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Different Approaches Toward the Enhancement of Drug Solubility and Or Dissolution Rate

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Different Approaches Toward the Enhancement of Drug Solubility and Or Dissolution Rate Different Approaches Toward The Enhancement Of Drug Solubility And Or Dissolution Rate. by Princy Ann Abraham A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey in partial fulfillment of the requirements for the degree of Doctor of Philosophy Graduate Program in Chemistry and Chemical Biology written under the direction of Professor Jing Li and approved by: ________________________ ________________________ ________________________ ________________________ New Brunswick, New Jersey October, 2011 © 2011 Princy Ann Abraham ALL RIGHTS RESERVED ABSTRACT OF THE DISSERTATION Different Approaches Toward The Enhancement Of Drug Solubility And/Or Dissolution Rate. By: Princy Ann Abraham Dissertation Director: Professor Jing Li Nontraditional methods such as supercritical antisolvent processing and ultrasonic processor rely on physical alterations to enhance drug solubility and dissolution rate. They are advantageous because of their application to a wide variety of drugs and relatively short processing time. Our works show reduced particle size and complexation with these techniques results in the modification of dissolution rate and or solubility. Crystalline form of a drug is preferable because most drugs occur in this form and tend to be stable at this condition. Towards this effort new nanosized crystalline coordination drug polymers are synthesized to enhance drug solubility or dissolution rate. γ-Indomethacin (IMC) is successfully processed with the supercritical antisolvent (SAS) technique. Pure, acicular (needle-like) particles of the α-polymorph are consistently obtained with SAS as the solvent, concentration, temperature and pressures are varied. Controlled changes in process parameters yield significant changes in particle size. Enhanced dissolution profiles are observed with IMC processed with SAS as opposed to the unprocessed IMC. The reduced particle size, as well as the α- polymorphic form of IMC, contributes to the enhanced dissolution rate. Hydroxypropyl-β- cyclodextrin complexation of γ-Indomethacin (IMC) was processed with the supercritical antisolvent (SAS) technique as well. SAS processing resulted in the highest initial dissolution rate of IMC complexed particles compared to ii both spray drying and the physical mixture. This initial increase in dissolution rate is attributed to the micronization of particles. The addition of the water soluble polymer polyvinylpyrrolidone (PVP) to the IMC complex enhanced the dissolution rate further. Finally, the synthesis of new nanosized crystalline coordination drug polymers is explored. These crystalline coordination drug polymers are composed of the drug molecules coordinated to zinc metal ion as a ligand. The dissolution is controlled mainly by the release of the bridging ligands. These new nanocrystalline CDPs serve as potential for enhanced dissolution. iii ACKNOWLEDGEMENT I would like to express my heartfelt gratitude to Dr. Jing Li for her continued support, friendship, motherly concern, and advice throughout my whole graduate career. I would like to thank Dr. Wayne Wang for his advice and for being a constant source of encouragement during my internship at Johnson and Johnson Pharmaceutical Research and Development (PRD) and now as he is serving as an outside member of my committee. I am grateful to Dr. Ralph Warmuth and Dr. KiBum Lee for being on my defense committee and for willing to take up another PhD defense. Thank you for your honest remarks and valuable comments. I would also like to thank Dr. Gene Hall and the late Dr. Theodore Madey (may his soul rest in peace), for serving on my proposal committee. I would like to thank IGERT for their support financially over the past few years and for all the meaningful discussions I was able to participate in. I would like to especially thank Prabhas Moghe for his useful critiques and Linda Anthony for her constant encouragement and support. I would also like to thank them for supporting my first internship at Johnson and Johnson PRD. Thank you to all the friends I made through this program. I would like to recognize and thank my friends, mentors, and colleagues at Johnson and Johnson Pharmaceutical Research and Development: Denita Winstead, Pei Chu, Lian Liu, Nagy, Ronnie, Michelle, Brett, Teresa, Gary, Alexandra, Brigitte. iv I would like to thank the chemistry graduate staff including Melissa, Ann, Eileen, Dawn, John, Alexei, Tom Chapin and Tom Emge. From the department of cell biology and neuroscience I would like to thank Valentine Starovoytov for help with the use of the SEM facilities. Many thanks to Bill (from the physics mechanics lab) and