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Solubility Enhancement of Hydrophobic Compounds in Aqueous Solutions Using Biobased Solvents as Hydrotropes

Cite this: Ind. Eng. Chem. Res. 2023, 62, 30, 12021–12028
Publication Date (Web):July 24, 2023
https://doi.org/10.1021/acs.iecr.3c01469

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

Improving the aqueous solubility of poorly soluble hydrophobic compounds is a topic of great interest to the pharmaceutical, chemical, and food industries. The poor solubility of these compounds in water poses a challenge in developing sustainable processes for their extraction, separation, and formulation. Therefore, in this study, the use as hydrotropes of biobased solvents such as γ-valerolactone (GVL), Cyrene, ethyl lactate, and alkanediols (1,2-propanediol, 1,5-pentanediol, and 1,6-hexanediol) to improve the solubility of two model compounds (syringic acid and ferulic acid) in water is investigated. The effects of the concentration and structure of biobased solvents on the solubility of phenolic compounds in aqueous solutions at (303.2 ± 0.5) K were studied. The results showed that the aqueous solubility of the phenolic compounds studied typically increased with the log (KOW) of the hydrotrope (1,2-propanediol < Cyrene < 1,5-pentanediol < GVL < ethyl lactate < 1,6-hexanediol) and the hydrophobicity of the solute; the hydrotropic dissolution of phenolic compounds is shown to depend on both the hydrotrope and the solute. This study shows that some biobased solvents, especially GVL, are excellent hydrotropes. Their renewable nature, low price, and low toxicity make these results particularly relevant to the field of extraction and separation of bioactive compounds.

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Introduction

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In the pharmaceutical, chemical, and food industries, there is strong interest in enhancing the solubility of hydrophobic compounds due to their diverse biological activities and potential health benefits. Phenolic compounds, which possess antimicrobial, anti-inflammatory, and antioxidant properties, are prominent examples of such compounds. (1,2) However, the low water solubility of hydrophobic compounds, including phenolic compounds, presents significant challenges in developing sustainable extraction, separation, and application processes. To overcome these limitations, the solubility of hydrophobic compounds in aqueous solutions can be increased by adding hydrotropes or other suitable additives.
Hydrotropes are a class of compounds that enhance the solubility of hydrophobic compounds in aqueous solutions, a phenomenon known as hydrotropy. (3,4) They are used in households, health care, solubilization of pharmaceuticals, and extraction of bioactive compounds, including phenolic compounds. (3−6) The mechanism of hydrotropy involves water-mediated aggregation of hydrotropes around hydrophobic solutes through apolar moieties, effectively minimizing water–solute contacts and, thus, enhancing solute solubility. (3,7,8) As such, hydrotropes are typically amphiphilic molecules possessing polar functional groups and reasonably large apolar volumes, which are also common characteristics across many biobased solvents. From a green chemistry perspective, the use of biobased hydrotropes in the processing of hydrophobic compounds is beneficial because it minimizes the use of organic solvents or multistage, energy-intensive extraction schemes.
Recent research indicates that biobased solvents, including glycerol ethers, (7,9,10) alkanediols, (11) dihydrolevoglucosenone (Cyrene), (12−14) γ-valerolactone (GVL), (15−18) and ethyl lactate, (17) can serve as efficient hydrotropes to increase the aqueous solubility of hydrophobic compounds. Moity et al. (10) showed that monoglycerol ethers improve the solubility of hydrophobic dyes. Another study (9) compared the alkyl chain of glycerol ethers and showed that hydrophilic hydrotropes can improve the solubility of phenolic compounds. In a recent study, the alkyl chain and relative position of polar groups in alkanediols (1,2-alkanediols and 1,n-alkanediols) were studied to increase the solubility of syringic acid (by up to 60-fold). (11) However, compared to the study of glycerol ethers, (9) the solubility enhancement, in diluted regions, increases with increasing alkyl chain size of the alkanediols, (11) suggesting different trends using different hydrotrope families. While the relative position of the hydroxyl groups did not affect the solubility in dilute regions, at higher concentrations, 1,2-alkanediols exhibit better performance than 1,n-alkanediols. (11)
De Bruyn et al. (14) demonstrated for the first time the hydrotropic ability of Cyrene, highlighting the chemical equilibrium established between Cyrene and water, yielding a geminal diol, and its ability to function as a reversible and switchable hydrotrope. Abranches et al. (12) further examined the mechanism of hydrotropy in water/Cyrene mixtures, finding the diol and ketone forms of Cyrene, which act as hydrotropes, although in different composition windows, with the diol being most prevalent at low Cyrene concentrations. Interestingly, the ability of Cyrene to increase the aqueous solubility of syringic acid (45-fold) is inferior to that of alkanediols (up to 60-fold) (11) or glycerol ethers (up to 77-fold). (9)
Kerkel et al. (15) proposed GVL as a promising green solubilizer for pharmaceutical, cosmetic, and agrochemical compounds. Klossek et al. (17) suggested that the degree of self-association of biobased solvents has a significant impact on their hydrotropic efficiency. More specifically, the authors found that GVL, as well as ethyl lactate, form clusters in water, in contrast to other solvents such as ethanol, which may explain their high ability to increase the solubility of hydrophobic molecules like Disperse Red 13.
Not only are the biobased solvents discussed above efficient hydrotropes, but they also offer a more environmentally friendly alternative to petrochemical solvents, as they are derived from renewable sources such as wood, starch, vegetable oils, and fruits. They are also less toxic, biodegradable, and biocompatible, with GVL (19) and 1,2-propanediol (20) being approved as food additives due to their toxicological safety. (21,22) Moreover, they are also economically competitive and already used in certain sectors of the chemical industry. For instance, Cyrene is now being industrially produced by Circa Group with an expected price of $2.5/kg. (23) GVL, which is a stable chemical that does not oxidize or degrade at standard temperatures and pressures, is commonly used as a food additive and occurs naturally in fruits, with an industrial-level price of around $2/kg. (24) Ethyl lactate, which has a high boiling point of around 481 K and a low melting point of 242 K, has a cost typically around $2/kg, (17,25) making it competitive with petroleum-derived solvents. Alkanediols such as 1,2-ethanediol, 1,2-propanediol, and 1,6-hexanediol are a subgroup of diols characterized by low toxicity and biodegradability, making them a potential alternative to conventional solvents in various applications. The prices of 2-ethanediol, 1,2-propanediol, and 1,6-hexanediol range usually from $1 to 10/kg, having potential to replace some petroleum-derived solvents.
The aim of this work is to investigate the hydrotropic effect of biobased solvents (1,2-propanediol, 1,5-pentanediol, 1,6-hexanediol, Cyrene, ethyl lactate, and GVL) with a broad range of hydrophobicities (log (KOW) varying from −1.4 to 0) in increasing the solubilization of two model compounds: syringic and ferulic acid. These solutes were selected based on their different hydrophobicities and their importance in natural extracts. Solubility results were interpreted using the Sestchenow equation (9) to better understand how the mechanism of hydrotropy operates in dilute domains, as it is often different from that in concentrated domains. For the concentrated regions, the cooperative hydrotropy model (26) was used to further investigate the mechanism of hydrotropy in the context of these solvents. The observed differences are discussed.

