Aerosol Science 37 (2006) 1520 1531

www.elsevier.com/locate/jaerosci

Standardized entrainment tubes for the evaluation of

pharmaceutical dry powder dispersion
Margaret D. Loueya,1 , Michiel Van Oortb , Anthony J. Hickeya,
a Dispersed Systems Laboratory, Division of Molecular Pharmaceutics, School of Pharmacy, Kerr Hall, CB#7360, University of North Carolina,

Chapel Hill, NC 27599, USA

b Inhalation Product Development, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC, USA

Received 1 June 2005; received in revised form 24 April 2006; accepted 24 April 2006

Abstract
A series of standardized entrainment tubes (SETs) were designed to provide a method for evaluation of aerosol dispersion of
pharmaceutical powders. The range of specic resistances (RD ) provided by the SETs encompassed those of commercial DPIs. The
airow conditions within the SETs were characterized in terms of pressure drop (
P ), power, Reynolds number (Re) and shear
stress (
s ) at airow rates of 28.3 and 60 L/min. The aerosol performance of a commercial powder formulation (Ventolin Rotacaps)
obtained using the SETs was measured by cascade impaction; and characterized using emitted dose (ED), ne particle mass (FPM),
mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). The use of SETs allowed the aerosol
performance of the powder formulation to be measured under well dened geometry and ow conditions. Good reproducibility in
ED, FPM and MMAD results were obtained from SETs. Comparable values were obtained from SETs at similar resistance levels to
the commercial inhaler devices (Rotahaler and Inhalator). The SETs enabled examination of fundamental relationships between
airow conditions and aerosol performance.
2006 Elsevier Ltd. All rights reserved.
Keywords: Standardized entrainment tubes; Dry powder inhaler (DPI); Specic resistance; Reynolds number; Pressure drop; Power; Shear stress;
Emitted dose; Fine particle mass (FPM); Mass median aerodynamic diameter (MMAD)

1. Introduction
Respiratory drug delivery from passive dry powder inhalers (DPIs) involves the aerosol dispersion of a dry powder
formulation from an inhaler device using the patients inspiration force. The airow through the inhaler device provides detachment forces which overcome the interparticulate forces within the powder formulation to produce drug
particles that are sufciently small to be deposited into the patients lungs. The interparticulate (adhesion and cohesion)
forces within dry powder formulations include van der Waals forces, electrostatic forces, capillary forces, mechanical
interlocking and frictional forces (Dunbar, Hickey, & Holzner, 1998). The magnitude of adhesion forces is proportional to the particle diameter (d). Particle detachment forces include aerodynamic forces (drag and lift), which are
Corresponding author. Tel.: +1 919 966 0223; fax: +1 919 966 0197.

E-mail address: ahickey@unc.edu (A.J. Hickey).

1 Present address: Inhalation Product Development, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC, USA.

0021-8502/$ - see front matter 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jaerosci.2006.04.002

M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

1521

proportional to d 2 ; inertial forces (vibration, rotation, centrifugal and collision) and shear and friction forces, all of
which are proportional to d 3 (Dunbar et al., 1998; de Boer, Hagedoorn, Gjaltema, Goede, & Frijlink, 2003).
The efciency of a DPI is dependent on a complex relationship between the dispersability of the powder formulation
and the dispersion efciency of the inhaler device and the detachment forces provided by the airow (patient or vacuum
pump). The dispersability of powder formulations may be optimized by drug and excipient properties and processing
parameters (Crowder, Louey, Sethuraman, Smyth, & Hickey, 2001). The dispersion efciency of inhaler devices is
considered to be directly related to specic resistance (RD ) (Clark & Hollingworth, 1993):

P = RD .Q.

(1)

