Molecular Mobility of Terfenadine: Investigation by Dielectric Relaxation Spectroscopy and Molecular Dynamics Simulation.

The molecular mobility of an amorphous active pharmaceutical ingredient, terfenadine, was carefully investigated by dielectric relaxation spectroscopy and molecular dynamics simulation for the first time. Comprehensive characterization on a wide frequency (10 to 10 Hz) and temperature (300 K) range highlights the fragile nature of this good glass-former ( = 112) and the relatively large nonexponentiality of the main relaxation (β = 0.53 ± 0.01). In the glassy state, a particularly broad secondary relaxation of intramolecular origin is evidenced. Terfenadine is a flexible molecule, and from molecular dynamics simulation, a clear link is established between the flexibility of the central part of the molecule (carrying, on the one side, the nitrogen group, and on the other side, the OH group) and the distribution of dipole moments, which explains that broadness. Terfenadine is one of the very few cases for which the molecular mobility of the glass obtained by the quench of the melt or by milling can be compared. From the present study, no major difference in terms of molecular mobility is found between these two glasses. However, terfenadine amorphized by milling (for 1-20 h) clearly shows a lower stability than the quenched liquid as we observed its recrystallization upon heating. Interestingly, it is shown that this recrystallization upon heating is not complete and that the 1-2% of the remaining amorphous phase has an original behavior. Indeed, it exhibits an enhanced main mobility induced by an autoconfinement effect created by the surrounding crystalline phase.