Amino–Imino Tautomerism in the Salt Formation of Albendazole: Hydrobromide and Nitrate Salts

Albendazole (ABZ) is a poorly soluble anthelmintic drug that can exist in amine and imine desmotropic forms. These facts can affect the solubility and bioavailability of the drug product. Here, we investigate the salt formation of ABZ with the acids HCl, HBr, and HNO3 associated with the tautomerism of the ABZ molecule. The reaction of ABZ with an excess of the acids HCl, HBr, and HNO3 results in the protonation of the imidazole ring, hiding the occurrence of tautomeric states. Thus, the ABZ HCl, ABZ HBr, and ABZ HNO3 salts were obtained and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, FT-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and aqueous solubility measurements. Furthermore, static and dynamic DFT calculations were carried out to understand how the albendazolium cation (ABZ-H+) is obtained from ABZ in amine and imine forms. An analysis of crystal structures reveals that cations and anions aggregate in 1D chains stabilized by NH···X (X = Cl–, Br–, O–) interactions, generating layered structures. In solution, the intramolecular amine ↔ imine conversion (ΔG⧧ ≈ 50 kcal mol–1) and the solvent-mediated deprotonation of the ABZ-H+ cation (ΔG⧧ ≈ 20 kcal mol–1) requires a higher energy barrier to occur, allowing the independence between tautomers to propitiate the crystallization process. Consequently, the process is dependent on the tautomer population in the starting material. All salts were demonstrated to be more soluble than pure ABZ. Given the good physical–chemical profile of these salts, our results show a notable effect on the multicomponent crystal design, manufacturability, and processing of the drug ABZ.