Conformational Change Initiates Dehydration in Fluconazole Monohydrate

Abstract

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.

Polymorphic solvates, ionic cocrystals and C–N bond formation to form ionic cocrystals in sulfamethoxazole and sulfathiazole-derived urea

“…8 In the present case, the two polymorphic cocrystals had very similar structural differences, which could be attributed to conformational adjustments. [30][31][32][33] The HSMZU molecules of the HSMZU.DMF-P1 were hydrogen-bonded by weak C-H⋯X (O, N) hydrogen bonds, as well as by moderate hydrogen N-H⋯O bonds (Fig. 1a).…”

“…3b) and indicated that they yielded a common form after the loss of the solvents. In general, desolvation processes are known to cause conformational changes of flexible hosts, 33 leading to a change in the packing from the solvated form. The difference in temperature of the desolvation of the two polymorphic solvates was 24 °C (∼0.2 kJ mol −1 ).…”

“…[31][32] There are examples where dehydration triggers conformational changes. 33 From these points of view, the cocrystals of urea derivatives show great promise to be understood through a crystal engineering approach. 34 We recently showed two different solvates possessing one or two solvent/s per host in a urea-based sulfonamide derivative due to the ability of the host to form monomeric and dimeric assemblies.…”

Crystal engineering and structural diversity of 2-aminopyridinium hypodiphosphates obtained by crystallization and dehydration

“…From the research to date, it may be concluded that the packing of molecules/ions in crystals and the presence of hydrogen bonds have a large impact on the dehydration process of organic compounds. 36,37 The stronger the hydrogen bonds between the water molecule and the organic part, the higher the desolvation threshold temperature. In 2016, the solid-state reversible dehydration-rehydration of monosodium alendronate (NaH 4 A) one of the bisphosphonate medications against osteoporosiswas reported.…”

Conformational Change in Molecular Crystals: Impact of Solvate Formation and Importance of Conformational Free Energies

“…Multiple polymorphic forms containing different conformers − as well as various solvates and a monohydrate are known for fluconazole. Two recent studies by Basford et al , investigate the hydration and dehydration mechanisms of fluconazole revealing that a minor conformational change around a hydroxyl group initiates the dehydration of the monohydrate form. As with axitinib, the polymorph obtained upon the dehydration of fluconazole monohydrate has a strong conformational similarity with the monohydrate.…”