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Synthesis and Structure-Property Evaluation of Novel Cellulosic Polymers As Amorphous Solid Dispersion Matrices for Enhanced Oral Drug Delivery

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Synthesis and Structure-Property Evaluation of Novel Cellulosic Polymers As Amorphous Solid Dispersion Matrices for Enhanced Oral Drug Delivery Synthesis and Structure-property Evaluation of Novel Cellulosic Polymers as Amorphous Solid Dispersion Matrices for Enhanced Oral Drug Delivery Haoyu Liu 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 Richey M. Davis Maren Roman Lynne S. Taylor S. Richard Turner December 2, 2013 Blacksburg, VA Keywords: cellulose ω-carboxyesters, amorphous solid dispersion, amphiphilicity, structure- property relationship, oral drug delivery Copyright © 2013 by Haoyu Liu Synthesis and Structure-property Evaluation of Novel Cellulosic Polymers as Amorphous Solid Dispersion Matrices for Enhanced Oral Drug Delivery Haoyu Liu ABSTRACT The use of amorphous solid dispersions (ASDs) is an effective and increasingly widely adopted approach for solubility and bioavailability enhancement of hydrophobic drugs. Cellulose derivatives have strong potential as ASD polymers. We demonstrate herein design, synthesis and structure-property relationship characterization of a new series of organo-soluble cellulose ω- carboxyalkanoates for ASDs, by two different synthetic approaches. These carboxyl-containing cellulose mixed-esters possessed relatively high Tg values with sufficient ∆T versus ambient temperature, useful to prevent drug mobility and crystallization during storage or transport. Screening experiments were utilized to study the impact of ASD polymers including our new family of cellulose ω-carboxyesters on both nucleation induction time and crystal growth rate of three poorly soluble model drugs from supersaturated solutions. Attributed to relatively rigid structures and bulky substituent groups, cellulose derivatives were more significant crystallization inhibitors compared to the synthetic polymers. The effective cellulose ω-carboxyesters were identified as possessing a similar hydrophobicity to the drug molecule and high number of ionization groups. Among them, cellulose acetate suberate prepared by us was an extraordinary solution crystal growth inhibitor for ritonavir and its formulated solid dispersions provided a substantial 15-fold enhancement of apparent solution concentration vs. the equilibrium solubility of the crystalline drug. To offset the issue of slow drug release from some cellulose ω-carboxyester-based formulations, a new class of amphiphilic cellulosic polymers with hydrophilic oligo(ethylene oxide)-containing side chains was developed via versatile synthetic pathways, and the evaluation of these materials alone or by pairwise polymer blends will be performed as ASD matrices for the enhancement of drug solubility and stability. iii ACKNOWLEDGEMENTS First of all, I would like to thank my beloved parents and grandparents, they have been always standing by my side, bearing my bad temper through difficult times and giving me heart- warming support and suggestions, even though I am far away and unable to take care of them for the past four years. I would like to thank Dr. Judy Riffle, the director of our Macromolecular Science & Engineering program. I was applying for graduate schools from China back in 2009 and never met her personally. Just after knowing my background through email, she was very kind to introduce me to my advisor Dr. Kevin Edgar. That was how I could talk with him and luckily receive the offer, and truly, joining our polysaccharide research group was the best and most correct decision that I have made. I sincerely thank Dr. Edgar for allowing me to study under his guidance for my Ph.D. He is extremely knowledgeable in the fields including polysaccharides, organic chemistry and drug delivery. His knowledge and experience are the major reasons that I could complete a productive work over these four years. His influence on me is much beyond this. I was very confused about blending into the new learning environment when I began graduate study in a different country, greatly thanks to Dr. Edgar’s patience and continuous guidance, I started to learn how to learn, make discoveries on my own and interact with other scientists happily and productively. I am also deeply grateful to Dr. Lynne Taylor, Dr. Maren Roman, Dr. Richard Turner and Dr. Richey Davis for serving on my graduate committee, providing invaluable resources during my study, and reviewing my dissertation. The next acknowledgement should be delivered to Dr. Nilanjana Kar, who taught me the basic knowledge and techniques in the field of cellulose chemistry when I started to work in the lab. I learned from her that punctiliousness is very important when working on projects, the experience working with her only lasted for less than a quarter but it really shaped me as a real, serious scientific researcher. The same thanks should go to all my collaborators, especially Dr. Grace Ilevbare who is now working at Merck as a senior scientist. She is the best collaborator I could expect, her knowledge, insight and great personality led me to get familiar with, and eventually love the pharmaceutical field. iv I would like to thank staff from Departments of Sustainable Biomaterials and Chemistry, Macromolecules and Interfaces Institute for all of their help, especially Ms. Debbie Garnand, Ms. Tammy Jo Hiner and Ms. Cyndy Graham for academic and research service, Dr. Hugo Azumendi and Mr. Geno Iannaccone for NMR service, Mr. Rick Caudill for XRD service and repairing lab equipment. I would also like to thank all of my lovely labmates, Dr. Carter Fox, Dr. Bin Li, Dr. Daiqiang Xu, Dr. Sidd Pawar, Dr. Junia Pereira, Joyann Marks, Xueyan Zheng, Ruoran Zhang, Thomas Simerly, Xiangtao Meng and Cigdem Arca. Thanks also go to all students, postdoctoral associates and professors who I have worked with and learned from in Macromolecular Science and Engineering program and the Departments of Sustainable Biomaterials and Chemistry. Please forgive me not mentioning all the names, I am very grateful and proud of being a part of Virginia Tech community in our beautiful town, Blacksburg. v TABLE OF CONTENTS ABSTRACT ................................................................................................................................... ii ACKNOWLEDGEMENTS .......................................................................................................... iv TABLE OF CONTENTS .............................................................................................................. vi LIST OF FIGURES ....................................................................................................................... x LIST OF SCHEMES ................................................................................................................... xiv LIST OF TABLES ....................................................................................................................... xv CHAPTER 1 INTRODUCTION ................................................................................................ 1 References .................................................................................................................................. 3 CHAPTER 2 LITERATURE REVIEW .................................................................................... 4 2.1 Introduction – Cellulose and Cellulose esters: Their Properties and Applications .............. 4 2.2 Importance of Novel Drug Delivery Systems ...................................................................... 7 2.3 Approaches to Enhance Dissolution of Poorly Soluble Drugs ............................................. 8 2.3.1 Cyclodextrin-drug complexation ................................................................................... 9 2.3.2 Nanosizing: Nanoparticles with large surface area ...................................................... 12 2.3.3 Lipid-based delivery .................................................................................................... 14 2.3.4 Micellar solubilization – The use of artificial surfactants as excipients ...................... 16 2.3.5 Amorphous solid dispersions ....................................................................................... 18 2.4 Polymer Matrices for Amorphous Dispersion Formulations ............................................. 20 2.4.1 Synthetic polymers....................................................................................................... 21 2.4.2 Conventional pH-independent cellulose esters and ethers ........................................... 24 2.4.3 pH-dependent cellulose derivatives ............................................................................. 27 2.5 Concluding Remarks .......................................................................................................... 38 2.6 References .......................................................................................................................... 39 CHAPTER 3 PIONEERING STUDIES ON SYNTHESIS OF CELLULOSE ADIPATE DERIVATIVES ........................................................................................................................... 46 3.1 Abstract ............................................................................................................................... 46 3.2 Introduction ........................................................................................................................ 46 3.3 Experimental Section ........................................................................................................
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