Crystallization of Amorphous Indomethacin during Dissolution: Effect of Processing and Annealing

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Abstract
The crystallization of amorphous drugs during dissolution is a type of solution mediated phase transformation that can reduce the bioavailability enhancement one hoped to gain from the amorphous state. The goal of this study was to explore the effects of processing on the dissolution performance of amorphous indomethacin. The amorphous solids were prepared by four techniques, quench cooling the melted solid, cryogrinding γ indomethacin amorphous for 1 or 3 h and quench cooling the solid followed by 1 h of cryogrinding. Dissolution results assessed in a flow-through intrinsic dissolution apparatus reveal decreases in the dissolution rate of amorphous indomethacin during the experimental time frame indicating that a solution mediated phase transformation has occurred. The amorphous solids prepared by melt quenching and melt quenching followed by cryogrinding showed a significant dissolution rate advantage over the γ form of indomethacin. In contrast, indomethacin that was cryoground amorphous for 1 or 3 h did not show any dissolution rate advantage over the crystalline material. Transformation was confirmed by in situ Raman microscopy and polarized light microscopy with differences seen in the nature of the crystals apparent on the surface of the dissolving solid. A portion of the melt quenched amorphous sample was annealed at 25 °C and 0% relative humidity to induce partial crystallization of γ indomethacin. As crystallinity increased, the dissolution rate decreased. The transformation time of partially amorphous indomethacin was not dependent on the level of crystallinity present, indicating only a small fraction of crystalline material needs to be present to affect the kinetics of crystallization. The solution mediated phase transformation of amorphous indomethacin is affected by the processing method even though all solids were confirmed amorphous by polarized light microscopy and X-ray diffraction. Dissolution may distinguish differences in amorphous solids that other methods cannot discern.

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