Determination of Octanol-Water Partition Coefficients for a Series of Imidazolidinediones by a Novel Combination of Micro Shake-Flask and HPLC Techniques

Abstract

Octanol-water partition coefficient (Log P) values for a series of 19 imidazolidinedione analogues have been determined by high performance liquid chromatography. To obtain a regression equation between log P and chromatographic log k′ values, a modified micro shake-flask method has been developed. In the shaking step, a simple syringe and test tube system was devised and has proved sufficient to ensure the proper distribution of analytes between the two phases. In addition, HPLC was used not only as a detector for the shake-flask method, but also as a technique for determining the capacity factors of the compounds. Further technique modifications include alternatives to the use of octanol and dimethyl sulfoxide (DMSO) in HPLC thereby eliminating the detrimental effect of these solvents on the stationary phase. Our micro shake-flask method is a modified version of the technique developed by Ford et al. which used a Mixxor-separator device for distribution of solute and an HPLC apparatus for the determination of the ratio of solute concentrations in the two phases [H. Ford, Jr., C. L. Merski, and J. A. Kelley, J. Liq. Chromatogr., 14, 3365, 1991]. Finally, calculated log P values for this imidazolidinedione series have also been determined and compared to experimental data. The relationship between lipophilicity and anticonvulsant activity for the molecules has thus been examined.