Ionic Liquid-Based Green Emulsion Liquid Membrane for the Extraction of the Poorly Soluble Drug Ibuprofen

Ibuprofen (Ibf) is a biologically active drug (BADs) and an emerging contaminant of concern (CECs) in aqueous streams. Due to its adverse effects upon aquatic organisms and humans, the removal and recovery of Ibf are essential. Usually, conventional solvents are employed for the separation and recovery of ibuprofen. Due to environmental limitations, alternative green extracting agents need to be explored. Ionic liquids (ILs), emerging and greener alternatives, can also serve this purpose. It is essential to explore ILs that are effective for recovering ibuprofen, among millions of ILs. The conductor-like screening model for real solvents (COSMO-RS) is an efficient tool that can be used to screen ILs specifically for ibuprofen extraction. The main objective of this work was to identify the best IL for the extraction of ibuprofen. A total of 152 different cation–anion combinations consisting of eight aromatic and non-aromatic cations and nineteen anions were screened. The evaluation was based upon activity coefficients, capacity, and selectivity values. Furthermore, the effect of alkyl chain length was studied. The results suggest that quaternary ammonium (cation) and sulfate (anion) have better extraction ability for ibuprofen than the other combinations tested. An ionic liquid-based green emulsion liquid membrane (ILGELM) was developed using the selected ionic liquid as the extractant, sunflower oil as the diluent, Span 80 as the surfactant, and NaOH as the stripping agent. Experimental verification was carried out using the ILGELM. The experimental results indicated that the predicted COSMO-RS and the experimental results were in good agreement. The proposed IL-based GELM is highly effective for the removal and recovery of ibuprofen.


Introduction
Ibuprofen (Ibf)-chemical formula C 13 H 18 O 2 -is a nonsteroidal anti-inflammatory drug (NSAID), listed as a contaminant of emerging concern (CECs) [1,2]. It is the world's third most consumed medication [3]. It is used for treating arthritis and musculoskeletal disorders in adults and children [4]. Ibf, when disposed of through various means such as from hospitals, manufacturing industries, excretion processes, etc., undergoes several reactions resulting in more hazardous compounds than the parent drug [5]. The concentration of Ibf in different aqueous streams is greater than 1000 ng/L and poses a great risk to the environment [6]. For the removal of Ibf, commonly used methods include liquid chromatography-mass spectrometry (LC-MS), high-performance liquid chromatography (HPLC) [7], solid-phase extraction (SPE) [8], dispersive liquid-liquid microextraction [9], ultrafiltration, nanofiltration [10], activated carbon [11], etc. These methods employ toxic solvents such as hexane, heptane, etc. [12], that are hazardous to

Results and Discussion
This section presents the results obtained using COSMO-RS for Ibf, the development of the ILGELM using the screened IL, and an experimental validation. Sigma surface along with σ-profile and σ-potential are shown in Figures 1 and 2, respectively. The sigma surface represents the polarity, charge distribution, nature of bonding [39,44]. The colors green, blue, and red represent neutral, positive, and negative charges corresponding to the non-polar, H-bond donor, and H-bond acceptor regions on the σ-profiles [45]. Figure 1 shows sharp and light peaks both in polar and non-polar areas. Ibf shows a sharp peak at 0.3 e/nm 2 in the non-polar area, revealing its capacity to be more attracted to non-polar molecules. The small peaks in the H-bond acceptor region are due to the presence of the (=O group), and those in H-bond donor regions are due to the OH − group [40]. The presence of peaks in the polar areas signifies an interaction with polar compounds [46]. A small peak is observed at −1.7 e/nm 2 in the H-bond donor region, and a sharp peak at 1.2 e/nm 2 in the H-bond acceptor region. As a result, the sigma potential revealed the interaction of Ibf with ILs. Figure 2 indicates that Ibf will function more as an H-bond acceptor (=O group); hence, it will interact and bond well with H-bond donor molecules. The polar nature of Ibf is due to the presence of the carboxylic acid group, and its non-polar nature is due to the presence of benzene and alkyl groups.

