Determination of pKa values of basic new drug substances by CE

During the discovery phase for chemical entities as potential new drugs, the determination of pK(a) values can be a very valuable parameter in the selection process. In general, at the very beginning, only small amounts of these active pharmaceutical ingredients (API) are available for analytical characterisation. One drawback of traditional methods such as titration and UV spectroscopy is that they require large amounts of high purity material. As an alternative technique, a method by capillary electrophoresis (CE) which is based on migration times or mobilities of the ionic species over a range of pH values has been evaluated for the determination of pK(a). From the relationship between measured mobilities and pH of electrolyte, a S-shaped curve was obtained and pK(a) values determined for some new API entering the screening phase. On the basis of our experience, the pK(a) determination by CE of early phase compounds can easily be performed with a very small quantity of material and in addition with insoluble compounds. pKa values, similar to those earlier observed by potentiometric titration or computational calculations, were obtained. The reported technique using CE can easily be automated and is able to cope with the high throughput needed at the screening stage of lead optimisation. (C) 2001 Elsevier Science B.V. All rights reserved.