| Preface |
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xi | |
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1 The Drug Discovery Process |
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1 | (8) |
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7 | (1) |
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7 | (1) |
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7 | (2) |
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2 Drug-Likeness and Physicochemical Property Space of Known Drugs |
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9 | (6) |
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12 | (1) |
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13 | (1) |
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13 | (2) |
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3 Basic Pharmacokinetic Properties |
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15 | (19) |
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17 | (3) |
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20 | (2) |
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22 | (1) |
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23 | (6) |
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Unbound Volume of Distribution |
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29 | (1) |
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30 | (1) |
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30 | (1) |
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31 | (1) |
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31 | (1) |
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32 | (1) |
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33 | (1) |
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4 Principles and Methods of Chromatography for the Application of Property Measurements |
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34 | (18) |
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Theoretical Background of Chromatography |
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35 | (2) |
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Retention Factor and Its Relation to the Distribution Constant Between the Mobile and the Stationary Phases |
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37 | (3) |
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Measure of Separation Efficiency |
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40 | (2) |
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Resolution and Separation Time |
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42 | (2) |
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44 | (3) |
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Applicability of Chromatography for Measurements of Molecular Properties |
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47 | (2) |
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49 | (1) |
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50 | (1) |
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50 | (2) |
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5 Molecular Physicochemical Properties that Influence Absorption and Distribution---Lipophilicity |
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52 | (60) |
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52 | (6) |
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Lipophilicity Measurements by Reversed Phase Chromatography with Isocratic Elution |
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58 | (10) |
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Lipophilicity Measurements by Reversed Phase Chromatography with Gradient Elution |
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68 | (4) |
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Lipophilicity of Charged Molecules---pH Dependence of Lipophilicity |
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72 | (6) |
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Biomimetic Lipophilicity Measurements by Chromatography |
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78 | (12) |
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Comparing Various Lipophilicity Measures by the Solvation Equation Model |
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90 | (12) |
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102 | (3) |
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105 | (1) |
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105 | (7) |
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6 Molecular Physicochemical Properties that Influence Absorption and Distribution---Solubility |
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112 | (38) |
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112 | (4) |
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Molecular Interactions with Water |
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116 | (3) |
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Various Solubility Measurements that can be Applied During the Drug Discovery Process |
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119 | (2) |
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Conditions that Affect Solubility |
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121 | (11) |
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132 | (2) |
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Solubility and Dissolution in Biorelevant Media |
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134 | (2) |
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Composition of Fasted State Simulated Intestinal Fluid (FaSSIF) |
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136 | (1) |
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Preparation of FaSSIF Solution |
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136 | (1) |
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Composition of Fed State Simulated Intestinal Fluid (FeSSIF) |
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136 | (1) |
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Preparation of FeSSIF solution |
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136 | (7) |
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143 | (3) |
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146 | (1) |
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146 | (4) |
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7 Molecular Physicochemical Properties that Influence Absorption and Distribution---Permeability |
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150 | (32) |
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150 | (3) |
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153 | (2) |
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Physicochemical Principles of Permeability |
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155 | (4) |
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Experimental Methods to Measure Artificial Membrane Permeability |
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159 | (7) |
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Relationships Between Permeability, Lipophilicity, and Solubility |
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166 | (5) |
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Chromatography as a Potential Tool for Measuring the Rate of Permeation |
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171 | (4) |
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175 | (3) |
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178 | (1) |
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178 | (4) |
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8 Molecular Physicochemical Properties that Influence Absorption and Distribution---Acid Dissociation Constant---pKa |
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182 | (31) |
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182 | (6) |
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Methods for Determining pKa |
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188 | (4) |
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Spectrophotometric Determination of pKa |
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192 | (3) |
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Determination of pKa by Capillary Electrophoresis |
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195 | (2) |
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Chromatographic Approaches for the Determination of pKa |
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197 | (10) |
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207 | (2) |
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209 | (1) |
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209 | (4) |
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9 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors---Absorption |
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213 | (29) |
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214 | (3) |
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Absorption Models with Lipophilicity and Size |
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217 | (4) |
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Biopharmaceutics Classification System (BCS) |
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221 | (6) |
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Absorption Potential---Maximum Absorbable Dose |
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227 | (5) |
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Abraham Solvation Equations for Modeling Absorption |
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232 | (3) |
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Effect of Active Transport and Metabolizing Enzymes on Oral Absorption and Bioavailability |
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235 | (1) |
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236 | (2) |
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238 | (1) |
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238 | (4) |
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10 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors---Distribution |
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242 | (61) |
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Models for Volume of Distribution |
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249 | (27) |
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276 | (12) |
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Blood/Brain Distributions |
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288 | (6) |
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294 | (2) |
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296 | (2) |
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298 | (1) |
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298 | (5) |
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11 Models with Measured Physicochemical and Biomimetic Chromatographic Descriptors---Drug Efficiency |
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303 | (27) |
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303 | (24) |
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327 | (1) |
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327 | (1) |
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328 | (2) |
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12 Applications and Examples in Drug Discovery |
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330 | (57) |
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Structure--Lipophilicity Relationships |
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330 | (16) |
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Structure--Solubility Relationships |
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346 | (8) |
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Structure--Permeability Relationships |
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354 | (8) |
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Structure--Charge State Relationships |
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362 | (4) |
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Structure--Protein Binding Relationships |
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366 | (5) |
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Structure--Phospholipid Binding Relationships |
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371 | (5) |
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376 | (3) |
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379 | (1) |
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379 | (8) |
| Appendix A Answers to the Questions for Review |
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387 | (40) |
| Appendix B List of Abbreviations and Symbols |
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427 | (6) |
| Index |
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433 | |
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