The effect of excipients on the molecular mobility of lyophilized formulations, as measured by glass transition temperature and NMR relaxation-based critical mobility temperature.

摘要

PURPOSE: The dependence of the molecular mobility of lyophilized formulations on pharmaceutical polymer excipients was studied. Molecular mobility as determined by NMR relaxation-based critical temperature of molecular mobility (Tmc) and glass transition temperature (Tg) is discussed in relation to the plasticizing effect of water in formulations. METHODS: The Tmc and Tg of lyophilized gamma-globulin formulations containing 6 different polymer excipients such as dextran, polyvinylpyrrolidone (PVP) and methylcellulose (MC) was determined by NMR and DSC. The molecular mobility of water in the formulations was determined by proton NMR and dielectric relaxation spectrometry (DRS). RESULTS: Tmc varied with polymer excipients. Tmc increased as the ratio of bound water to mobile water increased and as the molecular mobility of mobile water decreased. The formulation containing MC exhibited a lower Tmc than the formulation containing dextran because of the smaller ratio of bound water and the higher molecular mobility of mobile water. The Tmc of the formulation containing PVP was higher than that expected from the higher T2 values of water because of the lower molecular mobility of mobile water regardless of the higher ratio of mobile water. The Tmc of these lyophilized formulations was higher than their T(g) by 23 degrees C to 34 degrees C, indicating that the formulations became a NMR-detected microscopically liquidized state below their T(g). CONCLUSIONS: The quantity and the molecular mobility of mobile water in lyophilized formulations can be considered to affect the T(mc) of lyophilized formulations, which in turn governs their stability.