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An Investigation of the Properties of Mixtures of Starches with Mono-Myristic Acid Triglyceride As Potential Selectively Digestible Films

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An Investigation of the Properties of Mixtures of Starches with Mono-Myristic Acid Triglyceride As Potential Selectively Digestible Films An Investigation of the Properties of Mixtures of Starches with Mono-Myristic Acid Triglyceride as Potential Selectively Digestible Films. A dissertation submitted for the degree of Doctor of Philosophy by Christiane Charlotte Fertig at The School of Pharmacy Faculty of Medicine University of London October 2002 ProQuest Number: 10104897 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10104897 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Abstract The aim of this work was the production of melt-films based on a mixture of unprocessed starch and a mono-myristic acid triglyceride for use as a coating on colon delivery formulations. The starches were embedded in the triglyceride-matrix during a melting process and drug release across the films was obtained by the digestion of the starch fraction through colonic a-amylases. During the first part of this study, the physicochemical properties of 7 starches, whose amylose content ranged from 0 % to nearly 100 %, were investigated and sub­ sequently correlated by statistical analysis. The second part comprised the identification of the optimum film formula with respect to film-forming temperature, starch content and film thickness. A number of 4 and 7 starches were tested in a 3- and 2-factorial Central-Composite-Design experi­ ment, respectively, and the effects and interactions of the film-forming parameters analysed by Analysis of Variance. The third part consisted of enzyme studies using 4 a-amylases of different origins as well as whole pancreatin in order to simulate and assess the selective film digestibility in the human intestinal tract. The film performance was measured as film permeability for the model drug phenylpropanolamine prior and after enzymatic digestion using a 2-chamber diffusion cell. The 3-factorial experiment revealed non-significance for the film-forming temperature, whilst the 2-factorial approach identified an optimum film thickness of 20 pm and a starch content of 30 %. These specifications were confirmed during the enzyme studies, where a-amylase from B.Ucheniformis produced the highest film permeabilities. The results showed that the degree of amylose content in the starch product is not as critical for film digestibility as the film thickness and starch content in the melt film. The particle size and surface area of the starches were found to be relevant for the digestibility and interpreted with respect to their accessibility for enzymatic attack. Acknowledgments Acknowlegments My sincere thanks go to my supervisor Prof. Fridrun Podczeck, who provided constant guidance, advice and critique throughout this work. Her expertise and dedication as a scientist as well as her high standards and thoroughness as a teacher have enormously impressed and inspired me during the last three years and will surely resonate in the future. I have learned once again that periods of difficulty and sometimes doubt can be overcome by perseverance and a strong belief in the goal, which to approach and to attain becomes a stimulating and rewarding process itself. I would like to thank Dr. Roger Jeffcoat from the National Starch and Chemical Company, USA, for kindly supplying the starch samples as well as Dr. Roger Jee and Mark Smith for their assistance with the NIR analyses and the proofreading of the respective passages in the manuscript. I am furthermore indebted to The School of Pharmacy, London, for funding this work. Many thanks to Simon Ashdown and Dr. Gabriele Messina for their valuable help and availability at any time when computer-related problems needed to be solved instantly and competently. Their reliability and reassurance were immensely appreciated in moments near to disheartenment and exasperation. My thanks equally extend to Margaret Wallace, Dr. Clare Perkins and Dr. Charlotte Hanlon for the linguistic proofreading of the manuscript. Their suggestions helped to improve the clarity of the written work to which the writer so often grows oblivious. Finally, I am grateful to the English Baroque Choir and the Kensington Consort in whose musical and sociable environment I was able to replenish my energies at the beginning and end of each week spent on accomplishing this work. Table o f contents Table of Contents Abstract 2 Acknowledgments 3 List of Figures 10 List of Tables 13 Abbreviations 16 CHAPTER 1 : Introduction 1 Polysaccharides 19 2 Starch 20 2.1 Origin and makeup 20 2.2 Molecular structure and properties of amylose and amylopectin 21 2.2.1 Amylose 21 2.2.2 Amylopectin 23 2.3 Morphology of the starch granule 23 2.4 Use of starch 24 2.5 Starch modification and intestinal breakdown 25 2.6 Resistant starch 26 2.7 