Method Development and Validation for Determination of N-nitrosodimethylamine in Metformin Tablets
Method Development of N-nitrosodimethylamine Determination in Metformin Tablets
Keywords:
Nitrosamine impurity, N-nitrosodimethylamine, Metformin, NDMA, GC-MSAbstract
Nitrosamines have been detected in several drug products such as angiotensin II receptor blockers (ARB), ranitidine and metformin. However, N-nitrosodimethylamine (NDMA) is the only nitrosamine impurity found in metformin. Nitrosamines impurities in drug products may be occurred by raw materials, excipients, water, solvents, manufacturing process, and packaging materials. Since Nitrosamines are probably human carcinogen, quantity of nitrosamines impurity must be controlled to not exceeded the acceptance daily intake (ADI). The ADI of NDMA is 95 nanogram per day. The objective of this study was to develop an analytical method using gas chromatography-mass spectrometry (GC-MS) for the determination of low-level NDMA in metformin tablets. This method was developed from the method available from oversea drug regulation authorities. The method validation was performed according to International Council for Harmonisation (ICH) guideline which found that NDMA
and NDMA-d6 peaks were not interfered by N-nitrosodiethylamine (NDEA) metformin excipient and solvent. The limit of detection was 0.8 ng/mL and the limit of quantification was 3 ng/mL which was less than the NDMA acceptance limit for metformin tablets. The method showed linearity with a coefficient of determination (R2) greater than 0.999. The accuracy as expressed by %recovery was between 87.4 to 103.4%. The relative standard deviation values of repeatability and intermediate precision were less than 8% and 11%, respectively. Therefore, the developed method was suitable for monitoring NDMA quantity in metformin tablets.
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