Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products

FDA limited N-nitrosodimethylamine (NDMA) - a carcinogenic impurity formed during metformin (MET) tablets manufacturing - level to 96 ng/day; a step which led to recall of MET products. This work aims to investigate the root cause of NDMA formation during MET tablets manufacturing.

We focused on three main contributing causes: use of water and heat during intra-granulation, and the nitrite/nitrate quantities in excipients. Thirteen MET tablet formulations (immediate or sustained-release) were manufactured, on batch level. Each batch was manufactured using one excipient and excluding one cause at a time and NDMA level was assayed.

NDMA traces were undetectable in MET tablets manufactured using polyvinyl pyrrolidone or hydroxypropyl cellulose SSL, even when water and/or heat were employed during intra-granulation. Levels of NDMA in MET tablets with hydroxypropyl methyl cellulose (HPMC) E5 or carboxymethyl cellulose sodium 4000 were 67.08 ± 2.3 and 66.21 ± 2.5 ng/day, in the presence of water and/or heat. No impact of employing extra-granular Polyox^TM, HPMC E5 or HPMC K15 on NDMA formation, despite the high nitrite and nitrate content in these excipients.

Water, heat, and excipients' nitrite and nitrate levels are the key players, which should collectively exist, to cause NDMA formation during MET tablets manufacturing.