Thermodynamic Ideality Research Articles

Designing type V deep eutectic solvents with antimalarial pharmaceutical ingredients

This work studies the formation of deep eutectic solvents formed by one active pharmaceutical ingredient (quinine, pyrimethamine, or 2-phenylimidazopyridine) and a second component potentially acting as an excipient (betaine, choline chloride, tetramethylammonium chloride, thymol, menthol, gallic acid, vanillin, acetovanillone, 4-hydroxybenzaldehyde, syringaldehyde, propyl gallate, propylparaben, or butylated hydroxyanisole), aiming to address challenges regarding drug solubility, bioavailability, and permeability. A preliminary screening was carried out using the thermodynamic model COSMO-RS, narrowing down the search to three promising excipients (thymol, propyl gallate, and butylated hydroxyanisole). Nine solid–liquid equilibrium (SLE) phase diagrams were experimentally measured combining the three model drugs with the screened excipients, and using a combination of a visual melting method and differential scanning calorimetry. Negative deviations from thermodynamic ideality were observed in all nine systems. Furthermore, a total of four new cocrystals were found, with powder and single crystal X-ray diffraction techniques being employed to verify their unique diffraction patterns. In the thermodynamic modelling of the SLE diagrams, two COSMO-RS parametrizations (TZVP and TZVPD-FINE) were also applied, though neither consistently delivered a better description over the other.

Diffusion in multicomponent mixed solvent electrolyte systems

Thermodynamic ideality is often assumed in diffusion calculation, implying concentrations are assumed equal to the activities with activity coefficients of one. A general set of diffusion flux and molar flux equations are developed, incorporating equilibrium thermodynamic models for non-ideal conditions in well-known non-equilibrium diffusion theory. Derivations are based on the Maxwell-Stefan friction theory with the chemical potential as the driving force. Isothermal and isobaric conditions are assumed, and the theory does not include the Soret coefficient or the Onsager formalism.In this work, Fick's law is derived from the general diffusion theory, also as a function of activity gradients. The results illustrate that concentration cannot just be substituted by activity. Using a similar approach demonstrates that the Nernst-Planck (NP) equation may be derived from the general theory incorporating terms for migration and convection. An extended NP equation is derived including the thermodynamic correction factors (TCF) to account for the non-ideality of the liquid. The derived equation shows the improvement of the self-diffusion terms and friction coefficients in the NP equation and that the TCF enhances the observed effective diffusivities.Examples of TCF are presented using the extended UNIQUAC thermodynamic model. This is done for the CO2-NaOH-monoethyleneglycol-water system, which is typically found in wet natural gas pipeline CO2 corrosion systems. pH-stabilization is classically used in the prevention of corrosion, but the results show that glycol has a noticeable effect of the diffusion on key components in the corrosion mechanism. A TCF of 0.4 to 1.3 may be expected. This indicates that the flux calculation deviates up to 60 % from the real-life scenario if ideality is assumed. The thermodynamic model may therefore improve the diffusion calculations considerably.

Solute dynamics of a hydrophobic molecule in a menthol-thymol based type-V deep eutectic solvent: effect of composition of the components.

Type-V deep eutectic solvents (DESs) are a newly emerging unique class of solvents obtained by physical mixing and heating of non-ionic components. These solvents show deviation from the thermodynamic ideality. Compared to type-I to IV DESs, type-V DESs are less explored and their physical chemistry is in its nascent stage. In this work, we have chosen a type-V DES based on menthol-thymol (MT) for our working media. Solvent and rotational dynamics were studied with varying temperature using a well-known solvatochromic probe, Coumarin 153 (C153). We prepared the MT-based DES using a reported procedure at three molar ratios: 1 : 1 (M1T1), 1 : 1.5 (M1T1.5), and 2 : 1 (M2T1) of menthol (M) and thymol (T). Time-resolved emission spectra (TRES) were constructed with varying temperature. Utilizing TRES, the decay of the solvent correlation function (C(t)) was plotted. We have correlated the solvent relaxation time in these DESs as a function of viscosity. The time-resolved anisotropy decays were also collected to perceive the rotational relaxation dynamics of C153 as a function of temperature. The decay of solvent relaxation was found to be bi-exponential, and the average solvation time (〈τs〉) in M2T1 was found to be longer than those of M1T1.5 and M1T1. The rotational reorientation times (〈τrot〉) also follow the same trend. We have analysed the rotational dynamics of C153 in type-V DESs employing the Stokes-Einstein-Debye (SED) hydrodynamic model. The rotational dynamics in DESs demonstrate a good correlation with the SED model with a little deviation. In MT-based DESs, the solute's rotational relaxation times approach hydrodynamic stick boundary condition at low viscosity (or at high temperatures) for all molar compositions. Using the Arrhenius-type equations, we have correlated the activation energies for the rotational motion of C153, along with the viscous flow and non-radiative pathways for all the DESs.

