Tài liệu Pharmaceutical Coating Technology (Part 2) pptx

Page 6 2 Film-coating materials and their properties John E.Hogan SUMMARY The chapter commences by reviewing the properties of the broad classes of materials used in film coating, polymers, plasticizers, pigments and solvents (or vehicles). An initial consideration of the polymers shows that while processing is most commonly performed using these materials in solution, there are systems which utilize polymers in suspension in water. The mechanism of coalescence and film formation for these types of materials are discussed. The individual polymers are dealt with in some detail and an attempt is made to divide them into functional and non-functional coating polymers. Functional polymers being defined as those which modify the pharmaceutical function of the compressed tablet, for instance an enteric or modified releae film. However, this distinction is sometimes blurred as one coating polymer can fall into both groups. The essential polymer characteristics of solubility, solution viscosity, film permeability and mechanical properties are described in terms of ultimate film requirements. In the treatment and description of plasticizers, some prominence is given to their effect on the mechanical properties of the film and its permeability characteristics, especially to water vapour. A section is provided on the assessment of plasticizer activity on film-coating polymers. The section on pigments describes how they function as opacifiers and also their ability to modify the permeability of a film to gases. In considering the solvents and vehicles used in film-coating techniques a discussion is provided of the respective merits of aqueous and non-aqueous processing. The chapter is concluded by some examples of formulae of film-coating systems which illustrate several of the principles described previously. Page 7 2.1 INTRODUCTION A film coating is a thin polymer-based coat applied to a solid dosage form such as a tablet, granule or other particle. The thickness of such a coating is usually between 20 and 100 µm. Under close examination the film structure can be seen to be relatively non-homogeneous and quite distinct in appearance, for example, from a film resulting from casting a polymer solution on a flat surface. This non-homogeneous character results from the deliberate addition of insoluble ingredients such as pigments and by virtue of the fact that the film itself is built up in an intermittent fashion during the coating process. This is because most coating processes rely on a single tablet or granule passing through a spray zone, after which the adherent material is dried before the next portion of coating is received. This activity will of course be repeated many times until the coating is complete. Film-coating formulations usually contain the following components: However, while plasticizers have an established place in film-coating formulae they are by no means universally used. Likewise, in clear coating, pigments and opacifiers are deliberately omitted. Consideration must also be given to minor components in a film-coating formula such as flavours, surfactants and waxes and, in rare instances, the film coat itself may contain active material. 2.2 POLYMERS The vast majority of the polymers used in film coating are either cellulose derivatives, such as the cellulose ethers, or acrylic polymers and copolymers. Occasionally encountered are high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials. The characteristics of the individual polymers and the essential properties of polymers used for film coating will be covered in subsequent sections. Frequently, the polymer is dissolved in an appropriate solvent either water or a non-aqueous solvent for application of the coating to the solid dosage form. However, some of the water-insoluble polymers are available in a form which renders them usable from aqueous systems. These materials find considerable application in the area of modified release coatings. Basically there are two classes of such material depending upon the method of preparation; true latexes and pseudolatexes. 2.2.1 True latexes These are very fine dispersions of polymer in an aqueous phase and particle size is crucial in the stability and use of these materials. They are characterized by a particle size range of between 10 and 1000 nm. Their tendency to sediment is counter- • Polymer. • Plasticizer. • Pigment/opacifier. • Vehicle. Page 8 balanced by the Brownian movement of the particles aided by microconvection currents found in the body of the liquid. The Stokes equation can be used to determine the greatest particle diameter that can be tolerated in the system without sedimentation. At the other end of the size range the characteristic of colloidal particles is approached where such dispersions are barely opaque to light and are almost clear. One of the chief ways of producing latex dispersions is by emulsion polymerization. Characteristically the process starts with the monomer which after purifica-tion is emulsified as the internal phase with a suitable surfactant (Lehmann, 1972). Polymerization is activated by addition of an initiator. Commonly the system is purged with nitrogen to remove atmospheric oxygen which would lead to side reactions. As with any polymerization process, the initiator controls the rate and extent of the reaction. The reaction is quenched when the particle size is in the range 50–200 nm. Using this process the following acrylate polymers are produced: Eudragit L100–55 and NE30D (Lehmann, 1989a). 