation, leaving a fine dispersion of polymerparticles in water. Steuernagel (1989) has defined the composition of Aquacoat to have a solids contentof 30% w/w and a moisture content of 70%w/w, the solids being composed of ethylcellulose 87%, cetylalcohol 9% and sodium lauryl sulphate 4%. A food grade antifoam is also present. The cetyl alcohol andsodium 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 processbased on phase inversion technology (Warner, 1978). The ethylcellulose is heated in the presence ofdibutyl 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 aqueouscontinuous phase. The dibutyl sebacate (fractionated coconut oil can also be used) is to be found in theethylcellulose fraction while the oleic acid and the ammonia together effectively stabilize the dispersedphase in water. This siting of the dibutyl sebacate and oleic acid is important for the use of this materialas an effective coating agent. Both materials act as plasticizers and with the Surelease system arephysically situated where they are able to function most effectively, that is, in intimate contact with thepolymer. Surelease, unlike Aquacoat, does not require the further addition of plasticizer. Surelease also contains a quantity of fumed silica which acts as anantitack agent during the coating process. Its total nominal solids content is 25% w/w.

Aqueous dispersions have significant advantages, enabling processing of water-insoluble polymersfrom 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 byseveral authors (Bindschaedler et al., 1983; Zhang et al., 1988, 1989). In the wet state the polymer ispresent 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 surfacewill be wetted with the diluted dispersion. Under the prevailing processing conditions water will be lostas water vapour and the polymer particles will increase in proximity to each other—a process which isgreatly aided by the capillary action of the film of water surrounding the particles. Completecoalescence occurs when the adjacent particles are able to mutually diffuse into one another,Minimum film-forming temperature (MFT)This is the minimum temperature above which film formation will take place using individual definedconditions. It is largely dependent on the glass transition temperature (Tg) of the polymer, an attributewhich is capable of several definitions but can be considered as that temperature at which the hardglassy 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 onthe film-forming process. With aqueous dispersions Lehmann recommends to keep the coatingtemperature 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 ofimproved product appearance, improved handling, and prevention of dusting, etc. This is to make adistinction with functional film coats, which will be described in a later section, and where the

purposeof the coating is to confer a modified release aspect on the dosage form. An alternative term forconventional film coating, therefore, would be non-functional film coating.2.3.1 Cellulose ethersThe majority of the cellulose derivatives used in film coating are in fact ethers of cellulose. Broadly theyare manufactured by reacting cellulose in alkaline solution with, for example, methyl chloride, to obtainmethylcellulose. Hydroxypropoxyl substitution is obtained by similar reaction with propylene oxide.The product is 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 bereplaced, in such a fashion. If all three hydroxyl groups are replaced the degree of substitution (DS) isdesignated as 3, and so on for lower degrees of substitution. The term molar substitution (MS) coversthe situation where a side chain carries hydroxyl groups capable of substitution and takes into accountthe total moles of a group whether on the backbone or side chain. Both DS and MS profoundly affectthe 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 theviscosity of the polymer in solution. As a generality, film coating demands polymers at the lower end ofthe viscosity scale.This polymer provides the mainstay of coating with the cellulose ethers and its usage dates back tothe early days of film coating. It is soluble in both aqueous media and the organic solvent systemsnormally used for film coating. HPMC provides aqueously soluble films which can be coloured by theuse of pigments or used in the absence of pigments to form clear films. The polymer affords relativelyeasy processing due to its non-tacky nature. A typical low-viscosity polymer can be sprayed from anaqueous solution containing around 10–15%w/w polymer solids. From the regulatory aspect, in additionto its use in pharmaceutical products, HPMC has a long history of safe use as a thickener and emulsifierin the food industry.

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 groupswhile the final two specify the nominal percentage of hydroxypropoxyl groups. The EP has no specified ranges for substitution. Significantdifferences 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. Methodologydifferences also exist, particularly with regard to solution viscosity. The JP has a very low limit onchloride content.Methylcellulose (MC)Substituent group: —CH3This polymer is used rarely in film coating possibly because of the lack of commercial availability oflow viscosity material meeting the appropriate compendial requirements. As a distinction from the USPand the JP the EP has no required limits on the content of methoxyl substitution. However, the USP andJP have slightly different limits, which are 27.5–31.5% against 26.0–33.0% respectively.Hydroxyethyl cellulose (HEC)Substituent group: —CH(OH)—CH3This water-soluble cellulose ether is generally insoluble in organic solvents. The USNF is the solepharmacopoeial specification; there is no requirement on the quantity of hydroxyethyl groups to bepresent. The USNF allows the presence of additives to promote dispersion of the powder in water and toprevent caking on storage.Hydroxypropyl cellulose (HPC)Substituent group: —CH2 —CH(OH)—CH3HPC has the property of being soluble in both aqueous and alcoholic media. Its films unfortunatelytend to be rather tacky, which possess restraints on rapid coating; HPC films also suffer from beingweak. Currently this polymer is very often used in combination with other polymers to provideadditional adhesion to the substrate. The EB/BP has no requirements on hydroxypropoxyl content. TheUSNF states this must be less than 80.5% while the JP has two monographs differing in substitutionrequirements. The monograph most closely corresponding to the USNF material has a

substitutionspecification of 53.4–77.5%. The other monograph relates to material of much lower substitutioncontent 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.Methacrylate aminoester copolymerThis polymer is basically insoluble in water but dissolves in acidic media below pH 4. In neutral oralkaline environments, its films achieve solubility by swelling and increased permeability to aqueousmedia. Formulations intended for conventional film coating can be further modified to enhance swellingand permeability by the incorporation of materials such as water soluble cellulose ethers, and starches inorder 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 indecreasing the sticky or tacky nature of the polymer. In general, the polymer does not require theaddition 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. Severalexamples exist of polymers fulfilling both needs, hence there is a considerable overlap of use. However,the divisions used here represent perhaps the majority practice.

2.4.1 Methacrylate ester copolymers

Structurally these polymers bear a resemblance to the methacrylic acid copolymers but are totallyesterified with no free carboxylic acid groups. Thus these materals are neutral in character and

areinsoluble over the entire physiological pH range. However they do possess the ability to swell andbecome permeable to water and dissolved substances so that they find application in the coating ofmodified release dosage forms. The two polymers Eudragit RS and RL, can be mixed and blended toachieve a desired release profile. The addition of hydrophilic materials such as the soluble celluloseethers, polyethylene glycol (PEG), etc., will also enable modifications to be achieved with the finalformulation. The polymer Eudragit RL is strongly permeable and thus only slightly retardant. Its filmsare therefore also indicated for use in quickly disintegrating coatings. The polymers themselves havesolubility characteristics similar to the methacrylic acid copolymers.For aqueous spraying a latex form of each polymer is available. In addition the polymer EudragitNE30D has been made for this purpose. This materal is also used as an immediate-release nonfunctionalcoating in film coat formulations where relatively large quantities of water-soluble materialsare added to ensure efficient disruption of the coat.