Phenol-cyclohexanol eutectic mixtures: Phase diagram and microscopic structure by experimental and computational studies

• Non ionic eutectic solvents: phenol-cyclohexanol mixture. • SLE phase diagram by DSC experiment. • Microscopic structure and hydrogen bonding by IR spectroscopy, X-ray diffraction and theoretical calculations. Non ionic deep eutectic solvents (type V) have been recently proposed as innovative and alternative solvents. Prepared by mixing the starting components, their mixtures show strong deviations from thermodynamic ideality. An example of deep eutectic solvent is the 1:1 thymol-menthol mixture: deviations from ideality are originated from the strength of the hydrogen bond between different components. With the aim to investigate the role of hydrogen bonding in the non-ideality of mixtures of phenolic and alcoholic compounds, we studied the phase diagram and the structural properties of cyclohexanol and phenol mixtures coupling experimental and computational techniques. The phase diagram was measured by differential scanning calorimetry (DSC) providing a lowest melting point at about -35°C . The microscopic structure of eutectic composition was characterized by infrared spectroscopy (FT-IR), DFT and classical molecular dynamic simulations. The X-ray pattern was compared with MD results with the aim to describe the intermolecular interactions between phenol and cyclohexanol. The deviations from ideal mixing seem to be smaller than those observed for the 1:1 thymol-menthol mixture. The nature of intermolecular interactions in the phenol-cyclohexanol system has been compared with that of the thymol-menthol system by quantum chemistry calculations. In both the systems heteroassociation is energetically preferred to homoassociation because hydrogen bonding is stronger between different components, however van der Waals contributions involving alkyl groups can play an additional and significant role in the intermolecular association of the thymol-menthol system.

Hard-Soft Interactions in Solvent Extraction with Basic Extractants: Comparing Zinc and Cadmium Halides.

Solvent extraction is often applied to separate and purify metals on an industrial scale. Nevertheless, solvent extraction processes are challenging to develop because of the complex chemistry involved. For basic extractants, much of the chemical behavior remains poorly understood due to the conditions far from thermodynamic ideality. To elucidate the extraction mechanism, we studied the speciation and extraction of zinc(II) and cadmium(II) from chloride, bromide, and iodide media by using a basic extractant consisting of a trioctylmethylammonium cation and, respectively, a chloride, bromide, or iodide anion. These systems were specifically selected to increase the understanding of the less-studied bromide and iodide media and to focus on the effect of hard–soft interactions on solvent extraction systems. It was observed that, in general, a metal is more efficiently extracted when its hydration in the aqueous phase is lower and its stabilization in the organic phase is higher. In the investigated systems, these conditions are obtained by forming metal complexes with a lower charge density by coordinating the right number of halide anions and by selecting a halide with a lower charge density. In the organic phase, the stability of the metal complex can be increased by forming strong metal–anion bonds and by decreasing the water content. These insights might be of interest in the development and optimization of separation schemes for metals.

