Genuine antiplasticizing effect of water on a glass-former drug

Abstract

Water is the most important plasticizer of biological and organic hydrophilic materials, which generally exhibit enhanced mechanical softness and molecular mobility upon hydration. The enhancement of the molecular dynamics upon mixing with water, which in glass-forming systems implies a lower glass transition temperature (T _g ), is considered a universal result of hydration. In fact, even in the cases where hydration or humidification of an organic glass-forming sample result in stiffer mechanical properties, the molecular mobility of the sample almost always increases with increasing water content, and its T _g decreases correspondingly. Here, we present an experimental report of a genuine antiplasticizing effect of water on the molecular dynamics of a small-molecule glass former. In detail, we show that addition of water to prilocaine, an active pharmaceutical ingredient, has the same effect as that of an applied pressure, namely, a decrease in mobility and an increase of T _g . We assign the antiplasticizing effect to the formation of prilocaine-H ₂ O dimers or complexes with enhanced hydrogen bonding interactions.

Figure 1

Effect of water on the glass transition temperature. (a) DSC scans for different water molar fractions x of binary prilocaine/water mixtures, measured upon heating at 8 K/min right after aging during 1 hour at 215.2 K. Inset: molecular structure of prilocaine. (b) Onset T _g values for prilocaine as a function of water concentration (data corresponding to the thermograms in (a)). (c) Normalized glass transition temperatures for binary water-solute systems. Prilocaine: this work. T _g values for other systems are described with the Gordon-Taylor equation (see Supplementary information) based on the T _g values reported for sorbitol and for phospholipids DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and DOPE (1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine). The corresponding parameters of the Gordon-Taylor equation are provided in Table S1 of the Supplementary information.

Figure 2

Effect of water and pressure on the temperature-dependent relaxation dynamics of prilocaine. (a,c) Comparison of the ambient-pressure dielectric loss spectra of hydrated and pure prilocaine at 243 K (a), and of the dielectric loss spectra at 240.5 K of pure prilocaine at ambient (1 bar) and high (1000 bar) pressure (c). Continuous lines are fits. Insets: same data in ac conductivity representation. (b,d) Arrhenius plot of the primary relaxation times τ of pure and hydrated prilocaine (b) at ambient pressure, and of pure prilocaine at 1000 bar (d). Continuous lines are fits with the Vogel-Fulcher-Tammann Eq. 1.

Figure 3

Ionic dc conduction in pure and hydrated prilocaine. Arrhenius plots of the dc conductivity σ _dc for pure prilocaine at 1 and 1000 bars, together with that of hydrated prilocaine at 1 bar. Inset: logarithmic Walden plot (σ _dc vs τ) for the same three samples.

Figure 4

Vibrational spectra of pure and hydrated prilocaine. Attenuated total reflection infrared spectra measured at room temperature in the liquid phase (a) and Raman spectra acquired at 220 K on the glass (b), between 1605 and 1745 cm ⁻¹ (left panels) and between 3200 and 3400 cm ⁻¹ (right panels). Besides the spectra of pure and hydrated prilocaine, the spectra of a diluted prilocaine solution in water (liquid L ₂) are also shown for comparison.