2.4.2 Ethylcellulose (EC)

Substituent group (Fig. 2.2): —CH2—CH3Ethylcellulose is a cellulose ether produced by the reaction of ethyl chloride with the appropriatealkaline solution of cellulose. Apart from its extensive use in controlled release coatings, ethylcellulosehas found a use in organic solvent-based coatings in a mixture with other cellulosic polymers, notablyHPMC. The ethylcellulose component optimizes film toughness in that surface marking due to handlingis 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 undernormal 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 substitutiontypes 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 adventof water-dispersible presentations of ethylcellulose which have been especially designed for modifiedrelease coatings. The polymer is not usually used on its own but normally in combination withsecondary polymers such as HPMC or polyethylene glycols which convey a more hydrophilic nature tothe film by altering its structure by virtue of pores and channels through which drug solution can moreeasily diffuse. Only the USNF contains a monograph, an ethoxy group content of between 44.0 and51.0% is specified. The USNF also contains a monograph ‘Ethylcellulose Aqueous Dispersion’ whichdefines one type of such material which finds a use in aqueous processing. The monograph permits thepresence of cetyl alcohol and sodium lauryl sulphate which are necessary to stabilize the dispersion.

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: —CO—CH3, —CO—C6H4—COOHThis is the oldest and most widely used synthetic enteric coating polymer patented as an enteric agentby Eastman Kodak in 1940. It is manufactured by reacting a partial acetate ester of cellulose withphthalic anhydride. In the resulting polymer, of the free hydroxyl groups contributed by each glucoseunit of the cellulose chain, approximately half are acylated and one-quarter esterified with one of thetwo carboxylic acid groups of the phthalate moiety. The second carboxylic acid group being free to formsalts and thus serves as the basis of its enteric character.CAP is a white free-flowing powder usually with a slightly odour of acetic acid. Among thepharmacopoeias it is found in the EP, JP and USNF. The USNF and JP impose specifications for thepercentage 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 threepharmacopoeias require a maximum limit on the quantity of free acid (JP specifies phthalic acid) andloss on drying (EP specifies water content). The last two parameters are important as CAP is somewhatprone to hydrolysis.Of the generally accepted solvents used for tablet coating, CAP is insoluble in water, alcohols andchlorinated hydrocarbons. In the following solvents or solvent mixtures.A pseudolatex version of CAP is available (Aquateric) as a dry powder for reconstitution in water andoffers the convenience of aqueous-based processing.Owing to their chemical constitution, most of the phthalate-based enteric coating agents are to agreater or lesser degree unstable. This important aspect is dealt with in more detail in Chapter 14, alongwith 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 investigatedby Millar (1957) who studied the effect that the phthalyl content of the polymer had upon the pH ofdisintegration of tablets coated with the material. He found the optimal phthalyl content to be between60 and 70%. However, given the characteristics of the polymer commercially available nowadays, thisrange has been revised and now forms part of the USNF monograph. It is manufactured by reactingpolyvinyl alcohol with acetic acid and phthalic anhydride.The USNF contains a monograph specifying a total phthalate content of between 55 and 62%. Thepolymer characteristics are further controlled by imposition of a viscosity specification. The extent ofhydrolysis, while much less likely than CAP for instance, is controlled with a limit on free phthalic acidand 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%)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 ofthe Far East. Shellacs can be modified to suit specialized needs. For instance, bleached shellac isproduced 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 warmethanol.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 naturalorigin and consequently suffers from occasional supply problems and quality variation. As will bedescribed later, there are also stability problems associated with increased disintegration and dissolutiontimes 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 5.5Of the two organic solvent soluble polymers, Eudragit S100 has a lower degree of substitution withcarboxyl 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 willoccur.All the polymers shown in Table 2.5 are recommended to be used with plasticizers. Pigments

andopacifiers are useful additions as they counteract the sticky nature of the polymers. A feature of thesepolymers is their ability to bind large quantities of pigments—approximately two or three times thequantity of polymer used. Polyethylene glycols are frequently added as they provide a measure of glossto the final product. They also assist in stabilizing the water-dispersible form, Eudragit L30D. Pigmentand other additions to the water-dispersible forms Eudragit, L30D and L100–55, should be performedaccording 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 arelatively high apparent pKa of between 6.9 and 7.5 and leads to poor solubility of the film in theduodenum (Chambliss, 1983).• A modified release coating.These polymers comply with the USNF requirements for methacrylic acid copolymer as outlined inTable 2.5. Both Eudragit L100 and S100 are available in powder form and for convenience purposesthey are also available as concentrates in organic solvent solution, which are capable of further dilutionin 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.

2.5.5 Cellulose acetate trimellitate (CAT)

Substituent groups (Fig. 2.2): —CO—CH3, CO—C6H3—(COOH)2Chemically this polymer bears a strong resemblance to cellulose acetate phthalate but possesses anadditional carboxylic acid group on the aromatic ring. Manufacturer’s quoted typical values fortimellityl and acetyl percentages are 29 and 22% respectively. The useful property of this polymer is itsability to start to dissolve at the relatively low pH of 5.5 (Anon., 1988) which would help ensureefficient 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, themanufacturers recommend the use of ammoniacal solutions of CAT in water, and fully enteric resultsare claimed. The recommended plasticizers for aqueous use are triacetin, acetylated monoglyceride ordiethyl phthalate.

2.5.6 Hydroxypropyl methylcellulose phthalate (HPMCP)

Substituent groups: —CH3, —CH2CH(OH)CH3, —CO—C6H4—COOHHPMCP is prepared by treating hydroxypropyl methylcellulose with phthalic acid. The degree ofsubstitution of the three possible substituents determines the polymer characteristics, in particular thepH 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 asCAP 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 sixdigitnomenclature refers to the percentages of the respective Substituent methoxyl, hydroxypropoxyland 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.

