Direct chiral resolution of Praziquantel through preferential crystallization of a conglomerate cocrystal
Résumé
Due to the chirality of life, the two enantiomers of chiral molecules can exhibit different biological activities. In pharmacology, often only one enantiomer is active, the other one being either ineffective or even the source of side effects. However, chiral drugs are still widely marketed as racemic mixtures (equimolar mixtures) of both enantiomers. For example, Praziquantel (PZQ), used in the treatment against schistosomiasis, is still marketed as a racemic mixture, while only the R-enantiomer is active. Preferential crystallization (PC) is a method of choice for enantiomer separation: from a metastable supersaturated racemic solution, secondary nucleation of the eutomer (desired enantiomer) is stereoselectively triggered by seeding the solution with a seed of the eutomer [1]. However, the main drawback of this method is the requirement of a conglomerate system (i.e., the two enantiomers crystallize as a mixture of homochiral crystals), while around 90% of the racemic mixture of chiral molecules crystallize as racemic compounds (the two enantiomers crystallize together in the same crystal lattice).
A possible way to change the solid properties of racemic compounds (and herewith to separate the enantiomers) is their co-crystallization with an achiral coformer to generate a new solid phase, possibly a conglomerate cocrystal. Recently, two cocrystals of PZQ and vanillic acid (VA) as a coformer have been spotted and described [2]. Further studies identified one of them as a conglomerate cocrystal, containing one molecule of PZQ associated with two molecules of VA (i.e., a PZQ:2VA conglomerate cocrystal) [3]. Here we aim to describe the PC of the PZQ:2VA cocrystal in order to reach enantiopure PZQ. Phases diagrams, solubility lines and induction times have been determined to identify optimal conditions to perform PC. Results show good enantiopurity of the final product (enantiomeric excess > 90 %). To the best of our knowledge, this is the first direct resolution of PZQ at the solid state using an achiral coformer, and we expect this to reduce the cost of the separation of PZQ enantiomers.
Domaines
MatériauxOrigine | Fichiers produits par l'(les) auteur(s) |
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