Ana M. FERREIRA1,2, Ana S. PINTO1, Brayan CRUZ1, José G.p. SANTOS1, Dinis O. ABRANCHES1, Helena PASSOS1, Kosuke KURODA2, João A.p. COUTINHO1
1CICECO - Aveiro Institute of Materials, University of Aveiro, Aveiro, Portugal
2Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kanazawa, Japan
The pharmaceutical industry faces major challenges in formulating new pharmaceutical products, namely the poor solubility of oral drugs in water. The use of hydrotropes - compounds that increase the solubility of hydrophobic compounds in aqueous solutions - have been widely used to solve this problem. However, the search for new classes of more effective hydrotropes with low toxicity is crucial, and the understanding of their mechanism of action essential.
Inspired by recent developments showing that zwitterions analogous to ionic liquids (ZILs) exhibit lower cytotoxicity [1] and ecotoxicity [2], the present work investigated the use of ZILs to improve the aqueous solubility of various poorly water-soluble solutes. More specifically, different aqueous solutions of (i) sulfonate-based ZILs, (ii) carboxylate-based ZILs, and (iii) ILs analogous to ZILs were studied to enhance the solubility of four solutes: three model molecules - syringic acid, vanillic acid, pyrene, and one pharmaceutical drug - ibuprofen. The solutes were added to each hydrotrope solution up to saturation, and the mixture was kept at equilibrium for 72 hours at 30 ºC with constant shaking (1150 rpm).
Four important conclusions can be drawn from the results: (i) the longer the alkyl chain of ZILs, the higher their hydrotropic effect; (ii) the longer the spacers of ZILs, the higher their ability to increase the solubility of the solutes studied, especially for carboxylate-based ZILs; (iii) the higher hydrotropic effects are observed for the solutes more hydrophobic; and (iv) ILs are superior to their analogous ZILs in terms of hydrotropic effect for almost all solutes studied. In particular, sulfonate-based ZILs are shown to be able to increase the solubility of ibuprofen by up to 3000-fold, while carboxylate-based ZILs exhibit solubility enhancement by up to 9000-fold. On the other hand, the best ZIL and its analogous ILs (ZIL/IL pair) lead to an increase in ibuprofen solubility of 110- and 1600-fold, respectively. These results are particularly important for drug formulation because, although the ZILs have slightly lower hydrotropic behavior among the ZIL/IL pairs evaluated, they are favored by their low toxicity profile.
Acknowledgments
A.M. Ferreira acknowledges the Japan Society for the Promotion of Science (JSPS) for the postdoctoral Fellowship PE21045. H. Passos acknowledges FCT – Fundação para a Ciência e a Tecnologia, I.P. for the researcher contract CEECIND/00831/2017, under the Scientific Employment Stimulus - Individual Call 2017. This work was partly developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MCTES (PIDDAC).
References
1. Kuroda et al., Commun. Chem., 3, 163 (2020) 1-7.
2. Jesus et al., Green Chem, 10, 23, (2021) 3683.