Nasrallah, S.; Gavali, T.; Yavuz, I.; Minceva, M. Solubility of Incongruently Melting Active Pharmaceutical Ingredient Cocrystals: The Hydrochlorothiazide–Nicotinamide System. Mol. Pharmaceutics 2026. doi.org/10.1021/acs.molpharmaceut.5c01520

Abstract

Pharmaceutical cocrystallization is a promising strategy to enhance the solubility and bioavailability of hydrophobic active pharmaceutical ingredients (APIs). However, when API–coformer cocrystals exhibit incongruent melting, understanding and predicting their solubility in water becomes significantly more complex. In this work, a combined experimental and thermodynamic modeling approach is presented to investigate the API solubility enhancement in a ternary API–coformer–water system. Hydrochlorothiazide (HCT), a biopharmaceutics classification system (BCS) class IV diuretic, and nicotinamide (Nic), a generally recognized as safe (GRAS)-listed coformer, were selected as a representative system that forms an incongruently melting 1:1 cocrystal, which was confirmed experimentally using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Binary solid–liquid equilibrium (SLE) data for the HCT–Nic, HCT–water, and Nic–water systems were experimentally measured at different temperatures. The nonrandom two-liquid (NRTL) model was then used to regress the binary interaction parameters from the binary SLE data. These parameters were then used to predict ternary SLE phase diagrams of the HCT–Nic–water system at 310.15 K, 330.15 K, and 350.15 K. The NRTL-modeled SLE diagrams revealed the key features of the ternary system, including the absence of cocrystal formation at 310.15 K and the emergence of a cocrystal phase region with incongruent dissolution behavior at elevated temperatures. The highest HCT solubility was obtained at the ternary API-rich eutectic composition, with a solubility enhancement factor (Φ) of 2.1–2.4 across the studied temperatures. In contrast, dissolving the 1:1 cocrystal directly in water yielded significantly lower solubility enhancements (Φ ≈ 1.0–1.3). These findings clearly demonstrate that selecting a binary HCT–Nic mixture that, upon dilution in water, reaches the eutectic composition in the ternary HCT–Nic–water system yields greater solubility enhancement than starting from the cocrystal composition. This study emphasizes the importance of thermodynamic modeling in understanding solubility behavior and guiding the rational design of cocrystal-based pharmaceutical formulations, especially for API–coformer systems exhibiting incongruent melting.

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