Enthalpy–Entropy Compensation in the Structure-Dependent Effect of Nonsteroidal Anti-inflammatory Drugs on the Aqueous Solubility of Diltiazem
Takatoshi Kinoshita, Chihiro Tsunoda, Satoru Goto, Kanji Hasegawa, Hitoshi Chatani, Momoko Fujita, Hikaru Kataoka, Yuta Katahara, Yohsuke Shimada, Yuta Otsuka, Kazushi Komatsu, Hiroshi Terada
Abstract
Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.