Review

The use of computational fluid

dynamics in inhaler design
Conor A Ruzycki, Emadeddin Javaheri & Warren H Finlay†
1. Introduction University of Alberta, Department of Mechanical Engineering, Edmonton, Alberta, Canada

2. CFD modeling of
Introduction: Computational fluid dynamics (CFD) has recently seen increased
pharmaceutical aerosol
use in the design of pharmaceutical inhalers. The use of CFD in the design of
dispersion
inhalers is made difficult by the complex nature of aerosol generation. At
3. Pressurized present, CFD has provided valuable insight into certain aspects of inhaler
metered-dose inhalers performance, though limitations in computational power have prevented
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4. Nebulizers the full implementation of numerical methods in the design of inhalers.

5. Dry powder inhalers Areas covered: This review examines the application of CFD in the design of
6. Other aerosol delivery systems aerosol drug delivery technologies with a focus on pressurized metered-
dose inhalers (pMDI), nebulizers and dry powder inhalers (DPIs). Challenges
7. Conclusions
associated with the application of CFD in inhaler design are discussed along
8. Expert opinion with relevant investigations in the literature. Discussions of discrete element
modeling (DEM) and the simulation of pharmaceutical aerosol dispersion
are included.
Expert opinion: The extreme complexity of coupled fluid and aerosol
dynamics associated with aerosol generation has somewhat limited the use
of CFD in inhaler design. Combined CFD–DEM simulations provide a useful
For personal use only.

tool in the design of DPIs, though aerosol generation in pMDIs and

nebulizers has eluded CFD modeling. The most beneficial use of CFD typically
occurs when concurrent CFD and experimental analyses are performed,
significantly enhancing the knowledge provided by experiment alone.

Keywords: deagglomeration, discrete element modeling, dry powder inhaler, in silico modeling,
nebulizer, pharmaceutical aerosol dispersion, pressurized metered-dose inhaler, respiratory drug
delivery, simulation

Expert Opin. Drug Deliv. (2013) 10(3):307-323

1. Introduction

Computational fluid dynamics (CFD) has been used extensively in many branches
of science and engineering in the analysis of fluid flows. CFD provides an invaluable
tool in investigating a multitude of topics ranging from aircraft design to Earth
climate systems, and aerosol drug delivery devices are no exception. As a general
description, CFD is a technique in which the dynamic equations governing fluid
motion are solved numerically over a physical region of interest. The nature of
pharmaceutical aerosol drug delivery, being grounded in fluid dynamics, is well
suited for analysis using CFD.
For aerosol drug delivery, the most complete CFD model possible would calcu-
late the governing continuity, momentum and energy equations for the continuous
air phase and couple these with equations governing the discrete aerosolized drug
phase through all possible turbulence scales, ranging from macroscopic length scales
of flows to Kolmogorov microscales [1-4]. While this method of direct numerical
simulation (DNS) is the most accurate numerical approach, the associated compu-
tational costs are prohibitive, preventing the use of DNS in practical engineering
applications [3-5]. In practical applications to inhaler design, most CFD methods
solve the Reynolds-averaged Navier--Stokes (RANS) equations, which are time-
averaged versions of the actual governing equations. Time averaging introduces

10.1517/17425247.2013.753053 © 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 307
All rights reserved: reproduction in whole or in part not permitted
 C. A. Ruzycki et al.
Article highlights.
. CFD has recently seen increased use in the design of
inhalers for therapeutic drug delivery into the
respiratory tract.
. Random walk methods provide a useful tool for
modeling the dispersion of pharmaceutical aerosols,
though care is required in applying these methods in
situations where high accuracy is desired.
. The application of CFD to inhaler design is complicated
by the complex nature of aerosol formation in
pharmaceutical aerosol delivery technologies, including
pMDIs, nebulizers and DPIs.
. Insights into certain aspects of pMDI and nebulizer
performance have been gained through CFD, but
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Victoria on 04/15/13
models describing the entire process of aerosol
generation in these devices have yet to be developed.
. Recently developed coupled CFD--DEM models provide
an improved method for studying deagglomeration
mechanisms in DPIs compared with traditional
CFD methods.
. CFD, used concurrently with in vitro analyses,
complements and significantly enhances knowledge
provided by experiment alone.
This box summarizes key points contained in the article.
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additional terms in the equations, the closure of which neces-
sitate the use of turbulence models. Various turbulence
models are available, each suited for difference situations.
RANS approaches are relatively simple, computationally
inexpensive and allow for various simplifications. As such,
RANS CFD codes have been developed and tailored for a
wide range of flow conditions. However, time-averaging
incurs a loss of information, and turbulence models can
become inaccurate in certain situations [6,7]. Many of the
issues observed with RANS modeling can be mitigated using
large eddy simulation (LES), in which only small-scale turbu-
lent eddies are modeled. Time variations in large eddies are
calculated from the governing equations. LES has demon-
strated increased accuracy compared with RANS models
in predicting aerosol deposition [8,9], though unfortunately
this gain in accuracy comes at a significant increase in
computational requirements.
The above constitutes an exceptionally brief summary of
CFD; the literature on CFD theory and application is exten-
sive, and a number of texts [10-13] and best practice guides [14,15]
are available for the interested readers. To date, most applica-
tions of CFD in inhaler design have used RANS methods
in commercial CFD software such as ANSYS FLUENT,
ANSYS CFX, CD-ADAPCO STAR-CCM+, CFD-ACE+
or the freely available open source software, OpenFOAM.
Recent reviews by Longest and Holbrook [16] and Wong
et al. [17] cover the considerable amount of work performed
on in silico modeling of aerosol delivery to the respiratory tract
and the use of various computational approaches in inhaler
development. The focus of the present work lies on the use
of CFD in inhaler design, in which the application of
308 Expert Opin. Drug Deliv. (2013) 10(3)
computational methods has been relatively limited. Methods
behind modeling the dispersion of pharmaceutical aerosols
are first reviewed to identify important considerations in
the application of CFD when simulating aerosol transport
and deposition. The use of CFD in commonly used aerosol
drug delivery technologies, including pressurized metered-
dose inhalers (pMDIs), nebulizers and dry powder inhalers
(DPIs), is then discussed. For each of these devices, the
challenges associated with computational modeling are con-
sidered, followed by a review and summary of relevant CFD
investigations in the literature. The present state and applica-
bility of CFD in the design of these devices is then established
from these analyses.
2.CFD modeling of pharmaceutical aerosol
dispersion
The dispersion and deposition of pharmaceutical aerosols in
turbulent airflow is an important consideration when numeri-
cally investigating inhaler performance. Prior to discussing the
specifics of CFD in inhaler design, it is useful to examine the
techniques used in modeling these aspects of pharmaceutical
aerosols. Pharmaceutical aerosols are examples of multiphase
flows, consisting of a continuous phase (inhaled air) and a
discrete drug phase (particles or droplets containing an active
therapeutic agent). The behavior of the continuous phase can
be predicted numerically using the Navier--Stokes equations
governing fluid physics, which are well documented in the
CFD literature [10-13]. Of special importance in the application
of CFD in modeling pharmaceutical aerosols are the techniques
used in predicting the behavior of the dispersed drug phase.
Modeling the transport and deposition of the dispersed drug
phase can be achieved using either Eulerian or Lagrangian
approaches [18]. In the Eulerian approach, the dispersed drug
phase is regarded as a continuum, and the transport equations
for conservation of mass and momentum are considered for
both the fluid and particle phases [18]. Alternatively, the
Lagrangian approach treats the fluid phase as a continuum
and the drug phase as individual parcels of particles. Solving
the equations of motion for these parcels, representative of a
number of similar particles, allows for the simulation of
trajectories through the fluid phase [18-20].
The Lagrangian approach to particle transport has been
more commonly used than the Eulerian approach for aerosols
with particle sizes typical of inhalers. This is because the con-
siderable inertia of such particles, which is particle size-
dependent and is a primary determinant of wall deposition,
complicates an Eulerian treatment for the turbulent flows
expected within inhalers. While progress has been made in
Eulerian modeling of turbulent dispersed phase flows with
significant particle inertia (see, e.g., Refs. [21,22]), the natural
ability of Lagrangian models to handle particle inertia
and wall collisions makes them attractive for simulation of
inhaler aerosols, despite their higher computational expense
compared to an Eulerian approach.