Activity Coefficient at Infinite Dilution
AC id is an important parameter for the preliminary selection of solvents for extraction [45]. The AC id values of 8 selected cations and 19 different anions forming 152 ILs

Activity Coefficient at Infinite Dilution
AC id is an important parameter for the preliminary selection of solvents for extraction [45]. The AC id values of 8 selected cations and 19 different anions forming 152 ILs

Activity Coefficient at Infinite Dilution
AC id is an important parameter for the preliminary selection of solvents for extraction [47]. The AC id values of 8 selected cations and 19 different anions forming 152 ILs combinations were predicted using COSMO-RS at room temperature. Figure 3 shows the AC id values for different cation-anion combinations screened for Ibf. The lower the value of AC id , the better is the IL for separation. The order of cations in relation to the AC id was as follows: [ . Higher values of AC id are unfavorable for ILs. The results proved that for Ibf, the cations possessing aromatic structures have high AC id values and hence poor extraction capacity for Ibf. This is due to the delocalization of charges caused by pi bonds in ring structures, which imparts stability and poor bonding ability. In contrast, the cations without ring structures, such as ammonium, choline, etc., are favorable for Ibf extraction using an ELM. This is because cation interactions are mainly due to hydrogen bonding between the cation and the heteroatom of Ibf [48]. Table S3 presents the AC id values computed using COSMO-RS.
which imparts stability and poor bonding ability. In contrast, the cations without ring structures, such as ammonium, choline, etc., are favorable for Ibf extraction using an ELM. This is because cation interactions are mainly due to hydrogen bonding between the cation and the heteroatom of Ibf [49]. Table S3 presents the AC id values computed using COSMO-RS.
The anion trend in relation to the AC id , as shown in Figure 3, was as follows: SO4 2−, < Cl − < Br − < CH3CHOO − . The Hofmeister series could well explain this trend. The trend showed that intensely hydrated ions such as SO4 2− , Cl − , and Br − possess better extracting ability for Ibf. In contrast, anions such as PF6 − , SCN − , and Ntf2 − , which are weakly hydrated, have higher values of AC id and hence are not suitable for Ibf extraction because of their instability [50]. This can further also be explained on the basis of the H-bonding ability of these anions because of their high electronegativity. SO4 2− , Cl − , and Br − can form H-bonds quickly with the OH-group of Ibf and hence are better extracting agents for Ibf. In contrast, non-coordinating anions cannot form H-bonds due to their weak bonding nature and thus are unsuitable for Ibf extraction. In addition, anions possessing strong electronwithdrawing fluorinated group results in decreased charge density [51]. These results agree with our previous work on LA showing that quaternary ammonium ILs were potentially useful for its extraction [34]. A similar trend for anions was observed in another study on Ibf where imidazolium-based ILs were studied [40].

IL Capacity towards Ibf
The capacity of the 152 IL combinations was evaluated at 25 °C, and the results are presented in Figure 4.  The anion trend in relation to the AC id , as shown in Figure 3, was as follows: SO 4 2− < Cl − < Br − < CH 3 CHOO − . The Hofmeister series could well explain this trend. The trend showed that intensely hydrated ions such as SO 4 2− , Cl − , and Br − possess better extracting ability for Ibf. In contrast, anions such as PF 6 − , SCN − , and Ntf 2 − , which are weakly hydrated, have higher values of AC id and hence are not suitable for Ibf extraction because of their instability [49]. This can further also be explained on the basis of the H-bonding ability of these anions because of their high electronegativity. SO 4 2− , Cl − , and Br − can form H-bonds quickly with the OH-group of Ibf and hence are better extracting agents for Ibf. In contrast, non-coordinating anions cannot form H-bonds due to their weak bonding nature and thus are unsuitable for Ibf extraction. In addition, anions possessing strong electron-withdrawing fluorinated group results in decreased charge density [50]. These results agree with our previous work on LA showing that quaternary ammonium ILs were potentially useful for its extraction [34]. A similar trend for anions was observed in another study on Ibf where imidazolium-based ILs were studied [40].

