Rapid and high throughput separation technologies--steady state recycling and supercritical fluid chromatography for chiral resolution of pharmaceutical intermediates.

The SSR and SFC techniques were used for the enantiomeric resolution of three pharmaceutical intermediates at various sample scales. The separation conditions, the sample purities and yields, the productivities and the solvent consumptions were discussed in three case studies in this paper. In case (I), the SSR process was used for a low selectivity resolution of 2.0 kg of pharmaceutical intermediate. By using this separation process, a productivity of 750 g racemate/kg stationary phase/day was achieved, while solvent usage was minimized ( approximately 200 l/kg racemate). Case (II) pertained to the effectiveness of the SSR process. Productivity using SSR techniques increased by a factor of 4.5, while solvent usage decreased by a factor of 4.1 when compared to the productivity and solvent usage of batch HPLC. Case (III) compared SFC purification to HPLC purification. The SFC process was more effective in terms of an increase in productivity and a reduction in solvent usage. Based on these results, it appears that SSR and SFC are very useful choices at the early stage of the drug development for a high throughput and a rapid turn around of samples.