Complete chiral resolution in a continuous flow crystallizer with recycle stream

Abstract

Repeated temperature cycling of crystals from a conglomerate forming chiral substance suspended in their saturated solution has shown to be effective in converting a mixture of both enantiomers into an enantiomerically pure state. While by now a large number of different setups has been demonstrated, here we show for the first time how a continuous flow temperature cycler with recycle stream is capable of establishing enantiopurity while converting a racemic starting suspension. By capturing the most significant parameters influencing the process kinetics a competitive productivity could be achieved. We show, that fast crystal dissolution at high undersaturations and fast crystal growth at high supersaturations are speeding up the process as long as nucleation can be kept to a minimum or avoided at all. Temperature cycling has shown to result in a shift towards larger sizes for the particle size distribution of the crystals suspended, which is detrimental to the present process governed by size-dependent solubility. By implementing an ultrasound unit recycled material was comminuted, resulting in nearly stable deracemization rates. Graphical abstract

Solid-State Deracemization via Temperature Cycles in Continuous Operation: Model-Based Process Design

“…42 It is therefore straightforward, based on chemical reaction engineering principles, that only for the configuration, which does not contain crystals of the undesired enantiomer (i.e., base configuration), attaining complete enantiomeric purity is feasible. Note that the only feed strategy utilized as to date in continuous tubular temperature cycles experiments is the suspension feed, 26,27 which is not the preferred feeding strategy in an MSMPR crystallizer, as it is expected to underperform the other two feed strategies. However, one could overcome the intrinsic limitation of continuous mixed flow reactors, e.g., by using a cascade of reactors.…”

“…26 In a recent work, the feasibility of performing continuous temperature cycles in a continuous tubular crystallizer was demonstrated. 27 Nevertheless, to the best of our knowledge, application of periodic temperature cycles in mixed suspension mixed product removal crystallizers (MSMPRCs) for the purpose of solid-state deracemization has not been reported. Yet, forced periodic operation of reactors is not uncommon in the field of chemical engineering.…”

“…Another step toward industrial application is based on the batch temperature cycling experiments carried out in a microwave reactor, i.e., exploiting very fast heating and cooling rates, and its continuous alternative was presented by employing spatial thermal oscillations in a tubular flow millireactor . In a recent work, the feasibility of performing continuous temperature cycles in a continuous tubular crystallizer was demonstrated . Nevertheless, to the best of our knowledge, application of periodic temperature cycles in mixed suspension mixed product removal crystallizers (MSMPRCs) for the purpose of solid-state deracemization has not been reported.…”

Symmetry and chirality in crystals

“…The terms racemic conglomerate and racemic crystal are well established in the literature, but the corresponding terms for scalemic are much rarer, although not unknown. The first occurrence we could locate of scalemic conglomerate is in an article by Wei et al (2009), whereas scalemic crystal seems to have been used only recently (Neugebauer et al, 2021).…”