European Journal of Pharmaceutics and Biopharmaceutics 96 (2015) 291303

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European Journal of Pharmaceutics and Biopharmaceutics

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

Research Paper

Insights into the roles of carrier microstructure in adhesive/carrier-based

dry powder inhalation mixtures: Carrier porosity and fine particle
content
Ahmed O. Shalash a, Abdulla M. Molokhia a, Mustafa M.A. Elsayed b,,1
a
b

European Egyptian Pharmaceutical Industries, Alexandria, Egypt

Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

a r t i c l e

i n f o

Article history:
Received 24 May 2015
Revised 6 August 2015
Accepted in revised form 7 August 2015
Available online 11 August 2015
Keywords:
Dry powder inhaler
Carrier
Porosity
Pore size distribution
Surface roughness
Surface rugosity
Fines
Mercury intrusion porosimetry
Air permeability
Fluidization
Aerolizer
Fluticasone propionate

a b s t r a c t
To gain insights into complex interactions in carrier-based dry powder inhalation mixtures, we studied
the relationships between the carrier microstructural characteristics and performance. We used mercury
intrusion porosimetry to measure the microstructural characteristics and to also derive the air permeability of eight carriers. We evaluated the performances of inhalation mixtures of each of these carriers
and fluticasone propionate after aerosolization from an Aerolizer. We did not observe a simple relationship between the carrier total porosity and the performance. Classification of the porosity according to
pore size, however, provided interesting insights. The carrier nanoporosity, which refers to pores smaller
than micronized drug particles, has a positive influence on the performance. Nanopores reduce the carrier
effective contact area and the magnitude of interparticulate adhesion forces in inhalation mixtures. The
carrier microporosity, which refers to pores similar in size to drug particles, also has a positive influence
on the performance. During mixing, micropores increase the effectiveness of frictional and press-on
forces, which are responsible for breaking up of cohesive drug agglomerates and for distribution of drug
particles over the carrier surface. On the other hand, the carrier macroporosity, which refers to pores larger than drug particles, apparently has a negative influence on the performance. This influence is likely
mediated via the effects of macropores on the powder bed tensile strength and fluidization behavior. The
air permeability better represents these effects. The inhalation mixture performance improved as the carrier air permeability decreased. Interestingly, as the carrier fine particle content increased, the carrier
microporosity increased and the carrier air permeability decreased. This proposes a new mechanism
for the positive effect of fine excipient materials on the performance of carrier-based inhalation mixtures.
Fine excipient materials apparently adhere to the surface of coarse carrier particles creating projections
and micropores, which increase the effectiveness of mixing. The data also support the mechanism of
powder fluidization enforcement by fine excipient materials. The current study clearly demonstrates that
the microporosity and the air permeability are key dry powder inhalation carrier performance determinants. Mercury intrusion porosimetry is a useful tool in the dry powder inhalation field; it successfully
allowed resolution of carrier pores which contribute differently to the performance.
2015 Published by Elsevier B.V.

1. Introduction
Complex interactions in adhesive/carrier-based dry powder
inhalation (DPI) mixtures are till date not fully understood. This
is mainly underlain by the large number and variety of factors
which come into play. The use of analytical techniques that may
not quantify these factors to the relevant degree of detail also
Corresponding author at: Department of Pharmaceutics, Faculty of Pharmacy,
Alexandria University, El-Khartoum Square, El-Azarita, Alexandria 21521, Egypt.
E-mail address: mustafa.elsayed@alexpharmres.com (M.M.A. Elsayed).
1
Mustafa M.A. Elsayed, Ph.D., is the principal investigator.
http://dx.doi.org/10.1016/j.ejpb.2015.08.006
0939-6411/ 2015 Published by Elsevier B.V.

contributes to the poor understanding. The effects of the carrier

surface porosity/roughness on the performance are among the
interactions in this domain that are open till date. In carrierbased dry powder inhalation mixtures micronized drug particles
with aerodynamic size of 15 lm, i.e. respirable, are distributed
over coarse carrier particles. Coarse carrier particles improve flow
properties of cohesive drug particles.
The carrier surface porosity/roughness influences the
aerodynamic performance of carrier-based inhalation mixtures
[18]. Despite extensive investigations, reported observations
are inconsistent and the influence is not yet fully understood. To
the best of the current knowledge, the influence of the carrier

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A.O. Shalash et al. / European Journal of Pharmaceutics and Biopharmaceutics 96 (2015) 291303

surface porosity/roughness depends on the size of pores/discontinuities in comparison with the size of drug particles [2,9]. Pores
and discontinuities larger than drug particles increase the
drug-carrying capacity and thus promote drug emission from the
inhalation device [2,4]. These large pores, however, provide shelter
for drug particle from drag separation forces during aerosolization,
thus hinder drug detachment/dispersion from carrier particles, and
thus often decrease the drug respirable fraction [2,4]. This negative
effect does not apply when dry powder inhalation devices that rely
on inertial separation forces are used [8]. It is noteworthy that
large pores provide shelter for drug particle also from fictional
and press-on forces during mixing; this would have a positive
influence on the performance. Prediction of the net effect of large
pores is thus not always straightforward. On the other hand,
microprojections and pores smaller than drug particles increase
the drug respirable fraction, probably by reducing the effective
drug-carrier contact area [2,10].
Microscopic studies highlighted the influence of pore size. However, the surface porosity/roughness of dry powder inhalation carriers is most often quantified by air permeametry [1,3,4] and BET
gas adsorption [2,5,11], which are in this regard limited. One can
derive specific surface areas, but not pore size distributions, from
air permeametry measurements. Moreover, specific surface areas
derived from air permeametry reflect only large pores and
discontinuities. They do not reflect fine and deep pores which do
not contribute to air permeability. This explains why several air
permeametry studies have suggested carrier surface roughness
has a negative impact on the aerodynamic performance [1,3]. This
may be indeed true if only large pores and discontinuities are considered. On the other hand, BET gas adsorption provides specific
surface areas which include fine pores with diameters down to
0.3 nm. Fine pores may dominate specific surface areas derived
from BET gas adsorption. This may explain the outcome of a BET
gas adsorption study [7] which suggested carrier surface roughness
has a positive impact on the aerodynamic performance. BET gas
adsorption provides pore size distributions. Such distributions,
however, cover a limited pore diameter range from 0.3 to
300 nm. This range is far below the size range of micronized drug
particles used in dry powder inhalation. Pores over this distribution contribute similarly to drug-carrier particle interactions in
inhalation mixtures. Such distribution is thus of little value for
dry powder inhalation carriers. Laser profilometry [12], image
analysis [6], and atomic force microscopy [5,6] have been used
for topographic assessment of dry powder inhalation carriers.
These techniques are of limited applicability in routine analysis
of bulk materials.
The aim of the current study was to gain further insights into
the influence of the carrier microstructure on the performance of
carrier-based dry powder inhalation mixtures. To this end, we used
mercury intrusion porosimetry to study carrier microstructural
properties, such as the pore volume distribution and the surface
roughness. Mercury intrusion porosimetry allows determination
of pore size distributions over a broad pore diameter range from
0.003 to more than 300 lm, i.e. five orders of magnitudes broad.
This allows resolution of carrier pores on a scale relevant to the
size of micronized drug particles. It is noteworthy that the porosity
measured by mercury intrusion porosimetry includes interparticulate spaces and is not limited to surface pores. To our knowledge,
the use of mercury intrusion porosimetry for quantification of
the porosity of dry powder inhalation carriers has not been earlier
considered in the literature. Eight materials, with different chemical nature or crystalline structure, were tested as carriers. These
were hydroxypropyl-b-cyclodextrin (CD), dextrose anhydrous
(DA), dextrose monohydrate (DM), lactose anhydrous (LA), lactose
monohydrate (LM), mannitol (MN), xylitol (XL), and sucrose (SU).
These materials are widely available in pharmaceutical quality.

