Purdue University Purdue e-Pubs Open Access Dissertations Theses and Dissertations January 2015 Dissolution Behavior of Amorphous Solid Dispersions Matthew aJ mes Jackson Purdue University Follow this and additional works at: https://docs.lib.purdue.edu/open_access_dissertations Recommended Citation Jackson, Matthew James, "Dissolution Behavior of Amorphous Solid Dispersions" (2015). Open Access Dissertations. 1118. https://docs.lib.purdue.edu/open_access_dissertations/1118 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. Graduate School Form 30 Updated 1/15/2015 PURDUE UNIVERSITY GRADUATE SCHOOL Thesis/Dissertation Acceptance This is to certify that the thesis/dissertation prepared By Matthew James Jackson Entitled DISSOLUTION BEHAVIOR OF AMORPHOUS SOLID DISPERSIONS For the degree of Doctor of Philosophy Is approved by the final examining committee: Lynne S. Taylor Chair Stephen R. Byrn Elizabeth M. Topp Umesh Kestur To the best of my knowledge and as understood by the student in the Thesis/Dissertation Agreement, Publication Delay, and Certification Disclaimer (Graduate School Form 32), this thesis/dissertation adheres to the provisions of Purdue University’s “Policy of Integrity in Research” and the use of copyright material. Approved by Major Professor(s): Lynne S. Taylor Approved by: Lynne S. Taylor 8/7/2015 Head of the Departmental Graduate Program Date i DISSOLUTION BEHAVIOR OF AMORPHOUS SOLID DISPERSIONS A Dissertation Submitted to the Faculty of Purdue University by Matthew J. Jackson In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy i December 2015 Purdue University West Lafayette, Indiana ii For my wife, Melissa ii iii ACKNOWLEDGEMENTS I would first and foremost like to thank my advisor, Lynne S. Taylor, for all of her guidance and wisdom throughout my academic career. She continually goes well beyond any expectations a graduate student could have for an advisor and she truly knows how to get the best out of her students. She has an incredible devotion and passion for her work, and she puts mentoring above everything else to develop outstanding young people, both as professionals and individuals. I am forever indebted to her for the opportunities she has given me while under her guidance. I would also like to thank my thesis committee, Elizabeth M. Topp, Stephen R. Byrn, Michael Harris, and Umesh S. Kestur for their discussion, support, service, and guidance regarding my graduate research. I would like to acknowledge the Graduate School and the Department of Industrial and Physical Pharmacy for giving me the opportunity to pursue my graduate iii degree in a field I am very passionate about. Also, I would like to thank Purdue University for all the opportunities it has afforded me throughout my nine years as a student here. It truly is an outstanding University and I am forever a Boilermaker. I would like to thank all of the colleagues of the IPPH department, and specifically Niraj Trasi for the guidance, friendship and discussions both scientifically and personally over the years. Additionally, I’d like to thank Gregory T. Knipp for his direction while being a member of the AAPS Student Chapter at Purdue and as a student within the department. And the Taylor group members who I have worked beside every iv day for the last 7 years as both and undergraduate and graduate student, as we have formed lifelong friendships. And of course the students, faculty, and staff of the IPPH department who make up such a wonderful program which it has been a pleasure to be a part of. This thesis would not have been possible without the generous financial support of the Ross Fellowship, the Graduate Assistance in Areas of National Need Fellowship, and the Pharmaceutical Research and Manufacturers of America (PhRMA) Pre-doctoral Fellowship. Additionally, I am grateful for the financial support for my project from Bristol-Myers Squibb and the guidance of their collaborative discussions, specifically Umesh S. Kestur, Feng Qian, and Munir A. Hussain. I would also like to acknowledge Scott J. Toth and Garth J. Simpson for their collaborations between myself and their chemistry group. Lastly, I would like to thank my family and friends. I am forever grateful for the support and love you have given me over the years. To my parents, who have always pushed me and believed in me, who have been there every step of the way. And most iv importantly, my wife Melissa. Your love and support pushes me every single day to be the best person I can possibly be. I love you and without you this journey would have been infinitely more difficult. Thank you to everyone! v TABLE OF CONTENTS Page LIST OF TABLES .............................................................................................................. x LIST OF FIGURES ........................................................................................................... xi ABSTRACT ..................................................................................................................... xix CHAPTER 1. INTRODUCTION .................................................................................... 1 1.1 Pharmaceutical Significance and Objective ............................................................... 1 1.2 The Crystalline vs. Amorphous State ........................................................................ 3 1.2.1 Crystalline Systems ......................................................................................... 3 1.2.2 Amorphous Systems ........................................................................................ 7 1.2.3 Amorphous Solid Dispersions ....................................................................... 10 1.3 Thermodynamics and Kinetics ................................................................................ 11 1.3.1 Free Energy Diagram ..................................................................................... 11 1.3.2 Mixing Energy and Solubility ....................................................................... 13 1.3.3 The Amorphous Solubility Advantage .......................................................... 16 1.3.4 Supersaturation .............................................................................................. 19 1.3.5 Kinetics .......................................................................................................... 20 1.3.5.1 Dissolution ................................................................................................ 21 1.3.5.2 Diffusion ................................................................................................... 23 v 1.4 Crystallization .......................................................................................................... 24 1.4.1 Nucleation ...................................................................................................... 25 1.4.1.1 Classical Nucleation Theory ..................................................................... 26 1.4.1.2 Two-Step Nucleation ................................................................................ 28 1.4.2 Crystal Growth ............................................................................................... 30 1.4.3 Precipitation ................................................................................................... 32 vi Page 1.5 Liquid-Liquid Phase Separation .............................................................................. 34 1.5.1 Binodal/Spinodal of LLPS ............................................................................. 36 1.5.2 LLPS and Drug Solubility ............................................................................. 39 1.6 Overview of Research .............................................................................................. 40 1.7 Figures...................................................................................................................... 43 1.8 References ................................................................................................................ 63 CHAPTER 2. Impact of Polymers on the Precipitation Behavior of Highly Supersaturated Aqueous Danazol Solutions ............................................ 71 2.1 Abstract .................................................................................................................... 71 2.2 Introduction .............................................................................................................. 72 2.3 Materials .................................................................................................................. 74 2.4 Methods.................................................................................................................... 74 2.4.1 Solubility........................................................................................................ 74 2.4.2 Amorphous Solubility Estimation ................................................................. 75 2.4.3 UV Extinction Measurements ........................................................................ 77 2.4.4 Fluorescence Spectroscopy using an Environmentally Sensitive Probe ....... 77 2.4.5 Simultaneous Ultraviolet (UV) and Fluorescence Spectroscopy .................. 79 2.4.6 Dynamic Light Scattering (DLS)................................................................... 79 2.4.7 Induction Time Experiments using Second