Accurate automated log Po/w measurement by gradient-flow liquid–liquid partition chromatography: Part 1. Neutral compounds

There is a continuing need for a method which can measure log Poctanol/water accurately and precisely. Liquid–liquid partition chromatography is ideally suited for this as the retention time is a direct function of the partition or distribution coefficient. However, the range of measurements using isocratic-flow conditions is limited by the log-linear relation between run time and log Po/w. The use of gradient-flow programming and short columns gives a more versatile procedure, so that appropriate data points can be collected at both the low and high ends of the chromatographic run, corresponding to log Po/w values between 1 and 4. At the same time the precision, accuracy and versatility of the method are kept. This study is a validation of the procedure and measures the log Po/w on 23 representative pharmaceuticals, comprising a mixed set of neutral compounds. The linear plot fitting micropartition log Po/w and those found in literature shows a slope close to unity and a residuum close to zero. This indicates that gradient-flow micropartition chromatography is ruled by partitioning between octanol and the aqueous phase.