The variety allowed us to also test the roles of carrier chemical

composition and crystalline/polymorphic form. After processing,
the carriers also differed in their contents of fines (D < 10 lm),
but their coarse components were of almost the same size. Fluticasone propionate, a hydrophobic adhesive drug, was used as model
drug. The performances of the inhalation mixtures were assessed
after aerosolization from an Aerolizer. Separation forces generated in an Aerolizer during inhalation are mainly lift and drag
forces.
2. Materials and methods
2.1. Materials
Hydroxypropyl-b-cyclodextrin (Kleptose HPB), dextrose
monohydrate (Roferose SF; Dmean = 50 lm), mannitol (Pearlitol
50 C; Dmean = 50 lm), and xylitol (Xylisorb 300; Dmean = 300 lm)
were from Roquette, Lestrem, France. Dextrose anhydrous was
from SunTin MediPharma Co. Ltd., Hong Kong, China. Lactose anhydrous (Lactopress anhydrous 265; b-lactose anhydrous;
D50 < 150 lm; anhydrous lactose is crystallized by rapid drying of
a solution of lactose at high temperature; crystals are then milled
and sieved to the required particle size distribution) was from
Borculo Domo Ingredients, Zwolle, The Netherlands. Lactose
monohydrate (Lactohale LH200, milled a-lactose monohydrate;
D50 = 50100 lm) was from Friesland Foods Domo, Zwolle, The
Netherlands. Sucrose was from Daqahlia Sugar Co., Cairo, Egypt.
Fluticasone propionate (superfine micronized grade; D90 < 10 lm)
was from Jayco Chemical Industries, Maharashtra, India. All other
reagents were of analytical grade.
2.2. Preparation of the carriers
We prepared carriers with similar, narrow size-distributions
from the carrier original materials by sieving. We sieved each carrier original material through a stack of 150, 106, and 75 lm analytical sieves (Retsch GmbH, Germany) and collected the fraction
sieved between the 75 lm and the 106 lm sieves. To minimize
the content of fines smaller than 75 lm, we placed the collected
fraction below a 75 lm sieve and aerated it for 2 min at 2-bar
pressure by Schlick 970 S75 coating gun (Dsen-Schlick GmbH,
Germany), placed perpendicularly 5 cm above the sieve. This
procedure removes only loose fines. We stored the prepared
carriers in polyethylene bags at 20 C and 45% RH.
2.3. Preparation of the inhalation mixtures
Before mixing, we screened/sieved the carriers and the drug
fluticasone propionate, FPthrough a 250 lm sieve to break up
and remove agglomerates. We then prepared 1% FP inhalation mixtures (2-g each) in test tubes using the sandwich method. We first
vortexed each mixture for one minute. We then added three 4-mm
316 L stainless steel balls to each mixture and vortexed it again for
one minute. In order to take the effects of the mixing process on
carrier characteristics into consideration, we similarly processed
blank carrier samples before further characterization. We stored
the inhalation mixtures and the blank carrier samples in polyethylene containers at 20 C and 45% RH for at least one week to allow
for mechanical relaxation.
2.4. Characterization of the carriers
2.4.1. Crystallinity
We measured the crystallinities of the carriers and the drug by
differential scanning calorimetry (DSC) using a PerkinElmer DSC 6

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Table 1
The crystallinities, the losses on drying, and the shape parameters of the carriers.
Carrier

Crystallinity

Loss on drying
[%W]

CD
DA
DM
LA
LM
MN
XL
SU

Amorphous
Crystalline
Crystalline
Crystalline
Crystalline
Crystalline
Crystalline
Crystalline

11.41 0.40
0.58 0.09
9.23 0.09
0.55 0.05
0.94 0.20a
0.36 0.03
0.30 0.02
0.45 0.13

Shape analysis
(optical microscopy)
Aspect ratio, RA

Circularity, C

1.52 0.23
1.45 0.17
1.56 0.31
1.51 0.27
1.75 0.40
1.96 0.68
1.72 0.53
1.45 0.32

0.56 0.09
0.54 0.10
0.55 0.12
0.54 0.12
0.62 0.07
0.54 0.10
0.58 0.10
0.64 0.09

differential scanning calorimeter (PerkinElmer Inc., USA). In each

measurement an approximately 4-mg carrier sample was heated
in an aluminum pan under nitrogen purge from 30 C to 300 C
(to 400 C for CD) at a heating rate of 10 C min
1.
2.4.2. Loss on drying
We determined the losses on drying of the carriers using a Mettler Toledo HR73 halogen moisture analyzer (Mettler Toledo,
Switzerland). 1-g sample of each carrier was dried at 105 C for
15 min (sufficient to reach constant weight). The loss on drying
represents the amount of volatile matter of any kind that is driven
off under the conditions specified.
2.4.3. Shape analysis
We performed the shape analyses of the carriers using a Microvision LW1135C-GT1 image analysis system, which is comprised of
a microscope with 4 objective lens, a camera, and EllixTM version
7.6.2 software (Microvision Instruments, France). In each measurement we covered a small carrier amount (2 mg) with dimethicone and homogenously distributed it on a microscope slide.
We mounted the slide on the microscope and took images of at
least 100 randomly selected particles with diameters near the carrier D50, determined by laser diffraction particle size analysis (cf.
Table 2). We calculated the aspect (elongation) ratio, RA, and the
circularity, C, defined as follows:

L
W

Table 2
The particle size distributions of the carriers.a
Carrier

DV,Mean
[lm]

DV,Mode
[lm]

DV,10
[lm]

DV,50
[lm]

DV,90
[lm]

% Fines
(D < 10.0 lm)

CD
DA
DM
LA
LM
MN
XL
SU
FP
FPb

79.91
72.69
73.67
61.35
72.93
61.42
81.31
71.19
7.20
8.46

77.59
74.70
75.08
76.04
79.39
59.26
76.95
77.10
3.86
4.53

32.12
26.23
28.38
9.03
12.31
16.43
43.81
19.58
1.97
2.31

72.80
67.03
68.06
55.40
64.09
52.30
75.68
65.28
4.49
5.27

138.87
127.42
128.24
122.72
144.05
119.23
127.39
130.18
14.63
17.19

3.03
2.92
3.72
11.22
8.21
5.64
0.31
4.56
83.17
78.49

4pA
P2

where L is the length, W the width, P the perimeter, and A the projected surface area of the particle.

a
The conventional drying process does not remove lactose monohydrate water
of crystallization (cf. Section 3.1.1 and Fig. 1).

