Molecular Relaxations in Supercooled Liquid and Glassy States of Amorphous Quinidine: Dielectric Spectroscopy and Density Functional Theory Approaches

Abstract

In this article, we conduct a comprehensive molecular relaxation study of amorphous Quinidine above and below the glass-transition temperature (Tg) through broadband dielectric relaxation spectroscopy (BDS) experiments and theoretical density functional theory (DFT) calculations, as one major issue with the amorphous state of pharmaceuticals is life expectancy. These techniques enabled us to determine what kind of molecular motions are responsible, or not, for the devitrification of Quinidine. Parameters describing the complex molecular dynamics of amorphous Quinidine, such as Tg, the width of the α relaxation (βKWW), the temperature dependence of α-relaxation times (τα), the fragility index (m), and the apparent activation energy of secondary γ relaxation (Ea-γ), were characterized. Above Tg (> 60 °C), a medium degree of nonexponentiality (βKWW = 0.5) was evidenced. An intermediate value of the fragility index (m = 86) enabled us to consider Quinidine as a glass former of medium fragility. Below Tg (< 60 °C), one well-defined secondary γ relaxation, with an apparent activation energy of Ea-γ = 53.8 kJ/mol, was reported. From theoretical DFT calculations, we identified the most reactive part of Quinidine moieties through exploration of the potential energy surface. We evidenced that the clearly visible γ process has an intramolecular origin coming from the rotation of the CH(OH)C9H14N end group. An excess wing observed in amorphous Quinidine was found to be an unresolved Johari-Goldstein relaxation. These studies were supplemented by sub-Tg experimental evaluations of the life expectancy of amorphous Quinidine by X-ray powder diffraction and differential scanning calorimetry. We show that the difference between Tg and the onset temperature for crystallization, Tc, which is 30 K, is sufficiently large to avoid recrystallization of amorphous Quinidine during 16 months of storage under ambient conditions.

Acoustic Anomalies and Fast Relaxation Dynamics of Amorphous Progesterone as Revealed by Brillouin Light Scattering

“…Considering the typical value β ~ 0.3 for amorphous polymers [ 16 ], the activation energy E A may be deduced to be 11 kJ/mol. This value is similar to the activation barrier for the hydroxyl or methyl group rotations [ 34 ]. This result clearly shows that the change in the damping behavior in the sub- T g region is attributed to side group rotations instead of single-molecule rotations or conformational change.…”

Molecular Mobility of an Amorphous Chiral Pharmaceutical Compound: Impact of Chirality and Chemical Purity

“…A perspective of this work would consist in conducting theoretical density functional theory (DFT) calculations in order to gain insights into the origin of these secondary relaxations. 30 From the best fits of entire dielectric spectra obtained both in the liquid and glassy states of purified racemic and enantiopure DPL samples, the temperature dependences for all dielectric processes were determined and are presented in Figure 9.…”

“…18−23 The fundamental mechanisms related to the physical instability of amorphous single components remain considerably unexplained, and the scientific community tries to identify the physical factors governing the shelf life (i.e., recrystallization behavior) of noncrystalline pharmaceuticals. Among reported studies devoted to this issue, various internal factors have been outlined: mobility and molecular motions, 6,24−33 primary and secondary relaxations, 30,31,34,35 fragility, 36,37 density, 38 interfacial energy, 39 structures, 40 etc. However, experimental (i.e., external) conditions such as thermal history, 41 surface effects, 42,43 relative humidity, 44,45 defects or cracks, 46,47 and the amorphization itself 34,48−50 seem to impact the process of recrystallization from an amorphous state.…”

“…The access to the amorphous form of an API is of high concern as the dissolution properties and bioavailability are significantly higher than in crystalline form. − Nevertheless, the glassy state of an API might exhibit a poor physical stability that could be tricky for industrial process and/or scale-up. − In recent years, various studies were devoted to the improvement of the physical stability of the amorphous state by using multicomponent systems such as solid dispersions, i.e., involving an API and polymer − or a coamorphous drug. − The fundamental mechanisms related to the physical instability of amorphous single components remain considerably unexplained, and the scientific community tries to identify the physical factors governing the shelf life (i.e., recrystallization behavior) of noncrystalline pharmaceuticals. Among reported studies devoted to this issue, various internal factors have been outlined: mobility and molecular motions, ,− primary and secondary relaxations, ,,, fragility, , density, interfacial energy, structures, etc. However, experimental (i.e., external) conditions such as thermal history, surface effects, , relative humidity, , defects or cracks, , and the amorphization itself ,− seem to impact the process of recrystallization from an amorphous state.…”

Investigation of Drug–Excipient Interactions in Biclotymol Amorphous Solid Dispersions

“…Accurate temperature control was implemented using the Quatro system (Novocontrol Technologies), allowing a temperature stability of ±0.2 °C. Amorphous solid dispersions were analyzed using high-quality interdigitated electrodes from Novocontrol Technologies (sensor diameter 20 mm, gold-plated copper combs) as previously outlined in other papers. − …”