Phase Diagrams of Praziquantel and Vanillic Acid Cocrystals: Racemic Compound and Conglomerate System

Abstract

Praziquantel (PZQ) is widely used to treat schistosomiasis. However, this chiral active pharmaceutical ingredient (API) is still produced as a racemic compound while only the (R)-enantiomer is active. A possible way to control the solid properties of chiral APIs and herewith to separate the enantiomers is their cocrystallization with a coformer to form a conglomerate cocrystal. Vanillic acid (VA) has been previously identified as a coformer able to form two different cocrystal forms with PZQ. While the first one has been characterized and identified as an equimolar racemic cocrystal (i.e., a 1:1 (±)PZQ:VA racemic cocrystal), the properties of the second cocrystal remain unknown. In this paper, a variety of analytical methods (XRPD, DSC, and SHG) have been used to characterize the second cocrystal form. The results show that this second cocrystal form is a 1:2 (+)/(−)PZQ:2VA cocrystal, which crystallizes as a conglomerate, opening routes toward the separation of PZQ enantiomers through preferential crystallization. This study shows the importance of testing several stoichiometries in a screening context, as the desired form or properties, such as a conglomerate cocrystal, could be found in a nonequimolar cocrystal.