EVALUATION OF NEW FILM COATING PROCESSES AND MATERIALS Inaugural-Dissertation zur Erlangung der Doktorwurde im Fachbereich Biologie, Chemie, Pharmazie der Freien Universitat Berlin vorgelegt von NANTHARAT PEARNCHOB Berlin 2002
TABLE OF CONTENTS Page CHAPTER 1. Introduction 1 1 Single Unit Dosage Forms.-. 2 1.1 Tablets 2 1.1.1 Protective and Insulating Coatings for Tablets 2 1.1.2 Extended Release Matrix Tablets with Enteric polymers 3 1.2 Soft Gelatin Capsules 4 2 Multiparticulates 6 2.1 Therapeutic and Biopharmaceutical Advantages 6 2.2 Technological Advantages 8 2.3 Polymeric Coatings for Pellets 9 3 Shellac 9 3.1 General Background 9 3.2 Extraction and Production Processes 10 3.3. Physicochemical Properties of Shellac 11 3.4 Polymer Compatibility and Plasticization of Shellac Films 14 3.5 Shellac for Pharmaceutical Applications 15 4 Ethylcellulose 17 4.1 General Background 17 4.2 Solubility Parameters of Ethylcellulose 18 4.3 Ethylcellulose Solubility Diagrams 20 4.4 Solvents for Ethylcellulose 23 4.5 Ethylcellulose for Pharmaceutical Applications 26 5 Polymeric Coating Systems 27 5.1 Organic Polymer Solutions 28 5.2 Aqueous Polymer Solutions 30 5.2.1 Water-Soluble Polymers 30 5.2.2 Enteric Polymers 31 5.3 Aqueous Colloidal Polymer Dispersions 32 5.3.1 Latex Film Formation 32 5.3.2 Theoretical Aspects 34
5.4 Aqueous Micronized Polymer Dispersions 39 5.5 Dry Polymer Powders 41 6 Plasticizers for Polymeric Coatings 43 7 Research Objectives 49 CHAPTER 2. Materials and Experimental Procedures 52 1 Materials 52 2 Experimental Procedures 55 2.1 Neutralization Studies 55 2.2 Preparation of Polymer Solutions and Dispersions 56 2.3 Physical-Mechanical Properties of Polymeric Films 59 2.3.1 Preparation of Polymeric Films 59 2.3.2 Determinations of Water Content and Weight loss 59 2.3.3 Measurements of Mechanical Properties 60 2.4 Investigation of Pellets 61 2.4.1 Preparation of Drug-Loaded Pellets 61. 2.4.2 Coating of Pellets 62 2.4.3 Thermal treatment (Curing) of Pellets 65 2.5 Investigation of Soft Gelatin Capsules 65 2.5.1 Coating of Soft Gelatin Capsules 65 2.5.2 Disintegration Studies 66 2.5.3 Hardness of Coated Soft Gelatin Capsules 66 2.5.4 Medium Uptake of Coated Soft Gelatin Capsules 66 2.5.5 Moisture Uptake of Coated Soft Gelatin Capsules 67 2.6 Investigation of Tablets 67 ' 2.6.1 Preparation of Tablets 67 2.6.2 Coating of Tablets 68 2.6.3 Evaluation of Taste Masking Ability 69 2.6.4 Moisture Uptake and Drug Stability Studies 69 2.7 Plasticizer Soaking for Ethylcellulose Powder 70 2.8 Dissolution Studies 70 2.9 Thermal Analysis 71 2.10 Measurements of Minimum Polymer-Softening Temperature 72 ii
2.11 Particle Size Measurements 72 2.12 Scanning Electron Microscopy 72 2.13 Solubility Determinations of Polymers 73 2.14 Solubility of the Organic Acids 73 2.15 Contact Angle Measurements.-. 74 2.16 Liquid Penetration Experiments 74 CHAPTER 3. Results and Discussion 77 1 Pharmaceutical Applications of Shellac 77 1.1 Investigation of Shellac as Enteric Coating Material: Ethanolic Solution 78 1.1.1 Film Properties of Shellac 77 1.1.2 Ethanolic Shellac-Coated Pellets 82 1.1.3 Ethanolic Shellac-Coated Soft Gelatin Capsules 89 1.1.4 Film Properties of Synthetic Enteric Polymers 93 1.2 Investigation of Shellac as Enteric Coating Material: Aqueous. Solution 97 1.2.1 Properties of Aqueous-Cast Shellac Films 98 1.2.2 Aqueous Shellac-Coated Pellets 102 1.2.3 Aqueous Shellac-Coated Soft Gelatin Capsules 102 1.3 Improvement in the Disintegration of Shellac-Coated Soft Gelatin Capsules in Simulated Intestinal Fluids 109 1.3.1 Ethanolic Shellac Coating Ill 1.3.2 Aqueous Shellac Coating 118 1.4 Pharmaceutical Applications of Shellac: Moisture Protective and Taste / Masking Coatings and Extended Release Matrix Tablets 121 1.4.1 Moisture Protective Polymer Coatings 121 1.4.2 Taste Masking Polymer Coatings 128 1.4.3 Extended Release Matrix Tablets 131 2 Dry Powder Coating 137 2.1 Dry Powder Coating of Pellets with Eudragit RS for Extended Drug Release 137
2.2 Coating of Pellets with Micronized Ethylcellulose Particles by a Dry Powder Technique 152 2.3 Formulation and Processing Variables of Dry Powder Coating and Comparison with Conventional Coatings: Eudragit RS, ethylcellulose, shellac, 167 3 Phthalate-Free Coating Materials 186 3.1 Extended Release Coated Dosage Forms with Ethylcellulose Containing Phthalate-Free Plasticizers 186 3.1.1 Ethylcellulose and Plasticizer Compatibility 187 3.1.2 Thermal Properties of Ethylcellulose 191 3.1.3 Coating Formulations for Pellets Coated with Ethanolic Ethylcellulose Solution 194 3.1.4 Drug Release from Ethanolic Ethylcellulose-Coated Pellets 198 3.1.5 Drug Release from Aqueous Ethylcellulose-Coated Pellets 205 CHAPTER 4. Summary and Conclusions 209 CHAPTER 5. References 217 CHAPTER 6. Appendix. 242 CHAPTER 7. Publications 244 CHAPTER 8. Curriculum Vitae 247 iv