Separation and analysis of trace degradants in a pharmaceutical formulation using on-line capillary isotachophoresis-NMR

NMR spectroscopy is widely used in the pharmaceutical industry for the structure elucidation of pharmaceutical impurities, especially when coupled to a separation method, such as HPLC. However, NMR has relatively poor sensitivity compared with other techniques such as mass spectrometry, limiting its applicability in impurity analyses. This limitation is addressed here through the on-line coupling of microcoil NMR with capillary isotachophoresis (cITP), a separation method that can concentrate dilute components by 2-3 orders of magnitude. With this approach, 1H NMR spectra can be acquired for microgram (nanomole) quantities of trace impurities in a complex sample matrix. cITP-NMR was used in this work to isolate and detect 4-aminophenol (PAP) in an acetaminophen sample spiked at the 0.1% level, with no interference from the parent compound. Analysis of an acetaminophen thermal degradation sample revealed resonances of several degradation products in addition to PAP, confirming the effectiveness of on-line cITP-NMR for trace analyses of pharmaceutical formulations. Subsequent LC-MS/MS analysis provided complementary information for the structure elucidation of the unknown degradation products, which were dimers formed during the degradation process.     

Local structure at Mn2+ ions in vacuum annealed small cubic ZnS nanocrystals self-assembled into a mesoporous structure

A mesoporous structure of self-assembled nanocrystals of cubic ZnS doped with Mn2+ ions with a homogeneous distribution of pores of similar size was synthesized at room temperature by a surfactant-assisted liquid-liquid reaction. The component nanocrystals exhibit a high crystallinity and a tight size distribution centered at 2 nm, as well as the narrowest Electron Paramagnetic Resonance (EPR) spectra linewidth and the best resolution reported so-far, effects attributed to self-assembling. The observed EPR spectra consist of lines from the substitutional Mn2+(I) and surface Mn2+(II) and Mn2+(III) centers. Here we show that, in contrast with previous reports, our EPR spectra are highly sensitive to structural changes during pulse annealing in vacuum up to 500 degrees C. The changes are related to the transformation of the surface Mn2+ centers in new Mn2+ centers, attributed to an oxidation process in which the thermal decomposition of the Tween 20 additive, also observed by EPR, seems to be involved. We have also been able to observe, for the first time by EPR spectroscopy, the formation of the ZnO phase and the nanocrystals size increase, which occur during annealing up to 500 degrees C, structural changes confirmed by XRD and TEM observations on the samples previously investigated by EPR.     

Development of HPLC/ESI-MS and HPLC/1H NMR methods for the identification of photocatalytic degradation products of iodosulfuron

In the present study, HPLC/ESI-MS and stopped-flow HPLC/1H NMR methods were developed and applied to separate and characterize the byproducts arising from TiO2-catalyzed photodegradation of the herbicide iodosulfuron methyl ester (IOME) in aqueous solution under UV irradiation. Prior to identification, irradiated solutions of IOME (200 and 1000 mg.L(-1)) were concentrated by solid-phase extraction using two cartridges: Isolute C18 and Isolute ENV+. Analytical separation was achieved on a C18 reversed-phase column with ACN/H2O (HPLC/MS) or ACN/D2O (HPLC/NMR) as mobile phase and a linear gradient with a chromatographic run time of 35 min. The combination of UV and MS data allowed the structural elucidation of more than 20 degradation products, whereas 1H NMR data permitted an unequivocal confirmation of the identities of major products and the differentiation of several positional isomers, in particular, the hydroxylation isomers. The obtained results permitted us to propose a possible degradation scheme and to put in evidence the presence of privileged sites for the attack of OH radicals. This work shows, for the first time, the application of combined HPLC with UV, MS, and NMR detection for complete structural elucidation of photocatalytic degradation products, and it will be of particular value in studies on the elimination of pollutants in aqueous solutions by photocatalysis.     

Application of Continuous-Flow HPLC-Proton-Nuclear Magnetic Resonance Spectroscopy and HPLC-Thermospray-Mass Spectroscopy for the Structural Elucidation of Phototransformation Products of 2,4,6-Trinitrotoluene

An aqueous solution of 2,4,6-trinitrotoluene (TNT) was irradiated by natural sunlight for a period of 1 month to generate phototransformation products of this compound. After solid-phase extraction on a poly(styrene-divinylbenzene) copolymer at pH 1, the structures of several acidic nitroaromatic compounds were identified by means of continuous-flow HPLC/(1)H NMR and HPLC/TSP-MS measurements of this extract. By interpretation of both NMR and MS spectra, it was even possible to characterize noncommercially available phototransformation products of TNT. The results obtained by continuous-flow HPLC/(1)H NMR were compared with those obtained by the investigation of a groundwater sample of a former ammunition site near Elsnig, Germany. The results show that several identified phototransformation products of TNT are also present in this groundwater sample.     

