Inhalation

INH0622

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Inhalation June 2022 11 an inhaler system produces a more highly concen- trated region of aerosol in comparison to the net flow through the region, then the region can be consid- ered a dense flow-particle system [21]. In these sys- tems, both the effects of flow on discrete elements as well as the effects of the particles or droplets on the flow govern the aerosol transport. erefore, a "two- way" coupled modeling approach is better suited to simulate flow in these regions [16, 33]. In addition to the drag and gravitational force acting on the aerosol during its transport, collision, breakup, coalescence, agglomeration, deagglomeration and turbulent dis- persion forces may also have an influence [16]. Such sub-models may need to be incorporated when applicable, depending on the physics of the real sys- tem. For highly accurate simulations of dense mul- tiphase flows, depending on the complexity of the physics involved, advanced computational model- ing approaches such as spray-wall interaction mod- els, dense discrete phase models, population balance equation models, discrete element method models and smoothed particle hydrodynamics models may be incorporated into the underlying computational simulation of the flow field, but will significantly increase model complexity and required computa- tional power [1, 20]. While CFD modeling has many advantages, sim- ulation of the inhaler drug delivery systems and aerosol transport in respiratory airways is highly complex due to the underlying physics that must be captured [21]. erefore, setting up the model and running the simulation requires an understanding of the physics involved and numerical algorithms required to capture such phenomena [16]. ere are a number of commercial and open-source software packages available that can solve the CFD governing equations. Considering that highly complex CFD models require many sub-model assumptions, ver- ification of the numerical implementation and vali- dation of the model setup with experimental results are critical steps in developing an effective and sci- entifically accurate CFD model. e computational modeling aspects of nasal sprays and aerosol drop- let deposition in human nasal cavities using CFD, including two-way coupling effects, has recently been developed and validated [1, 4, 5]. e follow- ing sections of this article illustrate some recom- mended modeling practices that could be followed in setting up and running CFD simulations of nasal spray transport and deposition in the nasal airways. Finally, two case studies are provided to illustrate how CFD simulations can potentially be applied for sensitivity/bioequivalence analysis and for design optimization of nasal spray products. tems that include fluid motion [19]. e fluid flow inside an engineering system, which may include complex flow characteristics such as turbulence, com- pressibility, heat transfer and multiphase regimes, is determined by solving general governing trans- port equations based on first principles [16]. e use of general governing transport equations makes CFD a versatile research tool with wide portability and usability in many different fields. Of late, CFD has seen increased interest in the field of biomedi- cal engineering, especially for applications related to drug delivery [16, 20]. In the area of respiratory drug delivery, airflow fields, aerosol transport and depo- sition and even aerosol formation are simulated in realistic three- dimensional (3-D) models of inhal- ers and respiratory tracts using CFD [21]. Recently, there have been a number of advancements in CFD modeling that have enabled the simulation of com- plex respiratory drug delivery physics [16, 22-24]. Application of CFD in respiratory drug delivery has resulted in a number of new inhaler devices and designs [25-28]. Furthermore, CFD has been used as a dosimetric tool to quantify delivered dose to specific respiratory tract regions and for providing an under- standing of aerosol deposition mechanics [29-32]. Pharmaceutical inhaler systems produce millions of multicomponent droplets or particles during the delivery of drug formulations, regardless of whether the formulation is liquid or solid, or changes phase [21]. ese discrete elements emitted from aerosol generation devices can also be accompanied with jets or spray momentum arising from the process of aero- sol formation and flow through the device. An Euler- Lagrange modeling framework has been shown to be suitable for modeling such aerosol transport systems in many cases of respiratory drug delivery [1]. In the Euler-Lagrange framework, the fluid-carrier phase is considered as a continuum and solved using an Eulerian framework of governing equations, while the particles/droplets are solved as Lagrangian points inside the carrier phase [16, 33]. Instead of modeling all of the millions of individual particles or droplets in a spray system, a parcel-based model is a prefera- ble approach for pharmaceutical aerosol simulations. In the parcel-based approach, each parcel is a repre- sentative fraction of the total droplets/particles gen- erated by the device and the trajectory of a parcel is determined by tracking a droplet in the parcel with the specified diameter and mass flow rate. Within inhaler systems, regions that have relatively low concentrations of particles/droplets compared to the net flow through the region can be consid- ered as having dilute particle physics [21]. In parti- cle dilute regions, effects of the flow on the discrete elements primarily govern the aerosol transport and reverse effects are negligible. erefore, a "one-way" coupled modeling approach is better suited to simu- late the aerosol transport in such regions [16]. When

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