Integration of supercritical fluid chromatography into drug discovery as a routine support tool. Part I. fast chiral...

Supercritical fluid chromatography (SFC) has been implemented within our group as a purity assessment and purification tool to complement high performance liquid chromatography (HPLC) for diastereomer and chiral separations. Using a novel strategy, rapid chiral screening has been implemented using short columns, high flow rates and fast gradients. A primary screen delivers a separation assessment using one solvent modifier (methanol) and four columns (Chiralpak AD-H and AS-H, and Chiralcel OD-H and OJ-H) run serially in a total of 24 min. A secondary screen then uses ethanol and isopropanol (IPA) modifiers across the same columns. The screens can be combined to run a sequence of samples overnight where each racemate is analysed over 80 min. The fast analytical screening and optimisation process enables rapid identification of the purification method. Furthermore, subsequent preparative chiral SFC has decreased the overall sample turnaround time for the Medicinal Chemist, delivering high fraction purities and acceptable recoveries, substantial operational cost savings and increased flexibility with respect to large scale purification feasibility in comparison to HPLC. SFC has been so successful it is now used as the primary method for chiral analysis and purification within our laboratory.