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Thesis Title Transfer of Small Molecules Across Membrane-Mimetic Interfaces A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Engineering and Physical Sciences 2011 Matěj Velický School of Chemistry List of Contents Section Title Page List of Contents 2 List of Tables 5 List of Figures 6 Symbols 10 Abbreviations 14 Abstract 16 Declaration and Copyright Statement 17 Dedication and Acknowledgment 18 Chapter 1 Introduction 19 1.1 Drug Discovery 19 1.2 Parallel Artificial Membrane Permeation Assay 26 1.3 Permeation Assay under Hydrodynamic Control 29 1.4 Drug Absorption and pH-partition Hypothesis 31 1.5 Electrochemical Methods 33 1.5.1 Cyclic Voltammetry and Linear Sweep Voltammetry 33 1.5.2 Amperometry and Potentiometry 36 1.6 Liquid/Liquid Electrochemistry 37 1.6.1 Ion Transfer across Liquid/Liquid Interface 37 1.6.2 Ionic Partition Diagrams of Ionisable Drugs 42 1.6.3 Electron Transfer across ITIES 44 1.7 Bipolar Electrochemical Cell 46 1.8 Artificial Membrane Polarisation 48 1.9 Thesis Overview 50 Chapter 2 Materials, Equipment and Methods 52 2.1 Materials 52 2.2 Equipment 55 2.3 Methods 56 2.3.1 Permeation Assay under Hydrodynamic Control 56 2.3.2 Shake-Flask Method 60 2.3.3 Numerical Method 61 2.3.4 Permeation Assay with External Membrane Polarisation 62 2.3.5 Liquid/Liquid Electrochemistry 65 2.3.6 Rotating Bipolar Electrochemical Cell 73 2.3.7 Reference Electrodes 75 - 2 - Section Title Page In Situ Artificial Membrane Permeation Assay under Chapter 3 79 Hydrodynamic Control 3.1 Introduction 79 3.2 Method Development 84 3.3 Analytical Transport Model 85 3.3.1 Derivation of the Analytical Transport Model 85 3.3.2 Permeability Terms 89 3.3.3 Permeability Hydrodynamic Model 90 3.3.4 Permeability-pH Dependence 92 3.3.5 Lag Time Determination 92 In Situ Time-Dependent Permeation and Numerical Transport 3.4 93 Model 3.5 Dependence of Effective Permeability on Stirring Rate 99 3.6 Permeability-pH Profiles 100 3.7 Permeability Hydrodynamics 110 3.8 Lag Time 115 3.8.1 Dependence on Stirring Rate 117 3.8.2 Dependence on Lipophilicity 120 3.8.3 Dependence on Concentration Gradient 121 3.9 Permeability Dependence on Concentration Gradient 123 3.10 Conclusions 125 Chapter 4 Permeation Assay with External Membrane Polarisation 127 4.1 Introduction 127 4.2 Experimental 130 4.3 Results and Discussion 131 4.3.1 Resistivity of the Permeation Cell 131 4.3.2 Open Circuit Potential Measurements 131 4.3.3 Cyclic Voltammetry on the Permeation Cell 134 4.3.4 Amperometric Measurements 143 4.4 Conclusions 148 Chapter 5 Prediction of Drug Absorption in Humans 150 5.1 Introduction 150 5.2 Experimental 155 5.2.1 Correction of Bioavailability for First Pass Hepatic Clearance 155 5.2.2 Correction for Paracellular Transport 156 5.2.3 Extrapolation of Effective permeability to Set Unstirred Water Layer 158 5.2.4 Absorption Data Dependence on Effective permeability 159 5.3 Correlation of Permeability Coefficients with Bioavailability 161 5.4 Conclusions 172 - 3 - Section Title Page Chapter 6 Drug Transfer across Liquid/Liquid Interface 173 6.1 Introduction 173 6.2 Aqueous and Organic Electrolytes for Water/1,2-DCE System 177 6.3 Ion Transfer under Unstirred Conditions 180 6.3.1 Transfer of Fully Ionized Species across ITIES 180 6.3.2 Transfer of Partially Ionized Species across ITIES 188 6.3.3 Warfarin Water/1,2-DCE Partition Study 193 6.4 Drug Transfer Employing Rotating Membrane 198 6.5 Conclusions 203 Chapter 7 Reversible Electron Transfer in Rotating Bipolar Cell 204 7.1 Introduction 204 7.2 Experimental 207 7.3 Results and Discussion 208 7.3.1 Cyclic Voltammetry 208 7.3.2 Linear Sweep Voltammetry 209 7.4 Conclusions 214 Final Conclusions and Suggestions for Future Work 215 References 219 Appendix 233 A1 UV Spectra and Calibration Data of 31 Studied Drug Molecules 233 A2 Additional Optimization and Testing of the Permeation Cell 245 A3 Time-Dependent Permeation Profiles 252 A4 Additional Permeability and Lipophilicity Data 256 A5 ITIES Area Calibration 260 A6 Silver/Silver Sulphate Reference Electrode for L/L System 262 There are 59,468 words in this thesis, including endnotes and footnotes. - 4 - List of Tables No. Title Page Chapter 2 Purity of the BTPPATPBCl electrolyte verified by elemental 2.1 4 72 microanalysis Chapter 3 3.1 Lag time values for verapamil permeation at various donor pH 97 3.2 Lag time values of verapamil at different stirring rates and iso-pH 7.4/7.4 98 3.3 Permeability coefficients as function of the donor pH 101 Intrinsic and UWL permeability coefficients of warfarin, verapamil, 3.4 108 propranolol and cetirizine determined from permeability-pH dependence Comparison of the average intrinsic permeability values obtain from 3.5 109 hydrodynamic extrapolation and permeability-pH