Effect of different preparation methods on the dissolution behaviour of amorphous indomethacin.

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 µg/ml/cm(2)). 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 µg/ml/cm(2), respectively, when compared to crystalline indomethacin (≈0.06 and 0.05 µg/ml/cm(2) for α and γ-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.

Investigation of properties and recrystallisation behaviour of amorphous indomethacin samples prepared by different methods.

The aim of this study was to investigate if amorphous indomethacin samples, prepared using different preparation methods, exhibit different structural and kinetic characteristics and if these differences can be correlated to their physical stability (time to crystallisation). Samples were prepared by melt quenching, spray drying, ball milling, and cryo-milling. The resulting amorphous materials were characterised using X-ray diffraction, Raman spectroscopy and differential scanning calorimetry. All freshly prepared samples were completely X-ray amorphous (with a halo being the only feature in the diffractograms). The shape of the halos in the diffractograms, however, varied depending on the preparation method, suggesting structural variations in the near order of the molecules between the differently prepared amorphous forms. Principal component analysis of the Raman spectra of the various amorphous forms revealed that the samples clustered in the scores plot according to preparation method, again suggesting structural differences due to preparation method. The range of vibrations associated with the largest spectral differences in the loadings plot showed that these differences were due to a range of molecular conformations and intermolecular interactions. The ranking of the samples with respect to stability was: quench cooled amorphous samples>cryo-milled (α-form)>spray dried>ball milled (α-form)>ball milled (γ-form)=cryo-milled (γ-form). This ranking was not correlated with the diffractogram shapes or sample distribution in the scores plot of the Raman spectra, suggesting that physical stability was not directly affected by structural variation in the samples. However, ranking of stability of the differently prepared amorphous forms of the drug could be predicted by determining the relaxation time values, for all amorphous samples. The relaxation times, calculated by using the Adam Gibbs and Kohlrausch-Williams-Watts equations, were in accordance with the experimentally determined stability order. This study showed that correlation of physical stability with calculated relaxation time is possible for the same amorphous systems prepared by different methods. This could aid in selecting the most appropriate preparation techniques in situations where there are a variety of suitable methods.

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

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 γ-indomethacin cryogenic ball milled samples and the crude γ-indomethacin indicated that milled samples retained residual order of the γ-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 γ-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.