Experimental Section

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Chemicals

The chemical compounds used are summarized in Table 1, along with their abbreviation, CAS number, mass purity, and source. The chemical structures of all compounds studied as solutes and hydrotropes are depicted in Figure 1. The water used for all solubility measurements associated with the experiments was double distilled, passed across a reverse osmosis system, and further treated with a Milli-Q plus 185 water purification device.

Figure 1

Figure 1. Chemical structure of the solutes and hydrotropes used in this work.

Table 1. List of Substances Used in the Experimental Work, as well as the Logarithm of the Octanol–Water Partition Coefficients─log (KOW), CAS Number, Purity, and Source
substancelog (KOW) (27)CAS numberpurity (wt %)source
Solutes
ferulic acid1.51537-98-499.0TCI
syringic acid1.04530-57-4>97.0Acros Organics
Hydrotropes
1,2-propanediol–1.3457-55-699.5Sigma-Aldrich
1,5-pentanediol–0.60111-29-597.0Alfa Aesar
1,6-hexanediol–0.07629-11-897.0Acros Organics
cyrene–0.7153716-82-899.0Sigma-Aldrich
ethyl lactate–0.1997-64-398.0SAFC
γ-valerolactone (GVL)–0.27108-29-298.0Acros Organics

Solubility Measurements

The solubility of the two phenolic compounds (syringic and ferulic acid) in aqueous solutions of biobased solvents (GVL, Cyrene, 1,2-propanediol, 1,5-pentanediol, and 1,6-hexanediol) was determined using the analytical isothermal shake-flask methodology, previously described in the literature. (9) These aqueous solutions of biobased solvents or pure biobased solvents were prepared gravimetrically within ± 10–4 g using an analytical balance Mettler Toledo Excellence XS205 Dual Range. The solutes, including syringic acid and ferulic acid, were added in excess to a fixed volume of each aqueous solution of biobased solvents or water. The samples were equilibrated in an air oven under constant agitation (1150 rpm) at (303.2 ± 0.5) K and for a minimum of 72 h, using an Eppendorf Thermomixer Comfort equipment.
After equilibrium was reached, the mixtures were placed in an oven at (303.2 ± 0.5) K, for 72 h, in order to separate the macroscopic solid phase from the liquid phase. Then, the liquid phase of each sample was carefully collected and diluted in distilled water. The quantification of ferulic acid and syringic acid was carried out by UV spectrophotometry using a SYNERGY|HT microplate reader, BioTek, at wavelengths of 316 and 266 nm, respectively, using the calibration curves previously established. Blank control samples were made in order to eliminate the interference of aqueous solutions of biobased solvents. For each concentration, three individual samples were prepared to determine the average and standard deviation of the results.

Results and Discussion

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Hydrotropic Effect of Biobased Solvents

The solubility of ferulic acid and syringic acid in aqueous solutions of biobased solvents (1,2-propanediol, 1,5-pentanediol and 1,6-hexanediol, Cyrene, ethyl lactate, and GVL) was measured in this work. The solubility of these two phenolic compounds was determined over the entire hydrotrope concentration range, i.e., from pure water to pure biobased solvent or its saturated aqueous solutions if they are not fully water-soluble.
The solubilities measured for ferulic acid and syringic acid in pure water at (303.2 ± 0.5) K were (0.83 ± 0.05) g/L and (1.48 ± 0.03) g/L, respectively. The solubilities measured are in good agreement with the data reported in the literature for ferulic acid (0.53–0.92 g/L at 303.2 K) (28,29) and syringic acid (1.43–1.68 g/L at 303.2 K). (5,9,12) The obtained hydrotropic solubility curves are depicted in Figure 2 and the detailed experimental data can be found in the Supporting Information (see Tables S1 and S2). The results obtained are shown as solubility enhancement, S/S0, where S and S0 represent the solubility of phenolic compounds in each biobased aqueous solution and in pure water, respectively.

Figure 2

Figure 2. Solubility enhancement (S/S0) for syringic acid and ferulic acid in aqueous solutions of biobased solvents: (blue circle) GVL, (orange square) 1,6-hexanediol, (green triangle) Cyrene, (red square) 1,5-pentanediol, (black diamond) ethyl lactate and (pink square) 1,2-propanediol as a function of hydrotrope concentration (CH) at (303.2 ± 0.5) K. S and S0 represent the solubilities of the solute in aqueous solutions of biobased solvents (hydrotrope) and in pure water, respectively. The dashed lines are visual guides.

