Estimation of Ethanol /Water Solubility Profiles
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Estimation of Ethanol/Water Solubility Profiles Item Type text; Electronic Dissertation Authors Machatha, Stephen Gitu 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 23/09/2021 19:23:34 Link to Item http://hdl.handle.net/10150/193915 ESTIMATION OF ETHANOL /WATER SOLUBILITY PROFILES by Stephen Gitu Machatha ________________________ A Dissertation Submitted to the Faculty of the DEPARTMENT OF PHARMACY PRACTICE AND SCIENCE In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY In the Graduate College at THE UNIVERSITY OF ARIZONA 2006 2 THE UNIVERSITY OF ARIZONA GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Stephen Gitu Machatha entitled: Estimation of Ethanol/Water Solubility Profiles and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy _______________________________________________________________________ Date: 5/11/06 Samuel H. Yakowsky, Ph.D _______________________________________________________________________ Date: 5/11/06 Michael Mayersohn, Ph.D _______________________________________________________________________ Date: 5/11/06 Paul Myrdal, Ph.D _______________________________________________________________________ Date: 5/11/06 _______________________________________________________________________ Date: 5/11/06 Final approval and acceptance of this dissertation is contingent upon the candidate’s submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ________________________________________________ Date: 5/11/06 Dissertation Director: Samuel H. Yakowsky PhD. 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: Stephen Gitu Machatha 4 ACKNOWLEDGEMENTS I would like to express my deepest thanks to Prof. Samuel Yalkowsky for his guidance and insights during this journey. Also, express my deepest gratitude to my graduate committee, Dr. Mayersohn, Dr. Myrdal, Dr. Mash and Dr. Hruby. I would like to thank all of the students in the pharmaceutics group for the many discussions that have contributed to my education. Above all I would like to thank my Parents, Prof. Peter M. Gitu and Mrs. Rita W. Gitu, for their love, guidance, encouragement and for giving me this great opportunity. To my siblings, Wamaitha, Wanjiru and Karau thank you for all your support, advice and more so being there during the ups and downs. 5 DEDICATION This is dedicated to my family, for their inspiration, guidance, love and support. 6 TABLE OF CONTENTS LIST OF FIGURES........................................................................................................8 LIST OF TABLES .......................................................................................................10 ABSTRACT .................................................................................................................11 CHAPTER 1. INTRODUCTION................................................................................13 CHAPTER 2. ESTIMATION OF THE OCTANOL/WATER PARTITION COEFFICIENT…………………………………………………………………19 2.1 Introduction ...........................................................................................19 2.2 Method...................................................................................................20 2.3 Results and Discussion .........................................................................21 CHAPTER 3. DEVIATION FROM LINEARITY……………………………32 3.1 Introduction ...........................................................................................32 3.2 Method...................................................................................................35 3.3 Results and Discussion .........................................................................36 CHAPTER 4. ESTIMATION OF THE ETHANOL/WATER SOLUBILITY PROFILE FROM THE OCTANOL/WATER PARTITION COEFFICIENT………………………………………………...43 4.1 Introduction ...........................................................................................43 4.2 Method...................................................................................................46 4.3 Results and Discussion..........................................................................47 CHAPTER 5. BILINEAR MODEL……………………………………..….....53 5.1 Introduction .........................................................................................53 5.2 Method...................................................................................................57 5.3 Results and Discussion .........................................................................58 CHAPTER 6. CASE STUDY....... ……………………………………………65 6.1 Introduction .........................................................................................65 6.2 Materials and Methods ..........................................................................69 6.3 Results and Discussion .........................................................................71 7 TABLE OF CONTENTS - continued APPENDIX A. COMPARISON BETWEEN THE THREE LOGKOW PREDICTION PROGRAMS.............................................................................85 APPENDIX B.ABSOLUTE AVERAGE ERRORS AND ROOT MEAN SQUARE ERRORS CALCULATED FROM THE TWO MODELS [EQUATION (3.4) AND EQUATION (3.5)]....................................................89 APPENDIX C.COMPARISON BETWEEN PREDICTED AND EXPERIMENTAL FMAX VALUES...................................................................91 APPENDIX D.COMPARISON BETWEEN PREDICTED AND EXPERIMENTAL SIGMA 0.5(σ0.5) VALUES................................................93 APPENDIX E.COMPARISON BETWEEN PREDICTED AND EXPERIMENTAL FMAX VALUES...................................................................95 APPENDIX F.ROOT MEAN SQUARE ERRORS CALCULATED FROM THE PARABOLIC, BILINEAR AND LOG-LINEAR IN EQUATIONS 6.1, 6.8 AND 6.2 RESPECTIVELY ........................................................................................97 APPENDIX G.EXPERIMENTAL AND PREDICTED FMAX VALUES AND THE ABSOLUTE ERRORS. ............................................................................99 REFERENCES ...........................................................................................................101 8 LIST OF FIGURES Figure 2.1 Chemical Structure of Sulindac……………………………………..23 Figure 2.2 Plots of experimental against predicted logKow values for the three programs (KowWin, ACD/logP, ClogP) □- non tautomers/zwitterions and ∆- zwitterions and tautomers………………………………………………….........27 Figure 3.1: Comparison between experimental and the predicted solubilities (mg/ml) [(---) Ruckenstein, (▬) proposed model and () third order polynomial] of oxolinic acid plotted against mole fraction of ethanol……………………….40 Figure 3.2: Comparison between experimental and the predicted solubilities(mg/ml) [(---) Ruckenstein, (▬) proposed model and () third order polynomial] of oxolinic acid plotted against volume fraction of ethanol… .….41 Figure 4.1: Plot of Log Kow v/s σ0.5 with linear regression……………………...48 Figure 4.2. Plot of Log Kow v/s fmax where (♦) experimental fmax and (−) is the regression line using equation (4.8)…………………………………………….50 Figure 4.3 Comparison between predicted and experimental ethanol/water solubility profiles for A: paracetamol, B: caffeine C: formyl-leucine, D: benzamide, E: Theophylline………………………………………………..52 Figure 5.1 Water/ethanol solubility profile estimation of anthracene, barbital, caffeine and hydantoic acid using equation 5.8 with optimized σA and σB values. Where (□) experimental values and the solid lines are the theoretical curves….59 Figure 5.2 Plot of the predicted initial (σA) and terminal (σA) asymptotes from equation (4) against logKow….……………………………………………..…...60 Figure 5.3 Plot of the predicted vs experimental fmax values listed in APPENDIX G…………………………………………………………..….…...63 9 LIST OF FIGURES - continued Figure 6.1 Structure of Antalarmin (unionized and ionized form)……………..68 Figure 6.2: pH-solubility profile for Antalarmin……………………………….72 Figure 6.3 Solubilization using cosolvents at pH 2.0 (EtOH-X, PG-□and PEG-∆)………………………………………………………………………….75 Figure 6.4 Solubilization using surfactants (Tween 80 pH 2-○, Tween 80 pH 7-●; Cre-El pH 2-□, Cre-EL pH 7- ■, SLS pH 2, SLS pH 7;CTAB pH 2- ∆, CTAB pH 7- ………………………………………………………………………77 Figure 6.5 Solubilization using complexating agents at pH