Solid-liquid phase behavior of eutectic solvents containing sugar alcohols

Mixtures of carbohydrates are often reported in the literature as deep eutectic solvents yet, in most cases, their solid–liquid phase diagrams are poorly characterized and no evidence is available to validate this classification. In this work, the phase diagrams of the binary systems composed of the sugar alcohols mannitol or maltitol and meso-erythritol, xylitol, or sorbitol, were experimentally determined. The results obtained reveal that these systems have a thermodynamic ideal behavior, questioning their classification as deep eutectic solvents and showing that intermolecular hydrogen bonding between the components of a mixture is not a sufficient condition to prepare deep eutectic solvents.The phase diagrams of the systems composed of mannitol or maltitol and cholinium chloride were also measured in this work. In sharp contrast to the mixtures composed solely by sugar alcohols, and unlike numerous other choline-based eutectic systems reported in the literature, these systems revealed significant deviations to thermodynamic ideality, leading to significant melting temperature depressions. The Cl-OH interaction between cholinium chloride and the sugar alcohols is identified as the main reason for these deviations to ideality, paving the way for the rational choice of hydrogen bond acceptors to prepare deep eutectic solvents.

The role of ionic vs. non-ionic excipients in APIs-based eutectic systems

Aiming to contribute to drug pre-formulation, new eutectic mixtures were developed. Thymol, coumarin, or quaternary ammonium chlorides as excipients, were combined with the active pharmaceutical ingredients (APIs) acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen, or lidocaine. Their solid-liquid equilibrium (SLE) binary phase diagrams were measured to study eventual phase separation between the compounds, preventing manufacturing problems, and to study the molecular interactions between the APIs and ionic or non-ionic excipients. The Conductor-like Screening Model for Real Solvents (COSMO-RS) capability to predict the SLE of mixtures containing non-ionic excipients was further evaluated. COSMO-RS gives a good quantitative description of the experimental SLE being a tool with great potential in the screening of eutectic systems containing APIs and non-ionic excipients. While thymol presents strong interactions with the APIs, and consequently negative deviations to thermodynamic ideality, systems containing coumarin follow a quasi-ideal behavior. Regarding the ionic excipients, both choline chloride and the tetraalkylammonium chlorides are unable to establish relevant interactions with the APIs, and no significant negative deviations to ideality are observed. The liquefaction of the APIs here studied is favored by using non-ionic excipients, such as thymol, due to the strong interactions it can establish with the APIs.

Liquefying Compounds by Forming Deep Eutectic Solvents: A Case Study for Organic Acids and Alcohols.

The criterion to distinguish a simple eutectic mixture from a deep eutectic solvent (DES) lies in the deviations to thermodynamic ideality presented by the components in the system. In this work, the current knowledge of the molecular interactions in types III and V DES is explored to liquefy a set of three fatty acids and three fatty alcohols, here used as model compounds for carboxyl and hydroxyl containing solid compounds. This work shows that thymol, a stronger than usual hydrogen bond donor, is able to form deep eutectic solvents of type V with the fatty alcohols studied. This is particularly interesting, since these DES formed are hydrophobic. Regarding type III DES, the results suggest that the prototypical DES hydrogen bond acceptor, cholinium chloride, is unable to induce negative deviations to ideality in the model molecules studied. By substituting choline with tetramethylammonium chloride, it is shown that the choline hydroxyl group is responsible for the difficulty in forming choline-based deep eutectic solvents and that its absence induces strong negative deviations to ideality in the alkylammonium side. Finally, it is demonstrated that tetrabutylammonium chloride acts as a chloride donning agent, causing significant negative deviations to ideality in both fatty acids and alcohols and leading to the formation of deep eutectic solvents of type III.

Methanol-ethanol “ideal” mixtures as a test ground for the computation of Kirkwood-Buff integrals

Mixtures of 1-alkanols are a textbook example of the concept of ideal mixtures. Yet, such mixtures have a very strong local order due to the hydrogen bonding interactions, with a strong tendency for chain formation. Despite this apparent non-ideality, the Kirkwood-Buff integrals of such system exhibit near ideal behavior. This dual property can be used to test the calculations of the Kirkwood-Buff integrals in a controlled mixing situation, and clarify many points, in particular the statistical problems that can be encountered. By studying the methanol-ethanol mixtures, we uncover an interesting physical asymmetry between low methanol and low ethanol concentrations, which can produce statistical artifacts in the calculation of Kirkwood-Buff integrals, illustrating and exemplifying some of the difficulties encountered in such calculations. Finally, liquid state integral equations results for these mixtures are reported. They help demonstrate that thermodynamic ideality hides complex correlations and microscopic non-ideality.