Degradation of picloram by the electro-Fenton process

The degradation of the picloram, a widely used herbicide, has been undertaken by the electrochemical advanced oxidation process, namely electro-Fenton in aqueous solution. This process generates catalytically hydroxyl radicals that are strong oxidizing reagents for the oxidation of organic substances. Degradation kinetics of picloram was investigated. Kinetic results evidence a pseudo first-order degradation, with a rate constant of reaction between picloram and hydroxyl radicals of (2.73+/-0.08) x 10(9) M(-1) s(-1). The effect of applied current and catalyst concentration on the degradation and mineralization of picloram was also investigated. The optimum applied current and catalyst concentration values for the degradation of picloram was determined as 300 mA and 0.2 mM Fe(3+), respectively. Mineralization of picloram was followed by the total organic carbon (TOC) analysis. At the end of 8h of electrolysis, 95% of the initial TOC was removed. Several degradation products were identified by using HPLC, LC-MS, GC-MS, and IC analysis. The identified by-products allowed to propose a mineralization pathway for the picloram degradation.     

Microscale LC-MS-NMR platform applied to the identification of active cyanobacterial metabolites

An LC-MS-NMR platform is demonstrated, which combines two innovations in microscale analysis, nanoSplitter LC-MS and microdroplet NMR, for the identification of unknown compounds found at low concentrations in complex sample matrixes as frequently encountered in metabolomics or natural products discovery. The nanoSplitter provides the high sensitivity of nanoelectrospray MS while allowing 98% of the HPLC effluent from a large-bore LC column to be collected and concentrated for NMR. Microdroplet NMR is a droplet microfluidic NMR loading method providing severalfold higher sample efficiency than conventional flow injection methods. Performing NMR offline from LC-UV-MS accommodates the disparity between MS and NMR in their sample mass and time requirements, as well as allowing NMR spectra to be requested retrospectively, after review of the LC-MS data. Interpretable 1D NMR spectra were obtained from analytes at the 200-ng level, in 1 h/well automated NMR data acquisitions. The system also showed excellent intra- and interdetector reproducibility with retention time RSD values less than 2% and sample recovery on the order of 93%. When applied to a cyanobacterial extract showing antibacterial activity, the platform recognized several previously known metabolites, down to the 1% level, in a single 30-mug injection, and prioritized one unknown for further study.     

Molecular modification of a novel macroporous silica-based impregnated polymeric composite by tri-n-butyl phosphate and its application in the adsorption for some metals contained in a typical simulated HLLW

Using tri-n-butyl phosphate (TBP) as a molecular modifier, a novel macroporous silica-based 4,4',(5')-di-(tert-butylcyclohexano)-18-crown-6 (DtBuCH18C6) polymeric composite (DtBuCH18C6+TBP/SiO2-P) was synthesized. It was done by impregnating and immobilizing DtBuCH18C6 and TBP molecules into the pores of SiO2-P particles utilizing an advanced vacuum sucking technique. The adsorption of 10 fission and non-fission products Sr(II), Ba(II), Ru(III), Mo(VI), Na(I), K(I), Pd(II), La(III), Cs(I), and Y(III) onto (DtBuCH18C6+TBP)/SiO2-P was investigated by examining the influence of contact time and the HNO3 concentration in a range of 0.1-5.0M at 298 K. It was found that at the optimum concentration of 2.0M HNO3 (DtBuCH18C6+TBP)/SiO2-P exhibited strong adsorption ability and high selectivity for Sr(II) over all of the tested elements, which showed very weak or almost no adsorption except Ba(II). Moreover, the quantity of DtBuCH18C6 leaked from (DtBuCH18C6+TBP)/SiO2-P in 2.0M HNO3, 326.2 ppm, was obviously lower than 658.4 ppm that leaked from DtBuCH18C6/SiO2-P. This was ascribed to the effective association of DtBuCH18C6 and TBP through intermolecular interaction, i.e., hydrogen bonding. The significant reduction of DtBuCH18C6 leakage by molecular modification with TBP was achieved. It was of great benefit to application of the (DtBuCH18C6+TBP)/SiO2-P polymeric composite in chromatographic partitioning of Sr(II), one of the main heat generators, from high level liquid waste (HLLW) in reprocessing of nuclear spent fuel in MAREC process developed recently.     

