The formulation of drugs into soft gelatin capsules has gained popularity throughout the past decade due to the many advantages of this dosage form. The bioavailability of hydrophobic drugs can be significantly increased when formulated into soft gelatin capsules.1,2 Many problems associated with tableting, including poor compaction and lack of content or weight uniformity, can be eliminated when a drug is incorporated into this dosage form.3 Improved stability of drugs that are highly susceptible to oxidation can be achieved when formulated into a soft gelatin capsule.4
Solid dosage forms containing drugs that are susceptible to degradation in the stomach due to the acidic environment or gastric enzymes have been stabilized with an enteric film coating. A decrease in gastric irritation caused by drugs, such as aspirin, can also be achieved by enterically coating the solid dosage form.5 In addition, enteric coatings can be used to target drug release in the small intestine.6 Enteric coating of soft gelatin capsules combines the advantages of the delivery system with the protective properties of the film coating. However, the physicochemical properties of the gelatin and capsule shell present significant challenges to the pharmaceutical scientist when film coating soft gelatin capsules with enteric polymers.
ENTERIC POLYMERS USED FOR FILM COATING OF SOLID DOSAGE FORMS
Enteric polymers currently used to coat pharmaceutical dosage forms include cellulose, vinyl, and acrylic derivatives. These polymers exhibit resistance to gastric fluids yet are readily soluble or permeable in intestinal fluid. Enteric polymeric materials are primarily weak acids containing acidic functional groups, which are capable of ionization at elevated pH. In the low pH of the stomach, the enteric polymers are unionized, and therefore, insoluble. As the pH increases in the intestinal tract, these functional groups ionize, and the polymer becomes soluble in the intestinal fluids. Thus, an enteric polymeric film coating allows the coated solid to pass intact through the stomach to the small intestine, where the drug is then released for absorption through the intestinal mucosa into the human body where it can exert its pharmacologic effects.
Cellulose acetate phthalate (CAP) was synthesized in 1940 by Hiatt and was one of the first polymers used for its enteric properties.7 The CAP polymer exhibits rapid dissolution at a pH greater than 6 and is relatively permeable to moisture and gastric juices. Due to its high moisture permeability, CAP is susceptible to hydrolytic decomposition. Phthalic and acetic acid molecules may hydrolyze during storage and significantly compromise the degree of enteric protection that the film coating provides. The addition of a plasticizing agent has been shown to improve the water resistance of CAP films.8 The CAP polymer is commercially available from FMC Biopolymer under the proprietary name Aquacoat® CPD.
Polyvinyl acetate phthalate (PVAP) is another enteric polymer commonly used to coat solid dosage forms. This polymer is structurally similar to CAP containing the dicarboxylic phthalic acid in a partially esterified form. Faster release of drug components occurs with PVAP because dissolution of this polymer occurs at a pH of approximately 5.0. Due to its lower moisture permeability, PVAP is relatively more stable to hydrolysis than CAP. PVAP is commercially available from Colorcon under the proprietary name Sureteric®.
Several derivatives of hydroxypropyl methylcellulose (HPMC) also exhibit pH dependent solubility. Shin-Etsu Chemical Co., Ltd. esterified HPMC with phthalic anhydride to produce hydroxypropyl methylcellulose phthalate (HPMCP), which rapidly dissolves in the upper intestinal tract. Due to the limited compatibility of HPMCP with several types of plasticizers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was developed. The presence of ionizable carboxyl groups in the HPMCAS structure cause the polymer to solubilize at high pH (> 5.5 for the LF grade and > 6.8 for the HF grade). This polymer exhibits good compatibility with a variety of plasticizing agents and is commercially available from Shin-Etsu Chemical Co. Ltd. under the proprietary name AQOAT® in a powdered form to be redispersed in water.
In the mid 1960s, Lehmann and Dreher developed copolymers of methyl methacrylate and ethyl acrylate as ester components with methacrylic acid for use as enteric polymers.9 These polymers are produced by an emulsion polymerization process and are commercially available in several forms. The dissolution properties of these polymers are dependent on the content of carboxyl groups in the polymer. These acrylic derivatives are commercially available from Degussa Röhm America under the proprietary name Eudragit®. Eudragit L 30 D-55 is an aqueous-based dispersion containing USP/NF methacrylic acid copolymer Type C and exhibits dissolution above pH 5.5. Acryl-Eze®, commercially available through Colorcon, is a relatively new fully formulated acrylic enteric coating system based on spray-dried USP/NF methacrylic acid copolymer Type C, containing plasticizer(s), pigment(s), and neutralizing agents in a powder form for redispersion in water. Eudragit FS 30 D is an aqueous-based acrylic polymeric dispersion consisting of methacrylic acid, methyl acrylate, and methyl methacrylate. This polymer contains fewer carboxyl groups and thus dissolves at a higher pH (> 6.5).
