Spatial confinement can lead to increased stability of amorphous indomethacin

The aim of this study was to investigate whether the physical stability of amorphous indomethacin can be improved by separating the drug material into small units by the use of microcontainers. Crystallisation from the spatially confined amorphous indomethacin in the microcontainers was determined and compared with the crystallisation kinetics of amorphous bulk indomethacin. Amorphous indomethacin in both a bulk form and contained within microcontainers was prepared by melting of bulk or container-incorporated gamma-indomethacin, respectively, followed by quench-cooling. Microcontainers of three different sizes (diameters of 73 mu m, 174 mu m and 223 mu m) were used for the confinement of amorphous indomethacin, in order to elucidate whether the size of the microcontainer had an influence on the stability of the amorphous form. Following preparation, all samples were stored at 30 degrees C and 23% RH. A sample of 100 microcontainers of each size was selected and measured on a Raman microscope over a period of 30 days to ascertain whether the indomethacin in each container was amorphous or crystalline. Over time, a crystallisation number was obtained for the amorphous indomethacin in the microcontainers. The crystallisation numbers from the microcontainers were compared with the crystallisation kinetics of the amorphous bulk indomethacin, as determined by FT-Raman spectroscopy. Comparison of the numeric crystallisation in the microcontainers with the crystallisation kinetics of the amorphous bulk indomethacin showed that spatial confinement of indomethacin led to a significantly lower extent of crystallisation of the amorphous form. In the 174 mu m microcontainers, 29.0 +/- 2.6% of the amorphous indomethacin crystallised to the stable gamma-form over a period of 30 days, whilst 38.3 +/- 1.5% of the amorphous indomethacin crystallised in the 223 mu m microcontainers. Both these values were significantly different from that observed in the amorphous bulk indomethacin, where 51.0% crystallised to the gamma-form after 30 days. Comparing the 174 and 223 mu m microcontainers also revealed a significantly greater stabilising effect of the 174 mu m microcontainers (p-value of 0.0061). Surprisingly, for microcontainers with an inner diameter of 73 mu m, no stability improvement was found when compared to amorphous bulk indomethacin. It was observed that the amorphous indomethacin within these containers converted to the alpha-form of indomethacin (a metastable polymorph) which was unexpected at the storage conditions at 30 degrees C and 23% RH. (C) 2012 Elsevier B.V. All rights reserved.