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Particle Aerosolisation and Break-Up in Dry Powder Inhalers:

Evaluation and Modelling of Impaction Effects for Agglomerated


Systems
WILLIAM WONG,1 DAVID F. FLETCHER,2 DANIELA TRAINI,1 HAK-KIM CHAN,1 JOHN CRAPPER,3 PAUL M. YOUNG1
1

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

Received 18 July 2010; revised 5 January 2011; accepted 10 January 2011


Published online 1 March 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22503
ABSTRACT: This study utilised a combination of computational fluid dynamics (CFD) and
standardised entrainment tubes to investigate the influence of impaction on the break-up
and aerosol performance of a model inhalation formulation. A series of entrainment tubes,
with different impaction plate angles were designed in silico and the flow characteristics, and
particle tracks, were simulated using CFD. The apparatuses were constructed using threedimensional printing. The deposition and aerosol performance of a model agglomerate system (496.3789.2 :m agglomerates containing 3.91 :m median diameter mannitol particles)
were evaluated by chemical analysis and laser diffraction, respectively. Analysis of the mannitol recovery from the assembly and CFD simulations indicated that mass deposition on the
plate was dependent on the impactor angle (45 90 ) but independent of the airflow rate
(60140 Lmin1 ). In comparison, wall losses, perpendicular to the impactor plate were dependent on both the impactor angle and flow rate. Analysis of the particle size distribution
exiting the impactor assembly suggested mannitol aerosolisation to be independent of impactor
angle but dependent on the air velocity directly above the impactor plate. It is proposed that
particle-wall impaction results in initial agglomerate fragmentation followed by reentrainment
in the airstream above the impaction plate. Such observations have significant implications in
the design of dry powder inhaler devices. 2011 Wiley-Liss, Inc. and the American Pharmacists
Association J Pharm Sci 100:27442754, 2011
Keywords: CFD; dry powder inhaler; impaction; agglomerate; deagglomeration; aerosols; in
silico modelling; pulmonary drug delivery; simulations; particle size

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

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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.

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EVALUATION AND MODELLING OF IMPACTION EFFECTS FOR AGGLOMERATED SYSTEM

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.
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MATERIALS AND METHODS


Materials
Primary mannitol particles (spray-dried micronsized powder) were supplied by Pharmaxis Ltd.
(Sydney, New South Wales, Australia). Water was
purified by reverse osmosis (MilliQ; Millipore, Molsheim, France). All organic solvents were supplied
by Sigma (Sydney, New South Wales, Australia) and
were of at least analytical grade.
Preparation of a Model Particulate System
Model agglomerates were prepared by mixing the primary mannitol powder in a Turbula mixer (Bachofen
AG Maschinenfabrik; Basel, Switzerland), at 42 rpm
for 15 min. The mixing vessel was a custom-built
aluminium cylinder of 25 mm diameter and 26 mm
length. The agglomerated powder was post-processed
through a nest of sieves (ISO 33101 test sieves,
Endecotts Ltd.; London, UK) to produce a 500800
:m fraction. The agglomerated powders were stored
in sealed containers at 45% relative humidity and
25 C for a minimum of 48 h prior to their use.
Physical Characterisation of the Primary Mannitol
Particles and Agglomerated Systems
The primary mannitol powder and agglomerate systems were characterised in terms of particle size, morphology, density, mass, and surface area. The methods and results are reported in detail elsewhere.10
In general, the primary particle size distribution was
determined in a chloroform suspension using laser
diffraction (Malvern Mastersizer 2000; Malvern Instruments Ltd., Worcestershire, UK), whereas the agglomerate size distribution was determined in air,
using optical microscopy and image analysis (CX41
microscope; Olympus, Tokyo, Japan and ImageJ software; National Institute of Mental Health, Maryland). The density and surface area of the primary
mannitol particles was determined using helium pycnometry (Accupyc 1340 gas pycnometer; Micromeritics, Norcross, Georgia) and nitrogen adsorption
(Tristar II 3020; Micromeritics), respectively. In addition, agglomerate mass was measured using a Seven
Figure Cahn microbalance, (DVS-1; Surface Measurement Systems Ltd., London, UK). From these specific
measurements, values such as primary particle number and agglomerate density could be calculated. Ultimately, these parameters could be used in theoretical
calculation and in silico simulation.
Construction of the Impactor Assembly
The impactor apparatus was constructed using a
rapid three-dimensional prototyping technology. The
apparatus was designed to minimise the turbulence kinetic energy (TKE), to ensure a fully developed fluid flow prior to impaction and to induce
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WONG ET AL.

