Sokoloski, T. D.; Mitscher, L. A.; Yuen, P. H.; Juvarkar, J. V.; Hoener, B. Journal of Pharmaceutical Sciences 1977, 66, 1648-1650.
Tetracycline derivative concentrations in a 1.5 pH phosphate solution were monitored through a nonlinear regression based off of first-order epimerizations of the compounds. Rate constants were obtained for first-order tetracycline epimerization, as well as tetracycline degradation. The tetracycline epimerization allowed for the quantification of the kinetic rate of transformed, non-degraded products. It was found that tetracycline epimerization could occur at a pH as low as 1.5, showing that the range of acidity was lower than initially reported (pH=4.0).
Sheberstova, N. V.; Perel’son, M. E.; Kuzovkov, A. D. Chemistry of Natural Compounds 1974, 10, 61-65.
It was known from the previous article that tetracycline epimerizes in certain solutions with certain buffers. By using NMR tests, it was determined that one of the solutions that tetracycline hydrochloride undergoes a quick epimerization is pyridine. Since variable temperatures were used during each epimerization reaction, temperature dependence of the reaction was also gauged by its effect on the equilibrium constant.
Schlect, K. D.; Frank, C. W. Journal of Pharmaceutical Sciences 1973, 62, 258-261.
Standard reaction conditions allowing the epimerization of tetracycline to occur were used from article 1 above. Since a slight variance was found between the dimethylamino resonance structure of tetracycline and its C-4 epimer, NMR was used to differentiate between the two. In previous spectrophotometric methods, the tetracycline would have had to been acidified first. Fortunately, this was not necessary when using NMR, and the possibility of anhydro formation upon acidification was eliminated.
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