where
P is pressure drop across device and Q is the volumetric ow rate. The RD is dependent on the internal
dimensions and geometry of the airow path of the inhaler device, where smaller internal diameters produce higher
RD . The RD dictates the volumetric airow rate obtained through inhaler devices at a given pressure drop. Higher
volumetric airow rates are obtained from inhaler devices with lower RD . Higher airow rates produce higher ne
particle fractions (FPF) (Zanen, vanSpiegel, vanderKolk, Tushuizen, & Enthoven, 1992; Smith, Chan, & Brown, 1998;
DeLong et al., 2005) and greater lung deposition (Pitcairn, Lunghetti, Ventura, & Newman, 1994; DeLong et al., 2005).
Inhaler devices with higher RD are expected to generate greater turbulence and produce higher FPF for a given airow
rate (Srichana, Martin, & Marriott, 1998).
Inhaler devices contain specic design features, such as tortuous airow paths, grids or impactor plates, to enhance
the uidization and deaggregation of powder formulations (Dunbar et al., 1998; Crowder et al., 2001). Shear force
uidization (or saltation) is the predominant mechanism in many passive devices (Dunbar et al., 1998). It occurs
when the airstream passes over a powder bed within a pocket or on an open surface. The viscous shear stresses in
the boundary layer of the airstream cause the particles to lift from the powder bed surface. Shear force uidization
is dependent on the airow velocity. Other mechanisms of uidization include hydrodynamic (gas-assist or capillary)
and mechanical (vibration and impaction) (Dunbar et al., 1998). Turbulence is the main mechanism for deaggregation
of powder formulations cited in the pharmaceutical literature (Ganderton, 1992; Timsina, Martin, Marriott, Ganderton,
& Yianneskis, 1994; Srichana et al., 1998). Other mechanisms of deaggregation include relative motion, shear stress,
electrostatics and collision (Dunbar et al., 1998). Greater turbulence provided by the inhaler device is expected to
increase aerosol dispersion, resulting in higher FPF. However, the turbulence within the inhaler devices has been rarely
examined.
The complex geometries of the internal air channels of inhaler devices produce complicated ow elds. This creates
difculty in the complete characterization of airow within the inhaler devices. In addition, the airow within the
internal air channels of inhaler devices is unlikely to be fully developed due to their short length; instead, consisting
of an intermediate state where a turbulent core is surrounded by a laminar envelope, with neither laminar nor turbulent
airow being dominant (Dunbar et al., 1998).
The in vitro aerosol dispersion of powder formulations is generally evaluated using a specic commercial device.
A given powder formulation will produce differing performance results, depending on the inhaler device used, even
when operated at same airow rate. The comparison of powder formulations is only possible using identical inhaler
devices. Also, the prediction of aerosol dispersion of a specic formulation from one inhaler device is not possible from
the knowledge of its dispersion properties using a different inhaler device. Thus, a standardized method to evaluate
aerosol dispersion of powder formulations independent of a specic inhaler device would be ideal. However, this type
of method is not currently available.
The primary objective of the experiments described here were to examine the use of standardized entrainment tubes
(SETs) as a method to examine aerosol dispersion of pharmaceutical dry powder formulations. The use of SETs would
provide a standardized method to examine powder aerosol dispersion without reliance on a particular inhaler device,
thereby eliminating complexities provided by commercial inhaler devices, such as adhesion to capsules or blisters,
mouthpiece or torturous internal channel; or requirement of special lling equipment. This would enable the evaluation
of powder performance, as opposed to product performance which provides the combination of powder formulation
and inhaler device.
A secondary objective is to characterize the airow conditions provided by the SETs using the following parameters: pressure drop (
P ), power, Reynolds number (Re) and shear stress (
s ) at airow rates of 28.3 and 60 L/min
(equivalent to 4.716 104 and 0.001 m3 /s, respectively); and to examine their relationships with aerosol dispersion

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M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

I
a

b
e

f
28.4 MM

22 MM
INLET
OUTLET POWDER DOSAGE AREA

POWDER DOSAGE AREA

II

3.5
c
f

28.4 MM

OUTLET

INLET
POWDER DOSAGE AREA
d

POWDER DOSAGE AREA

22 MM

Fig. 1. Schematic diagram of standardized entrainment tubes (SETs) with I. peripherally-located dosage table and II. centrally-located dosage table.

Table 1
Dimensions (mm) of the standardized entrainment tubes (SETs) as shown in Fig. 1 with (I) peripherally-located dosage table and (II) centrally-located
dosage table
SET

External outlet length

(a)

Inlet length
(b)

Internal outlet length

(c)

Powder dosage length

(d)

Inlet outer diameter

(e)

Inlet inner diameter

(f)

A (I)
B (I)
C (II)
D (II)

150
135
127
100

300
300
600
600

140
125
117
90

10
10
10
10

6.3
7.9
9.5
12.7

4.5
6.2
7.7
11.0

of a commercially available powder formulation (Ventolin Rotacaps). The aerosol performance obtained using the
SETs will be compared to that obtained from two commercial inhaler devicesRotahaler and Inhalator, which
are representative of low and high resistance devices, respectively.
2. Design of standardized entrainment tubes
A series of four SETs were designed to be easy to use and provide a range of specic resistances (RD ) which
encompassed those of commercial DPIs. The airow elds at the immediate point of powder dispersion were fully
developed. This enables accurate characterization of airow conditions, since the ow is not inuenced by entrance
effects and the velocity prole does not vary along the primary ow axis (Geankoplis, 1993).
A schematic diagram of the entrainment tubes is provided in Fig. 1 with dimensions listed in Table 1. The inlet
internal diameters (4.511 mm) were limited to commercially available tubing sizes. The outlet internal diameter was
designated as 22 mm, which is equivalent to the internal diameter of the USP metal throat inlet. This eliminated eddy
formation during airow transit from the entrainment tube into the cascade impactor. This diameter is also comparable to
the size of a mouth opening. The outlet outer diameter was designated as 28.4 mm to allow insertion into the USP metal
throat inlet. Inlet tube lengths of at least 50 diameters were provided to allow sufcient length for full development
of turbulent airow proles (Welty, Wicks, & Wilson, 1984). A conical diffuser angle of 7 was used to minimize