agglomerate impaction at a set of specific angles. In


addition, the impactor geometry was modified to enhance the probability of agglomerate impaction whilst
minimising primary mannitol (deagglomerated) particle impaction. A cone geometry, perpendicular to
the air stream, was chosen as the best impactor design because it avoided geometric issues associated
with the use of curved tubes (i.e. variations in impact angle and airflow across the cross-section of
a curved tube). Initially, a three-dimensional model
of the impactor assembly was constructed in silico,
using computer-aided design software (ANSYS Design Modeler 12.0; ANSYS, Canonsburg, Pennsylvania) and analysed using CFD simulations (ANSYS
CFX 12; ANSYS). On the basis of these CFD simulation results, the structural parameters were modified using an iterative approach in order to minimise
turbulence whilst maintaining controlled impaction.
Parameters, such as cone geometry, internal void
space, and entrance port were studied and a final series of optimised models were designed. A schematic
representation of the final design is shown in
Figure 1. In general, a 2.2 m entry port (19 mm
core diameter) ensured a fully developed airflow
prior to entry into the impaction chamber (validated
previously10 ). The flow then impinges on an impaction
plate, set at angles of 90 , 75 , 60 , and 45 to the impinging flow (note that the 90 plate is effectively a
flat plate; as shown in Fig. 1). The impaction plates
were constructed atop a 20 angle converging cone
that tapered towards the exit port. This cone was supported in the main assembly via four mounting blades
designed to minimise the disturbance in the airflow
caused by these supports.
The entire impactor assembly was constructed with
interlocking sections so that the experimental apparatus could be taken apart and washed after each experiment, allowing for stage-specific drug deposition

analysis. The entire assembly was constructed from


acrylonitrile butadiene styrene using a rapid prototype three-dimensional printer (Dimension Elite, Dimension Inc., Eden Prairie, Minnesota) and the parts
were polished using 1200 grit glass paper (FH Prager,
Sydney, New South Wales, Australia) to ensure a uniformly smooth surface throughout the apparatus.
CFD Analysis
The commercially available CFD code, ANSYS CFX12
(ANSYS), was used to simulate the flow of air at
25 C through the impactor assembly, to predict turbulence properties and to track particles, so that
their velocity and impact parameters could be obtained. To reduce computational expense, the flow
field was modelled for a 90 sector of the geometry
having symmetry boundaries on the circumferential
faces. The Reynolds-averaged NavierStokes equations were used to determine the flow field throughout
the impactor assembly and the shear stress transport
model with scalable wall functions was used to model
turbulence. A finite volume method based on a tetrahedral mesh with inflation at the walls was used to
capture the boundary layer behaviour correctly.
Mesh independence analysis was conducted to ensure that the computational results were independent
of mesh size. This was achieved by studying the axial velocity profiles across the inlet section and impaction assembly, as a function of increasing mesh
density. Mesh independence was confirmed when the
mesh size contained 1.9 105 nodes. A higher resolution mesh (containing 4.5 105 nodes) was utilised
for computational analysis. A cyclical oscillation was
observed in the position of a recirculation zone downstream from the impaction zone. However, this was
deemed to have a minimal effect on the break-up of
the particles in comparison with the impaction events.
Lagrangian particle tracking was conducted at the

Figure 1. Schematic representation of the impaction assembly (X = 90 , 75 , 60 and 45 ).


Impactor components are: (1) inlet port, (2) outlet port, (3) impactor wall, (4) impactor exit cone,
and (5) the main impactor plate.
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end of the simulation. A fixed number of particles


with a given size and density specified at the inlet
port of the venturi tube were tracked and the characteristics of particle-wall impactions were determined
by setting the venturi walls to have a zero coefficient
of restitution (allowing the location of the initial particle impact to be visualised). All calculations were
conducted at volumetric flow rates of 60, 100, and
140 Lmin1 .

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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

