Assessing Physical Stability Risk Using the Amorphous Classification System (ACS) Based on Simple Thermal Analysis.

The purpose of this study is to develop a classification system utilizing milligram amounts of the compound for physical stability ranking of amorphous pharmaceuticals, which can be used as an early risk assessment tool for amorphous solid dispersion formulations. Simple thermal analysis utilizing a differential scanning calorimeter is used to characterize amorphous pharmaceuticals with respect to their molecular mobility and configurational entropy. Molecular mobility and configurational entropy are considered as two critical factors in determining the physical stability of amorphous phases. Theoretical arguments and numerical simulations suggest that the fragility strength parameter is a good indicator of the molecular mobility below Tg, and the heat capacity change at Tg is a good indicator of the configurational entropy. Using these two indicators, 40 structurally diverse pharmaceuticals with known physical stability were analyzed. Four classes of compounds are defined with class I being the most stable and class IV the least stable. The proposed amorphous classification system and methodology for estimating molecular mobility and configurational entropy provides an easily accessible framework to conduct early risk assessments related to physical stability challenges in developing amorphous formulations.