An integrated process for measuring the physicochemical properties of drugcandidates in a preclinical discovery environment

Automated log P, pK(a), solubility, and chemical stability systems comprise an integrated process that provides early stage physicochemical property d ata to the discovery research organization. Capillary electrophoresis (CE) techniques are used to experimentally determine pK(a) and log P. Solubility is determined using a quasi-equilibrium approach employing sample quantita tion by flow injection analysis with ultraviolet (UV) detection at 256 Jam. Chemical stability is assessed by challenging compounds with pH 2, pH 7, p H 12, and 3% hydrogen peroxide solutions overnight, and comparing the chrom atographic profiles of the stability challenged solutions to that of a fres hly prepared control. Validation of the log P method using a set of drug-li ke compounds demonstrates that the method yields log P values within +/-0.5 units of literature values. The log P method is valid over the range -0.5- 5.0, and the technique is compatible with acidic, neutral, and basic compou nds. The pK(a) technique yields results within +/-2 units of corresponding values obtained by potentiometric titration over a pK(a) range of 2 to 12. Solubility is reported in a 3-60 mug/mL range, and the results are generall y within 20% of values measured by equilibrium solubility techniques. The c urrent level of automation supports the measurement of the physicochemical properties of 100 compounds per week. Physicochemical property data for sim ilar to 2000 compounds have been generated to date. (C) 2001 Wiley-Liss, In c. and the American Pharmaceutical Association.