RA

293

a
The data represent volume-weighed size distributions, which are referred to by
the subscript V. The given values are means of at least triplicate measurements. The
relative standard deviations of the median diameters, DV,50, were always smaller
than 1.5%.
b
Aerodynamic diameters calculated using the relation: Daerodynamic = D(q/v)0.5.
The particles were assumed to be spherical, i.e. the dynamic shape factor, v, equals
1. Fluticasone propionate density, q, is 1.38 g cm
3 [22].

2.4.4. Particle size distribution

We measured the particle size distributions of the carriers and
the drug using a Malvern Mastersizer 2000 laser diffraction particle size analyzer, operating with HeNe laser (k = 632.8 nm) as
red light source and equipped with a Hydro 2000MU wet sample
dispersion unit (Malvern Instruments Ltd., United Kingdom). We
used acetone and isopropyl alcohol as the dispersing media for
CD and all the other carriers, respectively. For fluticasone propionate we used 10/90 w/w ethanol/water mixture containing 0.2%
polysorbate 80 and saturated with the drug as the dispersing
medium. Each measurement was set to collect data for 412 s
(1000 snap/s). Measurements were conducted in triplicates.
We used the Mie theory of light scattering for the data analysis
to ensure accurate measurement of fine particles (D < 25 lm), for
which the assumptions of the Fraunhofer approximation are invalid (the Fraunhofer assumptions are invalid for particles smaller
than 40 k [13]). Use of the Mie theory requires knowledge of both
the dispersing medium and the particle refractive indices. For the
dispersing media we used literature values of refractive indices
at k = 589 nm: These were 1.3588 for acetone, 1.3776 for isopropyl
alcohol, and 1.3395 for the hydroethanolic dispersing medium of
fluticasone propionate [14,15]. The expected differences between
the refractive indices of the dispersing media at k = 589 nm and
at k = 632.8 nm had negligible effects on size measurements. For
the carriers we measured the refractive indices using the following
procedure. For each carrier we prepared solutions of different concentrations in deionized water. We measured the refractive indices
of these solutions using an Abbe refractometer and daylight as a
light source. For each of the carriers the refractive index was a linear function of the concentration with R2 > 0.999. Extrapolating the
measured refractive indices to 100% concentration provided the
carrier refractive index. The refractive indices were accordingly
1.462 for CD, 1.511 for DA, 1.494 for DM, 1.531 for LA, 1.521 for
LM, 1.521 for MN, 1.551 for XL, and 1.544 for SU. The expected differences between the particle refractive indices measured using
white light and those at k = 632.8 nm had negligible effects on size
measurements. The measured refractive indices moreover always
led to the best fits of scattering data, i.e. the lowest residuals.
The imaginary refractive indices (absorption) were assigned the
values leading to best agreements between the calculated and
the measured data on the extinction channel. These were 0.01
for CD, 0.001 for DA and DM, 0.005 for LA and LM, 0.001 for MN,
0.02 for XL, and 0 for SU. For fluticasone propionate the real refractive index was set to 1.55 and the imaginary refractive index to
0.005.
2.4.5. Pore size distribution, surface roughness, and permeability
We measured the pore size distributions of the carriers by mercury intrusion porosimetry using a Micromeritics Poresizer 9320
(Micromeritics Instrument Corporation, USA). We placed an
approximately 0.4-g sample of the carrier into a 5-ml penetrometer (penetrometer constant = 22.07 ll/pF). The penetrometer was
then assembled, evacuated, and filled in a horizontal position with
mercury under vacuum. The applied pressure was increased in a
stepwise fashion from 1.17 to 30,000 psi. At each step the volume
of intruded mercury was recorded after 10-second equilibration.
The pore diameter, D, is related to the applied pressure, P, by
means of the Washburn equation:

4c
cos h;
P

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where c is the mercury surface tension (set to 485 dyne/cm) and h is

the contact angle of mercury on the sample (set to 130).
We calculated the surface roughness, SR, which we defined as

SR

SSAMIP
:
SSAPSD

SSAPSD is the specific surface area estimated from the particle size
distribution assuming spherical particle shape. For calculation of
SSAPSD we used literature values of densities: These were
1.533 g mL
1 for CD, 1.562 g mL
1 for DA [14], 1.540 g mL
1 for
DM [16], 1.59 g mL
1 for LA [14,16], 1.547 g mL
1 for LM [14],
1.514 g mL
1 for MN [16], 1.52 g mL
1 for XL [16], and 1.581 g mL
1
for SU [14]. SSAMIP is the specific surface area estimated from the
mercury intrusion porosimetry data.
We also calculated the air permeabilities of the carriers from
the mercury intrusion porosimetry data. A plot of log P versus
log V, where P is the applied pressure and V is the volume of
intruded mercury, approximates a hyperbola and can be expressed
mathematically by [17]:

log P log Pd

G
:
log V
log V 1

Pd is the displacement pressure, obtained by extrapolation to V  0.

V1 is the volume of the intruded mercury at infinite pressure, i.e.
the total interconnected pore volume. G is a pore geometrical factor
that reflects pore sorting and interconnection. We determined V1,
Pd, and G values for each carrier by nonlinear fitting (Levenberg
Marquardt) of the mercury intrusion porosimetry data to Eq. (5).
We excluded the data points with P > 200 psia, which correspond
to pores with D < 0.904 lm. These pores do not contribute to the
air permeability and their exclusion allows more robust identification of the pore geometrical factor. We then calculated the air permeability via the procedure suggested by Swanson [18].
Accordingly, the apex of the hyperbola is indicative of intrusion of
the major connected pore space which dominates fluid flow with
mercury. Swanson [18] suggested identification of the apex point
by the intersection of the hyperbola with a 45 line passing through
the origin of the hyperbolic axes. We alternatively calculated the
volume of intruded mercury, VA, and the applied pressure, PA, at
the apex point from the hyperbolic function using the relations:

log V A log V 1

p
G

p
log PA log Pd G

6
7

We then calculated the air permeability from the correlation suggested by Swanson [18]:

