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Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Australia
New Zealand's National School of Pharmacy, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand
a r t i c l e
i n f o
Article history:
Received 18 April 2013
Received in revised form 14 August 2013
Accepted 23 August 2013
Available online 31 August 2013
Keywords:
De-agglomeration
Agglomerate strength
Size
Shape
Intermediate lactose
Dry powder inhaler
a b s t r a c t
Purpose: The purpose of the study was to understand the role of particle size and shape changes in modifying agglomerate strength distribution and de-agglomeration of cohesive lactose powders.
Methods: The relative de-agglomeration of three lactoses of different particle size distributions (Lactohale 201 or
LH201, Lactohale 210 or LH210 and Lactohale 220 or LH220) was determined from laser diffraction particle sizing
of the aerosol plume at different air ow rates. The agglomerate strength distributions were estimated by Monte
Carlo simulation using the primary particle size, work of cohesion and tapped density distributions determined
by laser diffraction, inverse gas chromatography and tapping apparatus, respectively. The morphology and particle shape parameters were determined by scanning electron microscopy and the Morphologi G3.
Results: The estimated agglomerate strength correlated well with the de-agglomeration of all lactose samples at
different air ow rates. While the work of cohesion of the lactose samples was not signicantly different, the
packing fraction was dependent on the proportion and shape of intermediate-sized, cohesive particles between
5.4 and 14 m. For example, while the proportion of particles b5.4 m was similar for all lactose samples, the proportion of intermediate-sized, cohesive particles increased in the order of LH201 b LH210 b LH220. The
intermediate-sized, cohesive particles were more elongated than the b5.4 m fraction and the extent of elongation of the lactose samples increased in the order of LH220 N LH210 N LH201.
Conclusion: The study reinforced the role of agglomerate strength distributions in understanding deagglomeration of cohesive materials. Modication of particle size distributions and shape characteristics contributed to the agglomerate strength changes in the lactose samples. The study enhanced the fundamental understanding of powder de-agglomeration and provided strategic approaches that could be used to improve
inhalation product performance.
2013 Elsevier B.V. All rights reserved.
1. Introduction
Dry powder inhaler formulations often contain micron-sized drug
particles (usually b5 in size) mixed with large, free-owing lactose and
cohesive ne lactose. Due to high adhesion/cohesion of these micron
size particles, the drug is agglomerated alone, with ne carriers, with
large carriers or with both ne and large carriers resulting in complex
multi-particular agglomerates [1]. However, for effective drug delivery
to the deep lung/alveolar region, the agglomerates need to be deagglomerated and dispersed to particles b5 m [2]. De-agglomeration of
powders was found to be inuenced by the agglomerate strength which
was indirectly measured by air shear pressure using an Aerosizer [3,4]
or by the mechanical strength measured using a dual column physical
15:6
W
d
!
1
298
299
i 15:6
t W i
di
!
3
Fig. 1. The work of cohesion distributions of Lactohale 201 (LH201), Lactohale 210
(LH210) and Lactohale 220 (LH220) determined by inverse gas chromatography at nite
dilution (n = 2).
300
Fig. 3. The cumulative primary particle size distribution (PSD) of Lactohale 201 (LH201),
Lactohale 210 (LH210) and Lactohale 220 (LH220) determined by laser diffraction in liquid medium (n = 5, error bars indicate standard deviation of ve replicates).
Fig. 2. The work of cohesion versus percent surface coverage under calculated as average
of the three lactose samples by best t regression equation.
Parameters
LH201
LH210
LH220
d50
b5.4 m
5.414 m
b99% particles
24.2 0.6
10.3 0.3
17.3 0.5
100 m
20.4 0.6
10.8 0.4
21.7 0.5
85 m
18.2 0.7
11.1 0.7
24.3 0.8
63 m
301
Table 2
Representative agglomerate strength values of Lactohale 201 (LH201), Lactohale 210
(LH210) and Lactohale 220 (LH220) calculated by Monte Carlo simulation (n =
1,000,000).
