Novel diffusion-dominated mixing for dry powder inhalations development: implementation and mechanistic insights.

The Hummer acoustic resonance mixer (HAM) leverages high-frequency acoustic resonance to enable a novel mechanical shear-free mixing. This mixing technology induces diffusion-dominated mixing and localized pseudo-convective particle motion, minimizing drug loss and reducing shear damage to particles. This dual mechanism promotes efficient dispersion of micronized drug particles and ensures uniform drug-carrier adhesion, offering significant advantages for developing dry powder inhalations (DPIs). This study investigated the feasibility of HAM for DPIs development, analyzed impacts of mixing parameters on pulmonary drug delivery efficiency and elucidated the underlying modulatory mechanism through macroscopic and microscopic perspectives. DPI formulations were prepared with varying mixing times (5, 10 and 15 min) and accelerations (30×g, 60×g and 90×g). At the macroscale, the feasibility of HAM for DPIs development was assessed based on mixing performance and pulmonary drug delivery efficiency. All formulations exhibited a drug recovery exceeding 95%, confirming the high feasibility of HAM in DPIs development. Pulmonary drug delivery efficiency decreased with increasing acceleration, and reduced at both shorter and longer mixing times. The formulation prepared at 30×g for 10 min achieved the highest drug deposition of 49.53% in the lower respiratory tract. The underlying modulatory mechanism was evaluated by analyzing pulmonary drug delivery process and initial status of DPIs. At the microscale, pulmonary drug delivery process was analyzed with a focus on fluidization and dispersion, transportation, detachment and subsequent deposition. Notably, the impact of the mixing parameters on drug deposition at lower respiratory tract closely mirrors their effect on micronized drug particles detachment at the human bronchi bifurcation. The micronized drug particles detached at the bronchi bifurcation significantly decreased with the extension of mixing accelerations and slightly increased with extended mixing times. Material coverage and adhesive strength were assessed to analyze the impacts of key mixing parameters on the initial status of DPIs, which may determine the pulmonary drug delivery process of DPIs. Lower mixing acceleration increased material coverage and sharply decreased adhesive strength. These findings support a mechanism that weaker adhesive strength facilitates micronized drug particles detachment at bronchi bifurcations, thereby enhancing deep lung delivery. This work establishes the feasibility of novel acoustic resonance-based HAM for DPI development and provides mechanistic insights into key mixing parameters, demonstrating its practical utility in pharmaceutical powder mixing processes.