| Azelnidipine, a dihydropyridine calcium channel antagonists which has been jointly developed by Ube and Sankyo company, Japan. Dihydropyridine antagonists are first-line drugs to treat cardiovascular diseases. As reported, the azelnidipine enantiomers, R-azelnidipine is active, S-azelnidipine has no activity, the study about azelnidipine chiral separation is of great significance for its safe use and drug development due to the regulations on racemic drugs announced by US Food and Drug Administration(FDA) in the 1990 s.Among many methods of racemic separation, simulated moving bed(SMB) chromatography separation proved to be one of the most effective technologies. SMB can significantly reduce solvent consumption compared with HPLC. However, SMB is complicated involving many design and operating parameters. computer-based simulation and optimization are essential for SMB processes successful application. The determination of Henry constants and adsorption model that can provide important references for the SMB process design and optimization.Henry constants of azelnidipine enantiomers on Chiralpak AD column were obtained by experiments at different temperatures, the competitive adsorption isotherms were determined by the application of the inverse method(IM). Adsorption isotherm models(Langmuir, Linear + Langmuir, and competitive Bi-Langmuir) were compared based on the fits to experimental data. Best results obtained by Bi-Langmuir with 5 parameters. Competitive Bi-Langmuir model and the acquired parameters were used to identify the complete separation region of a 4-zone SMB process according the Triangle theory. With SMB operating parameters optimized by computer simulation, the product of a single enantiomer of azelnidipine were separated with the purity over 98%. Finally, effects of some key operating parameters, such as switching time and flowrates in different zones, on the SMB performance in terms of purity and recovery were systematically investigated by numerical simulations, which are instructive for the separation of azelnidipine enantiomers. |
