TY - JOUR
T1 - Conformational Change Initiates Dehydration in Fluconazole Monohydrate
AU - Basford, Patricia A.
AU - Cameron, Christopher A
AU - Cruz-cabeza, Aurora J.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
U2 - 10.1021/acs.cgd.0c00768
DO - 10.1021/acs.cgd.0c00768
M3 - Article
SN - 1528-7483
JO - Crystal Growth & Design
JF - Crystal Growth & Design
ER -