Abstract
Preferential crystallization is a cost efficient method to provide pure enantiomers from a racemic mixture of a conglomerate forming system. Exploiting small amounts of pure crystals of both enantiomers, several batch or continuous processes were developed, capable of providing both species. However, an intermediate production step has to be used when pure enantiomers are not available. In such cases, partially selective synthesis, chromatography, or crystallization processes utilizing chiral auxiliaries have to be used to provide the initial seed material. Recently, it was shown that a coupled Preferential Crystallization-selective Dissolution process (CPCD) in two coupled crystallizers can be applied if at least one pure enantiomer is available to produce both antipodes within one batch. The corresponding process is carried out in one reactor (crystallization tank) by seeding a racemic supersaturated solution with the available enantiomer at a certain temperature. The second reactor (dissolution tank) contains a saturated racemic suspension at a higher temperature. Both reactors are coupled via the fluid phase, allowing for a selective dissolution of the preferentially crystallizing enantiomer from the solid racemic feed provided in the dissolution vessel. The dissolution and crystallization processes continue until the solid racemic material is completely resolved and becomes enantiopure. At this point, both enantiomers can be harvested in their pure crystalline form. For a specific pharmaceutically relevant case study, a rational process design and the applied empirical optimization procedure will be described. The achieved productivities after optimization show the great potential of this approach also for industrial applications. Also, a strategy to control this process based on inline turbidity measurement will be presented.
Highlights
Enantiomers are molecules that are mirror images of each other with the same molecular structure and identical physicochemical properties
It was shown that a coupled Preferential Crystallization-selective Dissolution process (CPCD) in two coupled crystallizers can be applied if at least one pure enantiomer is available to produce both antipodes within one batch
The second reactor contains a saturated racemic suspension at a higher temperature. Both reactors are coupled via the fluid phase, allowing for a selective dissolution of the preferentially crystallizing enantiomer from the solid racemic feed provided in the dissolution vessel
Summary
Enantiomers are molecules that are mirror images of each other (optical isomers) with the same molecular structure and identical physicochemical properties. The stereoisomerism of two enantiomers can cause different effects if they are applied to biological systems due to chirality of enzymes, hormones, etc. There is evidence that commonly only one enantiomer induces the desired effect while the other is inactive or even harmful.[1,2] if chiral components are utilized as a racemic mixture (50/50 ratio of both enantiomers), half of the applied material can be toxic, cause stress for the biological system, or is wasted leading to environmental pollution. The development of processes to produce pure enantiomers is a prerequisite for economically and ecologically effective applications of chiral substances in, e.g., the pharmaceutical, food, and agrochemical industries. The substances can be conventionally produced as racemic mixtures and separated subsequently with appropriate techniques exploiting chromatography, membranes, or, like in the present study, preferential crystallization.[3−5]
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