2.2.2 Psuedolatexes Commercially there are two main products which fall into this category, both of them utilize ethylcellulose as the film former but are manufactured in quite a different way and their method of application also differs significantly. Characteristically pseudolatexes are manufactured starting with the polymer itself and not the monomer. By a physical process the polymer particle size is reduced thereby producing a dispersion in water; the characteristics of this dispersion need not differ significantly from a true latex, including particle size considerations. The pseudolatex is also free of monomer residue and traces of initiator, etc. The earliest of the two ethylcellulose products (Aquacoat) is manufactured by dissolving ethylcellulose in an organic solvent and emulsifying the solution in an aqueous continuous phase. The organic solvent is eventually removed by vacuum distillation, leaving a fine dispersion of polymer particles in water. Steuernagel (1989) has defined the composition of Aquacoat to have a solids content of 30% w/w and a moisture content of 70%w/w, the solids being composed of ethylcellulose 87%, cetyl alcohol 9% and sodium lauryl sulphate 4%. A food grade antifoam is also present. The cetyl alcohol and sodium lauryl sulphate act as surfactants/stabi-lizers during the later stages of production. The newer of the ethylcellulose products is Surelease. This is manufactured using a patented process based on phase inversion technology (Warner, 1978). The ethylcellulose is heated in the presence of dibutyl sebacate and oleic acid, and this mixture is then introduced into a quantity of ammoniated water. The resulting phase inversion produces a fine dispersion of ethylcellulose particles in an aqueous continuous phase. The dibutyl sebacate (fractionated coconut oil can also be used) is to be found in the ethylcellulose fraction while the oleic acid and the ammonia together effectively stabilize the dispersed phase in water. This siting of the dibutyl sebacate and oleic acid is important for the use of this material as an effective coating agent. Both materials act as plasticizers and with the Surelease system are physically situated where they are able to function most effectively, that is, in intimate contact with the polymer. Surelease, unlike Aquacoat, does not require the Page 9 further addition of plasticizer. Surelease also contains a quantity of fumed silica which acts as an antitack agent during the coating process. Its total nominal solids content is 25% w/w. Aqueous dispersions have significant advantages, enabling processing of water-insoluble polymers from an aqueous media (see Chapter 14 ). 2.2.3 Mechanism of film formation Film formation from an aqueous polymeric dispersion is a complex matter and has been examined by several authors (Bindschaedler et al., 1983; Zhang et al., 1988, 1989). In the wet state the polymer is present as a number of discrete particles, and these have to come together in close contact, deform, coalesce and ultimately fuse together to form a discrete film. During processing, the substrate surface will be wetted with the diluted dispersion. Under the prevailing processing conditions water will be lost as water vapour and the polymer particles will increase in proximity to each other—a process which is greatly aided by the capillary action of the film of water surrounding the particles. Complete coalescence occurs when the adjacent particles are able to mutually diffuse into one another, as shown in Fig. 2.1 . Minimum film-forming temperature (MFT) This is the minimum temperature above which film formation will take place using individual defined conditions. It is largely dependent on the glass transition temperature ( Tg) of the polymer, an attribute which is capable of several definitions but can be considered as that temperature at which the hard glassy form of an amorphous or largely amorphous polymer changes to a softer, more rubbery, consistency. Lehmann (1992) states that the concept of MFT includes the plasticizing effect of water on the film-forming process. With aqueous dispersions Lehmann recommends to keep the coating temperature 10–20°C above the MFT to ensure that optimal conditions for film formation are achieved. Examples of MFTs of Eudragit RL and RS aqueous dispersions are given by Lehmann (1989a). 2.3 POLYMERS FOR CONVENTIONAL FILM COATING The term conventional film coating has been used here to describe film coatings applied for reasons of improved product appearance, improved handling, and prevention of dusting, etc. This is to make a distinction with functional film coats, which will be described in a later section, and where the purpose of the coating is to confer a modified release aspect on the dosage form. An alternative term for conventional film coating, therefore, would be non-functional film coating. 