Development of a new methodology for the determination of N-nitrosamines impurities in ranitidine pharmaceuticals using microextraction and gas chromatography-mass spectrometry

Ranitidine drug products were recently recalled because they contained carcinogenic nitrosamines (NAs), such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). This episode emphasises the importance of developing analytical methods to determine NAs in this type of product. This study describes the development and validation of an analytical method for the determination of nine NAs (NDMA, N-nitrosomethylethylamine (NEMA), NDEA, N-nitrosopyrrolidine (NPYR), N-nitrosomorpholine (NMOR) N-nitrosodi-n-propylamine (NDPA) N-nitrosopiperidine (NPIP), N-nitrosodi-n-butylamine (NDBA) and N-nitrosodiphenylamine (NDPhA)) in ranitidine drug samples using a combination of microextraction and gas chromatography-mass spectrometry. The procedure involved the dissolution of 1 g of sample in 10 mL of water. For the dispersive liquid-liquid micro extraction, 0.5 g of NaCl was added to this aqueous solution, followed by a mixture containing 0.5 mL methanol as dispersant and 150 mu L chloroform as extractant solvent. The recovered organic phase was injected into the GC MS system and a 20 min oven programme was applied. Quantification limits were in the 0.21-21 ng g(-1) range, corresponding the lower limit to NDPhA and the higher to NDMA. Relative standard deviations lower than 12% were achieved in all cases, which indicates the adequate precision of the method. Seven pharmaceutical products containing two different amounts of ranitidine (150 and 300 mg) were analysed. None of the samples contained NDPA or while NDBA and NDPhA were found in three products.

Automated summary

This study developed and validated an analytical method for the determination of nine NAs in ranitidine drug samples, highlighting the importance of developing analytical methods in detecting potential carcinogens in pharmaceutical products. The method showed quantification limits in the 0.21-21 ng g(-1) range, with satisfactory precision indicated by relative standard deviations lower than 12%.