M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

1523

energy loss as a result of the pipe enlargement (Sakiadis, 1984). This gradual enlargement could only be implemented
in SETs with larger inlet diameters (C and D), due to physical manufacturing limitations. The outlet tube length was
dictated by the diameter ratio between inlet and outlet internal diameters and the enlargement angle of 7 (divergence
half angle of 3.5 ). The SETs with the smaller inlet diameters (A and B) contained a sudden enlargement and outlet
lengths were calculated taking into account a gradual enlargement of 7 . This allowed for spontaneous enlargement
of ow on the principle of vena contracta formation seen in orice meters (Ganderton & Hickey, 1997). The tubes
consisted of stainless steel with surfaces polished smooth to minimize frictional losses and disruptions to the airow
behavior.
The powder dosage area was located within the inlet tubes proximal to the outlet tube entrance. A centrally located
dosage platform, consisting of a Y-shaped stainless steel section sufciently large to accommodate 20 mg of powder,
was utilized in the larger SETs (C and D). This central location maximized airow velocity but minimized shear.
Maximum shear occurs at the boundary layer present at the tube walls (Ganderton & Hickey, 1997). Due to physical
limitations (insufcient space to accommodate 20 mg of powder on the dosage platforms) in the smaller SETs (A and
B), the powder formulation was loaded directly onto the peripheral walls at the same proximal location. This peripheral
location was more representative of the situation within DPI devices and provided maximum shear.
The inlet and outlet tube sections of the SETs were designed to be screwed apart to enable powder dosage loading.
For powder loading, the inlet and outlet tubes were separated. The powder formulation from one Ventolin Rotacap
was carefully emptied onto weighing paper and transferred onto the loading area of the SET using a spatula. In SETs
A and B, the powder was loaded directly onto the walls of the inlet section immediately proximal to where the outlet
section is attached. In SETs C and D, the powder was loaded onto a Y-loading section, which is located immediately
proximal to where the outlet section is attached. This elevated the powder dose to a central location within the circular
cross-section of the tube. Thus, the powder formulation was loaded in the same proximal location for all SETs and
although physical limitations prevented a Y-section to be used in tubes A and B, the powder dose was also located
centrally within tubes A and B, due to its bulk volume. Following powder loading, the inlet section was held to prevent
any spillage while the outlet section was carefully screwed into place. After the inlet and outlet sections were attached
together, the entire SET was held horizontal using retort stands and clamps and placed into the mouthpiece of the USP
throat of the cascade impaction.
3. Characterization of standardized entrainment tubes
Airow through the SETs may be laminar or turbulent, depending on the airow rate and internal diameter. Laminar
ow is an organized ow eld with postulated parallel non-overlapping ow streamlines where the viscous forces are
greater than the inertial forces. The uid layers may be visualized as sliding past without any lateral mixing or cross
currents perpendicular to the direction of the ow. Turbulent ow is a chaotic ow eld with eddies present, where uid
particles move in all trajectories relative to the direction of the ow and produce lateral mixing. Turbulent ow occurs
when the disruptive inertial forces overcome the retaining viscous forces (Reist, 1993; Geankoplis, 1993). Reynolds
number (Re) is a dimensionless number used to predict the transition from laminar to turbulent ow. For straight circular
pipes (such as the SETs), the laminar ow is present at Re values smaller than 2100; and turbulent ow is present at Re
values greater than 4000 (except in special circumstances). Within the transitional region (Re values between 2100 and
4000), the ow may be laminar or turbulent but cannot be predicted (Geankoplis, 1993). Re also represents a measure
of shear forces experienced within the pipe. In similar types of ow, such as provided by the SETs, a higher Re value
will correspond to higher shear forces. The Re represents the ratio of inertial forces (due to acceleration or deceleration)
to the viscous forces (due to the viscosity of the medium; or specically, air in this study) (Reist, 1993):
Re =