Evaluation of the grand-canonical partition function using expanded Wang-Landau simulations. V. Impact of an electric field on the thermodynamic properties and ideality contours of water.

Using molecular simulation, we assess the impact of an electric field on the properties of water, modeled with the SPC/E potential, over a wide range of states and conditions. Electric fields of the order of 0.1 V/Å and beyond are found to have a significant impact on the grand-canonical partition function of water, resulting in shifts in the chemical potential at the vapor-liquid coexistence of up to 20%. This, in turn, leads to an increase in the critical temperatures by close to 7% for a field of 0.2 V/Å, to lower vapor pressures, and to much larger entropies of vaporization (by up to 35%). We interpret these results in terms of the greater density change at the transition and of the increased structural order resulting from the applied field. The thermodynamics of compressed liquids and of supercritical water are also analyzed over a wide range of pressures, leading to the determination of the Zeno line and of the curve of ideal enthalpy that span the supercritical region of the phase diagram. Rescaling the phase diagrams obtained for the different field strengths by their respective critical properties allows us to draw a correspondence between these systems for fields of up to 0.2 V/Å.

Minimization of the Surface Area of a Radiating Cooler of Spacecraft NPP with a Combined Energy Conversion System

The possibility of reducing the surface area of the radiating cooler of a spacecraft NPP with direct energy conversion by transformation of the shed heat by means of machine converters (heat engines and heat pumps) operating in a direct or reverse thermodynamic cycle. It is shown that heat engines and heat pumps used as low-temperature attachments to a direct-conversion setup can reduce the specific surface area of a radiating cooler with a definite combination of thermodynamic ideality indices of direct and machine converters. The regions of expedient use of heat engines and heat pumps are determined.

Second-Order Derivatives of the Gibbs Energy for Liquid Mixtures of Alcohol + Heptane at Pressures up to 100 MPa

Second-order thermodynamic derivative properties, such as isobaric thermal molar expansions, isothermal and adiabatic molar compressibilities, and isochoric molar heat capacities of (ethanol, decan-1-ol, 2-methyl-2-butanol) + heptane mixtures at pressures up to 100 MPa and in the temperature range from 293.15 K to 318.15 K were derived from experimental speed-of-sound u(T, p), density ρ(T, p = 0.1 MPa), and isobaric heat-capacity Cp(T, p = 0.1 MPa) data using appropriate thermodynamic relations. Excess values for the given properties were calculated according to the criterion of thermodynamic ideality of a mixture (Douheret et al., Chem. Phys. Chem. 2, 148 (2001)), i.e., assuming that the chemical potential of component i in the ideal liquid mixture is equal to the chemical potential of component i in the mixture of perfect gases. The deviations from ideality for the mixtures under test have been explained in terms of the self-association of alcohols in solution which produces a strong departure from random mixing, the change in the non-specific interactions during mixing, and the packing effects.

Description of partition equilibria for uranyl nitrate, nitric acid and water extracted by tributyl phosphate in dodecane

Experiments were carried out on the partitioning of uranyl nitrate in nitric acid solution extracted by 30 vol.% of tributyl phosphate (TBP) in dodecane at 25 °C. The model proposed by Naganawa and Tachimori ( Bull. Chem. Soc. Jap. 70, 809, (1997)) for the case of aqueous solutions of nitric acid was used to additionally describe the extraction equilibria of uranyl nitrate. The treatment is based on the assumption of thermodynamic ideality for the organic solution composed of the diluent, the free extractant and the complexes. The stoichiometries of the metal complexes were determined one by one by a suitable procedure. The formation of 6 different complexes involving uranyl nitrate was found capable of representing the partition equilibria for the three extracted compounds: nitric acid, water and uranyl nitrate. This approach suggests the formation of 2:1 and 3:1 complexes for TBP and uranyl nitrate, respectively.

