Estimating thermodynamic equilibrium solubility and solute-solvent interactions of niclosamide in eight mono-solvents at different temperatures

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 x 10(-3) in PEG400, followed by PEG200 (5.272 x 10(-4)), 1-butanol (3.047 x 10(-4)), 2-propanol (2.42 x 10(-4)), ethanol (1.66 x 10(-4)), DMSO (1.52 x 10(-4)), methanol (7.78 x 10(-5)) and water (3.27 x 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. (C) 2022 Elsevier B.V. All rights reserved.