Deep eutectic solvents based on sugars for oral applications.

Solubility is a critical parameter in drug formulation to achieve the desired therapeutical concentration. Most drugs are weak acids or bases and, therefore, exhibit low solubility and poor oral availability. The main aim of this work is the use of Deep Eutectic Systems (DESs) for improving the solubility of drugs in aqueous medium. In this case, we use DESs formed by choline chloride and sugars (xylitol, fructose, glucose and sorbitol) at different proportions of water. These compounds present low toxicity, and thus can be used in syrups or liquid formulations. Different physicochemical properties, such as density, refractive index, and surface tension, were obtained. In addition, a rheological study of the different systems was carried out. Finally, these DESs were applied to analyse the solubility of the following active principles: caffeine (Class I) and furosemide (Class IV) of the Biopharmaceutics Classification System (BCS). The selection of the drugs attends to different reasons. On one hand, we want to develop a new liquid formulation for model drug furosemide and, on the other hand, the study of caffeine, instead, will be used as a model for comparing purposes. Solubility results show that the systems that best solubilize caffeine are those with the highest water content; however, they do not reach the levels of solubility of pure water. On the other hand, for furosemide, a great increase in solubility was observed, especially for systems formed by xylitol and, fundamentally, in the system with the lowest water content. Obtaining an increase in solubility of up to 4530 times. These systems provide an opportunity to improve the formulation of drugs in the liquid medium of active ingredients that are poorly soluble in an aqueous medium.

Deep Eutectic Solvents Formed by Glycerol and Xylitol, Fructose and Sorbitol: Effect of the Different Sugars in Their Physicochemical Properties.

The search for new eutectic solvents for different applications (extraction, drug formulation, chemical reactions, etc.) is booming thanks to their high solubility capacity and low toxicity. However, it is necessary to carry out a comprehensive physicochemical characterization of these mixtures to understand the molecular behavior at different experimental conditions. In this study, three deep eutectic solvents (DESs) formed by glycerol and xylitol, fructose and sorbitol and water in the molar ratio 1:2:3 were prepared and several physicochemical properties (refractive index, density, surface tension, viscosity, speed of sound, isobaric heat capacity and isentropic compressibility) were measured and analyzed in the 278.15-338.15 K temperature range. The results indicate a linear dependence with temperature for the following properties: surface tension, refractive index, density and isobaric molar heat capacity while viscosity values have been fitted to the Vogel-Fulcher-Tammann equation.

Ecotoxicological study of glucose:choline chloride and sorbitol:choline chloride at different contents of water.

The search of new solvents is currently focused on deep eutectic solvents (DES). However, there are not many ecotoxicological studies in different biomodels of DES that allow knowing how these chemicals affect to the environment along the trophic chain. In this manuscript, two DES at different proportion of water have been prepared and characterized from the ecotoxicological point of view. These solvents are glucose:choline chloride (2:5) and sorbitol:choline chloride (3:2) at different contents of water. To carry out the ecotoxicological study, three biomodels have been used: bacteria Aliivibrio fisheri (A. fisheri), crustacean Daphnia magna (D. magna) and algae Raphidocelis subcapitata (R. subcapitata). The obtained results show that the ecotoxicity of these chemicals depends on the biomodel used and the amount of water, being toxicity values lower for chemicals with higher water content. However, it is important to highlight that the ecotoxicity for all chemicals is quite low with effective concentrations, EC50 values above 1000 mg/L in all the studied cases.

Ecotoxicity interspecies study of ionic liquids based on phosphonium and ammonium cations.

This work studies the effects of different bromide-based ionic liquids, with phosphonium and ammonium cations, towards several environmental biomodels: Daphnia magna, Allivibrio fischeri, Raphidocelis subcapitata. Results indicate that toxicity clearly depends on the biomodel, Allivibrio fischeri being the least sensitive one while Daphnia magna is more severely affected in the presence of the studied ionic liquids. In most of the cases, phosphonium moieties are less toxic than ammonium ionic liquids. Furthermore, a prediction about the oral toxicity and carcinogenicity of the studied ionic liquids has been also carried out, showing that these chemical structures may suggest significant toxicity but not present genotoxic or nongenotoxic carcinogenicity.

