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Relationship between crystallization tendencies during cooling from melt and isothermal storage: toward a general understanding of physical stability of pharmaceutical glasses.

The lack of protocols to predict the physical stability has been one of the most important issues in the use of amorphous solid dispersions. In this paper, the crystallization behaviors of pharmaceutical glasses, which have large variations in their crystallization tendencies, have been investigated. Although each compound appears to have a wide variation in their crystallization time, the initiation time for crystallization could be generalized as a function of only Tg/T, where Tg and T are the glass transition temperature and storage temperature, respectively. All compounds in which crystallization was mainly governed by temperature had similar activation energies for crystallization initiation, ca. 210-250 kJ/mol, indicating that physical stability at any temperature is predictable from only Tg. Increased stability is expected for other compounds, where crystallization is inhibited by an large energetic barrier, and stochastic nucleation plays an important role in initiating crystallization. The difference in the dominant factor, either temperature or pressure, appeared to correlate with the nucleation mechanism, and this could be determined by a cool-heat cycle after melting using thermal analysis. This conclusion should make prediction of physical stability of amorphous formulations easier, although the investigation was conducted under ideal conditions, which eliminated surface effects.