Tuning molecular dynamics by hydration and confinement: antiplasticizing effect of water in hydrated prilocaine nanoclusters.

In glass-forming substances, the addition of water tends to produce the effect of lowering the glass transition temperature, Tg. In a previous work by some of us (Ruiz et al., Sci. Rep., 2017, 7, 7470) we reported on a rare anti-plasticizing effect of water on the molecular dynamics of a simple molecular system, the pharmaceutically active prilocaine molecule, for which the addition of water leads to an increase of Tg. In the present work, we study pure and hydrated prilocaine confined in 0.5 nm and 1 nm pore size molecular sieves, and carry out a comparison with the bulk compounds in order to gain a better understanding of the microscopic mechanisms that result in this rare effect. We find that the Tg of the drug under nanometric confinement can be lower than the bulk value by as much as 17 K. Through the concurrent use of differential scanning calorimetry and broadband dielectric spectroscopy we are able to observe the antiplasticizing effect of water in prilocaine also under nanometric confinement, finding an increase of Tg of up to almost 6 K upon hydration. The extension of our analysis to nanoconfined systems provides a plausible explanation for the very uncommon antiplasticizing effect, based on the formation of water-prilocaine molecular complexes. Moreover, this study deepens the understanding of the behavior of drugs under confinement, which is of relevance not only from a fundamental point of view, but also for practical applications such as drug delivery.

Reply to the 'Comment on "On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility" Phys. Chem. Chem. Phys., 2018, 20, DOI: '.

In his comment on a recent publication by us, G. Graziano claims that solubility differences of indole in methanol and water can be rationalized by the reversible work needed to create a cavity in the solvent of the size of the solute, in this case indole. This quantity, he argues, is closely related to the solvent accessible surface area, which is greater for methanol compared with water, thus making indole more soluble in the former solvent. G. Graziano asserts that it is this property which is responsible for the large difference between the solubilities of indole in methanol and water. Further, G. Graziano claims that the differences in excess entropies and in distance distribution functions of indole in methanol and water and in methanol and water as a cosolvent found in our original work (Henao, et al., Phys. Chem. Chem. Phys., 2016, 18, 23006) are too "small" to be able to account for the differences in solubility of the indole molecule. We show in this work that the differences found by us are not small, by displaying some selected distance distribution functions in an alternative way to that described in our original paper. In fact we conclude that the differences in these functions are quantitatively greater than those found by Graziano in his comment. Secondly, we show in this reply that although the increase of the solvent accessible surface area may rationalize the differences in the indole-methanol and indole-water binary systems, and thus the work required for cavity creation, it is insufficient to fully account for the increase of indole solubility in water by the addition of very small quantities of methanol in the ternary system indole-methanol-water. In other words, as stated in our original paper, methanol is actively changing the solvation shell and not just passively increasing the solvent accessible surface area around indole. As a result of these additional analyses, we conclude that our work on the solvation differences of indole in water and methanol successfully captures differences in the solvation shells of both solvents around indole in both binary and ternary systems. Finally, while we do agree that Graziano's calculations are able to capture the role of cavity creation to explain differences in solubility, we think that our results concerning the quantification of changes in molecular interaction should be added to the calculations suggested by him to lead to a full description of the solubility.

On the microscopic mechanism behind the purely orientational disorder-disorder transition in the plastic phase of 1-chloroadamantane.

Globular molecules of 1-chloroadamantane form a plastic phase in which the molecules rotate in a restrained way, but with their centers of mass forming a crystalline ordered lattice. Plastic phases can be regarded as test cases for the study of disordered phases since, contrary to what happens in the liquid phase, there is a lack of stochastic translational degrees of freedom. When the temperature is increased, a hump in the specific heat curve is observed indicating a change in the energetic footprint of the dynamics of the molecules. This change takes place without a change in the symmetry of the crystalline lattice, i.e. no first-order transition is observed between temperatures below and above the calorimetric hump. This implies that subtle changes in the dynamics of the disordered plastic phase concerning purely orientational degrees of freedom should appear at the thermodynamic anomaly. Accordingly, we describe, for the first time, the microscopic mechanisms behind a disorder-disorder transition through the analysis of neutron diffraction and QENS experiments. The results evince a change in the molecular rotational dynamics accompanied by a continuous change in density.

Thermodynamic and Kinetic Fragility of Freon 113: The Most Fragile Plastic Crystal.