In-Line Aerosol Particle Size Analysis


The particle size distribution of the mannitol powder at the exit port of the impactor assembly was
measured using laser diffraction to evaluate the
break-up of the model agglomerate system at different flow rates and impaction angles. The apparatus
(Fig. 1) was mounted vertically on a scaffold with
the impaction assembly exit port connected in-line
to a Spraytec particle sizer (Malvern Instruments
Ltd.). A Gast Rotary Vane pump (Erweka GmbH,
Heusenstamm, Germany) was connected to the outlet of the particle sizer and the flow was calibrated
using a flow meter (TSI 3063; TSI instruments Ltd.,
Buckinghamshire, UK). For each measurement, 50
mg of the agglomerated powder was introduced into
the centre of the airstream at the top of the impactor
assembly using a funnel.
The geometric particle diameter distribution at the
outlet of the impactor was measured in real-time
at a data collection rate of 2500 sweeps per second
over a range of 0.1 to 2000 :m. Three volumetric
flow rates (60, 100, and 140 Lmin1 ) and four impaction angles (45 , 60 , 75 , and 90 ) were studied in triplicate. After each experiment, the impactor
assembly was deconstructed and the surfaces were
washed with purified water into separate volumetric
flasks. Mannitol concentrations recovered from each
stage of the impaction assembly were analysed using
a validated high-performance liquid chromatography
(HPLC) method and system described previously.11
In general terms, an LC20AT pump, SIL20AHT autosampler, CBM-Lite system controller with a pccomputer running LC solution v1.22 software, and
an RID-10A refractive index detector (Shimadzu,
Sydney, New South Wales, Australia) hwere utilised.
An 8 mm Resolve C18 Radial Pack chromatography cartridge (Waters Asia Ltd., Singapore) was used
for separation, at a flow rate of 1 mLmin1 . Purified water was used as the mobile phase. The
deconstructed impactor assembly consisted of five
components/stages: (1) inlet port, (2) outlet port, (3)
impactor wall, (4) impactor exit cone, and (5) main impactor plate (corresponding to the components shown
in Fig. 1). After sample recovery, each stage of the
impactor assembly was washed with ethanol and airdried prior to reassembly.
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A representative scanning electron microscope image


of the primary mannitol particles is shown in Figure 2a. It can be seen that all the particles have a
diameter less than 10 :m and are spherical in nature (presumably due to the nature of the particles
produced via spray drying of droplets). This was confirmed by laser diffraction in which analysis of the
size distribution of the primary mannitol particles
(mean of triplicates standard deviation) indicated a
lognormal distribution with 90% of the particles having a volume diameter less than and equal to 6.82
0.37 :m and 10% having less than and equal to 1.95
0.02 :m, as shown in Figure 3. The median d0.5
particle diameter of the primary particles was 3.91
0.15 :m. This value was used for theoretical calculation of the agglomerate structure as outlined in
the following section. Such observations are in good
agreement with those reported in previous studies.11
Agglomerate Properties
The agglomerate properties used in this study were
investigated extensively in a previous paper.10 A representative optical microscopy image of the mannitol
agglomerates is shown in Figure 2b. Using the ImageJ software, the particle diameter of 300 agglomerates was measured. As shown in Figure 4, analysis of
the size distribution indicated a normal distribution
that could be fitted to the following equation (R2 =
0.99):
U% = 0.3414 dp 169.4

(1)

where dp is the agglomerate diameter (:m) and U% is


the percentage undersize. Subsequently, it was calculated that the minimum and maximum agglomerate
diameters were 496.3 and 789.2 :m, respectively. In
addition, the mass of a series of agglomerates (n =
25) were measured using a Cahn microbalance and
reported as 91.1 22.1 :g. Using the median primary mannitol particle diameter, mass and density
values, it is thus possible to calculate an agglomerate
density of 655 kgm3 .
Because the purpose of this paper was to investigate the influence of agglomerate impaction on primary mannitol aerosolisation, the agglomerate size
distribution, as well as the theoretical agglomerate
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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.

density, was used to model the agglomerates in silico


for the CFD analysis of the impactor during the design
process. This ensured that 100% of the agglomerates
would impact the plate assembly for all angles.
CFD Analysis of the Impactor Assembly
Velocity streaklines and TKE distributions in the impaction assembly at a flow rate of 140 Lmin1 are
shown in Figure 5a. Analysis of the 140 Lmin1 CFD
data suggests that the approach velocities are similar to the theoretical average fluid flow velocity for a
19 mm diameter tube (8.2 ms1 ). Upon entering
the impactor assembly, the streaklines follow a path
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Figure 4. Particle size distributions of the primary 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
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specialised entrainment tubes rather than an actual


DPI device.
Velocity, TKE, and particle tracking data for each
impactor assembly (45 , 60 75 , and 90 angle plates)
at each flow rate (60, 100, and 140 Lmin1 ) were
exported from the CFD simulation. These data are
discussed in terms of the in vitro aerosolisation performance below.
Aerosolisation Performance at Exit Port
of the Impactor Assembly
The aerosolisation efficiency of the deagglomerated
mannitol particles may be described by the aerodynamic size distribution measured at the exit port
of the impactor assembly. Figures 6a and 6b show
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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

