Decoding the interplay between protic ionic liquids and drug: spectrophotometric, electrochemical, and DFT exploration of mitoxantrone

Abstract

Thus far, ILs have attracted growing interest in pharmaceutical applications due to their systematic variation of physicochemical properties that can be tailored to overcome the relevant formulation hurdles associated with poorly soluble and unstable drugs. Beyond solvents, ILs could serve as media for stabilization or even as co-excipients to provide a versatile matrix for enhanced drug performance with decreased side effects. Although most anthracycline antibiotics, such as daunomycin and adriamycin, are cardiotoxic, others, such as mitoxantrone (MTX), are effective and less cardiotoxic. Because it has a planar tricyclic chromophore, MTX, with its protonated side chains, could potentially be involved in dynamic noncovalent interactions, particularly at the level of nucleic acids. In this work, we investigated the molecular interactions of MTX with three protic ILs, namely, ethanol ammonium acetate (EAAc), ethanol ammonium butyrate (EABu), and ethanol ammonium hexanoate (EAHx), using a combination of various techniques including spectroscopic, electrochemical and computational methods. In the UV-visible spectrum, the hypochromic effects observed with the addition of ILs indicate changes in the electronic environment around MTX. The corresponding fluorescence measurements demonstrated enhanced emission intensity with the formation of stable MTX–IL aggregates. Electrochemical studies unambiguously demonstrated an apparent effect of ionic liquid's alkyl chain length on binding affinity, with EAHx displaying the strongest interaction, as evidenced by the higher binding constants and lower Gibbs free energy changes. The experimental results were further supported by density functional theory calculations, indicating an enhancement in the thermodynamic stability and electrostatic complementarity of the MTX–EAHx complex. This combined evidence highlights protic ionic liquids as potential excipients for enhancing the solubility, stability and delivery efficiency of mitoxantrone, with potential for the formulation of safer and more efficient IL-assisted formulations against cancer.