Solanki Ravisinh, Wadhwana Pooja, Patel Ravi, Gayakvad Bhavinkumar, Kothari Charmy, Patel Chhaganbhai
Research Scholar, Gujarat Technological University, Ahmedabad, Gujarat, India.
Department of Quality Assurance, Graduate School of Pharmacy, Gujarat Technological University, Ahmedabad, Gujarat, India.
J Pharm Sci. 2023 May;112(5):1268-1276. doi: 10.1016/j.xphs.2023.02.016. Epub 2023 Feb 22.
Metformin and its combinations are widely used to treat type 2 diabetes. The drugs commonly used in combination with Metformin are Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride. Combination therapy is preferred over monotherapy of Metformin in most diabetics. About eighteen pharmaceutical manufacturers have lately recalled metformin formulation batches from the U.S. market due to N-nitrosodimethylamine (NDMA) impurities based on the food and drug administration (USFDA) guideline "Control of Nitrosamine in Human Drugs." European Medicines Agency (EMA) and Health Canada have also established guidelines for nitrosamine impurities. Nitrosamines are well-known mutagenic impurities and probable human carcinogens found in pharmaceutical formulations. Thus, global regulatory agencies require pharmaceutical and formulation manufacturers to complete risk assessments for nitrosamine impurities for patient safety. Therefore, drug manufacturers must develop analytical techniques for monitoring trace nitrosamine impurities. Quantifying nitrosamine impurities in formulations requires modern equipment like LC-MS/MS and great intellect. The present study intends to give a single pre-packaged LC-MS/MS method parameters, including liquid chromatography and triple quadrupole mass spectrometer configuration. This method could quantify eight nitrosamine impurities from five different Metformin combinations (Metformin with Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride). The atmospheric pressure chemical ionisation (APCI) was used as an ionisation source, and the mass spectrometer was set to multiple reaction monitoring (MRM) mode for all eight nitrosamine impurities. A unified pre-packaged analytical setup allows analytical chemists to develop a reliable, sensitive, robust, and precise method for quantifying eight nitrosamine impurities from five different Metformin formulations of varying manufacturers. This analytical method saves time, money, and the environment using fewer pharmaceutical chemicals.
二甲双胍及其复方制剂被广泛用于治疗2型糖尿病。与二甲双胍联合使用的常用药物有格列吡嗪、格列本脲、格列齐特、依格列净和格列美脲。在大多数糖尿病患者中，联合治疗优于二甲双胍单药治疗。最近，约有18家制药商根据美国食品药品监督管理局（USFDA）的指南“人用药品中亚硝胺的控制”，从美国市场召回了含N-亚硝基二甲胺（NDMA）杂质的二甲双胍制剂批次。欧洲药品管理局（EMA）和加拿大卫生部也制定了亚硝胺杂质指南。亚硝胺是在药物制剂中发现的众所周知的致突变杂质和可能的人类致癌物。因此，全球监管机构要求制药和制剂制造商为确保患者安全完成亚硝胺杂质的风险评估。因此，药品制造商必须开发监测痕量亚硝胺杂质的分析技术。定量制剂中的亚硝胺杂质需要诸如液相色谱-串联质谱仪（LC-MS/MS）之类的现代设备以及高超的智慧。本研究旨在给出一种单一的预包装LC-MS/MS方法参数，包括液相色谱和三重四极杆质谱仪配置。该方法可以定量五种不同二甲双胍复方制剂（二甲双胍与格列吡嗪、格列本脲、格列齐特、依格列净和格列美脲）中的八种亚硝胺杂质。采用大气压化学电离（APCI）作为电离源，质谱仪对所有八种亚硝胺杂质设置为多反应监测（MRM）模式。统一的预包装分析设置使分析化学家能够开发出一种可靠、灵敏、稳健且精确的方法，用于定量来自不同制造商的五种不同二甲双胍制剂中的八种亚硝胺杂质。这种分析方法使用较少的药物化学品，节省了时间、金钱和环境成本。
