Why does the niclosamide drug form solvates or hydrates?

Abstract

Niclosamide is a well-established anthelmintic drug included in the WHO's essential list of medicines. Recently, it has been repurposed for the treatment of COVID-19. This article delves into the solvate formation of niclosamide. The anhydrous forms of niclosamide (polymorphs I and II) seem to have an adequate ratio of donor to acceptor groups and these are well utilized for hydrogen bonding with a high crystal packing index (>70%). Nevertheless, niclosamide has been shown to incorporate solvent molecules into its crystal structure. So far, two hydrate polymorphs and five solvates have been reported in the literature with their crystal structures. We noticed that niclosamide has a high tendency for solvates/hydrates over anhydrous forms in our crystallization attempts and this has prompted us to investigate the solvate formation more in detail to find out possible reasons/driving forces for it. We have observed six new solvates of niclosamide, of which two are polymorphic forms of niclosamide with N,N-dimethylacetamide (1 : 1 and 2 : 2), two are variable stoichiometry solvates with dioxan (1 : 0.5 and 2 : 1.5) and two are 1 : 1 solvates with dimethylsulfoxide and dimethylformamide solvents. Single crystal and powder X-ray diffraction measurements were carried out for deeper structural insights on how solvent molecules are accommodated in the crystals. Thermal and computational studies were carried out and correlated with the structural details to understand the influence of solvents on the crystal stability and desolvation process. Solvent molecules have played an important role in altering the hydrogen bonding pattern of niclosamide and overall molecular arrangements inside the crystal. The strength of the hydrogen bonding is found to be the key factor that is responsible for solvate formation in niclosamide. Both anhydrous forms and solvates are sustained by O–H⋯O hydrogen bonding, but the bonding is relatively stronger in solvates. As a result, niclosamide shows a higher preference for solvates over anhydrous forms despite the latter having a better packing coefficient. These results may find their applications in crystal engineering for better understanding of pharmaceutical hydrates or solvates.