Relationship between amorphous solid dispersion in vivo absorption and in vitro dissolution: phase behavior during dissolution, speciation, and membrane mass transport

Enzalutamide is a fast crystallizing, hydrophobic compound that has solubility limited absorption in vivo. Given the low aqueous solubility of this compound, it was of interest to evaluate amorphous formulations in vitro and in vivo. Amorphous solid dispersions (ASD) of enzalutamide were prepared with the hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone (PVPVA). A side-by-side diffusion cell was developed as an in vitro characterization tool to discriminate enzalutamide ASDs based upon the solute thermodynamic activity achieved during dissolution and its impact on the subsequent membrane transport rates, phase behavior, and drug speciation. The same formulations were then tested in vivo in rats using oral dosing of ASD suspensions. Different levels of plasma exposure were observed between the ASDs, which could be correlated to the phase behaviors of the ASDs following dissolution. Unsurprisingly, ASDs that underwent crystallization show lower plasma exposures. However, differences were also observed between ASDs that dissolved to form nanosized amorphous drug aggregates versus those that dissolved to yield only supersaturated solutions, with the former outperforming the latter in terms of the plasma exposure. These observations highlight the importance of thoroughly understanding the phase behavior of an amorphous formulation following dissolution and the need to discriminate between different types of precipitation, specifically crystallization versus glass liquid phase separation to form nanosized amorphous aggregates.