Development and Performance of a Highly Sensitive Model Formulation Based on Torasemide to Enhance Hot-Melt Extrusion Process Understanding and Process Development
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The aim of this work was to investigate the use of torasemide as a highly sensitive indicator substance and to develop a formulation thereof for establishing quantitative relationships between hot-melt extrusion process conditions and critical quality attributes (CQAs). Using solid-state characterization techniques and a 10 mm lab-scale co-rotating twin-screw extruder, we studied torasemide in a Soluplus® (SOL)-polyethylene glycol 1500 (PEG 1500) matrix, and developed and characterized a formulation which was used as a process indicator to study thermal- and hydrolysis-induced degradation, as well as residual crystallinity. We found that torasemide first dissolved into the matrix and then degraded. Based on this mechanism, extrudates with measurable levels of degradation and residual crystallinity were produced, depending strongly on the main barrel and die temperature and residence time applied. In addition, we found that 10% w/w PEG 1500 as plasticizer resulted in the widest operating space with the widest range of measurable residual crystallinity and degradant levels. Torasemide as an indicator substance behaves like a challenging-to-process API, only with higher sensitivity and more pronounced effects, e.g., degradation and residual crystallinity. Application of a model formulation containing torasemide will enhance the understanding of the dynamic environment inside an extruder and elucidate the cumulative thermal and hydrolysis effects of the extrusion process. The use of such a formulation will also facilitate rational process development and scaling by establishing clear links between process conditions and CQAs.
KEY WORDShot-melt extrusion amorphous solid dispersion process development and understanding torasemide critical quality attribute
The authors wish to thank Karlheinz Rauwolf, Teresa Dagenbach, David Gessner, and Stefan Weber of AbbVie for their support in conducting the experiments and Mirko Pauli, Mario Hirth, Thomas Kessler, Christian Schley, and Ariana Low of AbbVie and Esther Bochmann of the University of Bonn for helpful and productive discussions.
Compliance with Ethical Standards
Rachel C. Evans, Samuel O. Kyeremateng, Lutz Asmus, Matthias Degenhardt, and Joerg Rosenberg are employees of AbbVie and may own AbbVie stock options. Karl G. Wagner is an employee of the University of Bonn. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
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