IL Capacity towards Ibf
The capacity of the 152 IL combinations was evaluated at 25 • C, and the results are presented in Figure 4.  Table S4 presents the capacity values. It was observed that cations consisting of π bonds, i.e., aromatic rings such as pyridinium and imidazolium, showed lower capacity values at infinite dilution (C ∞) than cations devoid of it. These results are in good agreement with the results reported in our previous study on LA [34]. Hence, it can be concluded that hydrogen bonding will favor the extraction of Ibf [51].
as pyridinium and imidazolium, showed lower capacity values at infinite dilution (C ∞) than cations devoid of it. These results are in good agreement with the results reported in our previous study on LA [34]. Hence, it can be concluded that hydrogen bonding will favor the extraction of Ibf [52].
The anion trend, as shown in Figure 4, was as follows: SO4 2− , Cl − , Br − , CH3CHOO − . The trend showed that the SO4 2 − anion possesses a high capacity compared to other anions. This can be explained as SO4 2− contains an extra negative charge, making it more suitable for H-bonding than other anions. The other anions that strongly showed higher capacity values were Cl − and Br − This can be explained based on the Hofmeister series indicating the ion specific effect, i.e., that smaller anions possess better H-bonding and are favorable for Ibf extraction. Hydrophobic anions such as PF6 − , SCN − , Ntf2 − , which are weakly hydrated and non-coordinating, have lower capacity values and hence are not suitable for Ibf extraction because of their instability [50]. This can also be explained based on the H-bonding ability of these anions. These results agree with work on eicosapentaenoic acid that found that quaternary ammonium ILs were suitable for extraction purposes [53].

Selectivity at Infinite Dilution
Selectivity is an important parameter governing the extraction ability of ILs. Selectivity towards Ibf with ammonium, pyrrolidinium, piperidinium, phosphonium, pyridinium, imidazolium, guanidinium, and choline cations along with 19 anions was estimated via COSMO-RS. The results are present in Figure 5.  Table S5 presents the values of selectivity of the ILs under study. Non-aromatic cations such as ammonium, choline, and pyrrolidinium showed higher selectivity values, hence better extraction ability for Ibf. These cations can form strong H-bonds with Ibf, hence have increased selectivity values. In contrast, aromatic cations showed less selectivity since, because of delocalization and steric hindrance, H-bonding formation was reduced [34].  The anion trend, as shown in Figure 4, was as follows: SO 4 2− , Cl − , Br − , CH 3 CHOO − . The trend showed that the SO 4 2 − anion possesses a high capacity compared to other anions. This can be explained as SO 4 2− contains an extra negative charge, making it more suitable for H-bonding than other anions. The other anions that strongly showed higher capacity values were Cl − and Br − This can be explained based on the Hofmeister series indicating the ion specific effect, i.e., that smaller anions possess better H-bonding and are favorable for Ibf extraction. Hydrophobic anions such as PF 6 − , SCN − , Ntf 2 − , which are weakly hydrated and non-coordinating, have lower capacity values and hence are not suitable for Ibf extraction because of their instability [49]. This can also be explained based on the H-bonding ability of these anions. These results agree with work on eicosapentaenoic acid that found that quaternary ammonium ILs were suitable for extraction purposes [52].

