Simultaneous Determination of NDMA and Other Impurities in Ranitidine by Liquid Chromatography-mass Spectrometry

OBJECTIVE  To establish a method for simultaneous determination of N-nitrosodimethylamine(NDMA) and other impurities in ranitidine.

METHODS Liquid chromatography-high resolution mass spectrometry or liquid chromatography-triple quadrupole mass spectrometry was used with Titank C₁₈ column(150 mm×4.6 mm, 3 μm) as the stationary phase, 0.1% ammonia water solution containing 5 mmol·L⁻¹ ammonium acetate-acetonitrile containing 0.1% ammonia water as mobile phase for gradient elution. The flow rate was 0.5 mL·min⁻¹. The mass spectrometry data were acquired using the heated electrospray ionization(HESI) source or atmospheric pressure chemical ionization(APCI) source, with the parallel reaction monitoring combined with alternating of Full MS/dd-MS² mode and multiple reaction monitoring respectively. The UV absorption spectrum and data were collected by UV or DAD detector. The qualitative and quantitative analysis of NDMA and other impurities in ranitidine were conducted simultaneously.

RESULTS NDMA and related substances of ranitidine were well separated from the ranitidine, and NDMA showed a good linear relationship within the concentration range of 2–1000 ng·mL⁻¹, with the correlation coefficient(r²) >0.99; the lower limit of quantification was 1.01 ng·mL⁻¹(HESI) or 2.08 ng·mL⁻¹(APCI), and the detection limit was 0.50 ng·mL⁻¹(HESI) or 1.04 ng·mL⁻¹(APCI); at 3 different spiking levels, the average recoveries of the 2 instruments ranged from 93.6% to 101.3% and 97.5% to 99.9%, respectively, with relative standard deviations(RSD, n=6) ranged from 1.6% to 2.7% and 3.5% to 4.8%, respectively. The NDMA content in 8 batches of samples ranged from 0.06 mg·kg⁻¹ to 66.55 mg·kg⁻¹, with the maximum single impurity ranged from 0.05% to 0.18% and the total impurity ranged from 0.15% to 0.97%. A total of 14 impurities were identified. Except for 1 batch of capsule sample in which the largest single impurity identified as EP impurity I, the largest single impurity in the other 7 batches of samples was EP impurity A.

CONCLUSION The proposed method is specific and sensitive for the simultaneous detecting of NDMA and other related substances in ranitidine, which is suitable for mass spectrometry detectors with different principles and ion sources, and can be used for quality studies of related products.