Mimicking DNA alkylation: Removing genotoxin impurities from API streams with a solvent stable polybenzimidazole-adenine polymer

Abstract

This study reports the application of a novel polybenzimidazole (PBI) polymer modified with an alkylated DNA base - adenine - as an effective scavenger for several families of DNA alkylating agents. This new material addresses an important issue in active pharmaceutical ingredients (APIs) manufacture, the removal of genotoxic impurities (GTIs) to strictly low regulated limits. Instead of targeting individual GTIs removal, PBI-adenine scavenger mimics the concept of DNA-GTI adduct formation that takes place in vivo, but in this case, in an organic solvent matrix where APIs are chemically synthesized. Removal of eleven GTIs from five different chemical families is assessed with >80% removal. Slow binding kinetics for some GTIs at room temperature was identified as one of the limitations of the PBI-adenine polymer. API purification is addressed and an efficient process is presented for two APIs studied, mometasone furoate and betamethasone acetate, affording high impurity removals (>96%) and high API recovery with low API loss (3.5%) for these case studies. The possible application of this straightforward strategy in API post-reaction stream purification, is able to attain GTI imposed limits as low as 0.6 mg GTI/g API respecting the Threshold of Toxicological Concern (TTC) value.