Study On The Separation Of Omeprazole Enantiomers By Solvent-Gradient Simulated Moving Bed

SMB (Simulated Moving Bed, SMB) technology applications cover the petroleum, sugars, organic acids and amino acid fermentation, and other fields. Since 1990s, SMB technology began to be used in chemical and drug separation, particularly in the separation of chiral drugs. SMB is usually carried out in the isocratic mode, i.e., by applying the same operating conditions (temperature, pressure, and mobile phase composition) in the whole SMB unit. However, it has been recently recognized that separation performance can be further improved by applying some sort of gradient mode operation (temperature gradient, pressure gradient and solvent gradient) to optimize the operating conditions of each individual section of the unit.Omeprazole (OME) is the largest single sales drug in the world of anti-ulcer chiral drug. Two isomers have different physiological activity, (S)-omeprazole is more effective than (R)-omeprazole.This paper took omeprazole enantiomers as study object, based on the triangle theory in solvent gradient mode, designed a solvent gradient simulated moving bed system, optimize the mobile phase component, switch, injection velocity, and other operating conditions, and successfully separated the omeprazole enantiomers. The purities of S-OME and R-OME reached 95.11% and 96.32%, respectively.This paper was divided into four chapters. Chapter I is review of literature, introduced the nature, preparation methods of omeprazole enantiomers, the characters of simulated moving bed and solvent-gradient simulated moving bed and their historical development, separation theory and application examples.Chapter II is separation of omeprazole enantiomers by fixed-bed. We prepared chiral packing TPCC, used the fixed-bed to separate the Omeprazole enantiomers, and determined the relationship between the equilibrium constant of Omeprazole enantiomers and the proportion of ethanol / hexane in mobile phase.Chapter III is design and optimization of solvent-gradient simulated moving bed. According to the triangle optimized theory in solvent gradient, based on the retention behavior of omeprazole enantiomers in mixed hexane-ethanol solvents, we determined the complete separation region of omeprazole enantiomers under the ideal state, chose separation conditions, and separated omeprazole enantiomers. The same of theoretical and experimental results verified the effectiveness of the complete separation region. And based on complete separation region and the solubility of OME in mobile phase, we optimized the mobile phase, the mobile phase component at x_F = 0.5, x_D = 0 was better. We also compared the the separation performance of SMB in balance modes and gradient mode. The gradient mode operation effectively increased the concentration of products, reduced solvent consumption, and increased production capacity.Chapter IV is separation of omeprazole enantiomers by solvent-gradient simulated moving bed. We optimized switch time, injection velocity, feed flow rate and feed concentration, and successfully separated the omeprazole enantiomers. The purities of S-OME and R-OME reached 95.11% and 96.32%, respectively. We also studied the required time for simulated moving bed in solvent gradient mode to achieve cycle-steady state. After four-cycle switch time, the SMB achieved cycle-steady state.