Hydrotrope Molecules Research Articles

Temperature Dependence of Hydrotropy.

The solubility of hydrophobic solutes increases dramatically with the temperature when hydrotropes are added to water. In this paper, the mechanism of this well-known observation will be explained via statistical thermodynamics through (i) enhanced enthalpy-hydrotrope number correlation locally (around the solute) that promotes the temperature dependence and (ii) hydrotrope self-association in the bulk solution that suppresses the temperature dependence. The contribution from (i), demonstrated to be dominant for urea as a hydrotrope, signifies the weakening of interaction energies around the solute (local) than in the bulk that accompanies incoming hydrotrope molecules. Thus, studying hydrotropic solubilization along the temperature and hydrotrope concentration provides complementary information on the local-bulk difference: the local accumulation of hydrotropes around the solute, driven by the enhanced local hydrotrope self-association, is also accompanied by the overall local weakening of energetic interactions, reflecting the fluctuational nature of hydrotrope association and the mediating role of water molecules.

Interfacial properties of aqueous solutions of butanol isomers and cyclohexane

Phase behavior at water-oil and water-air interfaces has received much attention in the past sixty years. The study of detergents as surfactants and their applications to industry is widely known and under constant study. Other molecules, such as alcohols, can also act like surfactants between water and nonpolar molecules. Hydrotropes are amphiphilic molecules, with both a hydrophobic and a hydrophilic section, that also reduce the interfacial tension between two liquids or a vapor and a liquid. Tert-butyl alcohol (TBA) is a well-studied hydrotrope, but its behavior is not completely understood at low molar compositions in aqueous solution. In addition, few studies have examined the influence of different butanol isomers on the interfacial dynamics of mixtures. We used molecular dynamics to study the behavior of all four butanol isomers at the interface of water and cyclohexane. We observed a rapid decrease in surface tension at very low hydrotrope concentrations, < 1 mol% in water, in agreement with previous experimental and simulation studies. The effect of different butanol isomers on the interfacial properties between an aqueous and an organic phase was examined looking at its dependence on hydrotrope concentration and chemical structure. We characterized the position of the hydrotrope molecules at the interface using atom number density profiles, radial distribution functions, and hydroxyl tilt angles with respect to the z-axis (perpendicular to the water-cyclohexane interface). There is statistical difference on the effect of some isomers on the disruption of the interface at low hydrotrope concentrations. Our studies show the chemical structure of these molecules affects the water-oil interface in different ways, which could potentially affect the use of one isomer over the other in different applications.

Unveiling the mechanism of hydrotropy: evidence for water-mediated aggregation of hydrotropes around the solute.

A recent proposal attributes the origin of hydrotropy to the water-mediated aggregation of hydrotrope molecules around the solute. Experimental evidence for this phenomenon is reported for the first time in this work, using 1H-NMR. A new computational technique to quantify apolarity is introduced and is used to show that apolarity of both solute and hydrotrope is the driving force of hydrotropy.

Thermodynamic aggregation behaviour of p-cymene in hydrotropic solution

The paper deals with the thermodynamic properties and aggregation behaviour of p-cymene through hydrotropy. Different hydrotropes namely urea, resorcinol, sodium cumene sulfonate and pyrogallol has been used to study the solubility under a wide range of hydrotrope concentrations (0 to 3.00 mol.kg–1) and different system temperatures (303.15 to 333.15 K). The effectiveness of hydrotrope with respect to the system was measured by Setschenow constant KS and reported for all hydrotropes used in this study. The influence of different system temperatures on thermodynamic properties like standard Gibbs free energy change (ΔG°), standard enthalpy change (ΔH°) and standard entropy change (ΔS°) of solubilisation with respect to p-cymene has been ascertained. The aggregation behaviour between the solute and the hydrotrope and among the hydrotrope molecules have also been studied using step wise association model.

Thermodynamic aggregation behaviour of p-cymene in hydrotropic solution

The paper deals with the thermodynamic properties and aggregation behaviour of p-cymene through hydrotropy. Different hydrotropes namely urea, resorcinol, sodium cumene sulfonate and pyrogallol has been used to study the solubility under a wide range of hydrotrope concentrations (0 to 3.00 mol.kg–1) and different system temperatures (303.15 to 333.15 K). The effectiveness of hydrotrope with respect to the system was measured by Setschenow constant KS and reported for all hydrotropes used in this study. The influence of different system temperatures on thermodynamic properties like standard Gibbs free energy change (ΔG°), standard enthalpy change (ΔH°) and standard entropy change (ΔS°) of solubilisation with respect to p-cymene has been ascertained. The aggregation behaviour between the solute and the hydrotrope and among the hydrotrope molecules have also been studied using step wise association model.

Hydrotropic Solubilization of Sparingly Soluble Riboflavin Drug Molecule in Aqueous Nicotinamide Solution.

