Assessing the hydrotropic effect in the presence of electrolytes: competition between solute salting-out and salt-induced hydrotrope aggregation.

Water solubility enhancement is a long-standing challenge in a multitude of chemistry-related fields. Hydrotropy is a simple and efficient method to improve the solubility of hydrophobic molecules in aqueous media. However, the mechanism behind this phenomenon remains controversial. Herein the impact of salt doping on the hydrotropy phenomenon is determined experimentally using the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride ([C4mim]Cl) as a hydrotope and vanillin as a solute. Hydrophobic interactions were found to be central to the aggregation of the hydrotrope around the solute, and seem to drive hydrotropy. Furthermore, 1H-NMR analysis indicates that hydrotrope-solute interactions present a degree of site-specificity. The addition of chloride salts in the presence of higher IL concentrations promotes a greater relative decrease of the vanillin solubility than in the corresponding system without the IL. This was assigned to the negative impact of increased hydrotrope pre-aggregation in the presence of inorganic salts. The results were rationalised using statistical thermodynamics through which hydrotrope aggregation prior to solute addition is shown to be detrimental to the hydrotropic effect, seemingly confirming solute-induced clustering of the hydrotrope to be the predominant mechanism of hydrotropy.

Cholinium-based ionic liquids as bioinspired hydrotropes to tackle solubility challenges in drug formulation.

Hydrotropy is a well-established strategy to enhance the aqueous solubility of hydrophobic drugs, facilitating their formulation for oral and dermal delivery. However, most hydrotropes studied so far possess toxicity issues and are inefficient, with large amounts being needed to achieve significant solubility increases. Inspired by recent developments in the understanding of the mechanism of hydrotropy that reveal ionic liquids as powerful hydrotropes, in the present work the use of cholinium vanillate, cholinium gallate, and cholinium salicylate to enhance the aqueous solubility of two model drugs, ibuprofen and naproxen, is investigated. It is shown that cholinium vanillate and cholinium gallate are able to increase the solubility of ibuprofen up to 500-fold, while all three ionic liquids revealed solubility enhancements up to 600-fold in the case of naproxen. Remarkably, cholinium salicylate increases the solubility of ibuprofen up to 6000-fold. The results obtained reveal the exceptional hydrotropic ability of cholinium-based ionic liquids to increase the solubility of hydrophobic drugs, even at diluted concentrations (below 1 mol·kg-1), when compared with conventional hydrotropes. These results are especially relevant in the field of drug formulation due to the bio-based nature of these ionic liquids and their low toxicity profiles. Finally, the solubility mechanism in these novel hydrotropes is shown to depend on synergism between both amphiphilic ions.

The impact of the counterion in the performance of ionic hydrotropes.

The efficiency of an ionic hydrotrope is shown to increase with the hydrophobicity of its counterion, challenging the common view that ionic hydrotropes should possess a small, densely charged counterion such as sodium or chloride.

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.

Synthesis and Characterization of Surface-Active Ionic Liquids Used in the Disruption of Escherichia Coli Cells.

Twelve surface-active ionic liquids (SAILs) and surface-active derivatives, based on imidazolium, ammonium, and phosphonium cations and containing one, or more, long alkyl chains in the cation and/or the anion, were synthetized and characterized. The aggregation behavior of these SAILs in water, as well as their adsorption at solution/air interface, were studied by assessing surface tension and conductivity. The CMC values obtained (0.03-6.0 mM) show a high propensity of these compounds to self-aggregate in aqueous media. Their thermal properties were also characterized, namely the melting point and decomposition temperature by using DSC and TGA, respectively. Furthermore, the toxicity of these SAILs was evaluated using the marine bacteria Aliivibrio fischeri (Gram-negative). According to the EC50 values obtained (0.3-2.7 mg L-1 ), the surface-active compounds tested should be considered "toxic" or "highly toxic". Their ability to induce cell disruption of Escherichia coli cells (also Gram-negative), releasing the intracellular green fluorescent protein (GFP) produced, was investigated. The results clearly evidence the capability of these SAILs to act as cell disruption agents.

Anti-inflammatory and antioxidant nanostructured cellulose membranes loaded with phenolic-based ionic liquids for cutaneous application.

The utilization of natural compounds, such as phenolic acids and biopolymers, in the healthcare domain is gaining increasing attention. In this study, bacterial nanocellulose (BC) membranes were loaded with ionic liquids (ILs) based on phenolic acids. These ionic compounds, with improved solubility and bioavailability, were prepared by combining the cholinium cation with anions derived from caffeic, ellagic and gallic acids. The obtained BC-ILs membranes were homogeneous, conformable and their swelling ability agreed with the solubility of each IL. These membranes revealed a controlled ILs dissolution rate in the wet state and high antioxidant activity. In vitro assays performed with Raw 264.7 macrophages and HaCaT keratinocytes revealed that these novel BC-ILs membranes are non-cytotoxic and present relevant anti-inflammatory properties. Diffusion studies with Hanson vertical diffusion cells showed a prolonged release profile of the ILs from the BC membranes. Thus, this work, successfully demonstrates the potential of BC-ILs membranes for skin treatment.