Figure 6. Particle size distribution of the mannitol


aerosol exiting the impactor assembly at (a) 60 Lmin1
and (b) 140 Lmin1 (mean values standard deviations).

size distributions of mannitol particles after passing


through the different impactor assemblies at 60 and
140 Lmin1 , respectively. Analysis of these data suggests a multimodal distribution for all data sets. The
higher value peak may be attributed to the primary
agglomerate size distribution, whereas the lower
peak corresponds to the primary mannitol particles.
The central peak, spanning from around 20100 :m
is likely to represent particle clusters, fractured from
the main agglomerate during impaction. Interestingly, there are a high percentage of agglomerates/
large-agglomerate clusters remaining after impaction
at any angle and all flow rates; however, the relative
percentages appear to be dependent on the angle and
flow rate. It is also important to note here, that the
data were represented as a conventional (pharmacopoeia) volume distribution, and thus, a weighting
towards the larger particle diameters will always exist (because one 500 :m sphere will have the same
volume as one million 5 :m spheres of equivalent
density).
In general, as the flow rate is increased for a specific angle, the percentage of particles less than and
equal to 10 :m in diameter increases (i.e. at a 90
impact angle the % of particles 10 :m increases
from 0.87 0.118% to 26.23 5.87% between 60 and
140 Lmin1 ). The effect of angle on particle break-up
appears to be dependent on flow rate. An increase in
agglomerate break-up is observed when the impact
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This study focussed on impactor-related particle


break-up, therefore, it stands to reason that significant impactor plate and internal component losses
occur due to wall deposition. To study this, the impactor assembly was carefully disassembled after
each experiment and mannitol deposition was measured using HPLC. The mannitol deposited on each
component of the impactor assembly at 60, 100, and
140 Lmin1 is shown in Figures 7a7c, respectively.
In general, particle deposition in the inlet port, cone,
and outlet port are small, with the highest deposition
being observed at 140 Lmin1 .
For example, 1.85 0.13 mg was recovered from the
inlet port at 140 Lmin1 using the 90 angle impactor
assembly. This was significantly higher than all other
flow rates and for all other angles, as it represented
around 3.7% of the loaded mannitol mass. Such observations are most likely due to the agglomerate/
particle clusters having enough residual momentum,
after ricocheting off the impactor plate, to deposit on
the inner surface of the induction port. At smaller
angles, the normal impact velocity will be lower and
agglomerate/particle reentrainment more likely. Subsequently, at higher flow rates, and for smaller angles,
an increase in outlet port deposition was observed
(e.g. 1.8% was recovered from the outlet port of the
45 angle impactor assembly at 140 Lmin1 ).
Analysis of the impaction plate and the surrounding wall suggested significantly higher mannitol deposition than for the inlet, outlet, and cone components. Furthermore, the relative deposition on either
the impactor or surrounding wall was dependent on
the impaction angle and flow rate. At high impact
angles and low flow rates (Fig. 7a), the majority of
the mannitol was found to deposit on the impaction
plate; however, as the angles approached 45 , a reduction in impactor deposition was seen with concurrent increase in wall losses. Conversely, at the
highest flow rate, both impactor and wall deposition
decreased with decreased angle (Fig. 7c).
Interestingly, the amount of mannitol deposited on
a specific angled impactor plate appeared to be independent of the flow rate (i.e. approximately 15 mg
mannitol is deposited on the 90 plate at all flow
rates). Such observations suggest that the impactor
plate may be overloaded due to the high mass of mannitol passing through the system (i.e. 50 mg).11 To
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agglomerate remaining on the impactor is due to the


nature of the impact event and the geometries of the
contacting surfaces. It is also important to consider
the total amount of mannitol retained within the device. Figure 8 shows the influence of both flow rate
and impact angle on overall mannitol retention in the
impactor assembly. As expected, an increase in impact angle and flow rate resulted in an increase in
overall impactor losses as the impact force increases.
However, analysis of the data suggests that this increase occurs on the impactor wall because mass deposits for any particular impaction angle remained
constant with respect to the flow rate.
Total and regional deposition, as well as agglomerate break-up and aerosolisation, is dependent upon three factors: (1) impact velocity
and inelastic component of momentum (agglomerate fracture/compressive forces), (2) forces imparted
by the airstream (to detach/reentrain particles), and
(3) the elastic component of the particles momentum (leading to particle bounce and reentrainment).
These factors and their relationship to the observations made here are discussed in more detail below.

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.

