Selection of hydrotropes for enhancing the solubility of artemisinin in aqueous solutions

Artemisinin is an antimalarial substance very sparingly soluble in water. In the attempt to identify environmental-friendly and non-toxic aqueous-based solvents to extract it from Artemisia annua L., the solubility of artemisinin in aqueous solutions of different hydrotropes was measured at 303.2 K, for hydrotrope concentrations up to 5 M. The ability of the studied hydrotropes for enhancing the artemisinin solubility increases in the following order: Na[N(CN)2] < Na[SCN] < [Chol][Van] < [Chol][Gal] < [N4,4,4,4]Cl < [Chol][Sal] < [P4,4,4,4]Cl < Na[Sal], with Na[Sal] allowing an increase in the solubility of 750 fold compared to pure water. The COSMO-RS model and experimental Kamlet-Taft solvatochromic parameters were applied to connect the solubility enhancement with solvent properties. At low hydrotrope concentration, the solubility increases with the decreasing of the difference between the Apolar Factors of the hydrotrope and artemisinin, while for higher hydrotrope concentration, the hydrogen-bond acceptor character of the hydrotrope seems to have an impact on the solubility enhancement. Even if some mechanistic understanding is still to unfold, quantitatively the empirical correlations of solubility enhancement with the hydrotrope concentration and the solvatochromic parameters show very high accuracy. In particular, 93% of the change on the artemisinin solubility enhancement could be explained using the hydrotrope concentration and two combined solvatochromic parameters (αβ and π∗2) as explaining variables.This work was developed within the scope of the projects CICECOAveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, CIMO-Mountain Research Center, UIDB/00690/2020, and Green Health (Norte-01-0145-FEDER-000042) all financed by national funds through the FCT/MEC and when appropriate co-financed by FEDER under the PT2020 and NORTE 2020 Partnership Agreement. Isabela Sales and Silvana Mattedi thanks the finantial support from CAPES and CNPq/ Brazil (CAPES: Proc. 88881.189075/2018-01 and 88887.494428/2020- 00. CNPq: Grant 303089/2019-9 and Proc.438036/2018-2).info:eu-repo/semantics/publishedVersio