Recently, temperature cycles have been shown to lead to total deracemization of conglomerate forming compounds, in the presence of a racemizing agent. Even though several experimental studies have been performed, a clear explanation of the phenomena involved in this process and a detailed model have not been reported yet. This contribution aims at filling this gap, by presenting a mathematical model of temperature cycle induced deracemization. The model, based on population balance equations, describes the interplay of several phenomena (size-dependent solubility, crystal growth and dissolution, agglomeration, and racemization), explicitly accounting for the dependence of their thermodynamic and kinetic parameters not only on the particle size, but also on temperature. After discussing how to numerically solve the model, we present several simulations investigating the effect of the main chemicophysical parameters and of the operating conditions. Our results not only illustrate the effect of each parameter on the process and the relative importance of the different phenomena, but also compare well qualitatively with the experimental results recently reported on the deracemization of N-(2-methylbenzylidene)-phenylglycine-amide in the presence of 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU).
Solid-state deracemization via temperature cycles is a technique to obtain a pure powder of the desired enantiomer of a conglomerate forming compound from an initial mixture of both solid enantiomers, through a combination of dissolution and growth due to size-dependent solubility, in the presence of racemization in solution. The complexity of the process requires a mathematical model to understand the effect of initial conditions and operating parameters on the process outcome and performance. To this aim, we use our recently developed population balance based model of deracemization through temperature cycles to explain the large variations in deracemization time and in process outcome that are observed in experiments. We show how the direction of the evolution toward one or the other pure enantiomer is influenced by the initial asymmetries between the crystal populations of the two enantiomers. We observe how the process response varies to changes in the initial conditions and compare performance based on productivity. As for the operating conditions, we have performed simulations in the presence of attrition to investigate the effect of process conditions and system properties.
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.
Solid-state deracemization via temperature cycles is a promising technique that combines crystallization and racemization in the same batch process to attain enantiomer purification. This method is particularly attractive because the target enantiomer can be isolated with a 100% yield, and a large number of operating parameters can be adjusted to do this effectively. However, this implies that several choices need to be made to design the process for a new compound. In this work, we provide a solution to this dilemma by suggesting a simplified model-free design approach based on a single dimensionless parameter, that is, the dissolution factor, that represents the cycle capacity. This quantity is obtained from a novel rescaling of the model equations proposed in previous work and acts as a handy design parameter because it only depends on the operating conditions, such as the suspension density, the enantiomeric excess, and the difference in solubility between high and low temperatures in the cycle. With extensive modeling studies, supported by experimental results, we demonstrate the primary and general effect of the dissolution factor on the deracemization process and thus its relevance for the process design. Through both experiments and simulations, we rationalize and evaluate the process performance when periodic and non-periodic temperature cycles are applied to the deracemization of virtual and real compounds with different properties, that is, growth rate and solubility. Based on the approach proposed here, we clarify how the combined effect of more operating conditions can be exploited to obtain quasi-optimal process performance, which results superior when deracemization via periodic temperature cycles is performed.
Inspired by deracemization via temperature cycles, which enables the collection of crystals of the desired enantiomer from an initially racemic mixture, we focus in this work on an alternative batch process, namely crystallization-induced deracemization. This process starts with a suspension of enantiomerically pure crystals, which undergoes a simple cooling crystallization, coupled with liquid-phase racemization. The experimental and model-based analysis of such a process, carried out here, revealed that: (i) deracemization via temperature cycles is a safe choice to operate with high enantiomeric purity, although its throughput is limited by the suspension density; (ii) if the distomer is less prone to nucleation, crystallization-induced deracemization is a simple process; however, its performance is strongly limited by the solubility; (iii) the purity achieved with crystallization-induced deracemization can be increased by utilizing large seed mass and by optimizing the cooling profile or catalyst concentration. Alternatively, the purity increases via partial dissolution of the seeds, which resembles the heating part of the deracemization process via temperature cycles.
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