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Abstract:
Usually racemic mixtures of chrial substances are produced in chemical industry although in most cases only one of the enantiomers shows the required properties with regard to therapeutic activities or metabolism. Consequently, the need of pure enantiomers in pharmaceutical industry, food industry, cosmetics and agrochemical industry is in tremendous increase. In order to separate enantiomeric mixtures, chromatographic as well as special methods e. g., classical non-biological resolutions via the formation of diastereomers, biological methods (resolution and asymmetric synthesis), non-biological asymmetric synthesis, and membrane technologies can be applied.
An attractive process for gaining pure enantiomers from racemic mixtures is the so-called enantioselective preferential crystallization [1-3]. In a batch crystallizer conglomerate systems tend to reach an equilibrium state in solution in which the liquid phase will have racemic composition and the solid phase will consist of a mixture of crystals of both enantiomers. However, before approaching this state, it is possible to preferentially produce just one of the enantiomers after seeding with homochiral crystals.
Fro all available crystallizer configurations, of course a batch mode is the easiest one to realize. The principle of this batch process is quite simple: the vessel is filled with a supersaturated solution of the racemate (Ep+Ec as 50%:50% mixture). After addition of homochiral seeds e.g., merely Ep is crystallizing within a limited time period.In order to gain this enantiomer as a product of high purity, the process must be stopped before the undesired counter-enantiomer occurs [2]. During this batch crystallization, the concentration of the desired enantiomer in the solution is decreasing, whereas the concentration of the counter-enantiomer remains constant. This phenomenon leads to an arrangement which might provide a better performance where two crystallizers are coupled via the liquid phase, i.e., the crystal free mother-liquor is exchanged between these two vessels. 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. The supersaturation level which corresponds to the crystallisation driving force is higher during the whole process in comparison to the case without an exchange (decoupled simple batch mode). Additionally, the concentration of the counter-enantiomer in the liquid phase for each of the vessels decreases. For the borderline case of infinite exchange flow rate racemic composition is reached in the fluid phase of both vessels. The described effect of decreasing the counter-enantiomer concentration in that crystallizer in which the preferred enantiomer shall be gained makes the probability for primary nucleation lower. This corresponds to higher product purity at the end of the process and enhances also the productivity.In particular, as a model system threonine-H2O has been studied. Based on a simplified approach the more attractive and effective operation mode using two batch crystallizers coupled via their liquid phases [4,5] has been investigated theoretically and experimentally as well. The influence of specific process parameters, like e.g. the size distribution and the mass of the seeds, and different temperature profiles has been analyzed. It can be shown that by varying the initial CSD of the seeds the final product properties as well as important process parameters (e.g., productivity) can be controlled.
The effect of racemization by exchanging the fluid phase allows the specific manipulation of concentration profiles and seems to be a suitable lever for process intensification on the apparatus level. Similar manipulation of the concentration profiles during the crystallization process can be also realized on molecular level if the racemization is achieved by an enzymatic reaction in which an excess of the counter-enantiomer in the liquid phase is transformed to the preferred one [6,7]. By coupling crystallization (for conglomerate systems) and racemization (for conversion of the unwanted enantiomer) expected theoretical yield of a pure enantiomer can lead up to 100%. Our goal is to develop a comprehensive study for each operating unit and their integration in a continuous process. As a model component for the investigation, the amino acid DL-asparagine in water has been chosen. The enzyme for racemization (racemase) was isolated from Pseudomonas putida bacteria (Institute for Biotechnology-2, Research Centre Jülich, Germany).
These different configurations for productivity enhancement with regard to preferential crystallization will be presented in this contribution.
References:
[1] Jacques, J.; Collet, A.; Wilen, S.H. (1994): Enantiomers, racemates and resolutions, Krieger, Malabar
[2] Elsner, M.P.; Fernández Menéndez, D.; Anlonso Muslera, E.; Seidel-Morgenstern, A. (2005): Experimental study and simplified mathematical description of preferential crystallization, Chirality 17 (S1), S183-S195
[3] Lorenz, H.; Perlberg, A.; Sapoundjiev, D.; Elsner, M.P.; Seidel-Morgenstern, A. (2006): Crystallization of enantiomers, Chem. Eng. and Proc. 45 (10), 863-873
[4] 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
[5] Ziomek, G.; Elsner, M.P.; Seidel-Morgenstern, A. (2008): Simultaneous preferential crystallization in a coupled, batch operation mode. Part II: Experimental investigations. Chem. Eng. Sci.(in preparation)
[6] Lütz, S.; Wandrey, C.; Seidel-Morgenstern, A.; Elsner, M.P. (2006): Verfahren zur Herstellung chiraler Substanzen durch selektive Kristallisation unterstützt durch eine enzymatische Racemisierungsreaktion. DE 10 2006 013 725.6 (24.03.2006)
[7] Würges, K.; Petrusevska, K.; Serci, S.; Wilhelm, S.; Wandrey, C.; Seidel-Morgenstern, A.; Elsner, M.P.; Lütz, S. (2008): Enzyme-assisted physicochemical enantioseparation processes - part I: Production and characterization of a recombinant amino acid racemase. (in preparation)
