Metformin, a commonly used hypoglycemic drug, helps patients control their blood sugar levels. In addition to the hypoglycemic effect, a number of literature projects have shown that metformin has something to explore in more therapeutic areas. At present, there are more than 40 kinds of metformin-related preparations approved for marketing in China, including single-component/multi-component ordinary tablets, sustained-release tablets, capsules, etc., among which the release speed is slower than that of other dosage forms of sustained-release tablets, which can make the efficacy more stable and have fewer side effects.
However, genotoxic impurities are an important part of the research of various preparations such as sustained-release tablets. Genotoxic impurities, also known as genotoxic impurities, can cause DNA damage to the body's genetic material at very low concentrations, which in turn can lead to genetic mutations leading to tumorigenesis. In this issue, the microsource testing laboratory takes the genotoxic impurities in a metformin sustained-release tablet as an example to bring you the research ideas and test results of genotoxic impurities.
According to the requirements of the Chinese Pharmacopoeia, the micro-source testing laboratory used liquid chromatography-mass spectrometry (LC-MS) to develop the impurity N-nitrosodimethylamine NDMA in a metformin sustained-release tablet. Although the structure of NDMA seems simple, it is a group 2A carcinogen recognized by the International Agency for Research on Cancer, according to WHO data, the AI value of NDMA is 0.005~0.016 μg/kg, which is converted to 0.375~1.2 μg/day. Therefore, the production process must be evaluated to determine the potential for the formation of N-nitrosodimethylamine impurities and, if necessary, the production process must be validated to demonstrate that the N-nitrosodimethylamine content in the finished product is compliant.
It has been verified that the blank solution of this method and the test solution do not interfere with the detection of N-nitrosodimethylamine. Within the limit of quantification ~200%, the linear correlation coefficient (r) of N-nitrosodimethylamine was 0.9989, the ratio of the absolute value of Y-intercept to the 100% response value was 0.95%, and the RSD % of the response factor (A/C) was 4.15%.
The recoveries, average recoveries and total average recoveries of N-nitrosodimethylamine were between 88.04%~111.52%, and the RSD was not more than 12.13%. The method of microsource testing laboratory for nitrosamine genotoxic impurities in metformin sustained-release tablets meets the requirements of validation indicators, and is suitable for the detection of basic toxic impurities N-nitrosodimethylamine in metformin sustained-release tablets.
The detection methods for nitrosamine impurities in pharmaceutical raw materials and preparations successively issued by the FDA, EMA, NMPA and other drug regulatory authorities will become higher and higher with the deepening of the understanding of such characteristics. The detection limit of genotoxic impurities is very low, which is a very challenging work, and the micro-source detection technical team has been specializing in basic toxic impurities for many years, and can start from drug synthesis, extraction, quality control, evaluation and other aspects under the premise of drug administration and regulations, and involve different control strategies in a targeted manner. Perform tests on different samples:
- Nitrosamine impurities in starting materials, solvents, reagents, catalysts, intermediates and excipients
- Nitrosamine impurities in final products such as formulations
- Nitrosamine impurities in the study of leachables in packaging materials
The laboratory is equipped with a number of high-sensitivity analytical instruments, combined with technical experts and engineers with rich testing experience, and applies different analysis and testing methods to different types of impurities, and has effectively carried out and successfully completed the verification and detection of a variety of nitrosamines in multiple batches of chemical drugs. Meet data accuracy, product validity. It is committed to providing pharmaceutical companies with customized genotoxicity and elemental impurity analysis, impurity methodology development, R&D analysis and testing and other testing services. If you have relevant testing needs, welcome to consult the homepage!