Seeking new polymorphs in pharmaceutical cocrystals: focus on furosemide–ethenzamide

Abstract

Polymorphism remains a critical challenge in the pharmaceutical industry due to its profound impact on the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs). While pharmaceutical multicomponent materials (PMMs) such as cocrystals were initially believed to mitigate polymorphic risks through stabilization via non-covalent interactions, while modulating the properties of different APIs, recent studies have revealed a growing number of polymorphic PMMs, highlighting the need for targeted screening and structural understanding of these materials. In this work, we report the discovery and selective synthesis of a novel polymorph of the furosemide–ethenzamide (FUR–ETZ) cocrystal through kinetic crystallization via fast solvent evaporation. Solid-state characterization confirmed the formation of a polymorph with morphotropic packing relative to the known form, despite maintaining similar molecular conformation and hydrogen bonding motifs. Crystal structure analysis revealed that formII exhibits a lateral layer shift and increased surface polarity, resulting in enhanced aqueous solubility and a slightly higher melting point. In contrast, formI was shown to be thermodynamically more stable, both in dry and aqueous environments, as supported by lattice energy calculations and competitive slurry experiments. These findings underscore the relevance of polymorph screening in PMMs and demonstrate how subtle variations in crystal packing can critically influence the stability and performance of pharmaceutical cocrystals.