Exploring Sublimation as a Tool for Polymorphic Screening in Niflumic Acid−Caffeine Pharmaceutical Cocrystals

Abstract

Sublimation has emerged as a powerful tool for polymorphic screening in pharmaceutical multicomponent materials. In this work, a combined strategy involving mechanochemistry and sublimation enables the selective synthesis and isolation of a novel polymorph (Form III) of the niflumic acid−caffeine (NIF− CAF) cocrystal. Solid-state characterization and complementary theoretical studies revealed that Form III is morphotropically related to Form II, sharing a similar molecular conformation with the −COOH and −CF3 groups positioned on the same side of the NIF molecule. However, Form III exhibits a distinct packing arrangement, featuring embedded −CF3 groups and alternating molecular tapes stabilized by π−π and F···F interactions. Thermal analysis also indicates an enantiotropic relationship between Forms II and III, with Form III becoming the more stable phase above the estimated transition temperature of ∼102 °C, and showing a melting point of 156 °C. These findings demonstrate the relevance of sublimation in polymorphic screening and its potential to expand the solid-state landscape of multicomponent materials with enhanced control and reproducibility