2.6 POLYMER CHARACTERISTICS

2.6.1 Solubility

Inspection of the solubility characteristics of the film-coating polymers show that the following have agood solubility in water: HPMC, HPC, MC, PVP, PEG plus gastrointestinal fluids and the

commonorganic 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 itsunmodified 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, theneed to minimize contact between the tablet core and water and, secondly, the need to achieve areasonable 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 thenominal viscosity of a 2%w/w aqueous solution at 20°C. Thus a 5mPa s grade will have a nominalviscosity of 5 mPa s in 2% aqueous solution in water at 20°C and similarly with 6 mPa s, 15 mPa s and50 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 viscositydesignation, such that for example Methocel E5 has a nominal viscosity of 5mPa s under the previouslydescribed standard conditions. While Pharmacoat 606 would have a nominal viscosity of 6 mPa s underthe same conditions.Considering the final polymer solution to be sprayed, a normal HPMC-based system would have aviscosity of approximately 500 mPa s. Inspection of Fig. 2.3 shows that if, for instance, a 5 mPa s gradeis used (E5) a solids concentration of about 15%w/w can be achieved. This has the advantage over, forexample, a coating solution prepared from a 50 mPa s grade (E50) where only a 5%w/w solidsconcentration could be achieved. The lower viscosity grade polymer permits a higher solidsconcentration to be used, with consequent reduction in solvent content of the solution. The

practicaladvantage to be gained is that the lower the solvent content of the solution, the shorter will be theprocessing time as less solvent has to be removed during the coating procedure. This beneficial interaction between polymer viscosity and possible coatingsolids is self-limiting in that very low viscosity polymers will suffer from poor film strength due to lowmolecular 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.Furthermore, Delporte advocated the use of elevated temperature coating media in order to additionallyincrease 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 atmospheresuch 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 ofstability due to sugar-coating techniques providing a better moisture barrier than that offered by simplenon-functional cellulosics or acrylics. Usually the moisture permeability of a simple film may bedecreased by the incorporation of water-insoluble polymers, however disintegration and dissolutioncharacteristics 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 asmall container of desiccant or saturated salt solution, the permeability to water vapour being followedby successive weighings to determine respectively weight gain or weight loss (Hawes, 1978). Inaddition to being tedious to perform, the results are only comparable when performed under identicalconditions. Using similar techniques Higuchi & Aguiar (1959) demonstrated that water vapourpermeability of a polymer is dependent on the relative polarity of the polymer. Both Hawes (1978) andDelporte (1980) have seen little difference in water vapour permeability between two commercialgrades of HPMC (E5 and E15) which differ only in molecular weight. Okhamafe & York (1983) haveused an alternative method of assessing water vapour permeability, and that is a sorption-

desorptiontechnique to evaluate the performance of two film-forming polymers, HPMC (606) and polyvinylalcohol (PVA). Addition of PVA to the HPMC was seen to enhance very effectively the moisture barriereffect of the HPMC. The authors ascribe this behaviour to the possible potentiation of the crystallinity ofthe HPMC by the PVA.Sometimes permeability of other atmospheric gases is of concern, particularly that of oxygen. Thisarea has been studied by Prater et al. (1982) who examined the permeability of oxygen through films ofHPMC. These workers used a specially constructed cell which held a 21 mm diameter sample of thefilm. The passage of gas into the acceptor portion of the cell was monitored by using a massspectrometer detection system. Earlier, Munden et al. (1964) had also determined oxygen permeabilitythrough free films of HPMC. They concluded that there was an inverse relationship between oxygenpermeation and water vapour transmission. These results were obtained using a technique of sealing thefilms across a container of alkaline pyrogallol and measuring the consequent solution darkening. AsPrater et al. (1982) point out, this method is not only tedious but water vapour from the pyrogallol iscapable 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 elasticityTo 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 uponfor 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 othertechniques such as indentation tests have a part to play. Much discussion has also taken place in theliterature on the merits and validity of examining isolated films as opposed to examination of a

filmproduced 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, inpractice, has demonstrated the validity of such techniques.

• work of failure• strain.• Tensile strength: The most important parameter here is the ultimate tensile strength, which is themaximum stress applied at the point at which the film breaks.• 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 theregion of linear elastic deformation. It can be regarded as an index of stiffness and rigidity of afilm.• Work of failure: This is numerically equivalent to the area under the curve and equates to thework done in breaking the film. It is an index of the toughness of a film and is a better measure ofthe film’s ability to withstand a mechanical challenge than is a simple consideration of tensilestrength 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 ofindividual polymers are available in various commercial viscosity designations. These designations relyon the description of a standard solution in a specified solvent, as previously indicated.2.6.5 TackinessIn a film-coating sense, tack is a property of a polymer solution related to the forces necessary toseparate two parallel surfaces joined by a thin film of the solution. It is a property responsible forprocessing difficulties and is a limitation on the use of some polymers, e.g. hydroxypropyl celluloseTable 2.6 Mechanical properties of polymers for film coating of drugsσR (N/mm2) R (%)Cellulose derivativeHP-50 39 12HP-55 33 6CMEC (Duodcell)d 11 5CAP+25% DEP 16 14Pharmacoat 606 44 13Pharmacoat 603e 22 3Methocel E5e 24 4

Poly(meth)acrylateMA-MMA 1:2 = Eudragit S100 52 3MA-MMA 1:1=Eudragit L100 24 1MA-EA 1:1=Eudragit L100–55a 10 14Eudragit RS100b 5 40Eudragit RL100b 5 22Eudragit E100b 2 200EA-MMA 1:1=Eudragit E30D 8 600Eudragit E30D/L30D 1:1 17 75Eudragit E30D/L100 7:3c 7 410Eudragit E30D/S100 7:3c 2 620Eudragit E30D/E100-citrat 4:1 4 400Eudragit E30D/E100-phosphat 4:1 5 360Other polymersPolyvinylacetate phthalatef 31 5Note: σR=tensile strength at break (after DIN 53455; R=elongation at break).a 10% PEG.b 10% Triacetinc 10% Tween 80d 30% Glycerylmonocaprylate.e 20% PEG.f 10% Diethylphthalate.(Porter & Bruno, 1990) and certain polymers intended for enteric use, e.g. Eudragit L30D and PVAP.Kovacs & Merenyi (1990) examined several polymers using a technique combining measure

2.7 PLASTICIZERS

Plasticizers are simply relatively low molecular weight materials which have the capacity to alter thephysical properties of a polymer to render it more useful in performing its function as a film-coatingmaterial. Generally the effect will be to make it softer and more pliable. There are often chemicalsimilarities between a polymer and its plasticizer—for instance, glycerol and propylene glycol, whichare plasticizers for several cellulosic systems, possess —OH groups, a feature in common with thepolymer.It is generally considered that the mechanism of action for a plasticizer is for the plasticizer moleculesto interpose themselves between the individual polymer strands thus breaking down to a large

extentpolymer-polymer interactions. This action is facilitated as the polymer-plasticizer interaction isconsidered to be stronger than the polymer-polymer interaction. Hence, the polymer strands now have agreater opportunity to move past each other. Using this model it can be visualized how a plasticizer isable to transform a polymer into a more pliable material.Most of the polymers used in film coating are either amorphous or have very little crystallinity.Strongly crystalline polymers are difficult to plasticize in this fashion as disruption of theirintermolecular structure is not an easy matter. Experimentally, the effect of a plasticizer on a polymericsystem can be demonstrated in many ways; for instance, isolated film work using tensile or indentationmethods will reveal significant changes in mechanical properties between the plasticized andunplasticized states.One fundamental property of a polymer which can be determined by several techniques is the glasstransition temperature (Tg). This is the temperature at which a polymer changes from a hard glassymaterial to a softer rubbery material. The action of a plasticizer is to lower the glass transitiontemperature. The transition can be followed by examining the temperature dependence of suchproperties as modulus of elasticity, film hardness, specific heat, etc. These properties will be expandedon later. Sakellariou et al. (1986a) have utilized a dynamic mechanical method, namely torsion braidanalysis, to characterize the effect of PEGs on HPMC and ethylcellulose.

