Cryo-Crystallization of Inhalable Budesonide Ultrafine Crystals with Enhanced Aerosol Performance: Mechanism and Evaluation

Dry powder inhalation (DPI) therapy offers effective treatment for pulmonary diseases, providing high drug delivery efficiency, minimal side effects, and enhanced patient compliance. The DPI efficacy depends critically on drug particle physicochemical properties and drug–carrier interactions, while the quantitative mechanisms and optimization policy are still unclear. Here, we introduce a microdroplet cryo-crystallization (MCC) strategy, producing superior powder properties in terms of particle size, shape, and crystallinity compared with traditional milling and spray drying techniques. The aerosol evaluation indicated that an obvious improvement in the fine particle fraction (FPF) to 58–62% depends on the variation of the air blowing speed, which is the highest value compared to the commercialized formulation. The subsequent formulation mechanism studies revealed improved powder flowability (basic flowability energy of 124 mJ vs 146 mJ for the conventional type). An AFM test demonstrated the cohesion of BUD mc ( F c = 70.50 nN) was lower than that of BUD ca ( F c = 93.20 nN), giving DPI mc a more desirable CAB than DPI ca (1.02 vs 1.07 for BUD ca ), which ensures the mixing homogeneity of DPI mc and facilitates the effective detachment of drug particles. These results suggest that MCC is a promising technique for producing inhalable budesonide (BUD) with superior physicochemical properties and aerosolization performance, and the quantitative mechanism study gives theoretical guidance for the further development of the DPI formulation.