Ultra-fast microscale purification of chiral racemates and achiral pharmaceuticals with analytical supercritical fluid chromatography

•Highlights rationale for the development of an analytical SFC micro-purification system.•Microgram-scale isolation of pharmaceuticals including chiral compounds with methods as fast as 1.0 min is shown using analytical SFC.•Custom gas liquid separator design and alterations to the fluidics pathways enables this novel platform for micro-isolations.•Small-quantity, high-purity compound arrays can be isolated in support of high-throughput experimentation. Improving efficiency while maintaining high quality separations is a central theme for specialized analytical/purification groups supporting discovery chemistry programs. Supercritical fluid chromatography (SFC) has become the prevalent technique for chiral separation and a complementary technique to reverse phase high-pressure liquid chromatography (RP-HPLC). In this manuscript we demonstrate the successful micro-isolation of chiral racemates, small molecules, and peptides using a sub-minute method on an analytical SFC system. The addition of a custom gas liquid separator (GLS) and alterations to the fluidic pathways allow the fractionation of desired products on a micro-scale SFC platform, providing analytical method development, purifications, and purity confirmation on a single SFC system. This enables micro-purification of pharmaceuticals including chiral racemates at high speed and reduced cost of materials. The resulting small-quantity, high-purity products enable follow-up enantioselective isolations from racemic products of parallel synthesis libraries. The processes established here will be beneficial for the isolations of other desired products in complex crude mixtures.