Experimental and numerical investigation of multi-phase multicomponent drug delivery through a patient-specific respiratory airway using pressurized metered-dose Inhalers (pMDIs)

Abstract

Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are among the leading causes of morbidity and mortality worldwide, and their treatment often relies on efficient delivery of aerosolized drugs to the lungs. Pressurized metered-dose inhalers (pMDIs) remain the most widely used devices for this purpose due to their portability, affordability, and rapid therapeutic action; however, their efficiency is limited by a complex interplay of actuator design, airway geometry, breathing pattern, and inhalation technique. To address these challenges, this thesis presents a comprehensive, multi-scale investigation that integrates computational fluid dynamics (CFD) with in vitro validation and patient-specific airway modelling. Large-eddy simulation (LES) resolved the transient airflow structures, while a Lagrangian discrete-phase model (DPM) and a four-way coupled dense-discrete-phase model (DDPM) captured aerosol transport and deposition behaviour. In-vitro experiments using 3D-printed airway replicas, a next-generation impactor (NGI), and high-performance liquid chromatography (HPLC) provided quantitative validation of the numerical results. The integrated approach systematically examined the coupled effects of actuator geometry, thermal conditions, mucus presence, airway dynamics, and real-life inhalation irregularities on pMDI performance. Twin-nozzle actuators produced higher jet velocities and plume collapse, leading to increased mouth–throat deposition. Thermal analysis revealed that cooling the plume from 10 °C to –54 °C reduced overall deposition by ~15% and enlarged the mean deposited particle size by ~34.5%. Mucus enhanced deposition efficiency by up to 11%, particularly under colder plume conditions. Patient-specific analyses revealed that female COPD airways experienced stronger turbulence and higher mouth–throat deposition, while transient breathing reduced upper-airway losses by up to 67% compared to steady inhalation. Dynamic wall motion slightly decreased overall deposition but had a limited influence due to the brief injection duration of pMDIs. Simulations of irregular breathing behaviors such as coughing and premature exhalation, indicated strong vortex formation and redirection of fine particles, leading to significant drug loss. Finally, a comparison between one-way and four-way coupled frameworks demonstrated that although the LES and k–ω–DPM models predicted similar overall deposition fractions, the k–ω–DDPM model revealed distinct flow attenuation and particle redistribution toward downstream regions, driven by interphase momentum exchange and particle–particle interactions. Despite slightly underestimating total deposition relative to in vitro data, the DDPM framework provided critical insight into the dense-phase behaviour of pMDI aerosols and their influence on jet dynamics. Altogether, this work establishes a unified understanding of aerosol transport mechanisms in realistic airways, emphasizing that optimal pMDI performance requires both improved device design and patient-tailored inhalation strategies for effective and consistent pulmonary drug delivery.