Figure 7. Mannitol deposition on the impactor assembly


at (a) 60, (b) 100, and (c) 140 Lmin1 (n = 3; 50 mg agglomerate samples).

test this hypothesis, the 90 impaction assembly was


tested at different agglomerate doses (5, 10, 20, 50,
and 100 mg) and the stage deposition evaluated. Analysis of the plate deposition versus agglomerate dose
over this range showed a dose-dependent response
(R2 = 0.995), suggesting the plate was not overloaded.
Subsequently, it may be concluded that the mass of
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Figure 8. A three-dimensional plot showing the influence


of flow rate and impact angle on mannitol wall loss within
the impactor assembly.
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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)

where an R2 of 0.978 was observed.


Mechanism of Break-Up and Aerosolisation

(3)

where Vi is the agglomerate velocity prior to impact


and i is the impaction angle.
Obtaining a physical value for the elastic and inelastic components of impaction of the particle momentum is difficult because neither the Youngs modulus nor the yield strength of the agglomerate and
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 7, JULY 2011

In general, analysis of the data indicate that there


is not a direct relationship between impaction plate
losses and aerosol performance, inferring that the
event is a lot more complicated than simply depending
on the impact force. Subsequently, in order to study
the process of agglomerate break-up and aerosolisation in the impactor assembly it is important to highlight the factors influencing (1) impactor deposition
DOI 10.1002/jps

EVALUATION AND MODELLING OF IMPACTION EFFECTS FOR AGGLOMERATED SYSTEM

2753

(b) particle size is dependent on the air velocity


directly above the impactor plate and not on
impact velocity.

Figure 9. d0.1 versus (a) normal impact velocity and (b)


air velocity as a function of angle and (c) angle as a function
of air velocity.

From such observations, it may be inferred that the


break-up and aerosolisation events are due to two distinct processes: bulk agglomerate fracture on impact
followed by powder dispersion and aerosolisation in
the airstream.
It is envisaged that, in this system, a critical
threshold for agglomerate fracture has been exceeded.
As such, regardless of the flow rate, particles will fracture and the difference in the amount deposited on the
plate at different angles is due to the difference in the
geometry of the plate (satisfying observations 1a and
1b above). During the collision, a significant amount
of fractured agglomerate and particulate clusters rebound into the airstream directly above the impaction
plate where they are reentrained. The velocity of the
air directly above the plate disperses the already fragmented agglomerate and the degree of aerosolisation
is directly proportional to the linear airflow velocity
(satisfying observations 2a and 2b above).
Interestingly, small variations in aerosolisation
performance with respect to impact angle at high and
low velocities were observed (see Fig. 10), and this can
be attributed to the variation in wall deposits adjacent
to the impactor plate due to secondary impaction of
lower momentum fragments (Fig. 7; satisfying observation 1c).
Previous studies using discrete element modelling
(DEM), to some extent, correlate with the experimental data described here. For example, work by Ning
et al.13 showed that lactose agglomerates (ranging
in size from 911 :m) underwent a ductile deformation upon impact, fragmenting into smaller clusters
which could be described by a damage ratio relating to
the number of broken particle contacts after impact.
Interestingly, they found that the degree of damage

and (2) aerosolisation performance, independently.


These observations are summarised below:

(1) Impactor and wall deposition:


(a) particle mass deposited on the impactor
plate is dependent on impactor angle;
(b) particle mass deposited on a specific impactor plate is independent of airflow rate;
(c) wall losses, perpendicular to the impactor
plate, are dependent on both impactor angle
and airflow rate.
(2) Aerosol performance:
(a) particle size is independent of impactor angle for a given flow rate;
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Figure 10. Percentage of particles less than 5 :m plotted


as a function of air velocity.
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2754

WONG ET AL.

was directly scalable with the impact velocity. 13,14


This group went on to show high-speed images of this
break-up process, in which the agglomerate clearly
fragmented and were deflected from the impact surface. More recently, Tong et al.15 used DEM to study
the impact of agglomerates containing 5000 monodispersed 5 :m particles (that had a similar density of
1450 kgm3 and packing density of 0.55 to those studied here). As with the study by Ning et al.13 , this group
reported a ductile transformation and the formation
of particle clusters. In addition, the group reported
that the damage ratio scaled with velocity, whereas
impact angle had little effect for angles more than 30 .
Ultimately, these simulations go some way to corroborate what is reported here; however, it is important
to note a limited number of particles were used with
confined physical parameters (such as fixed interfacial energies and narrow size distributions). More importantly, these previous models do not describe the
dynamic event of aerosolisation directly above the impactor plate. These should be considered in future
studies.

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

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 7, JULY 2011

those of the authors and are not necessarily those of


the Australian Research Council.

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