2.3.1 Cellulose ethers The majority of the cellulose derivatives used in film coating are in fact ethers of cellulose. Broadly they are manufactured by reacting cellulose in alkaline solution with, for example, methyl chloride, to obtain methylcellulose. Hydroxypropoxyl substitution is obtained by similar reaction with propylene oxide. The product is Page 10 Fig. 2.1 Mechanism of film formation of aqueous polymer dispersions thoroughly washed with hot water to remove impurities, dried and finally milled prior to packaging. The structure of cellulose permits three hydroxyl groups per repeating anhydroglucose unit to be replaced, in such a fashion. If all three hydroxyl groups are replaced the degree of substitution (DS) is designated as 3, and so on for lower degrees of substitution. The term molar substitution (MS) covers the situation where a side chain carries hydroxyl groups capable of substitution and takes into account the total moles of a group whether on the backbone or side chain. Both DS and MS profoundly affect the polymer properties with respect to solubility and thermal gel point. The polymer chain length, together with the size and extent of branching, will of course determine the viscosity of the polymer in solution. As a generality, film coating demands polymers at the lower end of the viscosity scale. Page 11 Individual cellulose ethers Various groups are capable of substitution into the cellulose structure, as shown in Fig. 2.2. Hydroxypropyl methylcellulose (HPMC) Substituent groups: —CH 3 , —CH 2 —CH(OH)—CH 3 This polymer provides the mainstay of coating with the cellulose ethers and its usage dates back to the early days of film coating. It is soluble in both aqueous media and the organic solvent systems normally used for film coating. HPMC provides aqueously soluble films which can be coloured by the use of pigments or used in the absence of pigments to form clear films. The polymer affords relatively easy processing due to its non-tacky nature. A typical low-viscosity polymer can be sprayed from an aqueous solution containing around 10– 15%w/w polymer solids. From the regulatory aspect, in addition to its use in pharmaceutical products, HPMC has a long history of safe use as a thickener and emulsifier in the food industry. Table 2.2 shows that the USP and JP recognize definite substitution types in separate monographs. The first two digits of the four-digit designation specify the nominal percentage of methoxyl groups while the final two specify the nominal Fig. 2.2 The structure of a substituted cellulose. (R can be represented as –H or, as in the text, under individual polymers.) Table 2.1 Substitution data of some cellulose ethers (after Rowe, 1984c) Polymer Methoxyl substitution Hydroxypropoxyl substitution %w/w DS %w/w DS MS Methylcellulose 27.5–31.5 1.64–1.92 — — — Hydroxypropyl methylcellulose 28.0–30.0 1.67–1.81 7.0–12.0 0.15–0.25 0.22–0.25 Hydroxypropyl cellulose — — ≤ 80.5 — ≤ 4.6 Page 12 percentage of hydroxypropoxyl groups. The EP has no specified ranges for substitution. Significant differences exist between the USP and EP monographs. These relate to tighter requirements for ash, chloride for the EP which also possesses tests on solution colour, clarity and pH. Methodology differences also exist, particularly with regard to solution viscosity. The JP has a very low limit on chloride content. Methylcellulose (MC) Substituent group: —CH 3 This polymer is used rarely in film coating possibly because of the lack of commercial availability of low viscosity material meeting the appropriate compendial requirements. As a distinction from the USP and the JP the EP has no required limits on the content of methoxyl substitution. However, the USP and JP have slightly different limits, which are 27.5–31.5% against 26.0–33.0% respectively. Hydroxyethyl cellulose (HEC) Substituent group: —CH(OH)—CH 3 This water-soluble cellulose ether is generally insoluble in organic solvents. The USNF is the sole pharmacopoeial specification; there is no requirement on the quantity of hydroxyethyl groups to be present. The USNF allows the presence of additives to promote dispersion of the powder in water and to prevent caking on storage. Hydroxypropyl cellulose (HPC) Substituent group: —CH 2 —CH(OH)—CH 3 HPC has the property of being soluble in both aqueous and alcoholic media. Its films unfortunately tend to be rather tacky, which possess restraints on rapid coating; HPC films also suffer from being weak. Currently this polymer is very often used in combination with other polymers to provide additional adhesion to the substrate. The EB/BP has no requirements on hydroxypropoxyl content. The USNF states this must be less than 80.5% while the JP has two monographs differing in substitution requirements. The monograph most closely corresponding to the USNF material has a substitution specification of 53.4–77.5%. The other monograph relates to material of much lower substitution content and is used for purposes other than film coating, e.g. direct compression. 