Emily Grace Benson
The pharmaceutical industry continues to face a persistent challenge in the development of orally administered drugs due to poor aqueous solubility, which limits dissolution in the gastrointestinal tract and, consequently, bioavailability. Among the various formulation strategies used to address this issue, amorphous solid dispersions (ASDs) are one of the most widely applied. In ASDs, a crystalline drug is molecular dispersed within a polymer matrix, enhancing apparent solubility through the higher free energy of the amorphous state while also leveraging the typically faster dissolution rate of the polymer. When properly formulated, the drug and polymer release congruently, leading to rapid drug release and improved absorption. However, ASD performance is highly dependent on the ratio of drug to polymer where at high drug loadings, drug release often drastically slows and does not release congruently with polymer. Previous studies have shown that this behavior arises from phase separation during dissolution, resulting in the formation of a drug-rich barrier later that limits release. The influence of formulation variables and polymer properties on phase separation and barrier formation remains incompletely understood, particularly for systems beyond neutral, non-cellulosic polymers and simple compositions.This work investigates how formulation factors (e.g., coatings and excipient selection) and polymer properties influence hydration, phase separation, and drug release in ASDs. A combination of direct visualization techniques, in vitro dissolution testing, in vivo studies, and advanced spectroscopic methods was employed to elucidate the mechanisms governing release behavior. The results demonstrate that poor hydration, arising from coatings, inadequate wetting, or polymer hydrophobicity, promotes poor release and can exacerbate barrier formation. In contrast, enhancing hydration through formulation strategies such as incorporation of disintegrants and fillers or by increasing the hydrophilicity of polymer can mitigate barrier formation and accelerate release. Notably, slower in vitro release from hydroxypropyl methylcellulose (HPMC)-based ASDs was found to correlate with reduced in vivo absorption. Overall, this work advances the mechanistic understanding of drug release to include cellulosic polymers, such as HPMC and hydroxypropyl methylcellulose acetate succinate (HPMCAS), and more complex formations such as tablets containing coated ASDs, providing guidance for the rational design of formulations for poorly water-soluble drugs.