Cocrystal formation of niclosamide and urea in supercritical CO2 and impact of cosolvent

Abstract

A cocrystal of niclosamide and urea was attempted for the first time using a crystallization in supercritical solvent (CSS). Experiments were conducted at 40 °C or 60 °C between 3.3 and 29.4 MPa in CO₂. Cocrystal formation showed a dependence on the state of CO₂ with no cocrystal formation below the critical point and consistently showed partial conversion above the critical point. The addition of 0.5 mL (2.7–3.5 mol%) cosolvent was found to have significant impact on cocrystal formation at 40 °C and 20 MPa. Addition of 2-propanol increased cocrystal formation by between 50 % and 60 % compared to neat scCO₂, while cyclohexane reduced cocrystal formation by between 20 % and 35 %, and water completely hindered cocrystal formation. The impact of hold time, cosolvent, solubility in relation to ternary phase diagrams, and inter- and intra-molecular hydrogen bonding are discussed.