An Expert System For Development of Powder Filled Hard Gelatin Capsule Formulations Thesis submitted to the University of London Faculty of Medicine for THE DEGREE OF DOCTOR OF PHILOSOPHY ky Samantha Miu Ha Lai B.Pharm., M.R.Pharm.S. September 1996 The School of Pharmacy University of London Brunswick Square London WCIN lAX ProQuest Number: 10104253 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 10104253 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 Dedicated to my Father ACKNOWLEDGMENT I would like to dedicate this thesis to my father, without whom I would not be able to achieve this PhD. My sister, Esther and my boyfriend, Eric were also very understanding and have been most supportive throughout my ‘ups and downs’. The guidance and supervision provided by my supervisor. Professor J M Newton and also by Dr F Podczeck also made this PhD possible. Special thanks must go to Professor Newton for being so incredibly patient and spending so much time with me on top of his busy schedule. The concise instructions given by Dr Podczeck also meant that the direction and the focus of the project was always clear for me. Mr Roland Daumesnil (Capsugel), the co-ordinator of the whole project is another person I am indebted to. I would like to thank him most sincerely for his energetic input in the project. Moreover, I would also like to express my gratitude to Mr Norito Takubo (Capsugel, Japan), Mr Ketan Mehta (Capsugel, US) and Mrs Anne Coutel-Egros (Capsugel, Europe) for organising the number of focus group meetings in each different region. My PhD has also brought me in contact with a number of experienced formulation scientists around the world and provided me with invaluable opportunities to learn about both the scientific and the practical aspects in the pharmaceutical industry. Dr Bécourt (Marion Rousell Uclaf, France) , Dr Pathak (SKB, UK), Dr Lewis (Synthlabo, France), Dr Collaveri (RPR, France), Dr Guitard (Sandoz, Switzerland), Dr Makarand Jawadekar (Pfizer,US), Professor Hashida (University of Kyoto, Japan) and Professor Augsburger (University of Maryland, US) together with all the other experts in the focus groups in Europe, Japan and US have been most helpful in building this Expert System. Constant encouragement from Dr D Peacock who coached me with the computation part of the project are deeply appreciated. Special thanks must go to my friends Amit Basu, Kenneth Man, Raymond Sung and Collin James for their inspirations in computer programming. My long suffering friends, Chuei Wuei, Chan, Voon Keat, Hwee, Pei Inn, Faith and many others not mentioned by name, also helped me to get through the difficult times in my PhD. I would also like to express my special appreciation to the help Chan offered throughout the final stage of my PhD. Last but not least, I would also like to thank Capsugel for the financial support. Expert System Development Teams The advice and help contributed by the members of the Expert System Development Teams were tremendous in developing this system. I would like to express my gratitude to all the following members for their support : European Focus Group (The Founder Group) Professor J M Newton (Chairman) Dr F Podczeck Dr G Lewis (Synthelabo, France) Dr P Bécourt (HMR, France) Mr R Pathak (SmithKline Beecham, UK) Mr J P Collaveri (RPR, France) Dr Guitard (Sandoz/Ciba-Geigy, Switz.) Japanese Focus Group Professor M Hashida (Chairman) Representatives from Daiichi Pharmaceutical Co., Ltd. Sankyo Co., Ltd. Eisai Co., Ltd Takeda Chemical Industries, Ltd. Fujisawa Pharmaceutical Co., Ltd Tanabe Seiyaku Co., Ltd. Kanebo, Ltd Yamanouchi Pharmaceutical Co., Ltd United States Focus Group Professor L Augsburger (Chairman) Representatives from Abbott Laboratories Hoechst Marion Roussel Bayer Merck Bristol-Myers Squibb Parke-Davis Ciba-Geigy/S andoz Pfizer Duquesne University Schering Plough FDA SmithKline Beecham Glaxo Upjohn Hoffman-La Roche W arner-Lambert Johnson & Johnson ABSTRACT The aim of my PhD project is to build up an expert system for development of formulation for powder filled hard gelatin capsules. An expert system is a program that attempts to capture the knowledge and experience from experts in the field. It is very often a time consuming process to develop formulations for drugs particularly new drugs. With the aid of an expert system, a logically devised formula can be recommended more efficiently. It can also be used as a training tool. C and DbaselV computer languages were used to develop the expert system. Relevant information such as dose; drug properties, for example, solubility and particle size; and incompatibility data of drug with gelatin and excipients were fed into the system and the output would include the recommended formula. This system was made up of three major components : the databases, the main program and the 'learning package'. The databases formed the knowledge base and the foundation of the system. The databases contained knowledge of marketed formulations, drugs and excipients; bibliography and expert knowledge in the subject; and results of statistical analysis of experiments carried out to derive missing information. Based on this knowledge base, rules and facts of developing formulations in powder filled hard gelatin capsules were derived. Decision trees of the main program were developed. After the initial trial which tested the logic of these rules, the decision trees were translated into programming language. The ‘Learning package’ is an important feature in the system. When the expert system is used for a longer period of time, there may be new knowledge in the subject. Some of the current rules may need to be changed or replaced. The lists of default excipients used may be updated using the learning package. In conclusion, the expert system is a learning system. It provides an efficient way to develop formulations for powder filled hard gelatin capsules. Table of contents DEDICATION..................................................................................................................... 2 ACKNOWLEDGEMENT................................................................................................... 3 EXPERT SYSTEM DEVELOPMENT TEAMS................................................................4 ABSTRACT...........................................................................................................................5 TABLE OF CONTENTS.............................................................................................. 6-12 LIST OF TABLES......................................................................................................... 13-14 LIST OF FIGURES.......................................................................................................15 -16 ABBREVIATIONS 17 - 18 LIST OF SYMBOLS.................................................................................................... 19 - 21 Chapter 1 : Introduction 1.1 Expert system as an aid in pharmaceutical formulation ........................................23 1.1.1 Use of an Expert System in pharmaceutical industry ............................................23 1.1.2 Advantages of Expert System ..................................................................................24 1.1.3 Disadvantages of Expert System .............................................................................25 1.1.4 Expert System technology .......................................................................................26 1.1.5 Why use an Expert System in capsule formulation?.............................................33 1.2 Background to Hard Gelatin Capsules ..................................................................... 34 1.2.1 Brief history of gelatin capsules ..............................................................................35 1.2.2 Manufacture of gelatin capsule shells.................................................................... 36 1.2.3 Properties of hard gelatin capsules ........................................................................ 37 1.2.4 Types of Hard Gelatin Capsules ..............................................................................38 1.2.5 Capsule size.............................................................................................................. 39 1.2.6 Storage condition ......................................................................................................40 1.3 Capsule formulation .....................................................................................................41 1.3.1 Physico-chemical properties of drug and excipients ...........................................41 1.3.1.1 Particle size........................................................................................................41 1.3.1.2 Particle shape .....................................................................................................48 1.3.1.3 Flow properties ...................................................................................................53