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Oxidation of Free L-histidine by tert-Butylhydroperoxide

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Abstract

Purpose

L-histidine, a commonly used buffer for protein formulations, has the potential to oxidize and form multiple byproducts. Previous studies were performed using metal catalyzed oxidation with Fe2+ or Cu2+. We re-examined the oxidation of L-histidine under conditions more appropriate to protein formulations.

Methods

Solutions of free L-histidine, protected from light, were initially reacted with tert-butylhydroperoxide and the products analyzed by UV absorption spectroscopy, reversed phase HPLC and mass spectrometric analysis and NMR. Experimental parameters investigated were oxidizing agent, pH, temperature, metal ion and metal chelator content.

Results

The initial reaction produced a number of known products, along with an unknown product that was identified as 4(5)-imidazolecarboxaldehyde. The reaction was highly pH and oxidizing-agent specific. The product was not observed at pH 5.0 or below, while there was a dramatic increase for reactions carried out at pH 6.0 or above. Addition of FeSO4 to the reaction dramatically increased the amount of 4(5)-imidazolecarboxaldehyde produced, while addition of the metal chelators EDTA or DTPA completely inhibited the reaction.

Conclusions

The presence of oxidants and trace concentrations of metal ions in high purity L-histidine solutions results in the formation of 4(5)-imidazolecarboxaldehyde which has the potential to covalently modify proteins.

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Acknowledgements

The authors would like to thank Carey Brennar and Dr. Scott Buckel for initially asking what the new peak was observed by SE HPLC and Drew Nichols for his initial work limiting some of the possibilities. We also would like to thank Dr. Songpon Deechongkit and Dr. David Hambly for many thoughtful discussions, Tsang-Lin Hwang for NMR analysis and Dr. Mike Treuheit for critical reading of the manuscript.

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Authors and Affiliations

  1. Amgen Inc., Process and Product Development, Analytical and Formulation Sciences Group, Thousand Oaks, California, 91320, USA

    Bruce D. Mason, Melissa McCracken & Edward J. Bures

  2. Amgen Inc., Process and Product Development, Analytical and Formulation Sciences Group, Seattle, Washington, 98101, USA

    Bruce A. Kerwin

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  1. Bruce D. Mason
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  2. Melissa McCracken
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  3. Edward J. Bures
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Correspondence to Bruce A. Kerwin.

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Mason, B.D., McCracken, M., Bures, E.J. et al. Oxidation of Free L-histidine by tert-Butylhydroperoxide. Pharm Res 27, 447–456 (2010). https://doi.org/10.1007/s11095-009-0032-y

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  • DOI: https://doi.org/10.1007/s11095-009-0032-y

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