Heteroassembly Ability of Dicationic Ionic Liquids and Neutral Active

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Article Cite This: ACS Omega 2018, 3, 2282−2291

Heteroassembly Ability of Dicationic Ionic Liquids and Neutral Active Pharmaceutical Ingredients Clarissa P. Frizzo,*,† Caroline R. Bender,† Paulo R. S. Salbego,† Carla A. A. Farias,† Marcos A. Villetti,‡ and Marcos A. P. Martins*,† †

Núcleo de Química de Heterociclos (NUQUIMHE), Department of Chemistry, and ‡Laboratório de Espectroscopia e Polímeros (LEPOL), Department of Physics, Federal University of Santa Maria, UFSM, 97105-900 Santa Maria, Rio Grande do Sul, Brazil S Supporting Information *

ABSTRACT: Extensive investigation of interactions and aggregation properties of IL + API systems is necessary to apply ionic liquids (ILs) with different hydrophobic characteristics to drug delivery or in active pharmaceutical ingredient (API) formulations. Therefore, this study aims to investigate the heteroassembly between dicationic ILs ([BisOct(MIM)2][2X], in which X is Br or BF4, and [BisOct(BnIM)2][2Br]), both in the absence and the presence of neutral APIs (salicylic acid, ibuprofen, and paracetamol) with different functional groups. Isothermal titration calorimetry results demonstrate that IL−API associations occur at very low concentrations of IL. These results were reinforced by electrospray ionization mass spectrometry with variable collision-induced dissociation, in which the IL dication interactions with APIs were detected. The strength of the dication−API interaction was determined from Ecm,1/2 data. The aggregation parameters (cac, ΔG°agg, and K) between ILs and APIs were evaluated by conductivity. The 1H NMR data showed that differences in chemical shifts provided relevant insights about interaction sites in both components.

1. INTRODUCTION In recent years, researchers have focused on solving pharmaceutical industry issues. The main challenges in this area are polymorphism, low bioavailability, low water solubility, degradations, and side effects of active pharmaceutical ingredients (APIs).1 These elements are serious obstacles for promising drugs, which fail and are unable to be commercially distributed.2 Efforts directly associated with the fine tuning of physicochemical properties of ionic liquids (ILs) have been made to increase the efficacy of new substances and formulations.1 In this manner, research in this area includes noncovalent modification of APIs, such as synthesis of multicomponent systems (e.g., cocrystals), which are generally formed by intermolecular interactions between an API of interest and a co-former.3−6 In an attempt to resolve these issues, ILs have been increasingly exploited as additives in the field of pharmaceutical drug delivery. Moreover, several studies have shown progress in the IL use in pharmaceuticals,7−11 and ILs can markedly improve the pharmacokinetic and pharmacodynamic properties of drugs.1 Furthermore, ILs act as solvents to biological systems and can both stabilize and destabilize protein, depending on its physicochemical properties.12−14 Some studies have even demonstrated the effect of monocationic ILs in IL + API systems or of additives in surfactants + API systems.10,11,15−20 Nevertheless, the literature on the evaluation of dicationic ILs and the understanding of © 2018 American Chemical Society

interactions in the drug delivery environments remain scarce.21,22 Dicationic ILs consist of a doubly charged cation linked by a spacer chain.23 These ILs with a long spacer chain (e.g., 8 and 10 carbons) possess excellent surface activity properties and are capable of forming aggregates in solution.24,25 Because of such characteristics, this new class of ILs is comparable with traditional surfactants and can be used, with advantages, in the same applications as monocationic structures. Nevertheless, the additional cationic head of ILs can improve physicochemical properties and, consequently, structure performance when used as alternative solvents in reactions, separations, lubricants, electrolytes in batteries, the stationary phase in gas chromatography columns, and in pharmaceutical sciences.26 Because of their distinct physicochemical properties,24,25 dicationic ILs may improve API permeability across biological membranes and increase their bioavailability and stability.15 Therefore, the elucidation of the influence of dicationic ILs micelles in pharmaceutical sciences is of great relevance. It has already been reported that monocationic ILs and conventional surfactants can act as carriers in biological fluids where the API contact with enzymes is minimized, which may increase API efficiency and reduce side effects.11,27 Furthermore, a broad Received: December 31, 2017 Accepted: February 13, 2018 Published: February 26, 2018 2282

DOI: 10.1021/acsomega.7b02097 ACS Omega 2018, 3, 2282−2291

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Figure 1. ILs and APIs used in the study.

