Single-Step Co-Crystallization and Lipid Dispersion by Supercritical Enhanced Atomization

Abstract

This work evaluates the feasibility of the supercritical enhanced atomization (SEA) process to improve stability and delivery of active pharmaceutical ingredients (APIs). This process was used to generate distinct microcomposites of pure theophylline (TPL), an API model, the theophylline-saccharin (TPL-SAC) cocrystal, and dispersions of each crystalline form in hydrogenated palm oil (HPO), TPL-HPO and TPL-SAC-HPO. The formation of the TPL-SAC cocrystal within the HPO suggests that the cocrystallization step anticipates the lipid dispersion during the formation of the microcomposites. The TPL-SAC cocrystal extended the TPL stability at 92% relative humidity by over 6 months, contrary to that of raw TPL, which converted into a monohydrate after a few days only, even when dispersed into HPO. The TPL-SAC cocrystal slowed the TPL release from the lipid particles, which is explained by its higher stability toward hydration. The feasibility of the cocrystal microcomposites for therapeutic application was evaluated by estimating the plasmatic concentration of TPL using a pharmacokinetic model (one compartment approach). This model revealed that the small therapeutic concentration window and high elimination rate of TPL raises serious limitations to control the TPL release. The microcomposites were able to attenuate the TPL burst effect and improve stability toward hydration but could not extend significantly its delivery.