In Situ Raman Spectroscopy as a Valuable Tool for Monitoring Crystallization Kinetics in Molecular Glasses

The performance of in situ Raman microscopy (IRM) in monitoring the crystallization kinetics of amorphous drugs (griseofulvin and indomethacin) was evaluated using a comparison with the data obtained via differential scanning calorimetry (DSC). IRM was found to accurately and sensitively detect the initial stages of the crystal growth processes, including the rapid glass-crystal surface growth or recrystallization between polymorphic phases, with the reliable localized identification of the particular polymorphs being the main advantage of IRM over DSC. However, from the quantitative point of view, the reproducibility of the IRM measurements was found to be potentially significantly hindered due to inaccurate temperature recording and calibration, variability in the Raman spectra corresponding to the fully amorphous and crystalline phases, and an overly limited number of spectra possible to collect during acceptable experimental timescales because of the applied heating rates. Since theoretical simulations showed that, from the kinetics point of view, the constant density of collected data points per kinetic effect results in the smallest distortions, only the employment of the fast Raman mapping functions could advance the performance of IRM above that of calorimetric measurements.