Spray drying at pilot scale - RCPE

Surface modification of dry 

powder inhaler carrier particles by 

spray drying 

Eva Maria Littringer, Axel Mescher, 

Hartmuth Schröttner, Peter Walzel, Nora 

Anne Urbanetz 

K1 Competence Center – Initiated by the Federal Ministry of Transport, Innovation & 

Technology (MMVIT) and the Federal Ministry of Economics & Labour (BMWA). 

Funded by FFG, Land Steiermark and Steirische Wirtschaftsförderung (SFG).

Outline 

� Introduction to dry powder inhalers 

�� Spray drying at pilot scale 

SPRAY 2010, Heidelberg 

3.-5.5.2010 - Seite 2 

� Analysis of atomizing spray 

� Design and implementation of a two-level factorial design 

� Characterization of spray dried particles of the factorial design 

� Results 

• REM- images to estimate surface roughness 

• Particle size distribution 

� Conclusion - Outlook

Introduction 

rubber cast of human lungs (Anatomical Institute, Bern) 


3.-5.5.2010 - Seite 3

Introduction 

-formulation concepts- 

� Carrier based formulations: 

ordered mixtures of active and carrier 

active: 1 µm - 5 µm, carrier: 50 µm - 200 µm 

� Carrier-free formulations: 

active or active-excipient agglomerates 

active and excipient: 1 µm – 5 µm 

S`PRAY2010, Heidelberg 

3.-5.5.2010 - Seite 4

Spray drying at pilot scale 

� Spray dryer (Prof. Walzel, TU Dortmund) 

▪ cylindrical part: diameter 2.7 m, height 1.5 m 

▪ conical part: height 2.2 m, 60° 

� Rotary atomizer 

▪ diameter 100 mm 

▪ 60 bores (3 mm diameter) 


3.-5.5.2010 - Seite 5 

product 

hot air supply 

seperation of fines 

feed


-analysis of atomizing spray- 


3.-5.5.2010 - Seite 6 

volume mean droplet size / µm 

180 

170 

160 

150 

140 

130 

5400 6300 7200 8100 

rotation speed / rpm 

feed conc.: 15,0 % (w) 

feed rate: 10 l/h 

feed conc.: 7,5 % (w) 


feed conc.: 15,0 % (w) 


feed conc.: 7,5% (w) 

feed rate: 20 l/h


-statistical design- 

• 2 4 -factorial design with 3 center points 

Parameter Low (-) Center (o) High (+) Unit 

A (feed concentration) 15,0 17,5 20,0 % [w/w] 

B (damper register temperature) 170 180 190 °C 

C C (feed rate) 10 15 15 20 20 l/h 

D (atomization rotation speed) 6300 7200 8100 rpm 


3.-5.5.2010 - Seite 7


-characterization- roughness- 


3.-5.5.2010 - Seite 8


-characterization- size- 

• Sympatec HELOS, RHODOS: 

dispersion pressure 0.2 bar 

• adjusted d 50,3: particles ‹ 125 µm were considered 


3.-5.5.2010 - Seite 9


-results- roughness- 


3.-5.5.2010 - Seite 10 

Parameter Effect Standard 

error 

Mean/ intercept 3,87500 0,047246 

Curvature 0,25000 0,237797 

A (feed concentration) -0,25000 0,094491 

B (damper register temp.) 1,25000 0,094491 

C (feed rate) -1,25000 0,094491 

D (atomization rotation speed) 0,00000 0,094491 

A by B 0,25000 0,094491 

A by C -0,25000 0,094491 

A by D 0,00000 0,094491 

B by C 0,25000 0,094491 

B by D 0,00000 0,094491 

C by D 0,00000 0,094491



A 

(feed conc.) 

B 

(damper reg. temp.) 

C 

(feed rate) 

D 

(rot. speed) 

T out/ °C d 50.3.a 

/ µm 

above + - + + 75 82,7 2 

below + + + + 85 78,7 4 


3.-5.5.2010 - Seite 11 

surface 

/1-5



A 

(feed conc.) 

