Abstract
Purpose. To elucidate the structure of a degradation product arising from a lyophilized formulation of a cyclic heptapeptide, and to provide a mechanism to account for its formation.
Methods. Preparative HPLC was used to isolate the degradate in quantities sufficient for structural studies. A structure assignment was made on the basis of the compounds spectroscopic properties (UV, MS, NMR) and the results of amino acid analysis.
Results. The degradate was identified as a benzaldehyde derivative arising from the oxidative deamination of an aminomethyl phenylalanine moiety. The extent of formation of this product is influenced by the amount of mannitol used as an excipient in the formulation. A mechanism is proposed whereby reducing sugar impurities in mannitol act as an oxidizing agent via the intermediacy of Schiff base adducts which subsequently undergo tautomerization and hydrolysis.
Conclusions. Reducing sugar impurities in mannitol are responsible for the oxidative degradation of the peptide via a mechanism that involves Schiff base intermediates. This mechanism may be a potential route of degradation of other arylmethyl amines in mannitol-based formulations.
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REFERENCES
D. R. Ramjit, J. J. Lynch, G. R. Sitko, M. J. Mellot, M. A. Holahan, I. I. Stabilito, M. T. Stranieri, G. Zhang, R. J. Lynch, P. D. Manno, C. T. C. Chang, R. F. Nutt, S. F. Brady, D. F. Weber, P. S. Anderson, R. J. Shebuski, P. A. Friedman, and R. J. Gould. J. Pharmacol. Exper. Therap. 266:1501–1511 (1993).
G. D. Hartman, M. S. Egbertson, W. Halczenko, W. L. Laswell, M. E. Duggan, R. L. Smith, A. M. Naylor, P. D. Manno, R. J. Lynch, G. Zhang, T. C. Chang, and R. J. Gould. J. Med. Chem. 35:4640–4642 (1992).
L. Braunschweiler and R. R. Ernst. J. Magn. Reson. 53:521–525 (1983).
A. Bax and D. G. Davis. J. Magn. Reson. 65:355–360 (1985).
D. J. States, R. A. Haberkorn, and D. J. Ruben. J. Magn. Reson. 48:286–292 (1982).
M. H. Levitt, R. Freeman, and T. Frenkiel. J. Magn. Reson. 47:328–330 (1982).
T. Geiger and S. Clarke. J. Biol. Chem. 262:785–794 (1987).
Y.-C. J. Wang and M. A. Hanson. J. Parenteral Sci. Tech. 42:S3–S26 (1988).
M. C. Manning, K. Patel, and R. T. Borchardt. Pharm. Res. 6:903–918 (1989).
D. H. Williams and I. Fleming. Spectroscopic Methods in Organic Chemistry, McGraw Hill, London, 1973.
J. A. Howard. Adv. Free Radical Chem. 4:49–174 (1972).
J. Graymore and D. D. Davies. J. Chem. Soc. 293–294 (1945).
Official Monographs/Mannitol. The United States Pharmacopeia. 23:929 (1995).
A. I. Vogel. A Textbook of Practical Organic Chemistry, Longmans, Green and Co., London, 1957.
J. W. McGinity, J. A. Hill, A. L. LaVia. J. Pharm. Sci. 64:356–357 (1975).
D. S. Bindra, T. D. Williams, and V. J. Stella. Pharm. Res. 11:1060–1064 (1994).
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Dubost, D.C., Kaufman, M.J., Zimmerman, J.A. et al. Characterization of a Solid State Reaction Product from a Lyophilized Formulation of a Cyclic Heptapeptide. A Novel Example of an Excipient-Induced Oxidation. Pharm Res 13, 1811–1814 (1996). https://doi.org/10.1023/A:1016024923002
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DOI: https://doi.org/10.1023/A:1016024923002