In both approaches, the main interest lies in the behavior of
particles in a turbulent flow. In dilute suspensions, where the
particle volume fraction is sufficiently low, particle--particle
interactions and the influence of particles on the fluid are
negligible, allowing for one-way coupling between phases [23].
This is typically the case for micrometer-sized drug particles
in turbulent airflow, and as such a one-way coupled
Lagrangian approach in modeling pharmaceutical aerosols is
widely accepted.
To determine particle trajectories in a Lagrangian
approach, the equations of motion describing the influence
of forces exerted on particles must be solved. Viscous drag is
the dominant force exerted on micrometer-sized particles,
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provided the particle density (rp) is much larger than the
surrounding fluid density (rf) [24,25]. In this case, the equation
of motion for a particle with velocity up in a fluid with
velocity uf simplifies to:
= − (u p − uf )
dup 1
τ
dt
where t is the particle relaxation time. Wall collisions, and
possibly particle bounce, occur when particle trajectories
intercept walls and are easily handled (in contrast to an
Eulerian approach where such effects must be treated via
For personal use only.
artificial boundary conditions). The largest challenge in
simulating particle trajectories lies in modeling fluid velocity
fluctuations encountered along particle paths [2], which is an
inherently stochastic problem.
The aforementioned velocity fluctuations that complicate
particle trajectory predictions can be modeled using one of
two approaches, involving either discrete random walk or
continuous random walk. In discrete random walk, individual
neous fluid velocity fluctuation uf′ is chosen randomly at the
eddy--particle interactions are considered [26,27]. The instanta-
beginning of a particle--eddy interaction as:
uf′ = ufrms N
where is the root mean square of the fluid velocity and N, the
stochastic component, is a random Gaussian number with
mean 0 and standard deviation 1. Normally, only the first
two statistical moments of the random fluctuations are
known. During interactions, N is held constant, while
ufrms is allowed to vary. The time over which particle--eddy
interactions occur is referred to as the Lagrangian integral
time scale. The second method for modeling velocity fluctua-
tions, continuous random walk, is based on the Langevin
equation [28-31], which is a stochastic linear first-order
differential equation initially developed for describing
Brownian motion [32]. Here, evolution of the fluid velocity
is described by:
duf′ u′
= − f +ξ
dt TL
where j is a random velocity increment and TL is the Lagrangian
integral time scale during which fluid particle motion remains
Expert Opin. Drug Deliv. (2013) 10(3)
The use of computational fluid dynamics in inhaler design
consistent. Solving the Langevin equation requires the deter-
mination of the statistical moments of j, which becomes
increasingly difficult in flows exhibiting strong inhomogeneous
turbulence [30].
Compared with continuous random walk, discrete random
walk is more widely accepted, and is typically implemented in
commercial flow simulation software. Discrete random walk
has been applied in investigations of capillary aerosol genera-
tion (CAG) systems [33], spray aerosol burst effects [34] and
deposition in the Respimat
inhaler [35]. However, when
turbulence is anisotropic and discrete random walk is com-
bined with two-equation turbulent models (e.g., k-e or
k-w), near-wall fluctuating velocity modifications are needed
to prevent overestimation of deposition [7,36]. Ilie et al.
employed a ‘frozen’ LES scheme that gave good agreement
with experimental deposition in an idealized mouth geome-
try, and captured relevant flow features that standard RANS
plus discrete random walk without near-wall corrections
could not reproduce [37]. In ‘frozen’ LES, a LES simulation
is first performed for the fluid flow without particles. Particle
trajectories are subsequently calculated using only the instan-
taneous velocity field at one point in time (a ‘frozen’ flow
field), treating the ‘frozen’ flow field as steady state. While
frozen LES can provide an improvement in computational
requirement compared with dynamic LES [37] (in which
groups of particles are released at different time steps
and tracked over time), LES simulations generally incur
considerable computational expense. With this in mind,
Ilie et al. suggested that a more practical approach than LES
was to use a RANS plus discrete random walk model with
accurate near-wall corrections [37].
Further issues are associated with turbulence. In most
pharmaceutical aerosol applications, turbulent fields are wall
bounded and inhomogeneous. Two major challenges arise
when applying random walk methods (both continuous and
discrete) to these cases. First, accurate determination of the
Lagrangian integral time scale (TL) for inhomogeneous turbu-
lence, particularly in near-wall regions, remains a point of
controversy [38,39]. Second, practical limitations mean that
all the statistical moments of j in the Langevin equation
and in the particle--eddy interaction formulation cannot be
specified, meaning random walk methods are approximate
by nature [30,40]. However, the level of detail required to accu-
rately apply random walk methods is highly situational [30,40].
When simulating deposition, knowing the moments of the
random terms and TL in wall distances on the order of
magnitude of particle size is important. In contrast, when
modeling only the dispersion of particles (ignoring deposi-
tion) such near-wall details are not necessary. For many
applications, and j are conventionally assumed, without
solid mathematical reasoning, to be Gaussian random varia-
bles [26,41]. The degree of uncertainty that stems from this
assumption depends on the characteristics of the turbulent
field [30]. With these considerations in mind, random walk
methods can produce physically sensible results in many
309
 C. A. Ruzycki et al.
