Amorphous solid dispersions (ASDs) are supersaturating formulations that enhance both the apparent solubility, and the bioavailability of poorly water-soluble drugs following oral administration. Upon dissolution, ASDs can generate nano-sized amorphous droplets of ∼100- 200 nm, when the concentration of the molecularly dissolved drug exceeds the amorphous solubility, thereby maximizing the diffusive flux during the supersaturation window. In this research, two poorly soluble drugs were prepared as ASDs with hydroxypropyl methylcellulose acetyl succinate (HPMCAS), to characterize supersaturation and crystallization kinetics in simulated and aspirated intestinal fluids. For each ASD, the onset of nucleation was found to be highly medium dependent. Moreover, membrane flux was attributed to the resulting phase behavior and remained high as long as supersaturation was maintained, whereas desupersaturation, induced by drug crystallization, was coincident with a noticeable decrease in flux. Importantly, it was shown that ASD dissolution in aspirated fluids led to the formation of drug-rich nanodroplets, confirming same observations made in simulated fluids. These observations provide insights into better understanding of the intraluminal supersaturation potential of ASDs as well as the selection of appropriate dissolution media to improve biopredictability for ASD formulations.
