Powder Technology 398 (2022) 117039

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Powder Technology

journal homepage: www.elsevier.com/locate/powtec

Newly designed mouthpiece to improve spray characteristics

of pharmaceutical particles in dry powder inhaler
Hyeonkang Park a,1, Chang-Soo Han b,1, Chun-Woong Park b,⁎, Kibum Kim a,⁎
a
Department of Mechanical Engineering, Chungbuk National University, Cheongju 28644, Republic of Korea
b
College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28160, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: This study presents the effects of mouthpiece designs in carrier-based dry powder inhalation on aerosol particle
Received 30 April 2021 characteristics. Simulation models are developed to investigate drug powder spray characteristics from mouth-
Received in revised form 1 October 2021 pieces of four different-shaped flow channels. The simulation results agree well with the results of two experi-
Accepted 1 December 2021
ments, one involving particle image velocimetry and the other the Anderson cascade impactor. A mouthpiece
Available online 7 December 2021
with a spiral channel and mixing chamber is discovered to be effective for low axial-flow velocities in the forward
Keywords:
direction and yielded a more uniform dispersion of particles in the radial direction as the drug particles are
DPI (dry powder inhaler) ejected through the mouthpiece. This results in more effective delivery of the drug particles to the peripheral tar-
Mouthpiece get regions of the respiratory system.
Aerosol © 2021 Elsevier B.V. All rights reserved.

1. Introduction particles [3–5]. Failure to maintain an accurate dose to the peripheral

Owing to issues pertaining to the rising of fine dust, numerous inves-
tigations are performed currently regarding respiratory diseases associ-
ated with fine dust. According to surveys performed by Samet et al., fine
dust levels have increased by 10 μg/m3 in 20 U.S. states, resulting in a
0.68% increase in deaths from cardiovascular and respiratory diseases
[1]. Dockery et al. investigated the composition of fine dust and its con-
nection to respiratory diseases [2]. Severe outbreaks of respiratory dis-
eases caused by fine dust and air pollution have brought interest in
the treatment of the disease.
A dry powder inhaler (DPI) is a pulmonary drug delivery device that
is conducive to the effective treatment of respiratory diseases, such as
asthma and chronic obstructive pulmonary disease [3]. It sprays
respirable-sized drug particles (e.g., 1–5 μm in aerodynamic diameter)
directly into the upper respiratory tract, unlike other treatments involv-
ing liquid or mist states. It can maintain a constant dose by controlling
the amount of drug powder and is user-friendly as it does not require
ancillary power but operates only through inhaling. However, as the
drug particles are injected into the mouth, they may be attached to
the upper respiratory tract and bronchial tubes via inertial impaction.
In addition, micronized particles are extremely cohesive, resulting in
particle aggregation, which complicates the optimal injection of the
⁎ Corresponding authors.
E-mail addresses: cwpark@cbnu.ac.kr (C.-W. Park), kimkb11@chungbuk.ac.kr (K. Kim).
1
These authors equally contributed to this work.
target regions of the respiratory system will reduce the effectiveness
of the drug [6]. To eliminate these causes that reduce the lung delivery
rate of the drug powder sprayed from the DPI, various efforts have
been implemented, such as modifying the DPI structure, changing the
drug particle injection velocity, and adding a grid-like structure to in-
duce particle collision to reduce interparticle aggregation [7,8]. The
amount of drug transfer relative to airflow and the particle diameter
for 14 commercial spray jets devices were evaluated [9,10]. Milenkovic
et al. modified the design of a commercial DPI and showed that the pro-
posed design improved the device performance in terms of total particle
deposition and fine particle fraction based on the computational study
[11]. They also investigated the effects of different particle diameters
on the behavior of drug particles passing through the internal flow
paths of a Turbuhaler DPI [12]. Ruzycki et al. discovered that the exten-
sion of the flow channel of the DPI affected the aerosol characteristics
and performance of the DPI [13]. Donovan et al. conducted a simulation
study to visualize airflow inside a DPI and optimized the DPI shape
through flow analysis [14]. Lee et al. designed a spiral-shaped mouth-
piece mounted on an existing product that can improve the lung
delivery rate of drug powder [15]. Gemci et al. mimicked the airway
to investigate the effects of medication on the shapes of bronchial
tubes and conducted an analytical and experimental study considering
the laryngeal shape [16]. Hopentoch et al. summarized the technical
and practical challenges of the DPI, and presented future research
directions [17].
Despite numerous studies pertaining to DPI development, more
research efforts can be expended to improve the medication effects of

