Solid state convergence to fluconazole monohydrate: Mechanochemical hydration, phase transitions, and solvent‑mediated conversion driving solubility.

Fluconazole (FLU) exhibits extensive polymorphism and hydrate formation, posing challenges for controlling its solid-state properties and pharmaceutical performance. Here, powder X-ray diffraction (PXRD) and thermal analysis (DSC/TGA) were used to elucidate solid-state transformation pathways and assess the pH-dependent equilibrium solubility of this important antifungal drug. A commercial FLU drug substance marketed in Brazil was identified as a mixture of polymorph 5 (FLU-P5) and FLU monohydrate (FLU-MH). Water-assisted mechanochemistry converted this mixture into phase-pure FLU-MH, whereas dehydration of FLU-MH produced FLU-P5 and melting yielded an amorphous solid (FLU-AM). Time-dependent PXRD showed that freshly prepared FLU-AM crystallizes over hours to days into a mixture of FLU-MH and FLU-P5. Equilibrium solubility was measured at 37 °C after 12 and 24 h in five media (water, buffers pH 4.5-7.2, and 0.1 M HCl). No significant differences were observed between 12 and 24 h of shaking, indicating that equilibrium was reached within 12 h. FLU-MH and FLU-P5 showed comparable equilibrium solubilities in water and three buffered media (average solubility of ∼6.5 g L-1), while solubility in 0.1 M HCl increased by ∼3.85-fold. PXRD of residual solids demonstrated complete solvent-mediated conversion of FLU-P5 to FLU-MH during equilibration, explaining the similar solubilities of the two starting solid forms. Therefore, this study advances the understanding of relationships among FLU solid phases, establishes a route to obtain phase-pure monohydrate, and provides PXRD evidence that FLU-MH forms at 37°C in water and across the physiological pH range from the pharmaceutically relevant polymorph FLU-P5, thereby governing drug solubility under physiologically relevant conditions even when another solid form is initially present.