Prediction of Glass Transition Temperature of Freeze-Dried Formulations by Molecular Dynamics Simulation

Purpose. To examine whether the glass transition temperature (T_g) of freeze-dried formulations containing polymer excipients can be accurately predicted by molecular dynamics simulation using software currently available on the market. Molecular dynamics simulations were carried out for isomaltodecaose, a fragment of dextran, and -glucose, the repeated unit of dextran, in the presence or absence of water molecules. Estimated values of T_g were compared with experimental values obtained by differential scanning calorimetry (DSC). Methods. Isothermal-isobaric molecular dynamics simulations (NPTMD) and isothermal molecular dynamics simulations at a constant volume (NVTMD) were carried out using the software package DISCOVER (Material Studio) with the Polymer Consortium Force Field. Mean-squared displacement and radial distribution function were calculated. Results. NVTMD using the values of density obtained by NPTMD provided the diffusivity of glucose-ring oxygen and water oxygen in amorphous -glucose and isomaltodecaose, which exhibited a discontinuity in temperature dependence due to glass transition. T_g was estimated to be approximately 400K and 500K for pure amorphous -glucose and isomaltodecaose, respectively, and in the presence of one water molecule per glucose unit, T_g was 340K and 360K, respectively. Estimated T_g values were higher than experimentally determined values because of the very fast cooling rates in the simulations. However, decreases in T_g on hydration and increases in T_g associated with larger fragment size could be demonstrated. Conclusions. The results indicate that molecular dynamics simulation is a useful method for investigating the effects of hydration and molecular weight on the T_g of lyophilized formulations containing polymer excipients, although the relationship between cooling rates and T_g must first be elucidated to predict T_g vales observed by DSC measurement. January 16