In this contribution the hydration kinetics of three anhydrous polymorphs (AH-A, AH-B and AH-C) of fluconazole [2-(2,4-difluorophenyl)-1,3-bis (1H-1,2,4-triazol-1-yl)-propan-2ol] were studied. The conversion kinetics from the anhydrous forms to the monohydrate (MH) were monitored at various relative humidities above the critical water activity. The studies revealed very different kinetic stabilities for the three anhydrous forms, with AH-A and AH-C converting much more easily to the MH than AH-B. Various energetic factors, which may be influencing the kinetics of hydration, were explored together with crystal structure and molecular conformation similarities between the anhydrous forms and the MH. The level of conformational and packing similarity between the anhydrous and MH structures was found to be consistent with the ease of hydration. We believe that surface similarity may be required for the nucleation of the hydrate, whilst the level of crystal packing similarity impacts the ease of growth. In terms of conformational variations, AH-B was found to require a significantly more dramatic conformational change to convert to the MH conformation than those in either AH-A or AH-C. Soft planes (low attachment energies) may allow for easier diffusion of solvent into the crystal structure to allow for solvation. The overall kinetic energy barrier of water diffusion into the lattice plus conformational change was found to correlate well with our observed hydration kinetics, indicating that both the crystal structure and the conformation play a role in the kinetic stability towards hydration of the various fluconazole polymorphs. * Those being the {001}, {020} and {002} for AH-A, AH-B and AH-C respectively. § This is calculated as the sum of the conformational energy barrier and the-E att of the softest plane.
Experimental and computational techniques have been used in combination, to monitor the dehydration process of fluconazole monohydrate (MH), this unveiling the dehydration mechanism at the molecular level. Experimentally, dehydration was observed to start at around 55 °C and complete around 100 °C, with metastable Pbca, Z'=1 polymorph (AH-C) as the sole product of dehydration (as determined by in-situ hot stage PXRD). Conformational and structural changes were identified as key in the initiation and progression of the dehydration process. Thermal expansion is most significant along the c-axis, with molecular dynamic (MD) simulations and experimental observations identifying that water migrates through the MH crystal lattice within the plane perpendicular to that direction. Water was found to migrate within the (001) plane along both the a and b-axis directions. The MD simulations revealed that water was not able to migrate within the lattice at room temperature. Migration at 70°C (342K) was plausible, but only after the hydroxyl group undergoes conformational change. The conformational change, around the hydroxyl group, is key to both the weakening of the fluconazole-water hydrogen bonding, found in the MH structure, and the promotion of the fluconazole-fluconazole hydrogen bonding, required for the formation of polymorph AH-C.
A study
on the hydration behavior of fluconazole demonstrates that
both sample age and polymorphic form impact the drug’s kinetic
stability to hydration. For two of the polymorphs, aged samples were
found to hydrate more readily than fresh samples. The aging effect
was attributed to the formation of monohydrate (MH) crystals over
time. The MH, despite being initially undetectable, had a seeding
effect, thus impacting the hydration kinetics.
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