Solution calorimetric investigation of fluor-chlorapatite crystalline solutions

Solution calorimetric measurements have been made on 17 synthetic fluorapatite-chlorapatite crystalline solutions at 50 °C in 20.0 wt% HCl under isoperibolic conditions. Analysis of the calorimetric data indicates that heats of mixing across the series may reach values as high as 8.3 kJ/mol. Normally such a high degree of thermodynamic nonideality would be associated with immiscibility, yet no such miscibility gap is indicated by either synthetic or natural fluor-chlorapatite specimens. Based on full chemical analyses, all Cl-rich samples (X Cl > 0.65) of this study have halogen deficiencies that imply the presence of 4-11 mol% vacancies in the anion sites, which are interpreted to be associated with oxyapatite substitution. Separate analysis of data for the vacancy-free samples produces a linear fit for enthalpy of solution vs. composition, which yields an alternative interpretation of thermodynamic ideality. Together these models define the limits of enthalpy behavior for the fluor-chlorapatite system.

Interdiffusion in ternary Fe–Cr –Al alloys with variable molar volume

For interdiffusion profiles obtained at 1000ºC in the Fe-rich corner of the ternary system Fe –Cr – Al the evaluation of these profiles with the method proposed by Dayananda and Sohn in 1999 has been performed. Further, an alternative mathematical model is presented which directly yields element mobilities and Kirkendall velocities from experiments if the Gibbs free energy of the system is given as a function of composition, temperature and pressure. Computer simulations show that, interestingly enough, already fairly weak deviations from (thermodynamic) ideality will lead to pronounced up-hill diffusion effects for the majority component, i.e. Fe.

Thermochemistry of jarosite-alunite and natrojarosite-natroalunite solid solutions

The thermochemistry of jarosite-alunite and natrojarosite-natroalunite solid solutions was investigated. Members of these series were either coprecipitated or synthesized hydrothermally and were characterized by XRD, FTIR, electron microprobe analysis, ICP-MS, and thermal analysis. Partial alkali substitution and vacancies on the Fe/Al sites were observed in all cases, and the solids studied can be described by the general formula K 1-x-yNa y(H 3O) xFe zAl w(SO 4) 2(OH) 6–3(3-z-w)(H 2O) 3(3-z-w). A strong preferential incorporation of Fe over Al in the jarosite/alunite structure was observed. Heats of formation from the elements, ΔH° f, were determined by high-temperature oxide melt solution calorimetry. The solid solutions deviate slightly from thermodynamic ideality by exhibiting positive enthalpies of mixing in the range 0 to +11 kJ/mol. The heats of formation of the end members of both solid solutions were derived. The values ΔH° f = −3773.6 ± 9.4 kJ/mol, ΔH° f = −4912.2 ± 24.2 kJ/mol, ΔH° f = −3734.6 ± 9.7 kJ/mol and ΔH° f = −4979.7 ± 7.5kJ/mol were found for K 0.85(H 3O) 0.15Fe 2.5(SO 4) 2(OH) 4.5(H 2O) 1.5, K 0.85(H 3O) 0.15Al 2.5(SO 4) 2(OH) 4.5(H 2O) 1.5, Na 0.7(H 3O) 0.3Fe 2.7(SO 4) 2(OH) 5.1(H 2O) 0.9, and Na 0.7(H 3O) 0.3Al 2.7(SO 4) 2(OH) 5.1(H 2O) 0.9 respectively. To our knowledge, this is the first experimentally-based report of ΔH° f for such nonstoichiometric alunite and natroalunite samples. These thermodynamic data should prove helpful to study, under given conditions, the partitioning of Fe and Al between the solids and aqueous solution.

The effect of multicomponent diffusion on NAPL dissolution from spherical ternary mixtures

