Investigating the Relationship between In Vitro and In Vivo Performance: The Role of Drug Loading, Release Rate, and Surface Area

Amorphous solid dispersions (ASDs) are a commonly used formulation approach for poorly water-soluble drugs to enhance release rates, generate supersaturated solutions, and improve oral absorption. Hypromellose (HPMC) has been used in commercial ASD formulations, but relatively little is known about drug release mechanisms from ASDs based on this polymer. Herein, confocal fluorescence microscopy (CFM) was employed to reveal the morphology of phase separation in tacrolimus/HPMC ASDs in aqueous media. Release and absorption performance of different drug loading (DL) ASDs were monitored in vitro and in vivo<i>.</i> CFM revealed that at 10% DL and above, a drug-rich network formed while the polymer diffused into the bulk solution. Surface area-normalized release rate measurements confirmed this observation revealing that HPMC was released 10× faster than tacrolimus at 10% DL, while at 5% DL, the release rates were congruent. Despite reduced drug release rates at 10% DL, sufficiently high surface area and moderate agitation enabled powder formulations to completely release within 40 min and achieve supersaturation under nonsink release conditions. At the commercial DL of 50%, a lower extent of supersaturation was achieved in comparison to the 10% DL. However, the surface area-normalized release rate was 100 times than that estimated for the crystalline form. In vivo absorption data in fasted dogs reflected this difference, with the 50% DL formulation significantly outperforming the crystalline drug with further improvements observed with the 10% DL formulation. This study connects the observations from CFM, surface area-normalized release rates, powder dissolution, and in vivo absorption data to the performance of ASDs at different drug loadings.