Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles

作者：Tu Van Duong, Hanh Thuy Nguyen, Lynne S. Taylor · 发表于：European Journal of Pharmaceutics and Biopharmaceutics · 年份：2022 · DOI：10.1016/j.ejpb.2022.04.002 · 被引用次数：39 · 研究领域：Drug Solubulity and Delivery Systems、Advanced Drug Delivery Systems、Crystallization and Solubility Studies

Poor solubility is a major challenge that can limit the oral bioavailability of many drugs, including delamanid, a weakly basic nitro-dihydro-imidazooxazole derivative used to treat tuberculosis. Amorphous solid dispersion (ASD) can improve the bioavailability of poorly water-soluble compounds, yet drug crystallization is a potential failure mechanism, particularly as the drug loading increases. The goal of the current study was two-fold: to enhance the stability of amorphous delamanid against crystallization and to improve drug release by developing ASDs containing the salt form of the drug. Various sulfonate salts of delamanid were prepared in amorphous form and evaluated for their tendency to crystallize and undergo chemical degradation following storage at 40 °C/75% relative humidity. Drug release was evaluated by a two-stage dissolution test consisting of an initial low pH stage, followed by transfer to a higher pH medium. For ASDs of the free base, small amounts of crystallinity during preparation were found to limit the drug release. Delamanid salts with sulfonic acids showed considerably improved amorphous stability. Tosylate, besylate, edisylate, and mesylate salts had high glass transition temperatures as well as good chemical and physical stability. In addition, a remarkable improvement in the drug release was observed when ASDs were prepared with these salts in comparison to the free base form. Specifically, ASDs with hydroxypropyl methylcellulose phthalate (HPMCP...