2.7.1 Classification

The commonly used plasticizers can be categorized into three groups:1. Polyols(a) glycerol (glycerin);(b) propylene glycol;(c) polyethylene glycols PEG (generally the 200–6000 grades).2. Organic esters(a) phthalate esters (diethyl, dibutyl);(b) dibutyl sebacete;(c) citrate esters (triethyl, acetyl triethyl, acetyl tributyl);(d) triacetin.3. Oils/glycerides(a) castor oil;

(b) acetylated monoglycerides;(c) fractionated coconut oil.

2.7.2 Compatibility and permanence

It follows from what has been described above regarding plasticizer-polymer interactions that oneattribute of an efficient platicizer could be that it acts as a good solvent for the polymer in question.Indeed, Entwistle & Rowe (1979) have used this as a measure of plasticizer efficiency. They found acorrelation between the intrinsic viscosity of the polymer/plasticizer solutions and the mechanicalattributes of polymer films plasticized with the specified plasticizers—the mechanical properties oftensile strength, elongation at rupture and work of failure being at a minimum when the intrinsicviscosity of the polymer/plasticizer solution was at a maximum.With the predominance today of aqueous-based film coating there is a concentration on thoseplastizers with an appreciable water miscibility. This includes the polyols and, to a lesser extent,triacetin and triethylcitrate. Glycerol has the added advantage that its regulatory acceptance for foodsupplement products (e.g. vitamin and mineral tablets) is greater than for other plasticizers in those partsof the world where this type of product is covered by food legislation. Permanence of the more volatileplasticizers, e.g. diethylphthalate (DEP), can be a problem with organic solvent-based processing andlikewise in the aqueous field utilizing propylene glycol as the plasticizer. Permanence is an attribute tobe taken into consideration as loss of plasticizer, for instance during storage of the coated tablets, couldhave serious consequences on the integrity of the dosage form. One such consequence could lead to thecracking of the coating under inappropriate storage. These considerations are of much greatersignificance in the realm of functional coatings. Permanence is obviously related to plasticizer volatility,however a change to a more non volatile plasticizer by changing to a higher molecular weight plasticizeris not always an advantageous move. An example here would be the change from a low molecular PEGto a high molecular PEG such as the 6000 grade. This move has unfortunately brought with it a

changeto a less effective plasticizer. Regarding losses during processing, Skultety & Sims (1987) have shownthat, in a statistically based study to determine the factors involved in the loss of propylene glycolduring the coating process, values of 81–96% of theoretical were shown. The only independent variablein the study having an effect was the initial concentration of propylene glycol. On the other hand, noloss was seen when either glycerol or PEG was used as the plasticizer.The possibility of plasticizer migration should also be considered. Conceivably this can occur in twoways:A related phenomena is the migration of materials from the tablet core into the film coating whichmay themselves have a plasticizer-like action on the polymer used. Abdul-Razzak (1983) demonstratedthe migration of several salicylic acid deriva-3. Oils/glycerides(a) castor oil;(b) acetylated monoglycerides;(c) fractionated coconut oil.• migration into the tablet core.• migration into packaging materials.A related phenomena is the migration of materials from the tablet core into the film coating whichmay themselves have a plasticizer-like action on the polymer used. Abdul-Razzak (1983) demonstratedthe migration of several salicylic acid deriva-tives into an ethylcellulose film coating where the derivatives concerned possessed plasticizer activityfor ethylcellulose. Later, Okhamafe & York (1989) examined the effect of ephedrine hydrochloride onboth HPMC and PVA. This drug was shown to display strong plasticizer characteristics for bothpolymers, namely a decrease in softening temperature Tg, crystallinity and melting point. Again, theconsequences of this are rather more serious with functional than non-functional coatings, as thepharmaceutical performance of the film could be compromised.

2.7.3 Effect of plasticizers on the mechanical properties of the film

This can be quite profound and capable of making significant alterations to its properties, eitheradvantageously or adversely.changes in relation to tensile properties can be summarized asfollows:Returning to the earlier proposed mechanism of plasticizer action, it can be seen that as a plasticizerinteracts with a polymer the structure of that polymer will be modified so as to permit increasedsegmental movement. The tertiary structure of the polymer will therefore be altered in such a way as togive a more porous, flexible and less cohesive structure. When a plasticized polymer is subjected to atensile force it can be seen that this structure would be less resilient and would deform at a lower forcethan without the plasticizer.Aulton et al. (1981) have utilized an ‘Instron’ materals tester to evaluate the effect of a series ofplasticisers on the mechanical properties of cast films of HPMC (Methocel E5). Of particular interestwas the finding that low molecular weight PEG was a more efficient plasticizer for this polymer thancorresponding high molecular weight grades (Fig. 2.7). The authors also examined films using thetechnique of indentation. This showed that the introduction of plasticizer to the polymer film promotedincreasing viscoelastic behaviour in the polymer. Indentation studies at low and high humidity alsoprovided experimental evidence for the plasticizing effect of water on HPMC films. Porter (1980) andDelporte (1981) are in general agreement with the findings of Aulton et al. (1981) and, interestingly,Porter used a technique whereby the film for investigation was obtained by spraying and not by casting.Okhamafe & York (1983) have also studied the effects of PEG and HPMC films. Again they are inagreement with the findings of Aulton et al. (1981) in that PEG 400 was preferable to PEG 1000. Thisview was also held by Entwistle & Rowe (1979) using their technique involving polymer/plasticizersolution viscosity determination. Okhamafe & York (1983) also showed that polyvinyl alcohol (PVA)had a quantitatively different effect on HPMC to that displayed by the PEGs. PVA decreases to a lesser