Finertial
d
,
=
Ffriction


(2)

where  is the density of air (1.20 kg/m3 at 20 C),  is the linear velocity, d is the diameter of the pipe and  is the
dynamic viscosity of air (1.81 105 kg/(m s) at 20 C). The linear velocity was calculated as the quotient of the
volumetric ow rate (Q) (i.e. 28.3 or 60 L/min) divided by the cross-sectional area of the critical orice (smallest internal
diameter) in the airow path. The Re values were calculated at the critical orice for the SETs and inhaler devices. The
critical orice for each SET coincides with the powder dosage area. Since the airow at the point immediately prior to
powder dispersion was fully developed, it is accurately characterized by the Re value. Although the internal diameter

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M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

widens past the critical orice in the SETs, this represents a location past the initial point of powder dispersion, where
powder entrainment and deaggregation occurs. The larger diameter produces smaller linear velocity and reduced Re
values and shear forces, therefore the effects on powder motion are expected to be less signicant than at the critical
orice.
The Re values of the inhaler devices (Rotahaler and Inhalator) were calculated at their smallest internal diameter
within the airow path. However, this area did not coincide with the powder dosage area for either inhaler. In addition,
the airow is not fully developed in inhaler devices due to their short length and complex geometries (Dunbar et al.,
1998). Thus, the calculated Re values of the inhaler devices provided an estimate of the potential maximum Re value
for each inhaler.
Re can also be used to describe the ow around an object, such as a particle or agglomerate. However, within this
study, Re will describe the ow within a pipe (SETs or inhaler devices). It is beyond the scope of this paper to examine
the airow around the particles or agglomerates of the powder formulation. This has been previously examined by
other researchers (French, Edwards, & Niven, 1996; Dunbar et al., 1998).
Shear stress is the force required for one layer of uid to slip over another layer. The viscous shear stress (
s ) for
turbulent airow was calculated from a nozzle ow applied from Kolmogorov theory (Shekunov, Feeley, Chow, Tong,
& York, 2003):



s = 
,
(3)

where


23
,
d

(4)

where
 0.2,

(5)

where  is the dynamic viscosity of air (1.81 105 kg/(m s) at 20 C),  is the kinematic viscosity of air (1.5
106 m2 /(m s),  is the mean turbulent energy dissipation rate,  is the root-mean square velocity uctuation of the
nozzle velocity () and d is the nozzle diameter.
The pressure drop (
P ) was calculated from the measured specic resistance of each SET and inhaler device using
Eq. (1).
The power is the rate of work done by the airow through the entrainment tube or inhaler device (Dunbar, Morgan,
Van Oort, & Hickey, 2000):
Power =
P .Q,

(6)

where
P is the pressure drop and Q is the volumetric airow rate. Power is equivalent to the rate of inspiratory effort
during inhalation.
4. Experimental methods
The pressure drop (
P ) across the SETs and inhaler devicesRotahaler (Glaxo Wellcome, RTP, NC) and
Inhalator (Boehinger Ingelheim, Germany)was measured using a glass U-tube manometer (30cm, Fisher Scientic Co., PA). The
P was measured at airow rates of 25, 30, 35, 40, 50, 60, 70 and 80 L/min. The
P of the inhaler
devices was determined with a Ventolin rotacap loaded into the capsule position, since this affected the size of the
critical orice. The specic resistance (RD ) was obtained from the linear plot of
P 0.5 against the airow rate. Values
of Reynolds number (Re), shear stress (
s ) and power for the entrainment tubes and inhaler devices were calculated
using Eqs. (2)(6).
The aerosol performance of a powder formulation was determined using an 8-stage, non-viable cascade impactor
with a preseparator (GrasebyAndersen, GA) at 28.3 and 60 L/min using SETs and inhaler devices. The preseparator
contained 10 mL of distilled water and the impaction plates were pre-coated with a 1% w/v solution of silicon oil in
hexane to prevent particle bounce and re-entrainment. The SET or inhaler device, throat and preseparator, individual

