RAPID METHOD FOR ESTIMATING OCTANOL-WATER PARTITION COEFFICIENT (LOG P_OCT) FROM ISOCRATIC RP-HPLC AND A HYDROGEN BOND ACIDITY TERM (A)

Abstract

The linear solvation equation approach has been used to describe the octanol/water lipophilicity scale (logPoct) and the isocratic retention factors (log k) obtained using reversed phase HPLC with acetonitrile. Both the octanol/water partition coefficients and the RP-HPLC retention data obtained from the literature, showed good correlation with the molecular descriptors such as size, excess molar refractivity, H-bond acidity/basicity, and polarity/dipolarity. However, the impact of the H-bond acidity term was very different on the two lipophilicity scales. The H-bond acidity term was not significant in describing the octanol/water lipophilicity, while the H-bond acidity of the molecules decreased significantly their RP-HPLC retention. As the other terms had very similar impact on the two lipophilicity scales, it made it possible to convert one scale to the other by incorporating only the H-bond acidity of the compounds as is shown by the equation below, where A is the compound H-bond acidity. Using the simpler hydrogen bond donor counts (HBC) also helped to align the two lipophilicity scales to each other. The validity of the above equations was tested using a test set of 41 drug compounds with our measured data. The log Poct values were estimated from isocratic RP-HPLC retention data with the H-bond acidity term and counts, with an error of 0.284 and 0.325 log unit, respectively.