Study of degradation mechanisms of cyclobenzaprine by LC-MS/MS

Liu, Yan; Zhao, Dantong; Zhao, Zhongxi

doi:10.1039/c3ay41409d

Cited by 17 publications

(6 citation statements)

References 15 publications

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“…It is known that amine moieties usually have high electro-oxidation potentials (i.e., greater than 0.65 V), what corroborates the results depicted herein. The higher potential of peak 1a for NOR may be attributed to its electronic configuration [17,20,21,22,23,24,25,26,27]; nonetheless, the HOMO energy levels also suggested that this region requires a higher overpotential to undergo its redox reaction, whereas CBP and AMP have higher HOMO levels and are thus more easily oxidized (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

Electrochemical Characterization of Central Action Tricyclic Drugs by Voltammetric Techniques and Density Functional Theory Calculations

et al. 2019

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This work details the study of the redox behavior of the drugs cyclobenzaprine (CBP), amitriptyline (AMP) and nortriptyline (NOR) through voltammetric methods and computational chemistry. Results obtained in this study show that the amine moiety of each compound is more likely to undergo oxidation at 1a at Ep1a ≈ 0.69, 0.79, 0.93 V (vs. Ag/AgCl/KClsat) for CBP, AMP and NOR, respectively. Moreover, CBP presented a second peak, 2a at Ep2a ≈ 0.98 V (vs. Ag/AgCl/KClsat) at pH 7.0. Furthermore, the electronic structure calculation results corroborate the electrochemical assays regarding the HOMO energies of the lowest energy conformers of each molecule. The mechanism for each anodic process is proposed according to electroanalytical and computational chemistry findings, which show evidence that the methods herein employed may be a valuable alternative to study the redox behavior of structurally similar drugs.

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Section: Resultsmentioning

confidence: 99%

Electrochemical Characterization of Central Action Tricyclic Drugs by Voltammetric Techniques and Density Functional Theory Calculations

et al. 2019

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“…Light microscopy images of the sublingual tablets showed a uniform flat surface after ambient storage; however, under stress conditions the surface appeared much more porous with yellowish crystals on the tablet surface as well as in more pronounced form in the primary packaging material. TOF-MS spectra of the rinsed primary packaging material showed an approximately tenfold higher intensity for cyclobenzaprine under stress compared to ambient conditions, and no substantial signals for cyclobenzaprine N-oxide—which is described as the main degradation product of oxidation [ 35 ]—for either storage ( Figure 4 E,F).…”

Section: Resultsmentioning

confidence: 99%

“…Liu et al reported a total of 15 degradation products for cyclobenzaprine based on three degradation pathways (exocyclic, endocyclic as well as oxidation of the tertiary amino group) by forced degradation studies [ 35 ]. None of the reported degradation products were detected in our studies.…”

Section: Resultsmentioning

confidence: 99%

Formulation Development of Sublingual Cyclobenzaprine Tablets Empowered by Standardized and Physiologically Relevant Ex Vivo Permeation Studies

et al. 2021

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Suitable ex vivo models are required as predictive tools of oromucosal permeability between in vitro characterizations and in vivo studies in order to support the development of novel intraoral formulations. To counter a lack of clinical relevance and observed method heterogenicity, a standardized, controlled and physiologically relevant ex vivo permeation model was established. This model combined the Kerski diffusion cell, process automation, novel assays for tissue integrity and viability, and sensitive LC-MS/MS analysis. The study aimed to assess the effectiveness of the permeation model in the sublingual formulation development of cyclobenzaprine, a promising agent for the treatment of psychological disorders. A 4.68-fold enhancement was achieved through permeation model-led focused formulation development. Here, findings from the preformulation with regard to pH and microenvironment-modulating excipients proved supportive. Moreover, monitoring of drug metabolism during transmucosal permeation was incorporated into the model. In addition, it was feasible to assess the impact of dosage form alterations under stress conditions, with the detection of a 33.85% lower permeation due to salt disproportionation. Integrating the coherent processes of disintegration, dissolution, permeation, and metabolization within a physiological study design, the model enabled successful formulation development for cyclobenzaprine sublingual tablets and targeted development of patient-oriented drugs for the oral cavity.

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“…With the development of AMS techniques, attempts have been made to introduce APCI into offline monitoring of reactions in recent years. For example, the degradation mechanisms of cyclobenzaprine under different conditions, such as acid/base hydrolysis, peroxide oxidation, UV light exposure, high heat, and humidity, were elucidated via LC-APCI-MS (Liu et al, 2014b). Furthermore, Cooks and coworkers recorded the region-selective oxidation of saturated hydrocarbons via a corona discharge in APCI without a catalyst.…”

Section: Apcimentioning

confidence: 99%

Chemical Reaction Monitoring by Ambient Mass Spectrometry

Sun

Yin

et al. 2020

Mass Spectrometry Reviews

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Chemical reactions conducted in different media (liquid phase, gas phase, or surface) drive developments of versatile techniques for the detection of intermediates and prediction of reasonable reaction pathways. Without sample pretreatment, ambient mass spectrometry (AMS) has been applied to obtain structural information of reactive molecules that differ in polarity and molecular weight. Commercial ion sources (e.g., electrospray ionization, atmospheric pressure chemical ionization, and direct analysis in real-time) have been reported to monitor substrates and products by offline reaction examination. While the interception or characterization of reactive intermediates with short lifetime are still limited by the offline modes. Notably, online ionization technologies, with high tolerance to salt, buffer, and pH, can achieve direct sampling and ionization of ongoing reactions conducted in different media (e.g., liquid phase, gas phase, or surface). Therefore, short-lived intermediates could be captured at unprecedented timescales, and the reaction dynamics could be studied for mechanism examinations without sample pretreatments. In this review, via various AMS methods, chemical reaction monitoring and mechanism elucidation for different classifications of reactions have been reviewed. The developments and advances of common ionization methods for offline reaction monitoring will also be highlighted.

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Study of degradation mechanisms of cyclobenzaprine by LC-MS/MS

Abstract: A systematic forced degradation study of cyclobenzaprine for the elucidation of the degradation mechanism was carried out to support the new formulation development.

Cited by 17 publications

References 15 publications

Electrochemical Characterization of Central Action Tricyclic Drugs by Voltammetric Techniques and Density Functional Theory Calculations

Electrochemical Characterization of Central Action Tricyclic Drugs by Voltammetric Techniques and Density Functional Theory Calculations

Formulation Development of Sublingual Cyclobenzaprine Tablets Empowered by Standardized and Physiologically Relevant Ex Vivo Permeation Studies

Chemical Reaction Monitoring by Ambient Mass Spectrometry

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