The role of histidine buffer in the iron-catalyzed formation of oxidizing species in pharmaceutical formulations: Mechanistic studies.

Iron-catalyzed oxidation reactions are common degradation pathways in pharmaceutical formulations. Buffers can influence oxidation reactions promoted by iron (Fe) and hydrogen peroxide (H₂O₂). However, mechanistically, the specific role of buffers in such reactions is not well understood. Here, we investigate the formation of radical intermediates using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a probe. Interestingly, over the time course of our experiments histidine (His) is the only buffer that promotes significant radical production during Fe(III)-catalyzed decomposition of H₂O₂, in contrast to other common pharmaceutical buffers such as citrate, succinate, adipate, and 2-(N-morpholino)ethanesulfonic acid (MES). The critical role of His in these degradation reactions is attributed to its unique, higher affinity for Fe(II) as compared to Fe(III), facilitating the reduction of Fe(III) to Fe(II) and subsequent Fenton and/or Fenton-like reactions with H₂O₂.