applications, thus providing additional insight into the
dispersion of pharmaceutical aerosols. As a cautionary note,
however, the results of random walk methods should be
examined carefully in situations where high accuracy
is desired.
2.1Computational models for pharmaceutical
aerosols
The analytical techniques discussed in the previous section
form the basis for numerical modeling using CFD. For
multiphase flow systems, CFD codes solve the equations
governing fluid and particle behavior in a systematic manner,
a process described in great detail in the literature [42]. As an
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extremely brief summary, first a mesh (or grid) is generated
that subdivides the overall flow domain into a number of
non-overlapping cells. Second, the governing equations are
transformed into a system of algebraic equations using discre-
tization techniques such as the finite volume method. Finally,
specific numerical techniques are used to solve the discretized
equations across the mesh representing the flow domain. As
described in the introduction, a number of well-developed
commercial CFD codes are available that can be applied to
pharmaceutical aerosol modeling. However, traditional CFD
does carry some limitations. Where traditional CFD methods
For personal use only.
fail to accurately account for particle--particle and particle--
wall interactions, discrete element modeling (DEM) more
accurately models these aspects of particle dynamics.
Wong et al. [17] recently reviewed the use of coupled
CFD--DEM models in inhaler developments. In these
approaches, the continuous phase and discrete particle phase
are modeled using CFD and DEM, respectively [43]. Coupling
can be either one-way, in which the influence of the fluid
phase on particles is considered, or two-way, in which both
the influence of the fluid phase on particles and the influence
of particles on the fluid phase are considered. CFD--DEM
methods are now increasingly used in the analysis of DPIs,
as discussed in Section 5.2.
3. Pressurized metered-dose inhalers
CFD modeling of the formation and delivery of pharmaceu-
tical aerosols from pMDIs incurs several inherent challenges.
From a basic physical perspective, pMDI actuation involves a
transient, cavitating, turbulent fluid that flashes into rapidly
evaporating droplets. The physics of this process is extremely
complex, involving turbulent and compressible flows, multiple
phases, heat transfer and evaporation and condensation [44-46].
Furthermore, some of these phenomena, such as the effect of
turbulence on cavitation, remain poorly understood [44]. The
combination of complex physical processes, transient effects,
small length and time scales and limited knowledge of initial
conditions all complicate the notion of CFD modeling of
pMDI aerosol formation and delivery. Perhaps as a result of
these complications, there have been relatively few CFD studies
performed on pMDI inhalers, especially on the process of
310 Expert Opin. Drug Deliv. (2013) 10(3)
aerosol formation in the production region of these devices.
Studies have primarily focused on modeling spray physics in
post-nozzle flow, often comparing numerical predictions with
in vitro experimental measurements of droplet velocity, size
and deposition. In addition to pMDIs, some studies have
examined spacer devices using CFD.
3.1 pMDI CFD modeling
Dunbar et al. performed one of the first CFD studies on
pMDIs in examining droplet transport and formation during
inhaler actuation [46]. A model of actuator flow from the
metered chamber to the nozzle provided the initial conditions
for a spray model describing the flow further downstream.
Results showed mixed agreement with experimental phase
Doppler particle analysis (PDPA) measurements [47]; good
agreement was obtained for droplet velocity and size distri-
butions a distance of 25 mm from the spray orifice, but not
further downstream. This was attributed to deficiencies in
the spray model in capturing flow characteristics [46] and cal-
ibration issues with the PDPA system [47]. Unfortunately,
since the computationally intensive nature of the solution pre-
vented the completion of sensitivity tests, the results of the
study were taken as preliminary.
Versteeg et al. used CFD to examine steady-state airflow
and aerosol plume behavior in two pMDI models [48]. Simu-
lated flow fields through an experimental pMDI and the
AstraZeneca Pulmicort
pMDI were found to be similar
and highly complex; multiple regions of recirculation,
carrying high levels of turbulence, were observed inside the
inhaler. The development of a confined aerosol plume was
then modeled in the mouthpiece region of an AstraZeneca
inhaler connected to a United States Pharmacopeia induction
port (USP-IP), revealing the evolution of the plume as it
travelled through the geometry. Droplet trajectories were
initially straight and dominated by inertia, but evaporation
and the entrainment of surrounding air quickly reduced
droplet speed and size. Further downstream, trajectories
were consistent with a stochastic random walk associated
with turbulent effects. The majority of deposition occurred
in the horizontal section of the induction port, consistent
with in vitro measurements by Stein and Gabrio [49]. Interes-
tingly, additional simulations showed that USP-IP deposition
decreased with increasing flow rates, a trend observed in
the experimental results of Shrubb [50]. Shrubb attributed
this trend to the influence of airflow velocities closer to the
velocity of the aerosol plume exiting the pMDI [50]. Though
the findings by Versteeg et al. correlated well with in vitro
measurements [49,50], technological limitations allowed only
qualitative agreement between the CFD model and
experiments to be achieved [48].
A comprehensive study by Kleinstreuer et al. examined air-
flow, droplet transport and deposition in a pMDI and human
upper airway model [51]. The effects of spacer use (discussed in
Section 3.2) and nozzle diameter were investigated, and
both chlorofluorocarbon (CFC) and hydrofluoroalkane-134a

