Film Coating with Aqueous Latex Dispersions

General Considerations for Formulating with Pigments

Nasser Nyamweya, Stephen W. Hoag, and Ketan A. Mehta*

Latex dispersions have proved to be very useful in aqueous-based film coating, especially in controlled-release applications. Film coatings commonly are colored with pigments to provide a means of product identification and to enable the manufacturer to distinguish similar products. Colored films allow the manufacturer to impart a distinct appearance to the dosage form, which is useful from a marketing standpoint. The use of pigments in film coatings also facilitates patient recognition and makes the product aesthetically appealing. Because both the latex polymer and pigment particles exist in the colloidal or near-colloidal state, interactions caused by surface properties may sometimes lead to unstable formulations. This article examines some of the issues that are important to consider when formulating latex dispersions with pigments.

Nasser Nyamweya is a graduate student and Stephen W. Hoag, PhD, is an associate professor in the Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy. Ketan A. Mehta, PhD, is a technical services manager at Rhm Pharma Polymers, Degussa Corporation, 2 Turner Place, Piscataway, NJ 08855, tel. 732.981.5366, fax 732.981.5484, ketan.mehta@rohmamerica.com.
*To whom all correspondence should be addressed.

ilm coating is a unit process that may serve one or more of the following functions: to mask odor or taste; to ease the swallowing of the dosage form; to improve mechanical integrity; to enhance product identification and elegance; to improve product stability; and to modulate the release properties (e.g., sustained-release and enteric coatings). With the decline of organic solventbased systems, aqueousbased film coating is currently the method of choice for film coating solid dosage forms. The introduction of latex-based systems has resulted in film coating formulations with lower viscosities and decreased coating times, even with high polymer (solids) contents, compared with aqueous solventbased systems. In addition, latex systems have facilitated coating through the use of water-insoluble polymers to modify the release characteristics of the dosage form (1). Latexes are aqueous polymeric dispersions in which the polymer particles typically have a submicron particle-size distribution. Therefore, they are subject to the factors that can influence the stability of colloids. The addition of electrolytes, pigments, pH changes, temperature changes, or high-shear forces can lead to irreversible coagulation, and such systems must be discarded (2). Lehmann has discussed how the effects of several of these factors on latex stability can be minimized (2). The formulation of stable film coating formulations requires an understanding of the factors that are important to latex stability (see Table I). Film coatings commonly are colored for identification and aesthetic purposes. Despite the widespread use of pigments in film coating, very few papers have been published in pharmaceutical literature about the aspects regarding their formulation. Some authors have reported that the addition of pigments can result in latex coagulation (2,3). The interactions leading to coagulation of aluminum lake pigments and Eudragit latex dispersions were the subject of a recent paper (4). This article aims to provide an overview of some of the factors that should be considered when formulating latex dispersions with pigments for the film coating of solid dosage forms.

Regulation
All color additives used in the United States are regulated by FDA and must meet certain specifications before they are sold (5). In
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Stern layer

Diffuse layer Bulk medium

Distance from surface Shear plane

Figure 1: Variation of potential from the surface of a colloidal particle to the bulk medium. Symbols: zeta potential, 0 surface potential.

addition, color additives may be either certified (by batch) or exempt from certification. The most commonly used colorants for film coating are aluminum lakes, titanium dioxide, and synthetic iron oxides. Aluminum lakes must be certified by FDA. The aluminum lakes that may be used for film coating (or ingested pharmaceuticals in general) fall into two categories FD&C lakes (certified for use in food, drugs, and cosmetics) and D&C lakes (certified for use in drugs and cosmetics). Titanium dioxide and synthetic iron oxides are exempt from certification, although iron oxides have a maximum ingestion limit of 5 mg/day (as elemental iron).

