(337f) Pharmaceutical HME Process Development: Understanding Non-Newtonian Fluid Flow

Hot-melt extrusion (HME) is a continuous manufacturing process that uses co-rotating intermeshing twin-screw extruders (TSE). The process is primarily used to produce amorphous solid dispersions of poorly soluble active pharmaceutical ingredients (APIs) when used in pharmaceutical applications. In addition, it can also facilitate the development of products with crystalline API embedded into a polymer matrix and nano-pharmaceuticals. 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 choosing the appropriate and efficient design for an unknown formulation. It is an additional reason for the 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 of the critical challenges of the pharmaceutical industry and is especially challenging for novel technologies like HME.

Methodology

Addressing these challenges, our group has worked on developing in silico and experimental tools for more straightforward process development and scale-up. To this date, most of the process setup and scale-up activities are performed experimentally and empirically; one of the goals of our group is 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 modeling is the breakdown and analysis of critical 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 a separate kneading section along the screw configuration has on the product quality in [9], [10], our work focused on increasing the number of physical quantities we can quantify using in silico tools. For this purpose, we use the Smoothed Particle Hydrodynamics (SPH) simulation tool to cover non-Newtonian fluids and melt temperature prediction. Model validation and the characterization of different screw types were performed. The choses screw types are shown in Figure 1.

Results

Our work included computing the shear rate distribution, viscosity distribution, melt temperature distribution, local residence time distributions, pressure, and power characteristics of conveying, kneading, and mixing elements. The generated data is analyzed in shear rate, viscosity, local residence time, and melt temperature distribution. Every element type, cross-section geometry, operating condition, and formulation viscosity results in a different flow field. Understanding this flow field is critical in predicting the mixing ability of the selected screws. Moreover, different processing conditions also create a spectrum of residence time and melt temperature distributions that should be considered when assembling the screw configuration. The obtained data is used to develop reduced-order models that are more precise than simplified equations usually used in the 1D extrusion models. Better 1D extrusion models will help to predict the quality of the product, even before the first extrusion experiments, de-risk the development, and 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.