Minimum Hydrotrope Concentration Research Articles

Thermodynamic Study on Hydrotropic Aggregation Behavior of Theophylline

Abstract: Objectives: A systematic study is required to enhance the solubility of insoluble fluid drugs that are only sparingly soluble. Hydrotropy may be a distinctive development to reinforce the liquid solubility of poorly water-soluble drugs. Materials and Methods: The term hydrotropic has been wont to designate the rise in the solubility of assorted substances in water because of the presence of enormous amounts of additives. Sodium salicylate, sodium benzoate, and resorcinol are utilized to reinforce the liquid solubility of many poorly soluble drugs. Varied organic solvents like methyl alcohol, chloroform, alcohol, dimethylformamide, and benzene are utilized for the solubilization of poorly soluble drugs. Theophylline drug was accessories to numerous hydrotrope concentrations (0-3 mol/L) and also the non-inheritable sample for a solubility determination was analyzed in an exploitation UV spectrophotometer. Results: The solubility of theophylline has been specifically found to improve with an increase in hydrotrope concentration and also with a device temperature likely to be close to that of other organic compounds and drugs. Conclusion: To initiate substantial solubilization of the theophylline compound, a minimum hydrotrope concentration (MHC) in the aqueous phase was needed. As a consequence of the improvement in the solubilization of theophylline, the coefficient of mass transfer was also observed to expand with an increase in the hydrotropic concentration at 303 K. To have a substantial enhancement within the mass transfer coefficient, a threshold value equivalent to MHC is to be maintained. For all sets of experiments, the maximal enhancement factor, which is the value ratio between the presence and absence of a hydrotrope, has been calculated. Thermodynamic parameters such as Gibb’s free energy, enthalpy, and entropy of theophylline were calculated to determine the hydrotropic aggregation activity of theophylline. With an increase in system temperature, Gibb’s free energy declines. It was found that the aggregation of hydrotropes was exothermic and preferred by a positive entropy value. Key words: Hydrotropy, Theophylline, Solubility, Enhancement Factor, Aggregation Properties.

Spontaneous Ouzo Emulsions Coexist with Pre-Ouzo Ultraflexible Microemulsions.

Even in the absence of surfactants, polymers, or particles, spontaneous emulsions produced by dilution with water can be stable over days. This "Ouzo effect" used by the industry is obtained by rapid dilution from an identified "pre-Ouzo" domain of composition where weak aggregates are present: nanometer-sized clusters covered by a surface layer enriched in a hydrotrope such as ethanol. In these systems, Ostwald ripening is not an effective destabilizing mechanism. Using in situ autodilution small-angle X-ray scattering (SAXS), we follow the morphological transitions occurring in a ternary mixture of water/n-octanol/ethanol throughout the monophasic and biphasic regions. This allows for the first time an online characterization of the multiscale coexisting microstructures. Small-angle neutron scattering (SANS) profiles on metastable emulsions as well as phase-separated samples complete the SAXS data, taking advantage of contrast variation via isotopic substitution. After crossing the phase boundary into the two-phase region, coexisting phases are both ternary solutions structured at the nanometer scale when the emulsion is stable. The transition from single phase to two phases is asymmetric around the plait point. When the initial concentration of the hydrotrope is below the minimum hydrotrope concentration (MHC), emulsification failure occurs, i.e., emulsions cream within seconds. Beyond MHC, the low interfacial tension between coexisting ternary fluids results in a Laplace pressure below 100 Pa, explaining the puzzling resilience of spontaneous emulsion to the universal mechanism of Ostwald ripening.

