(126a) Enantioseparation of Reboxetine Using Compact Simulated Moving Bed Shemes

Reboxetine, (RS)-2-[(RS)-α-(2-ethoxyphenoxy)benzyl]-morpholine is a antidepressant drug which belongs to the so-called norepinephrine reuptake inhibitors (NRI drugs), because its selectivity inhibits the uptake of this important neurotransmitter from the presynaptic neurones. Reboxetine has two asymmetrical carbons, thus it can exist as two enantiomeric pairs; however due to the stereoselectivity of the synthesis 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 norepinephrine reuptake inhibitor than the (R,R)- and that its is responsible for the vasomotor and cardiac side effects of reboxetine, which features the necessity to have reliable methods for the separation and analysis of reboxetine enantiomers.

Simulated moving bed (SMB) chromatography due to its many advantages with respect to discontinuous batch chromatography, such as higher product purity, less solvent consumption, and higher productivity per unit stationary phase; is an upright tool for the separation of reboxetine enantiomers. Thanks to recent developments in cyclic operation policies, a number of possibilities for improving SMB performance have emerged through variation of parameters during the switching interval. These include, among others, the nonsynchronous shift of the inlet and outlet ports within a global switching period, and cyclic modulation of feed flow and feed concentration. These advances are pushing the trend toward the use of units with smaller number of columns, because less stationary phase is used and the setup is more economical.

Two distinct compact SMB schemes with two and three columns were developed for the binary separation of reboxetine enantiomers on Chiralpak AD using as solvent a mixture of Hexane-Ethanol-DEA, for both linear and nonlinear isotherms. The developed compact schemes include a two-zone SMB with feed flow modulation, and a three-column four-zone SMB with asynchronous port switching and feed flow modulation, that were optimized using a full-discretization method implemented on AMPL and solved using a efficient interior-point solver.

Product quality control is mandatory for chiral chromatographic separations, and requires robust on-line monitoring of absolute enantiomer concentrations. In this work, our recent developed on-line monitoring system consisting of a high-speed HPLC setup with two UV detectors was implemented to monitor the concentration profile of each reboxetine enantiomer in the SMB unit. This monitoring scheme does not require the use of a polarimeter.

Keywords: enantiomers; reboxetine; chromatography; simulated moving bed; flow modulation; asynchronous port switching.