Life Science Technologies

Pharmaceutical Engineering
Investigation regarding high shear homogenization as an alternative for the
production of submicron lipid particles
G. Kutz, V. Salzmann, M. Weber
Pharmaceutical Engineering, FH Lippe und Höxter, University of Applied Sciences, Detmold, Germany (gerd.kutz@fh-luh.de)

1. Introduction
3

In common used processing plants the homogenization process can 2.1. Comparative studies
2,5 2,38
be mainly influenced by varying the speed of the rotor with respect

d50 [µm]
to the fixed stator or by concrete design of rotor and stator. The aim of these experiments was to investigate if Co-Twister 2 1,896
However, the maximum shear rate is limited by the dimension of the technology allows to imitate common used rotor/ stator processing 1,64 1,58
rotor/ stator system, and the maximum rotating speed of the drive devices, although having a different construction respective design 1,5 1,56
motor. of rotor and stator. Therefore solid/liquid dispersions were prepared
In this study a SYMEX CML 30 with a special designed at different shear rates and the resulting particle size distributions 1
homogenizer, the so-called “Co-Twister” system, has been used: were determined and compared.
To finish the comparison experiments with a high pressure 0,5
homogenizer were included additionally.
CIP- 0
Nozzle F The goal of these studies was, depending on the different model
formulations, to clarify which droplet size in minimum can be 0 2 5 10 15
achieved. Homogenization time [min]

2.2. Model formulations Fig. 9: Particle size depending on homogenization time (formulation
” III”; n= 6) produced on rotor/ rotor-system with shear rates from 5
Agitator Co-Twister to 57 m/s
„I“ „II“ „III“
Cetyl Palmitate 10,0% 20,0% 40,0% From an investigation regarding the influence of processing time on
Polyglyceryl-3 1,25% 2,5% 5,0% the reachable particle size one can conclude, that the minimum is
Methylglucose reachable within 15 minutes.
Distearate
Water ad 100,0% ad 100,0% ad 100,0%
3.2. Comparative studies
General View
Fig. 5: Model formulations Comparative studies using rotor/ stator-system were restricted
Fig. 1: Processing facility - Symex CML 30 through design of rotor and stator to 22 m/s in maximum.
2.3. Manufacturing process
In this picture a top-view of the homogenizer unit can be seen, too. Particle size
The so-called Co-Twister is mounted below the bottom of the vessel sampling distribution
an has a unique character. Temperature [80°C]
Visual control 25 Rotor/ stator-System

d50 [µm]
Nominal Value Vessel 30L Agitator rotation speed 18-163 rpm (~ 0,3 to 3 m/s)
Polyglyceryl-3 Methylglucose Distearate/
Minimum Batch size 5L Agitator (Power Consumption) 1.1 kW
Water dispersion 20
Maximum Batch size 45L Rotor (Power Consumption) 12.0 kW
Pressure (vessel) 0 to 3 bars Dynamic Stator (Power 9.8 kW 14,98 Rotor/ rotor-System
Pressure (double jacket) 1 to 5 bars
Consumption) 15
Rotor revolutions 300 – 9000 rpm Homogenization Mixing Cooling Characterization
Temperature (vessel) up to 133.5°C
Dynamic Stator revolutions -9000 rpm to + 9000 rpm
Temperature (double jacket) up to 151°C
10
to

Resulting shear rate 0 to 57 m/s Temperature

in

Product contacting surfaces Stainless steel

316 Ti resp. 316 L Pump rate („Flow“) 180L/min (at 10m/s) [25°C]
Cetyl Palmitate melt 5 ** **
1,4 2 1,29 1,48 1,36
Batch size 6 resp. 3 kg
Temperature [80°C] time CML 30 resp. RW 15
Fig. 2: Processing facility – Technical data 0
5 10 22
Fig. 6: Manufacturing process: submicron lipid particles shear rate [m/s]
„Dynamic“ stator Rotor The dynamic stator can be
driven in the same direction or Fig. 10: Droplet size of different batches ”I” produced at shear
contrary to the rotor, so that rates from 5 to 22 m/s; (n = 6 each)
the shearing effect can be
2.4. Equipment **: highly significant according F/t – test with α = 0,05
varied continuously within
Rotor/ rotor –homogenizer: Symex, type CML 30, Co-Twister,
great ranges. So the
homogenizing and Ser.-Nr.: SY900558 (2001)
transporting can be influenced Rotor/stator-homogenizer: Becomix, type RW 15, Ser.-Nr.: 011/1-20 Rotor/ stator-System
20
d50 [µm]

in a great variety of ways and (1986)

