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 (Tg) of polymers. In this paper, we use a similar approach to predict the Tg 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 Tg 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 Tg. The predicted Tg 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 Tg was found to be ∼65 °C, in good agreement with computational simulations.

Graphical abstractMolecular dynamic simulations have been successfully utilised with molecular modelling to estimate the glass transition temperature of a small drug molecule (beclomethasone dipropionate). Simulation results were in good agreement with solid-state experientially determined values. This approach opens up the opportunity to study fundamental properties and the behaviour of amorphous systems with respect to drug development (for example diffusion properties or the influence of impurities).Figure optionsDownload full-size imageDownload as PowerPoint slide