Electrochemistry as an adjunct to mass spectrometry in drug development

Abstract

Oxidation plays a number of critical roles in biology and drug metabolism. In addition to being the major process for generating energy in a living cell, it also is the major mechanism by which drugs are metabolized. Oxidation is a contributor to drug bioactivation and idiosyncratic toxicity, and is also involved in drug stability and degradation. Electrochemistry (EC) when used with HPLC has long been recognized as a sensitive and selective detection technique. Indeed more than 90% of pharmaceuticals in the market place are easily oxidized and can be detected using this technique. However, the inherent electrochemical nature of many drugs goes beyond simple analysis. This commonality of oxidation makes EC particularly well suited to studying the oxidative processes in pharmaceuticals – both in the formulation and by the organism. Presented here are techniques that combine EC and MS in a number of formats that can be used: a) to enhance ionization thereby extending the range of compounds measured by LC-MS; b) for the micro-synthesis and identification of drug metabolites; c) for the detection of reactive intermediates and their conjugates; d) identification of potentially problematic molecular “soft spots”; and e) to rapidly study drug stability and predict which antioxidant(s) should be included in formulations.