https://doi.org/10.1016/j.powtec.2021.117039
0032-5910/© 2021 Elsevier B.V. All rights reserved.
H. Park, C.-S. Han, C.-W. Park et al.
drugs through better DPI designs. Therefore, the objective of this study
is to understand better the effect of initial particle dispersion relevant
to targeted delivery and improve the delivery rate of drugs from a hy-
drodynamic perspective by changing the airflow through mouthpiece
attachments of various internal shapes in existing commercial products.
Four different mouthpiece models were proposed, and their perfor-
mances were compared in terms of the airflow rate, penetration and ve-
locity of drug particles, and the number of particles passing through a
particular plane using a numerical analytical method.
2. Preparation of inhaler device
To prepare the inhaler device, four mouthpieces with different ge-
ometries were designed in a three-dimensional (3D) modeling applica-
tion software (ProE, Creo R7.0), and the mouthpieces were fabricated
using a high-resolution direct light projector 3D printer (Anycubic Pho-
ton, Shenzhen Anycubic Technology). They were mounted on a com-
mercially available DPI device, Diskus™ (GlaxoSmithKline). The
mouthpieces formed an extended flow path and changed the airflow
pattern. To improve the hydrodynamics performance of the DPI devices,
all mouthpieces were designed based on the following criteria:
A. The area of the mouthpiece exit must be increased to reduce the
ejection speed of the flow;
B. When the drug particles are escaping from the mouthpiece, they
must possess a low possibility of attachment to the wall by diffusing
the airflow widely and reducing the airflow momentum in the for-
ward direction;
C. The drug particles should be distributed evenly in the airflow to
avoid aggregation.
Fig. 1 shows the geometries of the mouthpiece and assembled im-
ages with the DPI device. Fig. 1(a) shows prototype I, which is an
existing device exit without any mouthpiece. Fig. 1(b) shows prototype
II, designed to rotate the airflow through a helical flow path. Fig. 1
(c) shows prototype III, which is designed to disperse the airflow by seg-
regating the flow paths into six streams and placing them radially with-
out changing the cross-sectional area of the passage. Fig. 1(d) shows the
internal structure of prototype IV. The airflow has a swirl motion
through a conical wall and a spiral passage, and it enters the
Fig. 1. Shapes of DPI and different mouthpieces.
2
Powder Technology 398 (2022) 117039
spherical-shaped mixing chamber, where the momentum in the
forward direction decreases. Consequently, the injection velocity
decreases, and the flow disperses more widely in the radial direction
as soon as the flow exits from the mouthpiece.
3. Experimental apparatus and method
3.1. Particle image velocimetry (PIV)
A PIV experiment was conducted to visualize the velocity of drug
particles ejected from different-shaped mouthpieces. Fig. 2 shows a
schematic comprising a DPI device, mouthpiece, and box for the PIV ex-
periment. Seretide™ 250 Diskus™ comprises 72.5 μg of micronized
salmeterol xinafoate (SAL) and 250 μg of micronized fluticasone propi-
onate (FLU), and 12.5 mg of lactose monohydrate. The mixture of drugs
was prepared for a fixed-dose combination formulation, then packed
into blisters placed in the DPI. The DPI was inserted tightly into the
mouthpiece mounted on one side of a transparent acrylic cube of a
length of 200 mm to visualize the particle dispersion. The drug particles
were sucked from the other side using a vacuum pump at a flow rate of
60 LPM (TISCH Environmental, Inc., OH, USA) that was steadily con-
trolled using a flow meter (DFM 2000, COPLEY scientific, Nottingham,
UK). For the PIV experiment, a sheet beam was created parallel to the
exit area of the mouthpiece using a diode laser (532 nm) and positioned
perpendicular to a high-speed camera (HAS-D71M, Ditect Corporation,
Tokyo, Japan). The camera captured drug particle dispersion images re-
corded at 8000 frames/s and 480 × 480 pixels corresponding to an
image size of 200 mm × 200 mm. The interrogation window was suffi-
ciently large to prevent drug particles from colliding with the chamber
walls for 100 ms; therefore, critical distortions were avoided. The parti-
cle velocities were obtained by processing images between two frames
using an algorithm combining recursive cross-correlation and image-
transforming methods provided by the PIV analysis software (Flownizer
2D, DITECT Corporation, Tokyo, Japan).
3.2. Anderson cascade impactor
The aerosol performance of drug particles ejected from the devices
was investigated using an eight-stage nonviable Anderson cascade im-
pactor (ACI) (TE-20-800, TISCH Environmental, Inc., OH, USA) based
on the USP Chapter 〈6 0 1〉 specification for aerosol. A flow rate of 60
LPM was actuated prior to each set of experiments using a flow meter
(DFM 2000, Copley Scientific, Nottingham, UK). The collection plates
of the ACI stage were pre-coated with silicone oil to prevent particle
bounce and re-entrainment. The fixed-dose combination carrier-based
DPI formulation (12.8 mg) was blister-packed and placed in the DPI,
which was inserted tightly into the mouthpiece mounted in the induc-
tion port. Fifteen blisters were used for each set of experiments, and the
air was drawn at a controlled rate of 60 LPM for 4 s. Particles that re-
mained in the blisters and accumulated in each collection plate of the
stage were quantified using a modified high-performance liquid chro-
matography. At a flow rate 60 LPM, the aerodynamic cut-off diameters
of each stage were determined to be 8.6, 6.5, 4.4, 3.3, 2.0, 1.1, 0.54, and
0.25 μm for stages −1 to 6, respectively. The emitted dose (ED) was
expressed as the percentage of the difference between the initial and re-
maining masses of the particle in the blister after the aerosolization of
the initial mass. The fine particle fraction (FPF) was used to indicate
the ability of the particles to reach the respirable region with an aerody-
namic size of approximately 5.0 μm or less, and it is expressed as the
proportion of mass collected at stages −1 to 6 in the ED based on the
following equations:
Emitted dose ðEDÞ%
Initial mass of blister−Final mass of blister
¼ ∗100 ð1Þ
Initial mass of blister
H. Park, C.-S. Han, C.-W. Park et al. Powder Technology 398 (2022) 117039