We study the effect of hydrotrope nicotinamide on the solubilization of sparingly soluble riboflavin drug molecule. Nicotinamide molecules self-associate through stacking of their pyridine rings, and they also form complexes with riboflavin molecules. Water molecules only prefer to stay at the periphery of the riboflavin molecules, and they are replaced by the hydrotrope molecules with increasing concentration of the solution. The analyses of orientation distributions and distance measurements reveal that the riboflavin and nicotinamide molecules form 1:2 sandwich complexes. It is demonstrated that the self-aggregation of nicotinamide and the complexation between riboflavin and nicotinamide does not have much influence on the number of water-water average hydrogen bonds but they influence the riboflavin-water, nicotinamide-water, riboflavin-riboflavin, riboflavin-nicotinamide, and nicotinamide-nicotinamide hydrogen bonds. Favorable van der Waals interaction energy between riboflavin and nicotinamide plays an important role in the 1:1 or 1:2 complex formation between drug and hydrotrope molecules. The electrostatic energy component of drug and hydrotrope interaction also contributes to the solubilization process. The negative Flory-Huggins interaction parameter value suggests the favorable interactions between the hydrotrope and drug molecules.

Solution properties of phenothiazine drug promazine hydrochloride with cationic hydrotropes in aqueous/electrolyte solution at different temperature

The current work deals with the mixed micellization phenomena of surface active promazine hydrochloride (PMZ) drug with cationic hydrotropes (para-toluidine hydrochloride and ortho-toluidine hydrochloride) in absence and occurrence of 50 mmol kg−1 NaCl at five different temperature (293.15–313.15 K). PMZ is an amphiphilic phenothiazine drug and employed for the cure of mania and schizophrenia. Conductometry measurement was employed to gain a detailed picture of the interactions between drug and hydrotrope molecules. The experimental data were analyzed according to different mixing models within the outline of the pseudophase separation model. The evaluated values of critical micelle concentration (cmc) were found to be inferior than cmcid values signifying attractive interactions involving the both components in the solutions. NaCl further reduces the cmc of pure amphiphiles and their mixed systems as a result of screening of the electrostatic repulsion between the polar head groups. The micellar mole fractions (X1) of hydrotropes evaluated by various proposed models were constantly more than ideal values ( ) signifying high involvements of hydrotrope in mixed micelles. Activity coefficients ( and ) were always below one in all cases signifying synergism in mixed micelles. Thermodynamic parameters favor the process of micellization which is found to be entropy driven. The negative values of free energies of mixing demonstrated the stability of the mixed systems of drug and hydrotrope. Copyright © 2016 John Wiley & Sons, Ltd.

Mesoscale inhomogeneities in aqueous solutions of small amphiphilic molecules

Small amphiphilic molecules, also known as hydrotropes, are too small to form micelles in aqueous solutions. However, aqueous solutions of nonionic hydrotropes show the presence of a dynamic, loose, non-covalent clustering in the water-rich region, This clustering can be viewed as "micelle-like structural fluctuations". Although these fluctuations are short ranged (approximately 1 nm) and short lived (10 ps-50 ps), they may lead to thermodynamic anomalies. In addition, many experiments on aqueous solutions of hydrotropes show the occasional presence of mesoscale (approximately 100 nm) inhomogeneities. We have combined results obtained from molecular dynamics simulations, small-angle neutron scattering, and dynamic light-scattering experiments carried out on tertiary butyl alcohol (hydrotrope)-water solutions and on tertiary butyl alcohol-water-cyclohexane (hydrophobe) solutions to elucidate the nature and structure of these inhomogeneities. We have shown that stable mesoscale inhomogeneities occur in aqueous solutions of nonionic hydrotropes only when the solution contains a third, more hydrophobic, component. Moreover, these inhomogeneities exist in ternary systems only in the concentration range where structural fluctuations and thermodynamic anomalies are observed in the binary water-hydrotrope solutions. Addition of a hydrophobe seems to stabilize the water-hydrotrope structural fluctuations, and leads to the formation of larger (mesoscopic) droplets. The structure of these mesoscopic droplets is such that they have a hydrophobe-rich core, surrounded by a hydrogen-bonded shell of water and hydrotrope molecules. These droplets can be extremely long-lived, being stable for over a year. We refer to the phenomenon of formation of mesoscopic droplets in aqueous solutions of nonionic hydrotropes containing hydrophobes, as mesoscale solubilization. This phenomenon may represent a ubiquitous feature of nonionic hydrotropes that exhibit clustering in water, and may have important practical applications in areas, such as drug delivery, where the replacement of traditional surfactants may be necessary.