K a 399


1:691
V A  100 1

:
V bulk
PA

Ka is the air permeability in mD. PA is in psia. Vbulk is the bulk powder volume.
2.5. Evaluation of the inhalation mixtures
2.5.1. Assay and content uniformity
We randomly took one 100 mg and six 25 mg samples of each
mixture and dissolved the samples in 50% w/w ethanol in deionized water. We determined the fluticasone propionate concentrations in these solutions using the spectrophotometric method
described in Section 2.6.
2.5.2. Aerodynamic evaluation (in vitro deposition)
We filled the inhalation mixtures into size 3 hard gelatin capsules (Capsugel, France). Each capsule contained 25 2 mg inhalation mixture, corresponding to 250 lg fluticasone propionate. We

stored the capsules at 20 C and 45% RH for at least 3 days to allow

for mechanical relaxation and electrostatic charge dissipation.
We conducted the aerodynamic evaluation (in vitro deposition)
using a Next Generation Impactor (Copley Scientific, United Kingdom). The United States Pharmacopeia [19] suggests using a flow
rate which produces a pressure drop of 4 kPa (40.8 cm H2O) over
the inhalation device for a duration which draws 4 L of air from
the mouthpiece of the inhaler. If the flow rate required to produce
4 kPa pressure drop over the inhalation device is greater than
100 L/min, a flow rate of 100 L/min should be used. The Aerolizer
has a specific resistance of 0.055 cm H2O0.5 min/L [20]. A flow rate
of 116 L/min is accordingly required to produce the 4 kPa pressure
drop over the Aerolizer. However, we chose to adjust the flow
rate to 60 L/min for two reasons. First, a flow rate of 100 L/min is
not attainable by all asthma and chronic obstructive pulmonary
disease patients. Bronsky et al. [21] assessed the peak inspiratory
flow rate through the Aerolizer in asthma patients. 27% and 9%
of the adult patients had peak inspiratory flow rates <100 L/min
and <60 L/min, respectively. Second, a flow rate of 100 L/min is
so high that it may obscure the differences in performance among
the tested inhalation mixtures.
All experiments were performed under controlled temperature
(20 2 C) and relative humidity (45 5% relative humidity). The
flow rate was adjusted using a Critical Flow Controller Model
TPK 2000 (Copley Scientific, United Kingdom) and a Flow Meter
Model DFM 2000 (Copley Scientific, United Kingdom). The actuation time was set to 3 s using the Critical Flow Controller. Before
each experiment, the preseparator was filled with 15 mL of 50%
w/w ethanol in deionized water (the rinsing solvent). We did not
coat the collection surfaces of the stages since preliminary experiments confirmed coating was unnecessary (cf. Appendix B). In each
experiment five inhalation mixture capsules were aerosolized from
an Aerolizer. The drug deposited on each stage was then collected
by rinsing with 50% w/w ethanol in deionized water. We
determined the drug content in all samples using the analytical
method described in Section 2.5.1. Experiments were conducted
in triplicates.
We calculated the aerodynamic performance (in vitro deposition) parameters defined as follows. The recovered dose, RCD, is
the total collected drug amount (i.e. the total drug amount collected from the capsule shell, the inhalation device, the induction
port, the mouth piece adapter, the preseparator, and all the stages
of the impactor). We herein consider the micro-orifice collector as
stage 8 of the impactor. The retained fraction, RTF, is the ratio of
the amount of drug retained in the capsule shell and the inhalation
device to the recovered dose. The emitted fraction, EF, is the ratio
of the amount of drug emitted from the device (i.e. collected from
the induction port, the mouth piece adapter, the preseparator, and
all the stages of the impactor) to the recovered dose. The fine particle fraction, FPF8.06, ED, is the ratio of the amount of drug deposited
on stages 28 of the impactor to the emitted dose. Fine thus
herein refers to particles with aerodynamic diameter smaller than
8.06 lm. The respirable particle fraction, RPF4.46, ED, is the ratio of
the amount of drug deposited on stages 38 of the impactor to
the emitted dose. Respirable thus herein refers to particles with
aerodynamic diameter smaller than 4.46 lm. The subscript ED
clearly denotes the fractions are relative to the emitted rather than
the recovered dose.
We also calculated the mass median aerodynamic diameter
(MMAD) and the geometric standard deviation (GSD). For this purpose, the cumulative percentage of the mass less than an aerodynamic diameter (cumulative percentage mass undersize) is
plotted against the aerodynamic diameter. The percentage of mass
here is expressed relative to the total mass of drug collected from
all the stages of the impactor, i.e. excluding the preseparator. The
mass median aerodynamic diameter is the 50th percentile of the

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cumulative (undersize) aerodynamic particle size distribution by

mass. The geometric standard deviation (GSD) was calculated as
the square root of the ratio of the 84.13th percentile to the
15.87th percentile of the distribution.
2.6. Analytical method for quantification of fluticasone propionate
We determined the concentrations of fluticasone propionate in
the assay, the content uniformity, and the in vitro deposition
samples spectrophotometrically using a Shimadzu UV-2450
double-beam UVVis spectrophotometer, equipped with Shimadzu
UVProbe version 2.10 software (Shimadzu Corporation, Japan). The
analytical signal was the UV absorption spectrum first-order
derivative at k = 252 nm. The first-order derivative was used to
eliminate interference from some carriers. The method was
validated for linearity, accuracy, precision, specificity, limit of
detection, and limit of quantification. The method was linear over
the concentration range of 230 lg/mL with R2 = 0.9993. The limit
of detection was 0.37 lg/mL and the limit of quantification was
1.11 lg/mL.
2.7. Data analysis
We used OriginPro 2015 (OriginLab Corporation, USA) and
Mathcad version 15.0 (Parametric Technology Corporation, USA)
for mathematical data analysis.

295

3. Results
3.1. Characterization of the carriers
3.1.1. Crystallinity
The differential scanning calorimetry (DSC) measurements
(Fig. 1) suggest that CD was amorphous while all the other carriers
were crystalline. Fig.1 provides more details.
3.1.2. Shape analysis
Optical micrographs of the carriers are shown in Fig. 2. The
calculated shape parameters of the carriers are listed in Table 1.
The carriers were slightly elongated, with aspect (elongation)
ratios, RA, between 1.45 and 1.96. They had similarly irregular
shapes, with circularities, C, between 0.54 and 0.64 (a spherical
particle has a circularity of 1, cf. Eq. (2)). LM particles had the characteristic tomahawk, prismatic, or pyramidal shape. MN particles
were the most elongated and had characteristic surface corrugations. LA particles exhibited remarkable surface roughness, which
resulted from adherence of fine carrier particles (cf. Section 3.1.3
and Table 2). On the other side, XL particle surfaces appeared very
smooth, reflecting its low fine particle content.
3.1.3. Particle size distribution
The particle size distributions of the carriers and the drug are
shown in Fig. 2 and Table 2. Of the size distribution descriptors

Fig. 1. The differential scanning calorimetry thermograms of the carriers. LW refers to loss of water/dehydration. M refers to melting. DC refers to decomposition. The
temperature provided is endotherm temperature range, temperature at peak maximum (denoted by P), or temperature at endotherm onset (denoted by O). CD decomposition
started at 306 C (endotherm not shown). Sealed aluminum pans were used. For DM, sealing avoids escape of water of crystallization and transformation of dextrose
monohydrate to dextrose anhydrous during the measurement. The sharp melting peak at 82 C rather than a broad water evaporation peak confirms water escape during the
measurement was avoided. DM thus apparently comprised a mixture of dextrose monohydrate and dextrose anhydrous crystals. The heat flow scales of the MN and XL panels
are different from those of the other panels.

