Resolution of a racemic pharmaceutical intermediate. A comparison of preparative HPLC, steady state recycling, and...

Preparative HPLC and simulated moving bed (SMB) chromatography were used to resolve significant quantities of a racemic pharmaceutical intermediate. In addition, smaller scale studies using closed-loop recycling and steady state recycling (SSR) were performed so that a meaningful comparison of all these techniques could be made using the same real world separation. A highly optimized, six-column SMB process was clearly the superior technique and was used for the process-scale (247 kg of racemate) resolution. At the more moderate lab-scale (33 kg of racemate and 19 kg of racemate), a frequently used but less optimized eight-column SMB process was used. It was found that SSR was comparable to the lab-scale SMB process in productivity and solvent consumption. Thus, it appears that SSR can be a useful choice at such moderate scales. Finally, at moderate scales when neither SSR nor SMB is available, it was found that acceptable results were obtained with both closed-loop recycling and with a two-step preparative process.