INFLUENCE OF ADDITIVES ON ETHYLCELLULOSE COATINGS ONG KANG TENG (B.Sc. (Pharm.)(Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PHARMACY NATIONAL UNIVERSITY OF SINGAPORE 2006 ACKNOWLEDGEMENTS With great gratitude, I wish to thank my respectful supervisors, Associate Professor Paul Heng Wan Sia and Associate Professor Chan Lai Wah for devoting much time and effort in supervising and guiding me in my higher degree pursue. They have given me an education that is worth a lifetime. I could not have carried out my study without the generous financial supports from the National University of Singapore and the use of research facilities in the Department of Pharmacy and GEA-NUS Pharmaceutical Processing Research Laboratory. I wish to thank the laboratory officers in the Department of Pharmacy, especially Teresa and Mei Yin, who have never failed to render me their technical assistance whenever needed. My heartfelt thanks go to all my friends and colleagues in the Department of Pharmacy and GEA-NUS, especially Celine, Tin Wui, Chit Chiat, Liang Theng, Sze Nam, Gu Li, Wai See and Qiyun. They have not only shared with me their valuable experiences but also provided me with their friendship. My parents and siblings have showered me with much love and supports which kept me going, especially through difficult times. This journey has been blessed with many prayerful and spiritual supports of saints both at home and aboard, for whom I thank God for. All thanks and glory be to God the Father and Lord Jesus Christ, to whom I owe all things. Kang Teng Jan 2006 i TABLE OF CONTENTS CONTENTS ACKNOWLEDGEMENTS i CONTENTS ii SUMMARY vii List of Tables xii List of Figures xiv I. INTRODUCTION 1 A. Film coating 1 1. Reasons for coating 1 2. Film coating polymers 1 3. Organic versus aqueous coating systems 4 4. Aqueous coating systems 5 a. Latex and pseudolatex 5 i. Emulsion polymerization 5 ii. Emulsion - solvent evaporation 5 iii. Phase inversion 6 iv. Solvent change 6 b. Suspension 7 B. Mechanism of film formation 7 C. Substrates for film coating 9 D. Drug release mechanisms of coated pellets 10 1. Diffusion - controlled systems 11 2. Swelling - controlled systems 14 3. Chemically - controlled systems 15 4. Osmotically - driven release systems 16 ii TABLE OF CONTENTS E. Performance of film-coated products 17 1. Substrate 17 2. Coating formulation 19 a. Nature of the polymer 19 i. Cellulose derivatives 20 ii. Acrylic polymer 22 b. Additives 23 i. Plasticizers 23 ii. Colorants and opacifiers 29 iii. Surfactants 30 iv. Anti-tack agents 30 v. Hydrophilic additives 31 3. Coating process variables 31 F. Analysis and comparison of dissolution data 35 1. Zero order equation 36 2. First order equation 37 3. Hixson – Crowell equation 37 4. Higuchi equation 38 5. Baker and Lonsdale equation (Higuchi's model for spherical matrices) 40 6. Hopfenberg equation 40 II. OBJECTIVES 45 Part 1. 46 Part 2 47 III. EXPERIMENTAL 50 A. Materials 50 iii TABLE OF CONTENTS 1. Drugs, polymers and additives 50 B. Methodology 53 1. Preparation of film forming dispersions 53 a. EC and acrylic dispersions containing plasticizers 53 b. EC dispersions containing polymeric additives 53 2. Preparation of films 53 3. Evaluation of film properties 54 a. Surface morphology 54 b. Film transparency 55 c. Mechanical properties 55 d. Puncture test 56 e. Plasticizer content 57 f. Percent weight change of film 58 g. Moisture content 58 h. Water vapour permeability 59 i. Thermal properties 60 Glass transition temperature 60 Thermal mechanical spectra 61 j. Drug permeability 62 k. Swelling and leeaching of film 65 4. Preparation of pellets 66 5. Coating of pellets 67 a. Coating with Aquacoat 67 b. Coating with Surelease 68 6. In vitro dissolution studies 69 iv TABLE OF CONTENTS 7. Assay of drug content in coated pellets 69 IV. RESULTS AND DISCUSSION 70 Part 1. Influence of plasticizers and storage conditions on properties of films 70 A. Film morphology 70 B. Mechanical properties of films 73 1. Comparison between different polymeric films 73 2. Influence of plasticizers on properties of films 74 3. Influence of storage time on properties of films 75 4. Influence of storage humidity on properties of films 84 5. Water vapour permeability 87 C. Drug release 88 1. Influence of plasticizer on dissolution profiles of pellets coated with Aquacoat 88 2. Influence of storage conditions on dissolution profiles of pellets coated with plasticized Aquacoat 92 a. Citric acid esters (TEC and ATEC) 92 b. Phthalic acid esters (DEP) 101 c. Glycerol acid ester 104 3. Effect of storage temperature on drug release 107 Part 2. Influence of polymeric additives 109 A. Thermal and dynamic mechanical properties 109 B. Film morphology 121 C. Mechanical properties - tensile test 126 D. Mechanical