Beruflich Dokumente
Kultur Dokumente
Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia
School of Chemical and Biomolecular Engineering, University of Sydney, Sydney, New South Wales 2006, Australia
Pharmaxis Ltd., Unit 2, Frenchs Forest, Sydney, New South Wales 2086, Australia
INTRODUCTION
The delivery of dry powder particulates to the respiratory tract, for the treatment of local and systemic
disease states, requires the primary drug particles
to have an aerodynamic diameter less than approximately 5 :m.1 Although, there are many formulation
variables available to achieve adequate levels of drug
delivery to the lung, two are regarded as primary formulation methods: carrier-based and agglomerationbased systems.2 These methods are used to ensure
efficient entrainment of the active pharmaceutical
Correspondence to: Paul M. Young (Telephone: +61-2-90367035; Fax: +61-2-9351-4391; E-mail: py@pharm.usyd.edu.au)
Journal of Pharmaceutical Sciences, Vol. 100, 27442754 (2011)
2011 Wiley-Liss, Inc. and the American Pharmacists Association
2744
ingredient (API) into the airstream, whilst providing a means of sample dilution (when small microgram range of doses are required). Despite these approaches, conventional dry powder inhalation (DPI)
formulations have relatively low aerosol efficiencies,
with fine particle fractions (i.e. the percentage dose
of API with an aerodynamic diameter suitable for inhalation therapy) of less than 30% being observed
regularly.3 The reason for such poor performance is
due to the high surface area-to-mass ratios of the
API drug particles, inducing high cohesiveadhesive
forces between contiguous surfaces within the formulation. Subsequently, significant research has been
undertaken at both the fundamental and empirical
level to understand the complex processes driving
particle deagglomeration and aerosolisation.
There are many DPI devices on the market or under development, employing different approaches to
disperse the micron-sized API.35 Interestingly, little
research has been conducted to study the exact mechanism of break-up and in general these systems are
optimised through performance modification and empirical study design. Furthermore, where fundamental studies have been conducted, they have generally
focussed on the aerosolisation of micron-sized drug
particles from carrier-based formulations68 rather
than the break-up of agglomerate-based systems, containing micron-sized primary particles.
The investigation of the underlying mechanisms
behind the dispersion of dry powders usually involved
the use of entrainment tubes incorporating deagglomeration apparatuses. Although in some cases agglomerate systems have been studied using this approach,9
most of these studies have been cross-disciplinary
(e.g. in the printing or minerals industry); as such,
there is a large variation in the materials and particle
size distributions studied. The very different physical
mechanisms acting in these applications from those
important in the application of interest here limit the
relevance of such studies.
In order to study the aerosolisation process in
agglomerate-based DPI systems, the authors have
undertaken a series of studies to evaluate how
a standard formulation behaves with respect to
specific deagglomeration mechanisms (i.e. airflow,
turbulence, impaction, etc.) etc.). In a previous
study, the authors utilised a combination of computational fluid dynamics (CFD) and experimental
entrainment tube measurements to study the breakup and aerosolisation of a model agglomerate system (containing micron-sized mannitol particles) as
a function of airflow and turbulence variables.10
The study design utilised a series of venturi tubes
to induce turbulent flow with characteristics equivalent to commercial DPI devices, while minimising other potential break-up mechanisms (such as
wall or grid impaction). Interestingly, however, although this study focussed on the effect of turbulence on agglomerate break-up, the small amount
of impaction, which inevitably occurred in the venturi assembly as the core diameter was reduced
and the air velocity increased, appeared to dominate
agglomerate break-up.10
To further investigate the mechanism of breakup and aerosolisation in agglomerate-based DPI systems, the influence of impaction angle and speed
were studied. A series of entrainment tubes containing different impaction plates are designed and
their flow behaviour was evaluated using CFD
analysis, and subsequently compared with physical aerosol and deposition measurements to ascertain the influence of impaction on the aerosolisation
mechanism.
