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