Ecotoxicity and biodegradability of pure and aqueous mixtures of deep eutectic solvents: glyceline, ethaline, and reline.

Most of the works carried out on deep eutectic solvents (DESs) make reference to their physicochemical properties, and the analysis of their toxicological behavior on the environment and biodegradability are still limited. In this work, an exhaustive study on the ecotoxicity of three pure deep eutectic solvents (reline, glyceline, and ethaline) and their mixtures with water (reline-water, glyceline-water, and ethaline-water) was carried out in different biomodels: bacteria (A. fisheri), crustaceans (D. magna), and algae (S. capricornatum). In addition, the amount of chlorophyll in the algae after exposure to the DESs was analyzed. Finally, the biodegradability of the studied DESs was also analyzed. The ecotoxic behavior strongly depends on both the biomodel tested and the presence of water in the mixture, resulting in low toxicities in all cases. Furthermore, most of the deep eutectic solvents studied can be considered readily biodegradable. A comparison of the ecotoxicity and biodegradability of these solvents under other conditions has also been provided, and a complete analysis is given.

Ecotoxicological study of six drugs in Aliivibrio fischeri, Daphnia magna and Raphidocelis subcapitata.

The presence of drugs in the environment is an emerging issue in the scientific community. It has been shown that these substances are active chemicals that consequently affect aquatic organisms and, finally, humans as end users. To evaluate the toxicity of these compounds and how they affect the environment, it is important to perform systematic ecotoxicological and physicochemical studies. The best way to address this problem is to conduct studies on different aquatic trophic levels. In this work, an ecotoxicological study of six drugs (anhydrous caffeine, diphenhydramine hydrochloride, gentamicin sulphate, lidocaine hydrochloride, tobramycin sulphate and enalapril maleate) that used three aquatic biological models (Raphidocelis subcapitata, Aliivibrio fischeri and Daphnia magna) was performed. Additionally, the concentration of chlorophyll in the algae R. subcapitata was measured. Furthermore, EC50 values were analysed using the Passino and Smith classification (PSC) method, which categorized the compounds as toxic or relatively toxic. All of the studied drugs showed clear concentration-dependent toxic effects. The toxicity of the chemicals depended on the biological model studied, with Raphidocelis subcapitata being the most sensitive species and Aliivibrio fischeri being the least sensitive. The results indicate that the most toxic compound, for all the studied biological models, was diphenhydramine hydrochloride. Graphical abstract.

QSAR study for predicting the ecotoxicity of NADES towards Aliivibrio fischeri. Exploring the use of mixing rules.

(Eco)toxicological information of natural deep eutectic solvents (NADES) is scarce, and thus, quantitative structure activity relationship (QSAR) models are an important tool for achieving the prediction of toxicity in this case. For that reason, in this manuscript, a new QSAR model for predicting the ecotoxicity of NADES towards the Aliivibrio fischeri biomodel, using mixing rules, is proposed. The main advantage of the method is that the individual components of the mixtures are molecularly modelled, and then, a mixing rule is used, which simplifies the process. For developing the model, a total of 11 descriptors for each component is used: the dissociation constant, partition coefficient, Van der Waals volume, Van der Waals surface area, topological polar surface area, solvent accessible surface area, minimum projection area, maximum projection area, minimum projection radius, maximum projection radius and molecular weight. The final obtained model includes the topological polar surface area and the dissociation constant, mechanistically interpreted as the ability of a NADES to transport through biological membranes and the severe negative effect of pH on the toxicity and biological response of Aliivibrio fischeri bacteria. The OECD Guidance Document on the Validation of (Quantitative) Structure-Activity Relationships is followed to develop the mathematical model.

Is Green Chemistry a feasible tool for the implementation of a circular economy?

