Intensification of Solid-state Separation of Enantiomers via Thermal Cycles

Chirality is a geometric property of three-dimensional objects that has tremendous relevance in the biological world since enantiomers (non-superimposable mirror image molecules) display different physical and chemical properties in chiral environments such as those related to the vital functions of living organisms. Therefore, the manufacture of single enantiomers is pivotal in the pharmaceutical, fine chemicals, food and agrochemical sectors. On the other hand, obtaining enantiopure products at industrial scale is not straightforward as asymmetric chemical synthesis requires costly additives and lengthy procedures that usually suffer from low product yield. Thus, resolution of an equimolar mixture of the enantiomeric molecules can represent a more productive solution. Among the arsenal of techniques developed for downstream separation of enantiomers, solid state deracemization methods have gained the spotlight due to the possibility of achieving complete product recovery in the solid form while attaining full conversion of the undesired compound into the target product. Solid state deracemization processes are either based on mechanical or thermal treatment of a chiral suspension in which partial dissolution and re-crystallization of the crystals coupled with racemic composition of the solution lead to enantiopurity. In this context, temperature cycling-induced deracemization has been regarded as the most promising deracemization approach due to the easily applicable and controllable thermal cycles driving the process. Furthermore, no additional separation from the heating/cooling agent is required at the end of the process when the cyclic thermal oscillations stop. Nonetheless, this process is still characterized by long process times that negatively affect process productivity thus hindering its industrial application. The main focus of this research project is to intensify the temperature cycling method by means of process intensification strategies such as microwave heating and continuous flow processing. More specifically, rapid thermal cycles can be produced in a microwave apparatus where both heating and cooling rates are enhanced thus isothermal dissolution and crystallization stages drive the deracemization. Therefore, by intensifying the cycle duration the overall process time decreases whilst solid yield is enhanced by the limitation of side reactions that hamper the selectivity of the process. Hence, the microwave set-up outperforms the equivalent conventional system in terms of process productivity. Furthermore, the application of fast sweeps of temperature results in high solute supersaturation upon cooling that increases the likelihood of secondary nucleation which could compete with crystal growth in depleting the created supersaturation. Together with solute supersaturation, suspension density and agitation rate are also operational parameters that govern the occurrence of secondary nucleation. Whilst increasing agitation rate yields higher stereoselective secondary nucleation that enhances the deracemization rate, both supersaturation and suspension density display a non-monotonic trend with regards to enantiomeric enrichment. Therefore, optimal operating conditions exist in order to attain extensive stereoselective secondary nucleation that intensifies the deracemization process. The paramount role of secondary nucleation has been overlooked so far but it must be considered in future studies as this work clearly shows how this mechanism is fundamental in the enantiomeric enrichment attained during the crystallization phase of the thermal cycles. Ultimately, a scale-up strategy for this process is presented to show how a continuous process could tackle the limitations regarding long process times and low productivity of a temperature cycling-induced deracemization process. The enhanced heat transfer achieved by a flow reactor subject to spatial thermal cycles allows for extremely low cycle durations that together with the high solid recovery deliver unprecedented process productivity values. Therefore, the continuous configuration enables processing of higher suspension volumes than a batch process while maintaining control over the thermal profile and hence on the deracemization rate. Although not optimized, the hereby presented process could be already suitable for industrial application.status: publishe