Fig. 2. Schematics of experimental apparatus. (a) PIV system; (b) illustration of acrylic chamber with DPI mounted; (c) simulation model of acrylic chamber with DPI mounted.

Fine particle fraction ðFPFÞ% intensity of 5% were used to describe the turbulence flow. For the
Total drug amount on stages−1 through 6 boundary condition at the outlet of the PIV box, the negative velocity
¼ ∗100 ð2Þ
Total drug amount on all stages value was set in accordance with the flow rate of 60 LPM for the inlet ve-
locity condition. Table 1 summarizes the numerical values used in the
analysis.
The mass median aerodynamic diameter (MMAD) and geometric
Reynolds-Averaged Navior Stokes (RANS) approach was used with
standard deviation (GSD) were calculated from the drug mass deposi-
the k–ω SST turbulence model compute the transient process of turbu-
tion on the ACI stages.
lent flow up to 15 ms after injection. To calculate the turbulent fluid and
particle motion, various physical laws and models were applied. The
4. Simulation model and method
mass and momentum conservation equations applied in the fluid
mechanical model are as follows:
The flow of air and particles injected from the mouthpieces was in-
vestigated using a 3D computational model in commercial CFD software ∂ρ ∂
FLUENT 17.2 (ANSYS V6.3.26). The geometry of the airflow channel was þ ðρui Þ ¼ 0 ð3Þ
∂t ∂xi
extracted, and the mesh in the domain was generated via meshing in
ANSYS 17.2. A mouthpiece extension (height 45 mm) was added to
∂ ∂
 ∂P ∂τ ij
the DPI geometry to investigate the outflow characteristics. The total ðρui Þ þ ρui uj ¼ þ þ ρg i þ F i ð4Þ
∂t ∂xi ∂xi ∂xj
computational mesh of the device comprised 3 × 106 tetrahedral cells,
which were adequate for the grid-independent test. The grid for analy-
where the stress tensor (τⅈj) is expressed as
sis comprised a hexahedron in the observation box, a tetrahedron in the
interior, and a triangular column on the wall owing to the complexity of " !#
∂ui ∂uj
the shape. The grid size was adjusted to approximately 4 mm inside the τij ¼ μ þ ð5Þ
∂xj ∂xi
cube PIV observation box and at least 1 mm at the inlet and outlet areas
of the PIV box. A grid size of approximately 0.5 mm was used for chan-
nels in the DPI and mouthpiece due to the rapid airflow and the small In the equations above, P is the static pressure; ρ is the density; t is
passage size. the time; gi is the gravitational force; Fi is the external force; xi and ui
All simulations were conducted at 1 atm and 300 K in a gravitational are the position and velocity components, respectively. For modeling
field. Heat generation due to the loss of energy used for inhalation and turbulence, velocity and other physical quantities need to be
the electromagnetic force of the fine powder were disregarded. The separated into mean and fluctuating terms for time as shown below.
Diskus device was designed to scatter originally fixed drug powder by
ui ¼ ui þ u0i ð6Þ
airflow; however, because of interpretation difficulty, it was assumed
that the same dose of drug power was supplied steadily for 1 ms. The
∅ ¼ ∅ þ ∅0 ð7Þ
pressure at the DPI inlet was fixed at the atmospheric pressure, whereas
the hydraulic diameter of each device and the typical turbulence
Here, ui is the mean velocity, u′i is the velocity fluctuation, ∅ is the
mean physical quantity, and ∅′ is other physical quantity fluctuation,
Table 1
Conditions for CFD simulation. respectively. Subsequently, Eqs. (6) and (7) are organized into
separate variables to obtain a new expression for turbulence, which is
Diskus
called the Reynolds-Averaged momentum equation, as shown below.
Inlet Pressure (atm): 1 ! !
Flow rate (LPM): 60 ∂ρui ∂
 ∂P ∂ ∂ui ∂u j 0 0
Diameter (mm): 4 þ ρu j ui ¼ − þ μ þ −ρui u j ð8Þ
Boundary conditions Outlet
Average velocity (m/s): 79.5
∂t ∂x j ∂xi ∂x j ∂x j ∂xi
Reynolds number: 22,000
Wall No slip condition where the last term in the right side of Eq. (8) represents Reynolds
Gravity (m/s2) 9.81
stress solved through the Boussinesq assumption because they consist
Other conditions Turbulence Standard
Transient (ms) 0–100 of the multiplication of the two speed terms.
Density (kg/m3) 1420 Furthermore, a turbulence model was required to describe the swirl
Particle properties
Diameter (μm) 2.209 flow motion and vortex. Hence, the k–ω turbulence model using the
Insert time (ms) 5 turbulent kinetic energy and specific dissipation rate was selected as it
Total amount (mg) 12.5
enables ω to be expressed in simple mathematical expressions instead