Selectivity at Infinite Dilution
Selectivity is an important parameter governing the extraction ability of ILs. Selectivity towards Ibf with ammonium, pyrrolidinium, piperidinium, phosphonium, pyridinium, imidazolium, guanidinium, and choline cations along with 19 anions was estimated via COSMO-RS. The results are present in Figure 5.  Table S5 presents the values of selectivity of the ILs under study. Non-aromatic cations such as ammonium, choline, and pyrrolidinium showed higher selectivity values, hence better extraction ability for Ibf. These cations can form strong H-bonds with Ibf, hence have increased selectivity values. In contrast, aromatic cations showed less selectivity since, because of delocalization and steric hindrance, H-bonding formation was reduced [34]. and two H-bond acceptors. S=O is a good acceptor of protons, forming an H-bond with the Ibf OHgroup, thereby improving the solvent's extraction ability. These results correlate with the results reported for αdocosahexaenoic acid and lactic acid showing that tetramethylammonium sulphate is a potential IL for these BACs [34,54].

Performance Index
The ILs which possess higher selectivity also have higher values of capacity. Sometimes, ILs that possess high selectivity may not possess high capacities or vice versa. Hence, the performance index is used to find a suitable IL. The performance index is the product of capacity and selectivity. Figure 6 presents

Performance Index
The ILs which possess higher selectivity also have higher values of capacity. Sometimes, ILs that possess high selectivity may not possess high capacities or vice versa. Hence, the performance index is used to find a suitable IL. The performance index is the product of capacity and selectivity. Figure 6 presents

Solvation Free Energies
The solvation energy is related to a molecule's basic chemical structure in the aqueous phase [55]. The solvation free energies, ∆Gsolvation, for the best cation-anion combinations were estimated using COSMO-RS. The results revealed that SO4 2− and Cl − possess more negative solvation energy values for all the four cations, with the best solubility values, compared to BF4 − and PF6 − . These results are in correlation with the AC id values. The IL with the lowest values of AC id and ∆Gsolvation, is favorable for the extraction of Ibf. Figure  7 shows the values of solvation energy for the SO4 2− anion. Amongst the cations, the quaternary ammonium cation [TMAm] showed more negative energy values for SO4 2− and Cl − anions. Hence, these two anions along with [TMAm] will be better extractant for Ibf. In ELM, they can be used as carriers or extractants for increasing the membrane's stability and efficacy. The ILs as carriers form complexes, promoting the extraction of Ibf from an aqueous solution. The is due to the hydrogen bonding that takes place between Ibf and the ILs [56].

Solvation Free Energies
The solvation energy is related to a molecule's basic chemical structure in the aqueous phase [54]. The solvation free energies, ∆G solvation , for the best cation-anion combinations were estimated using COSMO-RS. The results revealed that SO 4 2− and Cl − possess more negative solvation energy values for all the four cations, with the best solubility values, compared to BF 4 − and PF 6 − . These results are in correlation with the AC id values. The IL with the lowest values of AC id and ∆G solvation, is favorable for the extraction of Ibf. Figure 7 shows the values of solvation energy for the SO 4 2− anion. Amongst the cations, the quaternary ammonium cation [TMAm] showed more negative energy values for SO 4 2− and Cl − anions. Hence, these two anions along with [TMAm] will be better extractant for Ibf. In ELM, they can be used as carriers or extractants for increasing the membrane's stability and efficacy. The ILs as carriers form complexes, promoting the extraction of Ibf from an aqueous solution. The is due to the hydrogen bonding that takes place between Ibf and the ILs [55].

Effect of Alkyl Chain Length upon AC id , Capacity, and Selectivity
The effect of alkyl chain length on AC id , capacity, and selectivity was studied for the cation-anion combinations for selected anions. As the alkyl chain length increased, AC id increased, resulting in decreased capacity and selectivity. This could be because, as the alkyl chain increased, the hydrophobicity increased due to reduced polarity. It was also observed that ammonium-based cations with a short alkyl chain possessed better values of AC id , capacity, and selectivity than those with a longer alkyl chain. As the alkyl chain

