Separation of Enantiomers by Continuous Preferential Crystallization: Experimental Realization Using a Coupled Crystallizer Configuration

Abstract

The experimental realization of a continuous preferential crystallization process, consisting of two mixed-flow crystallizers coupled via crystal-free liquid exchange streams and with only the liquid phases operating continuously, is addressed. Experiments in triplicate, using the conglomerate-forming system of dl-asparagine monohydrate in water, were conducted, and the achievement of nearly racemic composition of the liquid phase in the crystallizers was verified. An experiment was also carried out using seed crystals of a smaller average particle size than used in the reference experiments. Successful enantioseparation by crystal growth, with the repeatability being within ±10% deviation, was obtained. However, slow crystal growth, due to a low surface integration rate, led to a negligible consumption of the desired enantiomer added in the feed solution, resulting in low productivities. Productivities, yields, and purities of solid products were influenced by the morphological differences in the seed crystals. Due to irregularly shaped seed crystals, increase in the productivities and yields were achieved in the L-Tank. Lower purities of solid products from the L-Tank compared to purities of the solid products from the D-Tank were obtained. This could be due to surface nucleation of d-asparagine monohydrate, ascribed to the surface structure of the seeds of l-asparagine monohydrate supplied. Improvements in productivity, yield, and purity in the L-Tank, for the same process duration, were realized using seed crystals of lower average particle size having a smoother surface structure. The main advantages compared to other separation processes are low capital cost, high crystal purity and yield, ease of upscaling, increased safety, and reduced environmental impact due to reduction in the amount of solvent used. The application is currently limited to conglomerate-forming systems, but the separation concept may open new possibilities for process improvements regarding enantioseparation of racemic compound-forming systems as well.

Diastereomeric salt crystallization of chiral moleculesvia sequential coupled‐Batch operation

“…The presence of the counter enantiomer can also cause undesired side effects in patients such as in the case of thalidomide . In this tragic case, the (S)‐enantiomer of thalidomide was a potent teratogen, whereas the (R)‐enantiomer was prescribed to alleviate morning sickness for pregnant women . The unmonitored administration of the drug resulted in physical birth defects due to the drugs rapid enantioconversion under physiological conditions .…”

Separation of conglomerate forming enantiomers using a novel continuous preferential crystallization process

“…However, Qamar et al still used continuous or periodic seeding to accomplish their separation performance (in the case of Qamar et al seed crystals for both enantiomers were needed). An experimental implementation of a similar process was presented by Chaaban et al, who, however, only treated the liquid phase in a continuous fashion and needed to restart their process with fresh seeds after some time. Furthermore, the yield obtained from all three processes was rather low.…”

Designs of continuous-flow pharmaceutical crystallizers: developments and practice

“…The correct chemical (e.g., enantiomer 103 ) and solid forms are selected before deciding on seed crystal size and loading, as described in step 1 of section 2. Most in situ seed generation methods can be applied off line.…”