CHALLENGES IN ENTERIC COATING SOFT GELATIN CAPSULES
Challenges encountered during enteric coating of soft gelatin capsules are often attributed to the properties of the gelatin and the dosage form. Soft gelatin capsules generally contain the medicament dissolved or dispersed in oils or hydrophilic liquids (ie, fill liquid). The inherent flexibility of the soft gelatin capsule is due to the presence of plasticizers and residual moisture in the capsule shell. Thus, the soft gelatin capsule is a more dynamic system than conventional tablets. As shown in Figure 1, atmospheric moisture may permeate into the capsule shell or into the fill liquid. The drug or fill liquid may migrate into the capsule shell, while the plasticizer or residual water in the gelatin shell can potentially migrate into the fill. Volatile components in soft gelatin capsules may escape into the atmosphere. It is these characteristics that must be considered when enteric coating soft gelatin capsules.
Polymeric coatings are generally applied as aqueous-based solutions or dispersions, in which polymer-containing droplets are atomized with air and sprayed onto the substrates. Heat is generally added to the coating equipment to facilitate evaporation of the solvent and film formation. Thus, the processing parameters of spray rate and bed temperature are critical in the coating of soft gelatin capsules. Because gelatin is soluble in water, spraying the aqueous-based polymeric material at a high rate could lead to solubilization of the gelatin and capsule agglomeration. A high bed temperature may result in the evaporation of residual water from the capsule shell, causing the capsule to become brittle.
Soft gelatin capsules must be prewarmed prior to the initiation of the coating process. In the study reported by Felton et al, without this prewarming stage, soft gelatin capsules were very cold to the touch after coating.10 The outer layers of the film appeared to dry faster than the inner layers, causing bubble formation in the coating. Warming the capsules in the perforated coating pan increased the temperature of the fill liquid to that of the bed temperature, and allowed the coating to dry more uniformly, resulting in a smooth, homogenous film. Pissinati and Oliveira also suggested prewarming of soft gelatin capsules prior to coating in a spouted bed process.11
As discussed previously, soft gelatin capsules are dynamic systems, with components in the liquid or semi-liquid state capable of diffusional movement. The application of an enteric film coating adds to the complexity of this dosage form. Polymeric films are generally considered brittle, and the addition of a plasticizer is critical to obtain films free of cracks and other defects. The plasticizers in the coating are also capable of diffusional movement into the capsule shell, causing further plasticization and softening of the capsule. Moreover, the plasticizer or residual water in the capsule shell can migrate into the film coating, resulting in further plasticization of the polymer and creating a tacky surface. Finally, the fill material inside the capsule is also capable of permeating through the capsule shell into the polymer film. The migration of these various components, especially during storage, can influence the enteric performance or mechanical strength of the coated capsules.12 The application of a barrier film as a subcoat may minimize the potential interaction between the capsule shell and the enteric film coating. Subcoats may also improve polymer adhesion to the capsule shell.
Influence of Plasticizer & Fill Liquid on Enteric Performance
The addition of a plasticizer in a polymeric film system is generally necessary for the formation of smooth films that are free of cracks and other defects. Plasticizers function by weakening the intermolecular attractions between the polymer chains. These additives have been shown to influence various polymer properties, including the mechanical, adhesive, and drug-release characteristics.13-15 The effects of two plasticizers, triethyl citrate (TEC) and tributyl citrate (TBC), on the physical and enteric properties of soft gelatin capsules coated with Eudragit L 30 D-55 were studied.10 Size 6 oblong capsules containing ibuprofen dissolved in either hydrophilic polyethylene glycol (PEG 400) or hydrophobic Miglyol® 812 were used in the study. The disintegration results of this study are presented in Table 1. The water-soluble plasticizer TEC was found to be a good plasticizing agent for the Eudragit L 30 D-55 irrespective of the fill liquid, while the TBC provided satisfactory results only for capsules containing the hydrophobic fill liquid, Miglyol. The combination of TEC and TBC also provided effective plasticization for the acrylic coating regardless of the fill liquid.
