Elucidating mixing process effects on pulmonary delivery efficiency of dry powder inhalers: A dual-dimensional macroscopic and microscopic perspective

Dry powder inhalers (DPIs) have been widely recommended in lung diseases on account of direct pulmonary delivery, desired drug stability, and satisfactory patient compliance. More than 90% of DPIs products consist of micronized drugs mixed with larger carrier particles for required dose delivery uniformity and desired pulmonary delivery efficiency. In formulation development, researchers often focus on the influence of mixing process on the macroscopic quantitative results of pulmonary drug delivery efficiency. However, the critical influence and underlying modulatory mechanisms of mixing parameters remain poorly understood, posing formidable challenges to the optimization of DPI formulations. In the present study, an internationally recognized cascade impactor method was employed to investigate the effects of mixing parameters on the ultimate pulmonary drug delivery efficiency from a macroscopic perspective. Subsequently, Confocal Microscopic Raman Spectroscopy (CMRS) was applied to innovatively investigate the material distribution and adhesive status of the mixed DPI particles. Meanwhile, the self-constructed Modular Process Analysis Platform (MPAP) was employed the detached behavior during pulmonary delivery, allowing us to explore the influence mechanisms from a microscopic perspective. Ultimately, correlations were established between the mixing parameters and the drug adhesive status, pulmonary drug delivery process and efficiency. This study was expected to provide novelty pioneering paradigms and dual-dimensional perspective for the direction development and optimization of DPIs.