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Snapshots of QAILS + GA systems (Table S1, ESI †: 1-21) after the production runs. Each number on the bottom right corner of each snapshot indicates the system number according to Table S1 (ESI †). Control systems are QAILS aqueous solutions. QAILS cations polar heads are represented in purple and their alkyl chains in green. For GA, the carboxylic acid group is coloured in blue, the aromatic ring in yellow and the hydroxyls in red. Water, chloride and sodium molecules were removed for clarity.

Snapshots of QAILS + GA systems (Table S1, ESI †: 1-21) after the production runs. Each number on the bottom right corner of each snapshot indicates the system number according to Table S1 (ESI †). Control systems are QAILS aqueous solutions. QAILS cations polar heads are represented in purple and their alkyl chains in green. For GA, the carboxylic acid group is coloured in blue, the aromatic ring in yellow and the hydroxyls in red. Water, chloride and sodium molecules were removed for clarity.

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Article
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Solubilizing agents are widely used to extract poorly soluble compounds from biological matrices. Aqueous solutions of surfactants and hydrotropes are commonly used as solubilizers, however, the underlying mechanism that determines their action is still roughly understood. Among these, ionic liquids (IL) are often used not only for solubilization o...

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... CG version. The GA-AA forcefield parameters were taken from the OPLS-AA forcefield 68 while water molecules were represented by the SPC/E model. 69 The GA atomic partial charges were obtained by DFT optimization in the gas-phase at the B3LYP 70 /6-31G* level of theory with the CHELPG option 71 using the Gaussian 09 package 72 and are displayed in Fig. S2 (ESI †). A visual representation of electrostatic potential mapped of the electron density is also available as a guideline in Fig. S3 (ESI ...
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... discussion initially focuses in the higher GA concentration for clarity, as the overall phase behaviour is more evident. The MD snapshots after at least 0.5 ms of simulation time for all systems are depicted in Fig. 2. A visual inspection indicates the distinct behaviour of the three QAILS, and that the solvation of GA within the QAILS aggregates decreased in all systems when triply deprotonated. Overall, although the solvation of GA seems similar when considering both GA concentrations, this variable significantly affected the phase behaviour of ...
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... (red and orange curves) with the surfactant head groups (purple) suggests that Deprot. GA (À3) nearly adopts a flat conformation on the outer micelle surface. The [N 1,1,1,14 ]Cl phase behaviour and the GA solvation on these systems were the same in the systems with a lower GA concentration, although less visible in the latter as illustrated in Fig. 2. For increased clarity, a scheme of the different orientations of GA molecules, depending on their protonation state, on [N 1,1,1,14 ] + micelles is depicted in Fig. ...
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... GA solvation in [N 4,4,4,14 ]Cl. Unlike what can be observed in Fig. 2 for the [N 1,1,1,14 ]Cl system, the GA concentration has a marked influence on the phase behaviour of [N 4,4,4,14 ]Cl. At a GA concentration below its solubility limit in pure water, the QAILS remained in a micellar regime (Fig. 2), also evidenced in the micelle density profiles shown in Fig. S6 (ESI †) for all GA protonation states. However, when the ...
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... GA solvation in [N 4,4,4,14 ]Cl. Unlike what can be observed in Fig. 2 for the [N 1,1,1,14 ]Cl system, the GA concentration has a marked influence on the phase behaviour of [N 4,4,4,14 ]Cl. At a GA concentration below its solubility limit in pure water, the QAILS remained in a micellar regime (Fig. 2), also evidenced in the micelle density profiles shown in Fig. S6 (ESI †) for all GA protonation states. However, when the GA concentration is increased in the [N 4,4,4,14 ]Cl system, it evolves towards a phase separation (Fig. 2). Regardless of the GA concentration, the GA orientation in [N 4,4,4,14 ] + micelles is similar to that ...
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... 4,4,4,14 ]Cl. At a GA concentration below its solubility limit in pure water, the QAILS remained in a micellar regime (Fig. 2), also evidenced in the micelle density profiles shown in Fig. S6 (ESI †) for all GA protonation states. However, when the GA concentration is increased in the [N 4,4,4,14 ]Cl system, it evolves towards a phase separation (Fig. 2). Regardless of the GA concentration, the GA orientation in [N 4,4,4,14 ] + micelles is similar to that observed with [N 1,1,1,14 ]Cl as shown in the density profiles displayed in Fig. 5 and Fig. S6 (ESI †) for high and low GA concentrations respectively. For the systems with higher GA concentration, differences in the GA protonation ...
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... of repulsion between charged head groups and attracted solvophobic regions. 81,82 On the other hand, in the [N 4,4,4,14 ]Cl, the increased volume of the non-polar groups in the polar head screen the head-group density charge, rendering it closer to a non-ionic surfactant behaviour. 79 The phase transition from a micellar to a phase separation (Fig. 2) can thus be explained by the progressive aggregation, due to their more hydrophobic character, of the QAILS head-groups. 83,84 The deprotonation of GA also promotes the electrostatic interaction between the QAILS and GA, further enhancing this phenomenon. In this case, the variation of the deprotonation degree of GA seems to interfere ...
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... hydrophobic character, of the QAILS head-groups. 83,84 The deprotonation of GA also promotes the electrostatic interaction between the QAILS and GA, further enhancing this phenomenon. In this case, the variation of the deprotonation degree of GA seems to interfere with the overall phase behaviour favoured by the head group size difference of [ Fig. 2 Control. The GA solvation is discussed based in the simulation box density profiles shown in Fig. 6 and by visually inspecting the simulation snapshots displayed in Fig. 2. As mentioned the [N 4,4,4,4 ]Cl was fully dispersed in aqueous solution in absence of GA or even at low GA concentration as shown in Fig. 2. However, when the GA ...
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... phenomenon. In this case, the variation of the deprotonation degree of GA seems to interfere with the overall phase behaviour favoured by the head group size difference of [ Fig. 2 Control. The GA solvation is discussed based in the simulation box density profiles shown in Fig. 6 and by visually inspecting the simulation snapshots displayed in Fig. 2. As mentioned the [N 4,4,4,4 ]Cl was fully dispersed in aqueous solution in absence of GA or even at low GA concentration as shown in Fig. 2. However, when the GA concentration is increased, large clusters were observed not only for Prot. GA, as expected, but for all three GA protonation states. The [N 4,4,4,4 ]-GA cluster sizes at ...
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... the head group size difference of [ Fig. 2 Control. The GA solvation is discussed based in the simulation box density profiles shown in Fig. 6 and by visually inspecting the simulation snapshots displayed in Fig. 2. As mentioned the [N 4,4,4,4 ]Cl was fully dispersed in aqueous solution in absence of GA or even at low GA concentration as shown in Fig. 2. However, when the GA concentration is increased, large clusters were observed not only for Prot. GA, as expected, but for all three GA protonation states. The [N 4,4,4,4 ]-GA cluster sizes at high GA concentration were estimated to range from 74 Å in Prot. GA to 104 Å in Deprot. GA (À1) and 118 Å in the Deprot. GA ...
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... (C). The density profile was obtained along the z-axis. QAILS cation polar heads are shown in purple, tail atoms in green. GA was split in the three different bead types: indigo for the carboxylic acid moiety, red for the hydroxyls and brown for the aromatic ring. Chloride ions were represented in black, sodium ions in yellow and water in cyan. Fig. 2 suggests that all systems with a high concentration of GA induce a phase separation of [N 4,4,4,4 ] + from water, as confirmed in the density profile of Fig. 6. Although this phenomenon has not been experimentally observed for this system, phase separation resulting from the enhanced solubility in hydrotropic systems was previously ...
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... it cannot be rationalized in the same way as the two other systems. Indeed, as the deprotonation degree of GA was increased, the resolution of this phase separation was clearer, as noted by the more defined peaks of both water and the hydrotrope in Fig. 6, and the Deprot. GA (À3) system resulted in a single and larger cluster of [N 4,4,4,4 ] + (Fig. 2). These indicate that different underlying mechanisms, depending on the presence of GA as neutral or as a highly charged ion (deprotonated), are taking ...
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... discussion above revealed that the mutual QAILS and GA interactions affect both the GA solvation and the QAILS phase behaviour. This was particularly noticeable in systems with bulkier QAILS, namely [N 4,4,4,14 ]Cl and [N 4,4,4,4 ]Cl. The final simulation snapshots at higher GA concentration (Fig. 2) In [N 1,1,1,14 ]Cl systems, a stable micellar QAILS phase remains in presence of GA. However, individual micelles seem to interact and enlarge with increasing GA charge density. A similar scenario occurs with [N 4,4,4,14 ]Cl, albeit even more noticeable, as eventually it leads to a phase separation. Combining this with the GA solvation ...

