Structural Response of Amorphous Active Pharmaceutical Ingredients with Flexible Molecules to High Pressure

Abstract The objective of this study was to examine the intra- and intermolecular structure of two active pharmaceutical ingredients characterized by van der Waals flexible moleculesprobucol and loratadinein their liquid and glassy states under ambient and high-pressure conditions. We investigated how compression influences local packing motifs in these systems and whether the structural features observed in supercooled liquids under ambient and high-pressure conditions resemble those found in ordinary and pressure-densified glasses. Structural evolution was characterized using ambient- and high-pressure X-ray diffraction supported by molecular dynamics simulations. Total and partial structure factors, pair distribution functions, and local structural parameters were calculated from molecular dynamics models that were consistent with experimental diffraction data. The results show that compression primarily modifies local molecular packing and the distribution of various intermolecular contacts while inducing only minimal changes in the conformations of these flexible molecules. Regarding the intermolecular structure, compression affects the medium-range order, increases local structural heterogeneity, and enhances the population of short O−H···S and Cl···Cl contacts. These features are less pronounced in the corresponding liquid and glass states at ambient pressure, within the pressure and temperature ranges studied here, as well as in crystal structures. Upon decompression, these structural characteristics may either relax or exhibit partial similarity to those observed in supercooled pressurized liquids. While analogous phenomena have been discussed for glasses with highly interconnected networks (such as silica-based glasses), our results indicate that similar effects can also appear in molecular pharmaceutical systems. Our results provide molecular-level insight into pressure-induced structural organization in pharmaceutical liquids and motivate further studies on how such structural changes may relate to the properties of the resulting glassy states.