Pharmaceutical Excipients Enhance Iron-Dependent Photo-Degradation in Pharmaceutical Buffers by near UV and Visible Light: Tyrosine Modification by Reactions of the Antioxidant Methionine in Citrate Buffer

Advanced Oxidation Processes in Pharmaceutical Formulations: Photo-Fenton Degradation of Peptides and Proteins

“…Kaiser et al [ 7 ] only mention buffers in their formulations but not whether additional amino acids or surfactants were present. Our model studies on advanced oxidation processes described here show that amino acids such as Lys, His, or arginine (Arg) can promote the oxidation of Met residues in target peptides [ 24 ], suggesting that a similar effect may also operate with proteins. In the absence of added amino acids, therapeutic proteins can contain peptide sequences/domains which complex metals, enabling site-directed LMCT-dependent photo-degradation processes within specific protein domains even in the absence of added amino acids.…”

“…The addition of MEn to acetate buffer led to low yields of Met sulfoxide (product A ). However, for both citrate and acetate buffer, the addition of common amino acid excipients, specifically lysine (Lys) and histidine (His), significantly increased the yields of Met sulfoxide from MEn [ 24 ]. These increased yields of Met sulfoxide were not caused by an increased formation of H 2 O 2 .…”

“…These increased yields of Met sulfoxide were not caused by an increased formation of H 2 O 2 . Instead, we proposed that LMCT processes in amino acid/Fe 3+ complexes caused the formation of amino acid-derived peroxyl radicals, which directly oxidized Met to Met sulfoxide [ 24 ]. A potential mechanism for peroxyl radical formation is displayed in Scheme 4 (Reactions (17)–(19)), a representative for any peroxyl radical generated via the addition of O 2 to an intermediary carbon-centered radical.…”

“…Noteworthy, the addition of free Met to the formulations efficiently protected against the oxidation of the Met residue in MEn. However, specifically in citrate buffer, reaction products from free Met, such as methional, reacted with the N-terminal Tyr residue of MEn, generating a condensation product [ 24 ].…”

“…As an alternative, we recently started to evaluate the potential role of near UV and visible light-induced photo-degradation reactions driven by ligand-to-metal charge transfer (LMCT) processes of pharmaceutical excipient-metal complexes, specifically, complexes of iron [ 23 , 24 , 25 ]. These reactions are part of a larger class of processes, generally referred to as advanced oxidation processes (AOPs) [ 26 , 27 ].…”