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Continuous Processing of Micropellets via Hot-Melt Extrusion

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Abstract

Microparticulate drug delivery systems, e.g., micropellets (MPs), are used in a variety of pharmaceutical formulations such as suspensions, injectable systems, and capsules. MPs are currently manufactured mainly via batch, solvent-based processes, e.g., spray-drying and solvent evaporation-extraction. In this paper, we present a novel, solvent-free, continuous hot-melt extrusion–based approach with an inline cold pelletization step and the potential of unprecedented on-the-fly formulation changes, aiming at producing the smallest particles usable for injectable applications. A biodegradable, crystalline dispersion consisting of poly(DL-lactic acid) (PLA) filled with metformin as the model drug was chosen on purpose to elucidate the broad applicability of the process also to formulations with limited stretchability and complex pelletizability. Next to optical/statistical particle analyses and in-line high-speed camera investigations providing insights into the pelletization process, the injectability of the most promising micropellets was compared to that of one marketed formulation. Fast extrudate haul-off speeds and high numbers of pelletizer knives resulted in particles with a narrow and small particle size distribution with a d50 below 270 µm and aspect ratios close to 1. To omit protruding drug particles to ensure sufficient extrudate stretchability and allow for the smallest MPs, it was found that the d90 of the embedded drug must be significantly below the extrudate diameter. Upon adapting the syringe diameter, the produced micropellets revealed similar injectability parameters to the marketed formulation, showcasing the potential that the proposed setup has for the manufacturing of novel microparticulate formulations.

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Acknowledgements

The authors would like to thank Dr. Peter Böhling, Aygün Dogan, and Carolina Patricia Alva Zúñiga from the Research Center Pharmaceutical Engineering as well as Christoph Zauner and Michael Mayer from Fresenius Kabi, Austria, for their support with the injectability experiments and data treatment.

Funding

The Research Center Pharmaceutical Engineering (RCPE) is funded within the framework of COMET—Competence Centers for Excellent Technologies by BMK, BMAW, Land Steiermark, and SFG. The COMET program is managed by the FFG.

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Author notes

  1. Martin Spoerk and Ioannis Koutsamanis contributed equally.

Authors and Affiliations

  1. Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010, Graz, Austria

    Martin Spoerk, Ioannis Koutsamanis, Michael Piller, Manuel Rajkovaca, Amrit Paudel & Johannes Khinast

  2. Institute of Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, 8010, Graz, Austria

    Andreas Kottlan, Amrit Paudel & Johannes Khinast

  3. Maag Automatik GmbH, Ostring 19, 63763, Großostheim, Germany

    Christian Makert

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  1. Martin Spoerk
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Contributions

Martin Spoerk: Conceptualization, methodology, validation, formal analysis, data curation, writing (original draft), writing (review and editing), visualization, supervision, project administration.

Ioannis Koutsamanis: Methodology, validation, formal analysis, investigation, data curation, writing (original draft), visualization.

Andreas Kottlan: Methodology, validation, data curation, writing—review and editing.

Christian Makert: Methodology, writing—review and editing.

Michael Piller: Methodology, formal analysis, writing—review and editing.

Manuel Rajkovaca: Methodology, writing—review and editing.

Amrit Paudel: Methodology, writing—review and editing.

Johannes Khinast: Methodology, writing—review and editing.

Corresponding author

Correspondence to Martin Spoerk.

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Spoerk, M., Koutsamanis, I., Kottlan, A. et al. Continuous Processing of Micropellets via Hot-Melt Extrusion. AAPS PharmSciTech 23, 264 (2022). https://doi.org/10.1208/s12249-022-02405-7

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