A.
Canister
53.4% deposited
in oral airway
Soft palate
Q = 30 L/min
Pharynx
Actuator nozzle
Glottis
Larynx
Trachea
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46.6% to lung
Figure 1. Simulated deposition of droplets in the upper respiratory tract for (A) an HFA-pMDI and (B) an HFA-pMDI with a
spacer, showing improved lung deposition with spacer use.
Adapted from [51] with permission of Mary Ann Liebert, Inc.
(HFA) propellant aerosols were simulated to determine the
influence of propellant properties on deposition. Simulated
flow fields showed the formation of several vortices in
the inhaler body at a steady flow rate of 30 L/min. Lung depo-
For personal use only.
sition with the CFC-pMDI (5.2%) was significantly less than
that obtained with the HFA-pMDI (46.6%). These results
were generally in good agreement with both in vivo [52] and
in vitro [53] studies, with some minor inconsistencies that
may have originated from the assumptions made in the
CFD simulations; some physical processes, such as droplet
coalescence, were assumed negligible. From the comparison
of propellants, significantly better deposition performance
was obtained using HFA as compared with CFC. This was
partially attributed to differences in nozzle diameters used
with the two propellant types; the CFC-pMDI nozzle
diameter of 0.5 mm was larger than the 0.25 mm diameter
nozzle used in the HFA-pMDI. An additional simulation of
a CFC-pMDI with a 0.25 mm diameter nozzle yielded lung
deposition of 23.2%, still well short of that achieved
with the HFA-pMDI. Kleinstreuer et al. noted that HFA
properties, including a lower surface tension and lower boiling
point than CFC, aided in the formation of smaller
droplets [51].
Longest et al. [54] simulated aerosol transport and deposi-
tion in three spray delivery systems, including a pMDI, capil-
lary aerosol generator and Respimat Soft Mist inhaler. In the
pMDI, choked vapor flow was assumed at the nozzle, creating
a high-pressure spray that caused significant flow acceleration
and velocities exceeding 100 m/s. Simulations showed that
these high velocities generated significant regions of recircula-
tion in the pMDI mouthpiece, where turbulent dispersion
and vortical flow dominated particle trajectories. The amount
of recirculation in the pMDI mouthpiece exceeded that
observed in the other spray systems. In addition to compari-
sons between different inhalers, two separate CFD models
Expert Opin. Drug Deliv. (2013) 10(3)
The use of computational fluid dynamics in inhaler design
B.
Canister 3.5% deposited
in spacer
21.9% deposited
in oral airway
Soft palate
Pharynx
Actuator nozzle
Spacer
Q = 30 L/min
Glottis
Larynx
Trachea
74.6% to lung
were employed in the study to examine differences in
deposition obtained when either neglecting or accounting
for evaporation. Results showed that the model containing
droplet evaporation provided better agreement with in vitro
measurements of regional deposition in the pMDI mouth-
piece and induction port than the non-evaporating particle
approximation.
3.2 Spacer CFD modeling
The study by Kleinstreuer et al. [51] demonstrated the effect of
spacer use on deposition rates for pMDIs. Inserting a spacer
between the pMDI and upper airway model provided a
sudden expansion in volume that decreased flow velocity
and increased droplet residence time and evaporation.
A subsequent reduction in droplet speed and size resulted in
significantly reduced deposition in the oral cavity, while
simultaneously increasing drug delivery to the lungs. Perfor-
mance of both the CFC and HFA pMDIs improved with
spacer use, with lung deposition increasing from 5.2 to
52.9% for the CFC-pMDI and from 46.6 to 74.6% for the
HFA-pMDI. Figure 1 shows the simulated deposition
obtained for the HFA-pMDI with and without a spacer.
While the simulations by Kleinstreuer et al. [51] suggested
that spacer use increased lung deposition considerably, Leach
and Colice [55] observed in vivo that lung deposition was rela-
tively unaffected using small particle aerosols (HFA) and
either the same or less using large particle aerosols (CFC).
Leach and Colice [55] also found a higher proportion of depo-
sition in the spacer compared with the simulations by
Kleinstreuer et al. [51]. The discrepancy in deposition measure-
ments may arise from nozzle diameter or formulation diffe-
rences between the in vivo pMDI of Leach and Colice [55]
and the simulated pMDI of Kleinstreuer et al. [51], which
could lead to significant variations in droplet size and velocity
and subsequently influence deposition. Despite the observed
311
 C. A. Ruzycki et al.
differences in deposition, both studies demonstrated the
general trend of decreased oropharyngeal deposition with
spacer use [51,55], a trend further observed in an in vitro study
of HFA-pMDIs by Cheng et al. [53]. With this in mind, the
differences in deposition between the Kleinstreuer et al. simu-
lations and in vivo measurements by Leach and Colice suggest
this is an area requiring further exploration.
While the study by Kleinstreuer et al. suggested that spacer
use could increase lung deposition and decrease oropharyn-
geal deposition [51], the effects of spacer design were not con-
sidered. In a recent study, Oliveira et al. [56] used CFD to
optimize the design of the Volumatic
spacer for improved
deposition performance. It was proposed that modifications
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to the spacer body and valve could reduce the large areas of
recirculation observed in the Volumatic spacer. An optimized
spacer was designed by combining the best-performing
body and valve geometries following simulations of several
prototypes. Noticeable improvements in flow features
were observed in the optimized spacer. Reduced regions of
recirculation and decreased levels of turbulence kinetic energy
suggested that the improved design would increase drug
delivery to the patient while reducing deposition inside the
device. The design process employed by Oliveira et al. allowed
for the evaluation of several concepts using CFD prior to
For personal use only.
physical prototyping.
3.3 Summary of pMDI CFD modeling
Results of the aforementioned studies on pMDIs indicate that
in general, spray physics in post-nozzle flow can be accurately
modeled using CFD. Good agreement has been obtained
between CFD predictions and in vitro measurements for
droplet speed, size and deposition [48,51,54]. It is important to
emphasize that these studies have focused primarily on post-
nozzle flow; initial conditions, often based on experimental
measurements, are used to model the spray from the nozzle
rather than numerically calculating the entire process of
aerosol formation from the metering chamber upon actu-
ation. In one exception, Dunbar et al. created a model of
aerosol formation from the metering chamber through to
the nozzle, though the results were preliminary, and there
was limited success in predicting downstream flow characte-
ristics [46]. To the authors’ knowledge, no further studies
have attempted to model the entire process of aerosol forma-
tion upon pMDI actuation. The lack of accurate modeling in
this phase of pMDI operation prevents the intuitive design of
components such as the metering chamber, expansion
chamber and actuator nozzle. As such, the use of CFD in
the evaluation and design of pMDIs has yet to be fully
implemented [16,45].
4. Nebulizers
Unlike the volatile propellant spray used to deliver medication
from metered dose inhalers, nebulizers deliver aqueous
droplets for inhalation at comparatively low speeds. The
312 Expert Opin. Drug Deliv. (2013) 10(3)
mechanics of droplet formation vary depending on the type
of nebulizer. The most commonly used is the jet nebulizer [44],
though traditional ultrasonic nebulizers, vibrating mesh nebu-
lizers and soft mist inhalers are also available [57]. Aerosol for-
mation in a jet nebulizer involves several complex processes.
Primary production of droplets occurs as high speed air flows
across a water surface. Contact between these droplets and
faster moving airflow may result in aerodynamic breakup,
but most additional fragmentation occurs due to splashing
on primary baffles. Secondary baffles then force aerodynamic
size selection of droplets. Furthermore, interfacial phenomena
are important in determining the drug lost in drops clinging
to nebulizer surfaces and the induced charge on droplets.
The formation and delivery of aerosols from other types of
nebulizers is similarly complex [57]; direct modeling of aerosol
formation in nebulizers is therefore difficult and computa-
tionally prohibitive [44]. As a result of these complications,
and in a similar situation to pMDIs, relatively few CFD
studies have been performed on nebulizers.
4.1 Nebulizer CFD modeling
Shakked et al. [58] performed one of the first CFD studies
examining nebulizer performance by investigating aerosol
deposition in a nebulizer hood attached to an infant head
model. The dispersion of water droplets throughout the
hood was examined in three breathing phases: inspiration,
expiration and apnea. CFD simulations showed that
while droplet trajectories in the nebulizer funnel were
unaffected by the breathing phase, highly variable airflow in
other parts of the hood led to large differences in deposition.
A simulation of six consecutive breathing cycles showed
that 37% of the drug leaving the nebulizer reached the
mouth, 39% exited the hood, 10% deposited on the head
and 14% deposited on the surface under the infant model.
Further simulations showed that altering the design of
the hood influenced deposition; widening the funnel exit
reduced the efficiency of drug delivery to the mouth during
inspiration.
CFD has been used in studies of the performance of
piezoelectrically actuated nebulizers [59-61]. Jeng et al. [59]
investigated the performance of a traditional ultrasonic
nebulizer under varying operating conditions. Results
showed that the optimal nebulizer flow rate was achieved
at an operating frequency equal to the resonant frequency
of the piezoelectric actuator. Increasing the operating
frequency reduced droplet diameters but introduced more
air into the reservoir, thereby decreasing ejection perfor-
mance. In a similar study, Shen et al. [60] examined the
formation and ejection of droplets from a prototype low
power piezoelectrically actuated nebulizer. Simulations
showed optimal performance at a frequency of 120 kHz,
where droplets with a mean diameter of 4.04 µm were
generated at a flow rate of 0.5 mL/min. Su et al. [61]
used CFD to examine liquid droplet production from a
novel valveless micropump droplet generator (MDG).
 The use of computational fluid dynamics in inhaler design

