Structural landscape of new salts of the antihistamine drug bilastine: implications in physicochemical properties and anticancer activity against skin cancer†

Abstract

To enhance the solubility and study the anticancer activity of the drug bilastine (BLN), a European Medicines Agency-approved second-generation antihistamine drug, seven new salts were prepared with acid counterions, namely hydrochloric acid (HCl), hydrobromic acid (HBr), nitric acid (HNO₃), sulphuric acid (H₂SO₄), and orthophosphoric acid (H₃PO₄). All the prepared salts crystallize as hydrates except phosphate salt which crystallises as a methanol solvate. Anhydrous BLN⁺-H₂PO₄⁻ was prepared by the slurry method and was confirmed by ¹H NMR and TGA analysis. A di-salt of HCl and H₃PO₄ (BLN²⁺-H₂PO₄⁻-Cl⁻-3H₂O) was obtained as a single crystal from the residue after a solubility study. The salts, namely BLN⁺-Cl⁻-3H₂O, BLN⁺-Br⁻-H₂O, BLN²⁺-NO₃²⁻-H₂O, and BLN⁺-H₂PO₄⁻ were reproduced in the bulk scale and thoroughly characterized. The solubility study revealed that all the prepared salts showed improvement in solubility nearly 3 to 6 times higher than that of the parent BLN in pH 1.2 buffer medium, while in pH 6.8 buffer, the solubility is comparable to that of the parent BLN. The dissolution profile in pH 1.2 buffer showed similar drug release to BLN, whereas in pH 6.8 buffer, sustained drug release was noticed in the salts. Further, in vitro anticancer studies revealed that the prepared BLN salts exhibited excellent growth inhibitory activity against skin cancer by generating ROS and inducing apoptosis in B16F10 cells. Western blot analysis shows that BLN salts downregulate caspase 1, IL6, and IL-1β and upregulate Bax, p53 and p21, indicating that treatment of BLN salts induces apoptosis in skin cancer.