Application of the UHPLC method for separation and characterization of major photolytic degradation products of trazodone by LC-MS and NMR

Thummar, Mohit; Patel, Prinesh N.; Kushwah, Bhoopendra Singh; Samanthula, Gananadhamu

doi:10.1039/c8nj03545h

Cited by 10 publications

(6 citation statements)

References 17 publications

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“…As shown in Figure S7, it was dissociated into product ions of m / z 432, m / z 418, m / z 289, m / z 216 and m / z 162, with the only difference from BRZ‐4 in terms of formation of the product ion of m / z 418. It was observed that in all three DPs, BRZ‐8, BRZ‐9 and BRZ‐11, where there was oxidation at N‐15 position, the oxygen of N‐oxide was first rearranged to become a part of the piperazine ring, which was then followed by loss of CH 4 O 23,24 . This transformation was responsible for the generation of the specific fragment of m / z 418 in BRZ‐11.…”

Section: Resultsmentioning

confidence: 99%

Characterization of potential degradation products of brexpiprazole by liquid chromatography/quadrupole–time‐of‐flight mass spectrometry and nuclear magnetic resonance, and prediction of their physicochemical properties by ADMET Predictor™

Kushwah

Singh

Thummar

et al. 2022

Rapid Comm Mass Spectrometry

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Rationale Brexpiprazole (BRZ) was subjected to hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress degradation in solutions prepared in a mixture of acetonitrile–water (70:30 v/v). The oxidative study was additionally done in methanol–buffer mixture at pH 3, 7 and 11. Also, compatibility of the drug with selected excipients was investigated in the solid state. Additionally, physicochemical and ADMET properties of BRZ and its degradation products (DPs) were predicted using ADMET Predictor™ software. It provides the conditions for quality control of BRZ and its derivatives during manufacturing, processing and storage conditions. Methods The formed DPs were separated from the drug and among themselves on a C‐18 column utilizing mobile phase composed of methanol and ammonium formate buffer (10mM, pH 4.0), which was run in a gradient mode. Characterization of DPs was carried out by first establishing the mass fragmentation pathway of the drug based on its liquid chromatography/quadrupole–time‐of‐flight mass spectrometry (LC/Q‐TOF‐MS) data, followed by LC/Q‐TOF‐MS studies of DPs. Three DPs were isolated and, along with the drug, they were subjected to 1D (1H, 13C and DEPT‐135) and 2D (COSY and HSQC) NMR studies for confirmation of their structures. Results BRZ was observed to be susceptible to hydrolytic (neutral, acid and alkali), photolytic and oxidative degradation conditions; it was stable on thermal exposure. A total of 12 DPs (BRZ‐1 to BRZ‐12) were formed in solution state. Mechanisms of BRZ degradation were postulated. Conclusions The extent of degradation of BRZ in different stress conditions highlights that stability of BRZ in drug formulations can be improved (i) by using excipients that can impart a low‐pH microenvironment, (ii) by addition of antioxidants and (iii) through protection from light.

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Section: Resultsmentioning

confidence: 99%

Characterization of potential degradation products of brexpiprazole by liquid chromatography/quadrupole–time‐of‐flight mass spectrometry and nuclear magnetic resonance, and prediction of their physicochemical properties by ADMET Predictor™

Kushwah

Singh

Thummar

et al. 2022

Rapid Comm Mass Spectrometry

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“…The only degradation product obtained from trazodone is the corresponding N-oxide (DP6) formed on nitrogen N-14 of the piperazine ring, which has been reported by Thummar et al (2018), by photolytic degradation of trazodone and identified only by mass spectrometry [22].…”

Section: Dp6mentioning

confidence: 96%

Peracetic Acid vs. Sodium Hypochlorite: Degradation and Transformation of Drugs in Wastewater