Aggregation Behavior and Thermodynamic Studies of Hydrotropes: A Review

Abstract Under the aspect of strict environmental regulations, hydrotropy is accepted as an environmentally friendly (“green”) approach to solubilise hydrophobic compounds. Above the minimum hydrotrope concentration (MHC), hydrotropes are capable of self-aggregation; the MHC is considered the minimum requirement for solubilisation. In this article a comprehensive overview of the aggregation behaviour of different hydrotropes is presented. Details about the methods used for aggregation are given. The role of additives is discussed with respect to their influence on the MHC. Thermodynamic studies are used to evaluate the stability of a hydrotrope at different temperatures. A modern approach to the solubilization mechanism using hydrotropes is also presented in this review article. The aim of this article is to provide guidance for conducting such studies on a number of hydrotropes.

Sequential extraction of hemicelluloses and lignin for wood fractionation using acid hydrotrope at mild conditions

Sequential fractionation (SF) of woody biomass using acid hydrotrope p-toluenesulfonic acid (p-TsOH) as reaction medium was investigated. Hemicellulosic sugars, lignin, and cellulose-rich solid were harvested as the main products from the stepwise deconstruction of biomass as results of hemicelluloses hydrolysis and subsequent lignin dissolution. The first step of SF employed 2wt% p-TsOH, far below the minimum hydrotrope concentration (MHC) of 11.5wt%, and reached 23.5 % of biomass dissolution with 55.1 % removal of xylan from wood at 120 °C for 2 h. The second step of SF was characterized with mild conditions of 100 °C, 40wt% p-TsOH, and one hour, and achieved 83 % lignin dissolution with well-preserved structure. The obtained cellulose-rich solid from SF showed a high crystallinity index of 73.3 % and a complete recovery of glucan. This means excellent performance of SF for sustainable bio-refining.

Hydrotropic Action of Cationic Hydrotrope p-Toluidinium Chloride on the Solubility of Sparingly Soluble Gliclazide Drug Molecule: A Computational Study

We perform classical molecular dynamics simulations of sparingly soluble drug gliclazide (GLC) and hydrotrope p-toluidinium chloride (PTOL) in water with a regime of PTOL concentrations. Our results demonstrate that PTOL starts to self-aggregate above its minimum hydrotrope concentration (MHC). Further, these PTOL aggregates create a mixed micellar-like framework in which the hydrophobic small tail part of most of the PTOL molecules direct toward the inside, whereas in order to make favorable contact with water molecules its hydrophilic ammonium group points outward. But, in order to make hydrogen bonds with GLC molecules, the polar groups of a few of the hydrotropes direct inward also. This provides an environment for the incorporation of the drug molecules into the mixed environment (hydrophobic as well as hydrophilic core) of PTOL clusters. The average number of hydrogen bond calculations indicates that PTOL aggregate does not have much effect on the average number of water-PTOL hydrogen bonds, but it has an influence on the average number of water-GLC, GLC-GLC, and GLC-PTOL hydrogen bonds. Both electrostatic and van der Waals energy components of drug and hydrotrope interactions play vital roles in the solubilization process. Furthermore, the estimation of Flory-Huggins interaction parameters also suggests favorable interactions between hydrotrope PTOL and GLC drug molecules.

Computer Simulation Studies of the Mechanism of Hydrotrope-Assisted Solubilization of a Sparingly Soluble Drug Molecule.

The effect of hydrotrope sodium cumene sulfonate (SCS) on the solubility of a sparingly water-soluble drug, griseofulvin, is studied by employing classical molecular dynamics simulation technique. We mainly focus on the underlying mechanism by which SCS enhances the solubility of a sparingly soluble or insoluble solute in water. The main observations are the following: (a) The self-aggregation of SCS molecules (through its hydrophobic tail) above the minimum hydrotrope concentration (MHC) causes the formation of micellar-like frameworks. Interestingly, though the drug griseofulvin possesses both polar and nonpolar groups, it prefers to get encapsulated inside the hydrophobic core of SCS aggregates. The decomposition of total SCS-drug interaction energy into van der Waals and electrostatic components suggests that the former plays a major role in this interaction. (b) The calculated Flory-Huggins interaction parameter values give a strong indication of the mixing ability of hydrotrope SCS and griseofulvin drug molecules. (c) As expected, we do not observe any strong effect of SCS aggregates on SCS-water and water-water average hydrogen-bond number, but it affects water-drug griseofulvin average hydrogen-bond number. With the help of these observations we try to elucidate the hydrotropic action of hydrotrope SCS on the solubility of drug griseofulvin.