We present a dynamic and thermodynamic study of the orientational glass former Freon 113 (1,1,2-trichloro-1,2,2-trifluoroethane, CCl_{2}F-CClF_{2}) in order to analyze its kinetic and thermodynamic fragilities. Freon 113 displays internal molecular degrees of freedom that promote a complex energy landscape. Experimental specific heat and its microscopic origin, the vibrational density of states from inelastic neutron scattering, together with the orientational dynamics obtained by means of dielectric spectroscopy have revealed the highest fragility value, both thermodynamic and kinetic, found for this orientational glass former. The excess in both Debye-reduced specific heat and density of states (boson peak) evidences the existence of glassy low-energy excitations. We demonstrate that early proposed correlations between the boson peak and the Debye specific heat value are elusive as revealed by the clear counterexample of the studied case.

Implanted muon spin spectroscopy on 2-O-adamantane: a model system that mimics the liquid[Formula: see text]glasslike transitions.

The transition taking place between two metastable phases in 2-O-adamantane, namely the [Formula: see text] cubic, rotator phase and the lower temperature P21/c, Z = 4 substitutionally disordered crystal is studied by means of muon spin rotation and relaxation techniques. Measurements carried out under zero, weak transverse and longitudinal fields reveal a temperature dependence of the relaxation parameters strikingly similar to those exhibited by structural glass[Formula: see text]liquid transitions (Bermejo et al 2004 Phys. Rev. B 70 214202; Cabrillo et al 2003 Phys. Rev. B 67 184201). The observed behaviour manifests itself as a square root singularity in the relaxation rates pointing towards some critical temperature which for amorphous systems is located some tens of degrees above that shown as the characteristic transition temperature if studied by thermodynamic means. The implications of such findings in the context of current theoretical approaches concerning the canonical liquid-glass transition are discussed.

Thermal properties of halogen-ethane glassy crystals: Effects of orientational disorder and the role of internal molecular degrees of freedom.

The thermal conductivity, specific heat, and specific volume of the orientational glass former 1,1,2-trichloro-1,2,2-trifluoroethane (CCl2F-CClF2, F-113) have been measured under equilibrium pressure within the low-temperature range, showing thermodynamic anomalies at ca. 120, 72, and 20 K. The results are discussed together with those pertaining to the structurally related 1,1,2,2-tetrachloro-1,2-difluoroethane (CCl2F-CCl2F, F-112), which also shows anomalies at 130, 90, and 60 K. The rich phase behavior of these compounds can be accounted for by the interplay between several of their degrees of freedom. The arrest of the degrees of freedom corresponding to the internal molecular rotation, responsible for the existence of two energetically distinct isomers, and the overall molecular orientation, source of the characteristic orientational disorder of plastic phases, can explain the anomalies at higher and intermediate temperatures, respectively. The soft-potential model has been used as the framework to describe the thermal properties at low temperatures. We show that the low-temperature anomaly of the compounds corresponds to a secondary relaxation, which can be associated with the appearance of Umklapp processes, i.e., anharmonic phonon-phonon scattering, that dominate thermal transport in that temperature range.

Glassy Dynamics versus Thermodynamics: The Case of 2-Adamantanone.

The heat capacity and thermal conductivity of the monoclinic and the fully ordered orthorhombic phases of 2-adamantanone (C10H14O) have been measured for temperatures between 2 and 150 K. The heat capacities for both phases are shown to be strikingly close regardless of the site disorder present in the monoclinic crystal which arises from the occupancy of three nonequivalent sites for the oxygen atom. The heat capacity curves are also well accounted for by an evaluation carried out within the harmonic approximation in terms of the g(ω) vibrational frequency distributions measured by means of inelastic neutron scattering. Such spectral functions show however a significant excess of low frequency modes for the crystal showing statistical disorder. In contrast, large differences are found for the thermal conductivity which contrary to what could be expected, shows the substitutionally disordered crystal to exhibit better heat transport properties than the fully ordered orthorhombic phase. Such an anomalous behavior is understood from examination of the crystalline structure of the orthorhombic phase which leads to very strong scattering of heat-carrying phonons due to grain boundary effects able to yield a largely reduced value of the conductivity as well as to a plateau-like feature at intermediate temperatures which contrasts with a bell-shaped maximum shown by data pertaining the disordered crystal. The relevance of the present findings within the context of glassy dynamics of the orientational glass state is finally discussed.

A continuous mixture of two different dimers in liquid water.

