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Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-1: the Effects of Metal Ions and Buffers

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Abstract

Purpose

The effect of monovalent (Na+ and K+) and divalent (Ca2+, Mg2+, and Zn2+) metal ions combined with citrate or acetate buffers (pH 4.5) on the stability of dalbavancin in aqueous solutions was investigated.

Method

RP-HPLC and HP-SEC were used to evaluate the stability of aqueous solutions of dalbavancin in different combinations of buffers and metal ions after four weeks of storage at 5°C and 55°C. A long-term study of formulations with divalent metal ions was conducted over six months at 5°C., 25°C and 40°C using RP-HPLC.

Results

All formulations in citrate buffered solutions precipitated. Dalbavancin solutions in 10 mM acetate buffer at 55°C were more stable in 10 mM CaCl2, 5 mM ZnCl2 and 10 mM MgCl2 than those containing 2 mM NaCl or 5 mM KCl, although the MgCl2 formulations precipitated slightly. No significant effect was observed for any of the divalent metal ions at 40°C for six months.

Conclusion

Dalbavancin’s stability in solution was improved by a combination of acetate and divalent metal ions at 55°C for four weeks. No effect was observed with acetate or metal ions alone, and no effect was observed after six months at 40°C suggesting that acetate and divalent metal ions together interact with dalbavancin via a thermally activated step to inhibit hydrolysis of the drug.

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Data Availability

Hikma Pharmaceuticals will not share the data beyond what is presented in the paper.

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Acknowledgements

This research work was supported by Hikma Pharmaceuticals.

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Authors and Affiliations

  1. Hikma Pharmaceuticals, Bedford, OH, 44146, USA

    Sardar M. Jakaria & James Murtagh

  2. Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA

    Sardar M. Jakaria & David E. Budil

Authors
  1. Sardar M. Jakaria
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  2. David E. Budil
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  3. James Murtagh
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Contributions

The authors confirm contribution to the paper as follows;

Research work was conducted in the lab, and the manuscript was prepared by Sardar M. Jakaria. David E. Budil and James Murtagh critically reviewed and revised the draft for intellectual content. All authors reviewed, edited, and approved the final version of the manuscript.

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Correspondence to Sardar M. Jakaria.

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Jakaria, S.M., Budil, D.E. & Murtagh, J. Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-1: the Effects of Metal Ions and Buffers. Pharm Res 40, 2469–2478 (2023). https://doi.org/10.1007/s11095-023-03588-9

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  • DOI: https://doi.org/10.1007/s11095-023-03588-9

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