Pyrazinamide cocrystals and the search for polymorphs

Abstract

A number of polymorphic cocrystals have been reported in the recent literature, yet there is no clear understanding of the cause or the prevalence of this phenomenon. This study systematically screens for cocrystals of pyrazinamide (PZA) and examines polymorphism in these systems. Simple polymorphic coformers in which the orientation of the hydrogen bonding groups vary systematically (all isomers of amino- and hydroxybenzoic acids) were deliberately targeted. Cocrystals of PZA and all coformers formed under a number of reaction conditions including solvent-drop grinding, slurry, solution and melt crystallization. The cocrystals were characterized by PXRD, DSC, melting point determination and, in cases where single crystals were obtained, ¹H NMR and single crystal X-ray crystallography. Preliminary polymorph screen for previously reported PZA cocrystals and ones reported herein indicates that a single phase forms consistently and reliably for each cocrystal under a number of reaction conditions.