M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

1525

impaction plates and stages were rinsed with distilled water following impaction. The rinsing liquid was collected,
diluted to an appropriate volume and the drug content was determined. The temperature and relative humidity of the
surrounding environment was measured prior to each impaction. Cascade impactions were performed in triplicate.
A solenoid valve was employed to provide a square ramping of the airow into the cascade impactor. A commercial
product, Ventolin rotacaps (GlaxoSmithKline), was used as the model powder formulation. Each capsule contained
200 g albuterol sulfate in a lactose blend. This powder was chosen because it is a well-known and characterized
pharmaceutical powder, that is inexpensive and easy to remove from the capsules. The rotacaps were used as supplied
for the inhaler devices (Rotahaler and Inhalator). The entire contents of one capsule were emptied for powder
loading into the SETs (described above). Each dose was actuated for 10 s. Three separate doses were actuated for each
impaction. Although a dose actuation of 10 s is longer than the duration recommended in the USP and provides a larger
airow volume than physiological conditions, an identical method was performed for all measurements in the study
allowing comparison between aerosol dispersion from the inhalers and SETs.
Cascade impaction is commonly used as an in vitro method of evaluation of aerosol dispersion. The emitted dose
(ED) represents the degree of powder entrainment, where higher ED values indicate greater entrainment. The ED is
calculated as the mass of drug collected in the cascade impactor (which includes the USP throat and preseparator, all
impactor stages and lter), expressed as a percentage of the total mass of drug collected from the inhaler device or
entrainment tube and the cascade impactor.
The ne particle mass (FPM) represents the degree of drug deaggregation, where higher FPM values represent
greater deaggregation. The FPM is calculated as the total mass of dispersed drug particles collected on stages 2 and
below (smaller than 5.8 m aerodynamic diameter) using 28.3 L/min and deposited at stage 1 and below (smaller than
6.2 m aerodynamic diameter) using 60 L/min. The airow rate dictates the cut-off diameter for each given impactor
stage. The cut-off diameters for the Andersen cascade impactor stages are calibrated at 28.3 L/min and calculated at
60 L/min using Stokes law. Since matching cut-off diameters do not exist at airow rates of 28.3 and 60 L/min, the
cut-off diameters of 5.8 and 6.2 m were selected to provide similar values for the calculation of FPM.
The mass median aerodynamic diameter (MMAD) also represents the degree of deaggregation, where smaller
MMAD values represent greater deaggregation. The MMAD was calculated as the 50th percentile of the aerodynamic
particle size distribution by mass. The geometric standard deviation (GSD) was calculated as the ratio of the particle
size at the 84th percentile to that at the 50th percentile, assuming a lognormal distribution. The MMAD and GSD were
determined from the linear region of the plot (between the 16th and 84th percentile) of the cumulative mass distribution
as a function of the logarithm of aerodynamic diameter.
A spectrouorometric assay (Luminescense Spectrometer, Perkin Elmer, Norwalk, CT; ex = 230 nm and em =
310 nm) was employed for determination of albuterol sulfate. A linear range between 0.5 and 7.5 g/mL was obtained
(r 2 = 0.996). The limits of detection and quantitation were determined as 0.25 and 0.5 g/mL, respectively.
Statistical analysis between aerosol performance parameters obtained from entrainment tubes and inhaler devices
was performed using a one-way analysis of variance (ANOVA), at the 5% level (Sigmastat v1.0, Jandel Corporation,
CA). Statistical analysis between aerosol dispersion parameters obtained from 28.3 and 60 L/min was performed using
the Student t-test, at the 5% level (Sigmastat v1.0, Jandel Corporation, CA).
5. Results
The airow conditions provided by the SETs and inhaler devices at 28.3 and 60 L/min are listed in Table 2. Linear
regressions were obtained when
P 0.5 was plotted against volumetric ow rate (r 2 > 0.99 in all cases). The RD
obtained from the SETs ranged from 0.021 to 0.140 cm H2 O0.5 /(L/ min). This range encompassed the RD of the
commercial inhaler devices examined, with the Rotahaler being representative of a low resistance device (0.036 cm
H2 O0.5 /(L/ min)) and the Inhalator being representative of a high resistance device (0.123 cm H2 O0.5 /(L/ min)).
At a given airow rate, SETs with higher RD exhibited higher values of Re,
s ,
P and power. For each given SET or
inhaler device, higher values of Re,
s ,
P and power were obtained at the higher airow rate.
The aerosol performance data obtained at 28.3 and 60 L/min using SETs and inhaler devices are presented in Table 3.
The cascade impaction studies were undertaken in laboratory conditions of 21.5.24.0 C and 2244%RH. Signicantly
differences (p < 0.05 in all cases) were observed in the ED, FPM and MMAD values obtained at each given airow
rate, due to the SET or inhaler device used. As expected, higher ED and FPM values and lower MMAD values were
obtained for each given inhaler or SET at the higher airow rate (60 L/min) (p < 0.05 in all cases). By contrast, similar

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M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

Table 2
Airow parameters of inhaler devices and standardized entrainment tubes (SETs)
Specic resistence
(RD )

Reynolds number
(Re)

Pressure drop (
P )

(N/m2 )

Power
(Nm/s)

(cm H2 O0.5 /(L/ min))

