Mechanosynthesis of Therapeutic Deep Eutetic Solvents

A homogeneous mixture with a melting point lower than its components, typically using noncovalent interactions, at a certain molar ratio, is called an eutectic system. Deep eutectic solvents (DES), comprising or acting as solvents of active pharmaceutical ingredients, have recently emerged as promising alternatives to improve therapeutic efficiency due to their low toxicity. In addition, no solvents and no chemical reaction are required in their formation which implies better yields and less waste production, turning DES attractive “green solvents”. Due to the numerous advantages of mechanochemistry, especial in sustainable pharmaceutical industry, in this work we explored the formation of new therapeutic DES (THEDES) prepared by ball milling. To validate the mechanochemical synthetic route, these THEDES were compared with those prepared by conventional heating. In order to access the full range of available compositions, the solid-liquid equilibrium (SLE) diagrams of three new THEDES, flavone:thymol, flavanone:thymol and chalcone:thymol, were studied. The experimental SLE phase diagrams were measured using visual turbidimetry and DSC, and the results were compared with the ideal phase diagrams. Toxicity data was also determined. The results showed a deep decrease in the melting temperature of the eutectic point compared to the ideal mixture description. Overall, this work validated mechanochemistry as an alternative synthetic route for DES preparation and demonstrated the potential of flavonoids an interesting new class of THEDES.<br /