Continuous microfluidic manufacture of nano-in-microparticles combining 3D-printed micromixers and spray drying

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Kara, Aytug and Ongoren, Baris and Anaya, Bryan J. and Lalatsa, Aikaterini and Serrano, Dolores R. (2026) Continuous microfluidic manufacture of nano-in-microparticles combining 3D-printed micromixers and spray drying. Pharmaceutical Research, 43 (3). pp. 905-926. ISSN 0724-8741 (https://doi.org/10.1007/s11095-025-03994-1)

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Abstract

Purpose: Conventional nanoparticle manufacturing techniques remain costly, labor-intensive, and difficult to scale, while also being subject to batch-to-batch variability. These limitations hinder their clinical translation, particularly in first-in-human trials. Emerging transformative technologies such as microfluidics and three-dimensional (3D) printing offer opportunities to develop agile, continuous, and scalable manufacturing processes. This study aims to demonstrate the feasibility of continuous microfluidic production of nanoparticles using customizable 3D-printed chips, integrated with atomization technologies, to generate solid nano-enabled controlled release therapies. Methods: 3D-printed microfluidic chips were designed using computational fluid dynamics (CFD) to optimize flow characteristics. Nifedipine (NFD)–loaded nanoparticles were continuously manufactured with Eudragit L-100 and subsequently embedded into pullulan microparticles by spray-drying, yielding nano-in-microparticles (NIM). Particle size, encapsulation efficiency, solid-state properties, permeability, and release kinetics were assessed in ex vivo Franz cell studies across porcine intestinal membranes. Results: Continuous microfluidic processing produced NFD-loaded nanoparticles with 95% encapsulation efficiency. Spray-drying yielded spherical pullulan-based NIMs of ~ 10 µm, which, upon rehydration, released NFD nanoparticles of ~ 100 nm. The nanoparticles retained their amorphous state and displayed a three-fold increase in intestinal permeability compared to free drug, accompanied by a three-fold reduction in lag time. Release studies demonstrated reduced burst release and a sustained zero-order release profile over 24 h, favorable for blood pressure maintenance therapy. Conclusions: The integration of 3D-printed microfluidic chip design with continuous manufacturing and spray-drying enables scalable production of solid nano-enabled therapies. The NFD-loaded NIMs demonstrated enhanced permeability and controlled release, supporting the potential of this platform for the clinical translation of nanomedicines.

ORCID iDs

Kara, Aytug, Ongoren, Baris, Anaya, Bryan J., Lalatsa, Aikaterini ORCID logoORCID: https://orcid.org/0000-0003-4791-7468 and Serrano, Dolores R.;
CORE (COnnecting REpositories)