Rapid method for the estimation of octanol/water partition coefficient (log P-oct) from gradient RP-HPLC retention and a hydrogen bond acidity term (Sigma alpha(H)(2))

We propose a rapid method for the measurement of octanol/water partition co efficients (log P-oct) via fast gradient reversed phase retention and the c alculation of the hydrogen bond acidity of the compounds. The cycle time of the generic gradient HPLC method is 5 minutes. The general solvation equat ion obtained for the log P-oct values and the fast gradient Chromatographic Hydrophobicity Indices with acetonitrile (CHIACN) and methanol (CHIMeOH) h ave been established. It has been revealed that the major difference betwee n the log P-oct and CHIACN lipophilicity scales is their sensitivity toward s the hydrogen bond acidity (Sigma alpha (H)(2)) of the compounds. The CHIA CN values of the uncharged (neutral) compounds are measured, then the H-bon d acidity term (Sigma alpha (H)(2)) is calculated from the structures. The log P-oct values are expressed using the following equation that was establ ished 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 measu re 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 v alues 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 th roughput lipophilicity screen for combinatorial libraries.