Structural Elucidation and Dissolution Studies of a 1:2 Chlorthalidone–Isonicotinamide Cocrystal: A Rare Pathway to the Metastable Polymorph Chlorthalidone Form II with Enhanced Dissolution Performance

Chlorthalidone (CTD), a BCS class IV antihypertensive racemic drug, presents poor aqueous solubility and low absorption in the gastrointestinal tract, limiting its oral bioavailability. A novel 1:2 cocrystal of CTD with the coformer isonicotinamide (INA), having improved dissolution properties, was obtained and comprehensively characterized. The cocrystal structure was elucidated via single-crystal X-ray diffraction (SCXRD) and further examined by Hirshfeld surface analysis, revealing a unique supramolecular architecture sustained by a network of heterosynthons, distinct from all known solid forms of CTD. Complementary solid-state characterization was performed using powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The cocrystal presented solid-state stability under accelerated stress conditions. Dissolution studies under nonsink conditions revealed a sustained pH-independent 2-fold increase in drug concentration compared to CTD Form I. The enhancement is originated by a cocrystal dissolution–supersaturation–precipitation (DSP) process toward the more soluble CTD Form II. As a result of spontaneous chiral resolution, CTD-INA features as a common element with CTD Form II, the presence of a physical mixture of crystals containing the R and S enantiomers. CTD-INA is a rare example of a conglomerate cocrystal. The phase transformation of the cocrystal in solution to CTD Form II is attributed to a fast DSP occurring at the particle surface that releases the coformer and originates the conglomerate form of CTD. The results reveal that cocrystals can constitute a pathway for generating a metastable API polymorphic form, thereby providing access to a solid form with a significant and sustained dissolution advantage.