Breveglieri Francesca, Bodák Brigitta, Mazzotti Marco
Institute of Energy and Process Engineering, ETH Zurich, 8092 Zurich, Switzerland.
Org Process Res Dev. 2021 Nov 19;25(11):2551-2565. doi: 10.1021/acs.oprd.1c00310. Epub 2021 Nov 5.
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.
通过温度循环进行的固态外消旋化是一种很有前景的技术，它在同一批次过程中结合了结晶和外消旋化以实现对映体纯化。该方法特别有吸引力，因为目标对映体可以以100%的产率分离出来，并且可以调整大量操作参数来有效地实现这一点。然而，这意味着为一种新化合物设计工艺时需要做出几种选择。在这项工作中，我们通过提出一种基于单个无量纲参数（即代表循环容量的溶解因子）的简化无模型设计方法，为这一困境提供了解决方案。这个量是通过对先前工作中提出的模型方程进行新颖的重新标度得到的，并且作为一个方便的设计参数，因为它仅取决于操作条件，例如悬浮密度、对映体过量以及循环中高低温之间的溶解度差异。通过大量的建模研究，并得到实验结果的支持，我们证明了溶解因子对外消旋化过程的主要和普遍影响，从而证明了它与工艺设计的相关性。通过实验和模拟，我们对将周期性和非周期性温度循环应用于具有不同性质（即生长速率和溶解度）的虚拟和实际化合物的外消旋化时的工艺性能进行了合理化分析和评估。基于这里提出的方法，我们阐明了如何利用更多操作条件的综合效应来获得准最优工艺性能，当通过周期性温度循环进行外消旋化时，这种性能更优越。
