Simulation of dry powder inhalers: Combining micro‐scale, meso‐scale and macro‐scale modeling

Abstract

The flow of carrier particles, coated with active drug particles, is studied in a prototype dry powder inhaler. A novel, multiscale approach consisting of a discrete element model (DEM) to describe the particles coupled with a dynamic large eddy simulation (LES) model to describe the dynamic nature of the flow is applied. The model consists of three different scales: the micro‐scale, the meso‐scale, and the macro‐scale. At the micro‐scale, the interactions of the small active drug particles with larger carrier particles, with the wall, with the air flow, and with each other is thoroughly studied using discrete element modeling and detailed computational fluid dynamics (CFD), i.e., resolving the flow structures around the particles. This has led to the development of coarse‐grained models, describing the interaction of the small active drug particles at the larger scales. At the meso‐scale the larger carrier particles, and all of their interactions are modeled individually using DEM and CFD‐LES. Collisions are modeled using a visco‐elastic model to describe the local deformation at each point of particle‐particle contact in conjunction with a model to account for cohesion. At the macro‐scale, simulations of a complete prototype inhaler are carried out. By combining the relevant information of each of the scales, simulations of the inhalation of one dose from a prototype inhaler using a patient relevant air flow profile show that fines leave the inhaler faster than the carrier particles. The results also show that collisions are not important for particle‐particle momentum exchange initially but become more important as the particles accelerate. It is shown that for the studied prototype inhaler the total release efficiency of the fine particles is between 10 and 30%, depending on the Hamaker constant, using typical settings for the properties of both particles. The results are also used to study regions of recirculation, where carrier particles can become trapped, and regions where fines adhere to the wall of the device. © 2016 American Institute of Chemical Engineers AIChE J, 63: 501–516, 2017

In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

“…Early development of these models focused on mathematical relationships to characterize particle–particle and particle–wall phenomena such as van der Waals, electrostatic, capillary, and contact forces as well as particle–fluid interactions, whereas some models that actually modeled DPI drug delivery were newly available at the time of those reviews . Since 2015, when those reviews were published, several studies involving CFD‐DEM based models that consider DPI delivery have been published . Leung et al .…”

“…using a CFD‐DEM approach, as illustrated in Figure , where a correlation based on the ratio of collision to cohesion energy was able to describe differences in FPF according to differences in air inlet velocity, the Hamaker constant, and collision angle, which may be useful for guiding device design. Several other recent studies have provided insights on the influence of collisions on particle–particle momentum exchange, the relative difference in time required for API and carrier particles to leave the device, the influence of the Hamaker constant, the quality of a dry‐coating process based on certain parameters, and the influence of impact velocity, impact angle, and carrier rotation on the dispersion process …”

“…19,20 Since 2015, when those reviews were published, several studies involving CFD-DEM based models that consider DPI delivery have been published. [56][57][58][59][60][61][62] Leung et al 56 investigated the effect of two mouthpiece grid mesh designs on FPF of four different albuterol sulfate formulations from an Aerolizer DPI using an in vitro method. By switching from the original grid mesh to a cross-grid design, FPF was reduced for drugonly and 1:5 and 1:10 API-carrier ratio formulations, but not for a 1:100 API-carrier ratio formulation, where corresponding CFD-DEM simulations were able to describe the complex relationship between flow and impaction differences caused by the switch in mesh designs that explained differences in Figure 3 Velocity contours and breakup patterns of agglomerate-agglomerate collision as predicted by Tong et al 59 at times of (a) 0, (b) 0.15, (c) 0.26, and (d) 0.33 seconds after particle release.…”

Capturing the non‐spherical shape of granular media and its trickle flow characteristics using fully‐Lagrangian method

“…By using the DEM in the analysis of solid particle motion, it has become possible to track individual particle arrangement . Tsuji et al proposed the particle–fluid coupling simulation method, and it was recently developed for multi‐scale analysis of particle‐fluid interaction by coupling it with the LES method . There are studies that have extended the DEM for cases such as movement of square particles, mesh shape in the sieving, and particle breakage behavior …”

“…15 Tsuji et al proposed the particle-fluid coupling simulation method, 16 and it was recently developed for multi-scale analysis of particle-fluid interaction by coupling it with the LES method. 17 There are studies that have extended the DEM for cases such as movement of square particles, 18 mesh shape in the sieving, 19 and particle breakage behavior. 20 In this research, we introduced suitable compressibility to MPS and performed individual packing behavior calculations for non-spherical elements, based on DEM with expanded functions.…”