Effect of Alkyl Chain Length upon AC id , Capacity, and Selectivity
The effect of alkyl chain length on AC id , capacity, and selectivity was studied for the cation-anion combinations for selected anions. As the alkyl chain length increased, AC id increased, resulting in decreased capacity and selectivity. This could be because, as the alkyl chain increased, the hydrophobicity increased due to reduced polarity. It was also observed that ammonium-based cations with a short alkyl chain possessed better values of AC id , capacity, and selectivity than those with a longer alkyl chain. As the alkyl chain lengthend, the COSMO volume expanded, resulting in decreased capacity and selectivity [34]. Tables S7 and S8 present the capacity and selectivity values for ILs combinations with alkyl chains. The results suggest that short-chain quaternary-ammonium ILs will be suitable as extractants for Ibf.

Extraction Performance
The ability of extraction for cations and SO 4 2− , [Cl − ], and [BF 4 − ] anions can further be explained based on the σ-profiles computed using COSMO-RS. Figure S4a  . The results revealed that hydrophobic anions showed a smaller peak and hence less capacity for H-bonding than SO 4 2− and Cl − . Figure S1b presents

ILGELM Extraction for Ibf and Experimental Verification
For the experimental verification of the COSMO-RS results, seven ILs were chosen. Extraction was carried out utilizing an ionic liquid-based emulsion liquid membrane (ILELM  4 ]. The breakage must be less than 10%; however, the lower the breakage the better the performance of the ELM. The results revealed that, in the absence of the IL, the developed ELM was highly unstable, with a high breakage of 5.2%. The addition of the IL improved the stability of the ELM; the ELM was found to be highly stable with 0.25 wt.% of IL ([TMAm][SO 4 ]). The breakage was reduced to 1.2%, and the maximum extraction efficiency was obtained.

COSMO-RS Experimental Validation Using the ILGELM
There are no studies on the AC id values for Ibf-ILs using COSMO-RS. The extraction efficiency obtained using the ILGELM was compared to the AC id predictions determined using COSMO-RS for the specified ILs [32]. The correlation coefficient was computed after plotting the regression curves. The regression curve was also used to calculate the theoretical efficiency. The extraction efficiency was evaluated between theoretical and experimental extractions. The average absolute deviation was determined to validate the results. Figure S5 presents the regression curve for AC id and the extraction efficiency. A linear correlation was found between the predicted AC id values and the experimental efficiencies. The correlation coefficient was found to be approximately 0.96. Using this correlation, the theoretical extraction efficiencies were predicted. The average absolute deviation was found to be 2.9%. The validation of the COSMO tool was performed in our previous work upon the extraction of lactic acid. The predicted results were found to agree with the experimental results, with a deviation of 8.2% [34]. The upper organic phase was recovered and demulsified using a centrifuge. Two layers were formed. The organic layer was emulsified after adding the stripping agent. The formed ILGELM was reused for the extraction of Ibf.

