Conceptual Design and Feasibility Study of Combining Continuous Chromatography and Crystallization for Stereoisomer Separations

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Abstract

The separation of stereoisomers—diastereoisomers and enantiomers—constitutes an important class of problems in life science applications, namely in drug manufacture. Chromatography is often the method of choice to perform this task. To decrease the typically high investment and operational costs of the chromatographic separation, it can be beneficial to combine this process with a selective crystallization step. This work investigates such process combination of simulated moving bed chromatography and crystallization from solution. A short-cut method, based on only a few fundamental experimental parameters, is applied to evaluate the process combination for one enantiomeric and one epimeric system. While the enantiomeric system is characterized by a simple conglomerate phase diagram, the epimeric system shows some characteristic properties, like incorporation of the counter epimer and an additional impurity into the crystal lattice of the product epimer, that have to be accounted for by more detailed investigations.

Introduction

The manufacture of highly pure substances is an important issue in the field of pharmaceuticals and fine chemicals. A final purification step after synthesis often involves relatively difficult separations of stereoisomers. Especially, the separation of enantiomers is challenging. Such separations can be performed, e.g., via crystallization of diastereomeric salts (Kozma, 2002) and crystallization by entrainment (preferential crystallization) (Jacques et al., 1994, Reuter, 1999). Among the techniques available, preparative chromatography plays a significant role. Its increasing application was driven in the last decade by the design of improved (chiral) stationary phases and an increased process understanding (due to more detailed mathematical modelling), which in turn amplified the acceptance of more sophisticated operational concepts like the simulated moving bed (SMB) process.

However, chromatography is an expensive process with often costly stationary phases, high solvent consumption and relatively high investment costs. Efforts have been made to combine chromatography and selective crystallization on the flowsheet level, to obtain a process with an overall better performance (Lorenz et al., 2001). Some studies on that subject have been made in order to evaluate such a process combination (Ndzié et al., 2003, Ströhlein et al., 2003, Fung et al., 2005, Gedicke et al., 2005, Kaspereit et al., 2005). However, to promote this technology there is still a need to evaluate more examples.

Recently, Kaspereit et al. (2005) presented a methodology to evaluate quantitatively the coupling of chromatography and crystallization. In this work we apply it to two systems, one simple conglomerate system of enantiomers—a pharmaceutical intermediate—and a more complex example—the isolation of an epimer with a more complex phase diagram, involving partial miscibility of the epimers in the solid state.

Section snippets

Concept of the Process Combination

Although chromatography is the method of choice for many stereoisomer separations, it represents an expensive technique when comparing it to conventional processes like distillation. Productivity of chromatographic processes is usually limited, in particular for difficult cases like enantioseparations. Furthermore, in the latter case, investment costs for necessary chiral stationary phases can be very high. Finally, high purity requirements typical for the production of fine chemicals and

System of Enantiomers—S1

The first system to be separated is a racemic mixture of a chiral substance and will be denoted as S1. No further specific properties about this compound are available. Both enantiomers are of interest here and should be obtained as products. Details on the system and the necessary parameters are listed in Table 1. Adsorption isotherms were reported in (Kniep et al., 2000) and were measured using the ECP method (elution by a characteristic point, e.g., Guiochon et al., 1994). The parameters

Process Evaluation for the Two Example Systems

As was demonstrated for the crystallization step above, any binary separation process can be explained by an expression analogous to equation (1). In the case of considering continuous chromatography we only have to replace the superscript of the unit in equation (1) C (for crystallization) by S (for SMB-chromatography). With the yields of the individual steps given by this equation, the mass flux of crystalline product can be obtained from the mass flux of product from SMB-chromatography:mPC=yC

Summary and Conclusions

A process combination of SMB chromatography and crystallization was investigated for the separation of two different systems of stereoisomers. A shortcut method was applied for evaluation of overall process performance. Under the assumption of ideal behaviour of the systems, the method predicted that in both cases the combined process outperforms significantly a stand-alone separation by SMB chromatography.

For the first system, an ‘ideal’ enantioseparation with two target products, a throughput

Acknowledgements

The work presented was funded in part by the Federal Ministry of Education and Research Germany (BMBF, NMT-CT-C03C319). The valuable contributions of Dipl-Ing D. Sapoundjiev, Dipl-Ing V. Zahn and Dr A. Brandt are gratefully acknowledged.

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