The main goal of this research is to evaluate the contributions of Green Chemistry as a potential tool to drive the transition to circularity. For this, we have carried out a bibliographic study, analyzing those documents, process, or experiences that dealt jointly with the Green Chemistry aspects related to circularity such circular economy, industrial ecology, and closed loop. Findings show that few authors have treated that disciplines together in the last 10 years. Based on an analysis of academic literature, common strategies (design, raw materials, life cycle assessment, processes, normative, new business, and collaboration), specific experiences (catalyst, biobased products or methods, recycling, and reusing), and difficulties to overcome (metrics, transdisciplinary research, unawareness, and competitiveness) have been identified. Finally, different kind of measures, as behind such joint metrics, informal open spaces, closer the industry, education, standards and label are proposed to facilitate the development of Green Chemistry, circular economy, industrial ecology, and closed loop with the ultimate goal of improving sustainable development.From the evidences found, we finally conclude that it is possible to use Green Chemistry and its principles as a tool to drive the transition to circularity, being the development of open spaces for exchange information between different actors from academia, governments and regulatory actors, business and industrial sectors, with the aim of promoting disruptive advances in sustainability.

QSAR modelling for predicting the toxic effects of traditional and derived biomass solvents on a Danio rerio biomodel.

The increasing interest in the development of ecofriendly solvents has led to the synthesis of benign alternative chemicals with minimized environmental impacts. These kinds of chemicals are known as Green solvents. In this work, we selected three families of solvents (furfural, lactate and levulinate families) derived from biomass that are structurally related. Most of the previous ecotoxicological studies of these solvents have focused on invertebrate models such as bacteria, algae and crustaceans. To complete this information, in this work, the acute toxicity of these solvents was studied in Danio rerio (D. rerio). Sublethal and lethal effects were also observed, and the LC50 was obtained. The LC50 values ranged from 13.21 to 12073 mg L-1, with furfural being the most toxic compound and tetrahydrofurfuryl alcohol the least toxic. Furthermore, the results indicated that a frequent sublethal effect was heart oedema or malformation, even in some cases at concentrations lower than the LC50. A QSAR analysis was also performed to model the toxicological effect towards D. rerio for the studied solvents obtained from biomass and traditional solvents. A total of 15 molecular descriptors of the solvents were obtained using Gaussian 03 software. Finally, we also used the physicochemical property Log P, calculated from ACD/LogP, for QSAR modelling. Multivariable regression analysis showed that the minimum set of independent variables that leads to the best regression is Log P, the energy of the lowest unoccupied molecular orbital (ELUMO) and the heat capacity (CV). The proposed model was validated using several internal and external methods.

Acute and subacute effects of drugs in embryos of Danio rerio. QSAR grouping and modelling.

The final fate of many drugs is release into the natural aquatic environment. It is necessary to assess the toxicity caused by this situation and the associated concerns for human beings. Zebrafish (Danio rerio) is a common biomodel used to assess toxicity in aquatic environments. The zebrafish embryo toxicity test was selected to evaluate the acute toxicity of several drugs (diphenhydramine, gentamicin, tobramycin, enalapril and lidocaine) due to the lack of such information. Lethal and sublethal effects were detected, and the LC50 values of the drugs ranged from 11.0 mg/L to 422·102 mg/L. For all of the drugs tested, these values were higher than the concentrations found in the natural environment. Therefore, there was a low environmental toxicological risk. Nevertheless, teratogenic effects were also recorded when embryos of zebrafish were exposed to caffeine (control drug), diphenhydramine and lidocaine at lower concentrations than the respective LC50 values. Quantitative structure-activity relationship analysis was also performed to analyse these drugs and other chemicals with pharmaceutical uses as well as previous toxicological data in this vertebrate after 48 h of exposure. It is estimated that the partition coefficient, log P, is the main physicochemical property related to the ecotoxicological data and can be used for the development of a mathematical model.

Exploring the usefulness of key green physicochemical properties: Quantitative structure-activity relationship for solvents from biomass.

