An easy-to-use and general nuclear magnetic resonance method for the determination of partition coefficients of drugs and natural products

The lipophilicity of a drug is an important parameter for its eventual development by the pharmaceutical industry. It is usually measured by HPLC following partition of the compound between water and 1-octanol. We present here an alternative, simple, sensitive and quantitative ¹ H nuclear magnetic resonance (NMR) method for the experimental measurement of partition coefficients of natural compounds and pharmaceutical drugs. It is based on measuring concentrations in the water phase, before and after partitioning and equilibration between water and octanol, using the ERETIC (Electronic Reference To Access In Vivo Concentration) technique. The signal to noise ratio is improved by a Water Suppression by Excitation Sculpting sequence. Quantification is based on an electronic reference signal and does not need addition of a reference compound. The log P values of 22 natural metabolites and four pharmaceutical drugs were determined and the experimental results are in excellent agreement with literature data. The experiments were run on ~2 mg material. This technique proved to be robust, reproducible and suitable for log P values between -2 and +2.