L Hitzel1, A P Watt, K L Locker. 1. Merck Sharp and Dohme, Neuroscience Research Centre, Essex, United Kingdom.
Abstract
PURPOSE: To present an increased throughput automated shake-flask method for the direct determination of the partition coefficients of solutes between octan-1-ol and buffer. METHOD: The traditional shake-flask method has been transferred onto 96-well plate technology and a robotic liquid handler has been used for sample preparation. A custom programmed Gilson autosampler samples the organic and aqueous phases directly from the plate, circumventing the need for any manual separation. Analyses are performed by reverse phase high performance liquid chromatography (RP-HPLC). Generic fast gradient RP-HPLC conditions are used to eliminate chromatographic method development time and reduce analysis time. RESULTS: A full validation of the automated method is presented for a range of compounds with log D values between -2 and 4. CONCLUSIONS: The advantages and limitations of this direct measurement method are discussed. The use of this methodology provides a means to rapidly assess log D values for large compound arrays.
PURPOSE: To present an increased throughput automated shake-flask method for the direct determination of the partition coefficients of solutes between octan-1-ol and buffer. METHOD: The traditional shake-flask method has been transferred onto 96-well plate technology and a robotic liquid handler has been used for sample preparation. A custom programmed Gilson autosampler samples the organic and aqueous phases directly from the plate, circumventing the need for any manual separation. Analyses are performed by reverse phase high performance liquid chromatography (RP-HPLC). Generic fast gradient RP-HPLC conditions are used to eliminate chromatographic method development time and reduce analysis time. RESULTS: A full validation of the automated method is presented for a range of compounds with log D values between -2 and 4. CONCLUSIONS: The advantages and limitations of this direct measurement method are discussed. The use of this methodology provides a means to rapidly assess log D values for large compound arrays.
Authors: Mehtap Işık; Dorothy Levorse; David L Mobley; Timothy Rhodes; John D Chodera Journal: J Comput Aided Mol Des Date: 2019-12-19 Impact factor: 3.686