Prediction of glass transition temperature of
freeze-dried formulations by molecular dynamic simulation
The
purpose of the study was to examine whether the glass transition temperature (Tg)
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 a-glucose,
the repeated unit of dextran, in the presence or absence of water molecules.
Estimated values of Tg were compared with experimental values
obtained by differential scanning calorimetry (DSC). 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.
NVTMD using the values of density obtained by NPTMD provided the diffusivity of
glucose-ring oxygen and water oxygen in amorphous a-glucose and isomaltodecaose,
which exhibited a discontinuity in temperature dependence due to glass
transition. Tg was estimated to be approximately 400K and 500K
for pure amorphous a-glucose and isomaltodecaose, respectively, and in the
presence of one water molecule per glucose unit, Tg was 340K and
360K, respectively. Estimated Tg values were higher than
experimentally determined values because of the very fast cooling rates in the
simulations. However, decreases in Tg upon hydration and
increases in Tg associated with larger fragment size could be
demonstrated. 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 in order to predict Tg vales observed by DSC measurement.