Formulation
Examples of polymers that are available as latex dispersions include cellulose acetate phthalate, ethylcellulose, and several acrylic copolymers. The solids content of these dispersions is typically 2530% (w/w). Table II lists the components of a typical latexbased film coating formulation for colored films from an acrylic

Potential

Surface

copolymer. The polymer and pigment dispersions usually are made separately and mixed together just before coating. This procedure is necessary because dispersing pigments requires the use of high-shear forces that may lead to coagulation of the latex. When mixing the two dispersions, one should slowly add the pigment dispersion to the polymer dispersion while mixing gently (6). Because both the polymer and the pigment are insoluble in water, these formulations are mixed dispersions (systems containing more than one dispersed phase), and the small particle size of the components will enhance the effects of interparticle interactions. In addition to its use as an opacifier, titanium dioxide often is used as a white pigment. When used with colored pigments, several pastel shades of a given color are possible depending on the proportion of titanium dioxide to the other pigments. Bright or dark colors are difficult to obtain when titanium dioxide is used because of its extreme whiteness (7). Talc (used to prevent the dosage form from sticking when the coating is drying and impart a smoothness to the coating) also may serve as an extender or filler. Polyethylene glycol also has surfactant and plasticizing properties. The high-shear forces required to disperse pigments may result in foam formation and air entrapment, thereby necessitating the use of an antifoaming agent such as simethicone. The viscosity of a film coating formulation is an important consideration, although this is less of an issue for latex dispersions because of their relatively low viscosity, which is the result of the undissolved polymer. Because of the low viscosity of these systems, pigments tend to settle, and the formulation should be stirred well during spraying to ensure reproducible and uniform application of the film coating. The type of pump used to deliver the formulation may affect its stability, e.g., the higher pressures or shear forces developed in gear and piston pumps can lead to coagulation of latex-based formulations (8).

Methods for assessing stability

Long-term stability of pigmented film coating formulations is not an issue because the formulations usually are used soon after Table I: Factors important to latex stability. they are made. However, the forFactor Relevance mulation should be stable enough Particle size Submicron particle size is required to prevent settling, but a large to withstand the shear forces that specific surface area facilitates interparticle interactions. are encountered during the spraySurface charge Decreasing surface charge can lead to aggregation; ing processes and stable long zeta potential measurements are useful. enough for the coating to be apSurfactants Used for steric or electrosteric stabilization. plied. Because aggregation usupH Can alter surface properties by changing the ionization ally is manifested by changes in of functional groups and/or the binding of surfactants. the appearance of the film coatViscosity Affects the movement of dispersed particles. ing formulation, visual observaElectrolytes Can destabilize ionic latex dispersions by charge tion may serve as a qualitative neutralization or double-layer compression. measure of stability. For quantiWater-soluble Can stabilize or coagulate latex dispersions depending tative assessments of stability, sevpolymers on nature of interactions and concentration. eral methods are available. These Coagulation occurs by charge neutralization, bridging, include microscopy, particle conor depletion flocculation. tent (e.g., gravimetric and denInsoluble additives Surface charge may lead to interactions with latex; sity measurements), particle-size if opposite in sign, can cause coagulation. analysis, light-scattering techPharmaceutical Technology
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niques (e.g., turbidimetry, laser diffraction, and photon correlation spectroscopy), electrochemical methods (e.g., zeta potential measurements), sedimentation, filtration, and rheology (9). Because of the inherent limitations of each technique, a combination of various techniques often is useful. It is important to note that because latex-based film coating formulations have high solids contents, techniques such as light scattering and zeta potential measurements, which require sample dilution, may give results that do not reflect the state of the original dispersion. Recently, electroacoustic techniques have been developed that can be used to determine the particle size and zeta potential of highly concentrated dispersions (10). Chemical stability can be studied by spectroscopic techniques such as infrared and nuclear magnetic resonance spectroscopy.

