title: Influence of in line monitored fluid bed granulation process parameters on the stability of Ethinylestradiol.
abstract: Ethinylestradiol (EE) as a highly active and low dosed compound is prone to oxidative degradation. The stability of the drug substance is therefore a critical parameter that has to be considered during drug formulation. Beside the stability of the drug substance, granule particle size and moisture are critical quality attributes (CQA) of the fluid bed granulation process which influence the tableting ability of the resulting granules. Both CQA should therefore be monitored during the production process by process analytic technology (PAT) according to ICH Q8. This work focusses on the effects of drying conditions on the stability of EE in a fluid-bed granulation process. We quantified EE degradation products 6-alpha-hydroxy-EE, 6-beta-hydroxy-EE, 9(11)-dehydro-EE and 6-oxo-EE during long time storage and accelerated conditions. PAT-tools that monitor granule particle size (Spatial filtering technology) and granule moisture (Microwave resonance technology) were applied and compared with off-line methods. We found a relevant influence of residual granule moisture and thermic stress applied during granulation on the storage stability of EE, whereas no degradation was found immediately after processing. Hence we conclude that drying parameters have a relevant influence on long term EE stability.
authors.affiliation: Jenapharm GmbH & Co. KG, Otto-Schott-Str. 15, 07745 Jena, Germany; University of Leipzig, Pharmaceutical Technology, Institute of Pharmacy, Eilenburger Str. 15A, 04317 Leipzig, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Roßteuscher-Carl
authors.affiliation: Jenapharm GmbH & Co. KG, Otto-Schott-Str. 15, 07745 Jena, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Fricke
authors.affiliation: University of Leipzig, Pharmaceutical Technology, Institute of Pharmacy, Eilenburger Str. 15A, 04317 Leipzig, Germany.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hacker
authors.affiliation: University of Leipzig, Pharmaceutical Technology, Institute of Pharmacy, Eilenburger Str. 15A, 04317 Leipzig, Germany. Electronic address: schulz@uni-leipzig.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schulz-Siegmund
mesh_terms: D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D004997:Ethinyl Estradiol / Q000737:chemistry*; D010316:Particle Size; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D013607:Tablets; D004997:Ethinyl Estradiol
keywords: Ethinylestradiol; Fluid bed granulation; Microwave resonance technology; Process analytical technologies; Spatial filtering technology