A. Spray time 0.005 s Number of particles

in parcel

1 10 50 100 1000 10000

x = 2.4 cm

0 2 4 6 8 10 12
Distance (cm)
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B. Spray time 0.0175 s

Number of particles
in parcel

1 10 50 100 1000 10000

x = 4.5 cm

0 2 4 6 8 10 12
For personal use only.

Distance (cm)

C. Spray time 0.03 s Number of particles

in parcel

1 10 50 100 1000 10000

x = 6.1 cm

0 2 4 6 8 10 12
Distance (cm)

Figure 2. Simulated evolution of the aerosol spray emitted from the Respimat
Soft Mist inhaler at (A) 0.005 s, (B) 0.0175 s
and (C) 0.03 s with two-way droplet and airflow coupling.
Adapted from [35] with permission of Mary Ann Liebert, Inc.

A model of the proposed MDG was examined to determine
concept feasibility and characterize performance. CFD
simulations confirmed the feasibility of the design and
showed that droplet properties could be altered by modi-
fying the nozzle diameter and actuator frequency. This
suggested that the MDG could be used for targeted drug
delivery to multiple regions, including the lungs and the
nasal airways. Interestingly, the proof-of-concept study by
Su et al. was conducted entirely using CFD. Prototyping of
the MDG was left to future work.
The Respimat Soft Mist inhaler, which uses a spring-driven
mechanism to generate a slow moving aerosol, has also been
investigated using CFD [35,54,62]. Longest et al. examined
flow fields and deposition in the Respimat Soft Mist Inhaler,
Proventil
HFA pMDI and a capillary aerosol generator [54].
Increased mouthpiece deposition was observed in the Respi-
mat, resulting from a combination of low spray momentum
and recirculating flow downstream of the spray nozzle.
Performance of the Respimat was further evaluated using a
combination of CFD modeling and in vitro dispersions into
the USP-IP and realistic mouth--throat (MT) geometries [35].
The unconfined evolution of the Respimat spray plume in the
absence of any given throat geometry is shown in Figure 2.
Considerable deposition was observed in the mouthpiece

Expert Opin. Drug Deliv. (2013) 10(3) 313

 C. A. Ruzycki et al.
with comparatively little deposition measured in the throat
geometries. Computed flow fields revealed significant recircu-
lation zones in the inhaler mouthpiece that entrained and sub-
sequently prevented a large portion of respirable particles
from exiting the inhaler. Longest and Hindle [35] proposed
that intuitive modification of the Respimat mouthpiece using
CFD could significantly improve inhaler deposition efficiency
by reducing regions of recirculation. Wachtel et al. [62] opti-
mized the design of the Respimat inhaler using a combination
of CFD and flow visualization techniques. It was found that
increasing the size of the air vents at the base of the mouth-
piece reduced flow turbulence levels and minimized recircula-
tion, creating a more uniform airflow through the device that
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Victoria on 04/15/13
improved drug delivery.
CFD has also been used to examine issues extending
beyond aerosol aspects. Arulmuthu et al. [63] undertook a
study to determine the suitability of the MicroAIR
mesh
nebulizer for the delivery of aerosolized plasmid DNA
therapeutic solutions. Using a CFD model of fluid flow in
the nozzle of the mesh nebulizer, high strain rates capable
of damaging the sensitive plasmid DNA were identified near
the nozzle exit. Hydrodynamic forces on the plasmid struc-
tures were estimated based on the predicted strain rates and
experimentally measured molecule sizes. Results of the CFD
For personal use only.
simulation suggested that a 5.7 kb length plasmid DNA
would undergo reversible elastic stretching during delivery,
while a longer 20 kb plasmid would be irreversibly damaged.
These predictions were confirmed with experimental measu-
rements, with observations of no damage in 5.7 kb plasmids
and significant fragmentation in 20 kb plasmids. It should
be noted that the calculation of fluid strain rates in simplified
geometries does not necessitate the use of CFD; estimation
of fluid strain can sometimes be made using more
elementary methods.
4.2 Summary of nebulizer CFD modeling
To date, a comprehensive CFD study examining aerosol
formation in a jet nebulizer has not been performed. The
design of these devices using CFD will require more advanced
computing capabilities than are currently available. CFD has,
however, found use in the design of other types of nebulizers.
CFD simulations have provided insight into piezoelectrically
actuated nebulizer operating conditions [59,60] and concept
feasibilities [61]. Flow fields and deposition in the Respimat
Soft Mist Inhaler have been successfully predicted numeri-
cally, with proposals put forth for the intuitive modification
of the mouthpiece using CFD to reduce deposition within
the inhaler [35,54,62]. Furthermore, CFD simulations have
been used to determine the suitability of mesh nebulizers in
the aerosolization of delicate plasmid DNAs for therapeutic
treatments [63]. These studies show that certain aspects of
nebulizer design and performance are well suited for CFD
analysis. As technological capabilities of computing systems
improve, the practicality of design and evaluation of
nebulizers using CFD will continue to increase.
314 Expert Opin. Drug Deliv. (2013) 10(3)
5. Dry powder inhalers
Aside from pMDIs and nebulizers, DPIs provide another
common delivery method for pharmaceutical aerosols. The
basic operating principle of a DPI involves the dispersion of
small powder particles for inhalation and delivery to the
lungs. Though this concept is simple, the processes involved
in dose delivery from a DPI are highly complex and interre-
lated, including the aerosolization of the powder, deaggrega-
tion of active drug particles from larger carrier and/or
drug-only agglomerates, and aerosol dispersion and transport
through the device [1,44,64]. In addition, the irregular shapes
and rough-surfaces of small pharmaceutical powder particles
inhibit the quantitative prediction of adhesive and aerody-
namic forces, resulting in a relatively poor understanding of
DPI aerosol formation and delivery [44]. Mechanisms of deag-
glomeration are also complex, and include turbulence-
induced aerodynamic forces, particle--device impactions
within the inhaler body, mechanical vibration and particle--
particle collisions. Furthermore, the relative importance of
these mechanisms remains unclear [44,65,66] and varies with
inhaler design and powder properties. Further adding to the
complexity of DPI mechanics is the transient nature of aerosol
formation. Though these various processes complicate the
notion of numerical modeling, several studies have employed
CFD to investigate airflow and deagglomeration mechanisms
in DPIs. In addition, more recent work has investigated the
use of DEM in conjunction with CFD to better model
agglomerate breakup, allowing a more in-depth analysis of
DPI deagglomeration than was previously possible.
5.1 DPI CFD modeling
In 2004, Coates et al. performed one of the first CFD studies
on DPI performance by examining the flow fields generated
in the Rotahaler
and Aerolizer
inhalers [67]. CFD simula-
tions and experimental measurements were used to investigate
the effects of flow features and device design on inhaler
performance. Simulations showed that flow in the Aerolizer
was more turbulent than in the Rotahaler, with experimen-
tally measured fine particle fractions (FPF) reflecting this
difference in turbulence. Removal of the grids from the
inhalers was found to decrease the FPF emitted from
the unmodified Aerolizer (from 43 to 22%) and Rotahaler
(from 19 to 9%), but did not significantly alter flow turbu-
lence kinetic energies. This suggested that the inhaler grid
had a large effect on DPI performance.
Coates et al. then performed a series of investigations on
the influence of the Aerolizer grid structure and mouthpiece
length [68], mouthpiece geometry [69], capsule presence and
size [70], airflow [71] and air inlet size [72] on inhaler perfor-
mance. Coates et al. [68] found that the presence of the grid
straightened airflow at the inhaler exit (Figure 3). Increasing
the grid porosity decreased integral scale strain rates and
reduced the frequency of particle--grid impactions, but
increased the number of particle--mouthpiece collisions; this
 The use of computational fluid dynamics in inhaler design

A.
Velocity
50.0

37.5

25.0

12.5

0.0
(m s-1)
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Victoria on 04/15/13

B.
Velocity
50.0

37.5

25.0
For personal use only.

12.5

0.0
(m s-1)

C
Velocity
50.0

37.5

25.0

12.5

0.0
(m s-1)

Figure 3. Particle tracks (left) and velocity vectors (right) through the Aerolizer
DPI for (A) the full grid case, (B) the grid one
case and (C) the grid two case, illustrating the flow straightening effects of the grid.
Adapted from [68] with permission of John Wiley and Sons.