The ability of biobased solvents to enhance the aqueous solubility of ferulic acid and syringic acid is remarkable, as shown in Figure 2. Using a value of 6.0 mol/kg as a reference hydrotrope concentration, the solubility of phenolic compounds can be enhanced by biobased solvents in the following order: 1,2-propanediol < ethyl lactate < 1,5-pentanediol < Cyrene < 1,6-hexanediol < GVL. The solubility curve presents a sigmoidal shape for most of the systems in this study, typical of a hydrotropic mechanism of solvation. Moreover, many solubility curves depicted in Figure 2 pass through a maximum, which is related to the transition from a ″hydrotrope-driven″ to a ″water-driven″ regime and is accompanied by a change in the solvation mechanism. (13) Significant enhancements in the solubility of the phenolic compounds were obtained for the aqueous solutions of GVL, leading to increments up to 99- and 237-fold for syringic acid and ferulic acid, respectively, when compared to pure water. Furthermore, to achieve a high enhancement in the solubility of hydrophobic compounds, even those with high hydrophobicity such as ferulic acid (log (KOW) = 1.51), high concentrations of the hydrotrope were required. However, our results show that even at low to moderate concentrations of biobased solvents (up to 2 mol/kg), the solubility of syringic acid increased 14-fold and the solubility of ferulic acid increased 24-fold. Therefore, depending on the applications, low to moderate concentrations of hydrotropes may be sufficient to achieve the desired solubility level.
Since the aqueous solubility of the acidic solutes studied in this work can be affected by the pH of the medium, the starting and final pH of all solutions were assessed to detect interferences caused by changes in solute speciation (see Tables S3–S5 in the Supporting Information). It is important to highlight that no additives were introduced to the solutions in order to change their pH. The pH values obtained reflect the inherent pH of the aqueous solutions of these solvents. All water/solute/hydrotrope mixtures had a lower pH than the respective water/solute mixtures due to the higher solubility of the acid in these mixtures. Moreover, most pH values are lower than the first pKa of ferulic acid (pKa1 = 3.58) (30) or syringic acid (pKa1 = 3.93), (30) meaning that most of the solutes are present in their neutral form. This precludes any solubility enhancements due to a higher proportion of their more soluble ionic form. Thus, the improvement in solubility observed is due to a hydrotropic effect and not a pH effect.
When comparing the solubility enhancement of the model phenolic compounds studied achieved with biobased solvents or with other approaches such as using cholinium-based salts, De Faria et al. (31) observed a 1.6-fold increase in the solubility of syringic acid with cholinium chloride, while Yuan et al. (32) obtained a 7.8-fold increase in the solubility of ferulic acid with cholinium-based ionic liquids, particularly cholinium lysinate. In contrast, biobased solvents, including less efficient 1,2-propanediol, showed significant improvements, resulting in a 30-fold increase in the solubility of syringic acid and an impressive 97-fold increase in the solubility of ferulic acid. This suggests that biobased solvents are more promising for improving the solubility of poorly soluble compounds in aqueous solutions.

Analysis of Hydrotropy in Diluted Solutions by Setschenow Constants

The solubility results discussed above reveal different trends in the dilute and concentrated regions, emphasizing the need to investigate the hydrotropy mechanisms separately in each region for a precise understanding of the molecular mechanism. This is challenging when considering the multiple interactions that may take place between the three components present in the solution (hydrotrope, water, and solute). All of these interactions may have an impact on the solubility enhancement of the solute. To simplify the analysis, we start by looking into the dilute hydrotrope region, where the interactions between solute–solute and hydrotrope–hydrotrope are expected to be negligible. To study the diluted region, the Setschenow equation was used. (9) It quantifies the change in the solubility of a solute due to the presence of a hydrotrope in the dilute region according to eq 1
ln(S/S0)=KSCH
(1)
where S and S0 represent the solute solubility (mol/L) in the hydrotrope solution and pure water, respectively, CH represents the concentration of the hydrotrope (mol/kg), and KS is the Setschenow constant (kg/mol). This equation is only valid in a concentration region for which the variation of the natural logarithm of solute solubility remains linear.
Although the simplicity of the Setschenow equation may suggest that it is just an empirical relationship, actually it is related to Kirkwood–Buff Integrals (KBIs), through the following expression (33)
KSGS,HGS,W
(2)
where GS,H and GS,W quantify, respectively, the excess of the hydrotrope (H) or water (W) around the solute (S), respectively. The KBIs measures the excess of a component present in the local vicinity of another component. Statistical thermodynamics shows that hydrotropic solubilization is mainly driven by solute–hydrotrope preferential interactions relative to solute–water, making GS,HGS,W > 0. Thus, higher values of KS result from the preference of the solute to interact with the hydrotrope, with a consequent increase in its solubility.
The Setschenow constants for all solute–hydrotrope pairs here studied were calculated, and the results are reported in Table 2 and Figures S1 and S2 in the Supporting Information, along with the molality range used. The values of the constant give information about the efficiency of the hydrotrope in the solubilization of a specific solute. The higher the values of KS, the higher the ability of the hydrotrope to increase the solute solubility in water.
Table 2. Setschenow Constants (KS) for Syringic and Ferulic Acids in Biobased Solvents, and the Hydrotrope Concentration Range Considered in the Calculations
 KS (kg/mol)concentration range (mol/kg)
Syringic Acid
1,6-hexanediol1.8170–1
ethyl lactate1.3320–0.4
GVL1.2640–2
1,5-pentanediol1.2840–1
cyrene0.9000–0.4
1,2-propanediol0.4140–0.7
Ferulic Acid
1,6-hexanediol1.9370–0.4
ethyl lactate1.5480–0.4
GVL1.7430–0.5
1,5-pentanediol1.2830–0.5
cyrene1.2530–0.4
1,2-propanediol0.6470–0.7
According to the values of KS obtained (Table 2), the hydrotropic power of biobased solvents in general follows the order 1,6-hexanediol > ethyl lactate > GVL > 1,5-pentanediol > Cyrene > 1,2-propanediol, which correlates well with the hydrophobicity of each hydrotrope expressed in terms of its log (KOW) as shown in Figure 3. Note that, we used here the log (KOW) as a measure of the solvent hydrophobicity. These results support the hydrotropy mechanism according to which the higher the hydrophobicity of the hydrotrope, the larger the solubility enhancement in the diluted region, (7,11) showing that the hydrophobic part of the hydrotrope is an important factor for hydrotropic efficacy, as demonstrated by Kunz and co-workers. (34) This may be explained based on the relationship between the Setschenow constant and the Kirkwood–Buff Integrals represented in eq 2. Since GS,H and GS,W quantify the excess of the hydrotrope or water around the solute, the higher the preference of the solute to interact with the hydrotrope, GS,H, and not with water, GS,W, the higher the Setschenow constant and thus the solubility enhancement of a hydrophobic solute. The behavior in concentrated solutions is somewhat more complex, as will be discussed below.

Figure 3

Figure 3. Representation of KS as a function of the logarithm of the octanol–water partition coefficient of hydrotropes, log (KOW), for (blue circle) syringic acid and (orange triangle) ferulic acid.