Lactose
Variance
1%
80%
99%
LH201
LH210
LH220
2.81
2.41
1.42
195.71
164.13
85.46
0.14
0.15
0.06
8.65
8.66
6.16
19.16
18.09
12.12
Fig. 4. Cumulative packing fraction distributions of Lactohale 201 (LH201), Lactohale 210
(LH210) and Lactohale 220 (LH220) (n = 4, data represent mean standard deviation).
Fig. 5. Powder strength distributions of Lactohale 201 (LH201), Lactohale 210 (LH210) and
Lactohale 220 (LH220) determined from their cumulative particle size distributions, cumulative work of cohesion distributions and cumulative packing fraction distributions
by Monte Carlo simulation.
a
1 e
xx0
b
where, a, b and x0 represent the maximum percent relative deagglomeration, the change in percent relative de-agglomeration with
air ow rate, and the air ow rate required to achieve 50% relative deagglomeration, respectively. This approach has been used to characterize the aerosolisation behavior of the powders [32,33]), and the requirements for determining the best t have been described earlier [36]. The
estimated parameters of the lactose samples are shown in Table 3.
The estimated maximum percent relative de-agglomeration for
LH201 was higher than that for LH220 or LH210 (Table 3), which was
consistent with the experimental de-agglomeration versus air ow
rate proles for the three lactose samples (Fig. 6). The change in percent
relative de-agglomeration (b) with air ow rate, and the air ow rate
required to achieve 50% relative de-agglomeration (x0) were different
among the lactose samples.
4. Discussion
The correlation between the average agglomerate strength and the
sigmoidal modelling parameters, estimated from the de-agglomeration
versus air ow rate proles, of (1) ow rate required to achieve 50% relative de-agglomeration (x0) and (2) the change in percent relative deagglomeration with air ow (b) was shown in Fig. 7. Although no significant change was observed in either b or x0 when the agglomerate
strength was increased from 1.4 mPa to 2.4 mPa, both b and x0 rapidly
Fig. 6. The percent relative de-agglomeration proles of percent of particles less than
5.4 m versus air ow rate for the aerosolised plume of Lactohale 201 (LH201), Lactohale
210 (LH210) and Lactohale 220 (LH220) dispersed from Rotahaler and determined by
laser diffraction at different ow rates (30 l min1 to 120 l min1) (n = 5, error bars indicate standard deviations of ve replicates).
302
Table 3
Nonlinear least squares estimated parameters of a (the maximum percent relative deagglomeration), b (the change in percent relative de-agglomeration with air ow rate)
and x0 (the air ow rate required to achieve 50% relative de-agglomeration) for the 3parameter tting of the percent relative de-agglomeration versus air ow rate proles
for Lactohale 201 (LH201), Lactohale 210 (LH210) and Lactohale 220 (LH220).
Parameter
LH201
LH210
LH220
a
b
x0
106.57
29.42
44.91
87.87
10.55
30.07
87.55
6.83
29.24
LH220
514 m
b5 m
LH210
514 m
b 5 m
LH201
Fig. 7. The relationship between the change in percent relative de-agglomeration (b)
with air ow rate and the air ow rate required to achieve 50% relative deagglomeration (x0) with average agglomerate strength.
514 m
b 5 m
Elongation
mean
0.366
0.007
0.240
0.016
0.343
0.008
0.203
0.020
0.290
0.009
0.167
0.008
Aspect
ratio
mean
Convexity
mean
0.634
0.012
0.760
0.021
0.657
0.013
0.797
0.018
0.710
0.015
0.833
0.018
0.945
0.014
0.988
0.009
0.961
0.020
0.973
0.012
0.969
0.013
0.967
0.011
High
sensitivity
circularity
mean
0.680
0.012
0.878
0.011
0.741
0.014
0.861
0.014
0.798
0.013
0.856
0.016
303
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