Removal of Electrophilic Potential Genotoxic Impurities Using Nucleophilic Reactive Resins

Potential genotoxic impurities (PGI) are chemical compounds that could potentially damage DNA and lead to mutation. Controlling the occurrence of PGIs in active pharmaceutical ingredients (APIs) poses a big challenge for chemists, as levels of these compounds must be reduced well below the amounts required for other types of less toxic impurities. In situations where formation of PGIs cannot be avoided, an ideal solution would allow the complete removal of PGIs after the synthesis is complete, for example, by recrystallization, preparative chromatography or other downstream processing approaches. Some disadvantages of using these approaches are potential high yield loss, high solvent consumption, and additional time and resources required for process development. In this work, we present a simple and rapid approach to remove electrophilic PGIs from APIs. A selected nucleophilic resin can be added to the final API solution to reduce or totally remove the PGI. Esters of methanesulfonic acid (MSA), benzenesulfonic acid (BSA), and p-toluenesulfonic acid (pTSA) were used as model electrophilic PGIs. Several nucleophilic resins were screened, and the resins with the highest efficiency of PGI removal were chosen. A recommended procedure is presented for the removal of MSA, BSA, and pTSA esters. The kinetics of PGI removal, resin loading capacity, solvent effects, and API matrix effects are demonstrated.