Degradation of 17alpha-ethinylestradiol in aqueous solution by ozonation

This study investigates the ozonation of 17alpha-ethinylestradiol (EE(2)) in aqueous solution. The affecting factors on the degradation of EE(2) were studied and described in details, such as initial EE(2) concentration, initial pH value and ozone concentration. In addition, some parameters such as pH, electrical conductivity, mineralization efficiency and degradation products were monitored during the process. The mineralization efficiency of EE(2) could reach 53.9%. During the ozonation process the rapid decrease of pH and the sharp increase of electrical conductivity indicated the formation of acidic by-products, small fragments and ions which were confirmed by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC/MS) analysis. Results showed that there were intermediate products of smaller molecule with higher polarity produced during the course of EE(2) degradation. Then a possible reaction pathway for EE(2) degradation involving all intermediates detected is proposed. During the ozonation process EE(2) was first oxidized into hydroxyl-semiquinone isomers which were subsequently degraded into low molecular weight compounds such as oxalic acid, malonate, glutarate, and so on. Furthermore, these organic acids are easily oxidized by ozone into carbon dioxide (CO(2)). This work shows that ozonation process is promising for the removal of EE(2). The results can provide some useful information for the potential treatment of EE(2) by ozonation in aqueous solution.     

Untargeted analysis of mass spectrometry data for elucidation of metabolites and function of enzymes

A Matlab-based computer program termed Discovery of General Endo- and Xenobiotics (DoGEX) was developed, which uses wavelets and morphological analysis to process liquid chromatography-mass spectrometry (LC-MS) data. The output of the program is a list of integration areas as a function of retention time and molecular mass. A feature of the computer program is spectral filtering to facilitate the detection of chromatographic peaks with a particular isotopic ratio. The program DoGEX was used to automatically select oxidation products formed from felodipine (i.e., two chlorine atoms) and bromocriptine (one bromine atom) with cytochrome P450 3A4. The recognized isotope ratio can be changed to permit a natural or artificial mixture of isotopes to be monitored for selections. This computer program can be used to analyze LC-MS data for untargeted metabolic profiling experiments, e.g., to assign endogenous functions to newly characterized cytochrome P450 enzymes. In a representative example, an incubation of testosterone, NADPH, and a 1:1 16O2/18O2 mixture yielded products with M and M+2 ions resembling bromine doublets. Another use of the program is the subtraction of one set of tR, m/z data from another, e.g., in comparisons of changes in patterns during enzyme reactions.     

Oxidation of TiAl based intermetallics

The high temperature oxidation behaviour of the binary and ternary alloys of the Ti–48Al system was studied at different temperatures. The primary objectives of this work were the establishment of the activation energies, the migration tendencies of the alloy species, mechanism of oxidation and chemistry of the oxide scales. The ternary additions were Cr (1.5 at 19%), V (2.2 at%), W (0.2 at%) and Mn (1.4 at%). The addition of ternary additions did not play a significant role in the oxidation behaviour at 704°C. At 815°C the alloys with Cr and V exhibited linear oxidation behaviour with large weight gains while the base Ti–48Al alloys exhibited the best behaviour. At 982°C the Mn-containing alloy was the worst, exhibiting a linear oxidation behaviour while the alloy with V and W and the base alloy with 400 p.p.m. oxygen exhibited the best oxidation behaviour. At 982°C the outermost oxide layer in contact with air is always near stoichiometric TiO₂. In all the alloys a layer of porosity is created just below the outer TiO₂ layer by the Kirkendall mechanism due to the rapid outward diffusion of Ti atoms. The addition of trivalent atoms like Cr in small amounts appear to be detrimental to the oxidation process as they can generate additional oxygen vacancies while the addition of atoms with valence of 5, such as V, and 6, such as W, appear to have beneficial effect on the oxidation behaviour at 982°C by tying up oxygen vacancies. This revised version was published online in November 2006 with corrections to the Cover Date.     

