New insights in oxybutynin chemical stability: Identification in transdermal patches of a new impurity arising from oxybutynin N-oxide rearrangement

作者：Canavesi Rossana^*; Aprile Silvio; Giovenzana Giovanni B; Di Sotto Antonella; Di Giacomo Silvia; Del Grosso Erika; Grosa Giorgio

来源：European Journal of Pharmaceutical Sciences, 2016, 84: 123-131.

DOI：10.1016/j.ejps.2016.01.015

• Oxybutynin
• N-oxidation
• N-oxide rearrangement
• Chemical stability
• Genotoxicity

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, Oxy free 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 Oxy free base in oxidative conditions assigning, to Oxy-EK, the structure of (3E)-4-(N,N-diethylamino)-2-oxo-3-buten-1-yl1-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 alpha,beta-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.

• 出版日期2016-3-10