degree, the decrease seen in tensile strength and the increase seen in elongation compared with thePEGs. The authors postulate an increasing crystallinity as a result of PVA addition to the film. It is alsonoted from the results• Increase in strain or film elongation• Decrease in elastic modulus• Decrease in tensile strength.Returning to the earlier proposed mechanism of plasticizer action, it can be seen that as a plasticizerinteracts with a polymer the structure of that polymer will be modified so as to permit increasedsegmental movement. The tertiary structure of the polymer will therefore be altered in such a way as togive a more porous, flexible and less cohesive structure. When a plasticized polymer is subjected to atensile force it can be seen that this structure would be less resilient and would deform at a lower forcethan without the plasticizer.Aulton et al. (1981) have utilized an ‘Instron’ materals tester to evaluate the effect of a series ofplasticisers on the mechanical properties of cast films of HPMC (Methocel E5). Of particular interestwas the finding that low molecular weight PEG was a more efficient plasticizer for this polymer thancorresponding high molecular weight grades (Fig. 2.7). The authors also examined films using thetechnique of indentation. This showed that the introduction of plasticizer to the polymer film promotedincreasing viscoelastic behaviour in the polymer. Indentation studies at low and high humidity alsoprovided experimental evidence for the plasticizing effect of water on HPMC films. Porter (1980) andDelporte (1981) are in general agreement with the findings of Aulton et al. (1981) and, interestingly,Porter used a technique whereby the film for investigation was obtained by spraying and not by casting.Okhamafe & York (1983) have also studied the effects of PEG and HPMC films. Again they are inagreement with the findings of Aulton et al. (1981) in that PEG 400 was preferable to PEG 1000. Thisview was also held by Entwistle & Rowe (1979) using their technique involving polymer/plasticizer

solution viscosity determination. Okhamafe & York (1983) also showed that polyvinyl alcohol (PVA)had a quantitatively different effect on HPMC to that displayed by the PEGs. PVA decreases to a lesserdegree, the decrease seen in tensile strength and the increase seen in elongation compared with thePEGs. The authors postulate an increasing crystallinity as a result of PVA addition to the film. It is alsonoted from the results that the elongation effect obtained by the addition of PEG and PVA to the films exhibits anisotropy. Theauthors speculate as to whether this is a real effect or whether it is due to the experimental protocol.Dechesne and Jaminet (1985) have studied the mechanical properties of cellulose acetate phthalatewhen plasticized by triacetin, DEP and Citroflex A2 in a statistically designed study. One interestingfeature was that triacetin was shown to be a very potent plasticizer for CAP. A practical point ofsignificance is the ability of plasticizers to lower the residual internal stress within a film coating. This isaccomplished by the effect of the plasticizer on the modulus of elasticity of the film (Rowe, 1981). Thisaspect will be dealt with in greater detail in the problem-solving section, Chapter 13.Another important point is that film coatings which confer a modified release effect on the dosageform need to be mechanically tough in order that the coating is not inadvertently damaged duringnormal handling. Dechesne et al. (1982) emphasized the activity of plasticizers in their investigation ofthe effect that different plasticizers have on the diametral crushing strength of, in this case, sodiumfluoride tablets. At an application level of 10 mg of Eudragit L30D/cm2 for example, considerabledifferences were evident in the behaviour of six different plasticizers. Crushing strengths ofapproximately 4.75 kg were recorded employing dibutyl phthalate compared with a value of almost 10kg when propylene glycol was used.

2.7.4 Effect of plasticizers on permeability of film coatings

Occasionally it is required to optimize the permeability characteristics of a film in order to use the filmcoat to retard the entry of water vapour or other gases into the dosage form. This is another area

inwhich plasticizers have a part to play. The transport of a permeant across a barrier is defined by Crank’srelationship (see Okhamafe & York, 1983)P=D·S(2.2)where P, D and S are the permeability, diffusion and solubility coefficients respectively of the filmcoating. It can be envisaged that the passage of a permeant across the film is governed by two steps:1. Dissolution of the permeant in the film material.2. Diffusion of the permeant across the film.In turn, this later process can take place by the permeant diffusing through the polymer matrix itselfand/or diffusion through voids containing either true liquids or vapours. It follows, therefore, that as aplasticizer has the capacity to alter the structure of a polymer, these materials will have the ability toalter the permeability characteristics of a film coating. The above authors have determined the diffusioncoefficients for water through HPMC films plasticized with PEG 400 and 1000, and in both cases anincrease was observed. Previously Porter (1980) and Delporte (1981) had been unable to demonstrateany significant effect with PEG.

2.7.5 Measurement and characterization of plasticizer activity

Thermal methodThis method has proved ideally suited to investigate plasticizer activity, in particular determination ofthe glass transition temperature, Tg. This attribute of a polymer is readily detected as an endotherm priorto the endotherm resulting from melting or decomposition. Other endotherms may be seen usually atlower temperatures, resulting from loss of solvent from the polymer.Using these techniques several authors have demonstrated correlations between plasticizer concentrationand degree of lowering of Tg (Porter & Ridgway, 1983; Dechesne et al., 1984).Thermomechanical analysisLike DSC this method has the useful feature that actual plasticized films can be used for the

determination. Using the technique (Fig. 2.8) a film sample is placed in a holder, and at thecommencement of the experiment a weighted stylus is brought into contact with the specimen.Indentation of the stylus into the specimen as the temperature is gradually raised is followed by anLVDT. The temperature rise of the specimen is accompanied by changes in the polymer structure,which are reflected by movement of the LVDT trace. Hence changes due to softening, meltingdecomposition and glass transitions can be readily followed (Fig. 2.9) (see also Masilungan & Lordi1984; Majeed, 1984).Mechanical methodsMention has already been made of tensile and indentation methods. Depending on the area of interest,such parameters as decrease in tensile strength, increase in strain (elongation) or changes in the modulusof elasticity with changes in plasticizer concentration can be followed. Sinko & Amidon (1989) haveused low strain elongational creep compliance to analyse the intrinsic mechanical response of films ofEudragit S100 with different plasticizers. They studied plasticizer-induced changes on the rate ofmechanical response as solvent leaves the film and the polymer passes through a rubber to glasstransition. Using a free volume analysis, a plasticizing effectiveness term was calculated for theplasticizers used in this study. This showed, for instance, that for Eudragit S100 films, dibutyl phthalateis a more efficient plasticizer than PEG 200.Solubility methodsThese methods usually rely on a consideration of the solubility parameter.In order for a polymer to dissolve in a solvent (plasticizer) the Gibbs free energy of mixing, ΔG, mustbe negative:ΔG=ΔH−T·ΔS(2.3)where ΔH is the heat of mixing, T the absolute temperature and ΔS the entropy of mixing.Okhamafe & York (1987) have demonstrated how ΔH may be obtained from the followingrelationship due to Hildebrand and Scott (1950).

2.8 COLOURANTS/OPACIFIERS

• Identification of the product by the manufacturer and therefore act as an aid (not a replacement)for existing GMP procedures. Colourants also aid in the identification of individual products bypatients, particularly those taking multiple medication.

• They reinforce brand imaging by a manufacturer and thereby decrease the risk of counterfeiting.• Colourants for film-coated tablets have to a greater or lesser extent opacifying properties whichare useful when it is desired to optimize the ability of the coating to protect the active ingredientagainst the action of light.