28.3 L/min

60 L/min

28.3 L/min

60 L/min

28.3 L/min

60 L/min

28.3 L/min

60 L/min

Rotahaler
Inhalator

0.036
0.123

5102
12208

10810
25865

101.79
1188.21

457.53
5340.98

0.0480
0.5604

0.4575
5.3410

0.656
13.908

2.026
42.934

SET A
SET B
SET C
SET D

0.140
0.065
0.046
0.021

8705
6344
5223
3644

18443
13440
11066
7720

1539.35
331.82
166.19
34.64

6919.38
1491.55
747.01
155.69

0.7261
0.1565
0.0784
0.0163

6.9194
1.4915
0.7470
0.1557

4.257
1.407
0.712
0.202

13.143
4.342
2.199
0.624

Inhaler/SET

Shear stress (
s )

(N/m2 )

Table 3
Aerosol dispersion obtained for inhaler devices and standardized entrainment tubes (SETs) (Mean values, n=3 with standard deviation in parentheses)
MMAD (m)

GSD

22.4 (12.9)
57.8 (9.0)

6.0 (0.0)
4.1 (0.2)

1.6 (0.0)
1.7 (0.0)

52.4 (1.7)
52.8 (2.6)
80.4 (1.9)
73.6 (3.2)

76.4 (6.8)
72.1 (5.9)
52.8 (4.0)
23.1 (4.0)

4.9 (0.1)
5.1 (0.0)
5.8 (0.1)
7.0 (0.3)

1.7 (0.0)
1.7 (0.0)
1.6 (0.0)
1.6 (0.0)

60
60

58.7 (1.4)
70.4 (10.8)

85.4 (18.7)
131.6 (35.2)

3.7 (0.1)
2.8 (0.4)

1.6 (0.0)
1.7 (0.1)

60
60
60
60

78.8 (2.6)
67.5 (2.9)
87.1 (1.9)
90.8 (0.8)

157.5 (5.8)
121.6 (33.3)
94.5 (6.9)
96.1 (13.1)

3.6 (0.1)
3.6 (0.0)
3.8 (0.0)
4.0 (0.3)

1.6 (0.0)
1.6 (0.0)
1.6 (0.0)
1.6 (0.0)

Inhaler/SET

Flowrate (L/min)

ED (%)

Rotahaler
Inhalator

28.3
28.3

27.9 (15.8)
33.5 (2.7)

SET A
SET B
SET C
SET D

28.3
28.3
28.3
28.3

Rotahaler
Inhalator
SET A
SET B
SET C
SET D

FPM (g)

GSD values (1.61.7) were obtained from inhaler devices and SETs at all airow rates. The airow parameters
(Re,
s ,
P and power) were plotted against the FPM and MMAD obtained from SETs and inhaler devices (Figs. 2 and 3).
6. Discussion
SETs were developed to provide a standardized method for the evaluation of pharmaceutical powder formulations.
Currently, powder formulations are evaluated using specic inhaler devices. The airow behavior within inhaler devices
cannot be accurately characterized as the ow is not fully developed due to the short path lengths and complex geometries
(Dunbar et al., 1998). In contrast, airow within the SETs is fully developed and was characterized using a variety of
airow parameters (Re,
s ,
P and power). Different RD were obtained by varying the internal diameters of the SET.
Smaller internal diameters increased the RD . The RD range provided by the SETs emcompassed those of the commercial
inhaler devices. Thus, SETs enable powder formulations to be evaluated at different RD without the added complexities
of using different inhaler designs. As expected, the aerosol performance obtained from the SETs was dependent on
the RD value. Increasingly higher FPM and smaller MMAD were obtained using SETs with higher RD at each given
airow rate. In this study, the SETs were used to evaluate the aerosol dispersion of the Ventolin formulation. The
analysis demonstrated good reproducibility and low variability in the ED, FPM, MMAD and GSD results obtained
using SETs. The variability observed was smaller than or equivalent to that obtained using the commercial inhaler
devices (Rotahaler and Inhalator) examined. This indicated that the SETs provide a reproducible and robust
method for the evaluation of aerosol dispersion of pharmaceutical powders. However, further evaluation of different
powder formulations is required for conrmation.

M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

200
Fine Particle Mass (g)

Fine Particle Mass (g)

200

150

100

50

0
2000

4000

6000

100

50

8000

Pressure Drop (N/m2)

(A)

10

Power (Nm/s)

(B)
200
Fine Particle Mass (g)

200
Fine Particle Mass (g)

150

0
0

150

100

50

150

100

50

0
0
(C)

1527

10

20
30
Shear Stress (N/m2)

40

50

0
(D)

10000
20000
Reynold's Number

30000

SET, 28.3 L/min

SET, 60 L/min
Inhalers, 28.3 L/min
Inhalers, 60 L/min
Fig. 2. The relationship between airow parameters: A. pressure drop; B. power; C. shear stress; and D. Reynolds number and ne particle mass
(FPM) of Ventolin powder formulation obtained using standardized entrainment tubes (SETs) and inhaler devices (Mean St. dev, n = 3).

