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

Abstract

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 −2 to 10 9 Hz) and temperature (300 K) range highlights the fragile nature of this good glass-former (m = 112) and the relatively large nonexponentiality of the main relaxation (β KWW = 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.

Impact of Low Concentration of Strongly Hydrogen-Bonded Water Molecules on the Dynamics of Amorphous Terfenadine: Insights from Molecular Dynamics Simulations and Dielectric Relaxation Spectroscopy

“…Regarding the γ-relaxation, the log τ max values extracted from the Cole–Cole fit are close to the evolution of the relaxation time obtained for the non-annealed glass by Dudognon and et al (log τ ∞ = −14.1 ± 0.1 and E a = 40 ± 1 kJ mol –1 ) (cf. Figure S3).…”

“…It is very intense and characterized by a shoulder on the high-frequency side that can be seen especially at the lowest temperatures. For comparison, some dielectric spectra of a freshly obtained glass recorded in the same temperature range are also reported in Figure (open symbols) . It can be seen that this relaxation mode does not appear on the dielectric spectra of non-annealed glass.…”

“…TFD melting point is found at T m = 425 K . It can be vitrified by quenching from the melt, and the glass-transition temperature reported in the literature is T g = 327–332 K with a heating rate of 10 K min –1 . , …”

“…Calorimetric studies of TFD have shown the existence of two polymorphic forms I and II with melting temperatures T mI = 424.1 K and T m II = 416.5 K, respectively, but others forms are suspected. , Details about the crystalline structure of the two forms are lacking. The molecular mobility of TFD has been recently investigated by Dudognon et al by means of DRS experiments and MD simulations . TFD was shown to be a good glass former ( T g = 330 K) with fragile nature ( m = 112), which also has the advantage to be easily vitrified by different amorphization routes including melt-quenching or milling. , However, it was evidenced that these two routes of preparation weakly influence its dynamics .…”

“…The molecular mobility of TFD has been recently investigated by Dudognon et al by means of DRS experiments and MD simulations . TFD was shown to be a good glass former ( T g = 330 K) with fragile nature ( m = 112), which also has the advantage to be easily vitrified by different amorphization routes including melt-quenching or milling. , However, it was evidenced that these two routes of preparation weakly influence its dynamics . TFD is a hydrophobic molecule with solubility in water equal to 10.2 μg mL –1 , and consequently, the interactions between TFD and water are poorly documented.…”