(342d) Establishing a Procedure for Transferring HME Processes Using Physical Similarities

Introduction

Hot Melt Extrusion (HME) attracted
increasing interest in the pharmaceutical industry during recent years. The
majority of newly developed APIs (active pharmaceutical ingredients) is hardly soluble
in aqueous systems, thus, requires adequate formulations and manufacturing
technologies to achieve sufficient levels of bioavailability. HME is a potent
pathway to overcome this challenge by establishing solid solutions. Since the process parameters (e.g., screw design, temperature, screw
speed) are affecting the morphology of the API a transfer of a HME process from
one line to another needs proper considerations. In polymer processing such
scale up procedures are common practice especially for single-screw extruders
by using physical similarities [1]. Although
several guidelines for scaling up of twin-screw extruders exist, it is
necessary to know the limitation factors (volume scale-up, energy scale-up,
temperature scale-up) [2]–[5].

The
objective of this study is therefore to establish a suitable transfer of a HME
process from a model extruder (Pharma Extruder ZSK 18 from Coperion GmbH) to a target extruder (PHARMALAB 16 twin-screw extruder from Thermo Fisher Scientific Inc.), where the properties of the intermediate
products of both processes should be as identical as possible.

Theoretical
Basis

As
appropriate transfer methods, the existing method from Menges
and Feistkorn [3] as well as the one from Rauwendaal [2] were chosen. The
first one is based on the model theory and allows a
fully worked out transfer of twin-screw extruders (TSEs). The second method
does not allow a complete transfer of the extrusion process since it states to
hold critical process parameters, (e.g., the specific mechanical energy consumption (SMEC)) constant. By
using the suggested equations, the throughput, the screw speed and the SMEC of
the target extruder can be calculated. The two methods
are compared in this study.

In
pharmaceutical HME, product temperature and shear rates can be critical process
parameter since pharma polymers and API can be strongly sensitive to both. Due to the high shear rates in the
extrusion die and the impact on the processed material, it is essential to
consider the extrusion die properly in the transfer procedure, to avoid different
pressure or temperature development. This can be achieved
by calculating the die conductance of the die of each extruder [6].

Experimental
Methods

Materials

The
intermediate products consist of a binary material system. As API Fenofibrate F6020 from Sigma-Aldrich and as
polymer matrix Soluplus®, a graft
copolymer from BASF, was chosen. A premix (1:9)
was blended before the extrusion process.

Experiments

The set-up
of the trials on the model extruder is shown in Table
1. The screw and die configuration were not changed during the investigations.

The set-up
of the trials on the target extruder is shown in Table
2. The process input parameters have been calculated
according to the two existing transfer methods. As scale-factor for the
assembly of the screw configuration of the target extruder, the unrolled screw
length Z was used.

The residence time distribution (model and target extruder) was
investigated by means of a coloured tracer and video analysis.

Characterization methods

The
intermediate products, obtained from the HME process on the model and target extruder,
were characterized by differential scanning
calorimetry (DSC), dissolution test according to Ph.Eur. – 2.9.3 with apparatus 2 and content uniformity test according to Ph.Eur. – 2.9.40.

Table 3 shows the different glass transition temperatures (T_g) for the runs 1-4 and 1_M. As can be seen
especially the shear rate (represented through the screw speed) causes a shift
in glass transition to higher temperature, which indicates that the formulation
is sensitive to shear.  The T_g of Run
1_M is very close to Run 1, which indicates similar thermal properties.

Table 3: Glass transition
temperature of different runs

Figure 1 shows the DSC curves of run 1 in comparison to run 1_M,
which have been extruded according to the transfer method of Menges and Feistkorn. As can be seen the shape of the two
curves are similar with similar T_g (see
Table 3) indicating that the transfer process was successful regarding thermal
properties.

Figure 1: DSC curves (first
heating) of Run 1 and Run 1_M

Conclusion
and Outlook

By comparing
the process output parameters and product characteristics from the model and
target extruder, it will be shown if the selected
transfer methods are suitable. First results showed that the transfer regarding
thermal properties was successful for run 1 using the method of Menges and Feistkorn. Planned
analysis will reveal if the transfer was successful regarding dissolution
behaviour and content uniformity for all runs. The gained results and the
established procedure will help to build up profound knowledge and
understanding about scale up of hot melt extrusion processes in pharmaceutical
applications.

References

[1]  M. Zlokarnik, “Dimensionsanalyse,” in Scale-up:
Modelluebertragung in der Verfahrenstechnik,
Second Edition., Weinheim: Wiley-VCH Verlag GmbH
& Co. KGaA, 2005, pp. 3–15.

[2]  C. Rauwendaal, “10 - Twin Screw Extruders,” in Polymer
Extrusion (Fifth Edition), Fifth Edition., C. Rauwendaal,
Ed. Hanser, 2014, pp. 697 – 761.

[3]  G. Menges and W. Feistkorn,
“Scale-Up of twin screw extruders application and verification with the example
of PVC,” Adv. Polym. Technol., vol. 4, no. 2,
pp. 123–129, 1984.

[4]  A. Dreiblatt,
“13 - Technological Considerations Related to Scale-Up of Hot-Melt Extrusion
Processes,” in Hot-melt Extrusion: Pharmaceutical Applications,
Chichester: John Wiley & Sons Ltd., 2012, pp. 285–300.

[5]  K. Kohlgrueber, Co-rotating Twin-screw Extruders:
Fundamentals, Technology, and Applications. Munich:
Carl Hanser Publishers, 2008.

[6]  W. Michaeli, Extrusionswerkzeuge für Kunststoffe und
Kautschuk: Bauarten, Gestaltung und Berechnungsmoeglichkeiten,
2. Auflage. Munich, Vienna: Carl Hanser, 1991.