High-throughput determination of octanol/water partition coefficients using a shake-flask method and novel two-phase solvent system

A high-throughput method for determining the octanol/water partition coefficient (P-o/w) of a large variety of compounds exhibiting a wide range in hydrophobicity was established. The method combines a simple shake-flask method with a novel two-phase solvent system comprising an acetonitrile-phosphate buffer (0.1 M, pH 7.4)-1-octanol (25:25:4, v/v/v; AN system). The AN system partition coefficients (K-AN) of 51 standard compounds for which log P-o/w, (at pH 7.4; log D) values had been reported were determined by single two-phase partitioning in test tubes, followed by measurement of the solute concentration in both phases using an automatic flow injection-ultraviolet detection system. The log K-AN values were closely related to reported log D values, and the relationship could be expressed by the following linear regression equation: log D = 2.8630 log K-AN -0.1497(n=51). The relationship reveals that log D values (+8 to -8) for a large variety of highly hydrophobic and/or hydrophilic compounds can be estimated indirectly from the narrow range of log K-AN values (+3 to -3) determined using the present method. Furthermore, log K-AN values for highly polar compounds for which no log D values have been reported, such as amino acids, peptides, proteins, nucleosides, and nucleotides, can be estimated using the present method. The wide-ranging log D values (+5.9 to -7.5) of these molecules were estimated for the first time from their log K-AN values and the above regression equation. (C) 2015 Elsevier B.V. All rights reserved.