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

Abstract

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.

Exact and Ubiquitous Condition for Solid-State Deracemization in Vitro and in Nature

“…The number of cycles must in fact scale with the reciprocal of Δn cyc in eq 4; therefore, with the reciprocal of the solubility difference, Δc ∞ (proportional to the temperature difference for small amplitudes), and with the reciprocal of the cycle efficiency, η (largely independent of the temperature difference). To confirm this, we computed the value of η following the approach outlined in Supporting Information, Section S.1 not only for these three experiments where we found 0.12 ≤ η ≤ 0.18 but also for a large set of earlier NMPA temperature-cycling experiments with similar operating conditions and an amplitude up to 21 °C where we found 0.08 ≤ η ≤ 0.13 45 (see Supporting Information, Section S.1 for the details, as well as for consistent results obtained for two other chiral compounds).…”

Crystallization-Induced Deracemization: Experiments and Modeling

“…Through this study on crystallization-induced deracemization, which follows our previous work on deracemization via temperature cycles, 10 , 11 , 15 , 16 , 18 , 21 we have completed the analysis of a class of deracemization processes operated batchwise. We have proven that such batch processes are effective, also due to the simplicity of their operation, and we have highlighted their advantages and disadvantages in terms of key performance indicators.…”

“…The experiments presented in this work were performed with N -(2-methylbenzylidene)-phenylglycine amide (NMPA), which was already used as a model compound in previous works ,, and was synthesized in our laboratory according to the procedure reported in the literature . This compound is an imine derivative of phenylglycine that racemizes in solution in the presence of the base 1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU) as a racemizing agent.…”

“…Among these processes, 1−8 deracemization via temperature cycles has been the focus of experimental and modeling studies carried out by various research groups with the aim of identifying the relevant operating parameters and simplifying the process design. 5,9−20 In our recent work, 21 we identified a design parameter, i.e. the dissolution factor, demonstrated its primary role, and showed that high productivity values are attained for small values of the dissolution factor.…”

“…Solid-state deracemization processes are particularly appealing, thanks to the combination of crystallization and racemization, which enables the conversion of a suspension consisting of crystals of both enantiomers into an enantiomerically pure crystal suspension. Among these processes, − deracemization via temperature cycles has been the focus of experimental and modeling studies carried out by various research groups with the aim of identifying the relevant operating parameters and simplifying the process design. ,− In our recent work, we identified a design parameter, i.e. the dissolution factor, demonstrated its primary role, and showed that high productivity values are attained for small values of the dissolution factor.…”