Mechanism of Hydrotropic Action of Hydrotrope Sodium Cumene Sulfonate on the Solubility of Di-t-Butyl-Methane: A Molecular Dynamics Simulation Study.

Hydrotropes are special class of amphiphilic molecules that have an ability to solubilize the insoluble or sparingly soluble molecules in water. To find out the mechanism of hydrotropic action of hydrotropes on hydrophobic molecules, we have carried out classical molecular dynamics simulation of hydrophobic solute di-t-butyl-methane (DTBM) and hydrotrope sodium cumene sulfonate (SCS) in water with a regime of SCS concentrations. Our study demonstrates that, above the minimum hydrotrope concentration (MHC), the self-aggregation of SCS starts, and it creates a micellar-like environment in which the hydrophobic tail part of SCS points inward while its hydrophilic sulfonate group points outward to make favorable contact with water molecules. The formation of the hydrophobic core of SCS cluster creates a hydrophobic environment where the hydrophobic DTBM molecules are encapsulated. Interestingly, the determination of average water-SCS hydrogen bonds further suggests that the aggregate formation of SCS molecules has a negligible influence on it. Moreover, the calculations of Flory-Huggins interaction parameters also reveal favorable interactions between hydrotrope SCS and solute DTBM molecules. The implications of these findings on the mechanism of hydrotrope assisted enhanced solubility of hydrophobic molecules are discussed.

The origin of cooperative solubilisation by hydrotropes.

The signature of hydrotropic solubilisation is the sigmoidal solubility curve; when plotted against hydrotrope concentration, solubility increases suddenly after the minimum hydrotrope concentration (MHC), and reaches a plateau at higher hydrotrope concentrations. This sigmoidal curve is characteristic of cooperative phenomena, yet the true molecular basis of hydrotropic cooperativity has long remained unclear. Here we develop a theory, derived from the first principles of statistical thermodynamics using partially-open ensembles, to identify the origin of hydrophobic cooperativity. Our theory bears a close resemblance to the cooperative binding model used for protein-ligand binding. The cause of cooperativity is the enhancement of the hydrotrope m-body interaction induced by the presence of the solute; m can be estimated from the experimental solubility data.

Exploring molecular insights into aggregation of hydrotrope sodium cumene sulfonate in aqueous solution: a molecular dynamics simulation study.

Hydrotropes are an important class of molecules that enhance the solubility of an otherwise insoluble or sparingly soluble solute in water. Besides this, hydrotropes are also known to self-assemble in aqueous solution and form aggregates. It is the hydrotrope aggregate that helps in solubilizing a solute molecule in water. In view of this, we try to understand the underlying mechanism of self-aggregation of hydrotrope sodium cumene sulfonate (SCS) in water. We have carried out classical molecular dynamics simulations of aqueous SCS solutions with a regime of concentrations. Moreover, to examine the effect of temperature change on SCS aggregation, if any, we consider four different temperatures ranging from 298 to 358 K. From the estimation of densities of different solutions we calculate apparent and partial molal volumes of the hydrotrope. The changes in these quantities increase sharply at a characteristic minimum hydrotrope concentration. The determination of molal expansibility at infinite dilution for different temperatures indicates the water structure breaking by SCS molecules, which is further confirmed by the calculations of water-water pair correlation functions. In comparison with typical surfactants in micelles, a slightly lower value of volumetric change upon aggregation per carbon atom suggests the formation of a more closely packed structure of hydrotrope aggregates. A close examination of different structural properties of hydrotrope solutions reveals that the hydrophobic interactions through their hydrophobic tails significantly contribute in hydrotrope aggregation,and the dehydration of hydrophobic tail at elevated temperatures is also visible. Remarkably, the aggregates have little or no impact on the average number of water-SCS hydrogen bonds.

