Development of a novel laser

diffraction method for estimating fine

particle fraction of adhesive mixtures
DDL25, Edinburgh
Patrik U Andersson, Marcus Skogevall and Kyrre Thalberg
11 December 2014

Outline
1. Why use the laser diffraction technique for ordered mixtures?
2. Method development
3. Results for an AZ Development compound
4. Conclusion and outlook

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Laser diffraction vs impactors

Assessing the particle size distribution is key in development of inhaled products
Laser diffraction

NGI + UPLC

Speed

A few minutes

Typically 1 day

Diameter measured

Volume equivalent

Aerodynamic

Weight

Volume

Mass

Size range

0.5 185 m

0.1 10 m

Chemically sensitive?

No

Yes

PU Andersson | 11 Dec 2014

Set area descriptor | Sub DDL25

level 1

Method development
Off the shelf version

In-house modified version

Air suction giving 4 kPa

Closed cell

230 lpm air suction

Inhaler

Laser

Fill powder here!

Simple deaggregation tube
Pressurised air for dispersion
(around 4 kPa pressure drop)
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No recirculation !
No contamination of lenses !

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Laser diffraction from ordered mixtures

= lactose fine (0-10 %)
= API

(0-10 %)

= lactose carrier (90 %)

Lactose carriers with some fines

Note:
Fraction < 5 m

results independent
of fill weigh!

Lactose fines + API

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Results: Repeatability
Consecutive measurements at patient relevant deaggregation flow (60 lpm)

Variability is due to method, handling and formulation

Conclusions:
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Low method variability

Homogeneous formulation

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Results: Flow dependence

< 5 m

Increased flow gives more fines and lower VMD (compare MMAD)
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Results: FPF prediction

Same composition, different mixing times ( 10 - 180 min)

Higher FPF
Lower VMD

< 5 m
x10

Lower FPF
Higher VMD

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Results: FPF prediction

Same composition, different mixing times ( 10 - 180 min)
L D C u m u la t iv e v o lu m e <
5 m (% )

10

Q = 7 2 lm in

-1

Q = 8 0 lm in

-1

Composition:
5 % API
3 % Lactose fines
89 % Lactose carriers
3 % MgSt

Each point is an average of 4 measurements

0
0

10

20

30

40

50

60

70

Im p a c t o r F in e P a r t ic le F r a c t io n ( % < 5 m )

Excellent prediction for this formulation!

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Conclusions
1. We have developed a robust laser diffraction method for
ordered mixtures giving low shot-to-shot variability.
=>useful as screening tool for FPF-predictions in formulation development

=> useful as IPC-method prior to filling of device

2. Excellent FPF correlation found between laser diffraction and NGI
for a mixture with a high content of an AZ Development compound.

Outlook
1. Understand the role of lactose fines. Thesis work in progress.
2. Improve dispersion tubes further.

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Thank you for your attention!

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T: +44(0)20 7604 8000, F: +44 (0)20 7604 8151, www.astrazeneca.com

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