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Investigations on the effect of different cooling rates on the stability of amorphous indomethacin


European Journal of Pharmaceutical Sciences


P. Karmwar a, J.P. Boetker b, K.A. Graeser a, C.J. Strachan a, J. Rantanen b, T. Rades a,*


Amorphous forms of indomethacin have previously been prepared using various preparation techniques and it could be demonstrated that the way the material was prepared influenced the physicochemical properties of the amorphous form of the drug. The aim of this study was to use one preparation technique (transformation via the melt) to prepare amorphous indomethacin and to investigate the influence of the cooling rate (as a processing parameter) on the physical stability of the resulting amorphous form. The amorphous materials obtained were analysed for their structural characteristics using Raman spectroscopy in combination with multivariate data analysis. The onset of crystallisation was determined as an indicator of the physical stability of the materials using differential scanning calorimetry (DSC) and polarising light microscopy. The Johnson–Mehl–Avrami (JMA) model and Sestak–Berggren (SB) model were used in this study to describe the non-isothermal crystallisation behaviour. All differently cooled samples were completely X-ray amorphous. Principal component analysis of the Raman spectra of the various amorphous forms revealed that the samples clustered in the scores plot according to the cooling rate, suggesting structural differences between the differently cooled samples. The minimum cooling rate required to obtain amorphous indomethacin was 1.2 K min 1, as assessed from the time–temperature–transformation (TTT) diagram. The physical stability of the samples was found to increase as a function of cooling rate in the order of 30 K min 1 > 20 K min 1 > 10 K min 1 > 5 K min 1 > 3 K min 1   1.2 K min 1 and was in agreement with calculated descriptors for the glass forming ability (GFA), including the reduced glass transition temperature (Trg) and the reduced temperature (Tred). The JMA model could not be applied to describe the crystallisation process for the differently cooled melts of indomethacin in this study. The kinetic exponent M from the autocatalytic SB model however, showed a positive correlation with glass stability.