The Role of pH in Modulating the Electronic State Properties of Minocycline Drug and Its Inclusion within Micellar Carriers

A detailed investigation of the spectral and photophysical properties of minocycline (MC) in water at different pHs, solvents of different polarity, and micellar surfactant solutions was carried out in this study. An unusual behavior was highlighted with respect to other tetracyclines due to the presence of an additional dimethylamino group in the MC molecular structure. In particular, four equilibrium constants associated with mono-deprotonation reactions were characterized by steady-state spectroscopy. Femtosecond time-resolved pump-probe and fluorescence up-conversion measurements allowed the dynamics of the lowest excited singlet state of the five different acid-base species of MC to be characterized in terms of lifetimes and transient spectra. Two emissive species associated with keto-enol tautomerism resulting from excited-state intramolecular proton transfer (ESIPT) were revealed with time constants of a few and tens of picoseconds. TD-DFT quantum mechanical calculations were also performed to define the state order and nature of the differently protonated species, together with their absorption spectra. The role of pH proved to be fundamental in modulating the drug charge and therefore the interaction with cationic micelles where the neutral form of MC, that is the biologically active one, resulted efficiently included.