Electrochemical oxidation of fesoterodine and identification of its oxidation products using liquid chromatography and mass spectrometry Pavla Ku9 cerová a , Jana Skopalová b, *, Lukáš Ku9 cera a , Jan Hrbá9 c c , Karel Lemr a a Regional Centre of Advanced Technologies and Materials, Department of Analytical Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46 Olomouc, Czech Republic b Department of Analytical Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46 Olomouc, Czech Republic c Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic A R T I C L E I N F O Article history: Received 9 July 2014 Received in revised form 29 January 2015 Accepted 29 January 2015 Available online 31 January 2015 Keywords: Fesoterodine Oxidation Hydrolysis Voltammetry Mass spectrometry A B S T R A C T The electrochemical behavior of fesoterodine (FES), an antimuscarinic drug used for the treatment of urge incontinence and overactive bladder, was investigated using linear sweep and cyclic voltammetry at a stationary and rotating disc glassy carbon electrodes. A single two-electron anodic signal of FES was observed in neutral buffered aqueous methanolic solutions. Kinetics of alkaline hydrolysis of FES to its active metabolite 5-hydroxymethyl tolterodine was investigated by time dependent linear sweep voltammetry. Controlled potential electrolysis of FES solutions was performed at platinum gauze electrode in aqueous-methanolic media. Electrolyzed solutions were analyzed using ultra performance liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry. Two main products of electrochemical oxidation of fesoterodine were identified as 5-formyl fesoterodine (isobutyric acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-formyl-phenyl ester) and N-desisopropy- lated fesoterodine (isobutyric acid 4-hydroxymethyl-2-(3-isopropylamino-1-phenyl-propyl)-phenyl ester). The mechanism of the electrochemical oxidation of FES has been proposed and confirmed using on-line electrochemistry/mass spectrometry with porous glassy carbon electrode. ã 2015 Elsevier Ltd. All rights reserved. 1. Introduction Fesoterodine fumarate (FES, 1 in Scheme 1) is a muscarinic receptor antagonist used for the treatment of urinary urge incontinence (UUI) and other symptoms associated with an overactive bladder. This drug also increases functional bladder volume [1]. Isobutyric acid 2-((R)-3-diisopropylammonium-1- phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrogen fuma- rate (IUPAC) is the form of FES used in pharmaceutical preparations commercially available under the trade name Toviaz. Fesoterodine fumarate is white to off-white powder freely soluble in methanol (574 mg cm 3 ), water (542 mg cm 3 ), acetone (205 mg cm 3 ), 0.9% NaCl solution (551 mg cm 3 ), very slightly soluble in toluene (0.14 mg cm 3 ) and practically insoluble in heptane (0.03 mg cm 3 ). The melting point of FES is 105  C and the pK a value is (10.31  0.01) at 23.4  C [2]. According to recent studies, fesoterodine, a novel drug, proves superior efficacy in treatment of UUI over an older antimuscarinic drug tolterodine [3,4]. With tolterodine, FES shares the main active metabolite, 5-hydroxymethyl tolterodine (5-HMT, 2 in Scheme 1). After oral administration, FES is hydrolyzed in plasma by nonspecific esterases to 5-HMT, which is further metabolized principally via cytochromes P450 2D6 and P450 3A4 in the liver to its inactive metabolites – namely carboxy, carboxy-N-desisopropyl and N-desisopropyl metabolite [5]. All of the pharmacodynamic effects of FES in human body are thought to be mediated via 5-HMT [6]. Knowledge of drug stability is important not only for the pharmaceutical application but also for its analysis. It can prevent incorrect interpretation of the results. The stability of FES was investigated under acidic, basic, thermal, oxidative, and photolytic stress conditions. 10 % and 32 % of the drug was degraded after 6 h in 1 M HCl and 2 M HCl, respectively, 100 % after 36 h in 2 M HCl. FES was found to be highly susceptible to alkaline hydrolysis (Scheme 1) as its complete degradation occurred already after 15 min in 0.01 M NaOH (95 % after 10 min). FES was quite stable under oxidative conditions (in 2% H 2 O 2 ). * Corresponding author. Tel.: +420 585634442; fax: +420 585634433. E-mail address: jana.skopalova@upol.cz (J. Skopalová). http://dx.doi.org/10.1016/j.electacta.2015.01.190 0013-4686/ ã 2015 Elsevier Ltd. All rights reserved. Electrochimica Acta 159 (2015) 131–139 Contents lists available at ScienceDirect Electrochimica Acta journa l home page : www.e lsevier.com/loca te/ele cta cta