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Understanding the Thermodynamics and Oral Absorption Potential of Pharmaceutical Amorphous Solid Dispersions

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Understanding the Thermodynamics and Oral Absorption Potential of Pharmaceutical Amorphous Solid Dispersions University of Kentucky UKnowledge Theses and Dissertations--Pharmacy College of Pharmacy 2018 UNDERSTANDING THE THERMODYNAMICS AND ORAL ABSORPTION POTENTIAL OF PHARMACEUTICAL AMORPHOUS SOLID DISPERSIONS Nico Setiawan University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0002-4945-8851 Digital Object Identifier: https://doi.org/10.13023/ETD.2018.175 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Setiawan, Nico, "UNDERSTANDING THE THERMODYNAMICS AND ORAL ABSORPTION POTENTIAL OF PHARMACEUTICAL AMORPHOUS SOLID DISPERSIONS" (2018). Theses and Dissertations--Pharmacy. 85. https://uknowledge.uky.edu/pharmacy_etds/85 This Doctoral Dissertation is brought to you for free and open access by the College of Pharmacy at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Pharmacy by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Nico Setiawan, Student Dr. Patrick J. Marsac, Major Professor Dr. David J. Feola, Director of Graduate Studies UNDERSTANDING THE THERMODYNAMICS AND ORAL ABSORPTION POTENTIAL OF PHARMACEUTICAL AMORPHOUS SOLID DISPERSIONS DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Pharmacy at the University of Kentucky By Nico Setiawan Lexington, Kentucky Director: Dr. Patrick J. Marsac, Associate Professor of Pharmaceutical Sciences, Lexington, Kentucky 2018 Copyright © Nico Setiawan 2018 ABSTRACT OF DISSERTATION UNDERSTANDING THE THERMODYNAMICS AND ORAL ABSORPTION POTENTIAL OF PHARMACEUTICAL AMORPHOUS SOLID DISPERSIONS Supersaturating drug delivery systems, such as amorphous solid dispersions (ASDs), have been used extensively to elevate the apparent solubility and oral bioavailability of poorly water-soluble drugs. However, despite the numerous examples of success in increasing solubility and oral bioavailability using ASDs, physical stability challenges remain as formulators seek to employ high drug loading for cost reduction and improved patient compliance. Therefore, stability in both the solid and solution state must be considered for ASDs to be successful. In the solid state, the drug must remain amorphous in the solid matrix throughout the shelf life of the product. Although excipients, such as polymers, have been known to stabilize the amorphous drug in the solid state, stresses encountered during manufacturing and fluctuations in storage conditions may have a detrimental impact on the physical stability of ASDs. Numerous studies have been performed on the impact of each process on ASD stability, yet the relative quantitative impact of each process with respect to the overall energetics landscape is not well understood. Further, ASDs must dissolve after administration and maintain the intended supersaturation in the gastrointestinal (GI) tract during the GI transit time to achieve maximum oral absorption. In solution, the energetics advantage of the amorphous over the crystalline material is a “double-edged sword,” in that it produces not only a high absorption driving force but also an undesirable high crystallization potential. An approach to quantitatively measure the thermodynamic activity of amorphous materials is, thus, desirable. However, it is difficult to measure thermodynamic activity quantitatively, especially due to the speciation process induced by formulation excipients and endogenous materials. Hence, it is often difficult to assess the true enhancement in the absorption for a given ASD and to measure its crystallization tendency in solution. Overall, this dissertation aims to address the following: 1. The relative thermodynamics magnitude of various processes with respect to the crystallization energy associated with amorphous drugs 2. The development of a practical tool to measure the thermodynamic activity of amorphous materials over its crystalline counterpart in solution to assess the enhancement in absorption in the presence of excipients 3. The impact of measured thermodynamic activity on drug crystallization energetics in the presence of excipients KEYWORDS: supersaturation, crystallization, amorphous, poorly water-soluble drugs, excipients, absorption Nico Setiawan Author’s signature April 27, 2018 Date UNDERSTANDING THE THERMODYNAMICS AND ORAL ABSORPTION POTENTIAL OF PHARMACEUTICAL AMORPHOUS SOLID DISPERSIONS By Nico Setiawan Patrick J. Marsac, Ph.D. Director of Dissertation David J. Feola, Ph.D. Director of Graduate Studies April 27, 2018 Date To my beloved parents ACKNOWLEDGEMENTS I would like to express my sincere gratitude to all who have helped and supported me throughout my graduate work. This dissertation would not have been possible without all of you. First, I would like to thank my committee. Each of you has uniquely contributed invaluable guidance and support throughout my graduate study. I would like to offer special thanks to Dr. Paul Bummer, who, although no longer with us, continues to inspire by his example and dedication to the students he served over the course of his career. To my advisor, Dr. Patrick Marsac, thank you for challenging me to continuously think outside the box and to “tie up” the observations to the fundamentals. I am blessed by your kindness, patience, and friendship throughout my graduate study. To Dr. Eric Munson, thank you for serving as my co-advisor after the passing of Dr. Paul Bummer. Your guidance and support to this dissertation is truly appreciated. To Dr. Brad Anderson, thank you for challenging my thought process and helping me to be a better scientist and communicator. Your advice and support have been invaluable throughout my graduate study. To Dr. Barbara Knutson, thank you for contributing valuable advice and sharing your laboratory equipment. I would also like to thank all of the people in Marsac and Munson groups that I had the privilege to work with: Dr. Sadegh Poozesh, Dr. Jonas Alin, Matt Defrese, Freddy Arce, Dr. Matt Nethercott, Dr. Sean Delaney, Dr. Xiaoda Yuan, Kanika Sarpal, Ashley Lay, Julie Calahan, and Travis Jarrells. I would like to thank Poozesh for helping iii me to be a better writer and for our friendship. I would like to thank Jonas for your support on this dissertation. In addition, I would like to thank Matt Defrese for the advice on job hunting and his challenging questions. Many thanks to Freddy who helped me to execute SEM experiments. I would like to thank Matt Nethercott for your help with NMR and writing, and all memorable friendship. Thanks to Sean who helped me with NMR experiments and daily lab work; I truly cherished our friendship. In addition to the Marsac and Munson groups, I would like to thank the following people whose friendship and support have made my graduate work journey enjoyable: Dr. Xiaojian Li, Dr. Derek Reichel, Dr. Nilay Thakkar, Emily Denehy, and Na-Ra Lee. I would also like to thank several excellent undergraduate students whom I had the privilege to mentor: Emily Daley, Heather Campbell, Sean Gillette, Jack Oliver, and Endras Fadhilah. On a personal note, I would like to thank my family and friends for their love and support. To my mom and dad, thank you for your unconditional love and sacrifice. I certainly would not have made it this far if it were not for you. Above all, I acknowledge my Creator, who has given me the platform and wisdom to carry on my life purpose in improving the health and wellness of human beings. iv TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF TABLES ........................................................................................................... viii LIST OF FIGURES ........................................................................................................... ix Chapter 1 - Introduction .....................................................................................................
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