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

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.