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Background and Motivation


In pharmaceutical, food and agrochemical industry there is a distinct trend towards the marketing of chiral compounds as pure enantiomers. This has generated a demand for economical methods for the production of pure enantiomers. Despite the remarkable progress in the field of asymmetric synthesis, highly selective reactions leading in an economical manner to a variety of pure enantiomers are still the exception and thus, efficient separation processes that are more general applicable are of large industrial interest. On that background crystallization methods can be applied for enantioseparation purposes. Thus, pure enantiomers can be selectively crystallized from partially resolved mixtures of the two enantiomers or under certain conditions even directly from the racemic mixture [1]. The research work in this project is focused on the experimental and theoretical study and the development of advanced and innovative crystallization based processes for enantioseparation. The main topics we are actually dealing with are: Preferential Crystallization classical isothermal and advanced polythermal processes: batch and cyclic process mode innovative reactor concepts auto-seeded preferential crystallization extension of applicability of preferential crystallization to racemic compounds Application of optically active solvents In the following exemplary results of selected topics are presented.

Preferential Crystallization General


An attractive alternative to common enantioseparation methods is the enantioselection crystallization exploiting the entrainment effect. The principle of the preferential crystallization process which is known for conglomerates can be illustrated in a ternary phase diagram (cf. Fig. 1). Considering an initially undersaturated solution at a temperature Tcryst +DT, the solution becomes supersaturated but remains clear, if it is rapidly cooled down to a temperature Tcryst within the metastable zone. Retarded, its composition would change in order to reach the thermodynamic equilibrium. In the equilibrium state the liquid phase will have racemic composition (point E) and the solid phase will consist of a mixture of crystals of both enantiomers. However, after seeding with homochiral crystals it can be observed that the system does not reach the point E directly but moves along other trajectories. Thus, under special conditions and in a restricted time interval it is possible to preferentially produce crystals of just one of the enantiomers. Detailed treatises of the process of crystallization by entrainment can be found in the literature, e.g. [1-4]. Since both enantiomers show the same properties concerning the crystal growth as well as nucleation kinetics, the examination of a single-step should be sufficient for the estimation of kinetic parameters. The knowledge of the crystallisation kinetics is essential for the design as well as for controlling purposes of crystallizers. Furthermore, the physical description of the crystal growth and nucleation kinetics respectively, allows a prediction of several product features such as purity and crystal size distribution.

Fig. 1: Principle of the preferential crystallisation and a possible cyclic operation mode.

Investigation of the Preferential Crystallization Process

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The amino acid L-/D-threonine in water (conglomerate) was chosen as a first test substance. A single-step and a cyclic operation mode were investigated. The first one allows an estimation of kinetic data which provide together with an adequate model (isothermal operation, ideally mixed (semi-)batch crystalliser, constant overall volume of the liquid and solid phase, size-independent crystal growth rate, no interdependence of the growth rate for each of both enantiomers, both enantiomers obey the same growth rate law, nucleation at negligible size, no breakage, attrition or agglomeration) a basis for the mathematical description, whereas the latter demonstrates the possible quasi-continuous application of the process. For the investigation of the crystallisation kinetics single-step experiments, in which only one of the enantiomers was harvested, were performed in a batch crystalliser under variation of the process parameters. On-line polarimetry, in combination with density measurements as well as off-line surface area measurements of solid samples by microscopic investigation, were used for the estimation of crystal growth kinetics based on the method of moments [4-9]. Nevertheless, due to the inherent inaccuracies an experimentally based prediction of the nucleation rate seems to be difficult and leads to uncertain values. Therefore, the parameters for the nucleation rate were provided by estimation using experimental data as well as a rather simple model [4]. A typical experimental run, which was carried out for preferentially crystallising L-threonine (E1) at first, is shown in Fig. 2. It shows the profile of the optical rotation angle without an initial enantiomeric excess in comparison with a simulated profile based on the estimated parameters for the crystallisation kinetics (left). The profile is satisfactorily described by the model selected and for the established parameters for the time period (<300 min) in which the desired enantiomer E1 is exclusively crystallised. With increasing time (>300 min) the simulation shows a disagreement compared to the measured data, because the nucleation of the (undesired) counter-enantiomer E2 is rather difficult to determine. In order to enhance the productivity, a cyclic operation mode enables a quasi-continuous enantioseparation that is obviously much more attractive. The principle is illustrated schematically in Fig. 1.

Fig. 2: Typical optical rotation angle curve (left) and trajectories (right) for reproducible, complete batch experiments until the equilibrium state is established. Comparison (left) of the experimental a-curve obtained by seeding with L-threonine (E1) crystals with the a-curve simulated according to the ascertained crystallisation parameters.

