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Synthesis and Applications of Cellulose Derivatives for Drug Delivery Joyann Audrene Marks Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Macromolecular Science and Engineering Kevin J. Edgar, Chair Maren Roman Lynne S. Taylor Judy S. Riffle S. Richard Turner August 5, 2015 Blacksburg, VA Keywords: pairwise blends, amorphous solid dispersion, oral drug delivery, cellulose esters, bioavailability, cationic cellulose, extrusion Copyright © 2015 by Joyann A. Marks Synthesis and Applications of Cellulose Derivatives for Drug Delivery Joyann Audrene Marks ABSTRACT In an effort to produce new derivatives of cellulose for drug delivery applications, methods were developed to regioselectively modify C-6 halo cellulose esters to produce cationic derivatives via nucleophilic substitution. Reaction of C-6 substituted bromo and iodo cellulose with trialkylated amines and phosphines produced new cationic ammonium and phosphonium cellulose derivatives which can be explored as delivery agents for nucleic acids, proteins and other anionic drug molecules. It was anticipated that these new derivatives would not only be capable of complexing anionic drug molecules but would have greatly improved aqueous solubility compared to their precursors. The phosphonium derivatives described in this work are an obvious example of such improved solubility properties. Given the importance of cellulose derivatives in making amorphous dispersions with critical drugs, it has also been important to analyze commercially available polymers for the potential impact in oral drug delivery formulations. To do so pairwise blends of cellulosics and synthetic polymers commonly used as excipients were tested for miscibility using techniques such as DSC, mDSC, FTIR and film clarity. Miscible combinations highlight the potential to use combinations of polymers currently available commercially to provide drug delivery solutions for specific drug formulations. The use of melt extrusion in processing some of these drug/polymer dispersions provides a means of highlighting the capability for the use of these cellulosics in melt extruded amorphous dispersions. This solvent free, high pressure method significantly reduces cost and time and can be applied on a large scale. The analysis of long chain cellulose esters and ultimately the novel omega carboxy esters for melt processability significantly impacts the possibilities available for use of those excellent drug delivery agents on a much larger scale. Dedication For my mother -You have always been my rock and continue to be despite your illness. I am thankful for you and for all the encouraging words and prayers that have pushed me throughout this journey. Thank you for always being my ultimate motivation. I love you. iii Acknowledgements I would first like to express sincere gratitude to my advisor Dr. Kevin J. Edgar who has been a source of encouragement, guidance and inspiration for me throughout this journey. He has displayed great patience and understanding throughout the course of this work and has always been available to assist in providing much needed guidance throughout my time at Virginia Tech. I am eternally grateful for the opportunity to pursue my PhD under his mentorship and have gained a wealth of knowledge and opportunities during this time. I will always be grateful to him and his wife for their welcoming and encouraging nature. I am also grateful to the members of my graduate committee, Dr. Judy S. Riffle, Dr. Maren Roman, Dr. S. Richard Turner and Dr. Lynne S. Taylor for their guidance and suggestions that have proven very valuable throughout my research. I must say a big thank you to all my colleagues in the Cellulose Research group and Taylor group past and present who have played vital roles in my time at Virginia Tech. They have provided great advice, engaging discussions and made time spent both in and out of lab an enjoyable one. I am grateful to the Macromolecules and Interface Institute (MII), Sustainable Biomaterials and the Institute for Critical Technology and Applied Science (ICTAS) for academic, financial and facilities support and thankful for funding provided by NSF Fund DMR- 1308276. I am also immensely thankful for the help of various other students, professors and support staff in these and the Chemistry department who have been instrumental in providing necessary instrumentation and instruction. I must also acknowledge the encouraging professors at Fisk University who supported me throughout my undergraduate career and have continued to provide mentorship and advice throughout my PhD work. iv I am forever grateful for the patience, love and prayers of my immediate and extended family who have been my source of strength and of unconditional support. A big thank you to my dearest friends who have been like family, brightening some of the darkest moments along the way, praying for me and with me and providing much needed encouragement. Finally I am grateful to my Lord Jesus Christ, my ever present source of peace and guidance. v Attribution Several colleagues aided in data collection and research for the chapters within this dissertation. A brief description of their contributions is included here. Dr. Kevin J. Edgar was the principal investigator and was a primary contributor in the planning, organizing, and directing of the projects described in this dissertation. Chapter 3: Pairwise Polymer Blends for Oral Drug Delivery Dr. Lynne Taylor is a collaborator in the Department of Industrial and Physical Pharmacy at Purdue University and served as a coauthor on this paper. Dr. Lindsay Wegiel at Purdue University (Taylor Group) assisted with FTIR analyses described under section 3.3.5 and served as a co-author on this paper. Dr. Bruce Orler at Virginia Tech (Moore Group) assisted with the DSC analyses described under section 3.3.4. Chapter 4: Cationic Cellulose Derivatives for Drug Delivery: Synthetic Pathways to Regioselectively Substituted Ammonium and Phosphonium Derivatives Preliminary findings of Dr. S. Carter Fox at Virginia Tech (Edgar Group) assisted in research development for the results presented and he is a coauthor on the manuscript to be submitted for publication. Chapter 5: 6-Carboxycellulose Acetate Butyrate as a Novel Polymer for Amorphous Solid Dispersion and Extrusion Ms. Ruoran Zhang and Ms. Brittany Nichols at Virginia Tech (Edgar Group) assisted in data collection for the results presented in Chapter 5. Dr. Ann Norris at Virginia Tech (Department of Sustainable Biomaterials) assisted with XRD analyses described under section 5.3.8. vi Table of contents Abstract…..................................................................................................................................... ii List of Figures................................................................................................................................xi List of Schemes............................................................................................................................xiv List of Tables ...............................................................................................................................xv Chapter 1 Research Introduction................................................................................................1 Chapter 2 Literature Review .......................................................................................................5 2.1 Introduction ..............................................................................................................5 2.2 Cellulose ……...............................................................................................................6 2.3 The structure of cellulose.................................................................................................7 2.4 Hydrogen bonding and crystallinity.................................................................................8 2.5 Chemical modification of cellulose .................................................................................9 2.5.1 Cellulose swelling .............................................................................................10 2.5.2 Cellulose dissolution .........................................................................................11 2.5.3 Cellulose degradation.........................................................................................16 2.5.4 Thermal degradation of cellulose and cellulose derivatives………………......19 2.5.5 Reactivity of cellulose ………………………………………………………...23 2.6 Regioselective derivatization of cellulose......................................................................23 2.6.1 Tosylation ..........................................................................................................24 2.6.2 Direct regioselective halogenation.....................................................................29 2.6.3 Cationic derivatives in drug delivery……………………………………….....31 2.6.4 Conclusions........................................................................................................35 2.7 Cellulose derivatives in oral drug delivery.....................................................................35 2.7.1 Amorphous solid dispersions.............................................................................38 2.7.2 Preparation and analysis of amorphous solid dispersions (ASDs).....................39
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