M M M

OH OH OH

2 2 2

zeta potential

M M M

OH OH OH pH OH M M M O O O H2O

Surface chemistry
The surface properties of both the latex particles and pigments are important for determining the nature of interparticle interactions. Because of their small size, they behave like colloidal particles. Interactions between colloidal particles depend on the attractive and repulsive forces encountered when the particles interact. Charged particles develop an electrical double layer around their surface so the system can maintain electrical neutrality (see Figure 1). The charged particles attract ions of opposite charge (counter-ions), which are bound strongly to the surface forming the Stern layer. Beyond the Stern layer is the diffuse layer, which consists of counter-ions and ions of a charge similar to the charge on the particle surface. The distribution of ions in this outer layer is more diffuse because of repulsion from the charged surface and the counter-ions in the Stern layer. The existence of the double layer creates a potential that decreases from the surface of the particle until the bulk medium is reached. The zeta potential is the potential at the shear plane (a region in the double layer within which the particle and associated ions move as a unit). The zeta potential is useful for determining how particles interact with one another and for predicting the stability of dispersed colloidal systems. Interparticle interactions that result in coagulation are more likely to occur when the particles have opposite surface charges. In addition, factors that decrease the zeta potential (e.g., electrolytes) also will enhance the likelihood of instability. Stabilization of colloidal particles will involve either providing the

Figure 2: Effect of pH on the zeta potential of a metal (M) oxide or hydroxide.

particles with a sufficiently large like-surface charge, which leads to mutual repulsion; the adsorption of molecules that prevent the particles from approaching each other closely enough for attractive forces to predominate (steric stabilization); or a combination thereof.

Pigment considerations
Pigments are insoluble colorants that color by dispersion, as opposed to dyes that exhibit coloring power when they are dissolved (7). Insoluble colorants have been preferred more than dyes because they do not migrate with the solvent as it evaporates during the drying of the film coating, although recently Signorino et al. have developed uniform nonmottled coatings using dyes with the addition of an immobilizing agent (11). The absence of color migration results in products that are less prone to mottling and easier control of batch-to-batch consistency of the film coating color (12). In addition, pigments tend to be more stable than dyes. Most of the pigments used are (or are based on) metal oxides or hydroxides, e.g., iron oxide, titanium dioxide, and aluminum lakes (aluminum hydroxide substrate). When dispersed in aqueous media, these compounds acquire a surface charge, with H and OH as the potential-determining ions (see Figure 2). Therefore, they may have a positive or a negative surface charge depending on the pH of the medium (9). The isoelectric point (IEP) is the pH at which the zeta po-

Table II: Typical film coating formulation for colored films of an acrylic copolymer.
Polymer Dispersion Latex (30% solids w/w) Plasticizer* Water Example Eudragit RS 30 D TEC** % (w/w) 40 2.4 57.6 Pigment Dispersion Pigment Glidant Opacifier Glossing agent Antifoaming agent Water Example Aluminum lake Talc Titanium dioxide PEG Simethicone emulsion % (w/w) 5 15 7 2 0.1 70.9

For a 20% (w/w) plasticizer content on a polymer dry-weight basis triethyl citrate polyethylene glycol
**