properties - puncture test 131 E. Water vapour permeability 135 F. Drug permeability 137 v TABLE OF CONTENTS 1. Effect of polymer additives on drug permeability 138 2. Effect of drug properties on drug permeability 147 G. Correlation between physicomechanical properties and permeability of composite EC films 149 H. Release kinetics of pellets coated with EC and polymeric additives 151 1. Effect of coating levels on drug release from EC - coated pellets 151 2. Effect of curing on EC - coated pellets 161 3. Influence of PVP on EC - coated pellets 164 4. Effect of curing on drug release from EC-PVP coated pellets 181 5. Influence of PV/VA on drug release from EC - coated pellets 183 V. CONCLUSION 188 VI. REFERENCES 193 VII. APPENDICES 207 Symbols 207 Published communications and presentations 211 vi SUMMARY SUMMARY Many polymeric film coats applied onto dosage forms have been reported to undergo changes in mechanical properties upon storage. The extent of these changes is influenced by several factors, such as the amount of plasticizers added, type of plasticizers used, film forming conditions, film storage temperature and humidity. Changes in film mechanical properties may ultimately influence the drug release, stability and other physicochemical properties of the coated dosage forms. Ethylcellulose and acrylates are among the most commonly used polymers in the production of coated controlled-release dosage forms. Several researchers have studied the effects of different types of plasticizers on the mechanical properties of Aquacoat films. Plasticizers, such as dibutyl sebacate, tributyl citrate, acetyl tributyl citrate and oleyl alcohol were found to produce ethylcellulose films that showed greater elongation upon stretching, after the films had been stored under conditions of elevated humidity. However, the actual mechanisms that caused the above change and the extent of influence by the different types of plasticizers have not been reported. The primary objective of this study was to investigate the effects of different types of plasticizers on the stability and other properties of the films exposed to different storage conditions. Attempts were made to elucidate the mechanisms responsible for the changes observed and correlate these changes in film properties to the release profiles of coated pellets. This study demonstrated that ethylcellulose film stability is influenced by several factors, including type and amount of plasticizers remaining in the film, as well as the storage conditions. Plasticizers interact with ethylcellulose and affect its film properties primarily in the following three ways. Firstly, plasticizers with low permanence, such as glycerin triacetate and diethyl phthalate can cause formation of vii SUMMARY brittle films as these plasticizers are volatile or degrade on extended storage. Secondly, the extent of coalescence or ageing on ethylcellulose films varies with different plasticizers. In addition, the stability of ethylcellulose films under different storage conditions is also dependent on type of plasticizers used. At a commonly applied concentration of 30 percent, the citrate ester plasticizers, particularly triethyl citrate, have been shown to interact well with Aquacoat, while glycerin triacetate and diethyl phthalate were not able to plasticize Aquacoat films as effectively. Exposing the film membrane to low humidity or high temperature accelerates loss of bound water, thus enhancing the coalescence or fusion of polymer molecules. Storage environments with high moisture content, on the other hand could delay and reduce the coalescence of films but not prevent it. With the exception of glycerin triacetate, chlorpheniramine release from pellets coated with plasticized Aquacoat films were affected to varying degrees by storage conditions. Higher storage temperatures tend to cause greater changes for pellets coated with Aquacoat containing citric acid class of plasticizers (triethyl citrate and acetyl triethyl citrate) compared to other plasticizers. This study demonstrated that the physicochemical properties of the plasticizer coupled with the storage conditions have an important influence on the stability and performance of the final film coat. Hence it is important to exercise caution in the selection of plasticizers for film coating in order to ensure good product stability and performance. Ethylcellulose is used in controlled released preparations because of its good mechanical properties and poor permeability to water vapour. However, these properties strongly retard drug release and thereby limit the application of pure ethylcellulose coating as controlled release coating. Studies were undertaken to modify drug permeability through ethylcellulose coatings