Identification of hydrolytic and isomeric N-oxide degradants of vilazodone by on line LC–ESI–MS/MS and APCI–MS

Kalariya, Pradipbhai D.; Talluri, M.V.N. Kumar; Patel, Prinesh N.; Srinivas, R.

doi:10.1016/j.jpba.2014.09.033

Cited by 33 publications

(19 citation statements)

References 15 publications

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“…[10][11][12][13] An extensive literature survey revealed few reports on VLZ; viz, quantitative estimation of VLZ in rats, 14 neurochemical evaluation, 3 effect on 5-HT efflux and re-uptake in the guinea-pig, 15 autoreceptor inhibition by VLZ-electrophysiological evidence, 16 effect of CYP3A4 induction/inhibition on VLZ pharmacokinetics, 17 effect on anxiety in rats, 18 its mechanism of action 19 and a stress degradation study of VLZ. 20 However, there are no reports on the detailed identification and characterization of in vitro and in vivo metabolites. This has prompted us to undertake comprehensive metabolite profiling of VLZ using ultrahigh-performance liquid chromatography (UHPLC)/ quadrupole time-of-flight (QTOF) tandem mass spectrometry (MS/MS).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of vilazodone metabolites in rats and microsomes by ultrahigh‐performance liquid chromatography/quadrupole time‐of‐flight tandem mass spectrometry

Chavan

Kalariya

Tiwari

et al. 2017

Rapid Comm Mass Spectrometry

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Section: Introductionmentioning

confidence: 99%

Identification and characterization of vilazodone metabolites in rats and microsomes by ultrahigh‐performance liquid chromatography/quadrupole time‐of‐flight tandem mass spectrometry

Chavan

Kalariya

Tiwari

et al. 2017

Rapid Comm Mass Spectrometry

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“…indicates the formation of N ‐Oxide. Loss of formaldehyde, which presumably involves a Meisenheimer rearrangement (conversion of N‐CH 3 to O‐CH 3 ) to form the ion at m/z 424, clearly suggests that the N ‐oxide is formed on tert‐N with methyl group at second and sixth positions of indazole moiety, but not on the other N atoms of PZ (Schemes and ). The MS/MS spectra of protonated P‐4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The elemental compositions of product ions are given in Table 1. Based on all these information, P2 was characterized as N4- ( [14,15] to form the ion at m/z 424, clearly suggests that the N-oxide is formed on tert-N with methyl group at second and sixth positions of indazole moiety, but not on the other N atoms of PZ (Schemes 4 and 5). The MS/MS spectra of protonated P-4 ( Fig.…”

Section: Ms/ms Of Transformation Products (Tps)mentioning

confidence: 99%

Characterization of forced degradation products of pazopanib hydrochloride by UHPLC‐Q‐TOF/MS and in silico toxicity prediction

et al. 2015

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Pazopanib (PZ), an anti-cancer drug, was subjected to forced degradation under hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress conditions as per International Conference on Harmonization guidelines. A selective stability indicating validated method was developed using a Waters Acquity UPLC HSS T3 (100 × 2.1 mm, 1.7 µm) column in gradient mode with ammonium acetate buffer (10 mM, pH 5.0) and acetonitrile. PZ was found to degrade only in photolytic conditions to produce six transformation products (TPs). All the TPs were identified and characterized by liquid chromatography/atmospheric pressure chemical ionization-quadrupole-time of flight mass spectrometry experiments in combination with accurate mass measurements. Plausible mechanisms have been proposed for the formation of TPs. In silico toxicity was predicted using TOPKAT and DEREK softwares for all the TPs. The TP, N4-(2,3-dimethyl-2H-indazol-6-yl)-N4-methylpyrimidine-2,4-diamine, was found to be genotoxic, whereas all other TPs with sulfonamide moiety were hepatotoxic. The data reported here are expected to be of significance as this study foresees the formation of one potential genotoxic and five hepatotoxic degradation/transformation products.

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“…The latter subsequently hydrolyzes to carboxylic acid depending on the type of substituent present. In case of alogliptin 101 and vilazodone, 82 reaction halts at the amide product. Lomustine 102 degrades to secondary amines with the loss of NO 2 under hydrolytic conditions ( Figure 2).…”

Section: Conventional Hydrolytic Reactionsmentioning

confidence: 99%

Understanding unconventional routes to impurities from drugs in hydrolytic conditions

Kaur¹,

Bansal²,

Bansal³

2016

IJPER

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Introduction: Hydrolytic degradation is the most common cause of formation of impurities or degradation products in drugs during different stages of drug product development and/or shelf life of the drug/product. Degradation products formed by hydrolysis of ester, amide, urethane, sulfonamide, sulfonate and ether linkages, and of nitrile, hydroxyl and amino groups in drugs can be conveniently predicted and identified. Many drugs are known to degrade to such expected conventional hydrolytic degradation products, and the mechanisms of such degradations are also well known and reported. However, many drugs are reported to degrade under hydrolytic conditions to products, which cannot be justified by the conventional hydrolytic reactions. Objectives: Though structures of such unconventional hydrolytic products can be characterized through different spectral techniques, but there is a need to understand the mechanisms of such unconventional hydrolytic reactions in order to help in establishing intrinsic stability characteristics of a drug. Methodology: In the present review, we have studied and critically analysed all possible reports on hydrolytic degradation of various dugs to provide a thorough insight into unconventional routes of hydrolytic degradations of drugs. The various unconventional hydrolytic reactions found responsible for degradation of drugs are classified as oxidation, dehydrogenation, coupling/condensation, N-alkylation, C-C bond cleavage, C-N bond cleavage, dehalogenation, cyclization, decarboxylation and hydroxylation. Discussion: Varied types of reactions under hydrolytic conditions are triggered/controlled by the nature of substituent(s) across or around the susceptible bonds/groups. The mechanisms for such unconventional hydrolytic reactions have been discussed or proposed with support from the standard literature. The contents are expected to enable an analyst and a drug formulator to predict various possible as well as seemingly improbable hydrolytic degradation products of a drug well ahead of systematic forced degradation studies.

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Identification of hydrolytic and isomeric N-oxide degradants of vilazodone by on line LC–ESI–MS/MS and APCI–MS

Cited by 33 publications

References 15 publications

Identification and characterization of vilazodone metabolites in rats and microsomes by ultrahigh‐performance liquid chromatography/quadrupole time‐of‐flight tandem mass spectrometry

Identification and characterization of vilazodone metabolites in rats and microsomes by ultrahigh‐performance liquid chromatography/quadrupole time‐of‐flight tandem mass spectrometry

Characterization of forced degradation products of pazopanib hydrochloride by UHPLC‐Q‐TOF/MS and in silico toxicity prediction

Understanding unconventional routes to impurities from drugs in hydrolytic conditions

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