The roles of π … lone pair, π … sigma, π … π, and C-Cl … Cl-C interactions in vitrified and solvent-evaporated liquid crystalline phases of itraconazole: MD simulations and ab initio studies
Year: 2026
Type: dataset
Abstract: Due to lack of long-range molecular ordering, non-crystalline forms of active pharmaceutical ingredients show higher solubility compared to ordered crystalline structures, however, at the expense of physical instability that they’ve gained from higher internal energy. In this study, Molecular Dynamics (MD) simulations were performed in which the nematic-like phase of itraconazole (ITZ) was obtained in a solvent evaporation process, which was compared to the vitrified structures achieved either experimentally or computationally. Temperature variation of orientational order parameter, pair distribution functions, mean squared displacement, and X-ray scattering were calculated and presented. The main diffraction peak around 1.3 Å−1 slightly shifts to the higher scattering vectors upon cooling from the melt and gets contribution basically from the π … lone pair (nitrogen) interactions, indicating that dispersion forces are predominant for stabilisation. The peaks nearly at 0.25 and 0.5 Å−1 are the characteristics of long-range positional ordering and are mainly determined by the π … lone pair (nitrogen, oxygen, and chlorine atoms), π … π stacking, and π … sigma bonds, the latter in the C … H binding cooperativities. Moreover, it was observed, through MD simulations, that the bent-core smectic phase of ITZ exhibiting smectic layering, with the average opening angle of 163°, could be obtained from heating a semi-crystalline structure of ITZ, which has a quite analogous X-ray scattering compared to the vitrified sample at 348 K. During solvent evaporation simulations with dichloromethane (DCM), which led to the aggregation of ITZ molecules once it is in contact with DCM, it was observed that weak intermolecular C-Cl … Cl-C interactions (understood from intensity in the g(r) plot) with an intermolecular distance of 3.8 Å are dominant in the mixture. However, it lacks halogen and hydrogen bonding interactions. The MP2/6-31G++(d,p) calculations for the (1:1) dimer of ITZ + DCM predict quite similar orientation compared to the one that was observed in the combined distribution function extracted from the MD simulations. The interaction energy decomposition analysis of MP2 calculations revealed that dispersion energy is the dominant term in this binaryMD system acting chiefly through weak Cl … Cl interactions.
Source: Figshare
Author: Ali Aminian
Language: English
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7202117293