Hydrotrope accumulation around the drug: the driving force for solubilization and minimum hydrotrope concentration for nicotinamide and urea.

Nicotinamide is an effective non-micellar hydrotrope (solubilizer) for drugs with low aqueous solubility. To clarify the molecular basis of nicotinamide's hydrotropic effectiveness, we present here a rigorous statistical thermodynamic theory, based on the Kirkwood-Buff theory of solutions, and our recent application of it to hydrotropy. We have shown that (i) nicotinamide self-association reduces solubilization efficiency, contrary to the previous hypothesis which claimed that self-association drives solubilization and (ii) the minimum hydrotrope concentration (MHC), namely, the threshold concentration above which solubility suddenly increases, is caused not by the bulk-phase self-association of nicotinamides as has been postulated previously, but by the enhancement of nicotinamide-nicotinamide interaction around the drug molecules. We have thus established a new view of hydrotropy - it is nicotinamide's non-stoichiometric accumulation around the drug that is the basis of solubility increase above MHC.

THE APPLICATION OF HYDROTROPES AS MEDIUM IN THE EXTRACTION OF ANDROGRAPHOLIDE

Hydrotrope solutions provide safe and effective media for the microwave assisted extraction of andrographolide, the major bioactive chemical constituent of plant Andrographis paniculata. Microwave assisted extraction of androgpaholide was carried out by using hydrotropes, sodium benzoate and urea. The objective of this work were to determine the Minimum Hydrotrope Concentration (MHC) and to determine the effectiveness of each hydrotrope with respect to andrographolide at different system powers. The microwave assisted extractions of andrographolide were carried out at different concentration of hydrotropes (0.2-3M) and different system powers (39.9 and 119.7 Watt). Twenty grams of Andrographis paniculata dried powder were added to 200 ml of hydrotrope solutions and extracted in a microwave extractor for 15 minutes. The research result showed that the percentage of the microwave assisted extraction of andrographolide by using sodium benzoate and urea were up to 10.9% and 1.05% respectively. The Minimum Hydrotrope Concentration and the effectiveness of hydrotropes that was measured in term of Setschenow constant (K s ) were reported for two hydrotropes used in this study.

Hydrotropy: monomer-micelle equilibrium and minimum hydrotrope concentration.

Drug molecules with low aqueous solubility can be solubilized by a class of cosolvents, known as hydrotropes. Their action has often been explained by an analogy with micelle formation, which exhibits critical micelle concentration (CMC). Indeed, hydrotropes also exhibit "minimum hydrotrope concentration" (MHC), a threshold concentration for solubilization. However, MHC is observed even for nonaggregating monomeric hydrotropes (such as urea); this raises questions over the validity of this analogy. Here we clarify the effect of micellization on hydrotropy, as well as the origin of MHC when micellization is not accompanied. On the basis of the rigorous Kirkwood-Buff (KB) theory of solutions, we show that (i) micellar hydrotropy is explained also from preferential drug-hydrotrope interaction; (ii) yet micelle formation reduces solubilization effeciency per hydrotrope molecule; (iii) MHC is caused by hydrotrope-hydrotrope self-association induced by the solute (drug) molecule; and (iv) MHC is prevented by hydrotrope self-aggregation in the bulk solution. We thus need a departure from the traditional view; the structure of hydrotrope-water mixture around the drug molecule, not the structure of the aqueous hydrotrope solutions in the bulk phase, is the true key toward understanding the origin of MHC.

