Advanced reaction-monitoring of pharmaceutical processes enabled with Sub/supercritical fluid chromatography

Abstract Reaction monitoring is crucial in order to guide pharmaceutical chemical processes towards successful outcomes. Many drug substances require the application of water/additive-free solvents to guide process efforts which are intrinsically incompatible with reversed phase liquid chromatography (RPLC) conditions. Sub/supercritical fluid chromatography (SFC) helps to overcome many of these challenges delivering unmatched speed, with low cost, high-efficiency and an additive-free environment, ideal for reaction monitoring species chemically susceptible to water. Herein, we provide several examples where traditional RPLC fails or delivers sub-optimal performance in monitoring processes. These examples include using additive-free SFC-UV and SFC-MS methodologies to overcome difficulties associated with: 1) on-column RPLC keto-enol tautomerization, 2) avoiding RPLC imine hydrolysis, 3) improving normal phase liquid chromatography (NPLC) and capillary zone electrophoresis (CZE) methods, and 4) avoiding the use of tedious pre-column derivatization RPLC-UV procedures.