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tential is zero. In systems in which electrostatic repulsion is the sole stabilization mechanism, the particles will be least stable at the IEP because of the absence of repulsive charges. Because pigments are insoluble, their coloring power is a function of how well they are dispersed (13). When pigments are used in powder form, they often tend to agglomerate because of their small particle size and large surface area. The use of suitable dispersion techniques such as high-shear mixers, homogenizers, and/or mills is required to ensure that agglomerates are broken down so that a uniformly colored coating is achieved. If dispersion is a problem, predispersed color concentrates (dispersions) may be used. Lakes are formed by the precipitation and adsorption of a water-soluble dye onto an insoluble substrate such as aluminum hydroxide (7). Several colors are available depending on the type and amount of dye used. The stability of aluminum lakes in aqueous dispersions is pH dependent because of the dissolution of the aluminum hydroxide substrate at high and low pH values (14). The dissolution of the substrate leads to the release of the water-soluble dyes, which are electrolytes because of the presence of ionic functional groups. The dye content of the lake should be considered for two reasons: First, when bleeding occurs, lakes with higher dye contents can release greater amounts of dye, which will have a greater destabilizing effect on latexes that are sensitive to electrolytes. Second, the point of zero charge (the pH at which the surface charge is zero) is related inversely to the dye content (15). Therefore, it is possible that lakes made with the same dye but with different dye contents may interact differently with the same latex. Iron oxides are available in yellow, brown, red, and black. These colorants are prepared by the precipitation of iron salts (black and yellow iron oxides), calcination (red iron oxide), or by blending mixtures of the other iron oxides (brown iron oxide) (5). The synthetic forms of iron oxide are used because of the difficulties involved in purifying the natural forms (5). The color of the film coating may be a function of the particle size of the iron oxide (16,17). In such cases, consistent and reproducible dispersion procedures are required if the same color is to be maintained. Interactions with latex particles (and other particles in the formulation) that lead to coagulation will be favored when the pigments have a surface charge that is opposite to that of the latex particles (4). One way to avoid such interactions is to adjust the pH of the medium to a region in which both the pigment and the latex particles have like charges. Alternatively, surfactants or dispersants may be used. Polyethylene glycol and propylene glycol have been used to prevent the coagulation of methacrylic acidethyl acrylate copolymer latex dispersions, which occurs when the latex is formulated with red iron oxide (3). Sodium carboxymethylcellulose has been used to stabilize methacrylic acidethyl acrylate copolymer latex dispersions that coagulated in the presence of red iron oxide (18). When using water-soluble polymers for stabilization, their effect on the viscosity of the formulation should be taken into account.

anionic, and nonionic) may form unstable formulations in the presence of pigments, as illustrated by the following examples: q Eudragit RS 30 D (poly[ethyl acrylate, methyl methacrylate] trimethylammonioethyl methacrylate chloride, 1:2:0.1) has quaternary ammonium functional groups that are used to stabilize the latex particles without any requirement for surfactants. Because these groups are cationic, this latex is sensitive to the addition of anionic agents such as many of the dyes used to manufacture aluminum lakes. Dissolution of the lakes occurs outside the pH range of 47, which leads to the release of water-soluble dyes that can neutralize the stabilizing quaternary ammonium groups and lead to coagulation of the latex particles (4). However, no coagulation is observed if the pH is kept within the region of lake stability. The dyes can destabilize latex particles of similar charge such as the anionic latex Eudragit L 30 D-55 (poly[methacrylic acid, ethyl acrylate], 1:1) by double-layer compression (4). This is because of the shielding effect of electrolytes on the repulsive electrostatic forces that stabilize this latex. Because Eudragit L 30 D-55 has a pH-dependent surface charge, increasing the pH of the dispersion will increase its zeta potential and make the latex more stable in the presence of electrolytes (4). q Nonionic colloids usually will acquire a negative charge in aqueous media because of the preferential adsorption of OH ions on non-ionogenic colloidal particles because of the ioninduced dipole interaction (19). This can lead to electrostatic interactions, e.g., Eudragit NE 30 D (poly[ethyl acrylate, methyl methacrylate], 2:1) with positively charged lakes, that can result in aggregation (4). These systems can be stabilized by the addition of surface active agents such as ethylenediaminetetraacetic acid, polysorbate 80, or nonoxynol 100 (4,20).

Conclusions
The formulation of pigments with aqueous polymeric latex dispersions can be optimized by understanding the factors that control the stability of the components. In general, the interactions that lead to instability in latex dispersions are of a physical rather than a chemical nature and usually result from differences in the surface charge of the excipients used in the film coating formulation.

