Calculation of Abraham descriptors from solvent–water partition coefficients in four different systems; evaluation of different methods of calculation

Abstract

Partition coefficients for a set of drug compounds have been measured in four solvent–water systems, with octanol, chloroform, cyclohexane and toluene as solvents. The data have been used to test four different methods for the calculation of the three Abraham descriptors, dipolarity/polarizability S, hydrogen bond acidity A, and hydrogen bond basicity B. The methods involved (i) the use of Microsoft ‘Solver’, (ii) use of a series of regression equations developed from compounds with known descriptors, and use of two further methods that have been developed, (iii) a program similar to Solver that we denote as ‘Descfit’, and (iv) a program that uses a set of three simultaneous equations, and which we denote as ‘TripleX’. We show that partition coefficients for a given drug in only four solvent–water systems can be used to calculate the three Abraham descriptors reliably, and we test all four methods of calculation for reproducibility and ease of use. We finally test the applicability of descriptors calculated for the set of drug compounds, to predict properties of biological importance such as human intestinal absorption and blood/brain distribution.