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Pharmaceutical salts of fenbendazole with organic counterions: Structural analysis and solubility performance

DOI: 10.1021/acs.cgd.1c00413 DOI Help

Authors: Artem O. Surov (G.A. Krestov Institute of Solution Chemistry RAS) , Nikita A. Vasilev (G.A. Krestov Institute of Solution Chemistry RAS) , Mikhail V. Vener (G.A. Krestov Institute of Solution Chemistry RAS) , Olga D. Parashchuk (Lomonosov Moscow State University) , Andrei V. Churakov (Institute of General and Inorganic Chemistry RAS) , Oxana V. Magdysyuk (Diamond Light Source) , German L. Perlovich (G.A. Krestov Institute of Solution Chemistry RAS)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Crystal Growth & Design , VOL 32

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 26476

Abstract: In this work, three new pharmaceutical salts of fenbendazole (FNB), a benzimidazole-based anthelmintic drug, with sulfonic acids have been obtained and thoroughly investigated by different analytical techniques, including thermal methods, infrared/Raman spectroscopy, and theoretical methods (periodic DFT computations and Bader analyses of the crystalline electronic density). Single-crystal and high-resolution synchrotron powder X-ray diffraction data for the first time made it possible to determine the crystal structures of mesylate and tosylate salts of the drug, which were further validated by dispersion-corrected density functional theory calculations. All the solid forms were stabilized by a robust R22(8) supramolecular motif formed by relatively strong N–H···O hydrogen bonds. In the monohydrate of FNB tosylate, a considerable gain in the stabilization energy was due to the intermolecular interactions generated by the water molecules. A careful examination of the solubility–pH profile of the FNB salts revealed that, despite being thermodynamically unstable within the physiologically relevant pH range, the new solid forms demonstrated superior dissolution performance in terms of both the apparent solubility and the release rate in comparison to the parent drug. Since FNB has also been reported to possess anticancer activity, improving the drug’s poor physicochemical properties through salt formation with the selected sulfonic acids is expected to promote further investigations toward repurposing of this potent compound.

Journal Keywords: Crystals; Salts; Crystal structure; Diffraction; Solubility

Subject Areas: Chemistry, Medicine

Instruments: I12-JEEP: Joint Engineering, Environmental and Processing

Added On: 02/07/2021 14:26

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Cancer Drug Discovery Non-Communicable Diseases Chemistry

Technical Tags:

Diffraction X-ray Powder Diffraction