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A.O. Shalash et al. / European Journal of Pharmaceutics and Biopharmaceutics 96 (2015) 291303

Fig. 2. The particle size distributions and optical micrographs of the carriers.

tabulated, we find the mode diameter and the content of fine particles with D < 10 lm most useful for dry powder inhalation carriers. Coarse and fine carrier components contribute to the
aerodynamic performance of an adhesive inhalation mixture via
different mechanisms. The use of the mode diameter and the content of fine particles thus help distinguish between these contributions. The mode diameter reflects the size of the main, coarse
carrier particles and is not affected by the content of the
performance-modulating, fine carrier particles. In contrast, the
median and the mean diameters provide an averaged overview.
All the carriers except MN were similar in size, with mode diameters, DV,Mode, in the range of 74.7079.39 lm. MN was smaller with
mode diameter of 59.26 lm. The carriers differed in their contents
of fine particles with D < 10 lm. The contents of fine particles ranged from 0.31% for XL to 11.22% for LA. Fluticasone propionate had
a median diameter, DV,50, of 4.49 lm. We also estimated the aerodynamic particle size distribution of fluticasone propionate from
the laser-diffraction measurements as described in Table 2. This
provides just guidance and roughly highlights the theoretical maximum fine particle fraction. Accordingly, fluticasone propionate
had a median aerodynamic diameter of 5.27 lm, a fine particle
fraction (FPF8.06) of 70.56%, and a respirable particle fraction
(RPF4.46) of 40.95% (by volume).

3.1.4. Pore size distribution, surface roughness, and permeability

The pore size distributions of the carriers are provided in Fig. 3
and Table 3. We classified pores into three classes. The first class
includes pores with diameters smaller than 1.00 lm, i.e. pores
smaller than drug particles. The cumulative pore volume of this
class will be referred to as nanoporosity. The second class includes
pores with diameters between 1.00 lm and 8.06 lm, i.e. pores
similar in size to micronized drug particles. The cumulative pore
volume of this class will be referred to as microporosity. The third
class includes pores with diameters larger than 8.06 lm, i.e. pores
larger than drug particles. The cumulative pore volume of this class
will be referred to as macroporosity. Table 3 also provides other
parameters which we derived from the mercury intrusion
porosimetry data. These are the porosity, the specific surface area,
the surface roughness, and the air permeability.
3.2. Evaluation of the inhalation mixtures
3.2.1. Assay and content uniformity
The nominal drug content was 250 lg per 25 mg inhalation
mixture or per capsule. The inhalation mixtures exhibited mean
drug recoveries between 96.8% and 108.3% and satisfactory uniformities with RSD 6 5.2%.

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Fig. 3. The pore size distributions of the carriers. The vertical dashed lines refer to diameters of 1.00 and 8.06 lm; they serve as borderlines between the three pore size
classes.

Table 3
Microstructural characteristics of the carriers.
Carrier

Cumulative pore volume [mL g
1]a

VTotal

VD=0.0071lm

VD=18.06lm

VD>8.06lm

CD
DA
DM
LA
LM
MN
XL
SU

1.1934
0.7423
1.0257
0.7008
0.6307
0.8901
0.8453
0.7619

0.2057
0.0879
0.0999
0.0931
0.0615
0.0933
0.0767
0.0845

0.0533
0.0701
0.0339
0.1603
0.1033
0.0685
0.0138
0.0519

0.9167
0.5738
0.8812
0.4415
0.4583
0.7151
0.7461
0.6166

Porosity [%V]

64.65
50.71
61.45
50.88
49.69
56.02
58.74
56.42

Specific surface
area [m2 g
1]b
SSAPSD

SSAMIP

0.082
0.088
0.091
0.392
0.149
0.132
0.059
0.105

56.585
29.894
30.551
18.809
21.166
33.017
26.468
27.720

S. roughness

Air permeability [mD]

690.061
339.705
335.725
47.982
142.054
250.129
448.610
264.000

6796.6
2113.8
5551.0
975.6
1636.3
2792.2
8932.9
3643.3

a
In addition to the total pore volume, VTotal, we classified pores into three classes. The first class includes pores with diameters smaller than 1.00 lm, i.e. pores smaller than
drug particles. This class will be referred to as nanoporosity. The second class includes pores with diameters between 1.00 lm and 8.06 lm, i.e. pore similar in size to
micronized drug particles. This class will be referred to as microporosity. The third class includes pores with diameters larger than 8.06 lm, i.e. pore larger than drug particles.
This class will be referred to as macroporosity.
b
SSAPSD is the specific surface area estimated from the particle size distribution assuming spherical particle shape. SSAMIP is the specific surface area estimated from the
mercury intrusion porosimetry data.

3.2.2. Aerodynamic evaluation (in vitro deposition)

The aerodynamic performances of the tested mixtures are
described in Table 4. The different tested carries led to similar drug

emission. The emitted fraction ranged between 91% and 94% of the
recovered dose. Drug dispersibility, however, considerably varied
among the different inhalation mixtures. The fine particle fraction,

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Table 4
The aerodynamic performances of the inhalation mixtures.a
Carrier

Recovery, RCD [lg]

Retention, RTF [%]

Emission, EF [%]

FPF8.06, ED [%]

RPF4.46, ED [%]

MMAD [lm]

GSD [lm]

CD
DA
DM
LA
LM
MN
XL
SU

226.92 7.37
208.23 0.65
230.52 4.32
220.18 3.05
230.93 22.53
209.30 3.04
229.52 12.09
221.01 3.89

8.94 2.35
6.25 0.90
5.81 0.23
7.08 0.85
8.59 0.22
6.45 1.23
8.37 1.92
7.47 1.99

91.06 2.35
93.75 0.90
94.19 0.23
92.92 0.85
91.41 0.22
93.55 1.23
91.63 1.92
92.53 1.99

13.80 0.88
18.45 0.69
8.61 0.64
20.12 1.89
21.23 2.06
10.41 0.17
4.37 0.26
12.97 0.18

10.85 0.62
10.82 0.83
6.20 0.29
13.46 1.76
16.00 1.83
6.38 0.17
2.78 0.19
8.60 0.30

3.22 0.21
5.23 0.39
4.39 0.31
4.18 0.28
3.50 0.20
5.41 0.19
5.59 0.32
4.53 0.64

2.88 0.15
3.14 0.11
3.27 0.32
2.81 0.09
2.65 0.02
3.33 0.05
3.29 0.28
2.67 0.10

a
RCD is the recovered dose, i.e. the total drug amount collected from the capsule shell, the inhalation device, the induction port, the mouth piece adapter, the preseparator,
and all the stages of the impactor. RTF is the retained fraction, i.e. the ratio of the amount of drug retained in the capsule shell and the inhalation device to the recovered dose.
EF is the emitted fraction, i.e. the ratio of the amount of drug emitted from the device (i.e. collected from the induction port, the mouth piece adapter, the preseparator, and all
the stages of the impactor) to the recovered dose. The fine particle fraction, FPF8.06, ED, is the ratio of the amount of drug with aerodynamic diameter smaller than 8.06 lm to
the emitted dose. The respirable particle fraction, RPF4.46, ED, is the ratio of the amount of drug with aerodynamic diameter smaller than 4.46 lm to the emitted dose. Five
capsules were used in each experiment. Experiments were conducted in triplicates, i.e. N=3, except for SU where N=2.

FPF8.06, ED, ranged between 4.37% and 21.23% and the respirable
particle fraction, RPF4.46, ED, ranged between 2.78% and 16.00% of
the emitted dose.