It is hitherto thought that liquid water is composed of tetrahedrally coordinated molecules with an asymmetric interaction of the central molecule with neighboring molecules. Kühne et al., Nat. Commun., 2013, 4, 1450 suggested that this asymmetry, energetic rather than geometric, is the cornerstone to reconcile the homogeneous and inhomogeneous viewpoints of liquid water. In order to investigate the geometric origin of that asymmetry, we have scrutinized Molecular Dynamics (MD) simulations of water through a careful analysis of the five-dimensional probability distribution function of Euler angles in which the relative positions and orientations of water molecules are obtained. We demonstrate that, beyond the ubiquitous tetrahedral structure with well-defined molecular dimers, there is a series of possible molecular orientations that define the structure. These orientations are generated by rotating the neighboring molecule around the O-H axis that is involved in the hydrogen bond scheme. Two of the possible orientations have a higher probability, giving rise to two kinds of dimers: one close to the lowest energy of a water dimer in vacuum with an almost perpendicular alignment of the dipole moment, and another one with a parallel orientation of the dipole moment which is less tightly bound. These two different dimers have an effect on the orientation of further water dipole moments up to a distance of ≈6 Å. Liquid water can therefore be described as a continuous mixture of two kinds of dimers where the hydrogen bonds have the same geometry but the interaction energies are different due to a different mutual orientation of the dipoles of the participating water molecules.

Insights into the determination of molecular structure from diffraction data using a Bayesian algorithm.

The determination of the molecular ordering in a liquid is still a controversial subject. There is no general consensus either on the methods to obtain reliable liquid structures or on the way to analyze them. Regardless of the method, it is very important to have a realistic molecular structure available that allows simulations to faithfully reproduce the sample features, and that minimizes the computing time in structure refinements. However, attention is not always paid to this point and molecular models coming from general force-fields are frequently used to undertake many of the analyses. We propose in this work to use a Bayesian scheme to fit the experimental data and produce reliable molecular models that can be used as the starting point of any simulation or refinement. The algorithm behind the proposed method is based on a Markov chain Monte Carlo procedure, as many other refinement programs such as reverse Monte Carlo or empirical potential structure refinement.

Dynamic heterogeneity in the glass-like monoclinic phases of CBr(n)Cl(4-n), n = 0,1,2.

Glassy dynamics of rigid molecules is still a matter of controversy: the physics behind the relaxation process at time scales faster than that ruled by the viscosity, the so called Johari-Goldstein process, is not known. In this work we unravel the mechanism of such a process by using a simple molecular model in which the centers of mass of the molecules are forming an ordered lattice, and molecular reorientation is performed by jumps between equilibrium orientations. We have studied the dynamics of simple quasi-tetrahedral molecules CBr(n)Cl(4-n), n = 0, 1, 2, in their monoclinic phases by means of dielectric spectroscopy and nuclear quadrupole resonance: the first technique allows to measure in a broad time scale but it is insensitive to molecular particularities, while the second has a restricted time window but senses the movement of each chlorine atom separately. The dynamic picture emerging from these techniques is that the secondary relaxation process is related to the different molecular surroundings around each nonequivalent atom of the molecule. Dynamical heterogeneities thus seem to be the cause of the secondary relaxation in this simple model of glass.

Differences in first neighbor orientation behind the anomalies in the low and high density trans-1,2-dichloroethene liquid.

Trans-1,2-dichloroethene (HClC=CClH) has several structural and dynamic anomalies between its low- and high-density liquid, previously found through neutron scattering experiments. To explain the microscopic origin of the differences found in those experiments, a series of molecular dynamics simulations were performed. The analysis of molecular short-range order shows that the number of molecules in the first neighbor shell is 12 for the high-density liquid and 11 for the low-density one. It also shows that the angular position of the center of mass of the first neighbor is roughly the same although the molecular orientation is not. In both liquids the first neighbor and its reference molecule arrange mainly in two configurations, each being the most probable in one of the liquids. First neighbors in the configuration that predominates in the high-density liquid tend to locate themselves closer to the reference molecule, an evidence that they are more strongly bonded. This arrangement facilitates a better packing of the rest of molecules in the first neighbor shell so that on average an additional molecule can be included, and is proposed to be the key in the explanation of all the observed anomalies in the characteristics of both liquids.

Fitting in a complex χ(2) landscape using an optimized hypersurface sampling.

