IR spectra of proflavine in complex with polyethylene glycol. Quantum chemistry investigation vs experimental data

The possible existence and interactions of two tautomeric forms of proflavine dihydrochloride with polyethylene glycol (PEG) have been investigated using a combination of quantum chemistry calculations at the DFT B3LYP/6–31+G(d,p) level and experimental (IR spectroscopy) approach. The calculations have shown the energetic preference for the proflavine protonation at the nitrogen atom in the central ring (N⁺H). However, experimental investigations have not provided evidence supporting the existence of such a form in the condensed phase. At the same time, a less energetically favorable form of proflavine protonated at the peripheral amino group N⁺H₃ is clearly detected in the IR spectra. Calculations have demonstrated that the binding with polyethylene glycol is energetically favorable for both tautomeric forms of proflavine. The highest total energetic advantage occurred when the protonated amino group of proflavine (N⁺H₃) formed two hydrogen bonds with PEG. Experimental findings indicate that at a high relative content of polyethylene glycol in the mixture with proflavine, not only N⁺H₃ groups but also NH₂ groups of drug bind to the polymer. These complexes can form either within a single PEG molecule or between different polymer molecules.