2.8.1 Classification

Organic dyes and their lakesThis group would include such materials as Sunset Yellow, Patent Blue V, Quinoline Yellow, etc. Aswater solubles their use is extremely restricted regarding the colouring of any form of coated tablet.However, their water-insoluble complexes with hydrated alumina, known as lakes, are in widespreaduse as colours for coated tablets. The reason for this will be considered in the appropriate section below.In the laking process a substratum of hydrated alumina is produced by reacting aluminium chloride withsodium carbonate. The appropriate dye in aqueous solution is then adsorbed onto the prepared aluminahydrate. Finally additional aluminium chloride is added to ensure complete formation of the aluminiumsalt of the dye. Filtration and washing of the product complete the process.Inorganic coloursStability towards light is an important characteristic displayed by these materials, some of which have auseful opacifying capacity, e.g. titanium dioxide. Another great advantage of inorganic colours is theirwide regulatory acceptance, making them most useful for multinational companies wishing tostandardize international formulae. One drawback to their use is that the range of colours that can beachieved is rather limited.Natural coloursThis is a chemically and physically diverse group of materials. The description ‘natural’ is of necessityloose, as some of these colours are the products of chemical synthesis rather than extraction from anatural source, e.g. (β-carotene of commerce is regularly synthetic in origin. The term frequently appliesto such materials is ‘nature identical’, which in many ways is more descriptive. Some would

even makethe case that any product which is not a constituent of the normal diet should not be called ‘natural’.This viewpoint would remove colours such as cochineal and annatto from consideration. As ageneralization, natural colours are not as stable to light as the other groups of colours; their tinctorialpowers are not high and they tend to be more expensive than other forms of colour. They do, however,possess a regulatory advantage in that they have a wide acceptability. Even with these advantages theirpenetration into the pharmaceutical area has not been great.

This group of materials are commonly used as ingredients in film-coating formulae. They obviouslycontribute to the aesthetic appeal of the product, but they also enhance the product in other ways:Examples of colours:Organic dyes and their lakesInorganic coloursNatural colours

2.8.2 Regulatory aspects and specifications

Pharmaceutical colours are unusual in that, in most parts of the world, they are subject to requirementsover and above normal pharmacopoeial specifications. For example, within the EU they must meetcertain purity requirements laid down by current European Union Directives. Likewise, in the UnitedStates, the Code of Federal Regulations imposes its own set of purity criteria. Countries can andfrequently do differ in the colours that are permitted in pharmaceutical preparations. Specialistpublications exist which should be consulted in case of doubt (e.g. Anon., 1993).

2.8.3 Advantages of pigments over dyes

Previously it had been indicated that water-soluble colours were technically inferior to water-insoluble(pigments) colours. The reasons for this are given below.MigrationDrying is an integral part of the coating process and, as a consequence, water will leave the film coatcontinuously as the coat is formed. If the colour is in the form of insoluble particles, then no migration

takes place. However, a water-soluble colour tends to follow the escaping water molecules to the tabletsurface and produce a mottled finish to the coating.OpacityPigments are much more opaque than dyes, hence they offer a much greater measure of protectionagainst light than dye-coloured film coats.Colour stabilityEdible colours for medicinal products have an established use by virtue of their low order of toxicity.Some of their technical attributes, for example colour stability, can represent somewhat of acompromise. In general the inorganic pigments, e.g. iron• Sunset Yellow• Tartrazine• Erythrosine.• Titanium dioxide• Iron oxide yellow, red and black• Talc.• Riboflavine• Carmine• Anthocyanins.oxides, have an excellent stability while the synthetic organic dyes are much less satisfactory in thisrespect. The lake forms of many of the synthetic organic dyes, however, provide a degree ofimprovement in this respect.PermeabilityPigments decrease the permeability of films to water vapour and oxygen thereby offering thepossibilities of increased shelf-life.Coating solidsPigments contribute to the total solids of a coating suspension without significantly contributing tothe viscosity of the system. Thus faster processing times by virtue of more rapid drying is possible. Thisis particularly significant with aqueous-based processes.Anti-tack activityTack is a concept that is widely used to describe the forces involved in the separation of two parallelsurfaces separated by a thin film of liquid. Such considerations are important during the coating processas excess tack can cause troublesome adhesion of tablets to each other or to the coating vessel. Since the

early days of film coating it has been appreciated that solid inclusions, including pigments, in theformula have a part to play in combating the effects of tack. Chopra & Tawashi (1985) have quantifiedthe action of titanium dioxide, talc and indigo carmine lake on the tackiness of coating polymersolutions. They have shown that, at high polymer concentrations, increasing the pigment concentrationand decreasing the pigment particle size, reduced the effect of tack, whereas at low polymerconcentration only talc was effective in reducing tack. Alternative methods of tack evaluation have beenutilized by other workers such as Massoud & Bauer (1989) and Wan & Lai (1992).

2.8.4 Effects of pigments on film-coating systems

Because of their very diverse nature it can be expected that the effects of pigments on film-coatingsystems can be rather complex.Mechanical effectsIn general, the presence of pigments will reduce the tensile strength of a film, increase the elasticmodulus and decrease the extension of the film under a tensile load. All of these are, of course, negativeeffects. However, as pigments consist of discrete individual particles the need for efficient pigmentdispersion should be emphasized. Another generalization is that the lower the particle size of thepigment concerned, the smaller will be the deleterious effect on film properties. These effects are ofsome importance in the consideration of stress-related film-coating defects. Lehmann & Dreher (1981)describe the property displayed by several of the acrylic film-coating polymers, that of being able tobind substantially higher quantities of pigment than is possible for example with the cellulosics. Theauthors point to the advantages of mechanical stability and resistance to attrition achieved.Aulton et al. (1984) have examined the effect of a wide range of pigments on the mechanicalproperties of cast films of HPMC (Methocel E5). In addition to confirming the general effects above,they emphasized the need to consider the whole stress-strain diagram and not to merely one feature inisolation. For instance, a pigmented film may well show very little decrease in tensile strength comparedwith the unpigmented film; however, a consideration of the area under the curve could show significant

differences . The term ‘work of rupture’ was coined by the authors for this particularparameter. In comparing the effects of different pigments the authors concluded that there werepigment-specific effects and that the pigment was not merely occupying space in an inert manner orbehaving as an inert diluent. The pigment effect has also been discussed by Rowe (1982) in a study onthe effect of pigments on edge splitting of tablet film coats. Talc was seen to be an exception to thegeneral behaviour of pigments. The reason postulated was that as talc exists as flakes it orientates itselfparallel to the surface of the substrate in a restraint on volume shrinkage of the film parallel to the planeof coating .In another study, Okhamafe & York (1985a) have looked at the mechanical properties stated abovefor free films in combination with PVA or PEG 1000 and loaded with talc or titanium dioxide. Broadly,the results were in agreement with the findings of Aulton et al. (1984). The results were presented notonly in mechanical terms but polymer-pigment interactions were also taken into account in either rein-forcing the mechanical effect or working against it. For example, in the case of high pigment-polymerinteraction, the loss of film elongation was greatly potentiated.The same authors, in further work (1985b), have examined the effect of pigmented and unpigmentedfilms on the adhesion of those films to the surfaces of aspirin tablets. They found that pigmentsincorporated in an applied film can exert two opposing effects on adhesion: one decreases adhesion by increasing internal stress and the otherincreases adhesion by strengthening the film-tablet surface interation. From the results obtained, theadhesion of HPMC films was initially increased in the presence of talc because of a stronger film-tabletinterface and a smaller increase in the internal stress of the film, but above 10% by weight of thepigment, the internal stress factor began to dominate and adhesion fell.In a large comparative study (Gibson et al., 1988), the effect of the iron oxide pigments titaniumdioxide, talc, erythrosine lake, and sunset yellow lake were examined upon HPMC (Pharmacoat 606)films plasticized with PEG 200. The authors concluded that the Young’s modulus of the films is raisedby the pigments to an extent that largely depends upon pigment shape and can be predicted by existing