In recent decades there has been a growing interest in the development of new solvents from biomass. Some of these new solvents have been classified as green because of their renewable and sustainable source. However, characterization from the ecotoxicological and physicochemical points of view is needed to categorize them as green solvents. We have selected several key physicochemical properties that can reflect environmental features (density, boiling point, critical aggregation concentration, and log p) and explored their usefulness for preliminarily assessing the green character of the studied solvents. Specifically, we have studied several solvents from biomass: lactate family (methyl, ethyl, and butyl lactate), furfural family (furfural, 5-methylfurfural, furfuryl alcohol, and tetrahydrofurfuryl alcohol), and levulinate family (methyl, ethyl, and butyl levulinate). To fill the gaps and complete some toxicity data for the environment, we have measured the ecotoxicity using 2 of the most common and versatile biomodels, bacteria Vibrio fischeri and crustacean Daphnia magna, for furfural- and lactate-derived compounds. The results indicate that solvents from biomass can be categorized as green because their toxicity for the environment is low. Finally, a quantitative structure-activity relationship (QSAR) study was performed with the selected key properties and the ecotoxicological information. Despite the different structure of the chemicals under study, good correlations were found for the studied organisms. It seems that log p and critical aggregation concentration reflect the greatest part of the ecotoxic behavior, whereas density and boiling point cannot reflect toxicity signals. However, these properties are rather useful for assessing the final environmental fate of the studied chemicals. Environ Toxicol Chem 2018;37:1014-1023. © 2017 SETAC.

Ecotoxicity and QSAR studies of glycerol ethers in Daphnia magna.

Glycerol is currently considered a raw, renewable material, which can be used to synthesize new glycerol derivatives that may be used as green solvents. However, these compounds must be environmentally evaluated before their use. The acute ecotoxicity of a series of mono-, di-, and trialkyl ethers synthesized from glycerol for the crustacean Daphnia magna has been studied. The EC50 values of these ethers after 24 h of exposure were determined according to the OECD 202 protocol. Their possible structural-toxicity relationships according to different alkyl substituents have been discussed after applying different QSAR models (with the DARC-PELCO approach and topological parameters). The results of the immobilization test show that most of the glycerol derivatives studied exhibit relatively low ecotoxicity. There is a correlation between the lipophilicity and the increase of the toxic effect in the crustacean biomodel. Furthermore, the length and the number of the alkyl substituents and ecotoxicity are highly related.

Comparative ecotoxicology study of two neoteric solvents: Imidazolium ionic liquid vs. glycerol derivative.

In this study we have compared the acute ecotoxicity of two solvents, with very different structure and origin, but sharing many physical-chemical properties, so they can be used for similar purposes; a well-known ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) and a solvent partially derived from biomass, 3-bis(2,2,2-trifluoroethoxy)propan-2-ol (BTFIP). We have used three biomodels (Vibrio fischeri, Daphnia magna and Danio rerio) and performed the comparison applying the Environmental, Health and Safety (EHS) hazard assessment. According to the results, ecotoxicity of [BMIM][PF6] and BTFIP is quite similar in the simplest model Vibrio fischeri, while in Daphnia magna [BMIM][PF6] is clearly more toxic. However, in Danio rerio, toxicity of these chemicals is again quite similar and both can be classified as "nontoxic". The higher index value of [BMIM][PF6] in water mediate effect in the EHS assessment indicates that this ionic liquid is more dangerous than BTFIP, although accumulation and degradation properties have not been taken into account. Further studies will be necessary to ascertain these conclusions.

Ecotoxicity studies of the levulinate ester series.

