Crystallization of indomethacin from the amorphous state below and above its glass transition temperature.

The solid state crystallization of amorphous polymers, sugars, and inorganic glasses is often thought to be restricted to the region above the glass transition temperature, Tg, because insufficient molecular mobility (high viscosity) exists below Tg for nucleation and crystal growth. Here we report on the isothermal and nonisothermal crystallization of dry amorphous indomethacin in the temperature range of 20 degrees C above and below its Tg. These studies were carried out with two amorphous samples having different degrees of metastability relative to the crystalline state. It was shown that in both samples significant crystallization to the most stable polymorphic form occurred over several days when stored below Tg, and in some cases this process was preceded by the relaxation of one amorphous form to the other. At storage temperatures near to and above Tg the rates of crystallization increased as expected but a second less thermodynamically stable polymorph also appeared with the more stable crystal form. This behavior was explained by the possible relationship between the degree of metastability relative to the crystalline state of each amorphous form and the interfacial energy existing at the respective nucleation sites, in accord with the Ostwald step rule.