Mechanofusion-assisted magnesium stearate surface modification enhances dispersion and aerodynamic performance of carrier-based nintedanib inhalable dry powder formulations.

Oral administration of nintedanib, a multi-receptor tyrosine kinase inhibitor for idiopathic pulmonary fibrosis, is associated with gastrointestinal side effects and limited lung targeting. Pulmonary delivery using dry powder inhalers (DPIs) offers a promising alternative, but the strong cohesiveness of drug microparticles hinders aerosolization and deep lung deposition. This study developed carrier-based DPI systems using mechanofusion with magnesium stearate (MgSt) at 0%, 1%, and 5% (w/w) and compared their physicochemical and aerodynamic performance with physical mixtures. Respirable nintedanib particles produced by jet milling were combined with lactose and MgSt to prepare six blends. Solid-state analyses by differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy showed that mechanofusion enhanced drug-excipient interactions, with attenuated nintedanib peaks and modified thermal responses, while jet milling largely preserved the crystalline structure of nintedanib. Scanning electron microscopy, energy-dispersive X-ray spectroscopy, and Raman imaging confirmed more uniform adhesion and distribution of nintedanib and MgSt on the carrier surface. Bulk-density-derived flowability indices were numerically lower at higher MgSt contents. Aerodynamic evaluation using a next-generation impactor showed that mechanofusion, particularly with 5% MgSt, achieved higher fine and extra-fine particle fractions, confirming its synergistic role with MgSt in improving pulmonary delivery efficiency. These findings suggest that mechanofusion, particularly when combined with MgSt, is an effective strategy for improving the aerodynamic performance of carrier-based DPI formulations. By reducing particle cohesion and enhancing dispersion, this approach may facilitate more efficient pulmonary delivery of highly cohesive drugs such as nintedanib.