Shiva Kumar Gogikar, Sibu Sen, Shivashankar Pathinti, Gananadhamu Samanthula, Amol G. Dikundwar
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引用次数: 0
摘要
理由：本研究旨在建立2021年被批准用于治疗2型糖尿病的抗糖尿病药物依米明（IMG）的降解产物结构。提出了降解途径以及观察到的药物降解产物（DPs）的硅毒性评估。方法：采用反相高效液相色谱法（RP-HPLC），采用光电二极管阵列检测器，Phenomenex Luna PFP （250 × 4.6 mm, 5 μm）柱，以10 mm甲酸铵（pH 4.5）和甲醇为流动相分离所观察到的dp。采用液相色谱-四极杆飞行时间质谱（LC-Q-ToF-MS/MS）和核磁共振（NMR）谱法进行结构解析。Zeneth和Derek套件用于计算机评估。结果：共观察到4种降解产物，并在反相高效液相色谱上成功分离。利用LC-Q-TOF-MS/MS，利用电喷雾电离和常压化学电离对四种DPs中的三种进行了结构表征。此外，利用制备型高效液相色谱分离得到了DP-3，并对其进行了核磁共振表征。计算预测的结构与实验观察结果进行了比较。结论：根据ICH Q2（R1）指南，建立了一种高效液相色谱（HPLC）分离依米明及其4种DPs的方法，并进行了验证。结构解析揭示了以二甲双胍作为鉴定的DPs之一的多种产物以及代谢物。通过对接研究评估DPs的毒性潜力。
Forced Degradation Study of an Anti-Diabetic Drug Imeglimin: Impurity Profiling and Structure Elucidation Using LC-Q-ToF-MS/MS and NMR
Rationale
The present study aims to establish structures of the degradation products of an anti-diabetic drug, Imeglimin (IMG) approved for the treatment of type 2 diabetes mellitus in the year 2021. Degradation pathways are proposed along with in silico toxicity assessments of the observed degradation products (DPs) of the drug.
Methods
A reversed-phase high-performance liquid chromatography (RP-HPLC), equipped with a photodiode array detector, was used to separate the observed DPs with a Phenomenex Luna PFP (250 × 4.6 mm, 5 μm) column, using 10 mM ammonium formate (pH 4.5) and methanol as mobile phase. Liquid chromatography quadrupole time of flight mass spectrometry (LC-Q-ToF-MS/MS) and nuclear magnetic resonance (NMR) spectroscopy were employed for structural elucidation. Zeneth and Derek suites were used for in silico assessments.
Results
A total of four degradation products were observed, which were successfully separated on an RP-HPLC. The structural characterization of three of the four DPs was achieved using LC-Q-TOF-MS/MS by employing electro spray ionization as well as atmospheric pressure chemical ionization. Additionally, DP-3 was isolated using a preparative HPLC and was characterized by NMR. Computationally predicted structures were compared with the experimental observations.
Conclusion
An HPLC method, capable of separating the Imeglimin and its four DPs, was developed and validated as per the ICH Q2(R1) guideline. Structure elucidation reveals a variety of products with metformin as one of the identified DPs along with a metabolite. The toxicity potential of DPs was assessed through docking studies.
期刊介绍：
Rapid Communications in Mass Spectrometry is a journal whose aim is the rapid publication of original research results and ideas on all aspects of the science of gas-phase ions; it covers all the associated scientific disciplines. There is no formal limit on paper length ("rapid" is not synonymous with "brief"), but papers should be of a length that is commensurate with the importance and complexity of the results being reported. Contributions may be theoretical or practical in nature; they may deal with methods, techniques and applications, or with the interpretation of results; they may cover any area in science that depends directly on measurements made upon gaseous ions or that is associated with such measurements.
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