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. (2025) Continuous microfluidic manufacture of nano-in-microparticles combining 3D-printed micromixers and spray drying. Pharmaceutical Research. ISSN 0724-8741 (In Press)

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Abstract

Manufacturing techniques commonly employed for nanoparticles (solvent evaporation, emulsion, and nanoprecipitation) remain costly and challenging to upscale, suffer from batch-to-batch variability, and require specialized personnel and thus fail to deliver methods able to be employed in first in human clinical trials. Novel transformative technologies have significantly impacted the pharmaceutical industry such as microfluidic and three-dimensional (3D) printing. The pharmaceutical industry in the post-COVID era has embraced novel technologies based on microfluidics and three-dimensional (3D) printing manufacturing towards developing agile continuous manufacturing processes able to enable the clinical translation of nanomedicines. Continuous microfluidic manufacture of nanomedicines has been demonstrated but little is available for solid nano-enabled therapies. In this paper, we aim to demonstrate how continuous microfluidic manufacture of nanoparticles with 3D-printed customizable chips coupled with atomization technologies such as spray-drying can elicit solid nano-enabled controlled release therapies.The design of the 3D-printed microfluidic chips was guided by computational fluid dynamics (CFD) including two different flow regions. The continuous manufacturing of nifedipine (NFD) NFD-Eudragit L-100 nanoparticles within pullulan microparticles resulted in nano-in-microparticles (NIM) with a 95% drug encapsulation and a size of 10 µm that after rehydration in aqueous media releases NFD nanoparticles with a size 100 nm. NFD-nanoparticles maintained their amorphous state and exhibited a three-fold enhanced permeability in ex-vivo Franz cell permeation studies across pig intestinal membrane with a three-fold shorter lag time but reduced burst release following a sustained zero-order profile over 24 h, a release pattern that is ideal for maintenance of blood pressure control.

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)