Hydrotropy: binding models vs. statistical thermodynamics

Hydrophobic drugs can often be solubilized by the addition of hydrotropes. We have previously shown that preferential drug-hydrotrope association is one of the major factors of increased solubility (but not "hydrotrope clustering" or changes in "water structure"). How, then, can we understand this drug-hydrotrope interaction at a molecular level? Thermodynamic models based upon stoichiometric solute-water and solute-hydrotrope binding have long been used to understand solubilization microscopically. Such binding models have shown that the solvation numbers or coordination numbers of the water and hydrotrope molecules around the drug solute is the key quantity for solute-water and solute-hydrotrope interaction. However, we show that a rigorous statistical thermodynamic theory (the fluctuation solution theory originated by Kirkwood and Buff) requires the total reconsideration of such a paradigm. Here we show that (i) the excess solvation number (the net increase or decrease, relative to the bulk, of the solvent molecules around the solute), not the coordination number, is the key quantity for describing the solute-hydrotrope interaction; (ii) solute-hydrotrope binding is beyond the reach of the stoichiometric models because long-range solvation structure plays an important role.

Effect of temperature on aggregation behavior of aqueous solutions of sodium cumene sulfonate

Aqueous solutions of sodium cumene sulfonate are characterized by various experimental techniques for its aggregation behavior as a function of temperature. Surface tensiometry, volumetric changes, vapor pressure osmometry, fluorescence polarization studies and enthalpy changes show changes in the solutions with increasing concentration and temperature. The apparent and partial molal volumes of the hydrotrope, derived from the density measurements, show a sharp increase at a characteristic minimum hydrotrope concentration. The osmotic coefficient of NaCS, obtained from vapor pressure osmometry, shows a significant deviation indicating aggregation of the hydrotrope molecules in aqueous solutions. NaCS, when used as an intrinsic fluorescent probe, reveals a non-polar environment in the aggregate with substantial microviscosity. The enthalpies of micellization obtained directly from the calorimetric measurements show a trend towards lower values with increasing temperature.

Extraction of Piperine from Piper nigrum (Black Pepper) by Hydrotropic Solubilization

Hydrotropes, such as sodium alkyl benzene sulfonates and sodium butyl monoglycol sulfate, were used for the selective extraction of piperine by cell permeabilization of Piper nigrum fruits. Penetration of the hydrotrope molecules into the cellular structures and subsequent cell permeabilization were hypothesized to explain the enhanced extraction rates of aqueous hydrotrope solutions. Hydrotrope molecules, after adsorption on a cell wall, cause disorder in its structure and in the bilayered cell membrane to facilitate the rapid extraction of piperine. The hydrotrope solution showed selective and rapid extraction of piperine from black pepper. The recovered piperine was ∼90% pure and substantially free from oleoresins. The type and nature of the hydrotrope, the hydrotrope concentration, the temperature, and the particle size all had significant effects on the extraction process.

Examination of the Hydrotropic Effect of Sodium p-Toluenesulfonate on a Nonionic Surfactant (C12E6) Solution

Although hydrotropy is extensively used in industry, the molecular mechanism of hydrotropic solubilization has not been completely elucidated yet. In this paper the interaction between a nonionic surfactant (ethoxylated fatty alcohol containing between five and six oxyethylenic units) and sodium p-toluene sulfonate is examined. Surface tension measurements confirm that the hydrotropic effect occurs at a concentration in which the hydrotropes self-associate. Photon correlation spectroscopy studies show that for this concentration of hydrotropes a drastic reduction in the surfactant micellar radius occurs. Furthermore the luminescence of the hydrotrope used as a fluorescence probe indicates that at low concentrations p-toluene sulfonate dissolves in the surfactant micelles but beyond the minimum concentration for hydrotropic solubilization the hydrotrope is present in the aqueous phase. These results suggest that the hydrotropic effect is related to alterations in the water structure induced by the hydrotrope molecules and to the presence of hydrotrope aggregates that furnish an appropriate niche for the surfactant amphiphile.

Proline is a protein-compatible hydrotrope

Hydrotropes are a class of compounds that, at high concentrations, enhance the solubility of hydrophobic substances in water. Hydrotropy operates beyond a particular concentration known as the minimal hydrotrope concentration (MHC), above which the hydrotrope molecules begin to self-aggregate and form loose noncovalent molecular assemblies. In this context, we have studied the self-aggregation and hydrotropic behavior of the naturally occurring amino acid L-proline and its derivative 4-hydroxyproline. The solubilizing ability of proline is comparable to that of conventional hydrotropes, while hydroxyproline does not display significant hydrotropic ability, presumably due to the hindrance offered by the hydroxyl group toward self-aggregation. However, the microenvironmental features offered by the proline molecular assembly are found to be somewhat different from those displayed by the conventional hydrotropes and detergents. Proline is known to be a compatible solute in water-stressed cells. Proline delays the thermal unfolding of the protein α-chymotrypsin by approximately 10°C, indicating its stabilizing ability on protein structure and conformation and suggesting its ability to act as a protein-compatible hydrotrope.