theories. The exceptions are titanium dioxide and the lake pigments which have less of an effect on themodulus than expected due to polymer-pigment interactions or, in the case of the lake pigments, to aloose particle structure. The ultimate tensile properties of the films depend mainly on the concentrationof the particles added. Pigments cause a large decrease in tensile strength except in the cases of yellowor black iron oxides which are not weakened to such an extent because the shape of the particles allowsthe growth of flaws to be retarded. If the thermal expansion coefficients of the matrix and filler promotepremature cracking on cooling from the fabrication temperature, then the introduction of filler in anyconcentration is detrimental to the tensile strength of the system.

2.9 SOLVENTS/VEHICLES

These materials perform a necessary function in that they provide the means of conveying the coatingmaterials to the surface of the tablet or particle. The major classes of solvents capable of being used are:• water• alcohols• ketonesA prerequisite for a solvent would be that it has to interact well with the chosen polymer; this isneeded as high polymer solvent interaction permits film properties such as adhesion and mechanicalstrength to be optimized. Selection of the correct solvent can be predicted by a thermodynamic approachas described in section 2.7.5.Kent & Rowe (1978) utilized the solubility parameter approach in evaluating the use of ethylcellulosein various solvents for film coating. By evaluating the effect of solubility parameter on intrinsicviscosity for a range of solvents graded as to the extent of hydrogen bonding, they were able todetermine not only which was the best class of solvent to use but also what was the optimum solventsolubility parameter. Rowe (1986) has pointed out that ideally for this use the solubility parameter needsmodification to take into account components due to van der Waals’ forces, hydrogen bonding and

polarity. Thus, using a modification proposed by Hansen (1967), Rowe has produced solubilityparameter maps to evaluate the compatibility of ethylcellulose in admixture with methylcellulose andHPMC.Considering polymer solvents in a wider sense, a thermodynamically based compatibility is not theonly practical requirement. Kinetic considerations of the ability of the solvent to penetrate the polymermass effectively and solvate the polymer in such a way that polymer swelling and dissolution take placeeffectively are also very important. Thermodynamically good solvents do not always make kineticallygood solvents, and vice-versa. Hence the choice of a suitable solvent selected on the above criteria islikely to be a process of compromise.Another practical feature is that the chosen solvent should not pose volatility problems. Besidescausing processing difficulties, the controlled deposition of coating materials to form a coherent filmcoat could be compromised.The use of solvent mixtures should be fully validated. The problem here is that during the coatingprocess preferential evaporation of solvents from the mixture is liable to take place (unless, of course, aconstant boiling mixture is used). An extreme example would be that as a result, polymer precipitationwould occur with no film-formation. At the least, polymer solubility could be affected to the extent thatfilm-forming ability would suffer. This problem has been described by Spitael & Kinget (1977) inconsidering the effect of processing solvent on the film-forming property of cellulose acetate phthalate.Using three different methods of preparing films they demonstrated that entire films were formed onlywith certain solvents or combinations. For example, only two solvents gave consistently good results,namely acetone and the azeotropic mixture of 77% ethyl acetate and 23% isopropanol. The othersolvents, which were 1:1 mixtures of ethyl acetate with isopropanol and acetone with ethanol, gaveopaque, brittle films which lacked cohe-siveness. Less than optimal film-forming conditions for afunctional film such as this would have serious consequences.

• esters• chlorinated hydrocarbons.A prerequisite for a solvent would be that it has to interact well with the chosen polymer; this isneeded as high polymer solvent interaction permits film properties such as adhesion and mechanicalstrength to be optimized. Selection of the correct solvent can be predicted by a thermodynamic approach.Kent & Rowe (1978) utilized the solubility parameter approach in evaluating the use of ethylcellulosein various solvents for film coating. By evaluating the effect of solubility parameter on intrinsicviscosity for a range of solvents graded as to the extent of hydrogen bonding, they were able todetermine not only which was the best class of solvent to use but also what was the optimum solventsolubility parameter. Rowe (1986) has pointed out that ideally for this use the solubility parameter needsmodification to take into account components due to van der Waals’ forces, hydrogen bonding andpolarity. Thus, using a modification proposed by Hansen (1967), Rowe has produced solubilityparameter maps to evaluate the compatibility of ethylcellulose in admixture with methylcellulose andHPMC.Considering polymer solvents in a wider sense, a thermodynamically based compatibility is not theonly practical requirement. Kinetic considerations of the ability of the solvent to penetrate the polymermass effectively and solvate the polymer in such a way that polymer swelling and dissolution take placeeffectively are also very important. Thermodynamically good solvents do not always make kineticallygood solvents, and vice-versa. Hence the choice of a suitable solvent selected on the above criteria islikely to be a process of compromise.Another practical feature is that the chosen solvent should not pose volatility problems. Besidescausing processing difficulties, the controlled deposition of coating materials to form a coherent filmcoat could be compromised.The use of solvent mixtures should be fully validated. The problem here is that during the coatingprocess preferential evaporation of solvents from the mixture is liable to take place (unless, of course, a

constant boiling mixture is used). An extreme example would be that as a result, polymer precipitationwould occur with no film-formation. At the least, polymer solubility could be affected to the extent thatfilm-forming ability would suffer. This problem has been described by Spitael & Kinget (1977) inconsidering the effect of processing solvent on the film-forming property of cellulose acetate phthalate.Using three different methods of preparing films they demonstrated that entire films were formed onlywith certain solvents or combinations. For example, only two solvents gave consistently good results,namely acetone and the azeotropic mixture of 77% ethyl acetate and 23% isopropanol. The othersolvents, which were 1:1 mixtures of ethyl acetate with isopropanol and acetone with ethanol, gaveopaque, brittle films which lacked cohe-siveness. Less than optimal film-forming conditions for afunctional film such as this would have serious consequences.

