Isothermal Crystallization of Pharmaceutical Glasses: Toward Prediction of Physical Stability of Amorphous Dosage Forms

Abstract

Difficulty in predicting physical stability of drug molecules during long-term storage is one of the most important issues inhibiting the wide use of amorphous solid dispersions in the pharmaceutical industry. This chapter discusses the isothermal crystallization behavior of pharmaceutical glasses. Although the crystallization time of the different compounds appears to vary widely, initiation time for crystallization can be generalized as a function of T _g /T, where T _g and T are the glass transition temperature and storage temperature, respectively, if the crystallization is governed by temperature. Compounds, in which crystallization is inhibited by a large energy barrier, exhibit better stability. For these compounds, crystallization is likely to be dominated by local pressure, and stochastic nucleation plays an important role for initiating crystallization. An example, in which an increase in the surface area and adsorption of moisture on the surface changes the dominant factor from pressure to temperature, is also presented. The dominance of either temperature or pressure is related with the nucleation mechanism. This observation should help prediction of the physical stability of amorphous pharmaceuticals and enhance the effective use of amorphous solid dispersions for poorly soluble drugs.