Parametric Optimization and Thermo-dynamic Studies on the Influence of Electrolytes on Sodium Salicylate in Aqueous Solution

Abstract Hydrotropes (amphiphiles) start to aggregate at a certain minimum concentration known as the minimum hydrotrope concentration (MHC), above which an appreciable solubilization of insoluble compounds in aqueous solution is observed. However, the MHC values are very high, thus, limiting the applications of hydrotropes. The salts are found to increase the association tendency of hydrotropes and reduction in the MHC. The present study discusses the effect of various electrolytes (Na+, Mg2+ and K+ series) on the behavior of sodium salicylate at different temperatures. Design of experiment was employed to optimize the process parameters. Furthermore, thermodynamic parameters were investigated to observe the stability of the aggregates at higher temperatures.

Hydrotropic Aggregation Behavior of Butyl Stearate

On investigation for the solubility and mass transfer coefficient of butyl stearate through hydrotropy has been studied. This study was carried out using hydrotropes such as citric acid, urea, nicotinamide, sodium salicylate under the influence of a wide range of hydrotrope concentrations ((0 to 3) mol ·L -1 ) and different system temperatures ((303 to 333) K). It has been distinctively observed and noted that the solubility of butyl stearate increases with an increase in hydrotrope concentration and also with system temperature likely similar to the several organic compounds and drugs A Minimum Hydrotrope Concentration (MHC) in the aqueous phase was required to initiate significant solubilization of butyl stearate. Consequent to the increase in the solubilization of butyl stearate, the mass transfer coefficient was also found to increase with increase in hydrotrope concentration at 303 K. A threshold value similar to MHC is to be maintained to have an appreciable enhancement in mass transfer coefficient. The maximum enhancement factor, which is the ratio of the value in the presence and absence of a hydrotrope, has been determined for all sets of experimentations. To ascertain the hydrotropic aggregation behavior of butyl stearate, thermodynamic parameters such as gibb's free energy, enthalpy, and entropy of butyl stearate were determined. The gibb's free energy decreases with an increase in system temperature. The aggregation of hydrotropes was found to be exothermic in nature and favored by a positive value of entropy.

Enhancement of Solubility and Mass Transfer Coefficient of Benzoic Acid Through Hydrotropy

The effect of hydrotropes such as sodium salicylate, sodium benzoate, and nicotinamide on the solubility and mass transfer coefficient of benzoic acid has been investigated. The solubility studies were carried out under a wide range of hydrotrope concentrations (0 to 3.0 mol/L) and different system temperatures (303K to 333K). It has been observed that the solubility and mass transfer coefficient of benzoic acid increases with an increase in hydrotrope concentration and also with system temperature. A Minimum Hydrotrope Concentration (MHC) was found essential to initiate a significant increase in the solubility and the mass transfer coefficient. The maximum enhancement factor (φs), which is the ratio of the solubility value in the presence and absence of a hydrotrope, has been determined for all sets of experimentations. The solubility of benzoic acid has been enhanced to 19.98 times in the presence of 2.5 mol/L concentration of sodium salicylate hydrotrope at 333K.The effectiveness of hydrotropes was measured in terms of Setschenow constant Ks and the highest value has been observed as 0.502 for sodium salicylate.

Radiolysis of sodium p-cumenesulfonate in aqueous solution

The reactions of hydrated electron eaq−, hydrogen atom (H) and CO2− (reducing species) as well as Cl2−, Br2−, N3−, OH, O−, SO4− radicals (oxidizing species) with sodium p-cumenesulfonate (SCS) in aqueous solution below minimum hydrotrope concentration have been studied by the method of steady-state and pulse radiolysis. The spectra of transient intermediates, leading to the final products, are presented. The rate constants for the reduction or oxidation reaction of the SCS are also given. The fate of the primary products of the SCS reaction produced during the pulse radiolysis under reductive or oxidative conditions is discussed.

