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Assessment of crystalline disorder in cryo-milled samples of indomethacin using atomic pair-wise distribution functions


International Journal of Pharmaceutics


Johan P. Bøtkera,1, Pranav Karmwarb,1, Clare J. Strachanb, Claus Cornetta, Fang Tianc, Zoran Zujovicc, Jukka Rantanena, Thomas Radesb,∗


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.