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.

Intramolecular hydrogen bonding: An opportunity for improved design in medicinal chemistry

“…Log k’80 PLRP‐S measures the lipophilicity of neutral compounds in an apolar environment . Like EPSA, log k′80 PLRP‐S should be used in a pairwise way.…”

“…46 Log k'80 PLRP-S measures the lipophilicity of neutral compounds in an apolar environment. 67 Like EPSA, log k′ 80 PLRP-S should be used in a pairwise way. Indeed, for a pair of close analogs, we can assume that both the control and the sample have similar size and hydrophobic properties and their difference in log k′80 PLRP-S is mostly due to of the difference in the exposed HBD properties.…”

“…b) EPSA, an experimental descriptor of molecular polarity that can be obtained from supercritical fluid chromatography retention (normal-phase conditions),65,66 and c) log k'80 PLRP-S, a molecular descriptor obtained using a reverse-phase chromatographic system with a polystyrene/divinylbenzene polymeric column as a stationary phase and an acetonitrile:buffer mixture (80:20) as a mobile phase 67. …”

Log P as a tool in intramolecular hydrogen bond considerations

“…However, log Poct is not a convenient choice to assess IMHB properties. This is revealed by a Quantitative Structure-Property Relationship (QSPR) where log Poct was related to a set of Volsurf+ descriptors (https://www.moldiscovery.com/) by a Partial Least Square (PLS) algorithm and the final model was analysed using the BR analysis [13]. Shortly, BR analysis shows in one picture (see Fig.…”

Leveraging chromatography based physicochemical properties for efficient drug design

“…Furthermore, an RP HPLC method using a polystyrene-divinylbenzene stationary phase (PLRP-S) was developed to simulate a non-polar lipidic membrane environment [48], and to obtain experimental lipophilicity values.…”