Characterization of Photodegradation Products of Bepotastine Besilate and In Silico Evaluation of Their Physicochemical, Absorption, Distribution, Metabolism, Excretion and Toxicity Properties

Singh, Dilip Kumar; Sahu, Archana; Wani, Aabid Abdullah; Bharatam, Prasad V.; Chakraborti, Asit K.; Giri, Sanjeev; Singh, Saranjit

doi:10.1016/j.xphs.2020.03.004

Cited by 13 publications

(14 citation statements)

References 32 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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“…Previously, BEPO was shown to be stable in methanolic solution under standard ICH conditions of 200 Wh/m 2 and 1,200,000 lux h [ 23 , 24 ]. However, irradiation of BEPO with 0.8 W/m 2 and 4500 lux h and under basic conditions led to degradation of 23.9% [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…In a few studies [ 13 , 15 , 17 , 19 , 20 , 22 , 23 , 24 ], these drugs were exposed to artificial UV light or natural sunlight, in solid state, solutions and liquid formulations, but the breadth of these experiments was rather scarce, and no kinetic aspects were taken into account. Only one paper from the literature presented the experiments on BEPO photostability and proposed the possible structures of its five degradation products (DP2–DP6) [ 26 ]. The possible structures of the degradants of BEPO which have been reported in the literature are presented in Figure 4 .…”

Section: Introductionmentioning

confidence: 99%

Chemical Stability Study of H1 Antihistaminic Drugs from the First and the Second Generations, Diphenhydramine, Azelastine and Bepotastine, in Pure APIs and in the Presence of Two Excipients, Citric Acid and Polyvinyl Alcohol

2022

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The chemical stability of diphenhydramine (DIPH), azelastine (AZE) and bepotastine (BEPO) was examined in solutions and solids. The drugs were subjected to high temperature (70 °C for 35 h) or UV/VIS light (18.902–94.510 kJ/m2) at pH 1–13, to examine their percentage degradation and kinetics of degradation. Further, the stability of solid DIPH, AZE and BEPO was examined in the presence of excipients of different reactivity, i.e., citric acid (CA) and polyvinyl alcohol (PVA) under high temperature/high humidity (70 °C/80% RH) or UV/VIS light (94.510 kJ/m2). Under high temperature, DIPH degraded visibly (>19%) at pH 1 and 4, AZE was shown stable, while the degradation of BEPO was rather high (>17%) in all pH conditions. Under UV/VIS irradiation all the drugs were shown labile with degradation in the range 5.5–96.3%. As far as the solid mixtures were concerned, all drugs interacted with excipients, especially under high temperature/high humidity or UV/VIS light. As a result, DIPH, AZE and BEPO were compared in terms of their stability, with regard to their different structures and acid/base properties. All these results may be helpful for manufacturing, storing and applying these drugs in their topical (skin, nasal and ocular), oral and injectable formulations.

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“…In order to reveal the formation and mechanism of the ghost peaks, a study outlined in Section 2.10 was performed. According to the literature, generation of radicals by Fe (II) and Fe (III) species has been extensively investigated [8][9][10][11][12] ; the radical scavengers were always used in stress studies to confirm the involvement of the radical pathway, 13,14 among which the mannitol and SOD were used to protect against oxidation by hydroxyl radical 15 and superoxide radical, 16 respectively. In this study, a significant decrease in the formation of ghost peaks I and II was observed in the presence of mannitol and SOD (Table 4).…”

Section: Formation Mechanism Of Ghost Peaksmentioning

confidence: 99%

“Ghost peaks” of olmesartan medoxomil: Two solution degradation products of olmesartan medoxomil via oxidation mediated by metal ions

et al. 2022

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Two unknown solution degradants were found during the dissolution testing in 0.1-M HCl for olmesartan medoxomil (OLM) tablets. The structure of the degradants was identified and characterized by liquid chromatography-ultraviolet (LC-UV), liquid chromatography with tandem mass spectrometry (LC-MS/MS), and nuclear magnetic resonance (NMR) and demonstrated to be cyclization of tetrazole and benzene in the olmesartan (OL) and OLM structures. A series of studies including stress studies, simulation studies, and mechanism-based studies were performed to reveal the potential mechanisms that lead to the formation of the unknown degradants. The study results demonstrated that the degradation was catalyzed with radicals that originated from the metal ions leached from the inner surface of high-performance liquid chromatography (HPLC) glass vials with dissolved oxygen under acidic condition. Prerinsing the glass vials with acidic solution dissolved with EDTA can effectively avoid the generation of such oxidative impurities. The present work provides new insights into the understanding of degradation pathways of OLM, which might support the development of OLM tablets.

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Characterization of Photodegradation Products of Bepotastine Besilate and In Silico Evaluation of Their Physicochemical, Absorption, Distribution, Metabolism, Excretion and Toxicity Properties

Cited by 13 publications

References 32 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™

Chemical Stability Study of H1 Antihistaminic Drugs from the First and the Second Generations, Diphenhydramine, Azelastine and Bepotastine, in Pure APIs and in the Presence of Two Excipients, Citric Acid and Polyvinyl Alcohol

“Ghost peaks” of olmesartan medoxomil: Two solution degradation products of olmesartan medoxomil via oxidation mediated by metal ions

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