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 alpha-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 alpha-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 alpha-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 Tg of lyophilized formulations containing polymer excipients, although the relationship between cooling rates and Tg must first be elucidated to predict Tg vales observed by DSC measurement. January 16.