Monitoring crystallisation of drugs from fast-dissolving oral films with isothermal calorimetry.

The aim of this study was to evaluate the potential of isothermal calorimetry to monitor and characterize crystallisation in drug-loaded fast-dissolving oral films. Films of polyvinylpyrrolidone (PVP) containing indomethacin were cast into glass ampoules; stability was assessed by monitoring the power changes occurring with time. Three grades of PVP (K10, K25 and K40, where the number multiplied by 1000 gives the average molecular weight) were used. Indomethacin was seen to crystallise from all PVP grades over ca. 24-48 h at two study temperatures (25 and 37 degrees C), as denoted by a large exothermic event. At 25 degrees C the exothermic event was a single peak; at 37 degrees C two peaks were observed. Subsequent analysis of the crystals with differential scanning calorimetry (DSC) and polarized light microscopy determined that the stable gamma-polymorph of indomethacin formed at 25 degrees C while both the gamma- and metastable alpha-polymorphs formed at 37 degrees C. The calorimetric data were converted to relative crystallinity as a function of time and analysed with three crystallisation models (Avrami, Tobin and Urbanovici-Segal) to determine crystallisation kinetics. Of the three models applied the Urbanovici-Segal model best described the data, although this may be because this model contains a term that effectively accounts for deviation from the Avrami model. The rate constants determined were broadly consistent irrespective of the model used. Increasing polymer molecular weight did not generally affect the crystallisation rate, although an increase in temperature did result in a concomitant increase in crystallisation rate. The data suggest that isothermal calorimetry is able to monitor drug crystallisation in polymer films and therefore the technique could be a useful tool for conducting stability assays for fast-dissolving oral medicines.