Modelling of molecular phase transitions in pharmaceutical inhalation compounds: an in silico approach

Molecular dynamic simulations have been successfully utilised with molecular modelling to estimate the glass transition temperature (T_g) of polymers. In this paper, we use a similar approach to predict the T_g of a small pharmaceutical molecule, beclomethasone dipropionate (BDP). Amorphous beclomethasone dipropionate was prepared by spray-drying. The amorphous nature of the spray-dried material was confirmed with scanning electron microscopy, differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). Molecular models for amorphous BDP were constructed using the amorphous cell module in Discovery studio™. These models were used in a series of molecular dynamic simulations to predict the glass transition temperature. The T_g of BDP was determined by isothermal-isobaric molecular dynamic simulations, and different thermodynamic parameters were obtained in the temperature range of −150 to 400 °C. The discontinuity at a specific temperature in the plot of temperature versus amorphous cell volume (V) and density (ρ) was considered to be the simulated T_g. The predicted T_g from four different simulation runs was 63.8 °C ± 2.7 °C. The thermal properties of amorphous BDP were experimentally determined by DSC and the experimental T_g was found to be ∼65 °C, in good agreement with computational simulations.