Fast log P determination by ultra-high-pressure liquid chromatography coupled with UV and mass spectrometry detections |
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Authors: | Yveline Henchoz Davy Guillarme Sophie Martel Serge Rudaz Jean-Luc Veuthey and Pierre-Alain Carrupt |
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Institution: | (1) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai E-Ansermet 30, CH-1211 Geneva 4, Switzerland |
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Abstract: | Ultra-high-pressure liquid chromatography (UHPLC) systems able to work with columns packed with sub-2 μm 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 β-blockers, local anesthetics, piperazines, clonidine, and derivatives. Different organic modifiers and hybrid stationary
phases packed with 1.7-μm 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.
Figure The UHPLC approach described here greatly enhanced the time required for log P determination (5' min by compound using UV
detection) and, at least, 8 compounds measured in a 5' run when Mass Spectrometry detection in used. These developments offer
to medicinal chemists a high-throughput method to estimate the lipophilicity of NCEs
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Experimental section for capillary electrophoresis
(CE) measurements, list of the 38 compounds of the calibration set and solvatochromic analyses of the extrapolated retention
factors and partition coefficients. |
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Keywords: | Lipophilicity UHPLC Reversed-phase liquid chromatography Partition coefficients Physicochemical profiling |
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