Two-stage reduction/subsequent oxidation treatment of 2,2',4,4'-tetrabromodiphenyl ether in aqueous solutions: kinetic, pathway and toxicity

The effectiveness of a two-stage reduction/subsequent oxidation (T-SRO) treatment of BDE-47, consisting of Fe-Ag reduction and Fenton-like oxidation, was investigated in this study. As an oxidation-resisting pollutant, BDE-47 (5 mg L(-1)) was difficult to be degraded by homogeneous Fe-Ag/H(2)O(2) system coupled with ultrasound (US) in 30 min. However, when this solution was firstly treated with Fe-Ag/US, the final debrominated product could be rapidly oxidized by the succeeding Fenton-like reactions, resulting in an efficient debromination of BDE-47 and a 100% mineralization of diphenyl ether (DPE). To scrutinize the degradation mechanism, several analytical techniques including HPLC, LC-MS/MS and GC/MS, were employed to monitor the major intermediates and final products. Moreover, luminescent bacteria test showed that the acute toxicity of the original solution (before reduction) was evidently lower than that of Fe-Ag/US reduction-treated solution; no toxicity was detected after Fenton-like oxidation. Evidence for the significance of a T-SRO treatment to decompose BDE-47 was presented.     

Localization of Mn2+ ions in mesoporous NnS

Nanocrystalline cubic ZnS doped with 0.2% mol manganese, exhibiting a stable mesoporous structure, was synthesized at room temperature by a non toxic surfactant-assisted liquid-liquid reaction. The X-ray diffraction measurements demonstrate the formation of a sponge-like mesoporous material built from cubic ZnS nanocrystals of 1.8 nm average sizes, with a tight distribution of pores of 1.8 nm mean diameter. The transmission electron microscopy images confirm the formation of the mesoporous structure with walls of 3.1 nm mean thickness built from cubic ZnS nanocrystallites of 2.1 nm average size. The resulting tight distribution of crystallites and pores yields a well resolved Electron Paramagnetic Resonance spectrum, with the narrowest reported component lines attributed to three types of isolated Mn2+ centers, called Mn2+(I), Mn2+(II) and Mn2+(III). From the analysis of the spin Hamiltonian parameters it is shown that in the Mn2+(I) centers the paramagnetic ion is situated at substitutional Zn sites in the ZnS nanocrystals, being also subjected to a small axial distortion. The relative concentration changes under thermal treatment experiments strongly suggest that in both Mn2+(II) and Mn2+(III) centers the Mn2+ ion is localized on the surface of the ZnS nanocrystallites, being bond to an oxygen ion in the first case and to an additional water molecule in the second case.     

Photochemical degradation of 1,3-dichloro-2-propanol aqueous solutions

The photochemical oxidation of 1,3-dichloro-2-propanol (1,3-DCP) was studied by following the target compound degradation, the total carbon removal rate by a total organic carbon (TOC) analyzer and by identifying the oxidation products by gas chromatography-mass spectrometry (GC-MS). The reaction was performed in a batch recycle reactor, at room temperature, using UV radiation provided by a low pressure 12W Hg lamp and H(2)O(2) as oxidant. Chloride ions, formic, acetic and chloroacetic acid were measured by ion chromatography. Apart from the chloride ions and the organic acids, the presence of 1,3-dichloro-2-propanone and chloroacetyl chloride was also detected and a possible pathway is proposed for the degradation of the parent compound. Complete degradation of 1,3-dichloro-2-propanol was achieved and the TOC removal reached as much as 80% at the end of the reaction time. The effect of the initial concentration of hydrogen peroxide was investigated and it was established that higher concentrations of H(2)O(2) slow down the reaction rate. Finally, the effect of the initial concentration of 1,3-DCP was investigated.     

The stress stability of olanzapine: studies of interactions with excipients in solid state pharmaceutical formulations

Stress stability testing represents an important part of the drug development process. It is used as an important tool for the identification of degradation products and degradation pathways, as well as for the assessment of changes in physical form of drug molecules. The impact of excipients on the stability of olanzapine confirms that levels of impurities and degradants are limiting parameters and are therefore used for stability evaluation. The major degradation product of olanzapine was identified as 2-methyl-5,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepine-4-one (III). The structure of III was determined by using LC-MS, IR and NMR. Compatibility and stress stability results demonstrated that tablet formulations of olanzapine are sensitive to temperature and moisture. In samples protected from moisture, the increase in concentration of III was shown to be highly temperature dependent and the degradation followed zero-order kinetics. In addition, studies of olanzapine with excipients and in formulated tablets revealed polymorphic phase changes in some samples, influenced by a combination of stress temperature and humidity conditions. Polymorphic transitions were monitored using x-ray powder diffraction (XRPD) analysis and exhibited no correlation between the phase change (appearance of a new polymorph) and the degradation process.     

