Design, Development, and Analysis of an Automated Sampling Loop for Online Monitoring of Chiral Crystallization

Enantiomeric purity is of prime importance for several industries, specifically in the production of pharmaceuticals. Crystallization processes can be used to obtain pure enantiomers in a suitable solid form. However, some process variants inherently rely on kinetic enhancement (preferential crystallization) of the desired enantiomer or on complex interactions of several phenomena (e.g., attrition-enhanced deracemization and Viedma ripening). Thus, a process analytical technology able to measure the enantiomeric composition of both the solid phase and the liquid phase would be valuable to track and eventually control such processes. This study presents the design and development of a novel automated analytical monitoring system that achieves this. The designed setup tracks the enantiomeric excess (ee) using a continuous closed-loop sampling loop that is coupled to a polarimeter and an attenuated total reflection Fourier transform infrared spectroscopy spectrometer. By heating the loop and alternately sampling either the liquid or the suspension, the combination of these measurements allows tracking of the ee of both the liquid and the solid. This work demonstrates a proof of concept of both the experimental and theoretical aspects of the new system.