This paper investigates the dissolution characteristics of ternary nonaqueous phase liquid (NAPL) mixtures with the goal of comparing the relative contributions of multicomponent (intra-NAPL) diffusion, film transfer and thermodynamic nonideality. These contributions are compared at the pore scale and intermediate scale (several centimeters downstream from the source). Trichloroethene (TCE), tetrachloroethene (PCE) and 1,1,1-trichloroethane (TCA) were selected to model a reasonably ideal mixture; TCE, PCE and octanol were selected as a relevant nonideal mixture. A multicomponent diffusion-based dissolution model incorporating hydrodynamic theory was formulated to estimate intra-NAPL concentration gradients and associated aqueous interfacial concentrations for ideally shaped (spherical) NAPL blobs. Pore scale dissolution times for this model were compared to those generated using the conventional well-mixed NAPL dissolution model, applying the same film transfer boundary condition in both cases. Activity coefficients (spatially and temporally variable for the diffusion model, temporally variable for the well-mixed model) were estimated using UNIFAC. NAPL interfacial concentration histories generated using the pore scale models were used as input in a three-dimensional groundwater transport model (MT3DMS) to compare downstream concentration distributions. For the relatively large NAPL bodies simulated ( r=0.6 cm), intra-NAPL diffusion effects were found to be significant at the pore scale and were strongly impacted by the mixture's thermodynamic ideality. At the intermediate scale, and for the conditions tested, modest differences in the simulations suggested that intra-NAPL diffusion effects would be negligible compared to those associated with mixture composition uncertainty, dissolution rate processes related to NAPL-induced permeability effects and hydrodynamic issues associated with flow field heterogeneity.

Relations between interdiffusivities and intrinsic diffusivities in ternary and quaternary alloys

It is known that a reduction in the number of independent interdiffusivities and intrinsic diffusivities is possible if thermodynamic ideality of the (ternary) alloy is assumed or if the off-diagonal phenomenological coefficients are ignored. In the present letter we present a new analysis which shows generally, and exactly, that a reduction in the number of independent interdiffusivities and intrinsic diffusivities is always possible for ternary and higher alloys. In the general case, thermodynamic activities are also required.

Effects of inert volume-excluding macromolecules on protein fiber formation. I. Equilibrium models

The equilibrium Oosawa–Asakura model for nucleated assembly of rod-like protein fibers is recast in terms of dimensionless (scaled) quantities. The model is then generalized to treat arbitrarily large deviations from thermodynamic ideality arising from high fractional volume occupancy by an inert protein or polymer. Each state of association of the self-associating protein is modeled as an equivalent rigid convex particle (sphere or spherocylinder) and the crowding species is modeled either as an equivalent sphere or cylindrical rod. The resulting conservation of mass relation is readily solved to yield the fractional abundance of monomer, from which the entire equilibrium distribution of oligomeric species can be calculated, either directly or through the use of an additional scaling relationship. Results indicating the potential effect of volume occupancy on the equilibrium solubility of the self-associating protein and upon the equilibrium distribution of polymer size are presented. It is found that the fractional (logarithmic) change in both solubility and in the breadth of the polymer size distribution scale almost linearly with the fractional (logarithmic) change in the thermodynamic activity of monomer.

Structure and mucoadhesion of mussel glue protein in dilute solution.

Purified mussel adhesive protein mefp-1 (Mytilus edulis foot protein 1) has been studied regarding its state of oligomerization and gross conformation in dilute solution. Sedimentation equilibrium in the analytical ultracentrifuge of a dilute solution of protein (0.4 mg/mL) in acetate buffer at pH 4.5 and I = 0.10 M yielded an apparent molecular weight (whole distribution weight average, Mw, app) of 114 000 +/- 5000 via the "M" procedure, a value in almost exact agreement with the monomeric molecular weight obtained by MALDI mass spectrometry. At this low concentration, it is reasonable to assume thermodynamic ideality, i.e., Mw,app approximately Mw. This result, together with plots of point weight average apparent molecular weight versus concentration for three different loading concentrations (0.4, 0.8, 1.0 mg/mL), clearly demonstrates that this protein is essentially monomeric in dilute solution. Sedimentation velocity experiments yielded an estimate of the sedimentation coefficient s020,w = 2.34 +/- 0.17 S, which for M = 110 000 gives a frictional ratio f/f0 = 3.2 +/- 0.3. The interpretation of this, in terms of an extended rather than globular conformation for the structure of mefp-1 in dilute solution, is considered, within plausible limits of molecular hydration, and models for the structure in solution are considered, in light of the thermodynamic nonideality behavior of these molecules and previously published circular dichroism data. The significance of these observations in terms of the bioadhesive properties of mefp-1 is described, and the very strong interaction in dilute solution with a mucin glycoprotein is demonstrated.