Citations

... diffusion) could be obtained using the coarse-grained MD simulation [68]. Contrarily to the mostly researched structural and dynamical properties of ILs with coarse-grain models, a further understanding of the behavior of ILs in aqueous media has currently been available [69,70]. As shown in Fig. 2 [70]. ...
Article
Ionic liquids (ILs) have been widely used in biomedical and pharmaceutical fields as solvents or permeation enhancers. Recently, more and more researchers focused on optimizing the physicochemical properties of active pharmaceutical ingredient (API) by ILs technology. Converting APIs into ILs (API-ILs) has shown great potential for drug delivery by eliminating polymorphism, tailoring solubility, improving thermal stability, increasing dissolution, controlling drug release, modulating the surfactant properties, enhancing permeability of APIs and modulating cytotoxicity on tumor cells. In addition, API-ILs are also used in various formulations as active ingredients, such as solutions, emulsions, even tablets or nanoparticles. This paper aims to review current status of API-ILs, including the rational and design, preparation and characterization, the improvement on the physicochemical characteristics of APIs, the compatibility of API-ILs with various formulations, and the future prospects of API-ILs in biomedical and pharmaceutical fields.
... 118 Bastos et al. provide a clear understanding of the micellar and hydrotropic solubilization mechanisms of gallic acid using some aqueous solutions of quaternary ammonium ionic liquids. 119 These ionic liquids may be hydrotropes, surfactants, or the combined characteristics of other compounds. A new coarse-grain (CG)-based MARTINI force field for gallic acid was developed by them. ...
... These solubilization studies using MD simulations could complement the experimental studies, and a quick scan of molecules for these processes could be possible. 119 tert-Butyl alcohol was used as a nonionic hydrotrope, and OPLS force field parameters were utilized for this. 78 ...
... 118 Bastos et al. provide a clear understanding of the micellar and hydrotropic solubilization mechanisms of gallic acid using some aqueous solutions of quaternary ammonium ionic liquids. 119 These ionic liquids may be hydrotropes, surfactants, or the combined characteristics of other compounds. A new coarse-grain (CG)-based MARTINI force field for gallic acid was developed by them. ...
... These solubilization studies using MD simulations could complement the experimental studies, and a quick scan of molecules for these processes could be possible. 119 tert-Butyl alcohol was used as a nonionic hydrotrope, and OPLS force field parameters were utilized for this. 78 ...
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