The aim of this study was to investigate whether amorphous indomethacin samples prepared using different
preparative techniques and processing parameters exhibit different structural and thermodynamic
characteristics and whether these differences can be correlated to their dissolution behaviour. Samples
were prepared either by cooling the drug melt at different cooling rates or by cryo-milling the drug for
different milling times. The resulting amorphous materials were characterised using X-ray diffraction,
Raman spectroscopy and polarising light microscopy. All samples were entirely X-ray amorphous, except
for the sample cryo-milled for 15 min, which exhibited residual crystallinity. The shape of the halos in the
diffractograms, however, varied depending on the preparation method and processing parameters, suggesting
structural variations in the near order of the molecules between the prepared amorphous forms.
This finding was supported by principal component analysis of the Raman spectra, as the samples clustered
in the scores plot according to processing parameters for both of the preparative methods used.
When investigating the dissolution behaviour, the samples cooled at different cooling rates showed no
significant differences in their dissolution profiles and dissolution rates ( 0.55 lg/ml/cm2). In contrast,
for cryo-milled samples, dissolution rate depended on the milling time, with samples milled for 120,
180 and 240 min, showing significantly increased dissolution rates of 0.28, 0.48 and 0.59 lg/ml/cm2,
respectively, when compared to crystalline indomethacin ( 0.06 and 0.05 lg/ml/cm2 for a and
c-indomethacin, respectively). The milling processes appear to continue to affect the degree of disorder
in the solid material, enhancing its dissolution rate, although all samples milled for >30 min were X-ray
amorphous. Thus, choosing the right preparation technique and parameters for preparing amorphous
solids is critical for producing materials with enhanced dissolution profiles.
