According to ICH Q8 process analytic technology (PAT) should be established to monitor critical quality attributes (CQAs) during manufacturing processes. Ethinylestradiol (EE) is a highly active and low dosed steroid hormone that is prone to oxidative degradation. The stability of this compound is therefore a critical quality attribute that has to be considered during drug formulation development. Beside the stability of EE, granule particle size and moisture are CQAs influencing the tableting ability of the resulting granules and the stability of EE. Both CQAs should be monitored during the production process.
The investigations described in this thesis evaluate the implementation of in-line-sensors for monitoring of particle size (spatial filtering technology, SFT) and granule moisture (microwave resonance technology, MRT) during the fluid bed granulation process and the influence of process-variations on the stability of EE. The aim of these investigations was to develop an effective and mild fluid bed granulation process for a new model formulation based on microcrystalline cellulose as replacement for lactose as main filler excipient. The EE degradation products 6-alpha-hydroxy-EE, 6-beta-hydroxy-EE, 9(11)-dehydro-EE and 6-oxo-EE were quantified as an index for the stability of EE.
It could be demonstrated that the surface of the filler substance influences the stability of EE due to the impact of water molecules. Hence, spraying sequence was determined to be a useful tool to improve the stability of EE. Correlations could be established for 6-oxo-EE with granule moisture and thermic parameters. The implementation of the SFT-sensor in the granulation process was successful. Measurement with the MRT-sensor for monitoring of granule moisture has to be improved.:Chapter I 1
1 Introduction
Chapter II 41
2 Materials and Methods
Chapter III 54
3 In-line Monitoring of Particle Size in a Fluid Bed Granulator: investigations concerning positioning and configuration of the sensor
Chapter IV 72
4 Influence of in line monitored fluid bed granulation process parameters on the stability of Ethinylestradiol
Chapter V 90
5 Influence of filler excipients on stability of EE
Chapter VI 105
6 Discussion and Conclusion
Chapter VII 131
7 Summary
Chapter VIII 138
8 Zusammenfassung
Reference List 146
Appendix 158
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:33705 |
| Date | 03 April 2019 |
| Creators | Rossteuscher-Carl, Katrin |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/updatedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 10.1016/j.ijpharm.2015.10.074, 10.1016/j.ijpharm.2014.02.044 |
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