The increasing interest in the development of novel green solvents has led to the synthesis of benign alternative products with minimized environmental impacts. However, most of published studies on green solvents focus primarily on their physicochemical properties, with limited emphasis on absence of ecotoxicological assessment. In this study, we evaluated the acute ecotoxicity of four levulinates (levulinic acid, methyl levulinate, ethyl levulinate and butyl levulinate) on freshwater algae (Chlamydomonas reinhardtii), bacteria (Vibrio fischeri), daphnids (Daphnia magna) and earthworms (Eisenia foetida) using various dose-response tests. As a general trend, the toxicity of levulinate esters in aquatic exposure (assessed as the EC50) increased as a function of increasing alkyl chain length; accordingly, the most toxic compound for the aquatic organisms was butyl levulinate, followed by ethyl levulinate and methyl levulinate. The most toxic compound for E. foetida (terrestrial exposure) was methyl levulinate, followed by ethyl levulinate, butyl levulinate and levulinic acid; in this case, we observed an inverse relationship between toxicity and alkyl chain length. Based on both the lowest EC50 found in the aquatic media and the ratio between predicted environmental concentration and the predicted no-effect concentration, we have estimated the maximum allowable values in the environment for these chemicals to be 1.093 mg L(-1) for levulinic acid, 2.761 mg L(-1) for methyl levulinate, 0.982 mg L(-1) for ethyl levulinate and 0.151 mg L(-1) for butyl levulinate.

Physicochemical characterization of n-butyl-3-methylpyridinium dicyanamide [corrected] ionic liquid.

The room temperature ionic liquid n-butyl-3-methylpyridinium dicyanamide has been characterized. Physicochemical properties such as density, speed of sound, refractive index, surface tension, and kinematic viscosity of the studied liquid have been experimentally measured in a wide range of temperatures. From results, coefficients of thermal expansion, molar refractions, dynamic viscosities and entropies and enthalpies of surface formation per unit surface area at the studied temperatures have been derived. We have analyzed the achieved results for evaluating the effect of the anionic structure in these properties, getting interesting results which lead us to a better understanding of the behavior of the ions in the fluids. Moreover, thermal properties of several pyridinium-based ionic liquids have been investigated. Finally, from both dynamic viscosity values and glass transition temperature of the studied liquids, a detailed analysis of the behavior in fragility terms has been performed.

Thermophysic comparative study of two isomeric pyridinium-based ionic liquids.

A comprehensive thermophysical study of isomeric room-temperature ionic liquids n-butyl-3-methyl-pyridinium tetrafluoroborate and n-butyl-4-methyl-pyridinium tetrafluoroborate has been performed. This paper reports various experimental data including density, speed of sound, refractive index, surface tension, isobaric molar heat capacity, and kinematic viscosity. From the experimental results, coefficients of thermal expansion, dynamic viscosities and molar refractions of the studied ionic liquids have been determined. Results have been analyzed paying special attention to the different features of the isomers and their structural differences. Several theories and empirical relations have been applied in order to predict physical properties of ionic liquids. A good agreement between experimental and calculated data has been found. Furthermore, a study about the versatility and application of the different relationships has been carried out finding that in general density and coefficients of thermal expansion can be estimated with relatively good accuracy.

Phase equilibrium of liquid mixtures: experimental and modeled data using statistical associating fluid theory for potential of variable range approach.

A study of the phase equilibrium (experimental and modeled) of mixtures formed by a cyclic ether and haloalkanes has been derived. Experimental data for the isothermal vapor liquid equilibrium of mixtures formed by tetrahydrofuran and tetrahydropyran and isomeric chlorobutanes at temperatures of 298.15, 313.15, and 328.15 K are presented. Experimental results have been discussed in terms of both molecular characteristics of pure compounds and potential intermolecular interaction between them using thermodynamic information of the mixtures obtained earlier. The statistical associating fluid theory for potential of variable range (SAFT-VR) approach together with standard combining rules without adjustable parameters has been used to model the phase equilibrium. Good agreement between experiment and the prediction is found with such a model. Mean absolute deviations for pressures are of the order of 1 kPa, while less than 0.013 mole fraction for vapor phase compositions. In order to improve the results obtained, a new modeling has been carried out by introducing a unique transferable parameter k(ij), which modifies the strength of the dispersion interaction between unlike components in the mixtures, and is valid for all the studied mixtures being not temperature or pressure dependent. This parameter together with the SAFT-VR approach provides a description of the vapor-liquid equilibrium of the mixtures that is in excellent agreement with the experimental data for most cases. The absolute deviations are of the order of 0.005 mole fraction for vapor phase compositions and less than 0.3 kPa for pressure, excepting for mixtures containing 2-chloro-2-methylpropane which deviations for pressure are larger. Results obtained in this work in the modeling of the phase equilibrium with the SAFT-VR equation of state have been compared to the ones obtained in a previous study when the approach was used to model similar mixtures with clear differences in the thermodynamic behavior. We show how the SAFT-VR approach is capable of differentiating the molecular features of a relatively wide set of different mixtures.