4. Discussion
4.1. Microstructural determinants of the performance of carrier-based
inhalation mixtures
4.1.1. The carrier porosity
Fig. 4 shows the relationship between the carrier total pore
volume (upper panel) or the carrier surface roughness (lower
panel, Eq. (4)) and the performance of the carrier-based inhalation
mixture. The performance is expressed in terms of FPF8.06, ED, the
fraction of fine particles with aerodynamic diameter smaller than
8.06 lm. Presuming that the carrier chemical nature and crystallinity do not contribute to the performance, the data presented
in Fig. 4 suggest there is no simple relationship between the carrier
total porosity and the inhalation mixture performance.
Fig. 5 shows the relationship between the carrier pore volume
classified according to the pore size relative to the size of micronized drug particles and the performance of the carrier-based
inhalation mixture. Nanopores, i.e. pores smaller than drug particles, reduce the carrier effective contact area and increase the distance between drug and carrier particles. Nanopores thus reduce
the magnitude of interparticulate adhesion forces in an inhalation
mixture. The upper panel of Fig. 5 shows that all the carriers investigated in the current study except CD had similar nanoporosities
in the range of 0.07670.0999 mL g
1. The nanoporosity of CD
(0.2057 mL g
1) was 23-fold higher than those of the other
carriers, probably due to its amorphous nature. The upper panel
of Fig. 5 does not suggest an exceptional performance of CD. This
will, however, be reconsidered later.
The middle panel of Fig. 5 shows the relationship between the
carrier microporosity, i.e. pores similar in size to micronized drug
particles, and the inhalation mixture aerodynamic performance.
The FPF8.06, ED increased linearly with the cumulative volume of
micropores up to a cumulative volume of about 0.10 mL/g. This
corresponds to approximately 14 times the drug particle volume
per 1 g carrier in the inhalation mixtures. The FPF8.06, ED thereafter
almost remained constant. A positive contribution of the carrier
micropores to the performance is not expected to take place during
aerosolization. In contrast, micropores are therein expected to
increase the drug-carrier effective contact area and to provide shelter for drug particles from drag separation forces. The positive contribution of the micropores to the performance thus most probably
took place during mixing. Micropores, with similar diameters to
micronized drug particles, can therein increase the effectiveness

Fig. 4. The relationship between the carrier total porosity (upper panel) or the
carrier surface roughness (lower panel) and the performance of the carrier-based
inhalation mixture. The performance is expressed in terms of the fine particle
fraction, FPF8.06, ED, defined as the ratio of the amount of drug with aerodynamic
diameter smaller than 8.06 lm to the emitted dose. Linear regression analysis leads
to R2 = 0.2728 for the FPF8.06, ED vs. the total pore volume data (upper panel) and
R2 = 0.2398 for the FPF8.06, ED vs. the surface roughness data (lower panel). The data
of MN and CD, which exhibited exceptional performances, are presented as open
circles.

of frictional and press-on forces, which are responsible for breaking

up (de-agglomeration) of cohesive drug agglomerates and for distribution of drug particles over the carrier surface. The performance of the MN-based mixture was lower than that expected
from the microporosity-performance relationship suggested by
the data of the other carriers. MN was different in size and shape
from the other carriers. The mode diameter, representing the size
of the coarse carrier component, was smaller for MN than for the
other carriers (cf. Table 2 and Fig. 2). MN was also the most elongated with characteristic surface corrugations (cf. Table 1 and

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299

Fig. 6. A schematic illustration of the effects of the carrier porosity on the

performance of carrier-based inhalation mixtures. Light-grey particles represent
carrier particles. Dark-grey particles represent drug particles.

for drug particles from drag and lift separation forces during
aerosolization. Second, the carrier macroporosity influences its
tensile strength, cohesivity, and fluidization behavior. These properties are well represented by the powder air permeability. This is
discussed in the following section. Remarkably, the performance of
the CD-based mixture was higher than that expected from the
macroporosity-performance relationship suggested by the data of
the other carriers. Although CD had the largest macroporosity,
the CD-based inhalation mixture exhibited intermediate performance (cf. Fig. 5 lower panel). CD is here the only amorphous carrier and it had the highest nanoporosity (cf. Fig. 5 upper panel).
Amorphous domains are associated with high surface energy and
high interparticulate adhesion forces. This cannot explain the
better-than-expected performance of CD. The nanoporosity is thus
likely responsible for this exceptional performance. Fig. 6 provides
a schematic illustration of the effects of the carrier porosity on the
performance of carrier-based inhalation mixtures.

Fig. 5. The relationship between the carrier porosity and the performance of the
carrier-based inhalation mixture. The performance is expressed in terms of the fine
particle fraction, FPF8.06, ED, defined as is the ratio of the amount of drug with
aerodynamic diameter smaller than 8.06 lm to the emitted dose. Pores are here
classified according to their sizes into three classes. The effect of each class is
separately presented. The data of MN and CD, which exhibited exceptional
performances, are presented as open circles. The figure demonstrates there is a
relationship between the carrier microporosity and the performance. Nonlinear
fitting of the FPF8.06, ED vs. the cumulative micropore volume data, excluding MN
data, to the sigmoidal Boltzmann function y = Lf + [(Li
Lf)/(1 + exp (k(x
x0)))]
gave Lf = 20.8542, Li = 3.2333, k = 73.3502, and x0 = 0.0474 with adjusted R2 = 0.984;
this is represented by the dashed line. Linear regression analysis of the FPF8.06, ED vs.
the cumulative micropore volume data for cumulative micropore volume smaller
than 0.1 mL/g and excluding the MN data led to R2 = 0.9935.

Fig. 2). These two differences are probably responsible for the
exceptional performance of MN.
The relationship between the carrier macroporosity, i.e. pores
larger than drug particles, and the inhalation mixture aerodynamic
performance (the lower panel of Fig. 5) is similar to the relationship between the carrier total pore volume and the performance
(Fig. 4). This is expected since macropores constituted 6090% of
the total pore volume. It is noteworthy that the macroporosity here
(for the particle size of the studied carriers) includes most of the
interparticulate spaces. The carrier macroporosity apparently has
a negative influence on the performance. Two mechanisms can
explain this negative influence. First, macropores provide shelter

4.1.2. The carrier air permeability

We also derived the carrier air permeability from the mercury
intrusion porosimetry data. The differences in the air permeability,
which reflects powder bed tensile strength, cohesivity, and
fluidization behavior, were not associated with differences in the
drug emission from the inhalation device (cf. Table 4). However, a
relationship between the air permeability and the drug dispersion
was observed. As shown in Fig. 7, the performance of the inhalation
mixture improved as the carrier air permeability decreased, i.e.
resistance to air flow increased. Fluidization does not take place
until air flow provided by the patient reaches a minimum threshold
velocity. This minimum threshold velocity increases with the resistance to air flow. Increased resistance to air flow thus leads to stronger aerodynamic (drag and impaction) dispersion forces within dry
powder inhalation devices during aerosolization [11,23,24]. The
effect in a dry powder inhalation device may nevertheless be smaller than that expected from the air permeability measurements
since the amount of powder material in an inhalation dose is very
small as compared with a powder bed tested in a permeability
measurement. For capsule-based inhalers, one should also consider
that a very cohesive, very poorly flowing inhalation powder may be
retained in the capsule [25]. Similar inverse relationships between
the air permeability, measured by Blaines apparatus or a powder
rheometer, and the aerodynamic performance of inhalation
mixtures have been early reported [11,2224]. This suggests that
the air permeability derived from mercury intrusion porosimetry
data and that measured by Blaines apparatus or a powder
rheometer provide similar information about fluidization of dry
powder inhaler formulations. Although the air permeability is
derived mainly from the macroporosity data, it better correlates
with the performance (cf. Fig. 5 lower panel and Fig. 7).
Again, MN and CD exhibited exceptional performances. The performance of the MN-based mixture was lower and the performance of the CD-based mixture was higher than that expected