Luongo

Previtera²,

Ladhari

et al. 2020

Molecules

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Numerous substances from different chemical sectors, from the pharmaceutical industry to the many consumer products available for everyday usage, can find their way into water intended for human consumption and wastewater, and can have adverse effects on the environment and human health. Thus, the disinfection process is an essential stage in water and wastewater treatment plants to destroy pathogenic microorganisms but it can form degradation byproducts. Sodium hypochlorite is the most common disinfectant, but the most important drawback associated with this kind of compound is the generation of toxic disinfection byproducts. Many studies have been carried out to identify alternative disinfectants, and in the last few years, peracetic acid has been highlighted as a feasible solution, particularly in wastewater treatment. This study compares the transformations of five emerging pollutants (caffeine, tramadol, irbesartan, diclofenac, trazodone) treated with peracetic acid, to evaluate their degradation and the possible formation of byproducts with those obtained with sodium hypochlorite. Although peracetic acid has many advantages, including a wide field of use against microorganisms and a low toxicity towards animal and plant organisms, it is not as effective in the degradation of the considered pollutants. These ones are recovered substantially and are unchanged quantitatively, producing a very low number of byproducts.

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“…A minimum list of stress factors suggested for forced degradation studies should include hydrolysis of the acid and base, thermal degradation, photolysis, oxidation. There is no specification regarding the conditions of pH, temperature and specific oxidizing agents to be used in regulatory guidelines [20][21][22][23][24][25] . Forced degradation studies are very necessary for the development of new drugs and new pharmaceuticals.…”

Section: Importance Of Lc-ms / Ms For the Analysis Of Forced Degradation Studiesmentioning

confidence: 99%

“…The degradative pathways can be determined based on fragmentation patterns that are observed. After determination of degradant pathways, structure elucidations of degradants are done by synthesizing or isolating methods and further characterized by employing LC-MS, LC-UV, and LC-NMR techniques [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] .…”

Section: Characterisation Of Degradants By Lc-msmentioning

confidence: 99%

Importance of LCMS in Forced Degradation Studies for new Chemical Entities

Kota

Valli

2022

Int J Life Sci Pharm Res

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Forced degradation studies shows the chemical behaviour of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. In pharmaceutical industry, mandatory degradation tests are important to determine the mechanisms and measure the potential degradants during the analysis of drug material and to help to elucidate the composition of degradation materials. The Liquid Chromatography/ Mass Spectrum analysis (L.C.M.S) is a short term widely established liquid chromatography and a methodology utilizing a natural fluid process. L.C.M.S. is commonly employed in the laboratories for qualitative testing of drug substances, drugs and biological samples. Degradation studies, metabolic screening, metabolite identity and in vivo drug screening, impurity identification, amide mapping, glycoprotein mapping were consistently used in pharmaceutical development by LCMS. The FDA and ICH guidelines sets out the requirement for stability testing data to understand how the quality of the drug substance and drug product changes over time under the influence of various environmental factors. Knowledge of molecular stability helps to select the correct formulation and package as well as to provide proper storage conditions and shelf life, which is essential for regulatory documentation. Active pharmaceutical ingredients (APIs) may form impurities when exposed to excipients or environmental variables such as light, high temperatures, acidic or basic conditions, humidity; and the oxidative atmosphere. Considering that these impurities may have an impact on safety and efficacy, it is necessary to know how these impurities are produced from the drug product and to establish the path of their formation. In this context, forced drug degradation studies have been used to characterize the physicochemical stability of APIs. These studies are also essential in the validation of analytical methodologies, in order to demonstrate the selectivity of methodologies. The API and its impurities and to develop strategies to avoid the formation of degradation products. The objective of this review is to demonstrate how forced degradation studies have been conducted and application of LCMS tools in related studies.

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Application of the UHPLC method for separation and characterization of major photolytic degradation products of trazodone by LC-MS and NMR

Abstract: This article is about the characterization of degradation products of trazodone which is used in the treatment of depression.

Cited by 10 publications

References 17 publications

Characterization of potential degradation products of brexpiprazole by liquid chromatography/quadrupole–time‐of‐flight mass spectrometry and nuclear magnetic resonance, and prediction of their physicochemical properties by ADMET Predictor™

Characterization of potential degradation products of brexpiprazole by liquid chromatography/quadrupole–time‐of‐flight mass spectrometry and nuclear magnetic resonance, and prediction of their physicochemical properties by ADMET Predictor™

Peracetic Acid vs. Sodium Hypochlorite: Degradation and Transformation of Drugs in Wastewater

Importance of LCMS in Forced Degradation Studies for new Chemical Entities

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