A high-throughput method has been developed for lipophilicity measurement. It measures the partition coefficient of a solute between a polymer phase and an aqueous phase (P pw ) in a 96-well format. The polymer is plasticized poly(vinyl chloride) (PVC), which is widely used as a material for clinical containers and ion-selective electrodes. The composition is 2:1 (w/w) dioctyl sebacate (DOS) and PVC. With 6 repeats, log P pw values of 15 solutes have been determined in one 96-well microplate in 4 hours. A linear relationship between log P pw and log P ow (octanol-water partition coefficient) values exists with a correlation coefficient of 0.979. The slope and intercept of the log P pw vs. log P ow plot are statistically indistinguishable from 1 and 0, respectively. Similar to the HPLC method, by using the correlation line as a calibration curve, the measured log P pw values can be used to predict log P ow . This protocol is faster than the HPLC method. Moreover, it is straightforward to extend the protocol to the determination of the distribution coefficient and pK a of charged solutes. We show that the log P pw of the neutral form of racemic econazole is 4.83(±0.06), for the cationic form (presumably as a dihydrogen phosphate ion pair) 1.68(±0.04), and the pK a is 6.15(±0.04). This method has great flexibility as well, and is potentially fully automated.Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic environment. 1, 2 Over a century ago, Overton 3 and Meyer's 4 pioneering work demonstrated that the lipophilicity of a compound could be related quantitatively to its biological activity. As suggested by Collander 5 and Hansch, 6, 7 the logarithmic value of the n-octanol/water partition coefficient, log P ow , has been widely recognized in the pharmaceutical, biomedical and environmental sciences to describe the lipophilicity of various compounds. Numerous experimental methods exist to measure log P ow values. The shake-flask procedure is a standard method 8 to determine log P ow in the range of -2 to 4, but it is time and labor consuming, and requires relatively large amounts of pure compounds. 9, 10 In addition, entrainment and octanol/water emulsions can be severe problems for compounds having a log P ow value larger than 4. 11 The HPLC method is an indirect way to estimate log P ow values in the range of 0 to 6, and has also become a standard procedure. 12, 13 A series of reference compounds is injected onto a C18 column. The compounds' retention factors are used to create a calibration curve with their known log P ow values. Compounds with unknown log P ow values are then injected and their retention factors are used to predict log P ow from the calibration curve. However, this technique is only valid for neutral molecules since charged molecules have a far more complex retention behavior than simple partitioning. HPLC and other separation-based methods to determine log P ow have been reviewed. 11, 14, 15 Responding to the need for more speed and accuracy, workers have ...