(597b) Optimal Operation of Batch Enantiomer Crystallization: From Ternary Diagrams to Predictive Control

Authors: 
Marcellos, C. F. C., Federal University of Rio de Janeiro
Durand, H., University of California, Los Angeles
Christofides, P. D., University of California, Los Angeles
The compounds making up many useful molecules such as the active ingredients in pharmaceuticals appear in nature as enantiomers [1]. To produce a pure enantiomer, a variety of techniques can be used, including asymmetric synthesis and methods of chiral resolution such as chromatographic methods and crystallization [2]. When a set of enantiomers forms a racemic compound, production of pure crystals of one enantiomer in a batch operation requires that the original liquid mixture purity be above that of the eutectic composition due to thermodynamic restrictions [3]. These thermodynamic restrictions can be visualized through a ternary diagram for the mixture of the two enantiomers and a solvent [3]-[4].

In this work, we investigate the operation and control of a batch crystallization process for a racemic compound forming system with a fines trap and dissolution tank, and seeding of the initial liquid within the system (which is enriched in the desired enantiomer) with crystals of the desired enantiomer. We use the ternary diagram in the development of operating conditions for the system and for the development of constraints for an optimal control design for the system. We develop model equations for the batch crystallization process based on a population balance model for the crystals coupled with mass balances. We then apply a model predictive control strategy to the system to maximize the volume of crystals developed from the seeds while reducing the volume of crystals developed from nucleation, and show how the closed-loop trajectories are related to the ternary diagram thermodynamic data.

[1] Nguyen LA, He H, Pham-Huy C. Chiral drugs: An overview. International Journal of Biomedical Science. 2006;2:85-100.

[2] Lorenz H, Seidel-Morgenstern A. Processes to separate enantiomers. Angewandte Chemie International Edition. 2014;53:1218-1250.

[3] Kaspereit M. Separation of Enantiomers by a Process Combination of Chromatography and Crystallisation. PhD Thesis, Max Planck Institute for Dyanamics of Complex Technical Systems. Aachen, Germany: Shaker, 2006.

[4] Jacques J, Collet A, Wilen SH. Enantiomers, Racemates, and Resolutions. New York: John Wiley & Sons, 1981.