Application Notes LR-71

Investigating process parameter mechanism

for successful scale-up of a hot-melt extrusion
process

Katharina Paulsen and Dirk Leister, Thermo Fisher Scientific, Material Characterization, Karlsruhe, Germany
Andreas Gryczke, BASF SE, Lampertheim, Germany

Introduction The data of the three independent design-of-experiments

Hot melt extrusion (HME) is a suitable process to produce were analyzed in an ANOVA and the resulting multi-
a wide range of pharmaceutical dosage forms, like tablets, dimensional regression models where used to calculate
capsules, lozenges or implants. HME can be used for imme- the design spaces which are compared for their overlap
diate release as well as for sustained release formulations. between the different scales of the extruders.
Like freeze drying or spray drying the melt extrusion process
is used to achieve solid dispersions, what means that the Material and Methods
drug is embedded in a polymeric carrier. In this solid Material
dispersion the drug can be dispersed into the crystalline Soluplus® is used as a polymeric carrier. It is a polyvinyl-
or amorphous state or it can be dispersed on a molecular caprolactam – polyvinylacetate – polyethylenglycol graft
level in the polymer. In case of a molecular dispersed drug copolymer (BASF SE, Ludwigshafen, Germany) with an
in the carrier this solid solution may result in an increase amphphilic structure which was developed specifically for
of solubility, dissolution rate and also the bioavailability. increasing the solubility of poorly soluble substances via
Because of more and more poorly soluble drugs coming the HME process.
from the high throughput screening of drug development Ferric trioxide is used as a tracer, because of its intensive
departments into the formulation development laborato- red color.
ries, the hot melt extrusion process is rapidly gaining
interest. Since melt extrusion is still a relatively new process Parallel, co-rotating twin screw extruders
for the pharmaceutical industries it is more often used Three different sizes of parallel twin screw extruders are
for formulation development than in the production en- used to simulate the scalability of the HME process: As a
vironment yet. To handle such a continuous melt extrusion labscale Extruder a Pharma 11, for medium scale a Pharma
process it is absolutely necessary to understand the in- 16 and for production scale a Process 24 (Thermo Fisher
fluence of the variables process parameters on the resulting Scientific, Karlsruhe, Germany) are used. The index des-
process parameters and your final product. [1, 2] cribes the screw diameter. All barrel have a length of 40
The purpose of this work was to get a deeper understand- L/D.
ing of the influence of process parameters on the residence The settings were varied to a minimum, mid point and
time distribution of the material within the extruder and maximum value for the screw speed (100 rpm, 300 rpm
the specific mechanical energy consumption (SMEC) and and 500 rpm), the temperature program (130 °C, 165 °C
to determine the possibilities of up scaling this process from and 200 °C) and the feed rate (shown in Table 1).
a lab scale to a production line extruder. To save develop-
ment time and material the opportunity of predictability Through put [kg/h] min mid max
of the scale up step was determined with a design of ex- Pharma 11 0.17 1.33 2.40
periments approach. Therefore Soluplus® was extruded Pharma 16 0.50 4.00 7.50
on three different sizes of co-rotating twin-screw compoun- Pharma 24 1.13 6.60 12.0
der, in different process settings following a design-of- Table 1: Different feed rates used on a different twin screw
experiments plan. As important process parameters, the extruder sizes
residence time distribution was measured with a tracer
in each setup and the specific mechanical energy consump-
tion were calculated. Beside these special process parameters
all standard parameters e.g. temperature of the melt at the
extruder die, pressure at the die and torque were measured
as well.
From the residence time distribution the mean residence
time was calculated. Residence time distribution was
obtained by measuring the concentration of a color
pigment with a photometric and a colorimetric method.

