Estimation of alkane–water log P for neutral, acidic, and basic compounds using an alkylated polystyrene-divinylbenzene high-performance liquid chromatography column

• An HPLC method that can estimate alkane–water partition coefficients is described.
• Isocratic and gradient versions are shown to be equally effective.
• New method is compared against existing methods for predicting log Palk and log Poct.
• The new gradient HPLC method is rapid, accurate, and robust.
• Method may expand the use of log Palk as a lipophilicity descriptor in drug discovery.

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 log Palk. This study describes a high-throughput method for determining HPLC-log Palk, a chromatographic parameter closely related to log Palk, 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 log k was essentially linear. Thus, gradient retention time could be used as the sole input needed to determine an apparent log Palk by HPLC. HPLC-log Palk showed linear correlation (R2 > 0.96, n = 59) with reference log Palk 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.