3
H. Park, C.-S. Han, C.-W. Park et al. Powder Technology 398 (2022) 117039

of a complex attenuation function at the vicinity of the wall. The rele- density of 1340 kg/m3 and a diameter of 2.2 μm was interpreted using
vant equations for the k–ω turbulence model are as follows: the discrete phase model (DPM) in the FLUENT program. The DPM cal-
! culates the particle motion based on the Euler–Lagrangian method. The
∂ ∂ ∂ ∂k motion of the fluid was solved using the transport equation via the Euler
ðρkÞ þ ðρkui Þ ¼ Γk þ Gk −Y k þ Sk ð9Þ
∂t ∂xi ∂xj ∂xj method, whereas the motion equation of the particle was derived using
the Lagrangian method. The equation used to calculate the force acting
!
∂ ∂ ∂ ∂ω on a particle based on the DPM is as follows:
ðρωÞ þ ðρωui Þ ¼ Γω þ Gω −Y ω þ Dω þ Sω ð10Þ
∂t ∂xi ∂xj ∂ωj duP
 g ðρ −ρÞ
¼ F D u−up þ x P þ Fx ð12Þ
dt ρP
μ u
Γk ¼ μ þ i , Γω ¼ μ þ i ð11Þ
σk σω where up is the particle velocity, FD the drag acting on the particle, ρP the
particle density, and Fx the other force applied in certain situations. The
In the equations, k represents the turbulence kinetic energy; ω is the drag force in Eq. (12) is expressed as follows because the particle is
specific dissipation rate; Gk is the turbulence KE generation due to the assumed to be spherical:
average velocity gradient; Gω is the generation of the specific
dissipation rate; Yk and Yω are the extinction of k and ω due to the 18μ C D Re
FD ¼ 2
ð13Þ
turbulence, respectively; Dk is the cross-diffusion term; Sk and Sω are ρP dp 24
source terms; Г is the turbulence diffusion coefficient.
Drug particles of 0.05 mg were injected into the air to observe the where ⅆp is the particle diameter, and CD is the drag coefficient
movement of the medicinal powder. The motion of the particle with a [18–21].

Fig. 3. Comparison of PIV and simulation results at 100 ms post injection. (a) PIV image of sprayed powder particles; (b) contour map of particle velocity; (c) simulated image of sprayed
powder particles; (d) overlapped images of (a) and (c).