2.3.2 Acrylic polymers These comprise a group of synthetic polymers with diverse functionalities. Table 2.2 Compendial designations of HPMC typess in the USP and JP 2910 2208 2906 1828 a % Methoxyl 7–12 4–12 4–7.5 16–20 % Hydroxypropoxyl 28–20 19–24 27–30 23–32 a Monograph only in the USP. Page 13 Methacrylate aminoester copolymer This polymer is basically insoluble in water but dissolves in acidic media below pH 4. In neutral or alkaline environments, its films achieve solubility by swelling and increased permeability to aqueous media. Formulations intended for conventional film coating can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers, and starches in order to ensure complete disintegration/dissolution of the film. This material is supplied in both powder form or as a concentrated solution in isopropanol/acetone, which can be further diluted with solvents such as ethanol, methanol, acetone and methylene chloride. Talc, magnesium stearate or similar materials are useful additions to the coating formula as they assist in decreasing the sticky or tacky nature of the polymer. In general, the polymer does not require the addition of a plasticizer. 2.4 POLYMERS FOR MODIFIED RELEASE APPLICATION Despite the considerable difference in application between a polymer intended for a simple conventional (non-functional) coating and one intended to confer a modified release performance on the dosage form, the categorizing of the polymers themselves into these divisions is not such an exact process. Several examples exist of polymers fulfilling both needs, hence there is a considerable overlap of use. However, the divisions used here represent perhaps the majority practice. Table 2.3 Methacrylate aminoester copolymers (after Lehmann & Dreher, 1981) Scientific name n 1 :n 2 :n 3 MW USNF designation Eudragit type Marketed form Poly(butylmethacrylate), (2- dimethylaminoethyl) methacrylate, methylmethacrylate 1:2:1 150 000 None E12.5 12.5% solution in isopropanol/ acetone R=—CH2—CH 2 —N(CH 3 ) 2 None E100 Granulate Page 14 2.4.1 Methacrylate ester copolymers Structurally these polymers bear a resemblance to the methacrylic acid copolymers but are totally esterified with no free carboxylic acid groups. Thus these materals are neutral in character and are insoluble over the entire physiological pH range. However they do possess the ability to swell and become permeable to water and dissolved substances so that they find application in the coating of modified release dosage forms. The two polymers Eudragit RS and RL, can be mixed and blended to achieve a desired release profile. The addition of hydrophilic materials such as the soluble cellulose ethers, polyethylene glycol (PEG), etc., will also enable modifications to be achieved with the final formulation. The polymer Eudragit RL is strongly permeable and thus only slightly retardant. Its films are therefore also indicated for use in quickly disintegrating coatings. The polymers themselves have solubility characteristics similar to the methacrylic acid copolymers. For aqueous spraying a latex form of each polymer is available. In addition the polymer Eudragit NE30D has been made for this purpose. This materal is also used as an immediate-release non- functional coating in film coat formulations where relatively large quantities of water-soluble materials are added to ensure efficient disruption of the coat. 2.4.2 Ethylcellulose (EC) Substituent group (Fig. 2.2): —CH 2 —CH 3 Ethylcellulose is a cellulose ether produced by the reaction of ethyl chloride with the appropriate alkaline solution of cellulose. Apart from its extensive use in controlled release coatings, ethylcellulose has found a use in organic solvent-based coatings in a mixture with other cellulosic polymers, notably HPMC. The ethylcellulose component optimizes film toughness in that surface marking due to handling is minimized. Ethylcellulose also conveys additional gloss and shine to the tablet surface. In many ways ethylcellulose is an ideal polymer for modified release coatings. It is odourless, tasteless and it exhibits a high degree of stability not only under physiological conditions but also under normal storage conditions, being stable to light and heat at least up to its softening point of c. 135°C (Rowe, 1985). Commercially, ethylcellulose is available in a wide range of viscosity and substitution types giving a good range of possibilities for the formulator. It also possesses good solubility in common solvents used for film coating but this feature is nowadays of lesser importance with the advent of water-dispersible presentations of ethylcellulose which have been especially designed for modified release coatings. The polymer is not usually used on its own but normally in combination with secondary polymers such as HPMC or polyethylene glycols which convey a more hydrophilic nature to the film by altering its structure by virtue of pores and channels through which drug solution can more easily diffuse. Only the USNF contains a monograph, an ethoxy group content of between 44.0 and 51.0% is specified. The USNF also contains a monograph ‘Ethylcellulose Aqueous Dispersion’ which defines one type of such material which finds a use in aqueous processing. The monograph permits the presence of cetyl alcohol and sodium lauryl sulphate which are necessary to stabilize the dispersion. Page 15 2.5 ENTERIC POLYMERS As will be seen later, enteric polymers are designed to resist the acidic nature of the stomach contents, yet dissolve readily in the duodenum. 