Analysis of Hydrotropy in Concentrated Solutions by the Cooperative Model

The cooperative model of hydrotropy (26) is now used to analyze the mechanism of hydrotropy in the region of high concentration. This model is based on statistical thermodynamics and describes the enhanced solubility of a solute (S/S0) as a function of hydrotrope concentration xH, by the following equation
ln[1(S/S0)S/S0(S/S0)max]=mln(xH)+b
(3)
where S represents the molar solubility (mol/L) of the solute in the hydrotropic system, S0 is the molar solubility (mol/L) of the solute in pure water, (S/S0)max is the maximum attainable relative solubility, and xH is the mole fraction of the hydrotrope in the ternary mixture. Parameters m and b afford an insight into the hydrotropy mechanism and the interactions between the hydrotrope and the solute. Parameter m represents the average number of hydrotrope molecules aggregated around the solute, while b corresponds to the facility to insert that number (m) of hydrotrope molecules in the correspondent volume around the solute.
This model was used to fit the syringic and ferulic acids solubility curves studied in this work. The results presented in Figure 4 demonstrate the ability of the model to describe the solubility curves of these solutes in aqueous solutions of biobased solvents in a wide range of concentrations. The parameters of the linearized equation are presented in the Supporting Information (Figures S3 and S4). The parameter (S/S0)max of eq 3 was left as an adjustable parameter, since most of the solubility curves are not perfectly sigmoidal. Moreover, for solubility curves displaying a clear global maximum, eq 3 was fitted only to hydrotrope concentrations below it. This maximum is due to a change in the solvation mechanism of the solute, with the system moving from hydrotrope-driven solvation in water to water-driven solvation in the hydrotrope. Beyond (S/S0)max, which is reached at high hydrotrope concentrations, the water is no longer the main solvent, and thus, water-mediated hydrotrope–solute interactions are no longer predominant in the system. But this region, albeit interesting, is not the focus of this work and a discussion about the effect of water upon solubility in Cyrene can be found elsewhere. (12)

Figure 4

Figure 4. Representation of the cooperative model to fit the solubility curve (sigmoidal curve) of syringic and ferulic acid in the presence of aqueous solutions of biobased solvents: (blue circle) GVL, (orange square) 1,6-hexanediol, (red square) 1,5-pentanediol, (green triangle) Cyrene and (gray diamond) ethyl lactate, and (pink square) 1,2-propanediol as a function of hydrotrope mole fraction (xH) at (303.2 ± 0.5) K.

The model parameters (m and b) obtained for all solubility curves are presented in Table S6 and correlated against log (KOW) in Figures 5 and 6. There are clear positive trends between both parameters and log (KOW) that are similar to those observed in Figure 3 using the Setschenow constant, KS. However, rather than exhibiting a monotonical behavior, m goes through a maximum, as previously observed for alkanediols (11) and glycerol ethers. (7)

Figure 5

Figure 5. Parameter m of the cooperative model of hydrotropy as a function of the logarithm of the partition coefficient between octanol and water of the hydrotropes, log (KOW), for syringic acid (blue circle) and ferulic acid (orange triangle). Coefficients of determination pertain to the second-order polynomial regressions for each data set.

Figure 6

Figure 6. Parameter b of the cooperative model of hydrotropy as a function of the logarithm of the partition coefficient between octanol and water of the hydrotropes, log (KOW), for syringic acid (blue circle) and ferulic acid (orange triangle). The coefficient of determination pertains to a single linear regression of both data sets.

As mentioned above, hydrotropy is driven by the aggregation of hydrotrope molecules around the solute through their apolar moieties. This aggregation is favorable to, and thus mediated by, water (hydrophobic effect), in the sense that minimizing apolar–water contacts enhances water–water and water–hydrotrope contacts through hydrophilic moieties. (7) As such, the extent of this aggregation (quantified by parameter m) is expected to correlate positively with the apolar volume of the hydrotrope (here represented in a holistic fashion using KOW), as the results in Figure 5 demonstrate. However, as the hydrophobicity of the hydrotrope increases, so does the extent of hydrotrope–hydrotrope self-aggregation through apolar moieties. This effect, often known as hydrotrope preaggregation (aggregation without the presence of solute), limits the amount of hydrotropes available to aggregate around the solute. Thus, m displays a maximal value when hydrotrope–hydrotrope aggregation becomes more prevalent than solute–hydrotrope aggregation, as demonstrated in Figure 5 and in previous works. (7,11)
The behavior of m also demonstrates that the differences in hydrotrope performance observed between low- and high-concentration regions are related to the balance between solute–hydrotrope and hydrotrope–hydrotrope aggregation, with the latter being mostly relevant in the high-concentration region. This effect is particularly relevant when comparing the performances of 1,6-hexanediol (largest apolar volume) and GVL (largest solubility enhancement): 1,6-hexanediol is the best-performing hydrotrope in the low-concentration region because solute–hydrotrope aggregation is maximized, while hydrotrope–hydrotrope aggregation plays a negligible role, and GVL is the best-performing hydrotrope in the high-concentration region given its excellent balance between solute–solute and solute–hydrotrope interactions.
Comparing now parameter m across different solutes (instead of different hydrotropes), ferulic acid, being the most hydrophobic compound studied, is expected to be surrounded by a high number of hydrotropes, and thus, parameter m should be the highest for this system. The results reported in Figure 5 are in agreement with this idea, and parameter m follows the same trend of the hydrophobicity of the solutes: m (ferulic acid) > m (syringic acid). This relation between m and solute log (KOW) is in agreement with previous observations. (9,12)
Having discussed the relationship between m and hydrophobicity, it is interesting to note that parameter b displays a good linear correlation with the log (KOW) of the hydrotropes studied, as depicted in Figure 6. This may be due to the physical meaning of b, which is related to the fugacity of pure hydrotrope and the fugacity of inserting m hydrotrope molecules in the system. As long as m does not change significantly, b should depend mostly on hydrotrope–water interactions. Figure 6 supports this hypothesis given that (i) log (KOW), being a surrogate for the extent of hydrotrope–water interactions, correlates well with b, and (ii) both correlations are identical and independent of the solute (i.e., for any given hydrotrope, the values of b exhibited by ferulic and syringic acids are approximately the same).
The interpretation of parameter b, its linear dependence on the hydrophobicity of the hydrotrope, and its independence from the nature of the solute are further supported by the values of b obtained for a series of solutes in Cyrene. (11) These displayed reasonably small changes (roughly 30%) across solute log (KOW) values ranging from 0 to 4, which were attributed to large variations across parameter m. In addition, it is important to note that solubilization in water–Cyrene mixtures is a complex process due to the partial and reversible reaction of Cyrene with water to form its corresponding geminal diol. Although this was neglected in the present work, it was accounted for in the aforementioned correlation of Cyrene-based b parameters. All in all, the relationships identified in Figures 5 and 6 are excellent guidelines for the design of novel hydrotropes targeted at enhancing the aqueous solubility of hydrophobic solutes.

