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

Abstract

Solid-state deracemization via temperature cycles converts a racemic crystal mixture into an enantiopure product by periodic cycling of the temperature in the presence of a racemization catalyst. A continuous counterpart of this conventional batch-operated process is proposed that can be performed in mixed suspension mixed product removal crystallizers (MSMPRCs). More specifically, three different configurations are described to perform periodic forcing via temperature cycles, which differ from each other in the type of the feed and in the withdrawal system. We have developed a model by extending our recent population balance equation model of batch solid-state deracemization via temperature cycles, and we exploit this tool to analyze the start-up and periodic steady-state behavior. Moreover, we compare the performance of the different configurations based on the selected key performance indicators, namely, average periodic steady-state enantiomeric excess and productivity. The process with solution feed yields pure enantiomers, while the solid and suspension-fed process alternatives result in highly enantiomerically enriched crystals. We further design an MSMPRC cascade to overcome this purity limitation. This work discusses guidelines on how to transform the batch process of temperature cycles into a continuous operation, which enables stable, unattended operation and chiral crystal production with consistent product quality.

Crystallization-Induced Deracemization: Experiments and Modeling

“…How to realize a continuous deracemization process based on the same physicochemical mechanisms exploited in this study and how this compares in terms of process performance are beyond the scope of this work and are the subjects of an upcoming contribution. 31…”

“…It is worth noting that an alternative approach is offered by continuous processes, which can in principle achieve a higher level of operational stability and of product quality consistency. How to realize a continuous deracemization process based on the same physicochemical mechanisms exploited in this study and how this compares in terms of process performance are beyond the scope of this work and are the subjects of an upcoming contribution …”

“…The model requires the initial particle size distribution for each enantiomer, f 0 i ; for the distomer this is obviously 0, while for the eutomer this is a truncated Gaussian distribution, symmetric about its mean (the rescaled parameters of f 0 D are λ 1,0, i 0 and σ̃ i 0 , see Table ). As the model has been discussed in depth in previous works, ,, in this work, we summarize only the dimensional equations in Table . The values of the model parameters that were kept constant during the simulations are reported in Table , while the parameters varied in the simulations study are reported in Table .…”

Deracemization via Periodic and Non-periodic Temperature Cycles: Rationalization and Experimental Validation of a Simplified Process Design Approach

“…First, batch deracemization through periodic temperature cycles can be tuned and optimized by exploiting the combined effect of the different operating parameters grouped together in the initial dissolution factor, δ 0 , and should be preferred to the same process implementing non-periodic cycles. Second, deracemization through periodic temperature cycles can also be implemented in a continuous mode, as presented earlier 39 and discussed in an upcoming publication. 23 Finally, the potential for productivity enhancement at low values of the initial dissolution factor, that is, at δ 0 = 0, with an initial suspension consisting of an enantiopure solid in a racemic solution, that is, with ee 0 = 1, is going to be explored in a second upcoming publication; 28 this would be a simple batch cooling crystallization process with racemization in solution, which promises to exhibit attractive advantages but also a few disadvantages, with respect to the temperature cycles studied here.…”

“…The mathematical model of the deracemization via the temperature cycle process is a population balance equations (PBEs)-based model formulated in terms of rescaled equations derived in detail in Section 3 by Bodaḱ et al 14 The PBEs are solved with a high-resolution finite volume method 22 (for details on the solution of the equation, see Bodaḱ, in preparation 23 ). Table 1 summarizes the dimensional model equations, on which the theoretical part of this study is based.…”