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

Abstract

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.

Pharmaceutical Salts of Fenbendazole with Organic Counterions: Structural Analysis and Solubility Performance

“…For the carbonyl group ν­(CO) vibrations of the carbamate fragment, these bands were found to be shifted to higher frequencies in the spectra of the new solid forms, indicating a decrease in the strength of the intermolecular interactions with this group in comparison to the parent FNB structure. In addition, a new weak vibration band in the 1579–1584 cm –1 region can be caused by the loss of the double-bond character by the C–N bond in the benzimidazole ring due to the compound protonation, as has also been observed for the salts of structurally related benzimidazole derivatives. ,− …”

“…Since the crystal structure of the parent FNB remains unknown, a detailed assignment of the drug IR and/or Raman spectra is not straightforward because of the tautomeric equilibrium, which is expected to exist in the compounds carrying the benzimidazole carbamate moiety. 67 However, previous investigations on structurally related benzimidazole antihelmintic agents (albendazole, 68,69 In the IR spectra of the anhydrous FNB salts, the amide and imidazole N−H stretching bands appeared shifted to lower wavenumbers (3240 cm −1 for [FNB+TSA] (1:1) and 3150 cm −1 for [FNB+MSA] (1:1)), suggesting new patterns of hydrogen bonds in these solid forms. For [FNB+TSA+H 2 O] (1:1:1), the bands centered at 3530 and 3450 cm −1 were assigned to the ν(O−H) mode of crystallization water.…”

“…Similar conclusions can be drawn regarding the recently reported salts of albendazole that also appeared to be unstable in aqueous media at low pHs. 69 The experimental solubility−pH profile was further fitted and refined using the pDISOL-X software (Rev 3.093) developed by Avdeef. 119,120 The resulting values of the apparent pK a and intrinsic solubility (S 0 ) were estimated to be 2.6 and (2.0 ± 0.1) × 10 −6 M ((6.1 ± 0.2) × 10 −4 mg/mL), respectively.…”

“…Since the crystal structure of the parent FNB remains unknown, a detailed assignment of the drug IR and/or Raman spectra is not straightforward because of the tautomeric equilibrium, which is expected to exist in the compounds carrying the benzimidazole carbamate moiety . However, previous investigations on structurally related benzimidazole antihelmintic agents (albendazole, , mebendazole, − and flubendazole) enabled a tentative assignment of the bands associated with the main chemical groups of FNB and identification of the structural changes related to the formation of new multicomponent crystals. As Figure illustrates, the intense band at 3338 cm –1 was assigned to the N–H stretching mode of the carbamate moiety, while the broad band centered at ∼2650 cm –1 most likely corresponded to the a ν­(N–H) stretch of the benzimidazole ring, in accord with the literature data. , The carbamate carbonyl stretching vibrations (CO) appeared at 1708 cm –1 , and the N–H bending and the C–N stretching modes are expected for a relatively broad band centered at 1630 cm –1 .…”

“…Therefore, the obtained FNB mesylate and tosylate are expected to be highly soluble forms, as their pH max values lie clearly beyond the physiologically relevant pH range. Similar conclusions can be drawn regarding the recently reported salts of albendazole that also appeared to be unstable in aqueous media at low pHs …”