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

Abstract

The impact of low water concentration of strongly hydrogen-bonded water molecules on the dynamical properties of amorphous terfenadine (TFD) is investigated through complementary molecular dynamics (MD) simulations and dielectric relaxation spectroscopy (DRS) experiments. In this article, we especially highlight the important role played by some residual water molecules in the concentration of 1−2% (w/w) trapped in the TFD glassy matrix, which are particularly difficult to remove experimentally without a specific heating/drying process. From MD computations and analyses of the hydrogen bonding (HB) interactions, different categories of water molecules are revealed and particularly the presence of strongly HB water molecules. These latter localize themselves in small pockets in empty spaces existing in between the TFD molecules due to the poor packing of the glassy state and preferentially interact with the polar groups close to the flexible central part of the TFD molecules. We present a simple model which rationalizes at the molecular scale the effect of these strongly HB water molecules on dynamics and how they give rise to a supplementary relaxation process (namely process S) which is detected for the first time in the glassy state of TFD annealed at room temperature while this process is completely absent in a non-annealed glass. It also explains how this supplementary relaxation is coupled with the intramolecular motion (namely process γ) of the very flexible central part of the TFD molecule. The present findings help to understand more generally the microscopic origin of the secondary relaxations often detected by DRS in the glassy states of molecular compounds for which the exact nature is still debated.

Detecting Crystallinity Using Terahertz Spectroscopy in 3D Printed Amorphous Solid Dispersions

“…Low concentrations of water (less than 2% w/w) in the formulation can be detected with THz spectroscopy. 35 There is a decreasing absorption coefficient after 300 K for all formulations except for sample 1 (crystalline mixture), showing that all formulations except sample 1 contain water in the system and the formulations contain amorphous material. The more amorphous the formulation is the higher degree of absorption coefficient drop observed in the samples.…”

“…Therefore, when water is removed from the system, the absorption coefficient is decreased. Low concentrations of water (less than 2% w/w) in the formulation can be detected with THz spectroscopy . There is a decreasing absorption coefficient after 300 K for all formulations except for sample 1 (crystalline mixture), showing that all formulations except sample 1 contain water in the system and the formulations contain amorphous material.…”

Dielectric Spectroscopy Studies of Conformational Relaxation Dynamics in Molecular Glass-Forming Liquids

“…Hydrogen-bonding (HB) interactions [21,22] may hinder or slow down intramolecular relaxations; at the same time, they may lead to time-fluctuating HB clusters [23] that can contribute specific dielectric relaxations, such as the Debye relaxation of monoalcohols [24] or the water-induced relaxations in hydrated systems [25]. For example, no intramolecular relaxation is reported in dielectric spectroscopy studies of several alcohols, including 1-propanol [26,27], phenylpropanol [28], and 5-methyl-2-hexanol [27,29,30].…”