Salts of 2-hydroxybenzylamine with improvements on solubility and stability: Virtual and experimental screening

2-Hydroxybenzylamine (2-HOBA) is a drug used to effectively treat oxidative stress. To improve its aqueous solubility and thermal stability, salt screening and synthesis was carried out. The conductor-like screening model for the real solvents model (COSMO-RS) was applied to virtual screening of coformers among 200 commonly used candidates for salification of 2-HOBA. As a result, 40 hit compounds were subjected to experimental liquid assisted grinding (LAG) with 2-HOBA, then 21 systems were characterized as new solid phases by PXRD. Nine multicomponent single crystals of 2-HOBA with succinic acid, p-aminobenzoic acid, p-nitrobenzoic acid, o-nitrobenzoic acid, p-toluic acid, 2,3-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, p-nitrophenol, and 5-hydroxyisophthalic acid were obtained and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. All of them were salts and exhibited higher decomposition temperatures compared with pure 2-HOBA. The apparent aqueous solubility of three new salts, i.e., those with succinic acid, p-aminobenzoic acid, and p-nitrophenol were higher than the equilibrium solubility of 2-HOBA. The accelerated stability test indicated that all salts show excellent stability under conditions (40 degrees C and 75% RH) for 4 weeks. Overall, this work introduced a protocol that combined the virtual screening tool based on the COSMO-RS model and the experimental LAG method to screen new salts for a target compound. The feasibility of this protocol was confirmed in the case of 2-HOBA whose new salts were successfully obtained and represented an improvement for aqueous solubility and thermal stability.