The solubility of the drug substances in water is one of the major factors taken into account in the formulation of oral solutions and parenteral dosage forms. The present study was conducted to improve the solubility of acetaminophen in water by the use of phospholipids and nonionic surfactants (Tween® 80 and Solutol® 15HS). These excipients are well tolerated by the parenteral route and allow the solubilization through a micellar system. In our study, a design of experiments approach was tested using a mixture design of nonionic surfactants, phospholipids and acetaminophen. The results showed a significant increase in the solubility in all used mixtures. The analysis of the design space showed that the solubility of acetaminophen varies very closely with the concentration of the three surfactants in water and also with their association.