• Surface composition does impact dispersion, based on the comparison of neat SCT and 10% mannitol formulations.
• Both iGC surface energy and Sympatec dispersion profile provide a“cohesiveness” measurement that correlates with FPF.
• Aerosol dispersion is a complex function of surface and bulk properties andhighlights the importance of a systematic characterization of all powder properties through sophisticated methods.
• Dispersibility of spray-dried powders for inhalation is significantly improved by the presence of the peptide.
• There is an inherent difficulty in isolating single effects since all properties areinterdependent.
• Changes in composition induce changes in crystallinity, particle morphology andsize distribution, as well as changes in surface composition and cohesiveness.
• Comparison of neat SCT and 10% mannitol (similar morphology, similar particlesize distribution), reveal significant changes in surface energy, as measured byiGC and particle cohesiveness, estimated by the Sympatec dispersion profile.
Effect of Bulk and Surface Properties on the Aerosol Performance of Dry Powders for Inhalation
Hak-Kim Chan1, David Lechuga-Ballesteros2, Reinhard Vehring2, Willard R. Foss2, Jane C. Feeley2 and Andy Clark2
1Faculty of Pharmacy, University of Sydney, Australia 2Inhale Therapeutic Systems, Inc., San Carlos, California
To understand the role of bulk and surface properties on the aerosol performance of spray-dried powders for inhalation.
OBJECTIVES
The authors are grateful for the experimental work of Vathana Tep, Trixie Tan, Lisa Williams, Alex Mandel, and Yi Liang, all of Inhale Therapeutic Systems, Inc.
MATERIALS & METHODS
Presented at 2002 AAPS Annual Meeting and Exposition, Nov. 10-14, 2002, Toronto, Ontario, Canada
• Salmon calcitonin (SCT)/mannitol powders were produced with a Büchi 190 spray dryer.
• Surface concentration was determined by X-ray photoelectron spectroscopy (i.e., electron spectroscopy for chemical analysis or ESCA).
• Surface energies were measured by inverse gas chromatography (iGC).
• Emitted dose (ED), mass aerodynamic diameter (MMAD) and fine particle fraction (FPF) were measured by the Andersen cascade impaction method using a passive device (Dinkihaler™ made by Aventis).
• Particle size distribution and dispersion profiles were measured by Sympatec.
• Crystallinity was measured by Raman spectroscopy.
RESULTS & DISCUSSION
ACKNOWLEDGMENTS
CONCLUSIONS
Surface enrichment by mannitol increases surface energy measured by iGC.
y = -1.3516x + 127.69R2 = 0.8477
0
20
40
60
80
100
0 20 40 60 80
sd by IGC (mJ/m2)
FPF
by C
asca
de Im
pact
ion
(wt%
)
Powders with low surface energy exhibit improved FPF.
FPF is also a function of particle size, which depends on powder composition.
Mannitol Raman Spectra
200 400 600 800 1000 1200 1400 16000
50k
100k
150k
200k
delta
Raman Shift in cm-1
0
50k
100k
150k beta
Ram
an S
igna
l in
Cou
nts
0
50k
100k
150k
alpha
0 10 20 30 40 50 60 70 80 90 1000
20
40
60
80
100
SalmonCalcitonin
amorphousMannitol
Mas
s Fr
actio
n in
%
Mannitol Mass Fraction in %
Emitted dose is improved as SCT concentration increases.
Measured in a Dinkihaler™ with a 10-mg capsule at a flow rate of 28.3 l/min. in a ‘short-stack’ ACI gravimetric assay.Load dose is the amount of fine particles in the aerosol divided by the powder loaded to the inhaler device for dispersion.
FPF correlates with the surface composition of spray-dried particles.
1
1.5
2
2.5
3
3.5
4
0 0.5 1 1.5 2 2.5
x50,
m
PRESSURE, bar
100% sCal/0%Mannitol
0/100
10/9030/7050/50
70/30
1
1.5
2
2.5
3
3.5
4
4.5
5
0 0.05 0.1 0.15 0.2 0.25
x50,
m
PRESSURE, bar
100% sCal/0%Mannitol
0/100
10/9030/7050/50
70/30
Particle cohesiveness of spray-dried particles is a strong function of composition as reflected bySympatec dispersion profile.
d(p) = do + k(do)/pa
Neat SCT 10% Mannitol 30% Mannitol 50% Mannitol 70% Mannitol 90% Mannitol 100% Mannitol
SCT preferentially accumulates at the surface of spray-dried particles, as measured by ESCA.
DISCUSSION
Formulation crystallinity is a function of mannitol concentration.
y = 0.4996x + 50.45R2 = 0.9022
0
20
40
60
80
100
0 50 100SCT surface conentration (%)
FPF
(%)
y = -0.4716x + 98.17R2 = 0.8948
0
20
40
60
80
100
0 50 100Mannitol surface conentration (%)
FPF
(%)
80
0
20
40
60
0 50 100Mannitol (wt.%)Mannitol (wt.%)
ED(%
)
Load
Dos
e(%
)
0
20
40
60
80
100
0 50 100
Bulk
0
20
40
60
80
100
% SCT in Formulation100 90 70 50 30 10
Surface
SCT
wt./
%
Man
nito
lWt.%
0
20
40
60
80
100
100 90 70 50 30 10
Bulk
Surface
% SCT in Formulation
2y = 49.111x - 37.514
R = 0.8326
0
20
40
60
80
100
0 1 2 3
FPF
(%)
Particle size ( m)
y = 0.3724x + 20.315R2 = 0.9424
0
20
40
60
80
0 20 40 60 80 100 120
Surface Mannitol by ESCA (wt%)
dby
iGC
(mJ/
m2 )
s
blister
filter
MM
ED =100blisterM
MFPF
µm3.3<=100
Emitted Dose (ED) and
Fine Particle Fraction (FPF)
DinkihalerTM
1
2
3
4
5
6
7 8
50%
of p
artic
les
unde
r ind
icat
ed s
ize