Surprisingly, the aerosol dispersion results obtained for the commercial Ventolin formulation using the SETs
were very similar to those obtained using inhaler devices of similar RD . This was an unexpected observation when
the differences in geometry and complex nature of the commercial inhaler devices are considered. The FPM results
were especially well correlated. The FPM values obtained using the Rotahaler (22.4 g at 28.3 L/min and 85.4 g
at 60 L/min) were similar to those obtained using SET D (23.1 g at 28.3 L/min and 96.1 g at 60 L/min). The FPM
values obtained using the Inhalator (57.8 g at 28.3 L/min and 131.6 g at 60 L/min) was contained within the range
obtained using SETs B and C at 28.3 L/min (52.8.72.1 g) and SETs A and B at 60 L/min (121.6.157.5 g). These
similarities demonstrate that the SETs were able to produce a good representation of the performance of commercial
inhalers and can provide meaningful results.
Slight differences were observed between the ED and MMAD results obtained from the SETs and commercial inhalers. The ED values obtained using the SETs were generally higher than those obtained using the inhaler
devices. The lower ED obtained using inhaler devices was attributed to the powder formulation being contained
within gelatin capsules, which is likely to hinder the powder uidization and entrainment. In the Rotahaler, the
capsule is broken into two halves and powder is dumped into the main body of the inhaler by gravity. Powder

M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

MMAD (m)

MMAD (m)

1528

5
4
3

2
0

2000

4000

6000

8000

Pressure Drop (N/m2)

(A)

-2

5
4

10

Power (Nm/s)

(B)

MMAD (m)

MMAD (m)

4
3

5
4
3

2
0
(C)

10

20
Shear Stress

30
(N/m2)

40

50

0
(D)

10000

20000

30000

Reynold's Number

SET, 28.3 L/min

SET, 60 L/min
Inhalers, 28.3 L/min
Inhalers, 60 L/min

Fig. 3. The relationship between airow parameters: A. pressure drop; B. power; C. shear stress; and D. Reynolds number and mass median
aerodynamic diameter (MMAD) of Ventolin powder formulation obtained using standardized entrainment tubes (SETs) and inhaler devices
(Mean St. dev, n = 3).

entrainment occurs by mechanical vibration, impaction and shear force. In the Inhalator, the powder formulation
is entrained from the capsule through two pierced holes by capillary uidization (Dunbar et al., 1998). Following
uidization of the powder formulation, the powder may adhere to the internal surfaces (such as grids, mouthpiece)
of the inhaler which may further reduce ED. In contrast, powder uidization and entrainment from the SETs was
not hindered by capsules or grids allowing higher ED to be obtained. Another difference between SETs and the
commercial inhaler devices is the materials used. The commercial inhalers consist of plastic, compared to stainless steel used in the SETs; which is likely to inuence electrostatic charge of the powder formulations during
aerosolization.
The MMAD values obtained using the Inhalator were smaller than those obtained using the SETs. It was unlikely
that the impaction grids present in the Inhalator aided deaggregation of the powder formulation since a similar

