Isolation-free manufacturing of lipophilic API-ionic liquids (API-ILs) and their solidified products for oral solid...

Advances in continuous pharmaceutical manufacturing offer enhanced efficiency, scalability, and safety, particularly for oral solid dosage forms (OSDs). In this study, we present an integrated, isolation-free process that synthesizes and purifies lipophilic API-Ionic Liquids (API-ILs), followed by spray encapsulation into free-flowing powders. Applied to BCS Class III and IV drugs-specifically metformin and chlorpromazine-this method addresses the handling challenges associated with the physical properties of API-ILs and supports their clinical translation. API-IL synthesis is carried out in a continuous flow system using a 3D-printed PEEK mixer and tubular sections, followed by in-line liquid-liquid extraction (LLE) with a PEEK kenics mixer and annular tubular liquid-liquid membrane separator to efficiently remove inorganic by-products. The lipophilic API-ILs spontaneously self-assemble into micelles, and while isolation of such self-assembled micellar systems can, like stable emulsions, pose significant challenges under batch conditions, the continuous setup enables quantitative phase separation with residence times as short as 2.5 min. The continuous process significantly improved the purity of metformin API-IL, reducing counterion excess to 3.8% w/w compared to 20% in batch synthesis. The purified API-IL stream was then directly spray-encapsulated to produce powders with high drug loadings (up to 60%), suitable for standard OSD manufacturing. This work highlights a scalable, cost-effective strategy for the formulation of poorly bioavailable APIs through integrated continuous production, purification, and solidification of API-ILs.