Crystal defects cause nitrosamine formation in ranitidine under accelerated storage conditions

The formation of nitrosamines, a class of potent carcinogen impurities, in pharmaceutical products such as ranitidine hydrochloride (RAN) has raised significant public health concerns and led to widespread product recalls. Previous studies have shown that RAN can degrade to N-nitrosodimethylamine (NDMA) after storage at 60 °C for several days. These studies also suggested a link between the degradation rate and the crystal morphology of the RAN. This study shows that NDMA formation in RAN is primarily driven by solid-state reactive species (SSRS) introduced during pharmaceutical manufacturing processes such as crystallization, milling, and grinding. Using cryogenic milling to introduce SSRS systematically, we assessed the stability of RAN at 60 °C and 0 % RH. Our results show a clear relationship between the amount of SSRS in RAN and the amount of NDMA formed upon stability, with cryoground samples exhibiting degradation rates up to two orders of magnitude higher than unprocessed samples. Furthermore, RAN tablets prepared with increased SSRS also showed accelerated NDMA formation. This study demonstrates the importance of mitigating SSRS in pharmaceutical manufacturing by mitigating the presence of SSRS in drug substances/products.