COSMO-RS Simulation Study
The calculations were performed using COSMOtherm (18.0.2 version, ImbacherWeg, Leverkusen, Germany) software. Considering the molecular structure, COSMO performs geometry optimization and calculates the polarization charged density [39]. Figure S1 shows the step-by-step method for the screening of ILs. The charge density gives an idea of the polarity of the surface and is represented by a histogram. This is further used to evaluate the σ profile and σ potential of a molecule. The σ profile and potentials signify the H-bonding nature of the molecule under study [40]. Hydrogen bond energy E HB , misfit E misfit , and Van der Waals energy E vdW are the interaction energies that tell us about the molecule's bonding nature [40] and can be represented as such [56]. These parameters are expressed by: E HB=α e f f C HB min(0; min(0; σ donor + σ HB) max 0; σ acceptor − σ HB α = an interaction parameter α eff = the effective contact area C HB = strength of hydrogen bonds σ HB = hydrogen bonding cut-off τ vdW = interaction parameter for specific elements Using these interaction parameters, the chemical potential is calculated, which is further used to estimate AC id . The chemical potential and AC id are evaluated using Equations (5) and (6), respectively where, µ = are the chemical potential of the IL µ o = chemical potential of the pure compound The significance of AC id , capacity, and selectivity was highlighted. AC id is an important parameter for the preliminary selection of solvents for extraction [47]. The AC id values are used for the determination of capacity and selectivity. Capacity and selectivity are important for determining the required amount of an IL and governs the extractability. The multiplication of power and selectivity provides the performance index (PI). The lower the value of AC id , the higher the value of capacity, selectivity, and PI [28].
The aqueous phase inherent affinity of Ibf can be found by the evaluation of solvation energies [41]. Figure S2 presents the schematic of ILGELM development. An ionic liquid-based green emulsion liquid membrane was prepared using 10 mL of sunflower-canola oil in a conical flask. Span 80, 1 wt.%, and IL, 0.1 wt.%, were added. The resultant mixture was homogenized using a high-speed Ultraturrax homogenizer at 5000 rpm. Then, 2.5 mL of NaOH was added, followed by homogenization at 5000 rpm for 5 min to develop the ILGELM. This ILGELM was added to 25 mL of Ibf (100 µg/L). The solution was stirred using a magnetic stirrer at 240 rpm for 7 min of extraction time. The contents were then poured into a separatory funnel for the separation process to proceed. The solution was allowed to settle for 5 min., resulting in the formation of an upper organic and a lower aqueous phase. The upper phase was the extract phase containing the stripped Ibf, which had been removed from the lower raffinate phase. The upper phase was demulsified to recover Ibf. The lower aqueous phase was filtered, followed by concentration measurement. The concentration of Ibf in the aqueous phase was measured using a UV-vis spectrophotometer at a wavelength of 222 nm, the reference being distilled water. The calibration curve is presented in Figure S3.

ILGELM Development
The Ibf removal efficiency was calculated using the formula C o = conc. of Ibf in the external phase initially C = conc. of Ibf in the lower aqueous phase after extraction The stability of ILGELM can be determined by calculating the breakage of ELM. Breakage is defined as when the internal stripping agent spills into the external phase from the membrane phase. Breakage affects the extraction performance and hence is an important parameter.
Breakage can be calculated using the formula where V s is the amount of stripping agent leaked into the external phase, V i is the initial amount of stripping agent.

Conclusions
The recovery and removal of Ibf, an emerging contaminant of concern, using green alternatives are essential in light of the current and future environmental problems. Because of their superior characteristics and eco-friendliness, ILs are a viable alternative to traditional solvents. Since there are millions of ILs, experimentally selecting the best IL is tedious. In addition, the screening of ILs using COSMO-RS for Ibf has not been extensively performed. Hence, COSMO-RS was used to screen suitable IL combinations for the selection of potential ILs. A selected IL was used to develop an ILGELM. The developed ILGELM was applied for the extraction of Ibf. The COSMO-RS results revealed that the combinations of quaternary ammonium cations with SO 4 2− and Cl − anions proved to be the best. This is because of the high electronegativity and better bonding ability of these anions. Non-coordinating anions such as BF 4 − and PF 6 − were not suitable for removing Ibf because of their weak bonding abilities. Furthermore, the developed ILGELM was highly stable and proved efficient for the extraction of Ibf. This research will contribute to the selection of ILs for stable ELMs and other extraction techniques.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/molecules28052345/s1, Figure S1 Step by step COSMO-RS methodology to screen ILs for Ibf; Figure S2 Schematic representation of ionic liquid based green emulsion liquid membrane; Figure S3 Calibration curve for Ibf using UV-vis; Figure S4 σ-profiles a)for cations and b) for anions under study; Figure S5 Regression curve for ACid and experimental extraction efficiency; Table S1 ILs used for the removal of Ibf;

Conflicts of Interest:
The authors declare no conflict of interest. Di-(2-ethylhexyl)phosphoric acid