Identification and characterization of urapidil stress degradation products by LC-Q-TOF-MS and NMR: Toxicity prediction of degradation products

Velip, Laximan; Dhiman, Vivek; Kushwah, Bhoopendra Singh; Golla, Vijaya Madhyanapu; Samanthula, Gananadhamu

doi:10.1016/j.jpba.2022.114612

Cited by 7 publications

(6 citation statements)

References 16 publications

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“…DP4 was formed due to N ‐dealkylation of the drug (Dhiman et al, 2022). DP5 was formed in oxidative conditions from the drug by N ‐oxide formation of the tertiary amine group (Velip et al, 2022), which was proved by MS and NMR studies.…”

Section: Resultsmentioning

confidence: 97%

Chromatographic separation of tiropramide hydrochloride and its degradation products along with their structural characterization using liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry and nuclear magnetic resonance

Tidke

Golla

Kushwah

et al. 2023

Biomedical Chromatography

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Tiropramide HCl, an antispasmodic drug is subjected to various stress conditions (hydrolytic, oxidative, photolytic and thermal) as per ICH guidelines. The drug is widely used as an antispasmodic agent but there were no comprehensive degradation studies reported on it. Hence, forced degradation studies of tiropramide HCl were carried out to establish the degradation pro le and the storage conditions to maintain its quality attributes during the shelf life and usage. A selective HPLC method was developed to separate the drug as well as all of its degradation products using Agilent C18 (250×4.6 mm; 5 µm) column. The mobile phase of 10mM ammonium formate at pH 3.6 (solvent A) and methanol (solvent B) with gradient elution at a ow rate of 1.00 mL/min was used. Tiropramide was susceptible to acidic, basic hydrolytic exposure and oxidative stress conditions in the solution. This drug was found to be stable in neutral, thermal and photolytic conditions in both solution and solid-state. Five degradation products were detected under different stress conditions. The mass spectrometric fragmentation pattern of tiropramide and its degradation products was extensively studied using LC-Q-TOF-MS/MS for their structural characterization. The position of the oxygen atom in the N-oxide degradation product was con rmed by NMR studies. The knowledge gained by these studies was used to predict drug degradation pro les which is helpful in the development of the dosage form.

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Section: Resultsmentioning

confidence: 97%

Chromatographic separation of tiropramide hydrochloride and its degradation products along with their structural characterization using liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry and nuclear magnetic resonance

Tidke

Golla

Kushwah

et al. 2023

Biomedical Chromatography

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“…17 This study is the first to demonstrate a mass fragmentation mechanism and provide a mechanistic explanation for the fragmentation of OXC and its DPs. 17 The ADMET Predictor software was employed for assessing the physicochemical properties, distribution, absorption, metabolism, elimination and toxicity of both the OXC and its DPs. 18 (LC/MS G6540B, Agilent Technologies, USA) was utilised for obtaining the precise mass spectrum of OXC.…”

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confidence: 81%

“…Method validation was performed in accordance with ICH recommendations Q2(R1) 16 . ADMET Predictor software was used to predict the in silico toxicity and physicochemical properties of the drug and its DPs, which is discussed in the further section 17 . This study is the first to demonstrate a mass fragmentation mechanism and provide a mechanistic explanation for the fragmentation of OXC and its DPs 17 .…”

Section: Introductionmentioning

confidence: 99%

“…ADMET Predictor software was used to predict the in silico toxicity and physicochemical properties of the drug and its DPs, which is discussed in the further section 17 . This study is the first to demonstrate a mass fragmentation mechanism and provide a mechanistic explanation for the fragmentation of OXC and its DPs 17 . The ADMET Predictor software was employed for assessing the physicochemical properties, distribution, absorption, metabolism, elimination and toxicity of both the OXC and its DPs 18 …”

Section: Introductionmentioning

confidence: 99%

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Identification, characterisation and in silico ADMET prediction of ozenoxacin and its degradation products using high‐performance liquid chromatography‐photodiode array and liquid chromatography‐quadrupole time‐of‐flight‐tandem mass spectrometry