Conclusions

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The hydrotropic ability of some biobased solvents to enhance the solubility of model hydrophobic compounds was evaluated here. In general, all solvents presented a significant hydrotropic effect. According to the solubility curves here measured, the best biobased solvent was GVL, showing a 237-fold increase in solubility for ferulic acid and up to a 99-fold increase for syringic acid.
The behaviors and trends observed depended on the concentration and structure of the biobased solvents. The study of the low-concentration region based on the Setschenow equation demonstrated that the hydrotrope hydrophobicity plays the dominant role in the enhanced solubility observed in this region. The high-concentration region was analyzed using the cooperative hydrotropy model that was used to correlate the experimental data measured in this work. The parameters obtained revealed a relationship between parameter m and hydrotrope log (KOW), which was more complex than that observed in the dilute region, resulting from hydrotrope–hydrotrope interactions that are not negligible at high concentrations. On the other hand, parameter b showed a linear dependence on the hydrophobicity of the hydrotrope, which was surprisingly independent of the type of solute.
For the solutes studied, it was shown that the hydrophobicity of GVL represents the best balance between solute–hydrotrope and hydrotrope–hydrotrope aggregation, with this hydrotrope being the third best performing in the low-concentration region and the best performing in the high-concentration region. All in all, this work highlights useful relationships between the performance of hydrotropes and the hydrophobicity of both hydrotropes and solutes and reveals the highly attractive potential of biobased solvents as hydrotropes.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.iecr.3c01469.

  • Solubility data (Tables S1 and S2); pH of water–biobased mixtures (Tables S3–S5); Setschenow constant for the hydrophobic compounds in the study in aqueous solutions of biobased solvents (Figures S1 and S2); and parameters acquired from the cooperative model (Table S6 and Figures S3 and S4) (PDF)

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Author Information

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  • Corresponding Authors
  • Authors
    • Sandra S. Silva - CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro (UA), 3810-193 Aveiro, Portugal
    • Dinis O. Abranches - CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro (UA), 3810-193 Aveiro, Portugal
    • Ana S. Pinto - CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro (UA), 3810-193 Aveiro, Portugal
    • Bruna P. Soares - CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro (UA), 3810-193 Aveiro, PortugalOrcidhttps://orcid.org/0000-0002-3126-0900
    • João A. P. Coutinho - CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro (UA), 3810-193 Aveiro, PortugalOrcidhttps://orcid.org/0000-0002-3841-743X
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was partly developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020, and LA/P/0006/2020, financed by national funds through the FCT/MCTES (PIDDAC). H.P. and A.M.F. thank the FCT for contracts CEECIND/00831/2017 and CEECIND/00361/2022, respectively, under the Scientific Stimulus─Individual Call.

References

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This article references 34 other publications.