References
1. S.C. Porter, Coating of Pharmaceutical Dosage Forms, in Remington: The Science and Practice of Pharmacy, A.R. Gennaro, Ed. (Lippincott Williams and Wilkins, Baltimore, MD, 20th ed., 2000). 2. K. Lehmann, Chemistry and Application Properties of Polymethacrylate Coating Systems, in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, J.W. McGinity, Ed. (Marcel Dekker, New York, NY, 2nd ed., 1997). 3. A. Flosser et al., Variation of Composition of an Enteric Formulation Based on Kollicoat MAE 30 D, Drug Dev. Ind. Pharm. 26, 177187 (2000). 4. N. Nyamweya, K.A. Mehta, and S.W. Hoag, Characterization of the Interactions between Polymethacrylate Latices and Aluminum Lakes in Aqueous Film Coating Formulations, J. Pharm. Sci. (in press). 5. D.M. Marmion, Handbook of US Colorants for Foods, Drugs, and Cosmetics (John Wiley and Sons, New York, NY, 2nd ed., 1984). 6. K. Lehmann, Practical Course in Film Coating of Pharmaceutical Dosage Continued on page 26
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Latex considerations
In certain conditions, latex dispersions of any type (cationic,
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Continued from page 12 Forms with Eudragit (Rhm GmbH, Pharma Polymers, Darmstadt, Germany, 1999). 7. Warner Jenkinson Company, Inc., All About Lake Pigments (Warner Jenkinson Company, Inc., St. Louis, MO, 1999). 8. A.M. Mehta, Processing and Equipment Considerations for Aqueous Coatings, in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, J.W. McGinity, Ed. (Marcel Dekker, New York, NY, 2nd ed., 1997). 9. E. Kissa, Dispersions: Characterization, Test-

ing, and Measurement (Marcel Dekker, New York, NY, 1999). 10. R.W. Obrien, D.W. Cannon, and W.N. Rowlands,Electroacoustic Determination of Particle-Size and Zeta-Potential, J. Colloid Interface Sci. 173, 406418 (1995). 11. C.A. Signorino and H. Meggos, Dye Compositions and Methods for Film Coating Tablets and the Like, US Patent No. 5411746 (May 1995). 12. M.E. Aulton and M.H. Abdul-Razzak, The Mechanical Properties of Hydroxypropyl

13.

14.

15.

16.

17.

18.

19.

20.

Methylcellulose Films Derived from Aqueous Systems: Part 2: The Influence of Solid Inclusions, Drug Dev. Ind. Pharm. 10, 541561 (1984). L.L-S Wou and B.A. Mulley, Effect of Dispersion on the Coloring Properties of Aluminum Lake Dyes, J. Pharm. Sci. 77, 866871 (1988). A. Desai et al., The Effect of Aluminum Hydroxide Dissolution on the Bleeding of Aluminum Lake Dyes, Pharm. Res. 10, 14581460 (1993). A. Desai et al., "Effect of Dye Content on Point of Zero Charge of Anionic Lake Dyes, Drug Dev. Ind. Pharm. 17, 14051409 (1991). R.C. Rowe, The Effect of the Particle Size of Synthetic Red Iron Oxide on the Appearance of Tablet Film Coatings, Pharm. Acta Helv. 60, 56 (1985). J.E. Hogan, Coloring Agents, in Handbook of Pharmaceutical Excipients, A. Wade and P.J. Weller, Eds. (American Pharmaceutical Association, Washington, DC, 2nd ed., 1994). K.A. Maul and P.C. Schmidt, Influence of Different-Shaped Pigments on Bisacodyl Release from Eudragit L 30 D, Int. J. Pharm. 118, 103112 (1995). J.W. Vanderhoff, Theory of Colloids, in Pharmaceutical Dosage Forms: Disperse Systems, Volume 1, H.A. Lieberman, M.M. Rieger, and G.S. Banker, Eds. (Marcel Dekker, New York, NY, 2nd ed., 1996). C.A. Signorino and H. Meggos,Stable, Fluid, Aqueous Pigment Dispersions for Use in Film Coating Tablets and the Like, US Patent No. T 5059248, (October 1991). P

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