Coupling reaction and crystallization processes

Often crystallization is used at the end of a reaction-separation process chain to finally produce the solid product. However exploiting its inherent high selectivity at an earlier stage offers advantages. For example, the direct integration of crystallization within a synthesis reaction chain can benefit from circumventing reaction equilibria constraints, increasing selectivity, simplifying downstream processing and providing the target compound straightly as a solid product with desired solid-state properties. Within the last years, several processes combining a reactive and a crystallization step were studied in our group as for example: Coupling of racemization and preferential crystallization for efficient production of single enantiomers, Coupling biocatalytic synthesis with crystallization/precipitation for enantiomer production and Combination of reactive absorption and crystallization for development of a novel process for carbon-negative and sustainable production of soda ash. Current research also integrates reactive depolymerization with crystallization-based product recovery.

Coupling biocatalytic synthesis with crystallization for production of pharmaceutically relevant enantiopure amino acids

Amino acids and amino alcohols are chiral substance classes relevant in a wide range of industrial applications. For example, homophenylalanine is a precursor in the manufacturing of pharmaceutical products. In a collaboration project with the (Bio)Catalytic Synthesis Group at Otto-von-Guericke University, Magdeburg, Germany, the production of L-/D-homophenylalanine as a model substance by coupling biocatalytic synthesis with (continuous) crystallization processes to facilitate favorable process and product performance, e.g. in respect to yield and particle characteristics, is investigated.

Our focus is on the crystallization and integrated process design. First, fundamental crystallization-related data such as solid-liquid equilibria, solid state behavior, crystal structure, and various other physicochemical properties of the respective chiral systems were studied. Solid homophenylalanine showed a decomposition behavior at elevated temperatures. Solid-liquid equilibria investigations revealed very low solubilities in water which can significantly be changed by pH adjustment, and the formation of a racemic compound between the L- and D-enantiomers. Favorable process parameters will be validated experimentally in our Lab [1,2].

Figure 1: Ternary phase diagram of the aqueous chiral homophenylalanin/ water system at 25 and 55°C [2].

Figure 1: Ternary phase diagram of the aqueous chiral homophenylalanin/ water system at 25 and 55°C [2].

References

[1] Tenberg, V., Sadeghi, M., Schultheis, A., Joshi, M., Stein, M., & Lorenz H. (2024), Aqueous solution and solid-state behaviour of L-homophenylalanine: experiment, modelling, and DFT calculations, RSC Advances, 14, 10580-10589, doi: 10.1039/D4RA01897D

[2] Schultheis, A. Merz, K., Tenberg, V., & Lorenz, H. (2026), Solid-Liquid Equilibria in the Aqueous Chiral Homophenylalanine System and Solid-State Characterisation of the Racemic Species, CrystEngComm, 28, 2937-2946, doi: 10.1039/D6CE00109B