Solubility determination, model correlation and preferential solvation of methyldopa in binary mixed solvents from 278.15 K to 323.15 K

As an antihypertensive drug, methyldopa (MD) plays a vital role in for clinical treatment of moderate, severe or malignant hypertension, especially for secondary hypertension, pregnancy-induced hypertension, heart failure combined with hypertension and other diseases. The solid-liquid equilibrium data of MD was determined. The four binary mixtures were composed of the mixtures of three green organic solvents (methanol, ethanol and isopropanol) + water and DMF + water in this experiment, and HPLC was used to detect the mole fraction solubility of MD (T = 278.15–323.15 K). The maximum mole fraction solubility data of MD (x = 1.35E−01) is related to pure DMF (T = 323.15 K) and the minimum value (x = 1.41E−06) is related to pure water (T = 278.15 K). When the organic solvent in the binary solvent is an alcohol solvent, the mole fraction solubility of MD is negatively correlated with the carbon chain length of the alcohol solvent and positively correlated with the polarity of the alcohol solvent. In addition, five thermodynamic models were used to validate and predict experimental data and deviation analysis, the largest mean square deviation value (RMSD) is only 9.76E−04, indicating that the experimental data has superior correlation with the five models used and the data is real and reliable. Simultaneously, the KAT model was used to analyze the effect of solvent effect on its mole fraction solubility during MD dissolution, the results are demonstrated that among multiple factors that affect solvent effects in the KAT model, the ability of the solvent to receive hydrogen bonds (α) and the size of the polarity (π^∗) promote the dissolution of MD, but the main influence on the MD solvent effect is the cavity term demonstrating the solvent-solvent molecular interaction energy, and the contribution rates of these three items to the total solvent effect are 7.92%, 16.01% and 50.16%, respectively.