Separation of a racemic pharmaceutical intermediate using closed-loop steady state recycling

Closed-loop steady state recycling (formerly called closed-loop recycling with periodic intra-profile injection or CLRPIPI) is similar to simulated moving bed (SMB) chromatography. Both steady state recycling (SSR) and SMB are steady state, binary chromatographic techniques in which fresh sample is injected into the interior of the circulating chromatographic profile and two fractions or product streams are collected from either end of the profile. However, SMB is a continuous process, whereas SSR is a repetitive, though discontinuous, process. Underlying mechanisms of closed-loop SSR were studied using the separation of a racemic pharmaceutical intermediate. We have found that creation of a stable steady state chromatographic profile is crucial to obtaining high purity fractions. The structure of the steady state profile, also called the steady stare inventory, is controlled by the size of the fractions collected and by the location of the injection points. These SSR parameters have corresponding SMB parameters. For example, increasing the size of Fraction 1 in SSR is equivalent to increasing the raffinate flow-rate in SMB; increasing the distance from the injection point to fraction 1 in SSR is equivalent to increasing the size of zone III in SMB; etc. Finally, the SSR results were compared to those of an SMB separation of the same racemic pharmaceutical intermediate. Using the same chiral stationary phase (CSP) and mobile phase, the production rates (SSR, 255 S racemate/kg CSP/day; SMB, 240 g racemate/kg CSP/day), purities (SSR, 98% e.e. for both enantiomers; SMB, 98% e.e. for both enantiomers), and recoveries (SSR, 99% for both enantiomers; SMB, 99% for both enantiomers) for the two techniques were similar, but SSR used more mobile phase per gram of racemate than SMB. SSR, however, used less mobile phase than batch HPLC. (C) 1998 Elsevier Science B.V. All rights reserved.