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Functionalizable Biodegradable Polyesters For FUNCTIONALIZABLE BIODEGRADABLE POLYESTERS FOR DRUG DELIVERY APPLICATIONS A Dissertation Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Abhishek Banerjee May, 2012 FUNCTIONALIZABLE BIODEGRADABLE POLYESTERS FOR DRUG DELIVERY APPLICATIONS Abhishek Banerjee Dissertation Approved: Accepted: ______________________________ ______________________________ Advisor Department Chair Dr. Coleen Pugh Dr. Ali Dhinojwala ______________________________ ______________________________ Committee Chair Dean of the College Dr. Li Jia Dr. Stephen Cheng ______________________________ ______________________________ Committee Member Dean of the Graduate School Dr. Abraham Joy Dr. George R. Newkome ______________________________ ______________________________ Committee Member Date Dr. William J. Landis ______________________________ Committee Member Dr. Yang H. Yun ii ABSTRACT Current biodegradable polymers, like poly(lactic acid) (PLA), poly(glycolic acid) (PGA) and their copolymers (PLGA) do not have functionalities on their backbones. Such biodegradable polymer systems are therefore not able to covalently attach drugs or other therapeutic molecules, which could be useful for making drug delivery devices. Instead, the therapeutic molecules must be physically entrapped into these polymers, either by forming micelles or by nano-encapsulation, thereby limiting their loading capacity. Our research deals with the polyesterification of 2-bromo-3-hydroxypropanoic acid which is a halogenated isomer of lactic acid, yet has a primary alcohol group like glycolic acid. It is therefore an ideal co-monomer for incorporation into PLGA. Such co- polyesters are potentially biodegradable with halogen functionalities on the main chain. We have synthesized brominated copolymers with LA and GA of number average molecular weights around 20,000 Da (PS standards), under bulk co-polymerization conditions. The number of functionalizable sites on the main chain of this polyester is controlled by varying the feed ratio of the halogen co-monomer. The biodegradability of the polymer can also be tailored by varying the lactic acid and glycolic acid feed ratios. Solution polymerization using carbodiimide chemistry at room temperature has also been explored to prepare these co-polymers, with lesser success. iii The biodegradation behavior of these brominated polyesters were studied in the form of compression molded tablets under physiological conditions, Phosphate buffer saline (pH 7.4), at 37 °C and these polymers were found to degrade to around 80% of their initial molecular weights. iv DEDICATION This dissertation is dedicated to my grandfather, Subhash Chatterjee. I wish life allowed me to spend more time with him. This dissertation is also dedicated to my parents, Kalpana and Tarun Banerjee. It is their hard work, sacrifices and exceptional parenting that is mostly responsible for my successes in past, present and in future. This dissertation is also dedicated to my elder brother, Abhijeet Banerjee. He is a friend and mentor. v ACKNOWLEDGEMENTS I would like to begin by thanking my parents for supporting me, both financially and emotionally, throughout my academic career. Any success is a manifestation of their sacrifices, foresight and excellent parenting. I am extremely grateful to my doctoral advisor, and mentor, Dr Coleen Pugh, for giving me the opportunity to perform research in her lab. I have been fortunate to learn and practice not only chemistry but also valuable life lessons. I wish that I had even half of her intelligence, energy and dedication towards everything she does. I acknowledge my doctoral dissertation committee members, Dr. Li Jia, Dr. Abraham Joy, Dr William Landis, and Dr Yang Yun who took the time to read my dissertation and give constructive feedback. I thank my colleagues, both past and present, from Dr Pugh’s research group, Dr Anirudha Singh, Dr Chau Tang, Dr James Baker, Lisa Collette, Gladys Montenegro, William Storms, Colin Wright, Mina Garcia, Stephanie Vivod, Cesar Lopez, Xiang Yan, Ajay Amrutkar, Brinda Shah and Nicole Swanson. I would like to thank Dr Andrew Ditto, and Kush Shah from the Dr Yun research group who helped me formulate micro-particles and helping me with the dynamic light scattering experiments. vi I would like to thank Rajarshi Sarkar, for helping me with hydrogenation reactions, and wish him good luck the remaining of his doctoral research. I thank Dr Sachin Gokhale for proving me insight into silicon deprotection chemistry. I would like to thank Dr Boje Wang and Dr Sarang Bhawalkar who helped me with Scanning Electron Microscopy. I would like to thank my graduate school buddies, Kurt Chiang and Andy Heidenreich, who made graduate school fun. On a personal note, I would like to thank Adam Pilz, whose friendship over the years made life in akron enjoyable, and his influence helped me broaden my horizons beyond science – into the world of economics, finance and business. I would also like to acknowledge the friendship of Dr Abhimanyu Kumar, as an ‘almost roommate’, who was always motivating and great company. I am grateful to have known and been roommates with Sushil Sivaram, whose excellent cooking skills and conversations I still miss. I would like to thank my oldest friend, Dr Sunny Sethi, whose friendship and advice has stuck with me, thick and thin. Finally, I would like to acknowledge lady luck, who has always taken care of things beyond my control. vii TABLE OF CONTENTS Page LIST OF TABLES ............................................................................................................ xii LIST OF FIGURES .......................................................................................................... xiv LIST OF SCHEMES ........................................................................................................ xix CHAPTER I. INTRODUCTION ......................................................................................................... 1 II. LITERATURE REVIEW ............................................................................................. 4 2.1 Application of Biodegradable Polymers .............................................................. 6 2.1.1 Ecological Applications ............................................................................... 7 2.1.2 Medical Application .................................................................................... 8 2.2 Motivation and Scope ......................................................................................... 13 2.3 Synthesis of Poly(hydroxy acids) ....................................................................... 21 2.3.1 Bulk ........................................................................................................... 21 2.3.2 Solution ...................................................................................................... 22 2.3.3 Sequence Controlled Copolymers ............................................................. 26 2.4 Biodegradation ................................................................................................... 27 2.4.1 Effect of Structure and Environment on Biodegradation .......................... 33 2.4.1.1 Crystallinity ........................................................................................... 33 2.4.1.2 Hydrophilicity ....................................................................................... 35 2.4.1.3 Acid autocatalysis ................................................................................. 35 viii 2.4.2 Experimental aspects of Studying biodegradation .................................... 37 2.4.2.1 Sample Preparation ............................................................................... 38 2.4.2.2 Biodegradation Markers ........................................................................ 39 2.4.2.2.1 Visual Examination ...................................................................... 39 2.4.2.2.2 Water Absorption ......................................................................... 40 2.4.2.2.3 Weight Loss ................................................................................. 41 2.4.2.2.4 Molecular Weight Loss ................................................................ 42 2.4.2.2.5 Change in pH ............................................................................... 44 III. EXPERIMNETAL METHODS .................................................................................. 45 3.1. Materials ............................................................................................................. 45 3.2. General Techniques ............................................................................................ 46 3.3. Synthesis of 2-bromo-3-hydroxypropionic acid ................................................. 49 3.4. Synthesis of poly(lactic acid-co-glycolic acid-co-2-bromo-3-hydroxypropionic acid) (PLGB801010) by bulk polycondensation ................................................ 50 3.5. Synthesis of poly(lactic acid-co-2-bromo-3-hydroxypropionic acid) (PLB8020) by solution polymerization .............................................................. 51 3.6. Synthesis of benzyl (DL)-lactate (Bn-LA) ......................................................... 52 3.7. Synthesis of benzyl glycolate (Bn-GA) .............................................................. 53 3.8. Synthesis of methyl 2-(tert-butyldiphenylsilanyloxy) acetate ..........................
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