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

https://doi.org/10.1016/j.ijpharm.2011.09.024Get rights and content

Abstract

Purpose

The purpose of the current investigation is to understand the kinetics of de-agglomeration (kd) of micronised salbutamol sulphate (SS) and lactohale 300 (LH300) under varying air flow rates (30–180 l 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 (kd), estimated from non-linear least squares modelling, increased with increasing air flow rates. The kd vs. air flow rate profiles of SS and LH300 were significantly different at high air flow rates. The kd was highest from RH and lowest from MI. Differences in kd 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.

Introduction

The regulatory concern on ozone depleting effect of chlorofluorocarbons used in pressurized metered dose inhalers has accelerated the development of dry powder inhalation technology. The key challenge in dry powder inhalation is to generate fine particles which can deposit in the lower respiratory tract. However, these micronised fine particles are cohesive because the magnitude of gravitational forces is much less than interactive forces (Visser, 1989). In order to improve the de-agglomeration efficiencies in powders for inhalation, consideration needs to be given to factors relating both to the cohesive powder structure and to the device design.

The cohesive powder tensile strength is defined by its particle size, work of cohesion or adhesion and packing fraction (Kendall and Stainton, 2001). As the extent of de-agglomeration is related to tensile strength, aerosolisation of cohesive powders for inhalation can be manipulated by optimising work of cohesion/adhesion and packing fraction, since the particle size is fixed by functionality. The de-agglomeration behaviour of powders will therefore be determined by the structure of the powder including the distribution of particle size, particle interactions and packing fractions in the powder bed. Such behaviour has recently been seen in a study (Behara et al., 2011c) on single component systems [salbutamol sulphate (SS) and lactohale 300 (LH300)] and binary mixtures of SS and LH300 (Behara et al., 2011b). Powders (Behara et al., 2011c) were aerosolised using Rotahaler® (RH) over a range of air flow rates (30–180 l min−1) to construct relative de-agglomeration vs. air flow rate profiles. These profiles were modelled to estimate sigmoidal parameter to characterise cohesive powders. The relative de-agglomeration increased with increases in air flow rate for SS over the whole air flow rate range, while no significant increase in de-agglomeration was observed from 90 to 180 l min−1 with LH300. The powder micro-structure determined the de-agglomeration behaviour and this approach was able to distinguish between powders with dispersible and non-dispersible agglomerates.

Device related de-agglomeration will be associated with the cohesive powder–capsule processes and with the cohesive powder–device interactions. Recent studies demonstrated that the de-agglomeration associated with the capsule depended on capsule aperture size (Coates et al., 2005b, Chew et al., 2002) and de-agglomeration associated with the device design will depend on grid structure (Coates et al., 2004b), mouth piece length (Coates et al., 2004b), air inlet size (Coates et al., 2006) and resistance of the device (Srichana et al., 1998, Steckel and Muller, 1997).

The studies on the role of capsules on powder inhaler performance [Aerolizer® (AL)] (Coates et al., 2005b) demonstrated increased in vitro performance with decreased size of the capsule aperture using size 3 capsule. In addition, the study demonstrated that the in vitro performance primarily depended on the size of the capsule aperture rather than the total aperture area. Decrease in capsule aperture size led to increased shear on the agglomerates, where smaller apertures prevented larger agglomerates from escaping (Coates et al., 2005b) resulting in higher in vitro performance. The study by Coates et al. (2005b) were with a single inhaler device, AL which has similar device design (except inhalation port length and capsule aperture area) and mechanism of fluidization to that of Monodose Inhaler® (MI). A comparative study between devices (Chew et al., 2002), RH and Dinkihaler® (DH) (similar mechanism of fluidization as MI) concluded that the higher in vitro performance of DH at a given air flow was due to its greater resistance and higher pressure drop compared to RH. The in vitro performance vs. aerosolisation energy profiles showed that the higher in vitro performance of DH compared to RH at the same aerosolisation energy was due to enhanced collisions of the powder within DH caused by tangential air entrainment (Chew et al., 2002).

The effect of grid structure on the in vitro performance of AL at 60 l min−1 was studied using three different grid structures (Coates et al., 2004b). The study demonstrated that the in vitro performance referenced to the loaded dose decreased with increase in grid voidage. However, increased grid voidage increased powder retention in the device especially around the mouth piece. This study concluded that in vitro performance was related to the balance between particle-grid impactions causing de-agglomeration and particle-mouth piece impactions causing retention. In a comparative study between RH and AL at 60 l min−1, with and without grids (Coates et al., 2004a), the presence/absence of grid had no effect on overall turbulent kinetic energies. However, the study demonstrated higher in vitro performance of AL compared to RH with and without the grid as a result of higher turbulent kinetic energy of the former. This outcome was also supported by investigation of Voss and Finlay (2002) where it was reported that the turbulence may be one of the effective de-agglomeration mechanisms and that the mechanical impaction on the rig was less significant. However, the previous study (Coates et al., 2004a) concluded that the improved de-agglomeration of grid case compared to no-grid case was due to mechanical impaction of agglomerates on the grid. Therefore both the turbulent kinetic energy and mechanical impactions are likely to contribute to powder de-agglomeration.