2.10 AUXILIARY SUBSTANCES IN THE FILM-COATING FORMULAE

Mention has already been made of the occasional addition of substances such as flavours and waxes tofilm-coating formulae. In recent times there has emerged a new class of auxiliary substances which,when combined with the traditional ingredients of a film-coating formula, show advantageous properties. These are saccha-ride materals such aspolydextrose, maltodextrin and lactose. Perhaps their most remarkable property is to increase theadhesion of cellulosic systems to substrates. Jordan et al. (1992) have quoted examples where lactose-HPMC combinations under defined conditions demonstrated an adhesive force of 40 kN/m2 for a waxytablet core where an HPMC-HPC combination measured only 26 kN/m2 and a simple HPMC coatingfailed to show any measurable adhesion to the core. These saccharide-cellulosic combinations have alsobeen shown to improve the stability towards light of several unstable colours used as film-coatingcolourants. As yet, the mechanism of action of these auxiliary materials is not totally understood.

2.11 THE CHOICE BETWEEN AQUEOUS AND ORGANIC SOLVENT-BASED

COATING

Since the 1970s there has been a steady move away from the originally used organic solvents to the useof water as the coating medium (Hogan, 1982). The reasons for this change are not hard to find.Considerations of environmental pollution enforced by local legislation have made it impossible tooperate in the same manner as in the early days of the technology. This, coupled with safety and healthrelatedissues of people in the workplace, has meant that there is an increasing number of companieswho are willing to consider aqueous processing. Only since the advent of the aqueous dispersed formsof the original acrylic polymers has it been possible to utilize aqueous processing for these materials.However, the commonly used cellulosic polymers, with the exception of ethylcellulose, have anappreciable water solubility which has always made them theoretically available for aqueous processing.It must be remembered that in the early 1970s the sophistication of processing equipment was inferiorto the situation today. In particular, drying ability was defi-cient, thus placing a necessary emphasis onthe use of as low a boiling point solvent as practically possible. In addition, the cellulose derivatives incommon use, although water soluble, were not ideally suited to aqueous use as the grades available hadan excessively high viscosity in water, thus rendering their solutions difficult to atomize.Gradually the introduction of new purpose-built coating equipment and lower viscosity cellulosicpolymers enabled the interest in aqueous processing to be translated into activity. During this periodseveral of the misconceptions of aqueous processing were removed from the minds of workers in thisarea—notably that aqueous processing would mean overly long coating processes or that the use ofwater was bound to pose severe stability problems. As a generalization there are very few tabletformulations that cannot be aqueously film coated (Tonadachie et al., 1977). It is also true to say that therequirement for water-based processing is now so strong in certain parts of the world that film-coatingsystems and polymers are specifically designed with this requirement in mind. For modified releasecoatings, where water-insoluble polymers have traditionally been used, special water-dispersible

formshave been developed by manufacturers.

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Lehmann, K. & Dreher, D. (1981) Int. J. Pharm. Tech. Prod. Mfr 2, 31–43.Majeed, S.S. (1984) M.Phil. Thesis, C.N.A. A., Leicester Polytechnic.Masilungan, F.C. & Lordi, N.G. (1984) Int. J. Pharm. 20, 295–305.Massoud, A. & Bauer, K.H. (1989) Pharm. Ind. 51, 203–209.Millar, J. (1957) US Patent 2, 897, 122.Munden, B.J., DeKay, H.G. & Banker, G.S. (1964) J. Pharm. Sci. 53, 394–401.Nielsen, L.E. (1967) J. Macromol. Sci.-Chem. A1, 929.Nyqvist, H., Nicklasson, M. & Lundgren, P. (1982) Acta Pharm. Suec. 19, 1–6.Okhamafe, A.O. & York, P. (1983) J. Pharm. Pharmacol. 35, 409–415.Okhamafe, A.O. & York, P. (1985a) Pharm. Acta Helv. 60, 92–96.Okhamafe, A.O. & York, P. (1985b) J. Pharm. Pharmacol. 37, 849–853.Okhamafe, A.O. & York, P. (1987) Int. J. Pharm. 39, 1–21.Okhamafe, A.O. & York, P. (1989) J. Pharm. Pharmacol. 41, 1–6.Porter, S.C. (1980) Pharm. Tech. 4(3), 67–76.Porter, S.C. & Bruno, C. (1990) In Pharmaceutical dosage forms: Tablets, Vol. 3, Chap. 2, 2nd edn(Eds Lieberman, H.A., Lachman, L. & Schwartz, J.), Marcel Dekker, New York.Porter, S.C. & Ridgway, K. (1983) J. Pharm. Pharmacol 35, 341–344.Prater, D.A., Meakin, B.J. & Wilde, J.S. (1982) Int. J. Pharm. Tech. Prod. Mfr 3, 33–41.Rowe, R.C. (1980) J. Pharm. Pharmacol. 32, 116–119.Rowe, R.C. (1981) J. Pharm. Pharmacol. 33, 423–426.Rowe, R.C. (1982) Pharm. Acta Helv. 57, 221–225.Rowe, R.C. (1983) J. Pharm. Pharmacol. 35, 43–44.Rowe, R.C. (1984a) Int. J. Pharm. 22, 17–23.Rowe, R.C. (1984b) J. Pharm. Pharmacol. 36, 569–572Rowe, R.C. (1984c) Materials used in the film coating of oral solid dosage forms, in Materials used inpharmaceutical formulation (ed. Florence, A.T.), Critical Reports on Applied Chemistry 6, Soc.Chem. Ind., Blackwell Scientific PublicationsRowe, R.C. (1985) Pharm. Int. Jan., 14–17.Rowe, R.C. (1986) J. Pharm. Pharmacol. 38, 214–215.Sakellariou, P., Rowe, R.C. & White, E.F.T. (1986a) Int. J. Pharm. 31, 55–64.Sakellariou, P., Rowe, R.C. & White, E.F.T. (1986b) Int. J. Pharm. 31, 175–77.Sinko, C.M. & Amidon, G.M. (1989) Int. J. Pharm. 55, 247–256.Skultety, P.F. & Sims, S. (1987) Drug Dev. Ind. Pharm. 13, 2209–2219.Spitael, J. & Kinget, R. (1977) J. Pharm. Belg. 32, 569–577.Steuernagel, C.R. (1989) In Aqueous polymeric coatings for pharmaceutical dosage forms (ed.McGinity, J.W.), Marcel Dekker, New York, pp. 1–63.Tonadachie, M., Hoshi, N. & Sekigawa, F. (1977) Drug Dev. Ind. Pharm. 3, 227–240.Wan, L.S.C. & Lai, W.F. (1992) S.T.P. Pharma Sci. 2, 174–180.Warner, G.L. (1978) US Patent 4, 123, 403.Zhang, G., Schwartz, J.B. & Schnaare, R.L. (1988) Proc. 15th Int. Symp. Controlled Release ofBioactive Materials, Basel.Zhang, G., Schwartz, J.B. & Schnaare, R.L. (1989) Proc. 16th Int. Symp. Controlled Release ofBioactive Materials, Chicago.

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