Achim Epping

Optimal design of batch and simulated moving bed chromatographic separation processes

Preparative chromatography, especially simulated moving bed (SMB) chromatography, is a key technology for the separation of fine chemicals on a production scale. Most of the design methods for batch and SMB processes proposed in the open literature deal with the optimisation of the operating conditions for a given chromatographic unit only. Therefore, a comparison of the process economy may lead to incorrect results. In this contribution, an effective strategy for the optimal choice of all process parameters (operation and design parameters) is proposed. The main idea of this strategy is to apply a detailed and experimentally validated process model and to reduce the number of influencing parameters by introducing and optimising dimensionless process parameters. It is shown that there is an infinite choice of design and operating parameters to achieve maximum productivity or minimum separation costs and not at the maximum pressure drop only. The detailed design of the chromatographic unit and the selection of the operating conditions can be adjusted by considering the availability of columns and packing materials. As the model system, the separation of a racemic mixture (EMD53986) on Chiralpak AD was investigated. After complete optimisation of a batch and a SMB unit, a real comparison of the process economy can be achieved. Finally, the influences of two different objective functions, productivity and specific separation cost, are analysed.

DESIGN, OPTIMIZATION, AND OPERATION OF SMB CHROMATOGRAPHY IN THE PRODUCTION OF ENANTIOMERICALLY PURE PHARMACEUTICALS

The utility of simulated moving bed (SMB) chromatography for the preparative chromatographic enantioseparation on chiral stationary phases (CSP) is shown. A design and optimization methodology is proposed and verified with production scale enantioseparations. The study combines two modelling approaches. The equilibrium theory for true countercurrent (TCC) liquid chromatography is used to generate a first set of operating parameters. Afterwards, detailed process optimization is done by systematic simulation studies with the rigorous dynamic SMB process model. Using the preparative enantioseparations of two new drug candidates, EMD 53986 a precursor of a cardiovascular drug and a chroman ester derivative which is a precursor of EMD 128130, the model approaches are verified and compared. The necessity and benefit of careful system design and optimization by detailed process simulation is demonstrated. Chirality 11:440–450, 1999.