Department of Pharmaceutical Chemistry, University of Kansas, 2093 Constant Avenue, Lawrence, KS 66047, USA.
Department of Pharmaceutical Chemistry, University of Kansas, 2093 Constant Avenue, Lawrence, KS 66047, USA.
Eur J Pharm Biopharm. 2023 Sep;190:231-241. doi: 10.1016/j.ejpb.2023.08.001. Epub 2023 Aug 4.
Pharmaceutical formulations are sensitive to light-induced degradation. Recent studies have attributed some of the light sensitivity to the presence of Fe(III), the most prevalent metal leachable from pharmaceutical containers. Histidine (His) can promote Fe(III) leaching from stainless steel, especially at elevated storage temperatures. Since there is the chance that combinations of His and Fe(III) are present in pharmaceutical formulations, we investigated the photo-degradation mechanisms of Fe(III)-containing His buffer during expsoure to near UV light. Our results indicate the formation of carbon dioxide radical anion (CO), a powerful reductant, and other photoproducts such as aldehydes and His-derived radicals. The generation of CO can be promoted by increasing concentrations of Fe(III) and inhibited by the addition of the Fe(III) chelator EDTA. Mechanistically, product formation can be rationalized by photo-induced ligand-to-metal-charge-transfer (LMCT), followed by a series of radical transformations of reaction intermediates.
药物制剂对光诱导降解敏感。最近的研究将一些光敏感性归因于 Fe(III)的存在，Fe(III)是从药物容器中浸出的最常见的金属。组氨酸（His）可以促进不锈钢中铁（III）的浸出，特别是在较高的储存温度下。由于 His 和 Fe(III)的组合有可能存在于药物制剂中，因此我们研究了含 Fe(III)的 His 缓冲液在近紫外光照射下的光降解机制。我们的结果表明形成了二氧化碳自由基阴离子（CO），一种强大的还原剂，以及其他光产物，如醛和 His 衍生的自由基。通过增加 Fe(III)的浓度可以促进 CO 的生成，而添加 Fe(III)螯合剂 EDTA 可以抑制 CO 的生成。从机理上讲，可以通过光诱导配体到金属电荷转移（LMCT）来合理化产物形成，然后是一系列反应中间体的自由基转化。
