Mechanistic Elucidation of Fluticasone Propionate Aerosolization: Interplay of Particle Morphology and Process Parameters in Dry Powder Inhaler Systems

The performance of dry powder inhalers (DPIs) is governed by a complex interplay of deagglomeration, attachment, detachment, and dispersion. Here, we show that crystal morphology serves as a master variable that elucidates and redefines the mechanistic roles of process parameters in DPI systems. Through the deliberate engineering of four distinct crystal morphologies of fluticasone propionate (FP), we systematically decoupled the effects of blending time (15–120 min) and flow rate (40–80 L/min) on aerosolization. Analysis of the fine particle fraction (FPF) and particle deposition patterns allowed us to isolate the contributions of each parameter to the underlying aerosolization mechanisms. Our results reveal a sophisticated, morphology-dependent interplay. We found that for specific crystal habits, the role of blending time is not confined to modulating deagglomeration and attachment but extends to critically impacting detachment. Similarly, the influence of flow rate is not limited to detachment; for certain morphologies, it becomes a significant factor in driving deagglomeration. Ultimately, this work demonstrates that crystal morphology does not merely affect dispersion; it dictates the extent to which blending and flow rate control the entire cascade of aerosolization events. These findings establish a robust design principle for the rational engineering of inhalable crystals to achieve predictable and optimized therapeutic performance.