Understanding the interactions of imidazolium-based ionic liquids with cell membrane models.

Cell membrane models have been used to evaluate the interactions of various imidazolium-based ionic liquids (ILs) with Langmuir monolayers of two types of phospholipids and cholesterol. Data from surface pressure isotherms, Brewster angle microscopy (BAM) and polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS) pointed to significant effects on the monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol, used to mimic the membranes of eukaryotic cells, for ILs containing more than 6 carbon atoms in the alkyl chain (i.e. n > 6). For ILs with less hydrophobic tails (n ≤ 6) and low concentrations, the effects were almost negligible, therefore, such ILs should not be toxic to eukaryotic cells. The hydrophobicity of the anion was also proved to be relevant, with larger impact from ILs containing tetrafluoroborate ([BF4]-) than chloride (Cl-). Molecular dynamics simulations for DPPC monolayers at the surface of aqueous solutions of alkylimidazolium chloride ([Cnmim]Cl) confirm the penetration of the IL cations with longer alkyl chains into the phospholid monolayer and provide information on their location and orientation within the monolayer. For monolayers of dipalmitoylphosphatidyl glycerol (DPPG), which is negatively charged like bacteria cell membranes, the ILs induced much larger effects. Similarly to the results for DPPC and cholesterol, effects increased with the number of carbon atoms in the alkyl chain and with a more hydrophobic anion [BF4]-. Overall, the approach used can provide relevant information of molecular-level interactions behind the toxicity mechanisms and support the design of (quantitative) structure-activity relationship models, which may help design more efficient and environmentally friendly ILs.

Odd-even effect on the formation of aqueous biphasic systems formed by 1-alkyl-3-methylimidazolium chloride ionic liquids and salts.

This work provides a comprehensive evaluation of the effect of the cation alkyl side chain length of the 1-alkyl-3-methylimidazolium chloride series ([C n C1im]Cl, n = 2-14) of ionic liquids (ILs) on their capability to form aqueous biphasic systems (ABSs) with salts and self-aggregation derived properties. The liquid-liquid phase behavior of ternary systems composed of [C n C1im]Cl, water, and K3PO4 or K2CO3 and the respective Setschenow salting-out coefficients (ks ), a quantitative measure of the two-phase formation ability, were determined. An odd-even effect in the ks values along the number of methylene groups of the longest IL cation alkyl side chain was identified for the ABS formed by K2CO3, a weaker salting-out agent where the phenomenon is clearly identified. In general, cations with even alkyl side chains, being likely to display higher molar volumes, are more easily salted-out and thus more prone to undergo phase separation. The odd-even effect in the ks values is, however, more significant in ILs up to n = 6, where the nanostructuration/nanosegregation of ILs plays a less relevant role. Still, with the [C n C1im]Cl (n = 7-14) series of ILs, an odd-even effect was also identified in the ILs' ionization degree, molar conductivity, and conductivity at infinite dilution. In summary, it is shown here that the ILs' odd-even effect occurs in IL aqueous solutions and not just in neat ILs, an already well-established phenomenon occurring in a series of ILs' properties described as a result of the orientation of the terminal methyl groups to the imidazolium ring cation and consequent effect in the ILs' cohesive energy.

Impact of Surface Active Ionic Liquids on the Cloud Points of Nonionic Surfactants and the Formation of Aqueous Micellar Two-Phase Systems.

Aqueous micellar two-phase systems (AMTPS) hold a large potential for cloud point extraction of biomolecules but are yet poorly studied and characterized, with few phase diagrams reported for these systems, hence limiting their use in extraction processes. This work reports a systematic investigation of the effect of different surface-active ionic liquids (SAILs)-covering a wide range of molecular properties-upon the clouding behavior of three nonionic Tergitol surfactants. Two different effects of the SAILs on the cloud points and mixed micelle size have been observed: ILs with a more hydrophilic character and lower critical packing parameter (CPP < 1/2) lead to the formation of smaller micelles and concomitantly increase the cloud points; in contrast, ILs with a more hydrophobic character and higher CPP (CPP ≥ 1) induce significant micellar growth and a decrease in the cloud points. The latter effect is particularly interesting and unusual for it was accepted that cloud point reduction is only induced by inorganic salts. The effects of nonionic surfactant concentration, SAIL concentration, pH, and micelle ζ potential are also studied and rationalized.

Ecotoxicological evaluation of magnetic ionic liquids.

