Monitoring and Control of Genotoxic Impurity Acetamide in the Synthesis of Zaurategrast Sulfate

In this article we describe the strategy adopted to minimize the risk of acetamide presence in zaurategrast sulfate drug candidate. A risk of acetamide formation (a potential genotoxic impurity) was identified in the API formation step of the process during the early development phase. In order to keep the project development timelines unchanged and without having the appropriate analytical method ready developed, we chose to minimize the risk of acetamide impurity presence by applying an adequate chemical process design. The implementation of a workup sequence involving initially three aqueous washes was later proven to be successful when an appropriate analytical method to detect acetamide below ppm levels was available. Additionally the analytical tool gave us the opportunity to assess and fine-tune the designed process for acetamide elimination by spiking experiments. Data acquired during this evaluation showed that a single aqueous wash associated with two efficient crystallization steps were finally enough to deliver API with a content of acetamide below the level defined as the acceptance criterion.