Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal Ions
<b>Objectives:</b> The effect of 2-hydroxpropyl-β-cyclodextrin (2HPβCD) with or without divalent metal ions (Ca<sup>2+</sup>, Mg<sup>2+</sup>, and Zn<sup>2+</sup>) on the stability of dalbavancin in acetate buffer was investigated. <b>Methods:<...
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2024-11-01
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| author | Sardar M. Jakaria David E. Budil James Murtagh Graham Revilla |
| author_facet | Sardar M. Jakaria David E. Budil James Murtagh Graham Revilla |
| author_sort | Sardar M. Jakaria |
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| description | <b>Objectives:</b> The effect of 2-hydroxpropyl-β-cyclodextrin (2HPβCD) with or without divalent metal ions (Ca<sup>2+</sup>, Mg<sup>2+</sup>, and Zn<sup>2+</sup>) on the stability of dalbavancin in acetate buffer was investigated. <b>Methods:</b> Dalbavancin recovery from formulations with 2HPβCD and divalent metal ions after four weeks of storage at 5 °C and 55 °C was measured by RP-HPLC and HP-SEC; a longer-term study was carried out over six months at 5 °C, 25 °C, and 40 °C. Binding of 2HPβCD was characterized by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). <b>Results:</b> The stability of the dalbavancin formulations after 4 weeks at 55 °C in 10 mM acetate buffer was significantly improved with 0.6 mM, 5.5 mM, and 55 mM 2HPβCD relative to without 2HPβCD. No further improvement was observed with the addition of any of the divalent cations. Dalbavancin in a 1:10 molar ratio with 2HPβCD was more stable at a concentration of 1 mg/mL than at 20 mg/mL under accelerated conditions at 40 °C for six months. ITC revealed two 2HPβCD binding sites to dalbavancin in 10 mM acetate: one with a 1:1 stoichiometry and thermodynamics consistent with known cyclodextrin–drug interactions, and a second with 0.1:1 stoichiometry, a positive binding enthalpy, and an unusually large entropy of binding. NMR spectroscopy indicates that dalbavancin exhibits aggregation in acetate buffer that is disrupted by 2HPβCD binding. <b>Conclusions:</b> 2HPβCD significantly improves the short- and long-term heat stability of dalbavancin in pH 4.5 acetate buffer at and above molar ratios of 1:1. The strong 1:1 binding of 2HPβCD to dalbavancin demonstrated by ITC confirms that this stability is conferred by the formation of a stable complex. This observation, combined with the NMR results, points to the aliphatic hydrocarbon chain of the glycone moiety as the most likely site of 2HPβCD–dalbavancin interaction. |
| format | Article |
| id | doaj-art-62379041aa3b459399481e43a252ce14 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-11-01 |
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| series | Pharmaceutics |
| spelling | doaj-art-62379041aa3b459399481e43a252ce142024-12-27T14:46:19ZengMDPI AGPharmaceutics1999-49232024-11-011612150310.3390/pharmaceutics16121503Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal IonsSardar M. Jakaria0David E. Budil1James Murtagh2Graham Revilla3Hikma Pharmaceuticals, Bedford, OH 44146, USADepartment of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USAHikma Pharmaceuticals, Bedford, OH 44146, USADepartment of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA<b>Objectives:</b> The effect of 2-hydroxpropyl-β-cyclodextrin (2HPβCD) with or without divalent metal ions (Ca<sup>2+</sup>, Mg<sup>2+</sup>, and Zn<sup>2+</sup>) on the stability of dalbavancin in acetate buffer was investigated. <b>Methods:</b> Dalbavancin recovery from formulations with 2HPβCD and divalent metal ions after four weeks of storage at 5 °C and 55 °C was measured by RP-HPLC and HP-SEC; a longer-term study was carried out over six months at 5 °C, 25 °C, and 40 °C. Binding of 2HPβCD was characterized by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR). <b>Results:</b> The stability of the dalbavancin formulations after 4 weeks at 55 °C in 10 mM acetate buffer was significantly improved with 0.6 mM, 5.5 mM, and 55 mM 2HPβCD relative to without 2HPβCD. No further improvement was observed with the addition of any of the divalent cations. Dalbavancin in a 1:10 molar ratio with 2HPβCD was more stable at a concentration of 1 mg/mL than at 20 mg/mL under accelerated conditions at 40 °C for six months. ITC revealed two 2HPβCD binding sites to dalbavancin in 10 mM acetate: one with a 1:1 stoichiometry and thermodynamics consistent with known cyclodextrin–drug interactions, and a second with 0.1:1 stoichiometry, a positive binding enthalpy, and an unusually large entropy of binding. NMR spectroscopy indicates that dalbavancin exhibits aggregation in acetate buffer that is disrupted by 2HPβCD binding. <b>Conclusions:</b> 2HPβCD significantly improves the short- and long-term heat stability of dalbavancin in pH 4.5 acetate buffer at and above molar ratios of 1:1. The strong 1:1 binding of 2HPβCD to dalbavancin demonstrated by ITC confirms that this stability is conferred by the formation of a stable complex. This observation, combined with the NMR results, points to the aliphatic hydrocarbon chain of the glycone moiety as the most likely site of 2HPβCD–dalbavancin interaction.https://www.mdpi.com/1999-4923/16/12/1503dalbavancin in aqueous solutiondalbavancin liquiddalbavancin injection solutiondalbavancin with cyclodextrindalbavancin cyclodextrin interaction by ITC and NMR |
| spellingShingle | Sardar M. Jakaria David E. Budil James Murtagh Graham Revilla Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal Ions Pharmaceutics dalbavancin in aqueous solution dalbavancin liquid dalbavancin injection solution dalbavancin with cyclodextrin dalbavancin cyclodextrin interaction by ITC and NMR |
| title | Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal Ions |
| title_full | Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal Ions |
| title_fullStr | Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal Ions |
| title_full_unstemmed | Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal Ions |
| title_short | Strategies to Stabilize Dalbavancin in Aqueous Solutions; Section-2: The Effects of 2 Hydroxypropyl-β-Cyclodextrin and Acetate Buffer with and Without Divalent Metal Ions |
| title_sort | strategies to stabilize dalbavancin in aqueous solutions section 2 the effects of 2 hydroxypropyl β cyclodextrin and acetate buffer with and without divalent metal ions |
| topic | dalbavancin in aqueous solution dalbavancin liquid dalbavancin injection solution dalbavancin with cyclodextrin dalbavancin cyclodextrin interaction by ITC and NMR |
| url | https://www.mdpi.com/1999-4923/16/12/1503 |
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