Expert Opin. Drug Deliv. (2013) 10(3) 315

 C. A. Ruzycki et al.
had the effect of increasing powder retention without altering
the FPF of emitted powder. While the mouthpiece length [68]
and design [69] had a negligible effect on dispersion
performance, wider mouthpieces reduced throat deposition
by decreasing the axial velocity of air exiting the inhaler [69].
Presence of the capsule was found to significantly reduce
turbulence levels, while the capsule size had no effect on per-
formance [70]. The significant increase in turbulence levels and
device performance in the absence of the capsule suggested
that particle--capsule impaction was a weak mechanism for
deagglomeration [70]. Increasing the flow rate through the
Aerolizer increased the integral scale strain rates, the intensity
and number of particle--device impactions and overall levels of
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Victoria on 04/15/13
turbulence [71]. Optimal performance was achieved at a flow
rate of 65 L/min, where maximum FPF, low throat deposi-
tion and low capsule retention were observed. Increasing the
flow rate beyond 65 L/min provided no increase in perfor-
mance [71]. It was also observed that reducing the size of air
inlets increased turbulence and particle impaction velocities
at low flow rates, leading to improved dispersion perfor-
mance [72]. At higher flow rates, however, reducing the air
inlet size caused the release of a considerable amount of
powder prior to full flow development, thereby reducing
performance [72].
For personal use only.
In the series of investigation by Coates et al. [67-72], trans-
port characteristics obtained using CFD were used to explain
in vitro observations of various performance parameters.
Lagrangian particle tracking allowed for the observation of
particles under the influence of aerodynamic and turbulent
dispersion forces during transport through the inhaler.
Coates et al. noted that particle--device collision data was
not intended to be treated quantitatively, but rather to illus-
trate significant trends in impaction [68]. Actual deagglomera-
tion of particles was not modeled [72], meaning CFD could
not directly estimate dispersion performance of the Aerolizer.
Instead, performance was inferred from experimentally
measured FPFs and mass distributions. Furthermore, the
CFD models could not predict the frequency or intensity of
particle--particle collisions, meaning this entire mechanism
of deagglomeration was neglected. Despite these limitations,
these investigations provided considerable insight into the
influence of various design features on flow fields within
the Aerolizer and allowed for an estimation of the relative
strengths of different deagglomeration mechanisms.
Similar studies by other investigators have used CFD to
provide insight into airflow and deagglomeration mechanisms
in various DPIs. Nichols and Wynn [73] developed a CFD
model to calculate separation torques acting on carrier-
drug agglomerates in an Ultrahaler
DPI. CFD calculations
of impact-based torques in particle--device collisions and
fluid-based torques experienced during aerosol transport
were compared with the experimentally determined separa-
tion torque, allowing a prediction of carrier-drug particle
deaggregation. Results suggested that impaction was the
dominant deagglomeration mechanism in the Ultrahaler,
316 Expert Opin. Drug Deliv. (2013) 10(3)
since impact-based torques typically exceeded fluid-based
torques by several orders of magnitude.
Tibbatts et al. [74] correlated in vitro dispersion performance
with flow dispersion energy in three commercially available
DPIs. Results showed that the relative contributions of
collisions, drag and turbulence to the total dispersion energy
varied considerably among the TwinCaps
, HandiHaler

and Diskus
inhalers. Dispersion energy was related to two
factors, including the instantaneous energy in the airflow
(inspiratory power) and the duration over which this power
acted on the powder particles. From the results of the investiga-
tion, Tibbatts et al. suggested that maintaining a constant inspi-
ratory power was more important than attaining a specific
inspired volume during in vitro characterizations [74].
Donovan et al. [75] found that complex cyclonic flow in
the Aerolizer resulted in significantly more particle--device
impactions than were observed in the HandiHaler. A depen-
dence of Aerolizer performance on carrier particle size further
suggested that impaction was a major deagglomeration
mechanism in the Aerolizer but not in the HandiHaler.
Donovan et al. proposed that matching the physical proper-
ties of carrier particle formulations to the dominant deagglo-
meration mechanisms in a given inhaler could significantly
improve aerosol performance [75].
Shur et al. [76] investigated the influence of Cyclohaler

design modifications on aerosolization performance and
comparability to the HandiHaler. Simulated flow in the
HandiHaler was consistent with that observed in similar
CFD studies by Donovan et al. [75] and Wachtel et al. [62].
Flow in the Cyclohaler was found to be predominantly
cyclonic, with the air inlets supplying significant tangential
momentum to air entering the device. Modifications were
made to these air inlets to match the specific resistances of
the HandiHaler and Cyclohaler. Large differences in experi-
mental aerosolization performance between the modified
Cyclohaler designs and the HandiHaler suggested that
matching the specific resistance of test and reference DPIs
was not sufficient for attaining comparable in vitro
performance.
The use of spacers with DPIs has also been investigated
numerically. Matida et al. employed CFD in the development
of a spacer for the Turbuhaler
DPI [77]. An optimized spacer
was developed that dissipated jets emerging from the inhaler
and reduced turbulence kinetic energies in the flow. Concept
designs were optimized using CFD, and experiments con-
firmed a significant improvement in deposition performance
using the optimized spacer. The combination of a straight-
forward CFD optimization and experimental validation in
this proof-of-concept study eliminated the need for either
complex simulations or lengthy in vitro comparisons.
5.2Deagglomeration and DEM
While a considerable amount of work has been performed
examining flow characteristics in DPIs using CFD, the
study of deagglomeration in these devices has been less

