Advanced processes exploiting chromatography and crystallization for resolution of multicomponent mixtures

Many substances produced by chemical syntheses or biotechnological processes are obtained along with a number of by-products. Therefore, advanced purification techniques in downstream processing are necessary to isolate a target product from multicomponent mixtures. If the desired component and the impurities exhibit similar physical and chemical properties, the separation process becomes more difficult. This particularly concerns the isolation of fine chemicals and active pharmaceutical ingredients, for which the purity requirements have steadily increased over the past decades. This complicated and challenging issue is addressed in this work by introducing two attractive methods for separation of the target component, namely, a chromatographic multicolumn process with internal recycle and a hybrid technique of chromatography and crystallization with side-fraction recovery.

The first part describes the 8-zone simulated moving bed chromatography with internal recycle (8Z-SMB-IR), which is designed for direct center-cut separation, that is, isolating an intermediately adsorbed component out of a multicomponent mixture. Several configurations are examined. The realization involves characterization of the adsorption behavior of the investigated compounds and other parametric studies aimed at process optimization. The 8Z-SMB-IR process is analyzed in detail using a ternary mixture, and a strategy for determining reliable operating conditions is developed and experimentally validated. The applicability of the 8Z-SMB-IR system is further extended to separate a quaternary mixture of a molecule possessing two stereogenic centers, in which one of the intermediately eluting stereoisomers is targeted for purification. The results confirm the potential of the applied technique to produce a pure product stream of the target component even when the isolation of the particular fraction from the reaction mixture is very difficult. Capabilities to improve and predict the process performance are also described and evaluated. The most effective configuration of the 8Z-SMB-IR is independently identified for different separation problems.

In the second part, the isolation of one stereoisomer of a chiral substance is proposed by coupling multistage crystallization, side-fraction recovery and enantioselective chromatography (MC-FR-EC) as an alternative method to the one presented in the first part. The process is developed after a preliminary investigation of the solid-liquid equilibrium and adsorption behavior of the analyzed components. Crystallization is employed to enrich the raw material mixture with the target racemate containing the desired stereoisomer. To intensify the process, the mother liquor depleted with respect to the target racemate is recovered using diastereomeric conversion, which provides an equimolar mixture of all four stereoisomers. The purified racemate is then processed by chromatography to finally isolate the single stereoisomer, experimentally proving the applicability of process integration.

After the first and second parts, general conclusions are discussed regarding the prospects and pitfalls of the developed processes. This research introduces new possibilities for improving the existing methods of chiral separation.