Sweetening the Deal: Sweetener-Based Ionic Liquid of Albendazole Significantly Enhances Its Solubility and Oral Bioavailability

Abstract

Albendazole (ABZ) is a hydrophobic and weakly basic anthelmintic benzimidazole with a very low (5%) oral bioavailability. Conversion of hydrophobic ionizable drugs such as ABZ into ionic liquids (ILs) or liquid salts is an emerging strategy for improving their solubility and oral bioavailability. To date, FDA-approved non-nutritive anionic sweeteners have not been evaluated for the development of ILs of weakly basic and hydrophobic drugs. Hence, we evaluated the ability of various anionic non-nutritive sweeteners, acesulfame potassium (ACE-K), saccharin sodium (SAC-Na), and cyclamate sodium (CYM-Na), to transform ABZ into an IL. Interestingly, only ACE-K, upon interaction with ABZ at the ABZ to ACE molar ratio of 1:2, converted ABZ into a room-temperature IL [ABZ-ACE (1:2) IL], whereas SAC-Na and CYM-Na yielded salts or coamorphous systems. The interaction of ABZ with anionic sweeteners was confirmed using FT-IR and NMR. Compared to pure ABZ, all ABZ-sweetener ILs/salts/coamorphous systems displayed a 1.2- to 2-fold decrease in Log P value and a significant increase in the equilibrium solubility of ABZ in water, pH 1.2 buffer, and pH 6.8 buffer. ABZ-ACE (1:2) IL exhibited remarkably higher (∼92-fold) solubility in water and ∼5-fold improvement in pH 6.8 buffer solubility, with a complete lack of crystallinity at room temperature, even after 1 month of storage at room temperature. Finally, compared to ABZ oral suspension, orally delivered ABZ-ACE (1:2) IL showed an 11-fold increment in C_max and a 7.6-fold increase in the oral bioavailability of ABZ in mice. Hence, the development of a sweetener-based IL could be an effective approach to improving the solubility and oral bioavailability of hydrophobic weakly basic drugs, including ABZ.

Keywords: API-IL; coamorphous systems; room-temperature IL (RT-IL); salt metathesis; sweetener.