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Estimating the entropy of melting from structure Item Type text; Dissertation-Reproduction (electronic) Authors Dannenfelser, Rose-Marie, 1959- Publisher The University of Arizona. Rights Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. Download date 26/09/2021 04:06:30 Link to Item http://hdl.handle.net/10150/288729 INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI fihns the text dvectfy from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter &ce, whfle others may be from any type of computer printer. The quality of this reproductioii is dependent upon the quality of the copy submitted. 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Contact UMI directfy to order. UMI A Bell & Howell Iiifi>niiatioii Compai^ 300 North Zetb Road, Ann Aibor NO 48106-1346 USA 313/761-4700 800/521-0600 ESTIMATING THE ENTROPY OF MELTING FROM STRUCTURE by Rose-Marie Dannenfelser A Dissertation Submitted to the Faculty of the DEPARTMENT OF PHARMACEUTICAL SCIENCES In Partial Fulfilment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College THE UNIVERSITY OF ARIZONA 1997 UMX Number: 9806833 UMl Microform 9806833 Copyright 1997, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 2 THE DNIVERSITY OF ARIZONA ® GRADUATE COLLEGE As members of the Final Examination Committee« we certify that we have read the dissertation prepared by Rose-Marie Dannenfelser entitled Estimafno The Entroov Of Melting From Structure and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctgr gf Philosophy August 22. 1997 Sarp^H. Yalkowsky, Date August22. 1997 Michael MayersohnJPh.D. Date August 22, 1997 Hsiao-Hui Chow, Ph.D. Date Date Date Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College. 1 hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. Dissertatlon/Director Date 3 STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at The University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgment the proposed use of this material is in the interests of scholarship. In all other instances, however, permission must be obtained from the author. SIGNED 4 ACKNOWLEDGEMENTS I would like to express my sincere gratitude to Dr. Samuel H. Yalkowsky for his guidance, encouragement and the opportunity to continue my education. It has been a privilege and an honor to work with Or. Yalkowsky. I would also like to thank my commitee members Drs. Michael Mayersohn, Hsiao-Hui Chow. Srini Raghavan and Michael Burke for their encouragement; and all of the past and present graduate students in the pharmaceutics group for their encouragement and friendship. I am indebted to my husband, Paul, and my daughter, Ruth, for their love, support, and unending patience during graduate school. And finally I would like to thank God for making this degree possible. 5 TO MY HUSBAND AND DAUGHTER 6 TABLE OF CONTENTS Page LIST OF ILLUSTRATIONS 8 LIST OF TABLES 9 ABSTRACT 10 CHAPTER I. INTRODUCTION 11 Significance 11 Entropy 12 Estimation 14 CHAPTER 11. MOLECULAR ROTATIONAL SYMMETRY 17 Introduction 17 Methods 18 Molecular rotational symmetry number 18 Entropy of melting 22 Experimental 25 Data 25 Intercept 25 Entropy of melting 25 Results and Discussion 26 Intercept 26 Entropy of melting 26 CHAPTER III. MOLECULAR FLEXIBILITY 67 Introduction 67 Methods 68 Molecular flexibility number 68 Entropy of melting 71 Experimental 72 Data 72 Entropy of melting 72 Results and Discussion 72 Entropy of melting 72 7 TABLE OF CONTENTS - Continued Page CHAPTER IV. ESTIMATION OF THE TOTAL ENTROPY OF MELTING; APPLICATION TO AN INDEPENDENT DATA SET 121 Introduction 121 Methods 121 Molecular rotational symmetry number 121 Molecular flexibility number 122 Entropy of melting 122 Experimental 123 Data 123 Entropy of melting 123 Results and Discussion 124 CHAPTER V. SUMMARY 202 Introduction 202 Methods 203 Entropy of melting 203 Comparison of estimation schemes 203 Experimental 204 Entropy of melting 204 Comparison of estimation schemes 204 Results and Discussion 204 Entropy of melting 204 Comparison of estimation schemes 205 REFERENCES 232 8 LIST OF ILLUSTRATIONS Page Figure 2.1. Molecular symmetry for benzene 20 Figure 2.2. Molecular symmetry for carbon tetrachloride 20 Figure 2.3. Symmetry numbers for a variety of molecules 24 Figure 3.1. Observed versus predicted entropy of melting values for flexible compounds 75 Figure 3.2. Observed versus predicted entropy of melting values for linear alkanes 76 Figure 3.3. Observed versus predicted entropy of melting values for large cycloalkanes 77 Figure 4.1. Observed versus predicted entropy of melting for 1277 compounds 126 Figure 5.1. Observed versus predicted entropy of melting values for complex compounds 207 9 LIST OF TABLES Page Table 2.1. Comparison of equation 2-6 and Walden's rule 28 Table 2.2. Observed and predicted entropies of melting in J/deg mol 29 Table 3.1. Examples of some molecular flexibilities 69 Table 3.2. Observed and predicted entropies of melting in J/deg mol 78 Table 4.1. Comparison of evaluated data 125 Table 4.2. Observed and predicted entropies of melting in J/K mol 127 Table 5.1. Observed and predicted entropies of melting in J/K mol 208 Table 5.2. Comparison of estimation schemes 231 10 ABSTRACT The total entropy of melting for a wide variety of compounds is estimated by a modification of Walden's rule. This modification accounts for the effects of both molecular rotational symmetry and molecular flexibility on entropy. These effects are combined into a single simple semi-empirical equation. The intercept of the equation was modified from Walden's rule (56.5 J/K mol), which uses a small data set, to 50 J/K -mol, which uses a data set of 237 rigid and asymmetrical molecules. The molecular rotational symmetry number, a, and molecular flexibility number, ((), are separately defined and evaluated for a wide variety of molecules and are shown to be related to the entropy of melting in Chapters II and III, respectively. The two effects are combined so that a single equation can be used to predict the entropy of melting for any nonelectrolyte compound. This semi-empirical equation is tested on an independent data set. For over 930 different molecules, including those which are both rigid and flexible, the average absolute error between the predicted and observed entropy of melting values is only 12.5 J/deg-mol. This difference is within experimental error. 11 CHAPTER I: INTRODUCTION Significance Physico-chemical properties such as melting point, aqueous solubility, and vapor pressure are important in many scientific fields, including pharmacy and environmental sciences. These properties provide information about the potential hazards of chemicals in water and ground systems as well as in the atmosphere. For instance, a water-soluble compound improperly dumped or buried in the ground close to a well can become a health hazard when the water is consumed by the public. Likewise, if a highly toxic compound or even a potent drug is vaporized it can cause other health problems. The physical chemical properties of drugs can provide insight into the formulation of medicines. Their use in formulation development can minimize both time and money. Aqueous solubility is an important property for all potential drugs. An estimate of this property can aid in facilitating and/or eliminating the need for some experiments. For example, performing cosolvent solubility and stability studies are not relevant for a drug that has an estimated water solubility that is much greater than the required dose. Eliminating such studies will in turn reduce the amount of time and money that would have been devoted to the formulation. 12 Another important property is vapor pressure. The FDA requirement for either estimated or experimental vapor pressures for new drug applications can add to the cost of formulating a drug. Estimating this property would substantially lower the cost as well as decrease the time for product acceptance since it can take serveral months to obtain vapor pressure data.