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    Paul, R.; Chattaraj, K. G.; Paul, S. Role of Hydrotropes in Sparingly Soluble Drug Solubilization: Insight from a Molecular Dynamics Simulation and Experimental Perspectives. Langmuir 2021, 37, 47454762,  DOI: 10.1021/acs.langmuir.1c00169
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    Patel, A. D.; Desai, M. A. Progress in the Field of Hydrotropy: Mechanism, Applications and Green Concepts. Rev. Chem. Eng. 2023, 39, 601630,  DOI: 10.1515/revce-2021-0012
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    de Faria, E. L. P.; Ferreira, A. M.; Cláudio, A. F. M.; Coutinho, J. A. P.; Silvestre, A. J. D.; Freire, M. G. Recovery of Syringic Acid from Industrial Food Waste with Aqueous Solutions of Ionic Liquids. ACS Sustainable Chem. Eng. 2019, 7, 1414314152,  DOI: 10.1021/acssuschemeng.9b02808
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    Petigny, L.; Özel, M. Z.; Périno, S.; Wajsman, J.; Chemat, F. Water as Green Solvent for Extraction of Natural Products. In Green Extraction of Natural Products; Wiley Online Books; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015; pp 237264  DOI: 10.1002/9783527676828.ch7 .
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    Booth, J. J.; Abbott, S.; Shimizu, S. Mechanism of Hydrophobic Drug Solubilization by Small Molecule Hydrotropes. J. Phys. Chem. B 2012, 116, 1491514921,  DOI: 10.1021/jp309819r
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    Soares, B. P.; Abranches, D. O.; Sintra, T. E.; Leal-Duaso, A.; García, J. I.; Pires, E.; Shimizu, S.; Pinho, S. P.; Coutinho, J. A. P. Glycerol Ethers as Hydrotropes and Their Use to Enhance the Solubility of Phenolic Acids in Water. ACS Sustainable Chem. Eng. 2020, 8, 57425749,  DOI: 10.1021/acssuschemeng.0c01032
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    Moity, L.; Shi, Y.; Molinier, V.; Dayoub, W.; Lemaire, M.; Aubry, J.-M. Hydrotropic Properties of Alkyl and Aryl Glycerol Monoethers. J. Phys. Chem. B 2013, 117, 92629272,  DOI: 10.1021/jp403347u
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    Abranches, D. O.; Soares, B. P.; Ferreira, A. M.; Shimizu, S.; Pinho, S. P.; Coutinho, J. A. P. The Impact of Size and Shape in the Performance of Hydrotropes: A Case-Study of Alkanediols. Phys. Chem. Chem. Phys. 2022, 24, 76247634,  DOI: 10.1039/D2CP00496H
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    Abranches, D. O.; Benfica, J.; Shimizu, S.; Coutinho, J. A. P. The Perspective of Cooperative Hydrotropy on the Solubility in Aqueous Solutions of Cyrene. Ind. Eng. Chem. Res. 2020, 59, 1864918658,  DOI: 10.1021/acs.iecr.0c02346
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    Abranches, D. O.; Benfica, J.; Shimizu, S.; Coutinho, J. A. P. Solubility Enhancement of Hydrophobic Substances in Water/Cyrene Mixtures: A Computational Study. Ind. Eng. Chem. Res. 2020, 59, 1824718253,  DOI: 10.1021/acs.iecr.0c03155
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    De bruyn, M.; Budarin, V. L.; Misefari, A.; Shimizu, S.; Fish, H.; Cockett, M.; Hunt, A. J.; Hofstetter, H.; Weckhuysen, B. M.; Clark, J. H.; Macquarrie, D. J. Geminal Diol of Dihydrolevoglucosenone as a Switchable Hydrotrope: A Continuum of Green Nanostructured Solvents. ACS Sustainable Chem. Eng. 2019, 7, 78787883,  DOI: 10.1021/acssuschemeng.9b00470
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    Kerkel, F.; Markiewicz, M.; Stolte, S.; Müller, E.; Kunz, W. The Green Platform Molecule Gamma-Valerolactone – Ecotoxicity, Biodegradability, Solvent Properties, and Potential Applications. Green Chem. 2021, 23, 29622976,  DOI: 10.1039/D0GC04353B
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    Lê, H. Q.; Ma, Y.; Borrega, M.; Sixta, H. Wood Biorefinery Based on γ-Valerolactone/Water Fractionation. Green Chem. 2016, 18, 54665476,  DOI: 10.1039/C6GC01692H
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    Klossek, M. L.; Touraud, D.; Kunz, W. Eco-Solvents – Cluster-Formation, Surfactantless Microemulsions and Facilitated Hydrotropy. Phys. Chem. Chem. Phys. 2013, 15, 10971,  DOI: 10.1039/c3cp50636c
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    Granatier, M.; Lê, H. Q.; González, E. C.; Sixta, H. Birch Fractionation in γ-Valerolactone with the Emphasis on Pulp Properties: Prehydrolysis, Acid-Catalyzed, and Alkaline-Catalyzed Concept. RSC Sustain. 2023, 1, 97106,  DOI: 10.1039/D2SU00046F
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    Horváth, I. T.; Mehdi, H.; Fábos, V.; Boda, L.; Mika, L. T. γ-Valerolactone─a Sustainable Liquid for Energy and Carbon-Based Chemicals. Green Chem. 2008, 10, 238242,  DOI: 10.1039/B712863K
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    Api, A. M.; Belmonte, F.; Belsito, D.; Biserta, S.; Botelho, D.; Bruze, M.; Burton, G. A.; Buschmann, J.; Cancellieri, M. A.; Dagli, M. L.; Date, M.; Dekant, W.; Deodhar, C.; Fryer, A. D.; Gadhia, S.; Jones, L.; Joshi, K.; Lapczynski, A.; Lavelle, M.; Liebler, D. C.; Na, M.; O’Brien, D.; Patel, A.; Penning, T. M.; Ritacco, G.; Rodriguez-Ropero, F.; Romine, J.; Sadekar, N.; Salvito, D.; Schultz, T. W.; Sipes, I. G.; Sullivan, G.; Thakkar, Y.; Tokura, Y.; Tsang, S. RIFM Fragrance Ingredient Safety Assessment, γ-Valerolactone, CAS Registry Number 108-29-2. Food Chem. Toxicol. 2019, 134, 110950  DOI: 10.1016/j.fct.2019.110950
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    Krishna, S. H.; Huang, K.; Barnett, K. J.; He, J.; Maravelias, C. T.; Dumesic, J. A.; Huber, G. W.; De bruyn, M.; Weckhuysen, B. M. Oxygenated Commodity Chemicals from Chemo-catalytic Conversion of Biomass Derived Heterocycles. AIChE J. 2018, 64, 19101922,  DOI: 10.1002/aic.16172
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    Bangalore Ashok, R. P.; Oinas, P.; Forssell, S. Techno-Economic Evaluation of a Biorefinery to Produce γ-Valerolactone (GVL), 2-Methyltetrahydrofuran (2-MTHF) and 5-Hydroxymethylfurfural (5-HMF) from Spruce. Renew. Energy 2022, 190, 396407,  DOI: 10.1016/j.renene.2022.03.128
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    Bitencourt, R. G.; Cabral, F. A.; Meirelles, A. J. A. Ferulic Acid Solubility in Supercritical Carbon Dioxide, Ethanol and Water Mixtures. J. Chem. Thermodyn. 2016, 103, 285291,  DOI: 10.1016/j.jct.2016.08.025
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This article is cited by 1 publications.

  1. Anjali, Siddharth Pandey. Formation of Ethanolamine-Mediated Surfactant-Free Microemulsions Using Hydrophobic Deep Eutectic Solvents. Langmuir 2024, 40 (4) , 2254-2267. https://doi.org/10.1021/acs.langmuir.3c03324
  • Abstract

    Figure 1

    Figure 1. Chemical structure of the solutes and hydrotropes used in this work.

    Figure 2

    Figure 2. Solubility enhancement (S/S0) for syringic acid and ferulic acid in aqueous solutions of biobased solvents: (blue circle) GVL, (orange square) 1,6-hexanediol, (green triangle) Cyrene, (red square) 1,5-pentanediol, (black diamond) ethyl lactate and (pink square) 1,2-propanediol as a function of hydrotrope concentration (CH) at (303.2 ± 0.5) K. S and S0 represent the solubilities of the solute in aqueous solutions of biobased solvents (hydrotrope) and in pure water, respectively. The dashed lines are visual guides.

    Figure 3

    Figure 3. Representation of KS as a function of the logarithm of the octanol–water partition coefficient of hydrotropes, log (KOW), for (blue circle) syringic acid and (orange triangle) ferulic acid.

    Figure 4

    Figure 4. Representation of the cooperative model to fit the solubility curve (sigmoidal curve) of syringic and ferulic acid in the presence of aqueous solutions of biobased solvents: (blue circle) GVL, (orange square) 1,6-hexanediol, (red square) 1,5-pentanediol, (green triangle) Cyrene and (gray diamond) ethyl lactate, and (pink square) 1,2-propanediol as a function of hydrotrope mole fraction (xH) at (303.2 ± 0.5) K.

    Figure 5

    Figure 5. Parameter m of the cooperative model of hydrotropy as a function of the logarithm of the partition coefficient between octanol and water of the hydrotropes, log (KOW), for syringic acid (blue circle) and ferulic acid (orange triangle). Coefficients of determination pertain to the second-order polynomial regressions for each data set.

