Nanostructures and Dynamics of Isochorically Confined Amorphous Drug Mediated by Cooling Rate, Interfacial, and Intermolecular Interactions.

The production and stabilization of amorphous drugs by the nanoconfinement effect has recently become a research hotspot in pharmaceutical sciences. Herein, two guest/host systems, indomethacin (IMC) and griseofulvin (GSF) confined in anodic aluminum oxide (AAO) templates with different pore diameters (25-250 nm) are investigated by differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). The crystallization of the confined drugs is suppressed, and their glass transition temperatures show an evident pore-size dependency. Moreover, a combination of dielectric and calorimetric results demonstrates that the significant change in the temperature dependence of the structural relaxation time during the cooling process is attributed to the vitrification of the interfacial molecules and the local density heterogeneity under isochoric confinement. Interestingly, compared with the case of IMC/AAO, which can be described by a typical two-layer model, GSF/AAO presents an rare scenario of three glass transition temperatures under fast cooling (40-10 K/min), indicating that there exists a thermodynamic nonequilibrium interlayer between the bulk-like core and interfacial layer. In contrast, the slow cooling process (0.5 K/min) would lead confined GSF into the stable core-shell nanostructure. Using surface modification, the interfacial effect is confirmed to be an important reason for the different phenomena between these two guest/host systems, and intermolecular hydrogen bonding is also suggested to be emphasized considering the long-range effect of interfacial interactions. Our results not only provide insight into the glass transition behavior of geometrically confined supercooled liquids, but also offer a means of adjusting and stabilizing the nanostructure of amorphous drugs under two-dimensional confinement.