title: Fast log P determination by ultra-high-pressure liquid chromatography coupled with UV and mass spectrometry detections.
abstract: Ultra-high-pressure liquid chromatography (UHPLC) systems able to work with columns packed with sub-2 microm particles offer very fast methods to determine the lipophilicity of new chemical entities. The careful development of the most suitable experimental conditions presented here will help medicinal chemists for high-throughput screening (HTS) log P(oct) measurements. The approach was optimized using a well-balanced set of 38 model compounds and a series of 28 basic compounds such as beta-blockers, local anesthetics, piperazines, clonidine, and derivatives. Different organic modifiers and hybrid stationary phases packed with 1.7-microm particles were evaluated in isocratic as well as gradient modes, and the advantages and limitations of tested conditions pointed out. The UHPLC approach offered a significant enhancement over the classical HPLC methods, by a factor 50 in the lipophilicity determination throughput. The hyphenation of UHPLC with MS detection allowed a further increase in the throughput. Data and results reported herein prove that the UHPLC-MS method can represent a progress in the HTS-measurement of lipophilicity due to its speed (at least a factor of 500 with respect to HPLC approaches) and to an extended field of application.
authors.affiliation: School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai E-Ansermet 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Yveline
authors.initials: Y
authors.lastname: Henchoz
authors.forename: Davy
authors.initials: D
authors.lastname: Guillarme
authors.forename: Sophie
authors.initials: S
authors.lastname: Martel
authors.forename: Serge
authors.initials: S
authors.lastname: Rudaz
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Veuthey
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000032:analysis*; D000777:Anesthetics / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation / Q000379:methods; D003000:Clonidine / Q000032:analysis*; D013058:Mass Spectrometry / Q000295:instrumentation / Q000379:methods; D010879:Piperazines / Q000032:analysis*; D011312:Pressure; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013056:Spectrophotometry, Ultraviolet / Q000295:instrumentation / Q000379:methods; D013997:Time Factors
chemical_list: D000319:Adrenergic beta-Antagonists; D000777:Anesthetics; D010879:Piperazines; D003000:Clonidine