An applicable configuration can consist of two crystallisers connected in series in which the separation of each enantiomer is carried out. The principle of this configuration is quite simple: In the upper vessel there is initially a supersaturated solution of the racemate (E1+E2). The presence of an initial enantiomeric excess in the first half cycle may have an influence on the resolution rate, but does not affect the general feasibility of the process. After addition of homochiral seeds, merely E1 is crystallising 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. For harvesting the pure solid product a filtration device is located between the crystallisation vessels in each case. After removing of the product, the solution is put into the second vessel. To guarantee a quasicontinuous process a certain amount of racemate has to be added in advance and afterwards seeding with E2, crystals will entail the crystallisation of E2 in this following half cycle. The growth rate depends on the supersaturation which is inherently temperature-dependent. Usually, it is not possible only to increase the supersaturation of the wanted enantiomer without any limitations, because it would provoke nucleation of the undesired enantiomer at the same time. During a single-step batch crystallisation, the concentration of the desired enantiomer in the solution is decreasing, whereas the concentration of the counter-enantiomer remains constant. Consequently, the crystal growth rate drops with progress of the single-step batch process.

Fig. 3: Simultaneous preferential crystallisation process in a coupled, batch operation mode.

A simultaneous crystallisation of both enantiomers in two separated vessels with an exchange of crystal-free mother liquor enables to slow down this decrease of the growth rate (cf. Fig. 3). Since both crystallisers are coupled via the liquid phase, higher values regarding the supersaturation for each enantiomer in each vessel can be achieved. This leads to an increase of the overall process and therefore, to an increase of the attainable productivity. A comparison between these different crystalliser configurations as well as an evaluation of the potential, the robustness and the control is the main subject of our common research activity with the System and Control Threorie group (SCT) of Prof. Raisch [9-11].

Convenient process parameters as well as a targeted design of future experiments require optimisation of each crystalliser configuration where the productivity is taken as objective function. In our work a modified NELDER-MEAD simplex method was successfully implemented for optimisation of preferential crystallisation problem. In comparison with conventional deterministic methods this algorithm gives a higher probability to reach the global optimum. Using this robust optimiser it is possible to determine important process variables like mass of seeds, mass of racemate, initial seeds distribution, exchange flow rate between several crystallisers, temperature etc. The results obtained during these systematical optimisations allow a comparison and an assessment of the different rivaling configurations [12, 13].

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Fig. 4: Experimental setup for the cyclic operation mode.

ascertained crystallisation parameters (kg = 2.5 10 -7 m/s, kb = 6.6 10 3) s-1). Seeding with L-threonine and D-threonine, respectively is marked by arrows.

Fig. 5: Comparison of the experimental polarimetric signal for two subsequent separation cycles with the a-curves simulated according to the

harvesting the crystallised enantiomer. For this reason it was found that an exact time t for ending the process is rather difficult to realise. However, as can be seen in Fig. 5 the preferential crystallisation in a cyclic operation mode is feasible on principle [4].

The results performed in the cyclic operation mode (mode 1, cf. Fig. 4) are shown in Fig. 5 for two subsequent separation cycles with racemic composition at the beginning of the first cycle (ee0 = 0). After addition of E1 seed crystals, the crystallisation process started and E1 crystallised (first branch). For the interruption of the crystallisation in this half cycle a "stop" rotation angle was chosen corresponding to an enantiomeric excess of 2% concerning the counter-enantiomer. In practice the process was interrupted earlier, since the resolution still proceeded during filtering and

In spite of some differences between simulated and measured profiles shown in Fig. 5, the simplified model used enables to predict the trend of the optical rotation angle for this cyclic operation mode performed. The model described above supplies a satisfying description of the process as a first approach. Currently, further experiments are performed in which the influence of the crystallisation temperature, size of the seed crystals as well as the presence of the counter-enantiomer on the crystal growth of the desired enantiomer is studied in detail. These results shall be used for a

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refinement of the existing model. Moreover, the knowledge of the temperature-dependency enables studies on the fines dissolution and thus on the shape of the crystal size distribution.

In order to investigate the influence of the fluid dynamics on the crystallisation process, time-dependent numerical calculations for homogeneous crystallisation processes in a perfectly mixed crystallisation zone (zero-dimensional analysis) and in a CSBR (full three-dimensional analysis) were performed, and consequently the mass profiles and the crystal size distributions of both enantiomers were determined. The numerical model has been developed based on the classical and extended MOM and compiled into Fluent 6.2 [14-16].