M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

1529

impaction grid was present in the Rotahaler, which produced high MMAD values. Another function of the impaction
grid in the Rotahaler is to prevent inhalation of the capsule. Impaction has been observed to be an ineffective mechanism
of deaggregation (Voss & Finlay, 2002). A more likely explanation for the low MMAD values obtained using the
Inhalator was that shearing of aggregates during passage through the capsule holes provided an additional mechanism
for particle deaggregation, as previously observed where higher FPF were obtained with smaller capsule holes using
the Aerolizer (Coates, Fletcher, Chan, & Raper, 2005a).
Another benet of using SETs is that the airow was fully developed and was characterized using Re,
s ,
P and
power at the airow rates of 28.3 and 60 L/min. This allowed the relationships between airow parameters (Re,
s ,
P
and power) and aerosol dispersion (FPM and MMAD) to be examined. Increasing Re,
s ,
P and power produced
higher FPM and smaller MMAD (Figs. 2 and 3). Higher FPM and smaller MMAD represent greater drug deaggregation
within the powder formulation. Hyperbola-shaped relationships were observed when Re,
s ,
P and power were plotted
against FPM. Greater initial increases in FPM were observed at low values of Re,
s ,
P and power, followed by smaller
increases in FPM at the higher values of Re,
s ,
P and power with FPM appearing to reach a plateau (maximum).
Exponential decay relationships were observed when Re,
s ,
P and power were plotted against MMAD. Greater initial
decreases in MMAD were observed at low values of Re,
s ,
P and power until a minima was reached. The results of
this study show the FPM maxima and MMAD minima (maximum deaggregation) of the Ventolin formulation were
obtained at
s of 10 N/m2 ,
P of 2000 N/m2 and power of 2 Nm/s.
These general relationships may be explained in terms of drug adhesion and deaggregation of the powder formulation.
Initially, loosely-adhered drug particles are easily deaggregated from the lactose surface by detachment forces provided
by the airow resulting in a rapid initial increase in FPM and decrease in MMAD. More strongly-adhered drug particles
remaining attached to the lactose surface require greater detachment forces to further increase FPM and decrease
MMAD. Eventually, the detachment forces provided by the airow are unable to overcome the remaining adhesion
forces between the drug and lactose particles of the powder formulation, which results in a plateau in FPM (maxima)
and MMAD (minima). Further deaggregation may require even higher airow rates or additional mechanical forces or
may not be possible. The complete deaggregation of drug particles would produce a MMAD value equivalent to the
aerodynamic diameter of the primary drug particles. Unfortunately, the primary drug particle size is unknown since a
commercial formulation was examined. Further reduction of the MMAD to smaller diameters is unlikely since it would
require communition of the primary drug particle.
Although turbulence has been proposed as the primary mechanism for deaggregation (Ganderton, 1992; Timsina
et al., 1994; Srichana et al., 1998), the ow behavior within inhaler devices is rarely examined. In this study, the
airow behaviour within the SETs was determined by examining Re values. Turbulent ows (Re values greater
than 4000) were observed in the SETs at the airow rates of 28.3 and 60 L/min; with the exception of SET D
(largest diameter) at 28.3 L/min. SET D exhibited transitional ow (Re value of 3644) at 28.3 L/min. Although the
Re values for the inhaler devices were calculated to be greater than 4000, the airow likely consists of a turbulent
core surrounded by a laminar envelope (Dunbar et al., 1998). The insufcient development of fully turbulent ow
provides an explanation for the lower FPM obtained with inhaler devices at equivalent Re values, compared with
SETs. The larger laminar boundary layers present within the inhaler devices may reduce deaggregation of the powder
formulation.
Some previous studies have also examined the turbulent oweld within test inhalers and the effect on powder
dispersion. Higher FPF was obtained with increasing turbulence velocity using a powder deagglomeration rig with
impinging jets; however, turbulence was found not to be the sole mechanism of deaggregation. The relative velocity
and geometry between the powder and the entrainment air was proposed to affect the shear or drag forces acting
on the powder (Voss & Finlay, 2002). Computational uid dynamics (CFD) analysis of a Cyclohaler showed that
increasing airow rates produced higher turbulence levels, higher integral scale strain rates and increased the intensity
and number of particledevice impactions, which resulted in higher FPF (Coates, Chan, & Raper, 2005b). Increased
drug deaggregation from carrier particles was obtained with higher airow rates and dispersion time using a test inhaler
with air classier technology (de Boer et al., 2003). The results of this study indicate that Re,
s ,
P and power may
also provide surrogate measures of deaggregation. Both SETs and inhaler devices provided similar FPM values at
corresponding power values, indicating that power provides the best correlation with FPM when compared with the
other airow parameters examined. Both SETs and inhaler devices provided similar MMAD values at corresponding Re values, indicating that Re provides the best correlation with MMAD when compared with the other airow
parameters.

1530

M.D. Louey et al. / Aerosol Science 37 (2006) 1520 1531

7. Conclusion
A series of SETs with a range of specic resistances (RD ) were designed to provide a method for the evaluation
of aerosol dispersion of pharmaceutical dry powder formulations. The SETs enabled aerosol dispersion of powder
formulations to be evaluated without specic inhaler devices and their complex geometries and designs. The use of SETs
allowed aerosol dispersion to be measured under well dened geometry and fully developed airow conditions. The
SETs were used to examine the in vitro aerosol dispersion of a commercial powder formulation (Ventolin rotacaps).
Good reproducibility and low variability in ED, FPM and MMAD values were obtained using SETs. Comparable results
were obtained from SET at similar RD to commercial inhaler devices (Rotahaler and Inhalator). The adoption of
using SETs as a standard method to evaluate aerosol dispersion would improve knowledge of dry powder formulations.
Furthermore, the airow conditions within the SETs were characterized using Reynolds number (Re), shear stress
(
s ), pressure drop (
P ) and power. This enabled the relationship between there airow conditions and aerosol dispersion was investigated. Increasing Re,
s ,
P or power produced greater aerosol dispersion and resulted in higher
FPM and smaller MMAD.
Acknowledgments
This work was funded by a research grant from Inhalation Product Development, GlaxoSmithKline. The entrainment
tubes were manufactured at the Physics workshop at the University of North Carolina and the schematic diagrams were
provided by the Applied Technology department at GlaxoSmithKline.
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