Fitting a data set with a parametrized model can be seen geometrically as finding the global minimum of the χ(2) hypersurface, depending on a set of parameters {P(i)}. This is usually done using the Levenberg-Marquardt algorithm. The main drawback of this algorithm is that despite its fast convergence, it can get stuck if the parameters are not initialized close to the final solution. We propose a modification of the Metropolis algorithm introducing a parameter step tuning that optimizes the sampling of parameter space. The ability of the parameter tuning algorithm together with simulated annealing to find the global χ(2) hypersurface minimum, jumping across χ(2){P(i)} barriers when necessary, is demonstrated with synthetic functions and with real data.

Alpha-relaxation dynamics of orientanionally disordered mixed crystals composed of Cl-adamantane and CN-adamantane.

The alpha-relaxation dynamics of 1-cyano-adamantane (CNA) and its mixtures with 1-chloro-adamantane (ClA) has been studied by means of broadband dielectric spectroscopy. The existence of orientationally disordered (OD) face centered cubic mixed crystals (ClA(1-X)CNA(X)) for 0.5 < or = X < or = 1 has been put in evidence by thermodynamics and structural analyses. In addition to the OD phase of CNA, mixed crystals with compositions higher than the equimolar one exhibit a freezing of the orientational degrees of freedom into a glassy state, which involves also a strong increase of the antiferroelectric order at temperatures higher than the dielectric glass transition temperature. This experimental evidence is revealed by a stairlike effect in the variation of the Kirkwood factor with the temperature as a consequence of a twin effect in the dielectric strength without any anomaly in the temperature-density curves. The characteristic relaxation times are analyzed as a function of temperature and mole fraction. By setting a common temporal origin ("isochronal origin") at tau(T(g)) = 100 s for each mole fraction, it emerges that the substitution of ClA molecules by those of CNA (diminution of X) gives rise to a slow down in the dynamics, despite that the molecular volume of ClA molecules are smaller than those of CNA. This fact goes along and is accompanied by a diminution of the lattice packing with the decrease of composition. It is also shown that the heterogeneities produced by the concentration fluctuations due to the chemical disorder are the main contribution to the non-exponential character of the alpha-relaxation peaks.

Scaling the dynamics of orientationally disordered mixed crystals.

The evolution of the primary relaxation time of orientationally disordered (OD) mixed crystals [(CH(3))(2)C(CH(2)OH)(2)](1-X)[(CH(3))C(CH(2)OH)(3)](X), with 0 < X < or = 0.5, on approaching the glass temperature (T(g)) is discussed. The application of the distortion-sensitive, derivative-based procedure revealed a limited adequacy of the Vogel-Fulcher-Tammann parametrization and a superiority of the critical-like description tau proportional to (T - T(C))(-phi(') ), phi(') = 9-11.5, and T(C) approximately T(g) - 10 K. Basing on these results as well as that of Drozd-Rzoska et al. [J. Chem. Phys. 129, 184509 (2008)] the question arises whether such behavior may be suggested as the optimal universal pattern for dynamics in vitrifying OD crystals (plastic crystals). The obtained behavior is in fair agreement with the dynamic scaling model (DSM) [R. H. Colby, Phys. Rev. E 61, 1783 (2000)], originally proposed for vitrifying molecular liquids and polymers. The application of DSM made it possible to estimate the size of the cooperatively rearranging regions ("heterogeneities") in OD phases near T(g).

New microscopic mechanism for secondary relaxation in glasses.

The dynamics of simple molecular systems showing glassy properties has been explored by dielectric spectroscopy and nuclear quadrupole resonance (NQR) on the halogenomethanes CBr2Cl2 and CBrCl3 in their low-temperature monoclinic phases. The dielectric spectra display features which correspond to alpha- and beta-relaxation processes, commonly observed in canonical glass formers. NQR experiments, also performed in the ergodic monoclinic phase of CCl4, enable the determination of the microscopic mechanism underlying the beta dynamics in these simple model glasses: Molecules that are nonequivalent with respect to their molecular environment perform reorientational jumps at different time scales. Thus our findings reveal another mechanism that can give rise to typical beta-relaxation behavior, raising some doubt about the existence of a universal explanation of this phenomenon.

Broadband dielectric spectroscopy on benzophenone: alpha relaxation, beta relaxation, and mode coupling theory.

