Identification of an amorphous-amorphous two-step transformation in indomethacin embedded within mesoporous silica

A very unusual amorphous-amorphous two-step transformation was observed in indomethacin confined within MCM-41 mesoporous silica, via isothermal and non-isothermal routes. Isothermally, at room temperature, the first step corresponds to the 1-dimensional growth of γ-nanocrystals along the mesoporous channels from preexisting incipient nuclei. In the second step nanocrystals slowly transform into an undercooled liquid state structurally different from the original liquid and characterized by a higher molecular mobility. The instability of nanocrystals detected in the continuation of the isothermal growth was explained as resulting from a very high specific area of nanocrystals imposed by the geometrical confinement when the size of nanocrystals along the channels achieves a dimension much larger than the channel diameter. The mechanism of the slow dissolution of nanocrystals was identified as similar to a digestive ripening process, inverse to the Ostwald ripening, by which larger clusters dissolve to the detriment of smaller ones. This two-step transformation was also observed upon heating. In this case, the growth of nanocrystals is followed by a melting far below the melting point of γ-crystals, according to Gibbs-Thomson effects. This study shows that the original amorphous form of indomethacin transforms into a second amorphous form via the transient growth of nanocrystals which become unstable via two different mechanisms induced by the geometrical confinement.