Determination of Methyl Methanesulfonate and Ethyl Methylsulfonate in New Drug for the Treatment of Fatty Liver Using Derivatization Followed by High-Performance Liquid Chromatography with Ultraviolet Detection

Wang, Yue; Feng, Jing; Wu, Song; Shao, Huihui; Zhang, Wenxuan; Zhang, Kun; Zhang, Hanyilan; Yang, Qingyun

doi:10.3390/molecules27061950

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…Preclinical studies have suggested that IMM, the bicyclic morpholine mesylate of bicyclol, has better pharmacological activities and pharmacokinetic properties than bicyclol in the aspects of liver protection and therefore holds great promise as a useful drug for treating NAFLD in the future. Moreover, as a methanesulfonate drug, the residues of methyl methanesulfonate and ethyl methylsulfonate were well below control limits [9]. IMM is currently in Phase I clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Identification and Determination of Impurities in a New Therapeutic Agent for Fatty Liver Disease

Shao

Feng

Zhang

et al. 2023

Journal of Analytical Methods in Chemistry

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Methyl 7,7′-dimethoxy-5′-(morpholinomethyl)-[4,4′-bibenzo[d][1,3] dioxole]-5-carboxylate methanesulfonate (IMM) is an innovative drug for the treatment of nonalcoholic fatty liver disease (NAFLD) owing to its high efficacy and low toxicity. In this study, five minor impurities (I, II, III, IV, and V) were identified and analyzed using spectroscopic evidence, chemical synthetic methods, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The impurities included hydrolysates and oxidation by-products extracted from both the drug in its final formulation and during synthesis. Toxicity prediction revealed potential carcinogenicity of impurity V containing an N-oxygen fragment. A reliable and selective HPLC method for the quantitative analysis of impurities I–IV and a sensitive HPLC-MS/MS method for potential genotoxic impurity V were developed and optimized. The methods were validated based on the International Council for Harmonization guidelines. Satisfactory linearity was obtained for the analytes over the range of 0.1–2.0 μg/mL for impurities I–IV and 0.3–30.0 ng/mL for impurity V, and in all cases, the fitting correlation coefficients exceeded 0.999. The obtained limits of detection values were 0.05 ng/mL and 0.005 μg/mL for impurity V and impurities I–IV, respectively. The precision and repeatability of the methods were less than 1.08% and 8.72% for each impurity. The recovery percentages of all impurities were in the range of 91.18%–111.27%, with the relative standard deviation of less than 3.69%. The greenness assessment of the HPLC method and the HPLC-MS/MS method were evaluated by using AGREE software with a score value of 0.72 and 0.68, respectively. The recommended procedures that were accurate, specific, and ecofriendly were applied to the existing active pharmaceutical ingredients of IMM, and they generated satisfactory results.

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Section: Introductionmentioning

confidence: 99%

Identification and Determination of Impurities in a New Therapeutic Agent for Fatty Liver Disease

Shao

Feng

Zhang

et al. 2023

Journal of Analytical Methods in Chemistry

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“…For example, a selective high-performance liquid chromatography (HPLC) method and a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method have been developed and validated for quantitative analysis of impurities [18]. A novel derivatization HPLC method has also been developed for genotoxic impurities [19]. Reference materials (RMs) for active pharmaceutical ingredients (APIs) and their impurities at an accurate and reliable purity are essential for quality control studies.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Purity of IMM-H014 and Its Related Substances for the Treatment of Metabolic-Associated Fatty Liver Disease Using Quantitative Nuclear Magnetic Resonance Spectroscopy

Zhang,

Zhu,

et al. 2023

IJMS

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An accurate, rapid, and selective quantitative nuclear magnetic resonance method was developed and validated to assess the purity of IMM-H014, a novel drug for the treatment of metabolic-associated fatty liver disease (MAFLD), and four related substances (impurities I, II, III, and IV). In this study, we obtained spectra of IMM--H014 and related substances in deuterated chloroform using dimethyl terephthalate (DMT) as the internal standard reference. Quantification was performed using the 1H resonance signals at δ 8.13 ppm for DMT and δ 6.5–7.5 ppm for IMM-H014 and its related substances. Several key experimental parameters were investigated and optimized, such as pulse angle and relaxation delay. Methodology validation was conducted based on the International Council for Harmonization guidelines and verified with satisfactory specificity, precision, linearity, accuracy, robustness, and stability. In addition, the calibration results of the samples were consistent with those obtained from the mass balance method. Thus, this research provides a reliable and practical protocol for purity analysis of IMM-H014 and its critical impurities and contributes to subsequent clinical quality control research.

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“…Most of these analysis methods were performed using a gas chromatography or liquid chromatography system, altered according to the characteristics of each impurity, alongside a mass spectrometry detector capable of detecting trace amounts of impurities. Other literature studies used detectors other than the mass spectrometry detector along with their respective chromatographic systems [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. The analytical quality by design (QbD) approach can be a good tool for the development of an optimally robust analytical method for PGIs [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Analytical Method Development for 19 Alkyl Halides as Potential Genotoxic Impurities by Analytical Quality by Design

2022

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Major issues in the pharmaceutical industry involve efficient risk management and control strategies of potential genotoxic impurities (PGIs). As a result, the development of an appropriate method to control these impurities is required. An optimally sensitive and simultaneous analytical method using gas chromatography with a mass spectrometry detector (GC–MS) was developed for 19 alkyl halides determined to be PGIs. These 19 alkyl halides were selected from 144 alkyl halides through an in silico study utilizing quantitative structure–activity relationship (Q-SAR) approaches via expert knowledge rule-based software and statistical-based software. The analytical quality by design (QbD) approach was adopted for the development of a sensitive and robust analytical method for PGIs. A limited number of literature studies have reviewed the analytical QbD approach in the PGI method development using GC–MS as the analytical instrument. A GC equipped with a single quadrupole mass spectrometry detector (MSD) and VF-624 ms capillary column was used. The developed method was validated in terms of specificity, the limit of detection, quantitation, linearity, accuracy, and precision, according to the ICH Q2 guideline.

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Determination of Methyl Methanesulfonate and Ethyl Methylsulfonate in New Drug for the Treatment of Fatty Liver Using Derivatization Followed by High-Performance Liquid Chromatography with Ultraviolet Detection

Cited by 5 publications

References 22 publications

Identification and Determination of Impurities in a New Therapeutic Agent for Fatty Liver Disease

Identification and Determination of Impurities in a New Therapeutic Agent for Fatty Liver Disease

Assessment of the Purity of IMM-H014 and Its Related Substances for the Treatment of Metabolic-Associated Fatty Liver Disease Using Quantitative Nuclear Magnetic Resonance Spectroscopy

Analytical Method Development for 19 Alkyl Halides as Potential Genotoxic Impurities by Analytical Quality by Design

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