1
2 The feed rate for the different extruder sizes is calculated Results
in dependence on the equation of Schuler (Equation 1) [3]. To have a successful scale up, it is required to have the same
experience for the material on the lab scale extruder as on
the bigger, production scale extruder. Therefore it is assumed
that the residence time of the material within the extruder
must be the same, to allow melting and mixing on one hand
and to avoid degradation on the other.
Equation 1: Empirical equation of Schuler
Especially when working with very low feed rates, it needs
For all the experiments the screw setup was kept constant to make sure that there is no influence of the tracer itself
with two mixing sections, like shown in Figure 1. on the process and therefore on the measurement of the
residence time distribution. If we are thinking about the
low feed rates of the lab scale 11 mm extruder, where we
have only 0,17 kg/h, that means, that every second less then
50 mg is fed into the extruder. When then the amount of
tracer is too high then the value for the feed rate will be
Fig. 1: Set up of screws and barrel used for the scale up expe- higher at that moment the tracer is added and therefore
riments on the Pharma 11, Pharma 16 and Process 24. At the
feeding section the Soluplus® is added as well as the pigment also all the other parameters depending on the feed rate
is added at a given time T0. The degassing section at the left will change as well. So it is easy to imagine that the amount
hand side is an atmospheric degassing to allow water vapor of the tracer can have an influence. To determine the in-
to evaporate out of the polymer. fluence of the tracer concentration, with the same process
settings were measured the residence time distribution with
different amounts of tracer (Figure 3).
Measurement of the residence time
Obviously with increasing amount of tracer the distribution
The pigment is added as a tracer to the hopper of the feeding
gets broader and the mean residence time shifts to higher
section at a given time T0. The color concentration is
values. Therefore there should be always used a very small
measured at the die over the time.
amount and to get comparable results also always the
Picture method: a picture of the strand is taken every 0.2 sec.
same concentration of tracer.
On every picture a defined size of strand is detected regard-
For the scale up experiments at first, the feed rate was only
ing the amount of red pixel (Figure 2). calculated by the equation of Schuler. As shown in Figure 4
IR method: ExtruVis 2 is a colorimeter, developed by A. the throughput was increasing from 1 kg/h to 3 kg/h
Gryczke. It is measuring in line the concentration of the according to this equation when changing from a 11 mm
pigment in the melt at the die exit. screw diameter to an extruder with 16 mm.

Fig. 2: Residence time distribution measurement set up

Software for Data Analysis

Visual X-Sel 11.0 (CRGRAPH, C.U. Ronniger, Germany)
with a Design of Experiments (DoE) modul is used for
planning the experiments. For calculation the prediction
a modul for multi-dimensional regression models is used.
The optimization of the calculation was done with MS
Fig. 4: Influence of feed rate and SMEC on the residence time
Excel 2010 (Microsoft).
distribution; Orange curve: Lab scale extruder (11 mm);
Blue curves: middle size extruder (16 mm); continuous line:
feed rate calculated by Schuler; Dotted line: feed rate adjusted
regarding SMEC

When increasing the feed rate by Schuler the residence time

distribution on the next scale extruder is very similar. Never-
theless the distribution is narrow than the distribution of
the lab scale extruder and slightly shorter as well. It was
found that the residence time distribution is matching per-
fectly when matching the specific mechanical energy
consumption (SMEC) [4].
The SMEC is calculated by the torque, the screw speed and
the feed rate, like shown in Equation 2. While the screw
Fig. 3: Influence of tracer concentration:
green curve: 0.1 g, blue curve: 0.2 g, black curve: 0.3 g, red speed and the throughput are parameters which can be set
curve: 0.5 g and purple curve 1.0 g of tracer were added to individually the torque is a resulting value. Therefore the
the Pharma 16 with constant parameter and constant feed rate. SMEC needs to be adjusted by adjusting the feed rate.
2
 therefore also the torque will decreasing. And compared 3
to Equation 2, with decreasing torque the SMEC will
decreases as well.

