Size-Controlled Templating of Stable Drug Nanoparticles from Nanoemulsion Precursors for Versatile Nanoformulation

Nanosizing drug particles has emerged as a successful approach to enable the oral bioavailability of lipophilic small molecule drugs. Scalable “bottom-up” methods have been developed to overcome the limitations and resource-intensiveness of traditional “top-down” nanoparticle production. However, bottom-up approaches are still limited in their applicability across drug chemistries, their ability to control particle size distributions, and the long-term stability of the generated nanoparticles. Here, we overcome these limitations by applying a versatile nanoemulsion templating approach to generate drug nanoparticle formulations inside a hydrogel thin film. By using different dispersed phase solvents, we formulate four chemically diverse drug molecules. Nanoparticle size is precisely tuned by controlling precursor nanoemulsion droplet size, enabling customizable formulations between 100–1000 nm. The resulting nanoparticles retain stable size distributions and solid states for at least six months at room temperature. We demonstrate the in vitro bioavailability enhancement of our nanoformulations through dramatically faster dissolution, increased apparent thermodynamic solubility, and enhanced permeability across Caco-2 cell monolayers. Notably, we quantitatively measure the solubility enhancement as a function of nanoparticle size and report a rare validation of the Ostwald–Freundlich equation. The thin-film form factor of our nanoformulations could enable applications in buccal delivery, oral delivery for pediatric, elderly, or dysphagic patients, and “suspensions-on-demand” for stable storage of point-of-care nanoparticle suspensions. Together, this work introduces a general, tunable, and shelf-stable platform for rapid fit-for-purpose pharmaceutical nanoformulations.