title: High throughput log D determination using liquid chromatography-mass spectrometry.
abstract: A method has been developed which allows direct measurement of partition coefficients (log D, log P) using liquid chromatography-mass spectrometry (LC-MS). The high throughput, microtiter plate based protocol uses small quantities of 10 mM analyte in DMSO solution (5 microL) and is therefore amenable to standard archive and screening formats. Single Ion Monitoring (SIM) mass spectrometry is used to achieve optimal sensitivity. Experimental log D values for 34 known drugs have been determined, with partition coefficients ranging from -2 to 5, giving data very similar to literature values. In these analyses, deviations from known values average less than 0.3 log units. The sample handling and data processing have been significantly automated, and the protocol has been applied to over 800 in-house lead molecules to date. In its format, sensitivity, throughput, and amenability to automation, it represents significant progress in the direct measurement of partitioning behavior [1].
authors.affiliation: DuPont Pharmaceuticals Research Laboratories, 4570 Executive Drive, Suite 400, San Diego, CA 92121, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Wilson
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Walsh
authors.forename: R A
authors.initials: RA
authors.lastname: Rourick
mesh_terms: D002460:Cell Line; D002853:Chromatography, Liquid / Q000379:methods; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004121:Dimethyl Sulfoxide; D015195:Drug Design; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D012680:Sensitivity and Specificity
chemical_list: D004364:Pharmaceutical Preparations; D004121:Dimethyl Sulfoxide