• 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