Experimental and molecular modeling studies on interactions between drugs and Eudragit® RL/RS resins in aqueous environment

Abstract

In order to investigate the interaction between drugs and Eudragit® RL or Eudragit® RS resins under physiological conditions, molecular dynamics (md) simulations (AMBER-forcefield, 310 K, 50 ps) were performed on systems containing water molecules, Eudragit® molecule fragments and furosemide, indometacin, nicotinamide or etilefrine as model drug molecules. The interaction energies were monitored as well as the drug–Eudragit® distances to quantify and visualize the amount of drug binding. The nature of the calculated intermolecular interactions was examined by separate evaluation of H-bonding, ion–ion (electrostatic) and hydrophobic (van der Waals) interaction energies. It could be shown that van der Waals, electrostatic and H-bond energies may lead to a huge amount of furosemide and indometacin binding to Eudragit® RL rather than to Eudragit® RS. Nicotinamide and etilefrine showed no tendency to interact with the molecule fragments of the Eudragit® resins. The calculated results were verified by experimental determinations of the amount of drug binding to Eudragit® RL and RS in isotonic pH 7.2 buffer solution after an equilibration period of 24 h. The amounts of drug binding to Eudragit® RL were 93.1% for furosemide and 72.4% for indometacin, whereas the amounts of drug binding to Eudragit® RS were 31.4% for furosemide and 26.5% for indometacin. No drug binding to the Eudragit® resins was observed for nicotinamide and etilefrine. The experimentally obtained binding rates were in excellent agreement with the calculated binding energies. This may be interpreted as an indication for the correctness of the proposed intermolecular interaction mechanisms between the four model drugs and the Eudragit® resins in the presence of water.