Impact of Crystal Structure and Molecular Conformation on the Hydration Kinetics of Fluconazole

Abstract

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.

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

“…Apart from the already mentioned ssNMR and ‘NMR crystallography’, purely computational approaches are also undertaken. For that purpose, DFT calculations involving application of hybrid functionals (most commonly: B3LYP, M05) and polarizable function (an extended basis set like 6-31++G(d,p) or 6-311+G(2d,2p)) are performed [ 83 , 84 , 85 , 86 , 87 ]. Especially, the latter plays a crucial role, as polarizable functions are used to properly define the H-bonding.…”

“…It is a consequence of a presence of very large channels, which triggers a loss of whole water at once, instead of proceeding in stages. This example plainly shows how structural aspects are linked with the dehydration kinetics and explains why kinetics of water escape, H-bonding network breakdown, and molecules’ rearrangement within a crystal are analyzed simultaneously [ 84 ]. It has been shown even more clearly in the example of fluconazole [ 85 ].…”

X-ray structure of an unusual glycoluril derivative conformation: Structural analysis and influencing factors

“…This indicates the significant impact of the solvation effect in stabilizing the crystallization of this conformation. 28,29 In addition, some other factors also played important roles in the crystallization of the as conformation. As seen in Figure 3, an intramolecular hydrogen-bond (C5-H5⋯O 2 , H⋯O distance: 2.27 Å; C-H⋯O angle: 157°) was observed between the carbonyl oxygen atom O 2 and the aromatic hydrogen atom H5, which appeared beneficial in bringing them closer to each other and thus keeping the p-diphenyl substituted o-xylylene ring oriented in the opposite direction to the adjacent -COOEt groups.…”

“…This indicates the significant impact of the solvation effect in stabilizing the crystallization of this conformation. 28,29…”

Monohydrate and anhydrate of nylon 5I monomer 1,5-pentanediamine–isophthalate

“…It is common that compounds exists in both hydrate and anhydrous forms, 13 especially for bio-chemicals involving water as the solvent in their preparation process. 14 The hydrates of a compound may well have different physicochemical properties compared to its parent anhydrate forms, such as solubility, density, hygroscopicity, dissolution rate, chemical stability, and mechanical property. [15][16][17][18][19][20] Therefore, investigating the hydration state, possible transformation pathways and mechanism under different conditions is very helpful to guarantee the product quality.…”