EUTECTIC MIXTURES OF DRUGS WITH POOR AQUEOUS SOLUBILITY – SOLID STATE CHARACTERIZATION AND DISSOLUTION STUDIES A Dissertation Submitted to The Temple University Graduate Board In partial Fulfillment Of the Requirements for the Degree of DOCTOR OF PHILOSOPHY By Aditya V. Dinge May 2012 Advisory Committee David Lebo, Ph.D. (Dissertation Advisory Committee (D.A.C.) Chair) Daniel J. Canney, Ph.D. (Examining Chair) Magid Abou-Gharbia, Ph.D. Michael Borenstein, Ph.D. Reza Fassihi, Ph.D. Yunxia (Vivian) Bi, Ph.D., Ashland Specialty Ingredients (External Reader) i © Copyright 2012 By Aditya V. Dinge All Rights Reserved ii ABSTRACT It is a well reported fact that large number of drugs coming of the drug discovery pipeline show poor aqueous solubility. Eutectic mixture formation of poorly soluble drugs with hydrophilic carriers has been used to enhance the dissolution rate of such poorly soluble drugs. Eutectic mixtures are solid dispersions where the drug and the carrier are both in crystalline form. The eutectic mixture has a lower melting point than either component. Eutectic mixtures are thermodynamically stable systems. The feasibility of developing a dosage form from an eutectic mixture depends on the phase diagram. Poloxamers are polyoxyethylene-polyoxypropylene-polyoxyethylene block polymers which have surfactant properties. Phase diagram construction and dissolution rate enhancement mechanism in crystalline poloxamer based eutectics has not been reported in pharmaceutical literature. This thesis involved the detailed study of poloxamer 188 (PL 188) based eutectic mixtures. Eutectic mixture formation between PL 188 and drugs with diverse physicochemical properties was proved. Accurate experimental phase diagrams were constructed using solid state characterization techniques and theoretical phase diagrams were predicted using Lacoulonche et al’s model. The model was accurate in predicting the phase diagrams of most drugs. Discrepancies were observed in case of drugs showing hydrogen bonding interactions with PL 188. This was confirmed by a blue shift of the carbonyl band using fourier transform infra-red spectroscopy. A unique novel graphical method for estimating the accurate eutectic composition of PL 188 based eutectics with about 50 mg of drug was devised. PL 188 was effective in improving the dissolution rate of a poorly soluble drug ibuprofen in pH 1, 4.5 and 7.2. For the first time a detailed study establishing melting point depression due to eutectic formation as a reason for dissolution enhancement was described. Contrary to expectation it was realized that maximum dissolution rate enhancement takes place at iii drug ratios well above the eutectic composition. The utility of PL 188 as a eutectic mixture carrier was shown by comparing ketoprofen PL 188 eutectic mixtures with ketoprofen soluplus (glass solutions) and ketoprofen urea solid dispersions(amorphous precipitation in crystalline carrier). The ketoprofen PL 188 eutectic mixtures had better dissolution enhancing effect and physical stability. iv ACKNOWLEDGEMENTS One of the pleasures of completion is to look over the journey past and remember all the friends and family who have assisted and supported me along this long but satisfying road. I am heartily thankful to my Advisor, Dr. David B. Lebo for his patience, kindness, motivation and excellent guidance. I could not have imagined a better mentor for my PhD study. I am extremely grateful to Dr. Vivian Bi of Ashland Specialty Ingredients for her suggestions, invaluable advice, motivation and constructive comments. This work would not have been completed without her support. My sincere thanks are due to the members of my Dissertation Advisory Committee, Dr. Magid Abou-Gharbia, Dr. Michael Borenstein, Dr. Reza Fassihi and Dr. Vivian Bi for their detailed review, constructive criticism and advice during the preparation of the thesis. I am forever indebted to the AstraZeneca Pharmaceuticals, Early Development Group for giving me the opportunity to extensively and liberally use the solid state characterization instruments. I owe my most sincere gratitude to Mr. Michael Uczynski of AstraZeneca Pharmaceuticals for helping me collect DSC, TGA, PXRD, VTPXRD and DVS data. I would like to thank Dr. Yidan Lan of BASF Pharma Solutions for providing me with various polymer samples, polymer data and conducting porosity studies. I would like to thank Dr. Jianyong Yang of WiTec Instruments for performing Confocal Raman Microscopy Studies. My sincere thanks are due to Mr. Andrew Cohen for his assistance with bench work and ordering laboratory materials. I would also like to thank my lab mates Kalpana and Biji for their help and support. v I am additionally thankful to Dr. Peter Doukas, Dean School of Pharmacy, Dr. Daniel