Equation 2: Calculation of the specific mechanical energy

consumption (SMEC)

In the next step the knowledge space of the used extruder

sizes is explored with an DoE. Then an ANOVA (analysis
of variance) was performed and the design space was
described via multiple regression. Therefore the design
space of all the other sizes could be calculated.
The regression model was used to calculate the design
space from the 11 mm lab scale to the 24 mm production Fig. 6a: Overview of the correlation between the VSFL and
scale. The regression model was matched regarding resi- the SMEC, the 11 mm extruder
dence time, melt temperature and SMEC. The results are
shown in Figure 5.

Fig. 6b: Overview of the correlation between the VSFL and

the SMEC, the 16 mm extruder

Fig. 5: The design space of different sizes twin screw extruder,

calculated from the 11 mm scale extruder via regression mode

For the scale up from the design window of the Pharma

11 to the Pharma 16, only the feed rate need to be adjusted Fig. 6c: Overview of the correlation between the VSFL and
to the bigger size. In case of the scale up to a 24 mm sys- the SMEC, the 24 mm extruder
The different colors are linked to different barrel temperatures:
tem the feed rate needs to be adjusted of course, but also
Blue curve: 130 °C, yellow: 165 °C and 200 °C is shown in red
the screw speed needs to be increased as well.
What could be shown here is limitation of the scale up All these effects can be explained by the equation of the
process. When increasing the extruder equipment, than SMEC. With increasing feed rate and therefore increasing
the surface area will increase by the power of two. While VSFL there is a decreasing mechanical energy input,
when the feed rate increases, than this volume will increase because more material share the mechanical energy which
by the power of three. So, with increasing extruder size, is supplied by the system. Another point which is also
the ratio between the surface area to introduce heat and very important is that with increasing barrel temperatures
cooling energy to the system to the volume of the material the SMEC is decreasing. Actually with increasing barrel
is getting smaller. This is why additional energy needs to temperature the viscosity of the material will decreasing,
be added by increasing the screw speed. Also the design therefore also the torque will decreasing. And compared
space windows are growing with increasing scale up to Equation 2, with decreasing torque the SMEC will
steps. decreases as well.
Another effect which could be shown in this study is the
correlation of the SMEC with the degree of filling of the Conclusion
extruder (Figures 6a, 6b and 6c). For each of the three extruder scales a design space could
All these effects can be explained by the equation of the be calculated based on the residence time distribution and
SMEC. With increasing feed rate and therefore increasing the specific mechanical energy consumption.
VSFL there is a decreasing mechanical energy input, be- It could be shown that the residence time distribution and
cause more material share the mechanical energy which the specific mechanical energy consumption are crucial
is supplied by the system. Another point which is also parameters for an successful scale-up of an pharmaceutical
very important is that with increasing barrel temperatures melt extrusion process.
the SMEC is decreasing. Actually with increasing barrel It could be shown the amount of tracer influences the
temperature the viscosity of the material will decreasing, residence time distribution measurement.
3
 Application Notes LR-71
Fig. 7: Pharma 11 - Twin screw extruder with 11 mm screw
diameter
Fig. 9: Pharma 24 - Twin screw extruder with 24 mm screw
diameter

Reference
[1] Breitenbach, J.: Melt extrusion, from process to
drug delivery technology, European Journal of
Pharmaceutics and Biopharmaceutics, 2002
[2] Douroumis, D.: Hot melt Extrusion - Pharma-
ceutical applications, Willey 2012
[3] Bogun, M.: Untersuchungen zur kontinuierlichen
Herstellung von Kautschukmischungen basierend
auf Rubber/Filler-Composites am Doppelschnecken-
extruder, Thesis Hallee Germany, 2005
[4] Kohlgrüber, K.: Der gleichläufige Doppelschnecken-
extruder, Carl Hanser Verlag, 2007

Acknowledgements
Fig. 8: Pharma 16 - Twin screw extruder with 16 mm screw This work was performed in collaboration with the BASF.
diameter In this collaboration the BASF and Thermo Fisher
Scientific are working close together to investigate the
dependency and influences of process parameters in Hot
Melt Extrusion Processes. Also the link between Rheology
and HME is investigated.
Especially to understand the process and the way to scale
up HME processes are focus of this work.

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