Enhancing the solubility and dissolution rate of diflunisal through piperazine stoichiometric variants: Reversible transformation and dissolution advantages

To overcome the limitations of diflunisal (DIF) regarding its solubility and dissolution rate, two different ratios of DIF-piperazine (PIP) salts were synthesized using a salt formation strategy via proton transfer crystallization. The resulting DIF-PIP salts were characterized using various techniques, including crystal structure analysis, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FT-IR) spectroscopy. The results demonstrated a significant enhancement in solubility for both the DIF-PIP (1:1) and DIF-PIP (2:1) salts when compared to the DIF active pharmaceutical ingredient (API), with increases of 56.5-fold and 3.7-fold, respectively. Notably, the DIF-PIP (1:1) salt exhibited exceptional dissolution performance across various media. Specifically, its dissolution rates in water, pH 6.86 buffer, and pH 9.18 buffer increased by 338.5-fold, 104.8-fold, and 1.5-fold, respectively. This superior dissolution performance suggests potential advantages for pharmaceutical applications, particularly its high dissolution rate in water, which could improve the disintegration and dissolution properties of oral tablets. Additionally, we investigated the polymorphic transformation conditions between DIF-PIP (1:1) and DIF-PIP (2:1) salts in detail, providing both theoretical and experimental insights into controlling the physicochemical stability of pharmaceutical formulations during preparation and storage.