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Fig. 7. The relationship between the carrier air permeability, derived from the
mercury intrusion porosimetry measurements, and the performance of the carrierbased inhalation mixture. The performance is expressed in terms of the fine particle
fraction, FPF8.06, ED, defined as is the ratio of the amount of drug with aerodynamic
diameter smaller than 8.06 lm to the emitted dose. The data of MN and CD, which
exhibited exceptional performances, are presented as open circles. Linear regression
analysis of the FPF8.06, ED vs. the carrier air permeability data excluding CD and MN
data led to R2 = 0.9435. This is represented by the dashed line.

from the air permeability-performance relationship suggested by

the data of the other carriers. As discussed earlier, the inferior
performance of the MN-based mixture is probably due to the smaller size and/or elongated shape of MN, as compared to the other
carriers. The superior performance of the CD-based mixture is most
likely due to its high nanoporosity.
4.2. Effects of the carrier chemical/crystalline structure
Lactose monohydrate is the most commonly used dry powder
inhalation carrier. Its incompatibility with some drugs, such as
formoterol [26] and peptides, raised the need for investigation of
other materials as dry powder inhalation carriers. Alternative
materials, such as mannitol, sorbitol, xylitol, and trehalose, have
been earlier investigated as dry powder inhalation carriers
[27,28]. We herein tested eight carrier materials. The correlations
presented in Figs. 5 and 7 suggest the chemical composition and
the crystalline/polymorphic form of the carriers played a minor
role, if any, in the tested inhalation mixtures.
4.3. The role of fine excipient materials in carrier-based dry powder
inhalation mixtures
Addition of a fine excipient material to a coarse carrier has a
well-recognized, positive influence on the aerodynamic perfor-

Fig. 8. The relationship between the carrier fine (D < 10 lm) particle content and
the performance of the carrier-based inhalation mixture. The performance is
expressed in terms of the fine particle fraction, FPF8.06, ED, defined as is the ratio of
the amount of drug with aerodynamic diameter smaller than 8.06 lm to the
emitted dose.

mance of carrier-based inhalation mixtures [3,5,2938]. The drug

fine particle fraction (FPF) increases with the concentration of fine
excipient material up to a certain threshold value. With further
increase in the concentration of fine excipient material, the FPF
remains constant or decreases [29,31,34,35,38]. In the current
study we followed a different approach to investigate the effect
of fine particle content on the aerodynamic performance of
carrier-based inhalation mixtures. Instead of adding different concentrations of fine excipient material to a carrier, we tested several
carrier materials with different fine particle content. Fig. 8 shows
that there is no simple relationship between the content of fine
particles and the aerodynamic performance. The same conclusion
was reached by Pitchayajittipong et al. [24], who similarly tested
the functionality of anhydrous lactose and lactose monohydrate
grades as dry powder inhalation carriers. This suggests the magnitude of the effect of fine particle content is dependent on other carrier properties. Different mechanisms of action for the influence of
fine excipient material on the aerodynamic performance have been
proposed. Among these mechanisms, the active site theory, the
agglomerate theory, and the fluidization enforcement mechanism
have been most considered.
The active site theory suggests fine excipient particles competitively bind to high energy or active sites on coarse carrier particles, thereby leaving passive (low adhesion) sites for drug-carrier
adhesion. Several studies tested this hypothesis [2931,33]. The
results were contradictory and could not provide a consistent support to the active site theory. In agreement with the active site theory, Zeng et al. [33] has shown that a mixture prepared by blending
of a coarse carrier with a fine excipient material prior to drug addition is superior to a mixture prepared by blending of a coarse carrier with drug prior to fine excipient material addition. Several
other studies have shown, however, that improvement of the aerodynamic performance by the addition of a fine excipient material is
independent of the blending order [29,31] and that effects of
blending order, if any, diminish as blending time is increased
[30]. One should note that a mixing order effect does not form conclusive evidence in favor of the active sites theory; other proposed
mechanisms of action reasonably account for mixing order effects
[39]. Measurements of the effect of fine excipient material addition
on carrier surface adhesion forces were also inconsistent, with
some suggesting it decreases [5,35] and others suggesting it
increases drug-carrier adhesion forces [12,29].
The agglomerate theory suggests the drug particles redistribute
between coarse carrier surfaces and fine excipient particles
during blending. This produces drug-fine excipient mixed
agglomerates [31,32,36,37], from which drug is more easily
detached than from coarse carrier surfaces [36,37]. Agglomerates
are subject to stronger drag/deagglomeration forces during
aerosolization [40].
The Fluidization enforcement mechanism is a new term
which we herein introduce for the effect of fine particles on powder bed fluidization. Accordingly, fine particles increase cohesive
inter-particulate forces within a powder bed, thereby increasing
its tensile strength. This affects powder bed fluidization and
aerosolization behavior and leads to higher aerodynamic (drag
and impaction) dispersion forces within inhalation devices (cf. Section 4.1.2) [22,23,41].
Other mechanisms have been also speculated. Fine excipient
particles may not only compete with drug particles but also act
as carrier particles, thereby reducing the payload of coarse carrier
particles [9]. Fine excipient particles slightly larger than drug particles buffer press-on forces during mixing [9,39]. Fine excipient
materials affect the performance of carrier-based inhalation mixtures likely via a combination of different mechanisms. The balance between the different mechanisms is controlled by other
variables. We herein propose a new mechanism which contributes

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301

Fig. 10. The relationship between the carrier fine (D < 10 lm) particle content and
the carrier air permeability, derived from the mercury intrusion porosimetry data.
Nonlinear fitting of the data, excluding the outlying DA data, to the sigmoidal
Boltzmann function y = Lf + [(Li
Lf)/(1 + exp (k(x
x0)))] gave Lf = 1.2433,
Li = 9.2950, k = 0.9064, and x0 = 3.8355 with adjusted R2 = 0.993; this is represented
by the dashed line. Nonlinear fitting of the data, excluding the outlying DA data, to
the exponential function y = a  bx gave a = 10.0187 and b = 0.8249 with adjusted
R2 = 0.941; this is represented by the dotted line.