DOI 10.1002/jps
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WONG ET AL.
DOI 10.1002/jps
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Statistical Analysis
One-way ANOVA analysis (with Tukeys post hoc
analysis) was used to test significance. A difference
was considered significant when p was less than 0.05.
The commercial statistical software package, SPSS
Statistics 17.0 (SPSS Inc., Chicago, Illinois) was used.
RESULTS
Primary Mannitol Particle Properties
(1)
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WONG ET AL.
Figure 3. Particle size distributions of the primary mannitol particles. The solid line shows the volumetric diameter
distribution.
around the main impactor plate and a concurrent decrease in velocity was observed, due to the increase
in cross-sectional area, before acceleration at the exit
port. Interestingly, a small recirculation zone was observed in the peripheral void space above the impaction plate; however, the relative velocities were
low. Analysis of the TKE indicated that effect of turbulence in the impactor assembly on particle breakup could be eliminated because the average TKE values were lower than those observed in the 19 mm
diameter entrance port, in which previous studies
had indicated no significant effect on d0.1 (only 1.4
0.4% particles 10 :m at 140 Lmin1 ; Ref.10 ).
Figure 5b shows particle tracking data for a representative sample of 5 :m particles (n = 500; density
= 1435 kgm3 ), whereas the insert shows particle
tracking for the agglomerates (n = 500; density = 786
kgm3 with size distribution as given in Eq. 1). Analysis of the data showed that all of the agglomerates
Figure 2. (a) Scanning electron microscope images of the
primary mannitol particles and (b) an optical microscope
image of the mannitol agglomerates.
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Figure 5. (a) Turbulence kinetic energy (contour plot) and (streakline plot). (b) Particle tracking for 10 :m particles (agglomerate tracking shown in inset). Examples are shown for the 60
impaction plate at 140 Lmin1 .
impacted the plate, irrespective of impact plate angle. In comparison, the particle tracking of approximately 5 :m primary mannitol particles indicated
impaction efficiencies less than and equal to 10%, suggesting that deagglomerated primary particles would
pass through the impactor assembly.
Pressure drop across the impactor assemblies
ranged from 246.2 Pa for the 90 assembly at
140 Lmin1 to 53.8 Pa for the 45 assembly at 90
Lmin1 . This is significantly lower than the 4 kPa
specified in pharmacopoeia methodology for the testing of DPIs; however, it is important to note that the
aim of this study was to investigate the influence of
impaction forces on the break-up and aerosolisation
in agglomerate-based DPI systems through the use of
DOI 10.1002/jps
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WONG ET AL.
angle is decreased (i.e. 45 ) at low flow rates; however, conversely, particle break-up increased at high
flow rates and high angles (i.e. 90 ). Such observations, however, need to be put in context with respect
to mannitol retention within the impactor assembly
(because particle bounce and reentrainment may be
a dominating factor in this system).
Mannitol Deposition in the Impactor Assembly
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DISCUSSION
Agglomerate Impaction, Break-Up, and Reentrainment
In order to understand the process of agglomerate
break-up and powder aerosolisation, it is important
to consider the forces acting within the system during the impact event and to relate these to impactor
deposition and aerosol performance at the exit port of
the assembly.
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WONG ET AL.
Momentum at Impaction
Because the particle mass and velocity are known, it
is possible to calculate the maximum momentum ( p)
carried by each agglomerate upon impaction (where
p = mass velocity). Using the minimum and maximum agglomerate diameters (496.3 and 789.2 :m, respectively), and a theoretical agglomerate density of
655 kgm3 , the momentum at 9.88 ms1 (equivalent
to the impact velocity on a 90 plate at 140 Lmin1 )
will be between 0.4 and 1.7 :Ns. Similarly, at
60 Lmin1 (5.77 ms1 ) the momentum will be between 0.2 and 1.0 :Ns. For 75 , 60 , and 45 plate,
the linear momentum is equivalent to that of the 90
plate; however, the force encountered during the impaction event will depend upon the impact angle and
normal component of agglomerate momentum.
