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A new strategy to stabilize oxytocin in aqueous solutions: I. The effects of divalent metal ions and citrate buffer

Avanti, C., Amorij, J-P., Setyaningsih, D., Hawe, A., Jiskoot, W., Visser, J., Kedrov, A., Driessen, A. J. M., Hinrichs, W. L. J. & Frijlink, H. W., Jun-2011, In : Aaps journal. 13, 2, p. 284-290 7 p.

Research output: Contribution to journalArticleAcademicpeer-review

In the current study, the effect of metal ions in combination with buffers (citrate, acetate, pH 4.5) on the stability of aqueous solutions of oxytocin was investigated. Both monovalent metal ions (Na+and K+) and divalent metal ions (Ca2+, Mg2+, and Zn2+) were tested all as chloride salts. The effect of combinations of buffers and metal ions on the stability of aqueous oxytocin solutions was determined by RP-HPLC and HP-SEC after 4 weeks of storage at either 4°C or 55°C. Addition of sodium or potassium ions to acetate- or citrate-buffered solutions did not increase stability, nor did the addition of divalent metal ions to acetate buffer. However, the stability of aqueous oxytocin in aqueous formulations was improved in the presence of 5 and 10 mM citrate buffer in combination with at least 2 mM CaCl2, MgCl2, or ZnCl2and depended on the divalent metal ion concentration. Isothermal titration calorimetric measurements were predictive for the stabilization effects observed during the stability study. Formulations in citrate buffer that had an improved stability displayed a strong interaction between oxytocin and Ca2+, Mg2+, or Zn2+, while formulations in acetate buffer did not. In conclusion, our study shows that divalent metal ions in combination with citrate buffer strongly improved the stability of oxytocin in aqueous solutions. © 2011 The Author(s).
Original languageEnglish
Pages (from-to)284-290
Number of pages7
JournalAaps journal
Volume13
Issue number2
Publication statusPublished - Jun-2011

    Keywords

  • citrate buffer, divalent metal ions, improved stability, oxytocin, acetic acid, buffer, calcium chloride, calcium ion, citric acid, magnesium chloride, magnesium ion, metal ion, potassium ion, sodium ion, zinc chloride, zinc ion, aqueous solution, article, chemical analysis, concentration (parameters), controlled study, drug formulation, drug stability, drug storage, gel permeation chromatography, isothermal titration calorimetry, molecular interaction, pH, reversed phase high performance liquid chromatography, size exclusion high performance liquid chromatography, storage temperature

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