Matta,

Sundararajan

2023

Rapid Comm Mass Spectrometry

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RationaleOzenoxacin (OXC) is an antibiotic used topically to treat impetigo. This study aimed to evaluate the degradation products (DP) of OXC drug substance under different stress conditions, including hydrolysis, oxidation, thermal and photolysis, in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines Q1A(R2) and Q1B. The analytical technique was validated in compliance with ICH Q2(R1) requirements.MethodsThe drug substance underwent degradation under various forced degradation conditions, including thermal, oxidative, photolytic and hydrolytic (neutral, acidic and basic) degradation. Overall, four DPs were formed under oxidative stress conditions with AIBN. The formed DPs were identified and separated using a Shimadzu LC system with a reversed‐phase Phenomenex Kinetex C18 column (4.6 × 250 mm, 5 μm), using 10 mM NH4CH3COOH buffer (pH −5.0) as mobile phase A and acetonitrile as mobile phase B at a detection wavelength of 254 nm.Results and ConclusionThe drug was found to be stable in neutral, acidic, basic and oxidative degradation conditions with hydrogen peroxide. Liquid chromatography‐electrospray ionisation‐quadrupole time‐of‐flight‐tandem mass spectrometry‐ was employed in positive ionisation mode to analyse both the drug and the mass of the identified DP. The mechanism and the pathway of mass fragmentation have been proposed. The developed method was accurate, repeatable, linear and selective for further research. The ADMET Predictor software was applied to predict the in silico toxicity of the drugs and its DPs as well as their physicochemical characteristics.

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“…Mass spectrometry was also used in this work to characterise probable DPs and the degradation pathways were proposed. The proposed DPs along with the main drug, MLN, were tested for their in-silico toxicity using Pro Tox-II program 18 , 19 . In addition, no analytical review of the reported methods analysing MLN along with their greenness appraisal was found in the literature, so a concise review was discussed.…”

Section: Introductionmentioning

confidence: 99%

White targeted chromatographic screening method of Molnupiravir and its metabolite with degradation kinetics characterization and in-silico toxicity

Aboras,

Megahed,

El-Yazbi

et al. 2023

Sci Rep

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SARS-CoV-2 virus triggered a worldwide crisis, with world nations putting up massive efforts to halt its spread. Molnupiravir (MLN) was the first oral, direct-acting antiviral drug approved for nasopharyngeal SARS-CoV-2 infection with favorable safety and tolerability profile. This study aims at determination of MLN and N4-hydroxycytidine (NHC), its main degradation product and its main metabolite, using sensitive, simple, and green HPLC–DAD method. Moreover, under different stress conditions using NaOH, HCl, neutral, H2O2, dry heat and sun light, the method was applied for MLN assay along with kinetics degradation investigation. The linearity range for MLN and NHC were both 0.1–100 µg/mL with LOD and LOQ of 0.013 & 0.043 and 0.003 & 0.011 µg/mL, for MLN and NHC, respectively. MLN was found to be extremely vulnerable to alkali hydrolysis compared with acid and dry heat degradation. In contrast, MLN was stable under conditions of oxidative, neutral, and sunlight-induced deterioration. Acid and alkali-induced degradation followed pseudo first-order kinetics model. In addition, LC–MS-UV was used to suggest the mechanism of the stress-induced degradation route and to characterize the eluted degradation products. Toxicities of both MLN and its degradation products were evaluated using ProTox-II and they were found to be negligibly harmful. The proposed HPLC–DAD was effectively used for the analysis of MLN in commercial pharmaceutical formulations. The proposed method for MLN determination after greenness and whiteness appraisal was found to be superior compared to the reported methods for MLN analysis.

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Identification and characterization of urapidil stress degradation products by LC-Q-TOF-MS and NMR: Toxicity prediction of degradation products

Cited by 7 publications

References 16 publications

Chromatographic separation of tiropramide hydrochloride and its degradation products along with their structural characterization using liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry and nuclear magnetic resonance

Chromatographic separation of tiropramide hydrochloride and its degradation products along with their structural characterization using liquid chromatography quadrupole time‐of‐flight tandem mass spectrometry and nuclear magnetic resonance

Identification, characterisation and in silico ADMET prediction of ozenoxacin and its degradation products using high‐performance liquid chromatography‐photodiode array and liquid chromatography‐quadrupole time‐of‐flight‐tandem mass spectrometry

White targeted chromatographic screening method of Molnupiravir and its metabolite with degradation kinetics characterization and in-silico toxicity

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