(521b) Limitations and Optimization Potential of Continuous Chiral Resolution By Simultaneous Preferential Crystallization in Fluidized Bed Crystallizers

Enantiomers are optical isomers, which behave differently in living organisms but possess identical physical and chemical properties. Consequently, their separation is very important for the pharmaceutical and other life-science industries but at the same time very sophisticated. Preferential Crystallization is an efficient and cost-effective separation technique for chiral resolution, since it allows the direct crystallization of only one desired enantiomer without any chiral auxiliary from a racemic (50:50) solution. However, the inevitable nucleation of the unwanted enantiomer complicates the design of continuous Preferential Crystallization. A continuous and robust process can be achieved by applying Simultaneous Preferential Crystallization in conical-shaped fluidized bed crystallizers [1, 2]. In contrast to the well-studied continuous MSMPR (mixed suspension mixed product removal) concept, the application of fluidized bed crystallizers enables a narrow and adjustable product crystal size distribution, the selective removal of crystal fines and a short and narrow residence time distribution of the mother liquor. The two last mentioned effects support that this process can be operated robust against the nucleation of the unwanted enantiomer. Hence, higher supersaturations can be applied to exceed the current productivity benchmark for continuous crystallization processes for chiral resolution of around 20 g/L/h [3].

A remarkable high productivity of up to 100 g/L/h as well as the adjustable and narrow product crystal size distribution were recently demonstrated within a comprehensive experimental parameter study for the chiral resolution of the amino acid DL-asparagine monohydrate in water [4, 5]. Current efforts aim to study the limitations as well as the optimization potential of this auspicious process. Regarding the first goal, the process is tested for more challenging separation problems. A recent achievement was the successful chiral resolution of the API (RS)-guaifenesin in isopropanol [6], a compound characterized by particular slow crystal growth of needle-like crystals. To achieve the second goal, a reduced process model was developed and validated [5, 7]. This process model is currently applied for the model-based optimization of the operation parameters supersaturation, crystallization temperature, feed flowrate and product removal strategy, as well as for the optimization of the geometrical parameters of the conically shaped fluidized bed crystallizers.

In this contribution, the process as well as the utilized pilot plant will be explained and the good agreement between the experimental results and the process model will be demonstrated. Afterwards, the results of the model-based optimization of the above-mentioned operating parameters and geometrical parameters as well as their experimental validation will be shown and discussed for the substance system DL-asparagine monohydrate in water. The process performance of the separation experiments is evaluated by the productivity, the purity and the product crystal size distribution.

References:

[1] H. Lorenz, E. Temmel and A. Seidel-Morgenstern: Continuous enantioselective crystallization of chiral compounds. In: N. Yazdanpanah and Z. K. Nagy (Eds.): The Handbook of Continuous Crystallization, The Royal Society of Chemistry, 2020, pp. 422–468.

[2] D. Binev, A. Seidel-Morgenstern and H. Lorenz (2016): Continuous Separation of Isomers in Fluidized Bed Crystallizers, Cryst. Growth Des. 16, 1409-1419.

[3] T. Köllges and T. Vetter (2018): Design and Performance Assessment of Continuous Crystallization Processes Resolving Racemic Conglomerates, Cryst. Growth Des. 18, 1686−1696.

[4] E. Temmel, J. Gänsch, H. Lorenz and A. Seidel-Morgenstern (2020): Systematic Investigations on Continuous Fluidized Bed Crystallization for Chiral Separation, Crystals 10, 394-409.

[5] J. Gänsch, N. Huskova, K. Kerst, E. Temmel, H. Lorenz, M. Mangold, G. Janiga and A. Seidel-Morgenstern (2021): Continuous Enantioselective Crystallization of Chiral Compounds in Coupled Fluidized Beds, Chem. Eng. J. 422, 129627.

[6] F. Cascella, J. Gänsch, A. Seidel-Morgenstern and H. Lorenz (2022): Continuous enantioseparation of the API Guaifenesin in a fluidized bed crystallizer, manuscript in preparation.

[7] M. Mangold, L. Feng, D. Khlopov, S. Palis, P. Benner, D. Binev and A. Seidel-Morgenstern (2015): Nonlinear model reduction of a continuous fluidized bed crystallizer, J. Comput. Appl. Math. 289, 253-266.