(470d) Chiral Separation by Two-Column, Semi-Continuous, Open-Loop Simulated Moving-Bed Chromatography

Simulated moving bed (SMB) chromatography is a powerful tool for chiral separation, because of its many advantages with respect to discontinuous batch chromatography, namely higher product purity, less solvent consumption, and higher productivity per unit stationary phase. Despite the lower productivity and higher solvent consumption of batch processes, they are advantageous in other respects, such as in their simplicity (less design effort is necessary and the scale-up is easier), flexibility (changes in conditions can be easily handled), and versatility (multi- and center-cut separations from multi-component mixtures are easy to implement). Somewhere in between, and in an attempt to work with the best of ?two worlds?, we have developed and validated experimentally a two-column version of a multicolumn, semi-continuous, open-loop chromatograph for chiral separation. The heart of the process is a flexible node design and cyclic flow-rate modulation that succeed at keeping the mass-transfer zone inside the system without resorting to any recycling technique. One advantage of this streamlined design is the simplicity of its physical realization: regardless of the number of columns, it only requires two pumps to supply feed and desorbent into the system, while the flow rates of liquid withdrawn from the system are controlled by material balance using simple two-way valves. A rigorous model-based optimization approach is employed in the optimal cycle design to generate a solution that is physically realizable in the experimental apparatus. The optimized scheme for two-column operation supplies fresh feed into the system where the composition of the circulating fluid is closest to that of the feedstock fluid, and recovers the purified products, extract and raffinate, alternately at the downstream end of the unit while desorbent is supplied into the upstream end of the system. The feasibility and effectiveness of the two-column process are verified experimentally on the separation of reboxetine racemate, a norepinephrine re-uptake inhibitor, under overloaded conditions. The consider system is one in which there is clearly a lack of resolution between the two components. It is thus difficult to obtain both products with high purity and yield by HPLC for the chosen chromatographic conditions. Reboxetine, (RS)-2-[(RS)-α-(2-ethoxyphenoxy)benzyl]-morpholine is an antidepressive NRI drug. Only the (R,R)-, (S,S)-pair is present as a racemic mixture in the active principle and the commercial formulations. Recent studies support the hypothesis that the (S,S)-enantiomer is a more potent inhibitor than the (R,R)- and that it is responsible for the vasomotor and cardiac side effects of Reboxetine. Our set-up employs an automated on-line enantiomeric analysis system, comprising an analytical HPLC set-up with two UV detectors to monitor the composition profile at the downstream end of one of the columns; this monitoring system does not use a polarimeter.

ration, two-column process; chiral separation; reboxetine.