4
H. Park, C.-S. Han, C.-W. Park et al. Powder Technology 398 (2022) 117039

4.1. Experimental results and model validation

Fig. 3 shows the results (e.g., particle distribution and velocity) of the
PIV experiments and of CFD simulations pertaining to drug powder flow
at 100 ms after the start of injection based on the shape of the mouth-
piece flow path. Prototype I is a basic model without a mouthpiece, in
which particles gather in the shape of a sphere and move forward rap-
idly. Prototype II is a model equipped with a spiral mouthpiece that ex-
hibits unique characteristics of the two flow streams. Prototype III is a
model equipped with a radial mouthpiece. The width in which particles
were distributed did not differ significantly from that of the sprayed
particles of prototype I; however, it was confirmed that the spray length
in the progression direction increased significantly. Prototype IV is a
model equipped with a mixed-room mouthpiece and creates a fan-
shaped distribution of particles on a two-dimensional plane image.
The experimental and simulation results obtained in this study agreed
well; hence, it can be concluded that the computational model is reli-
able for predicting the particle distribution and velocity of sprayed
drug particles.

4.2. Simulation results and discussions

The different flow geometries inside the mouthpiece created unique
behaviors of drug powder particles ejected from the DPI, as shown in
Figs. 4–7 for the four prototypes. Fig. 4 shows the air velocity expressed
in the contour map, where arrows indicate the airflow direction. The
ejection velocity of the airflow from the mouthpiece reached approxi-
mately 50 m/s in prototype I (case (a) in all figures). The strong airflow
momentum induced a large vortex flow along the longitudinal direction
by the rotation of only the surrounding air. However, the air injected
from the mouthpiece proceeded in a straight line toward the exit of
the PIV box, as shown in Fig. 5(a), describing the streamline of the air-
flow. Fig. 6 shows the contour map of the air velocity distribution
from the horizontal cross-sectional view of the air spray, and the con-
tour plots were drawn in 1, 5, and 10 mm planes from the mouthpiece
exit. The velocity distribution of case (a) appeared in the form of a con-
centric circle, implying that the flow from the DPI proceeded at high
speed with little dispersion. Fig. 7 shows the lateral cross-sectional
view of the spray shapes and the individual particle velocity distribution
Fig. 4. Contour map of air velocity of four different models. (a) Prototype I, (b) Prototype II,
(c) Prototype III, and (d) Prototype IV.
Fig. 5. Air streamlines of four different models. (a) Prototype I, (b) prototype II,
(c) prototype III, and (d) prototype IV.
observed at 100 ms after the particles were ejected from the mouth-
pieces. The velocity of the particles in the spray front was less than
1 m/s. In case (a), most particles were barely affected by the longitudinal
vortex flow and remained in the mainstream of the airflow. Conse-
quently, the spray particles injected became a cluster of particles with-
out sufficient dispersion.
Meanwhile, the airflow was split into two streams in prototype II
(case (b) in all figures). The streams were rotated to reduce the air ejec-
tion speed in the forward direction significantly. As shown in Fig. 4(b),
the forward proceeding airspeed decreased significantly, but the
streamline (Fig. 5(b)) indicated that the air in the DPI proceeded with
a large spray angle. The velocity distribution of case (b) (as shown in
Fig. 6(b)) was bidirectional, and the airspeed decreased, particularly in
the center area compared with that of the case (a). A slight swirl motion
was formed in the airflow when the air passed through the spiral-
shaped passage inside the mouthpiece. However, as shown in Fig. 7
(b), the swirling momentum was not sufficiently strong to deliver the
drug particles; most particles initially moved in a straight manner be-
fore overcoming the proceeding momentum for rotational motion.
However, the large spray angle along with the strong proceeding mo-
mentum of the particles enabled most of the particles to collide with
the sidewall of the box, resulting in an ineffective drug particle delivery.
Prototype III was designed to segregate the airflow into six streams,
and the injection angle was tilted outward such that particles can be dis-
persed radially. However, Fig. 4(c) does not illustrate the intended effect
of the airflow injection. The injected air slightly decelerated because the
structure disrupted the airflow inside the mouthpiece for segregating
the main air stream into six small streams. The streamline pattern of
the airflow (Fig. 5(c)) was similar to that of case (a) except for the
shorter penetration length of the air spray. Fig. 6(c) shows that a high-
speed annular region was formed immediately after the injection but
disappeared rapidly as the flow progressed. Fig. 7(d) shows that the
drug particles remained near each other and formed a cluster that was
similar to the spray shape of case (a); however, the drug particles
were distributed as tails down the spray because the particles were
injected through small passages over a certain duration.
Finally, the desirable characteristics of the spray were obtained using
prototype IV. As the air passed through the conical structure in the
mouthpiece, the flow velocity increased through the passage. Next,