extensive. The complexities of agglomerate breakup and
dispersion that complicate numerical modeling are well
documented [1,44,78-80], and the contributions of DPI design
features to fundamental deagglomeration mechanisms are
difficult to determine [17]. To this end, deagglomeration
rigs have traditionally been used to study the breakup of
powders [66,79], and studies by Wong et al. have used CFD
in the investigation of aggregate breakup in these types of
devices [81-83]. While these studies provided welcome insight
into deagglomeration mechanisms in simplified deagglomer-
ation geometries, application of the numerical simulation
approaches used in these studies to the more complex
problem of deaggregation in actual inhaler geometries has
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Victoria on 04/15/13
rarely been implemented, partly because of the computa-
tional expense associated with modeling particle--particle
and particle--wall interactions.
Separate from CFD, DEM can account for the mechanics
of particle--particle and particle--wall interactions. A recent
review by Wong et al. [17] on the use of computational
approaches in inhaler development covered several aspects of
DEM. In DEM, Newtonian equations of motion are used
to determine the movement and rotational behavior of a finite
number of discrete particles that interact through contact and
non-contact forces [84,85]. DEM can provide dynamic infor-
For personal use only.
mation on trajectories and transient forces for individual
particles, allowing for more accurate modeling of particle
collisions. Coupled CFD--DEM modeling allows for the
mechanistic prediction of particle interaction effects [86]. As
a result, CFD--DEM models provide a vastly improved
method for studying the mechanics of deagglomeration com-
pared with traditional CFD. Unfortunately, the full number
of particles and collisions in pharmaceutical aerosols cannot
be modeled due to current computational limitations [17].
Accordingly, DEM studies on pharmaceutical aerosols have
been of a mostly fundamental nature.
Several studies have employed DEM to investigate both
model [87-92] and pharmaceutical [93-95] agglomerates. While
these investigations have improved the understanding
of various aspects of deagglomeration, of special interest are
studies using coupled CFD--DEM in the analysis of inhaler
design. In particular, Tong et al. investigated the dispersion
of agglomerates in a number of CFD--DEM studies examin-
ing the fundamental mechanisms of powder dispersion in
inhalers [43,96-98].
Tong et al. [43] examined the dispersion of agglomerates
with different particle sizes and polydispersities in a cyclonic
flow model similar to the Aerolizer. Results showed that the
fluid--particle interactions governing agglomerate motion
caused several particle--device collisions, resulting in a signifi-
cant increase in the number of agglomerate fragments.
Dominant factors in agglomerate breakup were identified as
particle--particle tensile strength and particle--wall impact
energy. Furthermore, particle size was found to have a signifi-
cant effect on dispersion performance depending on the flow
velocity; at high velocities, agglomerates of smaller particles
Expert Opin. Drug Deliv. (2013) 10(3)
The use of computational fluid dynamics in inhaler design
showed more efficient dispersion. Agglomerates with nar-
rower size distributions had better dispersion performance,
though this effect of polydispersity was less significant than
particle size.
Tong et al. [96] then investigated the dispersion of drug-
mannitol agglomerates in customized impaction geometries
using a fully coupled CFD--DEM model. This two-way
coupling allowed the model to fully capture the dynamics of
particle flow interactions. Results indicated that deagglomera-
tion was primarily due to particle--wall impactions, with
breakage governed by impaction energy and agglomerate
strength. Turbulence was found to play a minimal role on
mannitol agglomerate breakup, as interparticle cohesion far
exceeded numerical predictions of flow shear stresses. Gener-
ation of fine particles occurred mostly during the second
impaction of agglomerates, where fragments from the first
impaction underwent further disintegration. It was also deter-
mined that powder deposition was dependent on impact
angle and the inertial energy of fragments. Tong et al. sug-
gested that both device design and flow conditions should
be considered when investigating optimal dispersion [96].
A recent study by the same group examined dispersion in
the Aerolizer using the previously developed fully coupled
CFD--DEM model [97]. Consistent with the results of earlier
studies [43,96], the dominant breakup mechanism was parti-
cle--device impaction (Figure 4). Particle--particle collisions
were important only in the initial stages of actuation as
agglomerates were spun out from the Aerolizer capsule.
Fragments of agglomerates formed by strong impactions
with the Aerolizer base were further shattered by collisions
with the inhaler grid, creating a significant increase in fine
powders. In addition, inhaler performance showed a depen-
dence on flow conditions, with larger flow rates increasing
the dispersion performance but causing more powder reten-
tion in the device. Tong et al. noted that the findings of
the study were only applicable to the system under investi-
gation, in which loose agglomerates of fine powders were
dispensed. That being said, the CFD--DEM studies by
Tong et al. provided valuable insights into deagglomeration
that had previously eluded observation in traditional CFD
studies on DPIs.
5.3 Summary of DPI CFD modeling
Compared with pMDIs and nebulizers, CFD has been used
to a larger extent in the analysis of DPIs. This is partially
due to the strong dependence of DPI performance on airflow,
a dependence not as prevalent in other pharmaceutical aerosol
delivery systems [17]. CFD can provide insight into transport
characteristics in DPIs that can then be used to explain
in vitro observations of various performance parameters.
Though CFD analysis of DPIs is useful in this regard, limi-
tations prevent the quantitative analysis of deagglomeration
mechanisms. The investigation of these deagglomeration
mechanisms can be vastly improved using coupled
CFD--DEM methods. While much of the work in this field
317
 C. A. Ruzycki et al.

A. B. C.

mg mg mg
5.0x10+04 2.0x10+04 2.0x10+05
4.5x10+04 1.8x10+04 1.8x10+05
4.0x10+04 1.6x10+04 1.6x10+05
3.5x10+04 1.4x10+04 1.5x10+05
3.0x10+04 1.2x10+04 1.3x10+05
2.5x10+04 1.0x10+04 1.1x10+05
2.0x10+04 8.0x10+03 9.2x10+04
1.5x10+04 6.0x10+03 7.4x10+04
1.0x10+04 4.0x10+03 5.6x10+04
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Victoria on 04/15/13

5.0x10+03 2.0x10+03 3.8x10+04

0.0x10+00 2.0x10+04

Figure 4. Spatial distribution of (A) the particle--device contact force, (B) the particle--particle contact force and (C) the total
For personal use only.

force in the Aerolizer DPI.

Adapted from [98] with permission of the author.

has been of a fundamental nature, recent studies using
coupled CFD--DEM methods have successfully modeled
dispersion in DPIs [43,96-98]. As the capabilities of computing
systems continues to increase, coupled CFD--DEM methods
will likely see increased use in the design of DPIs.
6. Other aerosol delivery systems
While pMDIs, DPIs and nebulizers together make up the vast
majority of the inhaler market, CFD has also been used to
examine other inhaler designs. A CAG system was the subject
of a series of studies by Longest et al. In CAG, an aqueous
solution is pumped through a capillary and electrically heated,
resulting in partial or full vaporization. Droplets are then
dispersed from a turbulent spray jet at the capillary exit.
Longest et al. used a CFD model of CAG transport and depo-
sition developed in previous work [33] to investigate the effects
of spray momentum on deposition in throat geometries [99].
Simulations showed that significantly more throat deposition
was observed with a spray aerosol as compared with an ambi-
ent aerosol. Longest et al. then identified a significant ‘burst
effect’ arising from the initial entrance of the spray aerosol
into the throat that increased deposition in the early stages
of aerosol generation [34]. Longest and Hindle [100] found
that the size of the dilution air inlets and the flow conditions
near the nozzle had a significant influence on aerosol transport
and deposition with the CAG system. Primary transport
characteristics associated with drug deposition were identified
as turbulence intensity and the effective diameter of the
mouthpiece. Quantitative correlations were then developed
between these transport characteristics and mouthpiece drug
deposition. Longest and Hindle suggested that these correla-
tions would allow for more intuitive design modifications of
the CAG spray inhaler to achieve desired performance.
Enhanced condensational growth (ECG), a relatively new
concept for respiratory drug delivery, has also been studied
using CFD. In ECG, a submicrometer aerosol is inhaled in
combination with saturated water vapor. The small initial
size results in low extra-thoracic deposition, while subsequent
condensation onto droplets in vivo increases the aerosol size,
resulting in improved lung retention. Longest and Hindle [101]
developed a CFD model of ECG in a simple tubular geome-
try. They found that two-way coupling of mass and thermal
effects was important in modeling the ECG process. Using a
MT and upper tracheobronchial model in CFD simulations,
Hindle and Longest [102] found that ECG successfully
delivered nano-aerosols to the tracheobronchial airways with
minimal deposition in the extrathoracic region. While results
of these studies confirmed the validity of the ECG concept,
the need for further work on boundary conditions, more
realistic geometries, and transient breathing was identified.
7. Conclusions
From the studies examined in this review, it is evident that
CFD can provide an effective tool for understanding and

