(312i) An Integrated Computational Model of Powder Release, Dispersion, and Deposition in a Dry Powder Inhaler

Dry Powder Inhalers, DPIs, are the principle means of delivering pharmaceuticals due to their ease of use and cost-effectiveness. The main function of a DPI device is the adequate dispersion and delivery of particles. Initially the particles are in the forms of a loose powder which, under the action of airflow, is broken up and dispersed as particle aggregates which are then further broken up into fine particles. Powder properties, e.g., cohesion, charge, size, and size distribution, influence powder dispersion and the breakage of particle agglomerates. One of the problems with DPIs is the loss of powders due to deposition within the device which ranges from 20-40% of the total drug. In order to provide the maximum drug dose per inhalation and to ensure proper function of the DPI device for each dose (i.e., dose-to-dose variation) it is desirable to minimize the drug loses due to internal deposition. It is also desired to have good control over the dispersibility of the powder, release of drug (if attached to powder particles), and breakup of agglomerates in order to achieve the desired specification of particle/agglomerate size distributions at the exit flow of the DPI. The Turbuhaler (AstraZeneca) is a multidose dry powder inhaler that is widely used to deliver a number of drugs (typically for asthma) to the upper respiratory tract. Each dose is initially in the form of loosely packed drug aggregates, ~10-20μm in size, which are released into a mixing/dispersion chamber, where they are broken up into particles, ~1-2μm in size, which are then directed to the inhalation channel of the device (Tsima et al., 1994; Wetterlin, 1988).

In this work the airflow in a Turbuhaler DPI is determined by computational fluid dynamics, CFD, simulations. The DPI geometry is first constructed in a CAD/CAM environment (i.e., CATIA V5 R19) and then imported into GAMBIT (v2.1) where a tetrahedral grid is constructed. The computational grids consisted of 1-2 10⁶ tetrahedral cells with a maximum skewness of 0.85. The equations for flow were solved using commercial CFD software (i.e., FLUENT v6.3). The SST k-ω model for transient turbulent flows was employed. Different steady state airflows were simulated by imposing a wide range of pressure drops at the mouthpiece outflow of -200 to -10000Pa corresponding to airflow rates of 2.7 and 18.6 l/min, respectively. Dynamic airflow simulations were performed by imposing a transient pressure boundary condition at the mouthpiece channel. Eulerian/Lagrnagian simulations of particle motion and deposition were conducted for particles between 1-20μm in size corresponding to the single particle and particle agglomerate size ranges of the powder. Particles and particle aggregates are assumed to be released instantaneously and uniformly from a surface located upstream from the powder storage site. For dynamic simulations the particles are released either instantaneously or at a constant rate over a period of time < the inhalation time.

The computed airflow in the DPI revealed a strongly non-uniform flow field. Particle depositions occurred mostly in the dispersion chamber and the helical region of the DPI where strong tangential motion was observed. The computed pressure drops were in agreement to available experimental data. In order to compute realistic particle depositions in the device a nonideal sticking efficiency, determined from particle/wall adhesion models, was employed. The predicted total particle depositions were in agreement to available literature data. This work represents the first coupling of particle adhesion models with fluid dynamics simulations for inhalation devices and permits the investigation of the effect of particle formulation properties on the DPI outflow and internal loses.

M.P. Tsima, G.P. Martin, C. Marriott, D. Gardenton and M. Yianneskis, 1994. Drug delivery to the respiratory tract using dry powder inhaler, International Journal of Pharmaceutics, 101 () 1-13.

K. Wetterlin, 1988 Turbuhaler:A New Powder Inhaler for Administration of Drugs to the Airways. Pharmaceutical Research, Vol, 5, No.8.