Mechanochemical Engineering of High-Dose Inhalable Antibiotic Powders for Lower Respiratory Tract Infections

Lower respiratory tract infections require high local antibiotic concentrations in the lung, yet current dry powder inhaler (DPI) technologies are poorly suited to delivering high drug payloads while maintaining particle stability, dispersibility, and antimicrobial function. Here, we report a novel solvent-minimized mechanochemical strategy for the design of high-dose inhalable antibiotic powders based on ciprofloxacin-maleic acid (CIP-MA) salt formation. CIP-MA was prepared by oscillatory ball milling and co-processed with l-leucine (L-Leu), polyvinylpyrrolidone 10,000 (PVP), or D-mannitol (D-Man) using a design of experiment approach to tune the milling frequency, processing time, and excipient loading. The process generated crystalline, thermally stable powders with respirable particle sizes, controllable morphology, and reduced hygroscopicity compared with raw ciprofloxacin. Excipient selection provided distinct formulation functions. L-Leu improved dispersibility and achieved the highest proportion of particles with geometric diameter below 5 μm (89%) and fine particle fraction < 5 μm (∼37%) measured using a next-generation impactor at a 200 mg dose in the OrbitalTM high-dose DPI. However, PVP and D-Man favored improved device emptying and altered dissolution behavior. All CIP-MA formulations retained antimicrobial potency, with minimum inhibitory concentrations comparable to raw ciprofloxacin and approximately 95% reduction in viable Pseudomonas aeruginosa biofilm. Importantly, the formulations showed accelerated dissolution under pulmonary-relevant flow-through conditions, releasing 70-80% of ciprofloxacin within 30 min, compared with the slower dissolution of raw ciprofloxacin. These findings establish oscillatory ball milling as a lower solvent use, tunable solid-state approach that integrates salt formation, preservation of crystallininty, particle engineering, high-dose aerosol delivery, and biological performance for next-generation inhalable antibiotic formulations.