(486f) Development of an HME Based Extended-Release Formulation Using Experimental and in silico Approach

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, early process development and scale-up. 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 and imported production technologies like HME.

Methodology

Addressing these challenges, our groups have 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 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]–[3]. The fundamental idea behind process modelling is the breakdown 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], [4]–[9]. In this work we´ve followed the development of a novel extended-release product for oral administration. The process development starts with extrusions on the 9mm tabletop extruder (Three Tec ZE9) and continues to 16mm (Leistritz NANO16) and 18mm (Coperion ZSK18) extruders. The experimental development is closely followed with 3D Smoothed Particle Hydrodynamics (SPH) simulations of individual screw elements that comprises the screw configuration, and reduced-order 1D HME process simulations.

Results

The experimental setup on all three extruders is investigated in detail using information collected during the experiments and simulations. The produced extrudates are investigated in term of the material science, release profile, and stability. The extrudate quality is then connected to the prevailing extrusion state with the help of reduced order 1D HME simulations. The process was also scaled from the tabletop 9mm extruder to a triple-flighted 16mm extruder and a 18mm pilot plant size extruder. The differences found in the performance of the individual screw elements, differences in process setup and extruder design and scale are investigated and connected to the resulting extrudate quality.

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] 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.

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

[5] 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.

[6] 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.

[7] 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.

[8] 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.

[9] 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.

[10] 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.