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Research Paper
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.
292
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.
A.O. Shalash et al. / European Journal of Pharmaceutics and Biopharmaceutics 96 (2015) 291303
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
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 cm3 [22].
4c
cos h;
P
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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 mL1 for CD, 1.562 g mL1 for DA [14], 1.540 g mL1 for
DM [16], 1.59 g mL1 for LA [14,16], 1.547 g mL1 for LM [14],
1.514 g mL1 for MN [16], 1.52 g mL1 for XL [16], and 1.581 g mL1
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
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
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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).
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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
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 g1]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
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.
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
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 g1. The nanoporosity of CD
(0.2057 mL g1) 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.
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299
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
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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.
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.
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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
302
A.O. Shalash et al. / European Journal of Pharmaceutics and Biopharmaceutics 96 (2015) 291303
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
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.
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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