Insights into the Electrochemical Behavior of Manganese Oxides as Catalysts for the Oxygen Reduction and Evolution Reactions: Monometallic Core-Shell Mn/Mn3O4

Overcoming the sluggish electrode kinetics of both oxygen reduction and evolution reactions (ORR/OER) with non-precious metal electrocatalysts will accelerate the development of rechargeable metal-air batteries and regenerative fuel cells. The authors investigated the electrochemical behavior and ORR/OER catalytic activity of core-porous shell Mn/Mn₃O₄ nanoparticles in comparison with other manganese dioxides (β- and γ-MnO₂), and benchmarked against Pt/C and Pt/C-IrO₂. Under reversible operation in O₂-saturated 5 M KOH at 22 °C, the early stage activity of core-shell Mn/Mn₃O₄ shows two times higher ORR and OER current density compared to the other MnO₂ structures at 0.32 and 1.62 V versus RHE, respectively. It is revealed that Mn(III) oxidation to Mn(IV) is the primary cause of Mn/Mn₃O₄ activity loss during ORR/OER potential cycling. To address it, an electrochemical activation method using Co(II) is proposed. By incorporating Co(II) into MnO_x, new active sites are introduced and the content of Mn(II) is increased, which can stabilize the Mn(III) sites through comproportionation with Mn(IV). The Co-incorporated Mn/Mn₃O₄ has superior activity and durability. Furthermore, it also surpassed the activity of Pt/C-IrO₂ with similar durability. This study demonstrates that cost-effective ORR/OER catalysis is possible.     

M位与A位双固溶MAX相的磁学性能研究

三元层状化合物MAX相兼具金属与陶瓷优良的力学性质, 通常被认为是一类高安全结构材料。有研究显示, 通过熔盐法可以将副族元素插入到MAX相A位层间, 获得具有铁磁性能的V₂(Sn, A)C (A =Fe、Co、Ni和Mn)材料。因而, 如何构建新的MAX相结构并对实现其磁性调控备受关注。本研究通过MAX相M位和A位双固溶的方式设计了四种新型MAX相(V, Nb)₂(Sn, A)C (A =Fe、Co、Ni和Mn)。XRD、SEM、EDS结合TEM分析证实了上述新相的合成。超导量子磁强计(Superconducting quantum interference device magnetometer, SQUID)测试磁学性能发现, M位固溶后的MAX相的居里温度与其四方率(c/a)、元素组成有关。(V, Nb)₂(Sn, Fe)C、(V, Nb)₂(Sn, Ni)C、(V, Nb)₂(Sn, Mn)C相较于M位固溶Nb元素之前的V₂(Sn, A)C相, 其矫顽力H_c和剩余磁化强度M_r减小, 饱和磁化强度M_s增大。而V₂(Sn, Co)C在M位固溶Nb元素之后磁性变化均与前述MAX相相反。通过以上结果, 揭示了M/A位双固溶对MAX相磁性的影响规律, 为调控MAX相磁性提供了新的思路。     

Determination of the relative amounts of free and complexed manganese ions in aqueous solution by nuclear magnetic resonance.

The ratio of the transverse relaxation rate to the longitudinal relaxation rate of water protons (T1/T2) at 90 MHz can be used to determine the relative amounts of free Mn2+ ions (the hexaquo ion) and chelated manganese ions when both species are present in the same aqueous solution. This technique is demonstrated for simple aqueous solutions containing known concentrations of both the free Mn2+ ion and a manganese(III) porphyrin. The accuracy of the method is found to be +/- 7.3% for the solutions considered in this report. The determinations of the relative amounts of the free Mn2+ ion and the manganese(III) porphyrin by this T1/T2 method are shown to agree well with those determined by nuclear magnetic resonance dispersion profiles. The theoretical basis of this ratio method as well as the scope and limitations in its application to aqueous solutions containing both free Mn2+ ions and chelated manganese species other than manganese(III) porphyrins are also discussed. This work demonstrates a unique use of NMR as a means for the quantitative analysis of manganese in which the effects of the metal ion on the solvent, and not the metal itself, are observed.     