Although magnetic ionic liquids (MILs) are not yet industrially applied, their continued development and eventual commercial use may lead to their appearance into the aquatic ecosystem through accidental spills or effluents, consequently promoting aquatic contaminations. Furthermore, the deficient information and uncertainty surrounding the environmental impact of MILs could be a major barrier to their widespread industrial application and international registration. Thus, in the present work, a range of cholinium salt derivatives with magnetic properties was synthesized and their ecotoxicity was evaluated towards the luminescent bacteria Vibrio fischeri. The results suggest that all MILs structures tested are moderately toxic, or even toxic, to the bacteria. Furthermore, their toxicity is highly dependent on the structural modifications of the cation, namely the alkyl side chain length and the number of hydroxyethyl groups, as well as the atomic number of the metal anion. Finally, from the magnetic anions evaluated, the [MnCl4]2- is the less toxic. In order to improve the knowledge for the prospective design of environmentally safer MILs, it is important to expand this study to other aquatic organisms at different trophic levels.

Development of predictive QSAR models for Vibrio fischeri toxicity of ionic liquids and their true external and experimental validation tests.

Despite possessing an interesting chemical nature and tuneable physicochemical properties, ionic liquids (ILs) must have their ecotoxicity tested in order to be commercialized. The water solubility of ILs allows their easy access to the aquatic compartment of the ecosystem creating a potential hazard to aquatic organisms. Hence, it is relevant to design ionic liquids with lower toxicity while keeping the desired properties of interest. Considering the possibility of an enormous number of combinations of different cations and anions, a rational guidance for the structural design of ionic liquids is essential in order to prioritize the synthesis as well as testing of selected molecules only. Predictive in silico models, such as quantitative structure-activity relationship (QSAR) models, can play a pivotal role in exploring the important chemical attributes contributing to the response activity. These models may then lead to the design of novel ionic liquids. The present study aims at developing predictive QSAR models for the ecotoxicity of ionic liquids using the bacteria Vibrio fischeri as an indicator response species. Instead of a single model, here we have used multiple models to capture more complete structural information of ionic liquids for toxicity towards Vibrio fischeri. The derived chemical attributes have been implemented in designing new analogues, some of which have been synthesized and had their ecotoxicity tested for the same model organism. The predictive QSAR models reported here can be used for ecotoxicity prediction of new IL chemicals and for data-gap filling. Moreover, the synthesized low-toxic ILs could be considered for evaluation as well as for application in suitable processes serving the purpose of industry and academia.

Enhancing the antioxidant characteristics of phenolic acids by their conversion into cholinium salts.

Due to the close relation between oxidative stress and a plethora of inflammatory diseases, antioxidants have received an increased attention for incorporation into dermatological products. Their use and absorption is however limited by their low solubility in water-rich formulations. Herein, a set of novel cholinium-based salts, namely dicholinium ellagate and cholinium caffeate, syringate, vanillate, gallate and salicylate were synthetized and characterized. Their melting and decomposition temperatures, water solubility, and toxicological, antioxidant, cytotoxicity and pro-/anti-inflammatory activities were addressed. These new salts, exclusively composed of ions derived from natural sources, display a high thermal stability - up to 150 ºC. The synthesized compounds are significantly more soluble in water (in average, 3 orders of magnitude higher) than the corresponding phenolic acids. Furthermore, they present not only similar but even higher antioxidant and anti-inflammatory activities, as well as comparable cytotoxicity and lower ecotoxicity profiles than their acidic precursors. Amongst all the investigated salts, dicholinium ellagate is the most promising synthesized salt when considering the respective antioxidant and anti-inflammatory activities. Since all the synthesized salts are based on the cholinium cation, they can further be envisaged as essential nutrients to be used in oral drugs.

The effect of the cation alkyl chain branching on mutual solubilities with water and toxicities.

The design of ionic liquids has been focused on the cation-anion combinations but other more subtle approaches can be used. In this work the effect of the branching of the cation alkyl chain on the design of ionic liquids (ILs) is evaluated. The mutual solubilities with water and toxicities of a series of bis(trifluoromethylsulfonyl)-based ILs, combined with imidazolium, pyridinium, pyrrolidinium, and piperidinium cations with linear or branched alkyl chains, are reported. The mutual solubility measurements were carried out in the temperature range from (288.15 to 323.15) K. From the obtained experimental data, the thermodynamic properties of the solution (in the water-rich phase) were determined and discussed. The COnductor like Screening MOdel for Real Solvents (COSMO-RS) was used to predict the liquid-liquid equilibrium. Furthermore, molecular dynamic simulations were also carried out aiming to get a deeper understanding of these fluids at the molecular level. The results show that the increase in the number of atoms at the cation ring (from five to six) leads to a decrease in the mutual solubilities with water while increasing their toxicity, and as expected from the well-established relationship between toxicities and hydrophobicities of ILs. The branching of the alkyl chain was observed to decrease the water solubility in ILs, while increasing the ILs solubility in water. The inability of COSMO-RS to correctly predict the effect of branching alkyl chains toward water solubility on them was confirmed using molecular dynamic simulations to be due to the formation of nano-segregated structures of the ILs that are not taken into account by the COSMO-RS model. In addition, the impact of branched alkyl chains on the toxicity is shown to be not trivial and to depend on the aromatic nature of the ILs.