5
H. Park, C.-S. Han, C.-W. Park et al.
Fig. 6. Contour map of air velocity from horizontal cross-sectional view of each model. (a) Prototype I, (b) prototype II, (c) prototype III, and (d) prototype IV.
after the air passed through the two-pronged spiral, it rotated at high
speed and entered the mixing chamber, where the airflow lost a signif-
icant amount of momentum but maintained a strong centrifugal force
before it was discharged to the outside. A uniform air velocity in the ra-
dial direction was formed in the mixing chamber; consequently, the ve-
locity distribution of the air spray was short and wide, as shown in Fig. 4
(d). The streamline of the airflow supported the significantly reduced
injection speed and momentum in the forward-moving direction. The
size of the vortex flow of the surrounding air inside the box decreased
with speed at the mouthpiece outlet, as shown in Fig. 5(d). At the
cross-section of the air spray at 10 mm above the mouthpiece exit, a
considerably lower, uniform, and wider velocity distribution was ob-
served along the radial direction, as shown in Fig. 6(d). Consequently,
the drug particle spray demonstrated a short penetration length but a
large spray angle, as shown in Fig. 7(d).
The complex flow passage structure of mouthpieces causes airflow
resistance, which affects the spray characteristics. The airflow resistance
was explained in terms of pressure difference between the exit and in-
side of the DPI (see Fig. 8(a)). Prototype I shows the pressure deviation
of approximately 1 kPa, while other prototypes using mouthpieces have
a higher pressure deviation of 3 to 6 kPa, indicating that all mouthpieces
increase the air resistance to some extent. A quantitative analysis of the
drug particle sprays (as shown in Fig. 7) was performed to analyze the
penetration length, spray angle, particle velocity in the axial and radial
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Powder Technology 398 (2022) 117039
directions, and the results are presented in Fig. 8(b–e). Compared
with prototype I, prototypes II and IV decreased the penetration lengths
of the spray (Fig. 8(b)) by 42% and 28%, respectively, while increasing
the spray angles (Fig. 8(c)) by 214% and 173%, respectively. Fig. 8
(d) and (e) show the average speeds of particles that progressed more
than 10 mm from the mouthpiece exit in the forward and radial direc-
tions. Prototypes II and IV reduced the forward direction speed by ap-
proximately 40% but increased the radial speed by 188% and 100%,
respectively. In prototype III, the change in the spray characteristics
was insignificant compared with prototype I. Both prototypes II and IV
had a spiral flow passage that resulted in an airflow with a rotating mo-
tion, which reduced the momentum of the drug particles in the forward
direction, resulting in a decrease in the spray penetration length and
axial speed of the particles but an increase in the spray angle and radial
speed of the particles. Hence, this minimized the collision likelihood of
drug particles on the mucous membrane in the mouth and maximized
the drug delivery rate.
Fig. 9 shows the number of particles passing the imaginary plane at
positions 1, 5, and 10 mm from the mouthpiece exit as a function of
time. Over 99% of the particles injected from prototype I passed by the
positions within 1.5 ms (Fig. 9(a)). In addition, it was observed that
the plots overlapped one another for 1 ms, indicating the high average
moving speed and poor dispersion of the particles in the spray. Proto-
type II (Fig. 9(b)) decreased the peak number of particles passing the
H. Park, C.-S. Han, C.-W. Park et al. Powder Technology 398 (2022) 117039

same positions and delayed the peak number of particles passing the
same positions. Furthermore, a time lag between peaks was observed
in this case. No significant changes were observed in prototype III
(Fig. 9(c)); however, the peaks were lower and the travel time of the
particles between planes increased slightly compared with those
shown in Fig. 9(a). Finally, prototype IV (Fig. 9(d)) significantly reduced
the number of particles passing each position over 5 ms, and the parti-
cles of the spray were dispersed temporally and spatially.
Fig. 10 illustrates the number of particles that passed by the position
at 5 mm from the mouthpiece exit simultaneously and the time re-
quired for the peak number of particles to move between positions. As
shown in Fig. 10(a), the peak number of particles passing through a
plane at 5 mm decreased simultaneously when using prototypes II, III,
and IV; in particular, it decreased by 21% when using prototype IV com-
pared with prototype I. This means that the particles passed through the
plane at a relatively low density. Fig. 10(b) shows a comparison of the
time required for the particles to travel between planes. The time mea-
surements were based on the peak values of plots between positions 5
from 1 mm and 10 from 5 mm. Prototypes II, III, and IV increased the
delay in the travel time of the particles from one position. In particular,
the longest delay was achieved using prototype IV, and it was almost 10
times longer than that of prototype I, indicating the lower axial speed of
the particles.
Fig. 7. Distribution and velocity of particles ejected from four different models.
(a) Prototype I, (b) prototype II, (c) prototype III, and (d) prototype IV.

