Design of diastereomeric salt resolution via multicomponent system characterization: a case study with hydrate formation. Issue 4 (4th January 2023)

• Record Type: Journal Article
• Authors: Bosits, Miklós H.; Bereczki, Laura; Bombicz, Petra; Szalay, Zsófia; Pataki, Hajnalka; Demeter, Ádám
• Is Part Of: CrystEngComm. Volume 25:Issue 4(2023)
• Page Start: 641
• Page End: 652
• Publication Date: 2023-01-04
• Subjects: Crystals -- Periodicals; Crystal growth -- Periodicals; Crystallography -- Periodicals; Cristaux -- Périodiques; Cristaux -- Croissance -- Périodiques; Cristallographie -- Périodiques; 548
• DOI: 10.1039/d2ce01490d
• Languages: English
• ISSNs: 1466-8033

Abstract

Abstract : Design of a chiral resolution process with thermodynamic control. Abstract : 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.