Formation and stabilization of amorphous molecular level solid dispersions

Several factors described in the literature provide useful measures of the potential of drugs to crystallize from the amorphous form both alone and in the presence of the polymer. It has also been observed that materials which tend to be physically stable in the absence of a polymer are generally physically stable in the presence of a polymer and the thermodynamics of pure amorphous materials has been highlighted as a significant factor which will influence physical stability. However, the thermodynamic properties of a drug in an amorphous molecular level solid dispersion are expected to be different from the pure system and are not well understood. Therefore the goal of this research is to better understand the thermodynamic implications of polymer addition. In particular, this study attempts to address the following question: how does a polymer influence the thermodynamic activity of the drug in the amorphous molecular level solid dispersion relative to the thermodynamic activity of the pure amorphous drug? It is hypothesized that the greater the tendency for an amorphous drug to crystallize, the greater the modification of the amorphous form, through the addition of a polymer, that is required to maintain a physically stable amorphous molecular level dispersion. In order to address this hypothesis, there was a need to develop and apply experimental techniques and models which enable estimations of the thermodynamics of mixing drugs and polymers to be made. These models are described in this thesis and are based on the application of well developed solution theories to non-equilibrium glassy amorphous molecular level solid dispersions. These models, coupled with data extracted from various experimental techniques, provide (i) an estimation of the thermodynamics of mixing drugs and polymers and (ii) an understanding of the thermodynamic consequences of mixing a drug with a polymer.