Dr. Olson (chemistry department) for all their help in providing me with the resources to help me get my work to what it is now. Group members past and present, ever since Dr. Li came to the New Brunswick campus; with a deep heart of gratitude I want to thank you all for your help, support, comments, jokes, and care that I have experienced from you. I want to thank Jungling Sun and Longle Ma for providing all the H1NMR data. I also am very grateful to Yin Wang for his work with me on the CDP systems, providing some supporting information on this and his friendship. A special thanks to the Catholic center for their presence. Thanks to all the priests especially Fr. Tom, Fr. Peter, and Fr. Kevin for their example in holiness. I also want to thank Sister Jodie D Angiolillo (Director of evangelization of the diocese of Metuchen), for being my spiritual guide and for her guidance and encouragement as well to finish this race. To my Malankara ―Kara Krew‖ and all the friends I have met along my graduate life, I thank you for your kindness and for believing in me. A special thank you to Sandy for helping me access resources online to get much of my writing done. I would like to thank my Jesus Youth family, especially for all their constant prayers and support from all over the world. In a special way I would like to thank Sajichettan, Joseychi, Becky, Issac, Maria, and Joseph for opening up their home to me v to minimize my commute while I was pregnant. To Jottychettan and Jyothnichi, I thank them for bearing with me as faithful friends ever since my undergraduate days, and for always encouraging me even to the present day. To my siblings and nephews and niece gifted to me by my husband; Bobbychettan, Chechi, Liggy, Lukey, Mattymo and Lydiana. I thank you for your constant support, patience and for understanding when I could not spend the time very much meant for you, with you. To my sisters, Priyachi, Preetichi, Penny, my brothers in-law, Bobychettan, Shaunchettan and Szilvester, and my nephew and niece, Adrian and Kathryn: I thank you all for helping in more ways than one during these years of my graduate life. Thanks for believing in me, encouraging me and always knowing that if I put my heart into something that I will do a good job on it. To daddy and mummy (my parents in law) thanks for bearing with me and for taking charge of the things that I should have been up to. One thing is for sure: I know that when God chose you all to become my new family, He knew exactly what He was doing. To my parents, you have seen this from the very beginning and been with me through the toughest times of my graduate studies, the uncertain times, and the prosperous times. Now, in your much older age you have had to look after my Athu (who is less than 1 year old) for almost 24hrs on more than one occasion. First, thank you for bringing me into this world, even if things are not always easy. Thank you for always pushing and loving me regardless of my situation. Thank you for your unconditional love. Thanks for teaching me about God from my childhood. He is the main reason that I have vi gotten this far. Finally, thank you for your example of attending daily mass. It has become my daily source of my strength. To my Athanasius (Athu), I thank God for allowing me to give birth to you. It was a life experience which taught me to sacrifice and persevere with the hope of a joy that awaits us. You have helped me relax during my stressful moments and to just be me. To my husband Binu (Kuttan), my coach, my confidant, my love; your organization skills, intellectual capabilities, loving nature and most of all, your love for our God has continued to bless me. You have helped me in a huge way to carry me through this huge milestone and you know it. To the LORD who taught us that the last shall be first, I thank my God, the first in my life. You are the truth that I have felt, experienced, and can never deny the reality of, no matter how much I try. I thank You for being my hope, inner and outer strength, and guide especially through all these years of my graduate career. I thank God for placing all these amazing people in my life so I can become better in so many ways. These people include the ones I have mentioned, the ones who have prayed for me, and for any of those whom I have forgotten to mention here. Among the many Biblical verses there are two that have been the most encouraging throughout all these years. I have typed the verses in the way I have remembered it. The first is that God chooses the weak things of this world to do His greatest works through them (1 Corinthians 1:27) and the second verse is from (Philippians 1:6) He who began a good work in you will be faithful to complete it in you. vii TABLE OF CONTENTS ABSTRACT OF THE DISSERTATION.................................................................
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