Application of COSMO-SAC to Solid Solubility in Pure and Mixed Solvent Mixtures for Organic Pharmacological Compounds Paul Eric Mullins Thesis submitted to the Faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Master of Science In Chemical Engineering Dr. Y. A. Liu, Chair Dr. Richey M. Davis Dr. Amadeu K. Sum 24 January 2007 Blacksburg, Virginia Keywords: COSMO, COSMO-SAC, Solubility, Pharmaceutical, Mixed Solvent Application of COSMO-SAC to Solid Solubility in Pure and Mixed Solvent Mixtures for Organic Pharmacological Compounds Paul Eric Mullins Dr. Y. A. Liu, Chair Abstract In this work, we present two open literature databases, the VT-2005 Sigma Profile Database and the VT-2006 Solute Sigma Profile Database, that contain sigma profiles for 1,645 unique compounds. A sigma profile is a molecular-specific distribution of the surface-charge density, which enables the application of solvation-thermodynamic models to predict vapor- liquid and solid-liquid equilibria, and other properties. The VT-2005 Sigma Profile Database generally focuses on solvents and small molecules, while the VT-2006 Solute Sigma Profile Database primarily consists of larger, pharmaceutical-related solutes. We design both of these databases for use with the conductor-like screening model – segment activity coefficient (COSMO-SAC), a liquid-phase activity-coefficient model. The databases contain the necessary information to perform binary and multicomponent VLE and SLE predictions. We offer detailed tutorials and procedures for use with our programs so the reader may also use their own research on our research group website (www.design.che.vt.edu). We validate the VT-2005 Sigma Profile Database by pure component vapor pressure predictions and validate the VT-2006 Solute Sigma Profile Database by solid solubility predictions in pure solvents compared with literature data from multiple sources. Using both databases, we also explore the application of COSMO- SAC to solubility predictions in mixed solvents. This work also studies the effects of conformational isomerism on VLE and SLE property prediction. Finally, we compare COSMO- SAC solubility predictions to solubility predictions by the Non-Random Two-Liquid, Segment Activity Coefficient (NRTL-SAC) model. We find UNIFAC is a more accurate method for predicting VLE behavior than the COSMO-SAC model for many of the systems studied, and that COSMO-SAC predicts solute mole fraction in pure solvents with an average root-mean-squared error (log10(xsol)) of 0.74, excluding outliers, which is greater than the RMS error value of 0.43 using the NRTL-SAC model. Acknowledgments I would like to thank my advisor, Dr. Y. A. Liu, for his support and guidance during my tenure as a student at Virginia Tech. I would also like to thank the members of Dr. Liu’s research group, especially Stephen Fast, Anthony Gaglione, Adel Ghaderi, Bruce Lucas, Richard Oldland, and Kevin Seavey, for being an excellent sounding board for ideas. My parents, Phillip and Joalyn Mullins, and my family deserve special thanks for pushing me to try and be my best in all endeavors in life. I would also like to thank my professional collaborators, Dr. Stanley I. Sandler and his research group at the University of Delaware and Dr. Chau-Chyun Chen, Senior Technology Fellow at Aspen Technology, Inc. Both of these individuals have provided sound advice and guidance backed by many years of experience, and I greatly value their opinions. I would also like to thank our industrial sponsors, Alliant Techsystems, Aspen Technology, Inc., Formosa Petrochemical Co., Honeywell International, Milliken & Co., and SINOPEC Corporation., for providing the funding for the research presented here. Paul Eric Mullins January 24, 2007 Blacksburg, Virginia iii Table of Contents ABSTRACT ................................................................................................................................................................ ii ACKNOWLEDGMENTS......................................................................................................................................... iii TABLE OF CONTENTS ...........................................................................................................................................iv LIST OF FIGURES....................................................................................................................................................vi LIST OF TABLES......................................................................................................................................................ix 1 INTRODUCTION....................................................................................................................................................1 1.1 BACKGROUND AND SIGNIFICANCE OF THIS RESEARCH ...............................................................................1 1.2 OBJECTIVES OF THIS RESEARCH..................................................................................................................2 2 THEORY ..................................................................................................................................................................4 2.1 OVERVIEW OF COSMO-SAC MODEL.........................................................................................................4 2.1.1 Derivation of Segment Activity-Coefficient Model ................................................................................5 2.1.2 Sigma Profiles........................................................................................................................................8 2.2 OVERVIEW OF DENSITY-FUNCTIONAL THEORY ........................................................................................11 2.3 SOLUBILITY THEORY.................................................................................................................................12 2.3.1 Overview of Solubility..........................................................................................................................12 2.3.2 Derivation of Solubility Equation from Solid-Liquid Equilibrium.......................................................12 2.4 ESTIMATION METHODS FOR MELTING TEMPERATURE AND HEATS OF FUSION .........................................15 2.4.1 Estimation of Normal Melting-Point Temperature..............................................................................15 2.4.2 Estimation of Latent Heat of Fusion....................................................................................................16 2.5 OVERVIEW OF NRTL-SAC THEORY .........................................................................................................18 3 COMPUTATIONAL METHODS AND VALUES .............................................................................................20 3.1 PROCEDURE FOR GENERATING SIGMA PROFILES ......................................................................................20 3.1.1 Ideal Gas-Phase Geometry Optimization ............................................................................................21 3.1.2 Condensed Phase Energy Calculation.................................................................................................22 3.1.3 COSMO Calculation – Surface Segment Averaging............................................................................23 3.2 GEOMETRY OPTIMIZATION TOOLS ............................................................................................................24 3.2.1 Amber8.................................................................................................................................................24 3.2.2 MS Forcite Plus Annealing Dynamics.................................................................................................25 3.2.3 Qualitative Comparison of Methods....................................................................................................26 3.3 CONVERGENCE METHOD FOR SOLUBILITY PREDICTIONS..........................................................................28 4 VT-2005 SIGMA PROFILE DATABASE...........................................................................................................29 4.1 DESCRIPTION OF DATABASE......................................................................................................................29 4.2 VALIDATION OF VT-2005 SIGMA PROFILE DATABASE..............................................................................33 4.2.1 Pure Component Vapor-Pressure Predictions.....................................................................................34 4.2.2 Activity-Coefficient Predictions...........................................................................................................35 4.3 DETAILS OF VT-2005 SIGMA PROFILE DATABASE RELEASE AND REFINEMENT........................................35 4.4 EFFECT OF CONFORMATIONAL ISOMERISM ON THERMODYNAMIC PROPERTY PREDICTION ......................36 4.4.1 Small Molecule Example: 2-Methoxy-ethanol....................................................................................38 4.4.2 Medium-Sized Molecule Example: Benzyl Benzoate ..........................................................................47 4.5 CONFORMATIONAL IMPROVEMENTS OF SELECT RELEASED COMPOUNDS .................................................52 4.5.1 Polar Solvent: Ethanol.........................................................................................................................53