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.

Table 1: HME process set-up (model extruder)

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.

Table 2: HME process set-up (target extruder) – (R- Rauwendaal, M- Menges and Feistkorn)

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.