title: New insights in oxybutynin chemical stability: Identification in transdermal patches of a new impurity arising from oxybutynin N-oxide rearrangement.
abstract: Oxybutynin hydrochloride (Oxy), the first choice drug used for the management of urinary incontinence, is available in different types of formulations. However, due to its better lipophylicity and permeability, Oxyfree base was used in the new topical formulations such as transdermal patch and gel. The presence of an unprecedented impurity (Oxy-EK) in transdermal patches led to reinvestigate the chemical stability of Oxyfree base in oxidative conditions assigning, to Oxy-EK, the structure of (3E)-4-(N,N-diethylamino)-2-oxo-3-buten-1-yl 1-cyclohexyl-1-phenylglycolate. Oxy-EK arises from the prototropic rearrangement of oxybutynin N-oxides leading to the formation of an enamino ketone function which shows a long-wavelength UV-absorption. The total synthesis of Oxy-EK was performed, allowing to propose it as the indicator of stability for oxidative degradation of Oxy free base in transdermal formulations. The presence in the structure of Oxy-EK of an α,β-unsaturated carbonyl function, a potential Michael acceptor, suggested the need of evaluating its possible mutagenic power. Accordingly, the Ames test was performed: at nontoxic concentrations, Oxy-EK did not increase the number of revertant colonies in all strains tested both in the absence and presence of the exogenous metabolic activator S9.
authors.affiliation: Department of Pharmaceutical Sciences, University of Eastern Piedmont "Amedeo Avogadro", L.go Donegani 2, 28100 Novara, Italy. Electronic address: rossana.canavesi@uniupo.it.
authors.forename: Rossana
authors.initials: R
authors.lastname: Canavesi
authors.affiliation: Department of Pharmaceutical Sciences, University of Eastern Piedmont "Amedeo Avogadro", L.go Donegani 2, 28100 Novara, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Aprile
authors.affiliation: Department of Pharmaceutical Sciences, University of Eastern Piedmont "Amedeo Avogadro", L.go Donegani 2, 28100 Novara, Italy.
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Giovenzana
authors.affiliation: Department of Physiology and Pharmacology "V. Erspamer", Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Sotto
authors.affiliation: Department of Physiology and Pharmacology "V. Erspamer", Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Giacomo
authors.affiliation: Department of Pharmaceutical Sciences, University of Eastern Piedmont "Amedeo Avogadro", L.go Donegani 2, 28100 Novara, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Del Grosso
authors.affiliation: Department of Pharmaceutical Sciences, University of Eastern Piedmont "Amedeo Avogadro", L.go Donegani 2, 28100 Novara, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Grosa
mesh_terms: D004355:Drug Stability; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D008333:Mandelic Acids / Q000737:chemistry* / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000494:pharmacology; D009152:Mutagenicity Tests; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D057968:Transdermal Patch
chemical_list: D008333:Mandelic Acids; D018727:Muscarinic Antagonists; C032680:oxybutynin N-oxide; C005419:oxybutynin
keywords: Chemical stability; Genotoxicity; N-oxidation; N-oxide rearrangement; Oxybutynin