Fig. 9. The relationship between the carrier fine (D < 10 lm) particle content and
the carrier porosity. Pores are classified, according to their sizes, into three classes.
Linear regression analysis of the cumulative micropore volume vs. the carrier fine
particle content data for fine particle content larger than 3.5% led to R2 = 0.9951.

to, and may dominate, the overall effect. Our data also support the
fluidization enforcement mechanism.
4.3.1. Effect of fine excipient materials on the carrier porosity
Fig. 9 explores the effects of the carrier fine particle content on
the porosity. Carrier fines clearly did not considerably contribute to
the nanoporosity or the macroporosity. However, the increase
of the fine particle content above 3% (volume) was associated with
linear increase of the microporosity. CD and DA had higher
microporosities than that expected from this linear relationship.
They apparently had higher intrinsic microporosities than the
other carriers, i.e. the coarse carrier particles originally had higher
microporosity. This finding proposes a new mechanism for the
positive effect of fine excipient materials on the performance. Fine
excipient materials apparently adhere to the surface of coarse carrier particles creating projections and micropores, which increase
the effectiveness of mixing (c.f. Section 4.1.1). Excipient fines were
earlier observed to increase carrier surface roughness [5,7,10]; the
size and the role of the created surface pores/irregularities were,
however, not earlier resolved.
4.3.2. Effect of fine excipient materials on the carrier air permeability
Increase of the carrier fine particle content was associated with
decrease of the carrier air permeability, estimated from the
mercury intrusion porosimetry data (Fig. 10). This decrease of air
permeability, i.e. increase of resistance to air flow, results from
filling of inter-coarse-particle spaces by fine particles. The

dependence of the permeability on the packing properties of a

powder bed is thoroughly described by Carman [42]. Appendix A
proposes a simple phenomenological model to describe the effect
of the fine particle content on the air permeability. For the carriers
we tested, the powder air permeability drops in a sigmoidal or
quasi-exponential fashion as the fine particle content increases.
One can speculate that small quantities of fine particles adhere
onto the surfaces of the main, coarse carrier particles and little
affect the powder pore structure and resistance to air flow. Above
certain fine particle content threshold, fine particles progressively
fill the inter-coarse-particle spaces and decrease the powder air
permeability. Our data thus support the fluidization enforcement
mechanism (cf. Section 4.3). In the dry powder inhalation field,
Blaines apparatus and the Freeman FT4 powder rheometer are
often used for the measurement of the powder air permeability.
Such measurements [22,23,34] produced similar observations to
that shown in Fig. 10. This suggests estimation of the air permeability from mercury intrusion porosimetry data using the procedure described in Section 2.4.5 is similarly useful to these
techniques.
5. Conclusions
We explored the relationships between the carrier microstructural properties and the performance of carrier-based inhalation
mixtures. Our results suggest that the microporosity and the air
permeability are key performance determinants of dry powder
inhalation carriers. The nanoporosity is of importance for amorphous carriers. The current study, however, could not provide
detailed information about the relative contribution of each of
these characteristics to the performance since they varied simultaneously. This is the subject of an ongoing study. Mercury intrusion
porosimetry is a valuable tool in the field of dry powder inhalation.
It successfully resolves carrier pores which differently contribute
to the performance. The ability to derive powder air permeability
from mercury intrusion porosimetry data is an additional
advantage.
Acknowledgments
The study was funded by a Global Fellowship Award from the
United States Pharmacopeial Convention (USP). The authors would

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Table 5
Effect of coating of the collection surfaces of the Next Generation Impactor stages on the in vitro deposition of fluticasone propionate from two inhalation mixtures.
Stage

Amount collected [lg/capsule]

Inhalation mixture 1

Capsules
Device
IP + MPAb
Preseperator
Stage 1
Stage 2
Stage 3
Stage 4
Stages 58

Inhalation Mixture 2

With coating

No coating

p-valuea

With coating

No coating

p-valuea

7.44 0.34
7.64 0.10
44.61 0.56
105.30 0.93
11.96 0.16
13.49 0.04
10.75 0.49
8.34 0.56
8.55 1.48

7.84 1.65
7.77 0.44
45.54 3.07
105.61 1.98
12.28 0.09
13.62 0.22
11.11 0.87
8.29 1.18
8.13 1.43

0.720
0.654
0.653
0.826
0.049
0.408
0.573
0.951
0.744

9.36 0.85
8.14 1.26
30.14 5.63
166.44 0.47
5.35 0.08
3.30 0.08
1.72 0.06
1.51 0.07
2.79 0.33

10.10 3.16
9.08 2.23
29.69 11.33
166.13 1.42
5.34 0.23
3.32 0.14
1.77 0.10
1.52 0.14
2.57 0.75

0.728
0.567
0.955
0.746
0.913
0.846
0.549
0.947
0.680

a
Data were compared using unpaired, two-tailed Students t-test. The p-values suggest coating did not significantly affect the in vitro deposition of fluticasone propionate
from the two mixtures.
b
IP is the induction port. MPA is the mouth piece adapter.

like to acknowledge the support of Prof. Dr. Nawal M. Khalafallah,

Department of Pharmaceutics, Alexandria University, Alexandria,
Egypt.
Appendix A. A phenomenological model of the effect of the fine
particle content on the powder air permeability
In a phenomenological approach, we attempted to describe the
powder air permeability vs. the fine particle content data by the
exponential function y = a  bx. The intercept represents the powder
air permeability at zero fine particle content, i.e. for powder
comprising only coarse carrier particles. The base represents the
magnitude of the effect of the fine particle content on the powder
air permeability. The intercept, a, and the base, b, mainly reflect the
packing properties of the coarse particles. As the particle size
increases or the particle shape becomes more regular and less
interlocking, the inter-particle spaces enlarge, the intercept, a,
increases, and the base, b, decreases. Fitting our data (Fig. 10),
excluding the outlying DA data, to the exponential function gave
a = 10.0181 and b = 0.8249 with adjusted R2 = 0.941. Cordts and
Steckel [34] measured the air permeabilities of binary blends of
the coarse lactose grade Respitose SV003 (D50 = 56.76 lm;
DMV-Fonterra, Vehgel, The Netherlands) and increased amounts
of the fine lactose grade Lactohale LH300 (D50 = 3.25 lm;
Friesland Foods Domo, Zwolle, The Netherlands) by a Freeman
FT4 powder rheometer. Fitting the data reported by Cordts and
Steckel [34], assuming that the coarse lactose component Respitose SV003 (D10 = 14.13 lm) originally had fine particle content
of 7.0%, gave a = 5.2559 and b = 0.9582 with adjusted R2 = 0.965.
The intercept, a, is smaller and the base, b, is larger than those
derived from our data. This well reflects the different sizes of the
coarse carrier particles. The coarse lactose grade which Cordts and
Steckel used (Respitose SV003) had D90 = 93.04 lm. This is
smaller than the D90 values of all the carriers herein tested
(cf. Table 2). The phenomenological model lends itself for further
development and use.
Appendix B. Effect of coating of the collection surfaces of the
Next Generation Impactor stages on the in vitro deposition of
fluticasone propionate from the test inhalation mixtures
In preliminary in vitro deposition experiments, we coated the
collection surfaces of the stages of the Next Generation Impactor
before each experiment with 1% v/v glycerol solution in methanol.
Coating may be necessary to minimize particle bounce and reentrainment. The experiments were otherwise conducted as

described in Section 2.5.2. We confirmed glycerol does not interfere with the analytical method. Table 5 shows the results for
two selected inhalation mixtures. It demonstrates coating did not
affect the results.

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