Influence of Plasticizer & Fill Liquid on Mechanical Strength
The coating of soft gelatin capsules significantly alters the mechanical properties of the dosage form, causing the capsules to become less elastic.11 The plasticizing agent incorporated into the film coating, the fill liquid inside the capsule shell, and the amount of polymer coating all have been shown to influence the mechanical strength of the coated soft gelatin capsules. In a study conducted by Felton et al, size 7 round soft gelatin capsules were coated with Eudragit L 30 D-55 and subjected to diametral compression experiments.12 Force-deflection curves were obtained and mathematically manipulated to yield stress-strain diagrams. Figure 2 shows the stress-strain diagrams of the capsules as a function of the plasticizing agent incorporated into the acrylic coating. Both the tensile strength and tensile toughness (area under the stress-strain curve) of the capsules coated with the TEC-plasticized polymer were significantly greater than the TBC-plasticized coated capsules, suggesting that the hydrophilic TEC is a better plasticizer for the acrylic films.
Influence of Plasticizer & Fill Liquid on Polymer Adhesion
Good adhesion between a polymer and the surface of a solid is a major prerequisite for the film coating of pharmaceutical dosage forms.16,17 Loss of adhesion may lead to an accumulation of moisture at the film-capsule interface, significantly affecting the stability of drugs susceptible to degradation by hydrolytic mechanisms.18 Loss of adhesion may also compromise the mechanical protection that the film coating provides to the solid substrate.19 In addition, experiments on adhesion will be useful to the pharmaceutical scientist during preformulation studies to investigate the relationship between the capsule shell and polymeric film coating formulations.
The two major forces that have been found to affect polymer-tablet adhesion include the strength of the interfacial bond and the internal stresses within the film coating. For pharmaceutical products, hydrogen bond formation is the primary type of interfacial bonding mechanism. Dipole-dipole and dipole-induced dipole interactions also occur, however, to a lesser extent. Factors that affect the type or the number of bonds formed between the polymer and the solid surface will influence film adhesion.
The second major factor influencing polymer adhesion is the internal stress within the film. When a polymeric solution or dispersion is applied to a substrate, an internal stress inevitably develops within the film.20 The total stress within a film is the sum of all the stresses acting on the polymer, including stress due to shrinkage of the film on evaporation of the solvent, thermal stress due to the difference in thermal expansion of the film and the substrate, and volumeric stress due to the change in volume when a substrate swells during storage.
Felton et al used diametral compression experiments as a qualitative measure of polymer-capsule adhesion.12 The results demonstrated that in most cases, the gelatin shell and the film coating fractured simultaneously, usually at the seam of the capsule, indicating good adhesion between the polymer and the gelatin, as shown in Figure 3a. In contrast, PEG-containing capsules coated with the TBC-plasticized acrylic polymer showed poor adhesion, as evidenced by the fracture of the film coating followed by the rupture of the capsule shell, as shown in Figure 3b. The authors attributed the poor adhesion to higher internal stresses within the film coating. In another study conducted by Pissinatti and Oliveira, poor adhesion of an acrylic enteric polymer to soft gelatin capsules, as determined by two-point failure during compression experiments, was also attributed to high internal stress in the film due to inadequate plasticization of the coating.11
Stability of Enteric Coated Soft Gelatin Capsules
Temperature and humidity have been shown to influence stability of nearly all drugs and drug products. Enteric-coated soft gelatin capsules are particularly susceptible to environmental storage conditions due to the dynamic nature of the dosage form. Storage of coated capsules at high humidity may result in agglomeration of the product.
The mechanical strength of coated soft gelatin capsules has been shown to be directly proportional to the moisture content of the capsules.10 In another study, the acrylic polymer plasticized with TBC and coated on to soft gelatin capsules containing PEG 400 exhibited an increased adhesion of the polymer to substrate over time when stored at both high temperature and high humidity.12 The authors attributed these findings to the migration of PEG 400 from the capsule into the polymer film where it functioned to plasticize the polymer. Thus, the internal stresses within the film decreased, allowing for more interfacial interactions and improved adhesion.
ENTERIC-COATED HARD GELATIN CAPSULES
Hard gelatin capsules are similar to soft gelatin capsules in that both dosage forms contain gelatin. Thus, it is not surprising that some of the same problems encountered in enteric coating soft gelatin capsules have been reported with coating the hard shell capsules. Hard gelatin capsules rely solely on residual water in the shell for their mechanical strength and may therefore be more likely to become brittle during the coating process due to water evaporation. In addition, the two-piece design of hard gelatin capsules has caused problems in the film-coating process due to the separation of the cap and body, resulting in the polymeric dispersion gaining entrance into the fill powder. Banding the capsule shell has been shown to prevent separation of the capsule halves and markedly improve enteric protection.21 Other reported problems encountered during enteric coating of hard gelatin capsules have been related to adhesion and stability.22,23 The use of capsule shells made of alternative materials, such as hydroxypropyl methylcellulose or starch, may improve polymer adhesion and lessen the impact of moisture content on capsule shell strength.6
The physical properties of gelatin and the dynamic nature of the soft gelatin capsule present unique challenges to enteric coating. Special attention must be given to the processing parameters used, and the capsules should be prewarmed prior to coating. The plasticizer in the coating material may influence the mechanical, adhesive, and disintegration properties of the coated capsule. During storage at elevated humidity, the migration of water from the atmosphere can cause agglomeration of the capsules. Diffusion of the fill material into the polymeric film may also occur during storage.