B 


C 


D 

(rot. speed) 

Tout/ °C 

d50.3.a/ µm surface 

/1-5 

above + - + + 75 82,7 2 

below - - + + 74 74,4 3 


3.-5.5.2010 - Seite 12



A 

(feed conc.) 

B 


C 


D 

(rot. speed) 

Tout/ °C 


/1-5 

above - - + + 74 74,4 3 

below - - - + 86 71,4 4 


3.-5.5.2010 - Seite 13


-results- roughness- outlet temperature- 


3.-5.5.2010 - Seite 14 

outlet temperature/ °C 

100 5,5 

96 

92 

88 

84 

80 

76 

72 

4,5 

3,5 

2,5 

1,5 

T out/ °C 

surface 

category/ 

1-5


-results- particle size- 

Parameter Effect Standard error t(7) p 

Mean/ intercept 79,9146 0,3481 229,5749 0,0000 

Curvature -2,8918 1,7521 -1,6505 0,1428 

A (feed concentration) 7,0027 0,6962 10,0585 0,0000 

B (damper register temp.) 0,4670 0,6962 0,6708 0,5239 

C (feed rate) 1,6101 0,6962 2,3127 0,0540 

D (atomization rot. speed) -7,1252 0,6962 -10,2345 0,0000 

A by B -0,4701 0,6962 -0,6752 0,5212 

A A by C -0,6828 0,6962 -0,9807 0,3594 0,3594 

A by D -0,7581 0,6962 -1,0889 0,3123 

B by C -2,6654 0,6962 -3,8286 0,0065 

B by D -0,5330 0,6962 -0,7655 0,4690 

C by D 0,8354 0,6962 1,2000 0,2692 


3.-5.5.2010 - Seite 15



A 

(feed conc.) 

B 


C 


D 

(rot. speed) 

Tout/ °C 


/1-5 

above + + - + 98 79,3 5 

below + + - - 98 90,0 5 


3.-5.5.2010 - Seite 16



A 

(feed conc.) 

B 


C 


D 

(rot. speed) 

Tout/ °C 


/1-5 

above + - + + 75 82,7 2 

below - - + + 74 74,4 3 


3.-5.5.2010 - Seite 17

Conclusion - Outlook 

� Surface roughness and particle size could be successfully 

affected by the variation of spray drying process 

parameters 

� Outlet temperature was found to be an appropriate 

parameter to adujust surface roughness 

� To study the influence of surface roughness on the 

respirable fraction of the active 

� To understand the crystallization processes of particles of 

different surface structure 


3.-5.5.2010 - Seite 18

Acknowledgement 

�� DFG – SPP 1423 

� Axel Mescher and Prof. Dr. Peter Walzel, Mechanical 

Process Engineering, Technical University Dortmund 

� Hartmuth Schröttner, Austrian Centre for Electron Microscopy 

and Nanoanalysis, Graz University of Technology 

� Prof. Dr. Nora Anne Urbanetz, Research Center 

Pharmaceutical Engineering, Graz University of Technology 


3.-5.5.2010 - Seite 19

Surface modification of dry powder 

inhaler carrier particles by spray drying 


3.-5.5.2010 - Seite 20 

Thank you for your attention!

Ordered mixtures 

� Turbula® T2C (Bachofen, CH-Muttenz) 

� active: salbutamol sulfate, micronized, x 50 = 1,74 µm 

� carrier: mannitol, spray dried at 67 °C, 80 °C, 102 °C 

outlet temperature 

� � „sandwich „sandwich method“- 3 g- 600 mg- mg- 33 g 

� 65 min -1 

� 90 min 


3.-5.5.2010 - Seite 21

Interactive mixtures 

-67 °C- 


3.-5.5.2010 - Seite 22


-80 °C- 


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-102 °C- 


3.-5.5.2010 - Seite 24

Spray drying at pilot scale - RCPE

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