(460b) Enhancement of Crystallization Behavior for Solid Solution Separation Using Different Antisolvents

Crystallization is utilized in a multitude of different applications in the chemical, pharmaceutical, and food industries, for example to directly purify target compounds or to crystallize and separate impurities. It can also be used to design a product regarding specifications like particle size, shape and particle size distribution, as well as application-oriented properties like flowability, compressibility etc.. Designing an efficient crystallization process to meet the desired specification and purity goals is challenging, in particular, if the target compounds cannot be purified in a single crystallization step. This might occur when highly purified products are required or if solid solutions are formed. A solid solution is a one-phasic solid, which consists of two or more compounds with a statistical distribution within the crystalline solid. As opposed to a co-crystal, which has a specific composition, solid solutions are present over a limited composition range as a partial solid solution or over the whole composition range as a complete solid solution.

The separation of solid solutions requires a multistage approach. Fractional crystallization is a classical method in which the resulting solid phase is redissolved and recrystallized for further purification. However, considerable amounts of the target product are lost in the liquid phase. An efficient process is counter-current crystallization (see Figure 1). Counter-current crystallization is to fractional crystallization what is rectification to distillation [1]. Due to stagewise remixing, one component is enriched in the solid phase, while another component is enriched in the liquid phase.

In addition to classical techniques like evaporative or cooling crystallization, alternative strategies such as antisolvent crystallization have shown potential to improve the efficiency of the counter-current process. Hence, distributions diagram can be constructed to compare different crystallization methods. For a typical binary solid solution, such diagram is obtained by plotting the solid composition versus the solvent-free liquid composition of one of the two components (see Figure 2). Similar to the well-known distribution diagram in rectification, it can graphically show the theoretical separation stages and help judging the separation efficiency for various conditions.

Recently, we proposed an isothermal process to separate an alyotrope found in the example system L-valine/L-leucine using water as a solvent and ethanol as an antisolvent [2]. Figure 2 shows the distribution diagram illustrating the alyotrope. Similar to azeotropes, alyotropes limit the purification at a specific composition depending on the process conditions. The process consists of a dual counter-current crystallization setup, where one cascade uses evaporative crystallization in water while the other uses antisolvent crystallization with ethanol as the antisolvent. The alyotropic point is shifted with changing process conditions similar to shifting the azeotrope via pressure change in a pressure swing rectification process.

This process was validated by predictive process simulation and experiments at a pilot plant scale. A more extensive process simulation of a five stage process (three evaporative and two antisolvent stages) at 25 °C with a feed composition of 25/75 wt.% L-leucine/L-valine supplied to the center crystallizer has been conducted. The results showed purities of 95.4 wt.% for L-leucine and 88.3 wt.% of L-valine with yields of 90.1 % and 90.8 %, respectively. The lower purification of L-valine as compared to L-leucine can be attributed to the overall low separation efficiency near the alyotrope (see Figure 2.).

Further work is underway to provide a more potent purification setup. We are going to consider different antisolvents at various process conditions. Moreover, thermodynamic-based models can be used to describe the distribution diagrams. The overall goal is to shift the alyotrope more efficiently and to improve the separation. The results of this investigation as well as extensive process modelling and related pilot plant experiments are to be presented in this contribution, which can be a basis to efficiently design a counter-current crystallization process.

[1] S. Münzberg, T. Giang Vu and A. Seidel-Morgenstern, "Generalizing Countercurrent Processes: Distillation and Beyond," Chem. Ing. Tech., vol. 90, no. 11, pp. 1769 - 1781, 2018.

[2] V. Tenberg, M. Sadeghi, A. Seidel-Morgenstern and H. Lorenz, "Bypassing thermodynamic limitations in the crystallization-based separation of solid solutions," Sep. Pur. Technol., vol. 283, p. 120169, 2022.