2.5.1 Cellulose acetate phthalate (CAP) Substituent groups (Fig. 2.2): —CO—CH 3 , —CO—C 6 H 4 —COOH This is the oldest and most widely used synthetic enteric coating polymer patented as an enteric agent by Eastman Kodak in 1940. It is manufactured by reacting a partial acetate ester of cellulose with phthalic anhydride. In the resulting polymer, of the free hydroxyl groups contributed by each glucose unit of the cellulose chain, approximately half are acylated and one-quarter esterified with one of the two carboxylic acid groups of the phthalate moiety. The second carboxylic acid group being free to form salts and thus serves as the basis of its enteric character. Table 2.4 Methacrylate ester copolymers (after Lehmann & Dreher, 1981) Scientific name n 1 :n 2 :n 3 MW USNF designation a Eudragit type Marketed form Poly(ethylacrylate, methylmethacrylate 2:1 800 000 None NE30D 30% aqueous dispersion Poly(ethylacrylate, methylmethacrylate) trimethylammonioethylmethacrylate chloride 1:2:0.2 150 000 Type A RL12.5 12.5% solution in isopropanol/acetone RL100 Granulate R=CH 2 —CH 2 —N + (CH 3 ) 3 Cl − RL30D 30% aqueous dispersion Poly(ethylacrylate, methylmethacrylate) trimethylammonioethylmethacrylate chloride 1:2:0.1 150 000 Type B RS12.5 12.5% solution in isopropanol/acetone RS100 Granulate R=CH2—CH 2 —N + (CH3)3Cl − RS30D 30% aqueous dispersion a Ammoniomethacrylate co-polymer [...]... (data from the Handbook of Pharmaceutical Excipients, 1986) 2.6 POLYMER CHARACTERISTICS 2.6.1 Solubility Inspection of the solubility characteristics of the film -coating polymers show that the following have a good solubility in water: HPMC, HPC, MC, PVP, PEG plus gastrointestinal fluids and the common organic solvents used in coating Acrylic polymers used for conventional film coating include methacrylate... temperature coating media in order to additionally increase solids loadings via a decrease in viscosity 2.6.2 Permeability One of the reasons for coating tablets is to provide a protection from the elements of the atmosphere such that a shelf-life advantage for the product may be gained With the continuing change from sugar- to film-based coating has come associated problems of stability due to sugar -coating. .. solvent for film coating it is necessary to consider, first, the need to minimize contact between the tablet core and water and, secondly, the need to achieve a reasonable process time Both can be achieved by using the highest possible polymer concentration (i.e the lowest possible water content) The limiting factor here is one of coating suspension viscosity 2.6.2 Viscosity HPMC coating polymers,... applications, which have included • A seal coat for tablet cores prior to sugar coating • An enteric -coating material This application is really of historic interest only as shellac has a relatively high apparent pKa of between 6.9 and 7.5 and leads to poor solubility of the film in the duodenum (Chambliss, 1983) • A modified release coating For all these applications, shellac suffers from the general drawback... opposed to examination of a film produced under the actual conditions of coating Both arguments have been reviewed by Aulton (19 82) Suffice it to say that much useful data can be obtained relatively easily from isolated films which, in practice, has demonstrated the validity of such techniques A typical stress-strain curve for a coating polymer is shown in Fig 2.4 From this, several definitions become... stress within a film coating This is accomplished by the effect of the plasticizer on the modulus of elasticity of the film (Rowe, 1981) This aspect 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 dosage form need to be mechanically tough in order that the coating is not inadvertently... involved in the separation of two parallel surfaces separated by a thin film of liquid Such considerations are important during the coating process as 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 the formula have a part to play in combating the effects... most important parameter here is the ultimate tensile strength, which is the maximum stress applied at the point at which the film breaks Fig 2.4 Typical stress-strain curve for a coating polymer (after Aulton et al., 19 82) Page 24 • 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... properties is a well-under-stood phenomenon in polymer science and is not confined to tablet -coating polymers Generally, as molecular weight increases so does the strength of the film Ultimately a limiting value is reached, and Rowe (1980) has quoted this molecular weight value as 7–8×104 for the commonly used tablet -coating polymers In addition, increases in polymer molecular weight result in the polymer... weight result in the polymer film becoming successively more rigid owing to associated increases in the modulus of elasticity Page 25 Table 2.6 Mechanical properties of polymers for film coating of drugs σR (N/mm2)
R (%) HP-50 39 12 HP-55 33 6 CMEC (Duodcell)d 11 5 CAP+25% DEP 16 14 Pharmacoat 606 44 13 Pharmacoat 603e 22 3 Methocel E5e 24 4 MA-MMA 1:2 = Eudragit S100 52 3 MA-MMA 1:1=Eudragit L100 . before the next portion of coating is received. This activity will of course be repeated many times until the coating is complete. Film -coating formulations. (1989a). 2.3 POLYMERS FOR CONVENTIONAL FILM COATING The term conventional film coating has been used here to describe film coatings applied for reasons of improved