A comparative study of spray drying and jet milling in the preparation of nintedanib dry powder for inhalation

This study optimized nintedanib dry powder for inhalation (DPI) and compared it with organic solvent-based spray drying and jet milling. A solid dispersion of nintedanib, polyvinyl alcohol (PVA), and leucine was produced by spray drying from an ammonium carbonate (Ab) aqueous solution. Formulation and process variables-API:(PVA+leucine (L)) mass ratio, PVA:L ratio, API: Ab ratio, total solids, and feed flow-were systematically screened to yield particles with geometric size ≤5 μm. Powders were characterized for morphology, moisture, density, particle size distribution, crystallinity, assay, and aerodynamic deposition. The optimized formulation showed good flowability and stability, with API content >80% in DPI particles; mass median aerodynamic diameter (MMAD) was 4.18 μm and fine particle fraction (FPF) 36.59%, indicating effective deep-lung delivery potential. Compared with conventional methods, the aqueous spray drying route delivered comparable or superior <i>in vitro</i> inhalation performance and delivery efficiency, while improving safety during the preparation and usage process (such as reducing the risk of organic solvent residue and dust exposure). These results provide a practical strategy for safe, efficient nintedanib inhalation formulations and a platform to spray dry other poorly water-soluble drugs into DPI particles.