What We Need to Know about Solid-State Isothermal Crystallization of Organic Molecules from the Amorphous State below the Glass Transition Temperature

In this Perspective, the authors have examined various principles associated with the isothermal crystallization of organic molecules from the amorphous state. The major objective was to better understand the underlying principles influencing long-term crystallization from the glassy state at temperatures sufficiently low enough to prevent crystallization over a period of about 2-3 years; this time frame was chosen based on the requirements for ensuring the physical stability of solid drug products. As such, after considering the general thermodynamic, dynamic (molecular mobility), and structural properties of both supercooled liquids and glasses, current understanding from the literature of overall crystallization, nucleation and growth from glasses, was reviewed. Typically, in attempting to establish the appropriate storage temperature, T, in the glassy state, relative to the glass transition temperature, T_g, i.e., T_g - T, most studies have tended to emphasize the rates of bulk diffusional molecular mobility of molecules at such temperatures and classical crystal nucleation and growth theory. However, a closer analysis of factors affecting crystallization from the glassy state revealed that greater consideration should be given to other contributing factors, including methods of producing the glass, heterogeneous nucleation due to processing conditions, secondary Johari-Goldstein relaxations, nondiffusional crystal growth in the glass (GC-growth), and surface crystallization.