Effect of Mn substitution on the oxidation/adsorption abilities of iron(III) oxyhydroxides

In this study, divalent manganese ions [Mn(II)] were substituted a part of divalent iron ions [Fe(II)] present in Fe oxyhydroxides to prepare novel composites (Mn@Feox). The composites were prepared by (1) simultaneous hydrolysis of Fe(II) and Mn(II), and (2) rapid oxidation with H₂O₂. The resulting Mn@Feox prepared with different molar ratios of Fe and Mn was characterized and evaluated for their abilities to adsorb arsenic species [As(III) and As(V)] in aqueous solution. X-ray diffraction and field emission transmission electron microscope analyses revealed Mn@Feox has a δ-(Fe_1?x, Mn_x)OOH-like structure with their mineralogical properties resembling those of feroxyhyte (δ-FeOOH). The increase in Mn substitution in Mn@Feox enhanced the oxidative ability to oxidize As(III) to As(V), but it decreased the adsorption capacity for both arsenic species. The optimal Mn/Fe molar ratio that could endow oxidation and magnetic capabilities to the composite without significantly compromising As adsorption capability was determined to be 0.1 (0.1Mn@Feox). The adsorption of As(III) on 0.1Mn@Feox was weakly influenced by pH change while As(V) adsorption showed high dependence on pH, achieving nearly complete removal at pH?<?5.7 but gradual decrease at pH?>?5.7. The adsorption kinetics and isotherms of As(III) and As(V) showed good conformity to pseudo-second-order kinetics model and Freundlich model, respectively.     

Direct assay of enzymes in heme biosynthesis for the detection of porphyrias by tandem mass spectrometry. Uroporphyrinogen decarboxylase and coproporphyrinogen III oxidase

We report new assays of enzymes uroporphyrinogen decarboxylase (UROD) and coproporphyrinogen III oxidase (CPO) in the heme biosynthetic pathway. The assays were developed for use in clinical diagnostics of inherited disorders porphyria cutanea tarda and hereditary coproporphyria, respectively. Electrospray ionization tandem mass spectrometry is used to monitor the decarboxylation of pentaporphyrinogen I or uroporphyrinogen III catalyzed by UROD and to determine the enzyme activity in human erythrocytes by measuring the production of coproporphyrinogen I or III. The Km value for pentaporphyrinogen I was measured as 0.17 +/- 0.03 microM. A mass spectrometric assay was also developed for the two-step decarboxylative oxidation of coproporphyrinogen III to protoporphyrinogen IX catalyzed by CPO in mitochondria from human lymphocytes (Km = 0.066 +/- 0.009 microM). The assays show good reproducibility, use simple workup by liquid-liquid extraction of enzymatic products, and employ commercially available substrates and internal standards.     

Electrochemical oxidation by square-wave potential pulses in the imitation of oxidative drug metabolism

Electrochemistry combined with mass spectrometry (EC-MS) is an emerging analytical technique in the imitation of oxidative drug metabolism at the early stages of new drug development. Here, we present the benefits of electrochemical oxidation by square-wave potential pulses for the oxidation of lidocaine, a test drug compound, on a platinum electrode. Lidocaine was oxidized at constant potential and by square-wave potential pulses with different cycle times, and the reaction products were analyzed by liquid chromatography-mass spectrometry [LC-MS(/MS)]. Application of constant potentials of up to +5.0 V resulted in relatively low yields of N-dealkylation and 4-hydroxylation products, while oxidation by square-wave potential pulses generated up to 50 times more of the 4-hydroxylation product at cycle times between 0.2 and 12 s (estimated yield of 10%). The highest yield of the N-dealkylation product was obtained at cycle times shorter than 0.2 s. Tuning of the cycle time is thus an important parameter to modulate the selectivity of electrochemical oxidation reactions. The N-oxidation product was only obtained by electrochemical oxidation under air atmosphere due to reaction with electrogenerated hydrogen peroxide. Square-wave potential pulses may also be applicable to modulate the selectivity of electrochemical reactions with other drug compounds in order to generate oxidation products with greater selectivity and higher yield based on the optimization of cycle times and potentials. This considerably widens the scope of direct electrochemistry-based oxidation reactions for the imitation of in vivo oxidative drug metabolism.