The Effect of pH and Cocrystal Quercetin-Isonicotinamide on Quercetin Solubility and its Thermodynamic

This study aimed to improve the solubility of quercetin by solvent pH control method and crystal modification through co-crystal formation using isonicotinamide as its co-former. Solubility of quercetin was tested at nine pH levels using phosphate buffer solvents. Quercetin-isonicotinamide co-crystal was prepared by a solvent evaporation method. Co-crystal preparation was carried out using two different stoichiometric ratios of quercetin-isonicotinamide (1:1 and 1:3). The co-crystalline solubility test was performed in 50 mL citrate buffer (pH 5.0 ± 0.05) at a temperature of 37 ± 0.5C. The thermodynamic parameters of quercetin and co-crystal were analyzed to determine the mechanism of the quercetin solubility process. Increasing the pH of solvents has proven to increase the solubility of quercetin. The quercetin oxidation reaction starts at pH level of 7.4. The formation of quercetin-isonicotinamide co-crystal at ratio of 1:1 and 1:3 shows the increase of quercetin solubility by 1.36 and 1.27 times, respectively. The thermodynamic parameters of the quercetin and quercetinco-crystal, which include entropy, enthalpy, and free energy values, can be used to explain the solubility process of quercetin. Quercetin has increased solubility under alkaline pH conditions, but undergoes an oxidation reaction at pH 7.4 and easily oxidized at alkaline pH. Crystal modification of quercetin by the co-crystal formation method has proven to increase the solubility of quercetin so that it can be used for the development of quercetin as a candidate for effective, safe, and acceptable active pharmaceutical ingredient.