Three-dimensional organization and crystallinity of starch 27 2.8 Gelation, gelatinization and rétrogradation 29 2.9 Glass transition and melting 32 2.10 Starch gels 35 2.11 Swelling 35 2.12 Melting 36 2.13 Plasticizers 39 2.14 Analytical characterization of starch 39 2.15 Isolation and synthesis of amylose and amylopectin 40 2.16 Hydrolysis of starch gels 41 2.17 The enzyme a-amylase 41 Table o f contents 3 The colon 43 3.1 Anatomy and physiology 43 3.2 Nutrient absorption and breakdown in the colon 45 3.3 Transit of bowel contents 46 3.4 Colon diseases 48 4 Controlled drug delivery 48 4.1 Principles of controlled drug delivery 48 4.2 Modem colon-specific dmg delivery systems 49 4.3 Coatings 54 5 Powders in pharmaceutics 55 5.1 Definition and characterization 55 5.2 Particles 55 5.2.1 Size and shape 55 5.2.2 Size distribution 58 5.3 True, apparent and bulk density 59 5.4 Surface area determination 59 5.5 Particle size analysis 62 5.5.1 Sieve analysis 62 5.5.2 Light microscopy 62 5.5.3 Scanning electron microscopy 63 5.5.4 Laser light scattering 64 6 Methods for assessing the film forming materials 66 6.1 Thermal analytical methods 66 6.1.1 Differential scanning calorimetry 66 6.1.2 Thermal gravimetric analysis 67 6.1.3 Near-infrared spectroscopy 68 7 Statistical methods 71 7.1 Factorial design 71 7.2 Analysis of Variance 75 7.2.1 The F-ratio 75 7.2.2 One-way ANOVA 76 7.2.3 The ANOVA table 76 7.2.4 The t-test 76 7.3 Post-hoc tests 77 Table o f contents 7.4 Correlation analysis 79 CHAPTER 2: Materials and Methods 1 Materials 81 1.1 Starches 81 1.1.1 Hylon 5 and Hylon 7 82 1.1.2 LAPS 83 1.1.3 PURE 84 1.1.4 Acetate starch 84 1.1.5 Com starch 85 1.1.6 Waxy starch 85 1.1.7 Amylopectin 86 1.2 Melt matrix materials 86 1.2.1 Dynasan 114 86 1.2.2 Further materials screened 87 1.3 Enzymes 88 1.3.1 B. licheniformis-a-2my\?iS,Q 88 1.3.2Human-saliva-a-amylase 88 1.3.3 Hog-pancreas-a-amylase 89 1.3.4 B. amyloliquefaciens-a-amy\asQS 89 1.3.5 Pancreatin 89 1.4 a-amylase test kit 90 1.5 Buffers 91 1.5.1Phosphate buffer 91 1.5.2 Saline-calcium-phosphate buffer 91 1.6 Model dmg phenylpropanolamine hydrochloride 91 1.7 Cellulose nitrate membrane filters 92 1.8 Teflon discs 92 1.9 Plastic Petri-dishes 92 1.10 Water 93 2 Methods 93 2.1 Determination of melt temperature 93 2.1.1 Minimum-film-forming-temperature bar 93 2.1.2 Hot stage microscope 94 Table o f contents 22 Blending of the materials 94 2.3 Calculation of the blend weights per film 95 2.4 Film preparation 96 2.5 Measurement of film thickness 97 2.6 Assessment of film permeability 97 2.7 Enzymatic film incubation 98 2.8 Digestibility test for a cellulose nitrate membrane 99 2.9 Incubation in 0.1 N HCl 99 2.10 Measurement of degree of swelling 100 2.11 Measurement of water loss 100 2.12 Assessment of thermal behaviour during temperature rise 101 2.13 Measurement of apparent particle density 102 2.14 Measurement of particle size 102 2.15 Measurement of surface area 103 2.16 Scanning electron microscopy 104 2.17 Sample preparation of digested starches for SEM 105 2.18 Measurement of amylose-content by NIR 106 2.19 Statistical data processing 107 CHAPTER 3: Physicochemical Characterization 1 Introduction 108 2 Results and discussion 109 2.1 Scanning electron microscopic images 109 2.2 Amylose content 114 2.3 Particle size 123 2.4 Apparent particle density 126 2.5 Surface area 129 2.6 Swelling 132 2.7 Water loss 136 2.8 Thermal behaviour 142 3 Spearman’s rank test of the physicochemical properties of each starch 149 Table o f contents CHAPTER 4: Film Formula Identification 1 Introduction 160 2 Results and discussion 161 2.1 Identification of the film-forming material 161 2.2 Choice for starch types 171 2.3 Choice for model drug 171 2.4 Choice for enzymes 173 2.5 Film production 173 2.6 Film testing 174 2.7 Film digestion 174 2.8 Reference incubations 175 2.9 The 3-factorial experiment 156 2.9.1 The 3-factorial design 156 2.9.2 Spearman correlation 182 2.9.3 ANOVA results 184 2.10 The 2-factorial experiment 191 2.10.1 The 2-factorial design 191 2.10.2 Permeabilities of all 9 film combinations of 7 starches 193 2.10.3 ANOVA results 201 2.11 Diffusion kinetics 209 3 Conclusion 220 CHAPTER 5: Enzyme Studies 1 Introduction 222 2 Results and discussion 223 2.1 Choice of enzymes and required activities 223 2.2 Choice of buffer 224 2.3 Incubation in 0.1 M HCl 225 2.4 Reference incubations 227 2.5 Results of the films tested 229 2.6 Statistical analysis 234 2.6.1 Statistical analysis of a-amylases 234 2.6.2 Discussion of a-amylases 241 2.6.3 Statistical analysis of pancreatin 243 Table o f contents 2.6.4 Discussion of pancreatin 245 2.7 Microscopic images of digested starch granules 246 2.8 Discussion of enzymatic activity in relation to physicochemical properties of the substrate 252 3 Conclusion 258 CHAPTER 6: Conclusions and Future Work 1 Summary 259 2 Conclusions 261 3 Suggestions for future work 262 CHAPTER 7: References 266 List o f figures List of Figures Figure 1.1: Structure of starch.
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