Probability of N-Nitrosodimethylamine (NDMA) Presence and Its Quantification in Famotidine Dosage Forms

Abstract

Famotidine has been replaced by ranitidine after Recall of all pharmaceutical forms of ranitidine due to the presence of excessive amounts of the carcinogenic impurity NDMA in April2020. Aim: Examining Famotidine medicinal products in terms of the presence of nitrosamine and investigating the effect of various factors on the production of this substance with the help of liquid cromatography tandem mass spectrometry.Materials and Methods:After applying the appropriate method of analysis; NDMA presence was investigated in famotidine products and the effect of various factors in the production of this impurity such as Sodium Nitrate adition, environmental pH and excipients, which are known to have nitrate impurities, were investigated. Finally, the possibile pathway of NMDA production as an impurity in famotidine products was proposed.Results: The amount of quantified NDMA in all of aqueous solutions was from 3.7×104to 70.1×105 ng in 5 mg famotidine powder and in commercial tablet products this range was between 1.6×104 and 2.8×105 ng in 40mg tablets. After refluximg the samples at 40◦C NDMA disappeared in samples but except one, amount of NDMA increased aftr treatment in tablets. Excipient addition did not increased the amount of NDMA in the tested samples.Conclusion: The amount of NDMA in the tablets was178 times the lowest and¬ 2818 times the maximum allowed limit. High temperature or long reaction time during the test in the aqueous environment has reduced the amount of NDMA due to the possible destruction of this substance, but in commercial tablets and during the test in the solid environment,except one tablet, the opposite is observed. According to the obtained results, no significant relationship was found between the tested excipients, sodium nitrite and acidic, basic or neutral environments with the amount of NDMA.