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

✍ Scribed by Christopher E. Kibbey; Salwa K. Poole; Ben Robinson; J. Derek Jackson; Douglas Durham

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 257 KB
• Volume: 90
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.1070

✦ Synopsis

Automated log P, pK a , solubility, and chemical stability systems comprise an integrated process that provides early stage physicochemical property data to the discovery research organization. Capillary electrophoresis (CE) techniques are used to experimentally determine pK a and log P. Solubility is determined using a quasiequilibrium approach employing sample quantitation by ¯ow injection analysis with ultraviolet (UV) detection at 256 nm. Chemical stability is assessed by challenging compounds with pH 2, pH 7, pH 12, and 3% hydrogen peroxide solutions overnight, and comparing the chromatographic pro®les of the stability challenged solutions to that of a freshly prepared control. Validation of the log P method using a set of drug-like compounds demonstrates that the method yields log P values within AE0.5 units of literature values. The log P method is valid over the range À0.5±5.0, and the technique is compatible with acidic, neutral, and basic compounds. The pK a technique yields results within AE0.2 units of corresponding values obtained by potentiometric titration over a pK a range of 2 to12. Solubility is reported in a 3±60 mg/mL range, and the results are generally within 20% of values measured by equilibrium solubility techniques. The current level of automation supports the measurement of the physicochemical properties of 100 compounds per week. Physicochemical property data for $2000 compounds have been generated to date.