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

Purpose The effect of monovalent (Na + and K + ) and divalent (Ca 2+ , Mg 2+ , and Zn 2+ ) 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 CaCl 2 , 5 mM ZnCl 2 and 10 mM MgCl 2 than those containing 2 mM NaCl or 5 mM KCl, although the MgCl 2 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.