Co-amorphous salts of luteolin-arginine/lysine with enhanced solubility

Co-amorphous systems, including co-amorphous and co-amorphous salts, can enhance the solubility of poorly water-soluble small molecules. It is important to identify them because co-amorphous and co-amorphous salts have different physicochemical properties. Co-amorphous system of luteolin (LUT, a well-known poorly soluble flavonoid) and amino acids at a molar ratio of 1:1 was prepared using neat ball milling. Only amorphous luteolin-arginine (LUT-Arg) and luteolin-lysine (LUT-Lys) exhibit significant solubility enhancements in the media of water and PBS. The Δ p K a rule suggests that LUT-Arg (Δ p K a , 2.8) and LUT-Lys (Δ p K a , 2.9) are close to co-amorphous salts. Diffuse reflectance spectroscopy and Raman spectroscopy confirmed that LUT-Arg and LUT-Lys are co-amorphous salts, while IR spectroscopy, the most common used method, cannot distinguish them. Comprehensive multiple characterizations (>2) are essential to confirm the formation of co-amorphous or co-amorphous salts, such as applying the Δ p K a rule, diffuse reflectance spectroscopy, and Raman spectroscopy for LUT-Arg and LUT-Lys.