Mitigation of N-Nitrosamine formation in ranitidine hydrochloride by spray drying co-precipitation with mannitol, dextrin, and antioxidant

Abstract

The discovery of trace amounts of human carcinogen NNitrosodimethylamine (NDMA) in production batches of ranitidine hydrochloride (RAN) led to the global recall of RAN in 2019. While RAN degradation during storage had been shown as the root cause for NDMA formation, mitigating NDMA formation in RAN had not been investigated before. The present work proposed spray-drying co-precipitation of RAN with protective co-formers (i.e., mannitol or dextrin) to slow down RAN degradation and subsequently inhibit NDMA formation during storage. The RAN stability and NDMA content of spray-dried RAN solid dispersions prepared at different co-former proportions (50-80 wt. %) were characterized after three months of accelerated storage at 40 °C and 75 % relative humidity. The results showed that the optimal co-former proportions were equal to 50 and 60 wt. % for RAN-mannitol and RAN-dextrin, respectively. Above these values, RAN degradation was intensified which was postulated due to intramolecular RAN destabilization caused by extensive RAN-co-former hydrogen bonding. The optimal RAN-mannitol and RAN-dextrin formulations were comparably effective in mitigating RAN degradation (80-90 % stability) and NDMA formation (≤ 0.05 μg/mg of RAN) up to two months of accelerated storage, compared to approximately 70 % stability and 0.15 μg/mg of RAN for the native RAN. Their effectiveness, however, declined beyond two months of storage due to worsening RAN degradation. The addition of antioxidant ferulic acid to RAN-mannitol formulation did not lead to improved NDMA mitigation. The crystalline RAN-mannitol dispersion exhibited better overall stability and morphology, making it more promising formulation than the amorphous RAN-dextrin dispersion.

Keywords: Drug contamination; Ndma; Nitrosamine; Ranitidine; Ranitidine stability.