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

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.