CFD-DEM investigation of the effects of aperture size for a capsule-based dry powder inhaler.

Capsule based dry powder inhalers (DPIs) often require piercing of the capsule before inhalation, and the characteristics of the apertures (punctured holes) affect air flow and the release of powders from the capsule. This work develops a numerical model based on the two-way coupling of computational fluid dynamics and discrete element method (CFD-DEM) to investigate the effect of aperture size on powder dispersion in the Aerolizer® device loaded with only carrier particles (lactose). Powders (carrier particles) in the size range 60-140 µm (d50: 90 µm and span: 0.66) were initialized in a capsule which had a circular aperture at each end. Boundary conditions corresponding to an air flow rate of 45 L/min were specified at each inlet to the mixing chamber (i.e., a total flow rate 90 L/min), and a capsule spin speed of âˆ¼ 4050 rpm. The velocity magnitudes inside the capsule were considerably lower than those in the mixing chamber in the vicinity of the rotating capsule, with the exception of the capsules featuring 2.5 mm and 4 mm apertures. Larger apertures reduced the capsule emptying time and increased the particle evacuation velocity; the fluid drag force on the particles issuing from the capsule peaked for an aperture of 1.3 mm. Inside the capsule, particle-particle (PP) collisions were more frequent than particle-wall (PW) collisions due to high concentration of powder, but PP collisions had smaller (median) impact energy than PW collisions. Larger apertures resulted in fewer collisions in the capsule with higher PW and virtually unchanged PP collision energies. Outside the capsule (i.e., in the inhaler mixing chamber), PW collisions occurred more frequently than PP collisions with median collision energies typically two orders of magnitude higher than inside the capsule. Larger apertures resulted in more collisions with slightly reduced collision energy, but this effect plateaued for aperture sizes larger than 1.3 mm. Powder dispersion, expressed as the fine particle fraction (FPF) of the powder, was predicted using an empirical equation based on carrier PW collisions. Therefore, consistent with the model prediction of the effect of aperture sizes on the chamber collision frequency, FPF increased with aperture size but plateaued beyond 1.3 mm.

Powder strength distributions for understanding de-agglomeration of lactose powders.

PURPOSE: The purpose was to calculate distributions of powder strength of a cohesive bed to explain the de-agglomeration of lactose. METHODS: De-agglomeration profiles of Lactohale 300(®) (L300) and micronized lactose (ML) were constructed by particle sizing aerosolised plumes dispersed at air flow rates of 30-180 l/min. The work of cohesion distribution was determined by inverse gas chromatography. The primary particle size and tapped density distributions were determined. Powder strength distributions were calculated by Monte Carlo simulations from distributions of particle size, work of cohesion and tapped density measurements. RESULTS: The powder strength distribution of L300 was broader than that of ML. Up to 85th percentile, powder strength of L300 was lower than ML which was consistent with the better de-agglomeration of L300 at low flow rates. However, ~15% of L300 particles had higher powder strength than ML which likely to cause lower de-agglomeration for L300 at high air flow rates. CONCLUSION: Cohesive lactose powders formed matrices of non-homogenous powder strength. De-agglomeration of cohesive powders has been shown to be related to powder strength. This study provided new insights into powder de-agglomeration by a new approach for calculating powder strength distributions to better understand complex de-agglomeration behaviour.

Insight into pressure drop dependent efficiencies of dry powder inhalers.

PURPOSE: The purpose of this study was to assess the effectiveness of three commercial capsule-based dry powder passive inhalers [Rotahaler® (RH), Monodose Inhaler® (MI) and Handihaler® (HH)] in de-agglomerating salbutamol sulphate (SS) and micronized lactose (LH300) powders and their sensitivity to air flow rate changes and air flow resistance. METHODS: Aerosolisation was assessed in real-time using a laser diffraction method: this approach was possible as only single-component formulations were tested. Volume percent of the aerosolised particles with diameter less than 5.4 µm at air flow rates from 30 to 180 l min−1 was obtained with the RH, MI and HH and provided a parameter, relative de-agglomeration (RD), as a measure of de-agglomeration. The pressure drops across the device at various flow rates were obtained from a differential pressure meter. RESULTS: The relationship between RD of SS and LH300 and air flow rate appeared substantially different between the devices. It was surprisingly found that in some cases RD dropped at the highest air flows: this indicates a device specific maxima in RD occurs, and this may in part be attributed to changes in capsule motion. It is proposed that this relationship between RD and pressure drop provides a patient focussed simple way to assess RD performance. This assessment indicated that MI was the most efficient relative de-agglomerator at lower pressure drops, while HH increases its effectiveness at higher pressure drops. CONCLUSION: The approach of measuring RD as a function of pressure drop revealed instructive variations in the aerosolisation performances of different devices. This new approach helps compare device performances with different powders, and hence improve optimisation and consistency of performance.

Structural influence of cohesive mixtures of salbutamol sulphate and lactose on aerosolisation and de-agglomeration behaviour under dynamic conditions.

PURPOSE: The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutamol sulphate (SS) and micronized lactose (LH300) at ratios of SS:LH300 of 1:1, 1:2, 1:4 and 1:8 under varying air flow conditions. METHODS: Aerosolisation of particles less than 5.4µm at air flow rates from 30 to 180 l min(-1) was investigated by determining particle size distributions of the aerosolised particles using laser diffraction and fine particle fractions of SS using the twin stage impinger modified for different air flow rates using a Rotahaler(®). The de-agglomeration data were best fitted by a 3-parameter sigmoidal equation using non-linear least squares regression and characterised by the estimated parameters. RESULTS: De-agglomeration air flow rate profiles showed that SS:LH300 mixtures with increased lactose content (1:4 and 1:8) improved powder aerosolisation, but lactose had negligible effect on SS aerosolisation at the higher and lower limits of air flow rates studied. De-agglomeration flow rate profiles of SS-LH300 mixtures with increased lactose content (1:4 and 1:8) were greater than theoretically expected based on weighted individual SS and LH300 profiles. This indicated that interactions between the cohesive components led to enhanced de-agglomeration. The composition of the aerosol plume changed with air flow rate. CONCLUSION: This approach to characterising aerosolisation behaviour has significant applications in understanding powder structures and in formulation design for optimal aerosolisation properties.

The kinetics of cohesive powder de-agglomeration from three inhaler devices.

PURPOSE: The purpose of the current investigation is to understand the kinetics of de-agglomeration (k(d)) of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30-180l min(-1)) from three dry powder inhaler devices (DPIs), Rotahaler (RH), Monodose Inhaler (MI) and Handihaler (HH). RESULTS: Cumulative fine particle mass vs. time profiles were obtained from the powder concentration, emitted mass and volume percent <5.4 µm, embedded in the particle size distributions of the aerosol at specific times. The rate of de-agglomeration (k(d)), estimated from non-linear least squares modelling, increased with increasing air flow rates. The k(d)vs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The k(d) was highest from RH and lowest from MI. Differences in k(d) between the devices were related to device mode of operation while the differences between the materials were due to the powder bed structure. CONCLUSION: This approach provided a methodology to measure the rate constant for cohesive powder de-agglomeration following aerosolisation from commercial devices and an initial understanding of the influence of device, air flow rate and material on these rate constants.