    Figure 6

    Figure 6. Parameter b of the cooperative model of hydrotropy as a function of the logarithm of the partition coefficient between octanol and water of the hydrotropes, log (KOW), for syringic acid (blue circle) and ferulic acid (orange triangle). The coefficient of determination pertains to a single linear regression of both data sets.

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 34 other publications.

    1. 1
      Puangpraphant, S.; Cuevas-Rodríguez, E.-O.; Oseguera-Toledo, M. Anti-Inflammatory and Antioxidant Phenolic Compounds. In Current Advances for Development of Functional Foods Modulating Inflammation and Oxidative Stress; Hernández-Ledesma, B.; Martínez-Villaluenga, C., Eds.; Elsevier, 2022; pp 165180  DOI: 10.1016/B978-0-12-823482-2.00018-2 .
    2. 2
      Cory, H.; Passarelli, S.; Szeto, J.; Tamez, M.; Mattei, J. The Role of Polyphenols in Human Health and Food Systems: A Mini-Review. Front. Nutr. 2018, 5, 87  DOI: 10.3389/fnut.2018.00087
    3. 3
      Paul, R.; Chattaraj, K. G.; Paul, S. Role of Hydrotropes in Sparingly Soluble Drug Solubilization: Insight from a Molecular Dynamics Simulation and Experimental Perspectives. Langmuir 2021, 37, 47454762,  DOI: 10.1021/acs.langmuir.1c00169
    4. 4
      Patel, A. D.; Desai, M. A. Progress in the Field of Hydrotropy: Mechanism, Applications and Green Concepts. Rev. Chem. Eng. 2023, 39, 601630,  DOI: 10.1515/revce-2021-0012
    5. 5
      de Faria, E. L. P.; Ferreira, A. M.; Cláudio, A. F. M.; Coutinho, J. A. P.; Silvestre, A. J. D.; Freire, M. G. Recovery of Syringic Acid from Industrial Food Waste with Aqueous Solutions of Ionic Liquids. ACS Sustainable Chem. Eng. 2019, 7, 1414314152,  DOI: 10.1021/acssuschemeng.9b02808
    6. 6
      Petigny, L.; Özel, M. Z.; Périno, S.; Wajsman, J.; Chemat, F. Water as Green Solvent for Extraction of Natural Products. In Green Extraction of Natural Products; Wiley Online Books; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015; pp 237264  DOI: 10.1002/9783527676828.ch7 .
    7. 7
      Abranches, D. O.; Benfica, J.; Soares, B. P.; Leal-Duaso, A.; Sintra, T. E.; Pires, E.; Pinho, S. P.; Shimizu, S.; Coutinho, J. A. P. Unveiling the Mechanism of Hydrotropy: Evidence for Water-Mediated Aggregation of Hydrotropes around the Solute. Chem. Commun. 2020, 56, 71437146,  DOI: 10.1039/D0CC03217D
    8. 8
      Booth, J. J.; Abbott, S.; Shimizu, S. Mechanism of Hydrophobic Drug Solubilization by Small Molecule Hydrotropes. J. Phys. Chem. B 2012, 116, 1491514921,  DOI: 10.1021/jp309819r
    9. 9
      Soares, B. P.; Abranches, D. O.; Sintra, T. E.; Leal-Duaso, A.; García, J. I.; Pires, E.; Shimizu, S.; Pinho, S. P.; Coutinho, J. A. P. Glycerol Ethers as Hydrotropes and Their Use to Enhance the Solubility of Phenolic Acids in Water. ACS Sustainable Chem. Eng. 2020, 8, 57425749,  DOI: 10.1021/acssuschemeng.0c01032
    10. 10
      Moity, L.; Shi, Y.; Molinier, V.; Dayoub, W.; Lemaire, M.; Aubry, J.-M. Hydrotropic Properties of Alkyl and Aryl Glycerol Monoethers. J. Phys. Chem. B 2013, 117, 92629272,  DOI: 10.1021/jp403347u
    11. 11
      Abranches, D. O.; Soares, B. P.; Ferreira, A. M.; Shimizu, S.; Pinho, S. P.; Coutinho, J. A. P. The Impact of Size and Shape in the Performance of Hydrotropes: A Case-Study of Alkanediols. Phys. Chem. Chem. Phys. 2022, 24, 76247634,  DOI: 10.1039/D2CP00496H
    12. 12
      Abranches, D. O.; Benfica, J.; Shimizu, S.; Coutinho, J. A. P. The Perspective of Cooperative Hydrotropy on the Solubility in Aqueous Solutions of Cyrene. Ind. Eng. Chem. Res. 2020, 59, 1864918658,  DOI: 10.1021/acs.iecr.0c02346
    13. 13
      Abranches, D. O.; Benfica, J.; Shimizu, S.; Coutinho, J. A. P. Solubility Enhancement of Hydrophobic Substances in Water/Cyrene Mixtures: A Computational Study. Ind. Eng. Chem. Res. 2020, 59, 1824718253,  DOI: 10.1021/acs.iecr.0c03155
    14. 14
      De bruyn, M.; Budarin, V. L.; Misefari, A.; Shimizu, S.; Fish, H.; Cockett, M.; Hunt, A. J.; Hofstetter, H.; Weckhuysen, B. M.; Clark, J. H.; Macquarrie, D. J. Geminal Diol of Dihydrolevoglucosenone as a Switchable Hydrotrope: A Continuum of Green Nanostructured Solvents. ACS Sustainable Chem. Eng. 2019, 7, 78787883,  DOI: 10.1021/acssuschemeng.9b00470
    15. 15
      Kerkel, F.; Markiewicz, M.; Stolte, S.; Müller, E.; Kunz, W. The Green Platform Molecule Gamma-Valerolactone – Ecotoxicity, Biodegradability, Solvent Properties, and Potential Applications. Green Chem. 2021, 23, 29622976,  DOI: 10.1039/D0GC04353B
    16. 16
      Lê, H. Q.; Ma, Y.; Borrega, M.; Sixta, H. Wood Biorefinery Based on γ-Valerolactone/Water Fractionation. Green Chem. 2016, 18, 54665476,  DOI: 10.1039/C6GC01692H
    17. 17
