Rapid method for the estimation of octanol/water partition coefficient (log Poct) from gradient RP-HPLC retention and a hydrogen bond acidity term (Σα2H)

We propose a rapid method for the measurement of octanol/water partition coefficients (log P-oct) via fast gradient reversed phase retention and the calculation of the hydrogen bond acidity of the compounds. The cycle time of the generic gradient HPLC method is 5 minutes. The general solvation equation obtained for the log P-oct values and the fast gradient Chromatographic Hydrophobicity Indices with acetonitrile (CHIACN) and methanol (CHIMeOH) have been established. It has been revealed that the major difference between the log P-oct and CHIACN lipophilicity scales is their sensitivity towards the hydrogen bond acidity (Sigma alpha (H)(2)) of the compounds. The CHIACN values of the uncharged (neutral) compounds are measured, then the H-bond acidity term (Sigma alpha (H)(2)) is calculated from the structures. The log P-oct values are expressed using the following equation that was established from the data of 86 diverse compounds: Log P-oct = 0.054 CHIACN + 1.319 Sigma alpha (H)(2) - 1.877 N=86 r=0.970 s=0.29 F=655 A hydrogen bond count (HBC) is not as good as Sigma alpha (H)(2) as a measure of H-bond acidity but still gives an acceptable equation: Log P-oct = 0.047 CHIACN + 0.36 HBC - 1.10 N=86 r=0.943 s=0.39 F=336 In order to improve the correlation between the log P-oct and the CHIMeOH values several other terms, such as the H-bond basicity, polarisability and size term should also be considered. Therefore acetonitrile is suggested as the preferred organic modifier. This rapid method can be used as a high throughput lipophilicity screen for combinatorial libraries.