Design of diastereomeric salt resolution multicomponent system characterization: a case study with hydrate formation

• Published in: CrystEngComm Vol. 25; no. 4; pp. 641 - 652
• Main Authors: Bosits, Miklós H, Bereczki, Laura, Bombicz, Petra, Szalay, Zsófia, Pataki, Hajnalka, Demeter, Ádám
• Format: Journal Article
• Published: 23.01.2023
• ISSN: 1466-8033
• DOI: 10.1039/d2ce01490d

Diastereomeric salt crystallization is a convenient method to resolve chiral drug substances when other separation methods like preferential crystallization and solid-state deracemization cannot be applied directly. This is the case of the antiepileptic pregabalin, which is a racemate-forming compound with recently discovered hydrate-forming activity. In this study, the quaternary system of pregabalin enantiomers, l -tartaric acid and water was investigated by the characterization of relevant solid forms and the measurement of solubilities and solid-liquid equilibria. This information was used to outline phase diagrams in the specific quaternary space and create a thermodynamic model based on solubility product constants to simulate the effect of variable parameters on the resolution process. Thus, a set of optimal temperature pairs were identified with similar selectivity along the so-called purity line in the region of 10-40 °C. This line was adjusted experimentally, and a realistic correction of 3 °C was made. Our method provided a quick process with low material requirements to design diastereomeric salt resolution. Finally, a proof of concept resolution experiment was conducted, where a diastereomerically pure product was obtained with 51.6% yield and 153 mg (g water) −1 productivity. Design of a chiral resolution process with thermodynamic control.