D
Drive motor Drive motor High pressure-homogenizer: Niro Soavi, type Panda NS 1001 L, 14,51
Rotor “Dynamic” stator
can be adopted to the 15
particular production needs. Ser.-Nr.: 2651 (1997) Rotor/ rotor-System
Fig. 3 : Co-Twister unit 10
3. Results
57 m/s 28,5 m/s 0 m/s 5 ** 3,4 **
9000 rpm 9000 rpm 3.1. Rotor/ rotor-system 2,01 1,82 1,67 1,85
Increasing Shear rate Constant revolutions 2,5
ns 2,01
0
tio “II”-Formulation 1,8875 9000 rpm [5 m/s to 57 m/s] 5 10 22
lu
vo 1,8275 1,85 shear rate [m/s]
re 2
d50 [µm]

g
sin 1,5775
ea
cr Rotor
In 1,5
1,4 1,36 1,46 Fig. 11: Droplet size of different batches ”II” produced at shear
e 1,33
at 1,29 rates from 5 to 22 m/s; (n = 6 each)
rr 1,24
he
a
1,03 **: highly significant according F/t – test with α = 0,05
tS 0,84
an 1
st “I”-Formulation
0,8
on
9000 rpm C 0 rpm 9000 rpm The processing devices are different concerning their
Dynamic stator 0,5 homogenization efficacy:
d50 values for formulations produced on rotor/ rotor system are even
Fig. 4 : Co-Twister unit: combinations/correlations for certain “rotor/ at lowest rotating speed comparable to the in minimum reachable
rotor”- ratios with regard to shear rate and pump rate 0 d50 values on rotor/ stator system. On the other hand identical droplet
5 10 22 30 40 50 57 sizes are available at certain “pump rate”/ “shear rate” – ratios.
shear rate [m/s]
Co-Twister system offers the possibility to break-off the fixed
Fig. 7: Particle size of different batches ” I and II” (each n= 6)
combination between shear rate and flow rate
produced on rotor/ rotor –system with shear rates from 5 to 57 m/s Formulation I Formulation II Formulation III
The maximum shear rate (57 m/s) of this “rotor/ rotor”- system is
much higher compared to conventional processing plants.
It could be shown in the past, that high shear homogenization with The homogenizer speed was found to have a high impact on the Homogenization 100 200 100 200 150 500
Co-Twister technology might be in certain cases an alternative to the product quality. A strong dependency of the particle size on the shear pressure [bar]
well established high-pressure homogenisation. rate and the formulation could be seen. In certain cases lipid particles
smaller 1 µm can be observed. d50 [µm] 0,43 0,41 0,48 0,41 1,63 0,56

1,8 Fig. 12: Droplet size of different batches ”I, II, III” produced by
2. Investigation scheme (I,II n=4; III n=6) high pressure homogenization
1,6
1,56
1,4 High pressure homogenization of the chosen model formulations leads
First a manufacturing process for the production of lipid particles
1,33 to lipid particles which are distinctly smaller than those produced with
was established. 1,2
conventional rotor/stator-systems or rotor/rotor-systems.
d50 [µm]

For that purpose experiments in a larger laboratory scale have been 1

performed to answer the question, if there is a relationship between
process settings and product parameters, especially the particle size. 0,8 0,84 III
The particle size distribution of the prepared dispersions was
4. References
0,6
determined by laser light diffraction while the appearance was II [1] US 2001036125, (2001-11-01), Bachelier, H-J.; Boos, F-R., Pr.: DE
judged by visual inspection. 0,4 200020002920, (2000-02-18)
I [2] Liedtke, S., Wissing, S., Müller, R.H., Mäder, K., „Influence of high pressure
0,2
homogenisation equipment on nanodispersion characteristics“, Int. Journal of
0 Pharmaceutics, 196, 183 – 185 (2000)
[3] Kutz, G., Salzmann, V., Bruns, C., Lewandowski, A.; “Comparative studies on
processing facilities with special regard to the new Co-Twister System”,
Fig. 8: In minimum reachable particle sizes at rotor/rotor system Scientific poster on the “5th World Meeting on Pharmaceutics,
Biopharmaceutics and Pharmaceutical Technology”, Geneva, 29.03.2006
(9000rpm / 57 m/s)

FH Lippe und Höxter