Mechanisms of polysorbate 80 oxidation: Acetate and Fe(III) mediated near UV and visible light degradation enhanced by free fatty acids

Abstract

Polysorbate 80 (PS80) is a widely used nonionic surfactant in biopharmaceutical formulations. PS80 is prone to chemical degradation, potentially resulting in loss of surfactant properties essential for the stability of pharmaceutical formulations. A deep understanding of PS80 stability is critical to maintaining drug efficacy and safety. While general mechanisms of oxidation are known, specific mechanistic information on the initiation of PS80 oxidation in formulations is lacking. Here, we report on novel mechanisms of photo-degradation of PS80 in pharmaceutical buffers such as acetate, succinate, and adipate, containing Fe(III). Photo-degradation was monitored by fluorescence micelle assay (FMA) and mass spectrometry (MS). The mechanistic investigation suggests an intra-micellar PS80 photo-degradation mechanism, wherein buffer-derived carbon-centered radicals, generated from light-induced ligand-to-metal-charge-transfer (LMCT) and decomposition of Fe(III)-carboxylate complexes, enter the PS80 micelles and initiate degradation. Critical for the extent of photo-degradation is the presence of small levels of free fatty acids (FFAs), such as can be present in commercial multi-compendial PS80, facilitating the access of radicals into micelles via complexing with Fe(III) on the micelle surface.