Minimum Hydrotrope Concentration Behavior of Aqueous Solution of Sodium Salicylate in Presence of Additives

Hydrotropes are regaining importance in the currently blossoming field of self-organizing molecular systems. Their hydrophile-lipophile balance being on the higher side, their water solubility is significantly more than that of traditional surfactants, and, yet, they provide a sequestered niche or microenvironment for the solubilizate. Hydrotropes start aggregating at a certain concentration known as minimum hydrotrope concentration (MHC). The MHC values fall in the molar range because of which hydrotropes applications are reducing. In this article, the effect of various additives such as alcohols, electrolytes, surfactants, amines, and organic compounds on the behavior of sodium salicylate (NaSal) was investigated using viscosity measurement.

Enhanced Solubility and Separation of m/p – Aminonitrobenze Using different Hydrotropic Solution

The aqueous solubilit ies of m/p - amino nitrobenzene in d ifferent concentrations (0-3.0 mo l/ L) of hydrotropes such as sodium benzoate, Sodiu m saccharin, dimethyl benzamide at different system temperatures (303K to 333K) were studied. The percentage extraction (%E) o f m- amino nitrobenzene fro m m/p - amino nitrobenzene mixture increases with an increase in hydrotrope concentration. A Minimu m Hydrotrope Concentration (MHC) in the aqueous phase was required to initiate the significance of the %E of m- amino nitrobenzene. Percentage extraction (%E) is the ratio of mo les of m - amino nitrobenzene extracted in presence and absence of a hydrotrope. The sensitivity and feasibility of the proposed process are examined by carrying out solubilization and equilibriu m precipitation experiments with the mixtu res of various compositions. The effectiveness of hydrotropes was measured in terms of Setschenow constant Ks and reported for all hydrotropes used in this study and determination of aggregation behavior of all hydrotropes were also studied. Cost effective and eco friendly techniques of removal of less soluble compoments.

Enhanced Solubility and Reflection of Hydrotropy Technique in the Segregation of of m/p-Aminonitrobenze

The aqueous solubilities of m/p - amino nitrobenzene in different concentrations (0-3.0 mol/L) of hydrotropes such as sodium benzoate, sodium saccharin, dimethyl benzamide at different system temperatures (303 K to 333 K) were studied. The percentage extraction (%E) of m- amino nitrobenzene from m/ p - amino nitrobenzene mixture increases with an increase in hydrotrope concentration. A minimum hydrotrope concentration (MHC) in the aqueous phase was required to initiate the significance of the %E of m- amino nitrobenzene. Percentage extraction (%E) is the ratio of moles of m - amino nitrobenzene extracted in presence and absence of a hydrotrope. The sensitivity and feasibility of the proposed process are examined by carrying out solubilization and equilibrium precipitation experiments with the mixtures of various compositions. The effectiveness of hydrotropes was measured in terms of Setschenow constant Ks and reported for all hydrotropes used in this study and determination of aggregation behavior of all hydrotropes were also studied.

Separation of m/p‐Aminoacetophenone Using Hydrotropy

The aqueous solubilities of m/p‐aminoacetophenone in different concentrations (0‐3.0 mol/L) of hydrotropes such as diethyl nicotinamide, sodium pseudocumene sulfonate and sodium thiocyanate solutions at different system temperatures (303K to 333K) were studied. The percentage extraction (%E) of m‐ aminoacetophenone from m/p‐aminoacetophenone mixture increases with increase in hydrotrope concentration. A Minimum Hydrotrope Concentration (MHC) in the aqueous phase was required to initiate the significance of the %E of m‐aminoacetophenone. Percentage extraction (%E) is the ratio of moles of m‐aminoacetophenone extracted in presence and absence of a hydrotrope. The sensitivity and feasibility of the proposed process are examined by carrying out solubilization and equilibrium precipitation experiments with the mixtures of various compositions. The effectiveness of hydrotropes was measured in terms of Setschenow constant Ks. The extraction data are also fitted in a polynomial equation as the function of hydrotrope concentration. The solubilized material can be recovered by dilution with water.