.Extension of applicability of preferential crystallization to racemic compounds Over a long time the applicability of preferential crystallization was limited to conglomerate forming systems that just count for 5 to 10 % of the cases. The majority of chiral substances forms racemic compounds at the 1:1 composition of the enantiomers, where from thermodynamic point of view preferential crystallization does not provide the desired pure enantiomers. However, in those systems a preferential crystallization step can be integrated in a hybrid process. There, an established separation technique (e.g. SMB-chromatography) provides a certain enantiomeric enrichment that allows for a subsequent preferential crystallization of the desired pure enantiomer [B]. Exemplarily, successful resolution experiments were performed for the systems mandelic acid/water and propranolol hydrochloride/water via seeded isothermal preferential crystallization [25,26]. Fig. 6 shows the theoretical process trajectories in the ternary phase diagram and Fig. 7 experimental results for a cyclic preferential crystallization in the system mandelic acid/water. The single crystallization steps are formally comparable with the preferential crystallization in conglomerate forming systems (Fig. 1 and Fig. 5). However, instead of the two enantiomers, during preferential crystallization in the mandelic acid/water system eutectic feed material is divided into one enantiomer (the desired one) and racemic compound. The racemic compound as by-product can be recycled to the enantiomeric enrichment step avoiding loss of valuable substance.

Fig. 6: Theoretical process trajectories in the ternary phase diagram for enantioseparation in the system mandelic acid/water in the cyclic operation mode.

Fig. 7: Isothermal preferential crystallization for enantioseparation in the system mandelic acid/water in the cyclic operation mode shown as enantiomeric excess of the liquid phase as function of time [25, 27]

References
[1] [2] [3] [4] [5] Sheldon, R.A.; Hulshof, L.A.; Bruggink, A.; Leusen, F.J.J.; van der Haest, A.D.; Wijnberg, H. (1990):" Crystallization techniques for the industrial synthesis of pure enantiomers", Proceedings Chiral 90 Symposium Manchester, 101-107 Jacques, J.; Collet, A.; Wilen, S.H. (1994):" Enantiomers, racemates and resolutions", Malabar: Krieger Collet, A. (1999): "Separation and purification of enantiomers by crystallisation methods", Enantiomer 4, 157-172 Elsner, M.P.; Fernndez Menndez; D., Alonso Muslera, E.; Seidel-Morgenstern, A. (2005): "Experimental study and simplified mathematical description of preferential crystallisation." Chirality 17, S183 - S195 Polenske, D.; Elsner, M.P.; Lorenz, H.; Seidel-Morgenstern, A. (2006): Alternative Einsatzmglichkeiten der Bevorzugten Kristallisation zur Enantiomerentrennung. Chemie Ingenieur Technik 78(8), 1101-1110

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Lorenz, H.; Perlberg, A.; Sapoundjiev, D.; Elsner, M.P.; Seidel-Morgenstern, A. (2006): Crystallization of enantiomers. Chem. Eng. Process. 45(10), 863-873 Polenske, D.; Elsner, M.P.; Lorenz, H.; Seidel-Morgenstern, A. (2006): Alternative Einsatzmglichkeiten der Bevorzugten Kristallisation zur Enantiomerentrennung. Chemie Ingenieur Technik 78(8), 1101-1110 Polenske, D.; Elsner, M.P.; Lorenz, H.; Seidel-Morgenstern, A. (2006): Ermittlung relevanter Wachstumsparameter fr die Racemattrennung am Beispiel des verbindungsbildenden Systems Mandelsure/Wasser. Chemie Ingenieur Technik 78(9), 1353 Ziomek, G.; Elsner, M.P.; Seidel-Morgenstern, A. (2006): Enantiomerentrennung durch simultane bevorzugte Kristallisation. Chemie Ingenieur Technik 78(9), 1325-1326 Qamar, S.; Elsner, M.P.; Angelov, I.; Warnecke, G.; Seidel-Morgenstern, A. (2006): A Comparative Study of High Resolution Schemes for Solving Population Balances in Crystallization. Comp. Chem. Eng. 30(6-7), 1119-1131 Lorenz, H., Perlberg, A., Sapoundjiev, D., Elsner, M. P., Seidel-Morgenstern, A.: Crystallization of enantiomers. Chem. Eng. Process. 45 (2006), pp. 863873 Czapla, F., Lorenz, H., Elsner, M. P., Seidel-Morgenstern, A.: Einfluss unterschied-licher Prozessfhrungsstrategien auf die Produktivitt und Produkteigenschaften bei der Bevorzugten Kristallisation. In Teipel, U. (Hrsg.): Produktgestaltung in der Partikeltechnologie, Band 3, Fraunhofer-IRB-Verlag, Stuttgart, 2006, S. 219235 Polenske, D., Elsner, M. P., Lorenz, H., Seidel-Morgenstern, A.: Alternative Einsatzmglichkeiten der Bevorzugten Kristallisation zur Enantiomerentrennung. Chemie Ingenieur Technik 78 (2006), S. 11011110 Czapla, F., Lorenz, H., Elsner, M. P., Seidel-Morgenstern, A.: Model based experi-mental analysis for crystallization of DL-threonine in the presence of a chiral additive. Proceedings 13th Int. Workshop on Industrial Crystallization (BIWIC 2006), Delft (The Netherlands), 2006, pp. 98104 Czapla, F., Lorenz, H., Elsner, M. P., Seidel-Morgenstern, A.: Einfluss der Prozessfhrungsstrategie Produkteigenschaften einer Bevorzugten Kristallisation. Chemie Ingenieur Technik 79 (2007), S. 281286 auf Produktivitt und

