Strategic synthon approach in obtaining cocrystals and cocrystal polymorphs of a high-Z′ system deferiprone – an anti-thalassemia drug

Abstract

Compounds with more than one molecule in the crystallographic asymmetric unit (Z′ > 1) display a noticeably stronger propensity to form cocrystals. Deferiprone is an anti-thalassemia drug known to exhibit polymorphic behaviour. Previously, three polymorphs were reported out of which one of them exhibited Z′ > 1. In the present manuscript, a fourth polymorph of deferiprone was identified and it also possessed Z′ > 1. All the four polymorphs showed similar hydrogen bonding features and differed in crystal packing. The ability of deferiprone to crystallize as Z′ > 1 prompted us to investigate the hydrogen bonding and synthon variation upon cocrystallization of deferiprone with hydroxyl-group-containing coformers such as catechol, hydroquinone, phloroglucinol, resorcinol and pyrogallol. Crystallization attempts along with PXRD analysis aided in obtaining 11 new cocrystal structures which involve different stoichiometric cocrystals and some polymorphs. Synthon analysis, crystal packing as well as thermal behaviour were assessed and compared. The presence of multiple phases in each cocrystal system in its respective bulk powders was identified and quantified using PXRD and Rietveld analysis. Homosynthons were observed in three co-crystal systems, while a heterosynthon was observed in five systems. The combination of both homo- and heterosynthon was observed in three cocrystal systems. The phase transformation events were observed in most of the systems. In nine co-crystal systems, the melting points were observed intermediate between those of the API and the coformers.