We have performed a detailed dielectric investigation of the relaxational dynamics of glass-forming benzophenone. Our measurements cover a broad frequency range of 0.1 Hz to 120 GHz and temperatures from far below the glass temperature well up into the region of the small-viscosity liquid. With respect to the alpha relaxation this material can be characterized as a typical molecular glass former with rather high fragility. A good agreement of the alpha relaxation behavior with the predictions of the mode coupling theory of the glass transition is stated. In addition, at temperatures below and in the vicinity of T(g) we detect a well-pronounced beta relaxation of Johari-Goldstein type, which with increasing temperature develops into an excess wing. We compare our results to literature data from optical Kerr effect and depolarized light scattering experiments, where an excess-wing-like feature was observed in the 1-100 GHz region. We address the question if the Cole-Cole peak, which was invoked to describe the optical Kerr effect data within the framework of the mode coupling theory, has any relation to the canonical beta relaxation detected by dielectric spectroscopy.

Dielectric spectroscopy in benzophenone: the beta relaxation and its relation to the mode-coupling Cole-Cole peak.

We report a thorough characterization of the glassy dynamics of benzophenone by broadband dielectric spectroscopy. We detect a well-pronounced beta relaxation peak developing into an excess wing with increasing temperature. A previous analysis of results from Optical-Kerr-effect measurements of this material within the mode-coupling theory revealed a high-frequency Cole-Cole peak. We address the question if this phenomenon also may explain the Johari-Goldstein beta relaxation, a so-far unexplained spectral feature inherent to glass-forming matter, mainly observed in dielectric spectra. Our results demonstrate that according to the present status of theory, both spectral features seem not to be directly related.

Two-component system CCl4 + (CH3)3CBr: extrema in equilibria involving orientationally disordered phases.

Phase equilibria involving orientationally disordered (OD) and liquid phases of the two-component system between carbon tetrachloride (CCl4) and 2-methyl-2-bromomethane ((CH3)3CBr) have been determined by means of X-ray powder diffraction and thermal analysis techniques from 210 K up to the liquid state. The isomorphism relation between the OD stable face-centered cubic (FCC) phase of (CH3)3CBr and the metastable FCC phase of CCl4 has been demonstrated throughout the continuous evolution of the lattice parameters and the existence of the two-phase equilibrium [FCC + L] for the whole range of composition, despite the monotropy of the FCC phase for the CCl4 component with respect to its OD rhombohedral (R) stable phase. A continuous series of OD R mixed crystals is found, which confirms the R lattice symmetry of the OD phase II of (CH3)3CBr, for which the crystallographic results have been long-time misinterpreted. X-ray patterns of such a phase were indexed according to the recent single-crystal results obtained by Rudman (Rudman, R. J. Mol. Struct. 2001, 569, 157). In addition, some experimental evidences are given to confirm the number of molecules per unit cell (Z = 21). The thermodynamic assessment reproduces coherently the phase diagram for the stable [R + L] and [R + FCC] two-phase equilibria as well as for the partially metastable [FCC + L] two-phase equilibrium and provides a set of data for the thermodynamic properties of nonexperimentally available phase transitions of pure components. Surprisingly, the phase equilibrium involving R and FCC OD phases appears as one of the very few showing a solid-solid equilibrium with two extremes.

Alpha and beta relaxation dynamics of a fragile plastic crystal.

We present a thorough dielectric investigation of the relaxation dynamics of plastic crystalline Freon112, which exhibits freezing of the orientational degrees of freedom into a glassy crystal below 90 K. Among other plastic crystals, Freon112 stands out by being relatively fragile within Angell's [Relaxations in Complex Systems, edited by K. L. Ngai and G. B. Wright (NRL, Washington, DC, 1985), p. 3] classification scheme and by showing an unusually strong beta relaxation. Comparing the results to those on Freon112a, having only a single molecular conformation, points to the importance of the presence of two molecular conformations in Freon112 for the explanation of its unusual properties.

Direct experimental assessment of the strength of orientational correlations in polar liquids.

The strength of molecular orientational correlations in polar liquids is assessed by means of comparison of the diffuse scattering patterns of a liquid composed by molecules devoid of permanent electric dipole but having a weak quadrupole moment and those for a liquid composed by permanent molecular dipoles. The extent of orientational correlations within the liquid phases is in both cases assessed by comparison of the liquid radial distributions to those present in the rotator-phase (plastic) crystal phases of both compounds. For such disordered-crystal phases, information concerning orientational correlations is directly derived from the experimental scattering patterns by means of analysis of the diffuse scattering background present beneath the Bragg peaks. The results show that rather than long-ranged, orientational correlations in polar or polarizable liquids are confined within distances comprising the second coordination sphere.