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Polymorph Formation of Tolfenamic Acid: an Investigation of Pre-Nucleation Association

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Polymorph Formation of Tolfenamic Acid: an Investigation of Pre-Nucleation Association University of Kentucky UKnowledge Theses and Dissertations--Pharmacy College of Pharmacy 2012 POLYMORPH FORMATION OF TOLFENAMIC ACID: AN INVESTIGATION OF PRE-NUCLEATION ASSOCIATION Alessandra Mattei University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Mattei, Alessandra, "POLYMORPH FORMATION OF TOLFENAMIC ACID: AN INVESTIGATION OF PRE- NUCLEATION ASSOCIATION" (2012). Theses and Dissertations--Pharmacy. 7. https://uknowledge.uky.edu/pharmacy_etds/7 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 and attached hereto needed written permission statements(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). I hereby grant to The University of Kentucky and its agents the non-exclusive 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 a preapproved 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 dissertation including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Alessandra Mattei, Student Dr. Tonglei Li, Major Professor Dr. Jim Pauly, Director of Graduate Studies POLYMORPH FORMATION OF TOLFENAMIC ACID: AN INVESTIGATION OF PRE-NUCLEATION ASSOCIATION 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 Alessandra Mattei Lexington, Kentucky Director: Dr. Tonglei Li, Professor of Pharmaceutical Sciences Lexington, Kentucky 2012 Copyright © Alessandra Mattei 2012 ABSTRACT OF DISSERTATION POLYMORPH FORMATION OF TOLFENAMIC ACID: AN INVESTIGATION OF PRE-NUCLEATION ASSOCIATION The majority of pharmaceutical products are formulated as solids in the crystalline state. With the potential to exist in different crystalline modifications or polymorphs, each solid form bears its own physical and chemical properties, influencing directly bioavailability and manufacturability of the final dosage form. In view of the importance of crystalline form selection in the drug development process, it is imperative for pharmaceutical scientists to work arduously on various aspects of polymorphism, ranging from fundamental understanding of the phenomenon at the molecular level to practical utilization of a specific crystalline form. One common feature of organic crystals is the existence of distinct molecular conformations in different polymorphic structures, known as conformational polymorphism. Conformational polymorphs are routinely observed in drug development, produced when crystal growth conditions vary. Crystallization from solution involves nucleation and crystal growth, the mechanisms that influence the polymorphic outcome. The embryonic solute aggregate has been recognized to play a critical role in dictating the final crystal structure, and solution conditions are also known to drastically influence the self-association behavior of solute molecules during crystallization, affecting crystal packing of organic molecules. For the crystal growth of conformational polymorphs, changes in molecular conformation not only determine the growth kinetics, but also influence the nature and strength of interactions present in the crystal structures. How conformation and intermolecular interaction affect each other underlines the intricacy and the wonder of crystal growth of the organic. Thus, the overall goal of this research is to provide the fundamental understanding of the extent to which solution conditions influence the molecular conformation in the solid-state of a model drug, tolfenamic acid. By combining experimental studies with advanced computational tools, this dissertation offers novel insights into solution species during pre-nucleation and molecular packing of conformational polymorphs of tolfenamic acid. In-depth understanding of the underlying connection between molecular conformation and crystal packing will help advance the knowledge required for rational control of crystal growth. KEYWORDS: polymorphs, nucleation, self-association, molecular conformation, intermolecular interaction Multimedia Elements Used: TIF (.tif) Alessandra Mattei Student’s Signature September 2012 Date POLYMORPH FORMATION OF TOLFENAMIC ACID: AN INVESTIGATION OF PRE-NUCLEATION ASSOCIATION By Alessandra Mattei Tonglei Li, Ph.D. Co-Director of Dissertation Paul M. Bummer, Ph.D. Co-Director of Dissertation Jim Pauly, Ph.D. Director of Graduate Studies September 2012 Date To my parents and my brother ACKNOWLEDGEMENTS I would like to express my gratitude to several people who have helped and supported me through the course of my graduate studies. First, I would like to thank my advisor Dr. Tonglei Li for his guidance, support, and patience. I would like to thank my dissertation committee: my co-advisor Dr. Paul Bummer, Dr. Bradley Anderson, and Dr. Carolyn Brock for their time, support, and contributions to my development and the advancement of this research. I would also like to thank Dr. Steven Van Lanen and Dr. Zack Hilt for instrument support. I would like to give a special thanks to Dr. Anne-Frances Miller, Mr. John Layton, Xiaonan Mei, and Warintra Pitsawong for their training and guidance in NMR technique. Many thanks to the Institute for High Performance Computing and the Center for Computational and Computer Sciences at the University of Kentucky for providing the computer resources. I would like to thank all of the members of Dr. Li lab. Thanks especially to Christin Hollis for her support, help, and friendship. On a personal note, I would like to thank my family for their unconditional love and encouragement. iii TABLE OF CONTENTS ACKNOWLEDGEMENTS ........................................................................................... iii LIST OF TABLES ...................................................................................................... viii LIST OF FIGURES ....................................................................................................... ix LIST OF ABBREVIATIONS ........................................................................................ xv Chapter 1 – Introduction ..................................................................................................1 1.1 Polymorphism ...................................................................................................2 1.1.1 Conformational Polymorphism ...................................................................3 1.1.2 Disappearing and Concomitant Polymorphism ...........................................4 1.1.3 Thermodynamic Aspects of Polymorphism ................................................5 1.1.4 Polymorph Transformations .......................................................................9 1.2 Pharmaceutical Relevance and Implications of Polymorphism ......................... 10 1.3 Nucleation ....................................................................................................... 12 1.3.1 Classical Nucleation Theory ..................................................................... 14 1.3.2 Two-Step Nucleation Model ..................................................................... 19 1.4 Mechanistic Understanding of Polymorph Formation ...................................... 24 1.4.1 Pre-Nucleation Association ...................................................................... 24 1.4.2 Solution Conformation ............................................................................. 26 1.4.3 Control of Polymorph Formation .............................................................. 28 1.5 Statement of Problems ..................................................................................... 29 1.6 Objectives ....................................................................................................... 32 Chapter 2 – Polymorph Formation of Tolfenamic Acid .................................................. 35 2.1 Introduction ..................................................................................................... 35 2.2 Materials and Methods .................................................................................... 40 2.2.1 Materials .................................................................................................
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