Effect of Initial Conditions on Solid-State Deracemization via Temperature Cycles: A Model-Based Study

Bodák, Brigitta; Maggioni, Giovanni Maria; Mazzotti, Marco

doi:10.1021/acs.cgd.9b00988

Cited by 21 publications

(29 citation statements)

References 26 publications

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“…As a consequence, more beneficial conditions for the process can be found at lower values of the dissolution factor than at higher ones. As already illustrated in Figure 8 of a previous work, 25 the productivity does not increase monotonically with ee 0 and ρ 0 , but a maximum value can be found. In our case, this corresponds to a productivity of 14.3 g kg –1 h –1 , when ee 0 = 0.6 and ρ 0 = 0.5 g g –1 .…”

Section: Results On Periodic Temperature Cyclessupporting

confidence: 58%

“…First, we examine the fundamental effects of the operating and system parameters by looking at the total number of cycles required to reach a minimum ee value of 0.95; we call this quantity n 95 . Then, we assess how they affect the process performance by defining the productivity as follows (see eq 13 in an earlier paper 25 ): where t process is the total process time calculated as the sum of the cycle times of the n 95 cycles, ϕ 3 D is the third moment of the PSD, proportional to the crystal mass, of the desired enantiomer, and ϕ 3 L is that of the undesired one at the beginning and the end of the process with subscripts “0” and “final”, respectively.…”

Section: Theorymentioning

confidence: 99%

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

Breveglieri

Bodák

Mazzotti

2021

Org. Process Res. Dev.

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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.

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Section: Results On Periodic Temperature Cyclessupporting

confidence: 58%

Section: Theorymentioning

confidence: 99%

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

Breveglieri

Bodák

Mazzotti

2021

Org. Process Res. Dev.

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“…Several groups have studied the behaviour of the process of temperature-cycling-induced deracemization, either experimentally or computationally via the use of population balance equations. While earlier experimental studies relied on simple first-order kinetics expressions to describe the progress and the time-evolution of the enantiomeric excess [8], later more detailed models using population balance equations have been developed [10][11][12][13]. In the context of this work, we were looking for a simple way to quantify the efficiency of the deracemization process depending on the process settings of individual trials and relate it to the number of cycles performed.…”

Section: Evaluation Of Resultsmentioning

confidence: 99%

Complete chiral resolution in a continuous flow crystallizer with recycle stream

2021

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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

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“…It is worth noting that we are using a size-dependent solubility model, which enters into the definition of the driving force of both growth and dissolution. 43 − 45 …”

Section: Mathematical Modelmentioning

confidence: 99%

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

Bodák

Mazzotti

2022

Crystal Growth & Design

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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.

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Effect of Initial Conditions on Solid-State Deracemization via Temperature Cycles: A Model-Based Study

Cited by 21 publications

References 26 publications

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

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

Complete chiral resolution in a continuous flow crystallizer with recycle stream

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

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