Unraveling hydrogen bond interactions between ketoconazole and imidazolium-based ionic liquids: An experimental and theoretical study

The solubility and solvation mechanism of the Biopharmaceutical Classification System class II insoluble drug, ketoconazole (KCZ), were investigated in eight different types of imidazolium-based ionic liquids (ILs). An in vitro cytotoxicity test was conducted on Human immortalized keratinocytes cells to evaluate the potential toxicity of these ILs. The results showed no cytotoxicity for any of the imidazolium-based ILs tested. The solubility of KCZ was then examined in the eight imidazolium-based ILs at temperatures ranging from 298.15 K to 338.15 K. The findings revealed that the solubility of KCZ followed a specific order among the imidazolium-based ILs tested. The imidazolium-based IL [BMIM][Tf2N] exhibited the highest solubility of KCZ, followed by [HMIM][PF6], [EMIM][Tf2N], [BMIM][TfO], [BMIM][PF6], [EMIM][TfO], [BMIM][BF4], and [EMIM][BF4] in decreasing order. To understand the interaction mechanism between the imidazolium-based ILs and KCZ, the cations, anions and KCZ were analyzed using sigma-profiles computed from both the COSMO-RS model and quantum chemical calculations. The results indicated that KCZ had strong hydrogen bond (HB) acceptors, particularly the oxygen atom of the carbonyl group and the nitrogen atom of the imidazole ring. These HB acceptors contributed to the formation of stronger HBs with the hydrogen atoms of cations compared to the oxygen atoms of the anions. The trend of HB strength followed [Emim](+) > [Bmim](+) > [Hmim](+) > [Tf2N](-) > [TfO](-) > [PF6](-) > [BF4](-). Based on these findings, it can be concluded that [BMIM][Tf2N], which has a strong HB donor cation and a strong HB acceptor anion, displayed the most effective dissolution of KCZ.