title: A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment.
abstract: 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 Ptoluene (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 Ptol, 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.
authors.affiliation: Molecular Biotechnology and Health Sciences Dept., Università degli Studi di Torino , via Quarello 15, 10135 Torino, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Caron
authors.affiliation: Molecular Biotechnology and Health Sciences Dept., Università degli Studi di Torino , via Quarello 15, 10135 Torino, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Vallaro
authors.affiliation: Molecular Biotechnology and Health Sciences Dept., Università degli Studi di Torino , via Quarello 15, 10135 Torino, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ermondi
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
authors.forename: Gilles H
authors.initials: GH
authors.lastname: Goetz
authors.affiliation: Worldwide Pharmaceutical Sciences, Pfizer Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
authors.forename: Yuriy A
authors.initials: YA
authors.lastname: Abramov
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
authors.forename: Laurence
authors.initials: L
authors.lastname: Philippe
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut 06340, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Shalaeva
mesh_terms: D000097:Acetonitriles / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006863:Hydrogen-Ion Concentration; D008566:Membranes / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D012995:Solubility; D014050:Toluene / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D000097:Acetonitriles; D004364:Pharmaceutical Preparations; D011108:Polymers; D014867:Water; D014050:Toluene; C032159:acetonitrile
keywords: ElogD; block relevance analysis; drug molecules; intramolecular hydrogen bonds; ionization; lipophilicity descriptor; log Ptol; nonpolar environments; polymeric chromatographic column