Estimating thermodynamic equilibrium solubility and solute-solvent interactions of niclosamide in eight mono-solvents...

Niclosamide is an FDA-approved oral anthelmintic drug currently being repurposed for COVID-19 infection. Its interesting applicability in multiple therapeutic indications has sparked interest in this drug/ scaffold. Despite its therapeutic use for several years, its detailed solubility information from Chemistry Manufacturing & Controls perspective is unavailable. Thus, the present study is intended to determine the mole fraction solubility of niclosamide in commonly used solvents and cosolvents at a temperature range of 298.15-323.15 K. The polymorphic changes from crystalline to monohydrate forms post-equilibration in various solvents were observed. The maximum mole fraction solubility of niclosamide at 323.15 K is 1.103 × 10^-3 in PEG400, followed by PEG200 (5.272 × 10^-4), 1-butanol (3.047 × 10^-4), 2-propanol (2.42 × 10^-4), ethanol (1.66 × 10^-4), DMSO (1.52 × 10^-4), methanol (7.78 × 10^-5) and water (3.27 × 10^-7). The molecular electrostatic potential showed a linear correlation with the solubility. PEG400 has higher electrostatic potential, and H-bond acceptor count, which forms a hydrogen bond with phenolic -OH of niclosamide and thus enhances its solubility. This data is valuable for the drug discovery and development teams working on the medicinal chemistry and process chemistry of this scaffold.