The VariCol and ModiCon processes are two variants of the simulated moving bed (SMB) process, characterized by the modulation of the length of zones of the chromatographic column train and the feed concentration. These features give more flexibility than the conventional operation, leading to essential improvements in the separation and purification of mixtures. The optimal performance comparison of these two variants, the hybrid formed by their combination, and the conventional SMB process are scarce in the literature. This comparison helps discover new characteristics of each single and combined operation mode and creates guidelines to select the appropriate operation mode for possible real applications. In this work, the performance comparison of the ModiCon, VariCol, ModiCon+VariCol, and SMB processes is carried out in terms of maximal throughput for specific product purity values. Particular emphasis is placed on both the ModiCon and the hybrid ModiCon+VariCol processes characteristics. A strategy for combining and optimizing the ModiCon and the VariCol processes was determined. As a case study, the enantioseparation of guaifenesin was considered. In the ModiCon process, more than two modulation subintervals did not improve the performance in the separation. The optimal pattern, based on two subintervals, has zero feed concentration in the first subinterval and the maximal concentration in the second one. The best result for the hybrid operation (ModiCon+VariCol) was reached when the feed port moves simultaneously as the SMB process switching period. The optimal throughput of the ModiCon and the ModiCon+VariCol processes was almost doubled than that of the SMB process. These performances were based on larger zones I and II and not in zones II and III as occur with the SMB and VariCol process. The throughput in the hybrid operation increases more significantly than the ModiCon process when 5 columns were considered instead of 6. The hybrid operation could be more attractive for a system with a few numbers of columns.
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