Stability evaluation of lyophilized formulations by free volume measurements using positron annihilation lifetime...

The stability of lyophilized formulations composed of hydroxyethyl starch, saccharides, and polyols is evaluated through systematic measurements of the free volume using positron annihilation lifetime spectroscopy. The ortho-positronium pick-off annihilation lifetime, which is related to the free volume, decreases as the saccharide/starch mixing ratio increases, indicating a reduction in overall molecular mobility. This suggests that formulations with a high saccharide content exhibit greater pharmaceutical stability. In addition, no significant difference in the free volume of formulations containing different types of saccharides is observed. The free volume is also compared to stability indices obtained using other techniques, such as the glass transition temperature measured by differential scanning calorimetry and the relaxation time determined by solid-state proton nuclear magnetic resonance. A positive correlation is found between the free volume and the relaxation time, unlike the glass transition temperature. These results suggest that the free volume obtained by positron annihilation lifetime spectroscopy may be used to assess the pharmaceutical stability of more complex lyophilized formulations.