Abstract
Reliable HPLC methods are available to estimate octanol–water partition coefficients, but there is no comparable method for alkane–water partition coefficients that is accurate and applicable across a broad span of logPalk. This study describes a high-throughput method for determining HPLC-logPalk, a chromatographic parameter closely related to logPalk, using an alkylated polystyrene-divinylbenzene column and fast acetonitrile gradient. A structurally diverse set of neutral, acidic, and basic compounds was analyzed under ionization-suppressing pH conditions. In this chromatographic system, the relationship between gradient retention time and isocratic logk was essentially linear. Thus, gradient retention time could be used as the sole input needed to determine an apparent logPalk by HPLC. HPLC-logPalk showed linear correlation (R2>0.96, n=59) with reference logPalk values from shake-flask measurements over 8 orders of magnitude, ranging from −2.3 to +5.7. Linear solvation energy relationship (LSER) analysis revealed that the relative contributions of intermolecular forces effecting retention in the fast gradient system or its corresponding isocratic variant were highly similar to those governing partition in bulk alkane–water.
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