Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047, United States.
Mol Pharm. 2024 Sep 2;21(9):4618-4633. doi: 10.1021/acs.molpharmaceut.4c00513. Epub 2024 Aug 7.
Near UV and visible light photodegradation can target therapeutic proteins during manufacturing and storage. While the underlying photodegradation pathways are frequently not well-understood, one important aspect of consideration is the formulation, specifically the formulation buffer. Citrate is a common buffer for biopharmaceutical formulations, which can complex with transition metals, such as Fe(III). In an aqueous solution, the exposure of such complexes to light leads to the formation of the carbon dioxide radical anion (CO), a powerful reductant. However, few studies have characterized such processes in solid formulations. Here, we show that solid citrate formulations containing Fe(III) lead to the photochemical formation of CO, identified through DMPO spin trapping and HPLC-MS/MS analysis. Factors such as buffers, the availability of oxygen, excipients, and manufacturing processes of solid formulations were evaluated for their effect on the formation of CO and other radicals such as OH.
近紫外和可见光光降解会在药物制造和存储过程中对治疗性蛋白产生影响。尽管潜在的光降解途径通常并不清楚，但有一个重要的考虑因素是制剂，特别是制剂缓冲液。柠檬酸盐是生物制药制剂中常用的缓冲液，它可以与过渡金属（如 Fe(III)）形成络合物。在水溶液中，这些络合物暴露在光下会导致形成二氧化碳自由基阴离子（CO），这是一种强还原剂。然而，很少有研究对固体制剂中的这些过程进行了描述。在这里，我们通过 DMPO 自旋捕获和 HPLC-MS/MS 分析表明，含有 Fe(III) 的固态柠檬酸盐制剂会导致 CO 的光化学形成。我们评估了缓冲液、氧气的可用性、赋形剂和固体制剂的制造工艺等因素对 CO 和其他自由基（如 OH）形成的影响。
