Symmetric and asymmetric separations of bisoprolol enantiomers: Optimization and application

Symmetric and asymmetric separations of bisoprolol (BS) enantiomers were performed by fractional extraction with iso-butyl-L-tartrate (LT) as chiral extractant. The extraction process is complicated involving multiple chemical equilibrium, and the fractional extraction efficiency is strongly influenced by pH, boric acid (BA) and LT concentration, number of transfer units (NTU), feeding position, and phase ratios. An interfacial reaction phase equilibrium model was established and verified by experiment. A multistage model was further developed to model the extraction process to achieve the optimal operational parameters. Under the optimized parameters, S-bisoprolol (S-BS) was obtained by symmetric and asymmetric separations of racemic BS in a cascade of 10 centrifugal contactor separators (CCSs). The ee of S-BS in organic phase obtained by symmetric and asymmetric separations are 0.753 and 0.942, respectively. The relative errors of 3.12% and 4.24% show experiment is in good agreement with predictions. The required number of stage is greatly reduced to obtain high enantiomeric excess (ee) of S-BS by asymmetric separation.