Fig. 8. Quantitative analysis of drug particle spray at 100 ms after particles are ejected from mouthpiece exit. (a) Pressure difference between the exit and inside of the DPI, (b) Penetration
length (mm), (c) spray angle, (d) axial velocity, and (e) radial velocity.

7
H. Park, C.-S. Han, C.-W. Park et al.
Fig. 9. Number of particles passing through planes that were 1, 5, 10 mm from the mouthpiece exit. (a) Prototype I, (b) prototype II, (c) prototype III, and (d) prototype IV.
4.3. ACI experimental result and discussions
An ACI was used to investigate the aerosol performance based on the
device mouthpiece geometries. Fig. 11 and Table 2 present the distribu-
tions of the SAL and FLU in terms of the percentage of particle deposi-
tion at each stage and the corresponding aerosol performance
parameters, respectively. All devices with newly designed mouthpieces
(e.g., prototypes II, III, and IV) demonstrate improved aerosol perfor-
mances in terms of both SAL and FLU microparticles compared with
prototype I. The aerodynamic parameter, i.e., the ED values of the two
drugs in the four different prototypes are beyond 93%, indicating a sig-
nificantly low dose loss in the blister (p < 0.05, ANOVA/Tukey). Proto-
type IV emits a dose that is 2%–5% higher compared with those of
other types. Moreover, FPF values increase with mounting all the pro-
posed mouthpieces, compared with those of prototype I. In general,
higher FPF values are observed in prototype IV, and in particular, the
FPF (<1.1 μm) values of prototype IV are 22.04 ± 5.82% to 20.61 ±
5.27%, which are significantly higher than those of the basic model
(10.09 ± 1.09% to 11.82 ± 1.17%). This indicates a higher delivery of
Fig. 10. (a) Peak number of particles passing through a plane at 5 mm simultaneously; (b) time required by particles to travel between planes.
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Powder Technology 398 (2022) 117039
emitted particles to the lungs. The MMAD values of prototypes II-IV
are smaller than those of prototype I. The GSD values of SAL and FLU
of all prototypes differ insignificantly and stays within the error range.
The low axial velocity contributes primarily to the improvement in
the aerodynamic parameters, such as the MMAD and FPF values,
when the newly proposed mouthpieces are used. Although prototype
III exhibits a spray pattern similar to that of drug particles sprayed
using prototype I, it indicates improved MMAD and FPF values in the
ACI results. The increased velocity of airflow through the narrow flow
passages enhanced particle collision, which increased the detachment
of the drug particles in the carrier-based DPI [18]. Hence, it can be con-
cluded that prototype III produced a significantly higher amount of fine
particles than prototype I.
Finally, the drug particle deposit ratio shows that the design of
mouthpiece prototype IV can improve the DPI performance in terms
of drug delivery to the respirable region of the lungs. More SAL particles
were deposited at the −1 (8.6) layer in the order of prototypes I, III, II,
and IV owing to the higher airflow velocity during inhalation, as
shown in the simulation results. However, the DPI incorporating the
H. Park, C.-S. Han, C.-W. Park et al. Powder Technology 398 (2022) 117039

Fig. 11. Distribution of SAL and FLU in terms of percentage of particle deposition at each stage.

Table 2
Aerosol performance parameters of SAL and FLU for different prototypes.

Device type Drug Aerosol performance parameters

ED% FPF% FPF% FPF% MMAD (μm) GSD

(<4.4 μm) (<2.0 μm) (<1.1 μm)

Salmeterol 94.16 ± 2.02 30.96 ± 8.47 27.14 ± 9.02 10.09 ± 1.09 3.96 ± 0.20 1.39 ± 0.16
Prototype I
Fluticasone 92.74 ± 1.89 27.69 ± 5.89 23.52 ± 5.43 11.82 ± 1.17 3.69 ± 0.53 1.55 ± 0.14
Salmeterol 94.24 ± 0.60 40.03 ± 5.91 36.71 ± 5.34 22.41 ± 4.51* 3.25 ± 0.12 1.43 ± 0.02
Prototype II
Fluticasone 92.53 ± 0.88 37.74 ± 1.541 33.57 ± 2.60 15.81 ± 2.83 3.64 ± 0.15 1.41 ± 0.05
Salmeterol 93.78 ± 1.21 39.23 ± 1.30 35.89 ± 1.00 20.36 ± 1.14* 3.38 ± 0.98 1.60 ± 0.23
Prototype III
Fluticasone 92.75 ± 1.35 40.35 ± 0.72 36.85 ± 0.28 19.27 ± 1.67 3.47 ± 0.12 1.43 ± 0.06
Salmeterol 98.87 ± 0.33 38.15 ± 10.04 35.58 ± 9.60 22.04 ± 5.82* 3.17 ± 0.04 1.68 ± 0.07
Prototype IV
Fluticasone 94.35 ± 0.66 40.05 ± 10.14 36.85 ± 0.28 20.61 ± 5.27* 3.38 ± 0.04 1.51 ± 0.06