profile. Comparison of the unstirred water layer thickness determined from 3.6 114 hydrodynamic extrapolation, pH-profile and Levich equation Lag time and physicochemical properties of propranolol, quinine, 3.7 117 midazolam and verapamil. Permeability coefficients and the hydrodynamic exponent of propranolol 3.8 124 as a function of initial drug concentration in donor compartment Chapter 4 4.1 Molar ionic flux and ionic permeability coefficients 147 Chapter 5 Molar mass, charge state, pK , aqueous diffusion coefficient and absolute 5.1 a 154 human bioavailability of 31 selected drug molecules 5.2 Permeability coefficients of 31 studied drug molecules 165 Contribution of unstirred water layer, paracellular and transcellular 5.3 167 components to optimised effective permeability coefficient Chapter 6 Standard transfer potential, standard Gibbs energy of transfer, standard 6.1 partition coefficient and aqueous diffusion coefficient of perchlorate, 188 nitrate, iodide, TMA+ and TEA+ ions in water/1,2-DCE system 6.2 Partitioning of warfarin from the aqueous phase to 1,2-DCE 194 Appendix A1.1 Molar absorption coefficients of 31 studied drug molecules 233 A2.1 Effective permeability of verapamil for standard/reduced membrane area 251 Membrane retention and membrane diffusion coefficients of warfarin, A4.1 256 verapamil, propranolol, cetirizine as a function of donor compartment pH Membrane-donor distribution coefficients of warfarin, verapamil, A4.2 257 propranolol and cetirizine determined by shake-flask experiment A4.3 Membrane-donor distribution coefficients of 31 studied drug molecules 258 Membrane diffusion coefficients of 31 studied drug molecules determined A4.4 from membrane permeability and membrane/donor distribution 259 coefficients. Potential stability of reference electrodes prepared under various A6.1 263 conditions - 5 - List of Figures No. Title Page Chapter 1 1.1 LADMET concept of drug discovery 19 1.2 Structure of the small intestine in relation to drug absorption 23 1.3 Schematic of transport mechanisms across the epithelial cell monolayer 24 1.4 PAMPA method schematic 27 1.5 96-well microtitre plate used in PAMPA method 28 1.6 Schematic of a cyclic voltammogram in a redox couple system 34 1.7 Example of Randles-Ševčík plot 35 1.8 BTPPATPBCl4 38 1.9 Electric double layer formed at water/1,2-DCE interface 39 1.10 Potential profile across polarised water/1,2-DCE interface 39 1.11 Comparison of TMA+ transfer across ITIES and blank potential window 40 1.12 Ionic partition diagram of cetirizine in water/1,2-DCE system. 42 1.13 Detailed ionic partition diagram of cetirizine in water/1,2-DCE system. 43 1.14 Schematic of the ET between two redox couples across L/L interface 44 1.15 Schematic of the ET between two redox couples in the BEC 46 1.16 Schematic of the polarised artificial membrane permeation method 49 Chapter 2 Schematic diagram of the permeation cell used for in situ UV 2.1 57 measurement 2.2 Block scheme of the permeation and analysis procedure 60 2.3 Schematic diagram of the permeation cell with membrane polarisation 63 2.4 Block scheme of the membrane polarisation method 64 2.5 Schematic of the static L/L electrochemical cell 65 2.6 Schematic diagram of the rotating L/L electrochemical cell 67 2.7 Comparison of chloride and sulphate based electrolyte potential window 69 2.8 Metathesis reaction to produce the organic BTPPATPBCl4 electrolyte 70 2.9 Schematic of the organic BTPPATPBCl4 electrolyte preparation 71 2.10 Schematic diagram of the permeation cell modified to rotating BEC 73 Potential-time stability of the Ag/AgCl and Ag/Ag SO reference 2.11 2 4 76 electrodes 2.12 Potential-time dependence for Ag/AgTPBCl4 reference electrode 78 - 6 - No. Title Page Chapter 3 Schematic diagram of the concentration profile across the donor- 3.1 85 membrane-acceptor tri-layer 3.2 Example of concentration-time plots for warfarin and verapamil 93 3.3 Numerical simulation of concentration profiles 95 3.4 Schematic diagram of membrane loading with hydrophilic/lipophilic drug 96 3.5 Dependence of the inverse of effective permeability on the stirring rate 99 3.6 Permeability – donor pH profile of warfarin 102 3.7 Permeability – donor pH profile of verapamil 103 3.8 Permeability – donor pH profile of propranolol 105 3.9 Permeability – donor pH profile of cetirizine 106 3.10 Hydrodynamic exponent α as a function of pH 110 3.11 Dependence of α on the membrane/buffer distribution coefficient 112 Permeation ln(k)-time plots of propranolol, quinine, verapamil and 3.12 116 midazolam 3.13 Permeation ln(k)-time plots of propranolol at donor/acceptor pH 7.4/7.4 118 3.14 Dependence of the lag time on the inverse angular velocity of stirring 120 Dependence of the lag time on the membrane/donor
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