Strategy to Assess and Control Nitrosamine Formation in API during Storage: A Sitagliptin Case Study

A new strategy to identify, assess, and mitigate the nitrosamine formation in APIs during storage was developed and demonstrated on sitagliptin hydrochloride monohydrate, in which an increase in nitrosamine content was observed during stability studies. Comprehensive stress tests and stability assessments were carried out to evaluate the influence of various internal and external stimuli. Air exposure, secondary amine content, and optimum pH conditions emerged as the principal trigger factors. The results were consistent across all four distinct types of sitagliptin hydrochloride monohydrate tested, which were synthesized at different manufacturing sites and via diverse synthetic routes. A mitigation strategy was developed in which the secondary packaging material was modified to effectively prevent the ingress of air. This change yielded a clear reduction in nitrosamine formation, confirmed by 6-month stability studies at 40 °C.