The effects of moisture on pharmaceutical amorphous solid dispersion systems

Delivery of drugs with low aqueous solubility in the amorphous form can be exploited as a strategy to increase absorption, especially when dissolution is the rate-limiting step. To prevent drug crystallization over pharmaceutically relevant timescales, a second component (typically a polymer) can be mixed with the amorphous drug, to form what is commonly referred to as an amorphous solid dispersion. Often, the suitability of drugs and polymers for delivery in this form is determined empirically. In particular, a thorough understanding of the phase behavior of such systems when subjected to environmental stresses such as exposure to moisture is poorly understood. This study aimed to address this knowledge gap. It is hypothesized that, in amorphous molecular level solid dispersion systems comprised of a drug with low aqueous solubility and a hydrophilic polymer: (1) the extent to which different polymers inhibit drug crystallization in solid dispersions is related to the amount of moisture sorbed as a result of the polymeric components, as well as how moisture affects the different components in the system and the interactions between them. (2) absorbed moisture will affect drug crystallization through thermodynamic effects, specifically by increasing the thermodynamic driving force for drug crystallization and by introducing the potential for amorphous-amorphous phase separation in certain systems. (3) absorbed moisture will affect drug crystallization through kinetic effects by facilitating the diffusion of either the drug and/or the polymer. To test these hypotheses, the effects of moisture on the physical stability of different amorphous solid dispersion model systems were evaluated. In particular, the miscibility of several different drug-polymer systems was assessed before and after exposure to moisture. Finally, the effects of moisture on the crystallization behavior of a model drug were investigated when formulated as amorphous solid dispersions with different polymers