(719c) Towards Predicting the Quality of HME Products

Josip Matić^*, Carolina Alva*, Hannes Bauer*, Johannes Khinast^*,**

*Research Centre Pharmaceutical Engineering GmbH, Inffeldgasse 13/III, 8010 Graz, Austria

**Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13/III, 8010 Graz, Austria

Email for correspondence: khinast@tugraz.at

Introduction

Hot melt extrusion (HME) is a continuous manufacturing process primarily facilitated by co-rotating intermeshing twin-screw extruders (TSE). The process is mostly used in order to produce amorphous solid dispersions of poorly soluble active pharmaceutical ingredients (APIs), by dispersing them in polymer carriers. The process setup is extremely modular, allowing for a tailor made HME process for every formulation. On the other hand, the process setup flexibility leads to problems in achieving the desired product quality, i.e. the HME process setup is extremely challenging. This is the reason that HME might not even be considered as a possible manufacturing route. In addition, during HME, the product is exerted to high temperatures and significant shear input. The temperature and shear history (thermo-mechanical history) of the product determines the product quality after HME. Knowing the actual thermo-mechanical load exerted on the product is challenging, as accurate measurements are difficult to obtained and in some cases not even possible (melt temperature during the whole process).

Methodology

As a response to the challenges, simulations have been increasingly used as means for process understanding. In general, HME simulations have been used for understanding individual extruder screw elements, the HME process as a whole and to relate HME to other unit operations in a continuous manufacturing line. Most notable among them is the individual extruder screw investigation using the Lagrangian based Smoothed Particle Hydrodynamics (SPH) approach for understanding the melt flow and mixing in fully and/or partially filled extruder screw elements, for Newtonian and non-Newtonian fluids [1]–[5]. The knowledge gained is applied in a less complex and faster 1D HME code allowing for the accurate representation of the process as a whole[6]. All of these approaches have a focus on understanding the process, either by investigating the melt flow in detail and/or by investigating the influence of the process settings on the process state variables like melt temperature and RTD. Building on the knowledge gained from process simulations, experiments and product investigations, the developments of tools for predicting the product performance in-silico is the next challenge. Hence, relating the process state variables (melt temperature, SMEC, RTD…) with the product performance, is the next step in understanding the HME process.

Results

In accordance, the foundations are laid for in-silico product performance prediction of extruded products. Various experiments were carried out on a 12mm prototype TSE from Leistritz with the goal of testing the limits of the equipment and the formulation used. The resulting products obtained, with various process settings, were quantified in terms of their crystallinity, degradation, content uniformity and release profile, as measures of the product quality. The quality of the product was then overlaid with the HME state variables obtained via the 1D HME simulation code developed in-house, with the goal to find process descriptors for the product quality. The knowledge used will be applied in the HME setup and scale-up of various other formulations.

Literature

[1] J. J. Monaghan, “Smoothed particle hydrodynamics,” Reports Prog. Phys., vol. 68, no. 8, pp. 1703–1759, Aug. 2005.

[2] K. Kohlgrüber and W. Wiedmann, Co-Rotating Twin-Screw Extruders. Munich: Carl Hanser Verlag, 2008.

[3] A. Eitzlmayr and J. Khinast, “Co-rotating twin-screw extruders: Detailed analysis of conveying elements based on smoothed particle hydrodynamics. Part 1: Hydrodynamics,” Chem. Eng. Sci., vol. 134, pp. 880–886, 2015.

[4] A. Eitzlmayr, J. Matić, and J. Khinast, “Analysis of Flow and Mixing in Screw Elements of Corotating Twin-Screw Extruders via SPH,” AIChE J., 2017.

[5] R. Baumgartner, J. Matić, S. Schrank, S. Laske, J. G. Khinast, and E. Roblegg, “NANEX: Process Design and Optimization,” Internaitonal J. Pharm., vol. 506, pp. 35–45, 2016.

[6] A. Eitzlmayr et al., “Mechanistic modeling of modular co-rotating twin-screw extruders,” Int. J. Pharm., vol. 474, no. 1–2, pp. 157–176, 2014.