Wu Yaqi, Richards David, Zhang Yilue, Zhang Lin, Dodd Steve W, Schöneich Christian
Department of Pharmaceutical Chemistry, The University of Kansas, 2093 Constant Avenue, Lawrence, KS 66047, The United States of America.
Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, The United States of America.
Eur J Pharm Biopharm. 2025 Sep;214:114763. doi: 10.1016/j.ejpb.2025.114763. Epub 2025 Jun 6.
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.
聚山梨醇酯80（PS80）是生物制药制剂中广泛使用的非离子表面活性剂。PS80易于发生化学降解，这可能导致对药物制剂稳定性至关重要的表面活性剂性质丧失。深入了解PS80的稳定性对于维持药物疗效和安全性至关重要。虽然氧化的一般机制是已知的，但关于制剂中PS80氧化起始的具体机制信息却很缺乏。在此，我们报告了PS80在含有Fe(III)的醋酸盐、琥珀酸盐和己二酸盐等药物缓冲液中的光降解新机制。通过荧光胶束分析法（FMA）和质谱法（MS）监测光降解。机理研究表明存在一种胶束内PS80光降解机制，其中由光诱导的配体到金属电荷转移（LMCT）和Fe(III)-羧酸盐配合物分解产生的缓冲液衍生的碳中心自由基进入PS80胶束并引发降解。光降解程度的关键在于存在少量游离脂肪酸（FFA），例如在商业多药典PS80中可能存在的游离脂肪酸，它通过与胶束表面的Fe(III)络合促进自由基进入胶束。
