Coupled Isothermal Continuous Preferential Crystallization (CIC-PC) – A Novel Promising Technology for Gaining Pure Enantiomers with High Productivity

The recognition of differences in the pharmacological activity of enantiomeric molecules has induced the necessity to administer them as isolated enantiomers in order to ensure the desired optimum therapeutic effect. Driven by the becoming more and more restrictive policy of regulatory authorities such as US Food and Drug Administration and the EU Committee for Proprietary Medical Products the production of pure enantiomers is considerably increasing in several industrial branches, e. g. pharmaceutical, agrochemical, food industries as well as in cosmetic and fragrance industries [1]. An attractive process for gaining pure enantiomers from racemic mixtures is the so-called preferential crystallization (PC) which has been up to now usually investigated in a discontinuous operation mode [2-4]. According to the literature [5] there is still a deficiency and therefore some mandatory need for action in a systematic investigation of a continuous process in order to gain access to higher productivities being much more attractive for an industrial production. For elucidating the general principle of such a simple isothermal process (SIC-PC, Simple Isothermal Continuous Preferential Crystallization) one might consider a suspension crystallizer revealing MSMPR characteristics, i.e. a perfectly mixed tank (concerning both phases), which is continuously fed with mother liquor possessing a racemic composition. Of course, some suspension has to be continuously withdrawn from the crystallizer. By a continuous supply of homochiral seed crystals of the preferred target enantiomer E(p) the preferential crystallization of just this preferred enantiomer is initialized (i.e. crystal growth of the seed crystals and possibly secondary nucleation of those crystals), if the crystallization takes place within the metastable zone where spontaneous, uncontrolled primary nucleation is kinetically inhibited. During a starting-up phase which strongly depends on the properties of the system as well as on the process parameters the concentration of the goal enantiomer E(p) is decreasing until a steady state is reached where the composition is determined by the residence time τ. Due to the different kinetic mechanisms and their inherent different time constants for the phase transformation (liquid -> solid) a different depletion of the supersaturation for each enantiomer can be realized by an appropriate choice of the process conditions. As long as a critical residence time τcrit, where primary nucleation may appear, is not exceeded the concentration of the undesired counter enantiomer E(c) remains all the time constant. This reveals also the benefit of this continuous process in comparison to the batch one: a choice of the "right" process conditions allows a constant production of the goal enantiomer at a high purity level. Above all should be mentioned that relatively short residence times, assuring highly pure product, entail relatively low yields which can be improved and optimized. Therefore, an upgraded arrangement has been investigated theoretically which might even provide a better performance where two continuous suspension crystallizers are coupled via the liquid phase, i.e. the crystal free mother-liquor is exchanged between these two vessels (cf. Fig. 1). Because of this exchange, the liquid phase shows a higher overall concentration of the preferred enantiomer in that vessel in which the preferred enantiomer was seeded even if the chosen residence time exceeds the critical one. The supersaturation level which creates the crystallization driving force is higher during the whole process in comparison to the case without an exchange (DIC-PC, Decoupled Isothermal Continuous Preferential Crystallization). Additionally, the concentration of each counter enantiomer in the liquid phase decreases in both vessels. For the borderline case of infinite exchange flow rate, racemic composition is maintained in the fluid phase of both vessels. The described effect of decreasing the counter enantiomer concentration makes the probability for primary nucleation lower. This corresponds to higher product purity at higher residence times and enhances therefore the productivity. This more attractive and effective operation mode using two continuous crystallizers coupled via their liquid phases has been investigated theoretically considering as a case study the separation of the enantiomers of the amino acid threonine in water based on data and modified models published by our group before [6-8]. The influence of specific process parameters, as e. g. residence time, stirrer speed, crystallization temperature, subcooling, size distribution as well as mass of the seeds, has been analyzed and will be presented in this contribution. Some selected results in Fig. 2 depict the high potential of the coupled continuous mode in comparison to the decoupled one. [1] Caner, H.; Groner, E.; Levy, L.; Agranat, I. (2004): Trends in the development of chiral drugs. Drug Discovery Today. 9 (3), 105-110 [2] Jacques, J.; Collet, A.; Wilen, S.H. (1994): Enantiomers, racemates and resolutions, Krieger, Malabar [3] Elsner, M.P., Fernández Menéndez, D., Alonso Muslera, E., Seidel-Morgenstern, A. (2005): Experimental study and simplified mathematical description of preferential crystallization, Chirality 17 (S1), S183-S195 [4] Lorenz, H., Perlberg, A., Sapoundjiev, D., Elsner, M.P., Seidel-Morgenstern, A., (2006) Crystallization of enantiomers, Chem. Eng. and Proc. 45(10), 863-873 [5] Coquerel, G. (2007): Preferential crystallization. In: Novel optical resolution technologies. K. Sakai, N. Hirayama, R. Tamura (Eds.). Topics in Current Chemistry 269, 1-51 [6] Elsner, M.P.; Ziomek, G.; Seidel-Morgenstern, A. (2007): Simultaneous preferential crystallization in a coupled, batch operation mode. Part I: Theoretical analysis and optimization. Chem. Eng. Sci. 62 (17), 4760-4769 [7] Angelov, I.; Raisch, J.; Elsner, M.P.; Seidel-Morgenstern, A. (2008): Optimal Operation of Enantioseparation by Batch-Wise Preferential Crystallization. Chem. Eng. Sci. 63(5), 1282-1292 [8] Elsner, M.P.; Ziomek, G.; Seidel-Morgenstern, A. (2009): Efficient separation of enantiomers by preferential crystallization in two coupled vessels. AIChE Journal 55(3), 640-64