Pushing the speed limit in enantioselective supercritical fluid chromatography

Abstract

Chromatographic enantioseparations on the order of a few seconds can be achieved by supercritical fluid chromatography using short columns packed with chiral stationary phases. The evolution of ‘world record’ speeds for the chromatographic separation of enantiomers has steadily dropped from an industry standard of 20–40 min just two decades ago, to a current ability to perform many enantioseparations in well under a minute. Improvements in instrument and column technologies enabled this revolution, but the ability to predict optimal separation time from an initial method development screening assay using the tmin cc predictor greatly simplifies the development and optimization of high-speed chiral chromatographic separations. In this study, we illustrate how the use of this simple tool in combination with the workhorse technique of supercritical fluid chromatography on customized short chiral columns (1–2 cm length) allows us to achieve ultrafast enantioseparations of pharmaceutically relevant compounds on the 5–20 s scale, bringing the technique of high-throughput enantiopurity analysis out of the specialist realm and into the laboratories of most researchers.