Abstract
The kinetics of the degradation of an LH-RH antagonist, RS-26306,1, in aqueous solution from pH 1 to pH 11 were studied by reverse-phase HPLC. The pH–rate profiles at 50, 60, and 80°C were U-shaped with the rate law of k obs = k H a H + k w + k OH a OH. The predicted 25°C shelf life at the pH of maximum stability, pH ∼5, is greater than 10 years. The products from the degradation were analyzed by HPLC-MS using thermospray ionization. Below pH 3, the primary product, 2, forms from the acid-catalyzed deamidation of the C-terminal amide. Above pH 7, epimerization of the individual amino acids is the principal reaction. Between pH 4 and pH 6, intramolecular serine-catalyzed peptide hydrolysis becomes important, yielding a tripeptide, 3, and a heptapeptide, 4. At the pH of maximum stability all three pathways for degradation are observed.
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REFERENCES
K. H. Lee, D. VanAntwerp, L. Hedley, J. Nestor, Jr., and B. Vickery. Life Sci. 45:697–702 (1989).
D. M. Johnson, R. A. Pritchard, W. T. Taylor, D. Conley, G. Zuniga, and K. McGreevy. Int. J. Pharm. 31:125–129 (1986).
K. Nishi, H. Ito, S. Shinagawa, C. Hatanaka, M. Fugino, and M. Hattori. In H. Yonehara (ed.), Peptide Chemistry, 1979, Protein Research Foundation, Osaka, 1980, pp. 175–180.
J. A. Feldman, M. L. Cohn, and D. Blair. J. Liquid Chromatogr. 1:833 (1978).
D. C. Sertl, R. N. Johnson, and B. T. Kho. J. Liquid Chromatogr. 4:1135 (1981).
J. Winterer, D. Chaterjee, F. Comite, M. H. Decker, D. L. Loriaux, J. F. Gallelli, and G. B. Cutter, Jr. Contraception, 27:195 (1983).
C. R. Blakley and M. L. Vestal, Anal. Chem. 55:750–754 (1983).
A. J. Kirby and A. R. Fersht. Prog. Bioorgan. Chem. 1:1 (1971).
C. O'Connor. Q. Rev. Chem. Soc. 24:553–564 (1970).
G. G. Smith and T. Sivakua. J. Org. Chem. 48:628–634 (1983).
G. Zubay. In Biochemistry, Addison-Wesley, Chicago, Chaps. 1 and 3.
R. G. Strickley. Unpublished data.
W. P. Jencks and J. Regenstein. Handbook of Biochemistry and Molecular Biology, Chemical Rubber Company, 1968, p. 138.
P. R. Bevington. Data Reduction and Error Analysis for the Physical Sciences, McGraw-Hill, New York, 1969.
J. Yergey, D. Heller, G. Hansen, R. J. Cotter, and C. Fenselau. Anal. Chem. 55:353–359 (1983).
DMS. UV Atlas of Organic Compounds, Plenum Press, New York, 1966.
T. C. Bruice and F. Marquardt. J. Am. Chem. Soc. 84:365–367 (1962).
T. Yamana, Y. Mizukami, A. Tsuji, Y. Yasuda, and K. Masuda. Chem. Pharm. Bull. 20:881–891 (1972).
P. M. Masters and M. Friedman. Chemical Deterioration of Proteins, Am. Chem. Soc. Sym. Ser., 1980, pp. 165–294.
S. M. Steinberg, P. M. Masters, and J. L. Bada. J. Bioorgan. Chem. 12:349–355 (1984).
J. I. Harris, R. D. Cole, and N. G. Pon. J. Biochem. 62:154–159 (1956).
Y.-C. J. Wang and M. A. Hanson. J. Parent. Sci. Technol. 42:S2–S26 (1988).
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Strickley, R.G., Brandl, M., Chan, K.W. et al. High-Performance Liquid Chromatographic (HPLC) and HPLC-Mass Spectrometric (MS) Analysis of the Degradation of the Luteinizing Hormone-Releasing Hormone (LH-RH) Antagonist RS-26306 in Aqueous Solution. Pharm Res 7, 530–536 (1990). https://doi.org/10.1023/A:1015829119270
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DOI: https://doi.org/10.1023/A:1015829119270