Institute of Pharmacy Kiel University

Department of Pharmaceutics and Biopharmaceutics

Influence of blender type on the performance

of ternary dry powder inhaler formulations

Mats Hertel
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Theoretical background
Binary formulation:

1st blending

Ternary formulation:

1st blending 2nd blending

Advantages:
Saturation of active sites
Buffer effects during blending
Formation of agglomerates (fines + API)
Change in fluidisation behaviour
Lucas P, et al. (1998)
Dickhoff BHJ, et al. (2006)
Louey MD, et al. (2002)
Shur J, et al. (2008)
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Theoretical background

Blender type
Blending time Blending energy input
Blending Blending speed
process Blending sequence

Drug deagglomeration
Drug distribution on the carrier surface
Blending Press-on
Press-onforces
forcesonto
ontothe
thecarrier
carriersurface
surface
mechanism

Drug content homogeneity

Drug-carrier adhesion
Mixture Drug aerosolisation behaviour
properties

adapted from W. Kaialy (2016)

Kiel University
Department of Pharmaceutics and Biopharmaceutics

How to find the right process parameters?

Picomix high shear mixer module Turbula low shear tumble blender

Rotation speed = 500 - 5000 min-1 Rotation speed = 20 - 90 min-1

Volume = 180 mL Volume = 135 mL
Kiel University
Department of Pharmaceutics and Biopharmaceutics

How to find the right process parameters?

Methods:
A Picomix and a Turbula mixer were used to prepare blends with salbutamol sulfate and
a coarse lactose carrier
Mixing time and mixing intensity were varied

9
Fine particle fraction [%]

8
7
6 Blending energy input
5
4
3
Picomix: 500 rpm Turbula: 90 rpm
2
1
0

Cordts E, et al. (2012)

Kiel University
Department of Pharmaceutics and Biopharmaceutics

Used process parameters

Preparation of model DPI formulations:

Picomix high shear mixer module Turbula low shear tumble blender

Rotation speed = 500 min-1 Rotation speed = 90 min-1

Blending time = 2 - 10 min Blending time = 11 - 56 min
Total rotations: 1000 - 5000 Total rotations: 1000 - 5000
Batch size = 30 g Batch size = 30 g
Effective volume = 24 % Effective volume = 32 %
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Materials

Carrier (C) Fines (F) API

Lactose monohydrate Lactose monohydrate Budesonide
(InhaLac 70) (InhaLac 400) X50= 1.5 0.0 m
X50= 218.7 1.0 m X50= 6.3 0.0 m Share of blend = 1.5 %
Share of blend = 91 % Share of blend = 7.5 %
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Methods

D-optimal quadratic setup

Factors:

Blender type: Turbula & Picomix

Total rotations (Rot): 1000, 3000 & 5000
Blending order (BO): [C + F] + [API] & [C + API] + [F]

Responses:

Drug content homogeneity Determination of in vitro fine particle delivery

and recovery (FPF, FPD, MMAD)
10 samples, each 12 mg 3 runs per blend; 5 shots per run

+
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Results

Drug content homogeneity and recovery:

5 100
Rel. standard deviation [%]

4 95

Recovery [%]
3 90

2 85

1 80

0 75
1000 3000 5000 1000 3000 5000
Rotations Rotations
Turbula Picomix Turbula Picomix
error bars = min / max
 Kiel University
Department of Pharmaceutics and Biopharmaceutics

Results

Determination of in vitro fine particle delivery (FPF, FPD, MMAD):

Summary of fit (MLR) Coefficients plot (scaled and centered)

1 R2
R2 8
0.987 0.966 0.996

Fine particle fraction [%]

Q2
Q2 6
0.8
RP
4
0.6 p
2
0.4 0
-2
0.2
0.218*
-4
0
-6
Fine particle fraction
-8
* The poor model validity is a result of an artificial lack of fit.
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Results

[Carrier + API] + [Fines] before dispersion [Carrier + API] + [Fines] after dispersion

100 m 100 m

20 m 20 m
Kiel University
Department of Pharmaceutics and Biopharmaceutics

1st blending step

Carrier + API Carrier + Fines

Press-on Press-on
forces forces

Press-on Press-on
forces forces
Kiel University
Department of Pharmaceutics and Biopharmaceutics

2nd blending step

[Carrier + API] + Fines [Carrier + Fines] + API

Press-on Press-on
forces forces

Press-on Press-on
forces forces
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Inhalation

[Carrier + API] + Fines [Carrier + Fines] + API

FPF FPF
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Conclusion

How does blender type influence the performance of ternary dry

powder inhaler formulations?

No significant influence on blend homogeneity and API recovery

The blender type had the lowest impact on the in vitro fine particle
delivery

How does blending process influence the performance of ternary dry

powder inhaler formulations?

The number of rotations was the most important factor influencing the
FPF, due to an increase of press-on forces
SEM pictures showed saturation of active sites and gave an
explanation for blending order results
Kiel University
Department of Pharmaceutics and Biopharmaceutics

Thank you for your attention!