318 Expert Opin. Drug Deliv. (2013) 10(3)


predicting the performance of various inhalers. CFD investi-
gations of pMDIs, nebulizers and DPIs have improved our
understanding of aerosol transport and deposition in these
devices. CFD has also allowed for the intuitive optimization
of inhaler technologies, saving time, resources and labor
when compared with conventional empirical design. In addi-
tion, the recent development of coupled CFD--DEM models
provides an improved method for studying deagglomeration
in DPIs over traditional CFD.
While CFD can provide an effective tool for analysis, the
highly complex nature of aerosol formation and transport
complicates the application of computational methods in
inhaler design. Care is required to ensure that CFD models
Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by University of Victoria on 04/15/13
capture the relevant physics involved in inhaler operation.
Simplifications should be justified, and some degree of valida-
tion may be needed to confirm the accuracy of numerical
predictions. It is important to note that CFD is not meant
to wholly replace traditional experimental techniques but
rather to provide an additional means for analysis. Even
then, regulators have yet to approve significant changes to
inhalers using combinations of computational and experi-
mental methods [45,103]. Furthermore, current limitations in
computational power have prevented the full implementation
of CFD in the design of inhalers.
For personal use only.
Moving forward, Longest et al. [54] commented on the need
for concurrent in vitro and CFD analyses to develop correlations
for predicting in vivo inhaler performance. Concurrent CFD
and experimental analyses could address issues related to spray
physics and geometric factors. In this approach, in vitro experi-
ments provide initial conditions and validation data for the final
CFD model. Insights from this analysis could then guide assess-
ments of remaining in vivo correlation issues related to respira-
tory physiology and variability. Future work involving CFD in
both powder and spray inhaler design may well use this
approach to predict aerosol drug deposition, offering a
convenient method of comparison and optimization of inhaler
performance [45]. With these considerations in mind, as compu-
tational technologies improve, the practicality and prevalence of
CFD and DEM in inhaler design will continue to increase.
8. Expert opinion
CFD has emerged over the past few decades as a powerful tool
in the design of devices that depend on fluid flow for their
operation. While CFD is heavily used to guide design in
traditional engineering applications, it has only recently seen
increased use in the design of inhalers for therapeutic delivery
of aerosols into respiratory tract. Although CFD simulation of
aerosol and fluid behavior has successfully played a role in the
Expert Opin. Drug Deliv. (2013) 10(3)
The use of computational fluid dynamics in inhaler design
improved design of several inhalers, part of the reason for the
relatively limited use of CFD during inhaler design is the
extreme complexity of the coupled fluid and aerosol dynamics
that occurs within inhalers during aerosol generation. Inroads
into modeling of aerosol generation and powder deaggrega-
tion in DPI have been made by combining CFD with DEM
that captures certain aspects of the mechanics of particle--
particle and particle--wall collisions. An important part of
such models are the interparticle adhesion forces, which can
be supplied by experimental measurements. However, such
CFD--DEM simulations are forced by their extreme computa-
tional demands to track the behavior of only a small portion
of the full powder dose. Despite this limitation, detailed
exploration of powder deaggregation within inhaler proto-
types can be made, giving DPI designers a highly useful
tool in their quest to improve inhaler design. Unfortunately,
aerosol generation in the most common type of inhaler, the
pMDI, has not yet yielded to CFD modeling due to the com-
plex, turbulent, highly transient multiphase flow that occurs
in the production region of these inhalers. Droplet produc-
tion within traditional jet nebulizers is also exceptionally com-
plex and remains impractical to model with CFD during
design. However, the use of experimentally measured aerosol
properties in the post-production region of pMDIs and
nebulizers as input to CFD modeling has allowed previous
researchers to examine post-production aerosol behavior.
The placement and shape of internal walls and dilution air
inlets, for example, has been examined with CFD, allowing
inhaler designers to reduce the number of design cycles
needed to achieve an optimized inhaler design. Inexorable
increases in computing power will inevitably see the day
when CFD expands its horizons to modeling of the entire
aerosol generation process within all inhaler types. While
that day is some decades away, in the meantime, CFD has
proven its ability to model various important aspects of aero-
sol behavior in inhalers. As a result, for the knowledgeable
user, CFD is an important tool that can reduce design time-
lines and yield improved inhaler designs. The most beneficial
use of CFD is typically seen when it is coupled with judicious
experimental measurements, allowing CFD to complement
and significantly enhance the knowledge that can be provided
by experiment alone.
Declaration of interest
WH Finlay and CA Ruzycki gratefully acknowledge funding
from the Natural Sciences and Engineering Research Council
of Canada. The authors state no conflict of interest and have
received no payment in preparation of this manuscript.
319
 C. A. Ruzycki et al.
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for pulmonary drug delivery - a review
for multidisciplinary researchers.
Med Eng Phys 2012;34(4):409-27
. Reviews recent advances in DPI
technologies and discusses challenges
associated with DPI aerosol
drug delivery.
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The use of computational fluid dynamics in inhaler design
drug delivery with comparisons to Affiliation
in vitro data. J Aerosol Sci Conor A Ruzycki1 BSc,
2010;41(8):805-20 Emadeddin Javaheri1 MSc &
102. Hindle M, Longest PW. Evaluation of Warren H Finlay†2 PhD
enhanced condensational growth (ECG)
†
Author for correspondence
for controlled respiratory drug delivery in
1
University of Alberta,
a mouth-throat and upper Department of Mechanical Engineering,
tracheobronchial model. Pharm Res Edmonton, Alberta, T6G 2G8, Canada
2
2010;27(9):1800-11 Professor,
University of Alberta,
103. Borgstr€om L, Clark A, Olsson B.
Department of Mechanical Engineering,
Introduction 1000 years of
Edmonton, Alberta, T6G 2G8, Canada
pharmaceutical aerosols: what remains to
Tel: +1 780 492 4707;
be done? J Aerosol Med Pulm
Fax: +1 780 492 2200;
Drug Deliv 2010;23(Suppl 2):S1-4
E-mail: warren.finlay@ualberta.ca
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