title: Simultaneous determination of hydrophobicity and dissociation constant for a large set of compounds by gradient reverse phase high performance liquid chromatography-mass spectrometry technique.
abstract: Fast and reliable methods for the determination of hydrophobicity and acidity are desired in pre-clinical drug development phases to eliminate compounds with poor pharmacokinetic properties. Reversed-phase high-performance liquid chromatography (RP HPLC) coupled with time-of-flight mass spectrometry (RP HPLC-ESI-TOF-MS) is a convenient technique for that purpose. In this work we determined the chromatographic measure of hydrophobicity (logkw) and dissociation constant (pKa) simultaneously for a large and diverse group of 161 drugs. Retention times were determined by means of RP HPLC-ESI-TOF-MS for a series of pH and organic modifier gradients. We were able to measure retention times for 140 out of 161 (87%) compounds. For those analytes logkw and pKa parameters were calculated and compared with literature and ACD Labs-calculated data. The determined chromatographic measure of hydrophobicity and dissociation constant was closely related to literature and theoretically calculated values. Applied methodology achieved the medium-throughput screening rate of 100 compounds per day and proved to be a simple, fast and reliable approach of assessing important physicochemical properties of drugs. This technique has certain limitations as it is not applicable for very hydrophilic analytes (logP<0.5) and compounds with identical molar masses.
authors.affiliation: Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Kubik
authors.affiliation: Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Wiktoria
authors.initials: W
authors.lastname: Struck-Lewicka
authors.affiliation: Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Roman
authors.initials: R
authors.lastname: Kaliszan
authors.affiliation: Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gen. J. Hallera 107, 80-416 Gdańsk, Poland. Electronic address: wiczling@gumed.edu.pl.
authors.forename: Paweł
authors.initials: P
authors.lastname: Wiczling
mesh_terms: D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D056148:Chromatography, Reverse-Phase / Q000379:methods*; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
chemical_list: D004364:Pharmaceutical Preparations
keywords: Acidity; Gradient RP HPLC; Hydrophobicity; Throughput analysis; pH/organic modifier