(372d) Pharmaceutical HME Process Development: Understanding the Impact of Kneading Elements in the Screw Configuration and Product Quality

Hot melt extrusion (HME) is a continuous manufacturing process primarily carried out using co-rotating intermeshing twin-screw extruders (TSE). In the pharmaceutical context, HME is primarily used to produce amorphous solid dispersions of poorly soluble active pharmaceutical ingredients (APIs). In addition, it can also facilitate the development and production of products with crystalline API embedded into a polymer matrix and nanopharmaceuticals. Being a continuous manufacturing technology, HME based drug development typically requires prohibitively high amounts of API (kilograms of premix vs grams available in the early development stages) for successful formulation screening and early process development. The process setup itself is modular, allowing the process to be tailor-made for any formulation. This might however be problematic in the context of choosing the appropriate and efficient setup for an unknown formulation and it is an additional reason for relatively high quantities of material usually needed for the screening. Effectively solving the multidisciplinary challenge of formulation development, early process screening, effective scale-up and transfer to GMP production represents one the key challenges of the pharmaceutical industry and is especially challenging for novel technologies like HME.

Methodology

Addressing these challenges, our group has worked on the development of in silico and experimental tools for simpler process development and scale-up. Since to this date most of the process setup and scale-up activities are performed experimentally and empirically, one of the goals of our group was to create in silico tools for a rational, science-based process setup and scale-up, while addressing other important aspects, such as API degradation and overall product quality [1], [2]. The fundamental idea behind process modelling is the break down and the detailed analysis of the key process aspects, among which the most prominent might be the analysis of flow patterns developed as a result of the rotation and geometry of the individual screw element pairs [1], [3]–[8]. Following our work showing the impact an individual kneading section along the screw configuration has on the product quality in [9], [10], our work focused on detailed analysis of kneading elements and understanding their impact on the melt flow. For this purpose, we performed a number of Smoothed Particle Hydrodynamics (SPH) simulations of different kneading elements typically used in the pharmaceutical HME. Kneading elements with an angle of 30°, 45°, 60° and 90° between the individual kneading discs were investigated, with kneading block thicknesses of 1.1 mm, 2.55 mm and 4.1 mm, Figure 1.

Figure 1. Example of a 30° kneading element with three different disc thicknesses (1.1 mm, 2.55 mm and 4.1 mm).

Results

The kneading elements were analyzed in terms of their pressure and power characteristics, mixing efficiency, shear rate distribution and residence time. The data collected from the pressure and power characteristics shows the impact the kneading element angle and disc thickness have on the ability of the screw to convey melt, build pressure and dissipate energy. The differences found have an impact on the use of the individual kneading elements in the full screw configuration and processing tools. In addition, the analysis of the shear rate distribution and residence time distribution made it possible to produce reduced order models of those quantities that can be used in simplified 1D models of the process. This allows us to move from simplified equations representing the process state in 1D process models and directly use the data generated from detailed 3D screw simulations. In the light of the work presented in [9] and [10], this will help in developing a fully in silico based process development and scale-up framework that will be able to accurately calculate the process state and predict the resulting product quality. This will help to significantly reduce the time to market, cost and waste produced in the development of novel drug forms.

Literature

[1] J. Matić, A. Witschnigg, M. Zagler, S. Eder, and J. Khinast, “A novel in silico scale-up approach for hot melt extrusion processes,” Chem. Eng. Sci., vol. 204, pp. 257–269, Aug. 2019.

[2] J. Matić, A. Paudel, H. Bauer, R. A. L. Garcia, K. Biedrzycka, and J. G. Khinast, “Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch,” AAPS PharmSciTech, vol. 21, no. 5, p. 176, Jul. 2020.

[3] A. Eitzlmayr and J. G. 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. 861–879, Sep. 2015.

[4] A. Eitzlmayr and J. G. 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. 861–879, Sep. 2015.

[5] A. Eitzlmayr, J. Matić, and J. G. Khinast, “Analysis of flow and mixing in screw elements of corotating twin-screw extruders via SPH,” AIChE J., vol. 63, no. 6, pp. 2451–2463, Jun. 2017.

[6] A. Eitzlmayr et al., “Experimental characterization and modeling of twin-screw extruder elements for pharmaceutical hot melt extrusion,” AIChE J., vol. 59, no. 11, pp. 4440–4450, Nov. 2013.

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

[8] R. Baumgartner, J. Matić, S. Schrank, S. Laske, J. Khinast, and E. Roblegg, “NANEX: Process design and optimization,” Int. J. Pharm., vol. 506, no. 1–2, pp. 35–45, Jun. 2016.

[9] J. Matić et al., “Towards predicting the product quality in hot-melt extrusion: Small scale extrusion,” Int. J. Pharm. X, vol. 2, p. 100062, Dec. 2020.

[10] J. Matić et al., “Towards predicting the product quality in hot-melt extrusion: Pilot plant scale extrusion,” Submitted.