Abstract

Drug discovery programs that generate hundreds of new molecular entities need efficient methodologies for physicochemical profiling. Several high-throughput methods for pK_a screening have been developed in the last 15 years to determine this key physicochemical parameter. Separation techniques such as HPLC–MS or capillary electrophoresis are particularly well-suited due to their high throughput and capacity to deal with impure or complex samples. In addition, potentiometric and (mostly) UV-metric-based methods (plate-based and automated systems), find their place as very precise methodologies for pK_a determination despite of somewhat lower throughput. Finally, pK_a prediction software packages are useful estimator tools but, to date, they cannot replace experimental measurements when accurate pK_a values are required.