The objective of this work was to access thymol-excipient compatibility using an alternative protocol of mixture design subsidizing the development of nanostructures lipid carriers containing this drug. Simultaneous DTA-TG analyses associated with infrared spectroscopy were performed according to simplex centroid mixture designs with three components. Two designs were used: the design A containing stearic acid (SA), soybean lecithin (LC), and sodium taurodeoxycholate (TAU) and the design B, where TAU was replaced by polysorbate 80 (P80). Assays allowed for a quantitative evaluation of thermal events involved with thymol (TML) – melting and evaporation –, as well as events related to excipients decomposition and overall system stability. Although the anionic surfactant TAU did not interact with TML in solid state, chemical and physical stability were compromised after drug melting. Alternatively, nonionic surfactant P80 could be a good excipient option, as TML formulation stability was not influenced by it. Fatty acid SA did not compromise TML stability alone, but, when in combination with other formulation components, negative interaction leading to a possible decomposition of the system was observed. Finally, phospholipid LC solubilizes TML extending its evaporation to higher temperatures; hence, drug stability may be increased. In conclusion, the use of mixture design in the evaluation of multicomponent systems is a valuable tool for identification of synergistic effects of excipients, providing more complete information on formulation development. In addition, the association of techniques employed allowed inferring with certainty if thermal interactions could compromise formulation stability.