(316e) Numerical Investigation of Particle Shape and Actuation Flow Rate Effects on Lactose Carrier Delivery Efficiency through a Dry Powder Inhaler (DPI) Using CFD-DEM

Irreversible asthma and chronic obstructive pulmonary disease (COPD) are worldwide pulmonary healthcare concerns, which affected approximately 533 million individuals and resulted in 3.2 million fatalities in 2015 [1]. The administration of medicines via inhalation is one of the most popular treatments. Capsule based dry powder inhalers (DPIs) are widely used to deliver active pharmaceutical ingredients (APIs) attached to micron-sized carrier particles into human respiratory systems. However, such methods are not effective since only a small fraction of the medication, i.e., less than 30%, can reach the designated small airways [2, 3]. Thus, it is necessary to develop a method to increase the delivery efficacy to enhance the curative results and reduce undesired side effects. Previous research has shown that the actuation flow rate and aerodynamic particle size distribution (APSD), are key factors that can influence the localized particle deposition patterns in human respiratory systems [4]. Besides, modulating particle shapes is another promising approach to improve small-airway drug delivery efficacy [5]. In this study, the influence of actuation flow rate and particle shape on lactose carrier dynamics in a representative DPI, i.e., Spiriva^TM Handihaler^TM [6], has been investigated numerically. A one-way coupled computational fluid dynamics (CFD) and discrete element method (DEM) has been developed, verified, and employed to model the particle-particle and particle-device interactions and the transport and deposition of particles with different shapes in the DPI flow channel.

2. Materials and Methods

The flow channel of Spiriva^TM Handihaler^TM with grids was reconstructed to simulate the particle dynamics and deposition under various steady-state actuation flow rates (see Fig. 1 (A)). Four actuation flow rates, i.e., 30, 39, 60, and 90 L/min [7] were used to simulate different coordination scenarios between patients and the DPI. The final CFD mesh was generated using polyhedrons with a total of elements. Six prism layers were created to resolve the near-wall gradients. The one-way coupling method was employed for calculating the interactions between particles and the airflow. Using the verified - model [8], the turbulence airflow field was simulated using ANSYS Fluent 2019 R3 (ANSYS Inc., Canonsburg, PA). The airflow data was then transferred into Rocky DEM (ESSS, Woburn, MA) to compute the fluid-particle and particle-particle interactions, and the particle trajectories in the DPI flow channel. The surface energies are 0.06 J/m² between lactose carriers particles and 10 J/m² between the carrier and the DPI surface[9]. The Hertz-Mindlin (H-M) model [10] with Johnson-Kendall-Roberts (JKR) cohesion [11] was employed for the calculation of inter-particulate van der Waals force. A total of 15,514 spherical and sphero-cylinder particles (aspect ratio=2.0) with an equivalent diameter of 3.0 μm were injected at time t=0 through the two holes on the capsule (see Figs. 1 (A) & (B)). The rolling resistance was set to 0 for both spherical and sphero-cylinder particles for modeling the rotational motions of both types of particles. The total physical time duration simulated was 0.01 s, ensuring the change in DPI delivery efficiency less than 1%.

3. Results and Discussion

Results in Fig. 1 indicate that both particle shape and actuation flow rate can significantly influence the delivery efficiency and distribution of carrier particles emitted from the mouthpiece. Figs. 1 (B) and (C) show that more than 99% of spherical particles deposited in the capsule chamber, including the grid and the cap enclosing the grid. In contrast, the deposition of sphero-cylinder particles is more complex. At the flow rates lower than 39 L/min, more than 99% sphero-cylinder particles deposited in the capsule chamber. At the flow rates higher than 60 L/min, a significant amount of sphero-cylinder particles deposit not only in the capsule chamber but also the tube between the grid and the mouthpiece. Such differences are possibly due to the particle resuspension effects of the elongated sphero-cylinder particles. At higher flow rates, the torque acting on the sphero-cylinder is higher than spheres which are able to separate more deposited sphero-cylinders from the device surfaces. The resuspended sphero-cylinders result in a more dispersed deposition pattern (see Fig. 1 (B)). The simulation also predicts opposite trends of delivery efficiency vs. flow rate between the sphere and sphero-cylinder particles (see Fig. 1 (C)). Indeed, with the increase in flow rate from 30 to 90 L/min, the delivery efficiency of the spherical particle increases from 27.1% to 43.0%. In contrast, the delivery efficiency of sphero-cylinder particles decreases from 45.3% to 36.3% as more resuspended particles either deposit on the grid or the tube wall connecting the mouthpiece and the grid.

The emitted particle distribution at the mouthpiece opening is a crucial factor determining lung deposition distribution. The results in Fig. 1 (D) show that the emitted distribution is affected by both the particle shape and the actuation flow rate. Specifically, the higher flow rate induces more dispersed distribution due to higher particle momentums obtained from the airflow, and the emitted distribution of sphero-cylinder particle is more scattered than spherical particles due to the particle resuspension effect. The findings mentioned above can provide insight into the optimization of DPI performance with selected particle shapes and actuation flow rates.

4. Conclusions

In this study, a one-way coupled CFD-DEM approach has been developed and applied to investigate the effects of actuation flow rate and particle shape on the transport and deposition of lactose carrier in a representative DPI. Compared with in vitro tests, numerical simulation is noninvasive and time-saving, while providing accurate results to reduce the cycle of DPI product innovations. Based on the high-resolution numerical results, it can be concluded that to enhance the delivery efficiency to the mouth front, using spherical lactose carriers is recommended for a high actuation flow rate (90 L/min), while elongated sphero-cylinder carriers are preferred for an actuation flow rate less or equal to 60 L/min. The different resuspension effects induced by the particle shape play a significant role in the particle deposition and distribution inside the DPI flow channel.

5. Future Work

Future work includes: (1) Simulating the interactions between API and carriers, and the resultant delivered dose in human respiratory systems; (2) Employing a two-way coupled CFD-DEM to simulate the particle dynamics with a rattling capsule; and (3) Investigating the aspect ratio effects of non-spherical particles on the delivery efficiency.

Acknowledgment

The research was made possible by funding through the award for project number HR19-106, from the Oklahoma Center for the Advancement of Science and Technology. The use of Rocky DEM (ESSS, Woburn, MA) as part of the ESSS-CBBL academic partnership is gratefully acknowledged (Dr. Rahul Bharadwaj). The use of ANSYS software (ANSYS Inc., Canonsburg, PA) as part of the ANSYS-CBBL academic partnership is also gratefully acknowledged (Dr. Thierry Marchal).