Local Mobility in Amorphous Pharmaceuticals--characterization and Implications on Stability

In recent years, considerable effort has been directed towards correlating molecular mobility with the physical as well as chemical stability of amorphous pharmaceuticals. Global mobility (molecular motions associated with glass transition) has been the focus of most of these studies. However, in several instances, global mobility could not explain the instability. It is becoming recognized that local mobility (beta-relaxations), which is significant below the glass transition temperature, could be influencing stability. Generally, information on the mobility of an amorphous pharmaceutical below the glass transition temperature (T(g)) has been obtained by extrapolation of data from above T(g). Such studies, while providing information about overall mobility, are unsuitable for directly characterizing the local mobility. Our overall objective is to highlight the pharmaceutical significance of local motions in amorphous pharmaceuticals, primarily the Johari-Goldstein relaxations. The coupling model, which correlated the local motions with global mobility, has been discussed in order to emphasize the potential impact of local mobility on amorphous phase stability. The influence of additives including water on the local motions in an amorphous matrix, as in molecular dispersions, has been reviewed. Finally, we have provided a brief overview, including the strengths and limitations, of the common instrumental techniques used to characterize local motions.