The solubility of bortezomib, a boronic acid, in water and normal saline is often misquoted in the literature. Here we confirm that bortezomib equilibrium solubility in water and normal saline is 0.59 ± 0.07 and 0.52 ± 0.11 mg/mL, respectively. The aqueous solubility is significantly enhanced, 1.92 ± 0.14 and 3.40 ± 0.21 mg/mL, respectively, in the presence of 55 mM and 137 mM D-mannitol in normal saline, as in the commercial formulation, Velcade®, after reconstitution. This is due to reversible ester formation between bortezomib and D-mannitol. Based on the pH-solubility profile curve for bortezomib in the absence of added D-mannitol, bortezomib's pKa value is estimated to be 8.8 ± 0.2. Boric acid, glycine and a combination of the two, used in an alternative formulation to that of Velcade® do not enhance the equilibrium aqueous solubility of bortezomib.

Bortezomib Aqueous Solubility in the Presence and Absence of D-Mannitol: A Clarification With Formulation Implications

Lopalco A.
Writing – Original Draft Preparation
;
Iacobazzi R. M.;Denora N.;
2021

Abstract

The solubility of bortezomib, a boronic acid, in water and normal saline is often misquoted in the literature. Here we confirm that bortezomib equilibrium solubility in water and normal saline is 0.59 ± 0.07 and 0.52 ± 0.11 mg/mL, respectively. The aqueous solubility is significantly enhanced, 1.92 ± 0.14 and 3.40 ± 0.21 mg/mL, respectively, in the presence of 55 mM and 137 mM D-mannitol in normal saline, as in the commercial formulation, Velcade®, after reconstitution. This is due to reversible ester formation between bortezomib and D-mannitol. Based on the pH-solubility profile curve for bortezomib in the absence of added D-mannitol, bortezomib's pKa value is estimated to be 8.8 ± 0.2. Boric acid, glycine and a combination of the two, used in an alternative formulation to that of Velcade® do not enhance the equilibrium aqueous solubility of bortezomib.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/350943
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