Canney, Director of Graduate Studies and Dr. Robert Raffa, Department Chairman for their support. Additionally, I would like to show gratitude to Dr. Mark Ilies and Dr. Reza Fassihi for allowing me access to their laboratory facilities. I would also like to thank my roommates Jay and Sandeep for their help and support. I would not have contemplated this road if not for my parents, Padma and Vijay, who instilled within me a love of science and creativity both of which find a place in this thesis. To my parents, thank you for the love, understanding, support and “aashirwad”. I owe my loving thanks to my wife Mayuri. Without her encouragement and understanding it would have been impossible for me to finish this work I owe my utmost respect and gratitude to my entire extended family for providing a loving environment. Last but not the least I would like to thank the students(Siva in particular), staff and faculty of Temple University, Department of Pharmaceutical Sciences for their support and encouragement. vi This dissertation is dedicated to: My Parents, Padma and Vijay Dinge, My Late Grandmother, Laxmi Bai Dinge and My Wife, Mayuri vii TABLE OF CONTENTS Page ABSTRACT………………………………………………………………………………………iii ACKNOWLEDGEMENTS……………………………………………………………………….v DEDICATION……………………………………………………………………………………vii LIST OF TABLES……………………………………………………………………………….xi LIST OF FIGURES…………………………………………………………………………….xiv CHAPTER 1. INTRODUCTION………………………………………………………………………..1 Abbreviations……………………………………………………………………1 Drug Solubilization Techniques……………………………………………….1 Solid Dispersions……………………………………………………………….6 Eutectic Mixture Review……………………………………………………...23 Objectives of The Thesis……………………………………………………..35 2. EXPERIMENTAL AND THEORETICAL PHASE DIAGRAM CONSTRUCTION OF DRUG POLOXAMER 188 EUTECTIC MIXTURES…………………………...37 Abbreviations…………………………………………………………………..37 Introduction…………………………………………………………………….37 Materials………………………………………………………………………..41 Experimental Methods………………………………………………………..42 viii Results and Discussion………………………………………………………47 Conclusions……………………………………………………………………73 3. SOLID STATE CHARACTERIZATION AND DISSOLUTION STUDIES OF IBUPROFEN POLOXAMER 188 EUTECTIC MIXTURES………………………..77 Abbreviations…………………………………………………………………..77 Introduction…………………………………………………………………….77 Materials………………………………………………………………………..81 Experimental Methods………………………………………………………..81 Results and Discussion………………………………………………………86 Conclusions…………………………………………………………………..133 4. COMPARISON OF KETOPROFEN POLOXAMER 188 SOLID DISPERSIONS WITH KETOPROFEN SOLUPLUS ® AND KETOPROFEN UREA SOLID DISPERSIONS……………………………………………………………………….136 Abbreviations………………………………………………………………...136 Introduction…………………………………………………………………..136 Materials……………………………………………………………………...139 Experimental Methods………………………………………………………139 Results and Discussion……………………………………………………..143 Conclusions…………………………………………………………………..171 5. CONCLUSIONS OF THE THESIS……………………………….........................172 REFERENCES………………………………………………………………………………..174 APPENDICES ix A. PHASE DIAGRAMS USED IN CHAPTER 2………………………………………192 B. SOLID STATE AND DISSOLUTION DATA USED IN CHAPTER 3……………207 C. SOLID STATE AND DISSOLUTION DATA USED IN CHAPTER 4……………219 x LIST OF TABLES Table Page 1.1. Limitations of drug solubilization techniques and possible advantages of solid dispersions…………………………………………………………………...............5 1.2. Classification of solid dispersions……………………………………………………….13 1.3. Some of the marketed solid dispersions………………………………………………..20 2.1. Types of solid dispersions………………………………………………………………..38 2.2. Physicochemical properties of the selected compounds……………………………..49 2.3. Properties of PL 188 and PEG 8000 …………………………………………………...51 2.4. Exclusion criteria of drug-PL188 solid dispersions from various classes………….53 2.5. Experimental and theoretical phase diagram values, drug dosage and formulation practicability …………………………………………………………………65 2.6. Band assignments for the IR spectra of MA, 30% MA-PL188 eutectic mixture and PL188……………………………………………………………...71 2.7. Band assignments for the IR spectra of IBU, IBU-PL188 30% eutectic mixture and PL188…………………………………….………………….71 2.8. Experimental and predicted EC of KETO, ACE and PI……………………………….84 3.1. Properties of various polymers…………………………………………………………..88 3.2. EC and T e of various eutectic mixtures…………………………………………………92 3.3. Enthalpy values of IBU endotherms…………………………………………………….96 3.4. Crystallinity of IBU in IBU PL 188 CMs ……………………………………………….104 xi 3.5. The wavenumbers of prominent IBU and PL 188 bands in IBU-PL 188 CMs and PMs…………………………………………………………………….….......107 3.6. Comparison of the crystalline IBU in CM and PMs………………………………..…109 3.7. Absolute solubilization capacity ( κ) and the amount of IBU solubilized per gram of hydrophobe (S H) values for various polymers…………….…………....119 3.8. Factors