Phase equilibrium of binary mixtures of cyclic ethers + chlorobutane isomers: experimental measurements and SAFT-VR modeling.

The phase equilibria (experimental and modeled) of eight binary mixtures each formed by a cyclic ether (1,3-dioxolane or 1,4-dioxane) and a chlorobutane isomer (1-chlorobutane, 2-chlorobutane, 1-chloro-2-methylpropane, or 2-chloro-2-methylpropane) are presented. New experimental vapor-liquid equilibrium data at isothermal conditions (298.15, 313.15, and 328.15 K) has been obtained, and the statistical associating fluid theory for potentials of variable range (SAFT-VR) is used to model the mixtures. The results are discussed in terms of both the molecular characteristics of the pure compounds and the unlike intermolecular interactions present in the mixtures. The SAFT-VR approach is first used together with standard combining rules without adjustable parameters in order to predict the phase behavior at isothermal conditions. Good agreement between experiment and the prediction is found with such a model. Mean absolute deviations for pressures lie between 1 and 3 kPa, while for vapor phase compositions are less than 0.03 in mole fraction. However, a better agreement, can be obtained by introducing one adjustable parameter kij, which modifies the strength of the dispersion interaction between unlike components in the mixtures. This parameter is adjusted so as to model the phase equilibrium of the whole family of mixtures studied here at isothermal and isobaric conditions. We find that a unique unlike parameter kij is valid for all the studied mixtures and it is not temperature or pressure dependent. This unique transferable parameter together with the SAFT-VR approach provide a description of the vapor-liquid equilibrium of the mixtures that is in excellent agreement with the experimental data. In this case, the absolute deviations are of the order of 0.001 in mole fraction for vapor-phase compositions and less than 1 kPa for pressure.

Study of weak molecular interactions through thermodynamic mixing properties.

The electron donor-acceptor abilities of some cyclic ethers (tetrahydropyran or tetrahydrofuran), benzene, and halobenzenes (fluorobenzene or chlorobenzene) and the molecular interactions between these compounds have been investigated through a wide set of thermodynamic mixing properties of their mixtures. The mixing properties have been derived from experimental measurements of density, speed of sound, refractive index, surface tension, heat of mixing, and vapor-liquid equilibrium at the temperature of 298.15 K.

Proton sponge and fatty acid interactions at the air-water interface. Thermodynamic, spectroscopic, and microscopic study.

Mixed Langmuir and Langmuir-Blodgett (LB) films of a proton sponge, namely, diphenyl bis(octadecylamino)phosphonium bromide, and a fatty acid, docosanoic acid, with different molar ratios have been fabricated. Surface pressure versus area per molecule isotherms were registered, and the excess areas and excess Gibbs energy of mixing were calculated. Strong interactions between the proton sponge and the fatty acid take place at the air-water interface. The existence of a stoichiometric 1:1 acid-base reaction between the two components forming a complex on the water surface at high surface pressures has been demonstrated. Furthermore, the reaction had an efficiency close to 100% at the air-water interface; meanwhile, it hardly takes place in organic solvents such as chloroform or even a mixture of chloroform and dimethyl sulfoxide. The floating films were transferred to solid supports and characterized by means of several techniques including IR spectroscopy, X-ray diffraction, and atomic force microscopy, revealing the presence of highly ordered alkyl chains and a constant architecture along the different layers as well as the presence of different domains in the LB films, except those having a 1:1 proton sponge-fatty acid ratio that are homogeneous. Such domains have been interpreted as the presence of two different phases, the 1:1 complex plus the excess component in the mixture.