A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment

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• 作者：Giulia Caron ; Maura Vallaro ; Giuseppe Ermondi ; Gilles H. Goetz ; Yuriy A. Abramov ; Laurence Philippe ; Marina Shalaeva
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：March 7, 2016
• 年：2016
• 卷：13
• 期：3
• 页码：1100-1110
• 全文大小：513K
• ISSN：1543-8392

文摘

This study describes the design and implementation of a new chromatographic descriptor called log k′80 PLRP-S that provides information about the lipophilicity of drug molecules in the nonpolar environment, both in their neutral and ionized form. The log k′80 PLRP-S obtained on a polymeric column with acetonitrile/water mobile phase is shown to closely relate to log P_toluene (toluene dielectric constant ε ∼ 2). The main intermolecular interactions governing log k′80 PLRP-S were deconvoluted using the Block Relevance (BR) analysis. The information provided by this descriptor was compared to ElogD and calclog P_tol, and the differences are highlighted. The “charge-flush” concept is introduced to describe the sensitivity of log k′80 PLRP-S to the ionization state of compounds in the pH range 2 to 12. The ability of log k′80 PLRP-S to indicate the propensity of neutral molecules and monoanions to form Intramolecular Hydrogen Bonds (IMHBs) is proven through a number of examples.