      Klossek, M. L.; Touraud, D.; Kunz, W. Eco-Solvents – Cluster-Formation, Surfactantless Microemulsions and Facilitated Hydrotropy. Phys. Chem. Chem. Phys. 2013, 15, 10971,  DOI: 10.1039/c3cp50636c
    18. 18
      Granatier, M.; Lê, H. Q.; González, E. C.; Sixta, H. Birch Fractionation in γ-Valerolactone with the Emphasis on Pulp Properties: Prehydrolysis, Acid-Catalyzed, and Alkaline-Catalyzed Concept. RSC Sustain. 2023, 1, 97106,  DOI: 10.1039/D2SU00046F
    19. 19
      Organization, W. H. Summary of Evaluations Performed by the Joint FAO/WHO Expert Committee on Food Additives - gamma-VALEROLACTONE. https://inchem.org/documents/jecfa/jeceval/jec_2378.htm (accessed May 4, 2022).
    20. 20
      Organization, W. H. Summary of Evaluations Performed by the Joint FAO/WHO Expert Committee on Food Additives - Propylene glycol. https://www.inchem.org/documents/jecfa/jeceval/jec_2031.htm (accessed Apr 17, 2023).
    21. 21
      Horváth, I. T.; Mehdi, H.; Fábos, V.; Boda, L.; Mika, L. T. γ-Valerolactone─a Sustainable Liquid for Energy and Carbon-Based Chemicals. Green Chem. 2008, 10, 238242,  DOI: 10.1039/B712863K
    22. 22
      Api, A. M.; Belmonte, F.; Belsito, D.; Biserta, S.; Botelho, D.; Bruze, M.; Burton, G. A.; Buschmann, J.; Cancellieri, M. A.; Dagli, M. L.; Date, M.; Dekant, W.; Deodhar, C.; Fryer, A. D.; Gadhia, S.; Jones, L.; Joshi, K.; Lapczynski, A.; Lavelle, M.; Liebler, D. C.; Na, M.; O’Brien, D.; Patel, A.; Penning, T. M.; Ritacco, G.; Rodriguez-Ropero, F.; Romine, J.; Sadekar, N.; Salvito, D.; Schultz, T. W.; Sipes, I. G.; Sullivan, G.; Thakkar, Y.; Tokura, Y.; Tsang, S. RIFM Fragrance Ingredient Safety Assessment, γ-Valerolactone, CAS Registry Number 108-29-2. Food Chem. Toxicol. 2019, 134, 110950  DOI: 10.1016/j.fct.2019.110950
    23. 23
      Krishna, S. H.; Huang, K.; Barnett, K. J.; He, J.; Maravelias, C. T.; Dumesic, J. A.; Huber, G. W.; De bruyn, M.; Weckhuysen, B. M. Oxygenated Commodity Chemicals from Chemo-catalytic Conversion of Biomass Derived Heterocycles. AIChE J. 2018, 64, 19101922,  DOI: 10.1002/aic.16172
    24. 24
      Bangalore Ashok, R. P.; Oinas, P.; Forssell, S. Techno-Economic Evaluation of a Biorefinery to Produce γ-Valerolactone (GVL), 2-Methyltetrahydrofuran (2-MTHF) and 5-Hydroxymethylfurfural (5-HMF) from Spruce. Renew. Energy 2022, 190, 396407,  DOI: 10.1016/j.renene.2022.03.128
    25. 25
      De Jong, E.; Stichnothe, H.; Bell, G.; Jørgensen, H. Bio-Based Chemicals: A 2020 Update. IEA Bioenergy, 2020, ISBN 978-1-910154-69-4.
    26. 26
      Shimizu, S.; Matubayasi, N. The Origin of Cooperative Solubilisation by Hydrotropes. Phys. Chem. Chem. Phys. 2016, 18, 2562125628,  DOI: 10.1039/C6CP04823D
    27. 27
      ChemSpider. http://www.chemspider.com/ (accessed Jun 30, 2022).
    28. 28
      Mota, F. L.; Queimada, A. J.; Pinho, S. P.; Macedo, E. A. Aqueous Solubility of Some Natural Phenolic Compounds. Ind. Eng. Chem. Res. 2008, 47, 51825189,  DOI: 10.1021/ie071452o
    29. 29
      Bitencourt, R. G.; Cabral, F. A.; Meirelles, A. J. A. Ferulic Acid Solubility in Supercritical Carbon Dioxide, Ethanol and Water Mixtures. J. Chem. Thermodyn. 2016, 103, 285291,  DOI: 10.1016/j.jct.2016.08.025
    30. 30
      ChemAxon. https://chemaxon.com/products/marvin (accessed Oct 28, 2021).
    31. 31
      De Faria, E. L. P.; Shabudin, S. V.; Claúdio, A. F. M.; Válega, M.; Domingues, F. M. J.; Freire, C. S. R.; Silvestre, A. J. D.; Freire, M. G. Aqueous Solutions of Surface-Active Ionic Liquids: Remarkable Alternative Solvents to Improve the Solubility of Triterpenic Acids and Their Extraction from Biomass. ACS Sustainable Chem. Eng. 2017, 5, 73447351,  DOI: 10.1021/acssuschemeng.7b01616
    32. 32
      Yuan, J.; Zhou, N.; Wu, J.; Yin, T.; Jia, Y. Ionic Liquids as Effective Additives to Enhance the Solubility and Permeation for Puerarin and Ferulic Acid. RSC Adv. 2022, 12, 34163422,  DOI: 10.1039/d1ra07080k
    33. 33
      Abbott, S.; Booth, J. J.; Shimizu, S. Practical Molecular Thermodynamics for Greener Solution Chemistry. Green Chem. 2017, 19, 6875,  DOI: 10.1039/C6GC03002E
    34. 34
      Bauduin, P.; Renoncourt, A.; Kopf, A.; Touraud, D.; Kunz, W. Unified Concept of Solubilization in Water by Hydrotropes and Cosolvents. Langmuir 2005, 21, 67696775,  DOI: 10.1021/la050554l
  • Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.iecr.3c01469.

    • Solubility data (Tables S1 and S2); pH of water–biobased mixtures (Tables S3–S5); Setschenow constant for the hydrophobic compounds in the study in aqueous solutions of biobased solvents (Figures S1 and S2); and parameters acquired from the cooperative model (Table S6 and Figures S3 and S4) (PDF)


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