Dokument: Scale-up in twin-screw wet granulation
| Titel: | Scale-up in twin-screw wet granulation | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=65379 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240416-080751-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Franke, Marcel Amin [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Dr. h.c. Kleinebudde, Peter [Gutachter] Prof. Dr. Breitkreutz, Jörg [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Over the last few decades continuous manufacturing has become a highly discussed topic in the pharmaceutical industry as it offers a multitude of benefits over traditional batch manufacturing. One technology that has been subject to thorough investigations is twin-screw wet granulation as a continuous alternative to traditional (batch) processes for wet granulation. However, despite its ability to scale out by increasing the runtime in continuous manufacturing, there is still a need to implement some scale-up steps between research and development, and commercial production of a globally relevant drug product as the difference in demand can vary by several orders of magnitude. Therefore, this thesis focusses on scaling up the twin-screw wet granulation process from a laboratory scale to a potential production scale.
In the first part of the thesis, the general impact of various process parameters on the granulation behavior was investigated on the smaller scale to ensure a sufficient process understanding of the selected setup and formulation. The results showed a strong impact of the applied liquid to solid ratio on granule and tablet properties and an overall high reproducibility when process parameters were kept constant. Therefore, in the next and central parts of the thesis, different scale-up strategies were developed and applied for further investigations. Even though major differences in the granule size distributions directly after the granulation process were found based on the device scale, the size distribution, granule properties and resulting tablet properties were unexpectedly similar when the granules were milled afterwards and the liquid to solid ratio kept constant among scales during granulation. The relatively high process robustness was then confirmed in further experiments with additional formulations, as it was initially unclear whether these observations were simply proof of a very robust formulation or if the process scale-up itself would be relatively robust. There, the observed variations in e.g., the tensile strengths of tablets were slightly higher, which could not be explained by a systematic impact of any process parameter or scale-up strategy. However, the properties of milled granules and the resulting tablets for all formulations were still relatively similar independent of the applied scale-up strategy or device scale. As the milling process was identified as an essential processing step to achieve similar product properties, the final part of the thesis investigates whether the modus operandi of downstream processes after the granulation would impact the final product properties. Significant differences in both granule size distributions and tablet tensile strengths were found based on whether the downstream processing was performed fully continuously on the line or manually in isolated processes after granulation. The lower number of fines could be attributed to the vacuum applied for transportation during the fully continuous milling, that likely led to a shorter residence time within the mill. However, the significantly higher tensile strength for fully continuous runs could not be fully explained as the effect was seemingly not caused by the differences in granule size distribution but potentially connected to the additional storage time (~1 day) between granulation and tableting. These findings would have to be confirmed and further analyzed in additional studies to find a suitable explanation. Overall, twin-screw wet granulation process itself offers a relatively broad design space for process scale-up if the liquid to solid ratio is kept constant. Differences in GSDs caused by the different granulator sizes are usually mitigated by a consecutive milling process. However, formulators should keep in mind that the fully continuous nature of additional up- and downstream processes might pose additional challenges regarding e.g., the flowability of the powder blend prior to granulation. | |||||||
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| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Technologie und Biopharmazie | |||||||
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