newly proposed mouthpieces delivered more drug particles to the
deeper layers, such as 5 (0.54) and 6 (0.25), which agrees well with
the FPF results. The simulations and PIV experiments results indicate
that the spiral channel created a swirl flow motion from the mouthpiece
exit. The swirl flow decreased the axial velocity and resulted in a more
uniform particle distribution in all spaces. A high central air-velocity,
such as that in the non-spiral device, induced an inertial impact on the
particles on the upper airway, preventing particle sedimentation and
diffusion into the deeper lungs [20,21]. The spiral structure distributed
the air velocity evenly in all directions, and this irregular dispersion
eliminated the particle agglomerates and liberated the fine drug parti-
cles from the carrier surface by sufficient collision and drag forces. In
Fig. 5(d), the streamlines indicate that prototype IV induces the stronger
vortex flow near the mouthpiece outlet. Although the pressure drop ac-
cording to the flow path design is about twice as low as prototype II
(Fig. 8(a)), prototype IV has similar FFP values but superior ED and
MMAD values listed in Table 2. In addition, the results in Fig. 11 reveals
that the loss of the drug particles is less, and more drug particles could
be delivered deep into the lungs.
5. Conclusions
Four different mouthpiece prototypes were proposed, and the
change in aerodynamic characteristics for each prototype was investi-
gated through experiments and simulations. It was discovered that
injecting drug particles with an innovative mouthpiece design of the
DPI changed the airflow characteristics and particle dispersion patterns,
thereby significantly improving the drug particle delivery on the target
region of the respiratory system. A helical air path was generated in the
mouthpiece to induce a strong swirl motion as air flowed through it to

9
H. Park, C.-S. Han, C.-W. Park et al.
change the spray characteristics. A mouthpiece designed to have only a
helical air path decreased the penetration length and axial velocity by
43% and 40%, respectively, whereas it increased the spray angle by up
to 214%. However, these effects did not result from the swirl motion of
the air. Instead, the prototype increased the speed of the drug particles
in the radial direction, which increased the possibility of inertial colli-
sion in the oral cavity. Therefore, an optimal point must be identified
by adjusting the rotational speed. This can be achieved by adding a
mixing room for particles before injection, which will decrease the par-
ticle speed in the radial direction and result in a more radially uniform
particle dispersion. In addition, the effect of a high-speed collision be-
tween particles in the mixing chamber is anticipated. However, in this
study, all the particle sizes were assumed to be identical, and the de-
struction of the particles was not considered; hence, the collision effect
could not be evaluated. Another mouthpiece designed to induce a radial
dispersion of drug particles without air rotation barely indicated any ef-
fect from increasing the spray angle. This was because the angle of the
air passage was not sufficiently large in the external condition of the
mouthpiece, which had to be adjusted to the size of the mouth opening.
From the aerodynamics standpoint, segregating the passage into several
streams in the same exit area would result in an undesirable effect
owing to the increase in the airflow resistance and flow velocity rather
than a gain in the changing direction. A ring-shaped exit surface that can
be directed outward without segregating the passage should be applied
for further improvements.
Declaration of Competing Interest
The authors whose names are listed immediately below certify that
they have NO affiliations with or involvement in any organization or en-
tity with any financial interest (such as honoraria; educational grants;
participation in speakers’ bureaus; membership, employment, consul-
tancies, stock ownership, or other equity interest; and expert testimony
or patent-licensing arrangements), or non-financial interest (such as
personal or professional relationships, affiliations, knowledge or beliefs)
in the subject matter or materials discussed in this manuscript.
Author names: Hyeon-kang Park, Chang-Soo Han, Chun-Woong
Park, Kibum Kim
The authors whose names are listed immediately below report the
following details of affiliation or involvement in an organization or en-
tity with a financial or non-financial interest in the subject matter or
materials discussed in this manuscript.
Acknowledgments
This research was supported by National Research
Foundation of Korea Grant, funded by the Korean government
10
Powder Technology 398 (2022) 117039
(NRF-2018R1A1A1A05023012, NRF-2018R1D1A1B07050538, and
2017R1A5A2015541) and a grant of the Korea Health Technology
R&D Project through the Korea Health Industry Development
Institute (KHIDI), funded by the Ministry of Health &Welfare,
Republic of Korea (grant number: HI14C1069).
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