Effects of hydrostatic compression and kinetic vitrification on structural relaxation behaviors of amorphous drugs: how to predict them via simple theoretical models?

Abstract

Amorphization is considered one of the most promising strategies for enhancing pharmaceuticals' aqueous solubility and oral bioavailability. However, amorphous systems are susceptible to recrystallization because of their disordered atomic structures and elevated free energies. To resolve this problem, one needs accurate information about molecular mobilities under various physical conditions. Unfortunately, it is difficult to investigate the relaxation processes of amorphous drugs beyond the uncompressed supercooled region. Hence, we aim to develop a simple but effective toolkit to predict pharmaceuticals' relaxation time and dynamic fragility at high pressures and low temperatures. First, we apply the elastically collective nonlinear Langevin equation theory to determine the impact of local and non-local interactions on the motion of drug molecules. Then, based on the similarity between the melting transition of crystalline solids and the glass transition of soft materials, a new chemical mapping is created to connect the hydrostatic pressure, the absolute temperature, and the packing fraction. This combined approach allows us to capture the primary relaxation behaviors of amorphous drugs with minimal computational cost. Our theoretical analyses agree quantitatively well with broadband-dielectric-spectroscopy experiments in both supercooled and glassy states. Therefore, they promise to be valuable for improving the physical stability and the practical applicability of amorphous pharmaceuticals.