The aim of this study was to investigate the usefulness of the atomic pair-wise distribution function (PDF)
to detect the extension of disorder/amorphousness induced into a crystalline drug using a cryo-milling
technique, and to determine the optimal milling times to achieve amorphisation. The PDF analysis was
performed on samples of indomethacin obtained by cryogenic ball milling (cryo-milling) for different
periods of time. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), polarised light
microscopy (PLM) and solid state nuclear magnetic resonances (ss-NMR) were also used to analyse the
cryo-milled samples. The high similarity between the -indomethacin cryogenic ball milled samples and
the crude -indomethacin indicated that milled samples retained residual order of the -form. The PDF
analysis encompassed the capability of achieving a correlation with the physical properties determined
from DSC, ss-NMR and stability experiments. Multivariate data analysis (MVDA) was used to visualize the
differences in the PDF and XRPD data. The MVDA approach revealed that PDF is more efficient in assessing
the introduced degree of disorder in -indomethacin after cryo-milling than MVDA of the corresponding
XRPD diffractograms. The PDF analysis was able to determine the optimal cryo-milling time that facilitated
the highest degree of disorder in the samples. Therefore, it is concluded that the PDF technique
may be used as a complementary tool to other solid state methods and that further investigations are
warranted to elucidate the capabilities of this technique.