Reentrainment Forces
Reentrainment of primary drug particles, particle
fragments, and unbroken agglomerates will be dependent upon the nature of the impaction event (i.e.
whether it is inelastic or elastic) and the adhesion between the agglomerate components and the plate surface. Assuming an inelastic collision event, the force
required to reentrain impacted particles in the air
stream (Fair ) will increase as the impaction angle becomes perpendicular to the airflow (i.e. approaches
90 ; Eq. 2):12
Fair =
f Fad
cos 2 f sin 2
(2)
where f is the coefficient of friction, Fad is the adhesion force, and is the angle of the impinging air
stream.
It is also important to note that simultaneously
there will be an elastic component to the collision,
resulting in particle bounce and reentrainment above
the impactor surface. It is expected that the elastic
response would increase as the impact angle increases
because the normal component of velocity must be
taken into consideration.
Whilst the agglomerate particle velocity in the air
stream prior to impact may be calculated using Lagrangian particle tracking, the normal impact velocity
(VN ) can be calculated from Eq. 3:
B 2i
VN = Vi sin
180
primary particles can be measured (allowing prediction of the elastic and inelastic components relating
to the conservation of momentum). Also, because the
inelastic deformation component is not known, it is
not possible to predict the contact area and thus Fad .
However, the relationships between momentum or
impaction velocity and agglomerate break-up may be
studied.
Relationship Between Impaction/Flow Parameters and
Agglomerate Aerosolisation
The relationship between normalised (impaction) airflow or linear airflow (above the impaction plate) and
the 10th percentile particle diameter (d0.1 ), as a function of impaction angle is given in Figures 9a and 9b.
Furthermore, the relationship between the d0.1 and
impact angle as a function of linear airflow is given in
Figure 9c.
From Figure 9 it can be seen that a decrease in
the d0.1 is observed as both impact and air velocity
are increased, indicating more efficient agglomerate
break-up and primary particle aerosolisation. Interestingly, however, analysis of the normalised impact
velocity data indicates that there is not a direct relationship between angle of impact and d0.1 (Fig. 9a).
For example, the d0.1 for the 45 angle plate at an impact velocity of 4 ms1 is not significantly different
than the d0.1 for the 90 plate at an impact velocity of
7 ms1 . Furthermore, when plotting the airflow rate
(directly above the impaction plate) as a function of
d0.1 (Fig. 9b) or the d0.1 as a function of impact angle
(Fig. 9c), no change in particle break-up is observed as
angle is increased for any specific linear flow velocity.
Conversely, the direct relationship between the linear air velocities directly above the impaction plate is
and d0.1 was observed to be independent of angle. This
is further exemplified in Figure 10 when the percentage of particles less than and equal to 5 :m is plotted
as a function of air velocity above the plate. Analysis
of the data for all impaction plates at all flow velocities indicated an exponential relationship between
velocity (v; ms1 ) and percentage of particles less
than and equal to 5 :m, as shown in Eq. 4:
% 5:m = 0.0205 e0.6936v
(4)
(3)
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WONG ET AL.
CONCLUSIONS
This study focussed on the influence of impaction geometry effects on the aerosolisation and break-up of
pharmaceutical agglomerates for inhalation. The impaction assemblies were designed to minimise other
potential powder deagglomeration mechanisms (such
as turbulence), and the influence of velocity and impaction was studied. It appears that for agglomerated inhalation powders, particle-wall impaction results in initial agglomerate fragmentation followed
by deagglomeration in the airstream above the impaction plate. Direct visualisation of this event, as
well as the evaluation of turbulent aerosolisation, after impaction will be considered in further studies.
ACKNOWLEDGMENTS
This research was supported by the Australian Research Councils Linkage Projects funding scheme
(project LP0776892). The views expressed herein are
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