Modeling the solid-state vibrational spectroscopic properties of morphine-based formulations with hybrid meta density functional theory

Solid state vibrational spectroscopic properties of morphine sulphate pentahydrate were studied combining experimental and theoretical approaches. Experimental studies involved a Fourier Transform infrared spectroscopic (FT IR) study of the title compound with the attenuated total reflection (ATR) technique. From theoretical side, a detailed study of the main possible constituents of the investigated molecular crystals: neutral morphine molecule and N-protonated morphine-H+ cation was carried out, employing meta hybrid density functional theory (DFT) approach with the M06-2X exchange-correlation functional, using 6-311G(dip) basis set. Potential energy surfaces (PES) of the studied systems were explored in details, paying particular attention to the intramolecular torsional flexibility. In both cases, four stable minima on the explored PES were located. Subsequently, harmonic vibrational analyses were carried out for each minimum, with the method of diagonalization of the mass-weighted Hessian matrices. Experimental data strongly suggest the presence of hydrogen sulphate anionic species in the investigated solid phase. Accounting for the stoichiometry of the compound, it is suggested that both neutral (unprotonated) morphine along with the N-protonated morphine-H+ cation could be present in the solid state as well. The agreement between experimental and theoretical spectra in the regions of appearance of bands due to morphine (or N-protonated morphine-H+ cation) intramolecular vibrational modes is remarkable. Thus, the present theoretical calculations enable solid theoretical support to the empirical assignments of the spectral bands and the present work could serve as a starting point for further studies of spectroscopic manifestations of morphine incorporation into specific drug dosage forms.