The effect of the length of inhaler mouth piece (Coates et al., 2004b) 0.5 and 0.75 of original length and original inhaler mouth piece length was evaluated for the powders aerosolised at 60 l min−1 using AL. The decrease in mouth piece length decreased the device powder retention. However, the in vitro performance (referenced against loaded and emitted doses) was least affected by inhaler mouth piece length due to similar levels of turbulence.

The air inlet size role on in vitro performance of AL between 30 and 90 l min−1 was investigated (Coates et al., 2006). This study used full air inlet size of AL along with and 0.33 and 0.67 of full air inlet sizes leading to device resistances of 0.072, 0.100 and 0.148 (cmH2O)1/2 (l min−1)−1 respectively. The increased resistance increased in vitro performance of the device only at low air flow rate (30 l min−1). Similar findings were demonstrated by Srichana et al. (1998) in testing formulations with dry powder inhalers having low, medium and high resistances between 30 and 90 l min−1 where the in vitro performance depended on device resistance only at low air flow rates. Further testing of the effect of air inlet size (Coates et al., 2006) at higher air flow rates resulted in either statistically insignificant or reduced in vitro performance. Decreasing air inlet size increased flow development time (time to develop specified air flow rate) and therefore the authors (Coates et al., 2006) demonstrated that large fraction of powder exited from the device prior to full flow and therefore a minimum fraction of the powder experienced the maximum turbulence levels leading to reduction in in vitro performance at higher air flow rates.

The studies described provided valuable insight into the impact of powder structure and device design on in vitro performance. It is not possible to define the major causes of powder de-agglomeration in a device, although the capsule aperture size has been shown to be important (Chew et al., 2002, Coates et al., 2005b). The outcomes of the studies described above provided an overview of the in vitro performance of a device in response to changing design parameters over the total powder emptying time. While these outcomes were important and help to understand the aerosolisation behaviour, the kinetics of cohesive powder behaviour may provide further insights into aerosolisation processes. Although, there were studies focusing on kinetics of de-agglomeration, they related to (a) de-agglomeration of particles in suspensions (Ding and Pacek, 2008), (b) non-cohesive particles of size range 250–1000 μm (De Villiers, 1997) or (c) carrier based dry powder formulation and focused on drug detachment from carrier surface (De Boer et al., 2004).

A recent study (Behara et al., 2011a) investigated the kinetics of emitted mass of single components (SS and LH300) by making use of laser diffraction particle sizing to compare three successful commercial devices of different designs and resistances of low (RH), medium (MI) and high [Handihaler® (HH)] (Clark and Hollingworth, 1993). The proposed study builds on this approach and examines the rate of de-agglomeration over the whole aerosolisation time for the three different devices above. The major purposes of this study were to develop a methodology for determining de-agglomeration vs. time profiles and to apply a numerical approach to estimate de-agglomeration rate constants. The study used SS and LH300 as model cohesive materials.

Section snippets

Materials

The materials used in the current investigation were SS (Combrex Profarmaco, Milan, Italy) and LH300 (Borculoingredientsdomo, Borculo, The Netherlands). The volume median diameters (n = 6; mean ± sd) as determined by MasterSizer S were 3.4 ± 0.2 μm and 4.1 ± 0.1 μm respectively for SS and LH300. The primary size distributions of SS and LH300 are presented elsewhere (Behara et al., 2011c). RH (GSK, Middlesex, UK) and HH (Boehringer Ingelheim, Germany) were bought from a local pharmacy and MI was a kind

Particle size distributions of the aerosolised plume at various flow rates using different inhalers

The influence of air flow rate on the aerosolisation of micronised SS and LH300 was determined to measure the mean particle size distribution of the aerosolised plume from the three devices over the full aerosolisation time. In this manuscript, LH300 was used in the figures to illustrate specific behaviours; however, data for both LH300 and SS are summarised in tables and in the summary figures describing kinetic behaviour. The typical variability in the frequency vs. size distribution of the

Conclusions

The study has developed a robust methodology to measure the kinetics of de-agglomeration during aerosolisation of cohesive powders from commercial inhaler devices. Cumulative fine particle mass vs. time profiles were obtained from the powder concentration, emitted mass and volume percent <5.4 μm, data which were embedded in the particle size distributions of the aerosol at specific times. Comparative cumulative de-agglomeration vs. time profiles showed exponential increases in de-agglomeration

Acknowledgements

Srinivas Ravindra Babu Behara is a recipient of Monash International Postgraduate Research Scholarship and Monash Research Graduate Scholarship. The authors would extend their thanks to Advent Pharmaceuticals Pty Ltd., BorculoIngredientsDomo and Capsugel for supplying salbutamol sulphate, lactohale 300 and gelatine capsules respectively and NanoMaterial Technology Pte Ltd., Singapore for providing MIs.

References (28)

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