Nitrosamine impurities are potential carcinogens, which are forming from the synthesis of drug substance as byproduct and also forming in presence of NaNO2/HNO3 and secondary amines (e.g., dimethyl amines, diethyl amine etc.,), which should be controlled in the medication of the human beings. Hence, robust and sensitive analytical method is required to control the nitroso amine impurities in drugs. The object of this method is to quantify the N-Nitrosodimethylamine (NDMA) impurity at 0.01 ppm level in ranitidine drug substance (form-1 and form-2) and drug product (tablets and capsules) of different geography. The source of NDMA impurity is also from the dimethyl amine as a key starting material using the ranitidine synthetic process. NDMA is forming when dimethyl amine is reacting with nitrous acid. The optimized LC method conditions were ACE C18-AR 3 µm, 150 × 4.6 mm column, mobile phase A as 0.1% formic acid in water, mobile phase B as 100% methanol, 0.8 ml/minute flow with gradient (time/%mobile phase B): 0/3, 3/3, 15/15, 15.1/100, 17/100, 17.1/3, 22/3, column temperature: 40°C, injection volume 50 µl, and total run time as 22 minutes. The final response achieved with multiple reaction monitoring (MRM) type: MRM [Q1 Mass (Da):75 Q3:58.2 Time (msecond)] in atmospheric chemical ionization positive mode. The optimized method was validated against the International Council for Harmonisation Q2 (R1) and United States of Pharmacopeia general chapter for compendial method validations 1225. This method can detect up to 0.01 ppm and quantify up to 0.03 ppm, the method shows linearity from 0.03 to 20 ppm.
Key words: Method development, method validation, tablets, capsules
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