Effects of sorbed water on the crystallization of indomethacin from the amorphous state.

The water sorption isotherm and the crystallization rates for amorphous indomethacin were determined at 30 degrees C as a function of relative humidity (RH), along with the effects of water content on the glass transition temperature (T(g)). Below 43% RH, only the stable gamma crystal form appears, whereas at higher RH, only the metastable alpha crystal form appears. The tendency for the alpha crystals to form at higher RH is consistent with the Ostwald step rule. The crystallization rate of the alpha form continuously increased with increasing RH due to increasing molecular mobility. The crystallization mechanism of the gamma form changed from surface-initiated to bulk-initiated crystallization at 21% RH, and although crystallization rates of the gamma form increased with increasing RH in both cases, they were higher when crystallization was surface-initiated. The complex crystallization behavior of the gamma form is explained by the higher water content and molecular mobility of the surface relative to the bulk and the general effect of water on alpha or gamma crystal form selection as described by the Ostwald step rule.