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Lorenz, H., Czapla, F., Polenske, D., Elsner, M. P., Seidel-Morgenstern, A.: Crystallization based separation of enantiomers (Review). Journal of the University of Chemical Technology and Metallurgy Sofia 42 (2007), pp. 516 Qamar, S.; Ashfaq, A.; Warnecke, G.; Angelov, I.; Elsner, M.P.; Seidel-Morgenstern, A. (2007): Adaptive High Resolution Schemes for Multidimensional Population Balances in Crystallization Processes. Comp. & Chem. Eng. 31(10), 1296-1311 Czapla, F.; Lorenz, H.; Elsner, M.P.; Seidel-Morgenstern, A. (2007): Einfluss der Prozessfhrungsstrategie auf Produktivitt und Produkteigenschaften einer Bevorzugten Kristallisation. Chemie Ingenieur Technik 79(3), 281-286 Lorenz, H.; Czapla, F.; Polenske, D.; Elsner, M.P.; Seidel-Morgenstern, A. (2007): Crystallization based separation of enantiomers (Review), Journal of the University of Chemical Technology and Metallurgy 42 (1), 5-16 Czapla, F., Elsner, M. P., Lorenz, H., Joshi, M., Seidel-Morgenstern, A.: Parameterization of population balance models for polythermal auto-seeded preferential crystallization of enantiomers. Proceedings 3rd Int. Conference on Population Balance Modelling (PBM 2007), Qubec City (Kanada), 2007, pp. 18 Qamar, S.; Warnecke, G.; Elsner, M.P.; Seidel-Morgenstern, A. (2008): A Laplace transformation based technique for reconstructing crystal size distributions regarding size independent growth. Chem. Eng. Sci., 63 (8) 2233-2240 Qamar, S.; Warnecke, G.; Elsner, M.P. (2008): Numerical simulation of population balances for combined particulate processes. Chem. Eng. Sci. (submitted) Czapla, F., Haida, H., Elsner, M. P., Lorenz, H., Seidel-Morgenstern, A.(2008): Parameterization of population balance models for polythermal auto seeded preferential crystallization of enantiomers. Chem. Eng. Sci. (in print), online available: doi:10.1016/j.ces.2008.05.008 Qamar, S.; Warnecke, G.; Elsner, M.P. (2009): On the solution of population balances for nucleation, aggregation and breakage processes. Chem. Eng. Sci. (in press) Lorenz, H., Polenske, D., Seidel-Morgenstern, A.: Application of preferential crystallization to resolve racemic compounds in a hybrid process. Chirality 18 (2006), pp. 828840 Polenske, D., Lorenz, H., Seidel-Morgenstern, A.: Separation of propranolol hydrochloride enantiomers by preferential crystallization: Thermodynamic basis and experimental verification. Crystal Growth & Design 7 (2007), pp. 16281634 Polenske, D., Lorenz, H., Seidel-Morgenstern, A.: Potential of different techniques of preferential crystallization for enantioseparation of racemic compound forming systems. Chirality (2009), available online Polenske, D., Levilain, G., Lorenz, H., Coquerel, G., Seidel-Morgenstern, A.: Isothermal and auto-seeded polythermal preferential crystallization in the mandelic acid system. Proceedings 14th Int. Workshop on Industrial Crystallization (BIWIC 2007), Cape Town (South Africa), 2007, pp. 245249

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Patents
[A] Ltz, S., Wandrey, C., Seidel-Morgenstern, A., Elsner, M.P. (2006): Verfahren zur Herstellung chiraler Substanzen durch selektive Kristallisation untersttzt durch Racemisierungsreaktion. DE 10 2006 013 7 25.6 (24.03.2006) Seidel-Morgenstern, A., Lorenz, H., Polenske, D.: Verfahren zur Trennung verbin-dungsbildender chiraler Systeme. Patent DE 10 2005 039 501 A1, Offenlegungstag: 22. 02. 2007; Method for separating compound-forming chiral systems. Internationales Patent WO 2007/023129 A3, Verffentlichung: 01. 03. 2007

[B]

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