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- Schettler T, Paris S, Pellett M, Kidner S, Wilkinson D. Comparative pharmacokinetics of two fast-dissolving oral ibuprofen formulations and a regular release ibuprofen tablet in healthy volunteers. Clin Drug Invest. 2001;21:73-78.
- Seager H. Soft gelatin capsules: a solution to many tableting problems. Pharm Tech. 1985;9:84-104.
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- Felton LA, Haase MM, Shah NH, Zhang G, Infeld MH, Malick AW, McGinity JW. Physical and enteric properties of soft gelatin capsules coated with Eudragit® L 30 D-55. Int J Pharm. 1995;113:17-24.
- Pissinati R, Oliveira P. Enteric coating of soft gelatin capsules by spouted bed: effect of operating conditions on coating efficiency and on product quality. Eur J Pharm Biopharm. 2003;55:313-321.
- Felton LA, Shah NH, Zhang G, Infeld MH, Malick AW, McGinity JW. Physical-mechanical properties of film-coated soft gelatin capsules. Int J Pharm. 1996;127:203-211.
- Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and insoluble plasticizers on the physical and mechanical properties of acrylic resin copolymers. Int J Pharm. 1994;103:293-301.
- Felton LA, McGinity JW. Influence of plasticizers on the adhesive properties of an acrylic resin copolymer to hydrophilic and hydrophobic tablet compacts. Int J Pharm. 1997;154:167-178.
- Amighi K, Moes A. Influence of plasticizer concentration and storage conditions on the drug release rate from Eudragit RS-30D film coated sustained release theophylline pellets. Eur J Pharm Biopharm. 1996;42:29-35.
- Rowe RC. The adhesion of film coatings to tablet surfaces-the effect of some direct compression excipients and lubricants. J Pharm Pharmacol. 1977;129;723-726.
- Felton LA, McGinity JW. Adhesion of polymeric films to pharmaceutical solids. Eur J Pharm Biopharm. 1999;47:3-14.
- Okhamafe AO, York P. The adhesion characteristics of some pigmented and unpigmented aqueous-based film coatings applied to aspirin tablets. J Pharm Pharmacol. 1985;37:849-853.
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- Rowe RC. A reappraisal of the equations used to predict the internal stressed in film coatings, applied to tablet substrates. J Pharm Pharmacol. 1983;35:112-113.
- Felton LA, Friar AL. Enteric coating of gelatin and cellulosic capsules using an aqueous-based acrylic polymer. Pharm Sci. 2002;4:Abstract T3320.
- Thoma K, Bechtold K. Enteric coated hard gelatin capsules. Capsugel Tech Bull. 1986:1-16.
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Dr. James W. McGinity, Professor and Division Head of Pharmaceutics at the University of Texas at Austin, College of Pharmacy, has been issued 20 US patents and currently has 2 US patent applications under review. His past research interests included physical pharmacy and pharmaceutical technology, and his current research focuses on novel drug delivery systems, including solid dosage forms, microencapsulation, powder technology, transdermal systems, and hot-melt extrusion. He has been published extensively in many journals, including Journal of Pharmaceutical Sciences, Pharmaceutical Development and Technology, Journal of Controlled Release, Journal of Microencapsulation, and International Journal of Pharmaceutics. Dr. McGinity has participated in several national and international scientific symposia and conferences, served as a consultant to the FDA and many national and European pharmaceutical and chemical companies, and served as USA Editor for the European Journal of Pharmaceutics and Biopharmaceutics since 1995. He earned his BS in Pharmacy from the University of Queensland, Australia, and his PhD in Physical Pharmacy from the University of Iowa.
Dr. Linda A. Felton is an Associate Professor of Pharmaceutics at the University of New Mexico. She earned her BS in Pharmacy (1986) and her PhD in Pharmaceutics (1997) from the University of Texas at Austin. Her research interests are focused on polymeric film coating technology and topical/transdermal drug delivery. In addition to her academic duties, Dr. Felton has a joint appointment with the Department of Veteran's Affairs Cooperative Studies Program, where she is responsible for the formulation development of oral solids for clinical trials.