Figure 2. Observed enthalpy (ΔHobs) vs concentration (C) for pure ILs and mixed ILs + APIs obtained by nano ITC for (a) [BisOct(MIM)2][2Br], (b) [BisOct(MIM)2][2BF4], and (c) [BisOct(BnIM)2][2Br].

association between these components by intermolecular interactions, and (iv) the strength of the interactions between IL and API. The ILs and APIs [salicylic acid (SA), paracetamol (Par), and ibuprofen (Ibu)] addressed in this study are demonstrated in Figure 1.

range of studies on interactions between IL and APIs are carried out with ionic APIs, in which the association with ILs are mostly favored by ionic interactions.10,11,16 Our research group has already verified the influence of the alkyl chain length25 and the nature of the anions in the selfaggregation behavior of dicationic IL structures in solution,23,24 in addition to evaluating thermodynamic properties of aggregation using [BisOct(MIM)2][2Br] as a study model.28 Thus, this study aims to assess if dicationic ILs can interact with APIs in solution by investigating the following: (i) a systematic study related to heteroassembly between IL + API in ethanol− water solution (1:1), (ii) thermodynamic differences in the aggregation behavior of the ILs with different structural changes in the presence and the absence of distinct APIs, (iii)

2. RESULTS AND DISCUSSION 2.1. Isothermal Titration Calorimetry. The interactions of ILs and APIs were evaluated by isothermal titration calorimetry (ITC) in an ethanol−water solution. The API solutions at 3 g L−1 were titrated with IL solutions. The curves were compared with pure IL curves, in which the solvent was titrated with IL solution. The calorimetric titration curves of the 2283


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ACS Omega observed enthalpy changes (ΔHobs) as a function of the IL concentration are depicted in Figure 2. In a typical ITC experiment, when the IL concentration of the titrated solution is below the critical aggregation concentration (cac), the ΔHobs is attributed to the break-up of added aggregates into monomers and further into monomer dilution. However, when the concentration reaches values greater than cac, the ΔHobs only expresses the dilution of the added micelles and usually decreases.29 In this study, we were unable to reach concentration values above cac because of limitation in the operational range of the equipment. Although the range of the concentration evaluated does not include the cac value for the IL, the ITC is a very sensitive technique capable of predicting the occurrence of the first interactions between the components (IL monomers and APIs molecules), which is before the IL aggregation formation (Figure 2). As the components are injected into solvent or API solution, endothermic changes in ΔHobs indicate the beginning of the interaction process between IL + IL or IL + API.29 Furthermore, all the curves of IL + API systems revealed a change in the enthalpy of the solution at each addition of IL, in addition to presenting a distinct ΔHobs magnitude in relation to pure ILs curves (representing the IL self-assembly). For [BisOct(MIM)2][2Br], the interaction with APIs has an endothermic character in comparison with IL self-assembly. On the other hand, for [BisOct(MIM)2][2BF4] and [BisOct(BnIM)2][2Br], the IL−API interactions have an exothermic behavior. This can be attributed to the great hydrophobicity of these ILs. In general, when hydrophobic interactions occur, they lead to a decrease in ΔHobs.30,31 Chabba et al.,29 in the titration of three surface-active ionic liquids (SAILs) into a polymer solution of Pluronic F108, showed that the titration of all three SAILs into the polymeric solution resulted in endothermic heat changes when compared to the titration of SAILs into water at 25 °C. The curves were treated using Carpena’s method to obtain an association concentration (Cass) and an association enthalpy (ΔHass).32 The slope change in the straight line of the IL concentration as a function of ΔHobs was taken as the association concentration between IL−API (heteroassembly) and IL−IL (self-assembly) for the systems in both the presence and the absence of API, respectively. The curves of [BisOct(MIM)2][2BF4] and pure [BisOct(BnIM)2][2Br] were not analyzed by Carpena’s method because they do not have a rectangular hyperbole tendency. In this case, Cass and ΔHass were established in the intersection point between two straight lines of the IL concentration versus the ΔHobs plot. Nevertheless, it was not possible to estimate the association data (Cass and ΔHass) for [BisOct(MIM)2][2BF4] + SA because of the absence of an intersection point in the profile of the ITC curve. Table 1 shows the data acquired by ITC. The components associate at very low concentrations. For the pure IL compounds, the Cass of self-assembly, the following order was established where [BisOct(MIM)2][2Br] > [BisOct(MIM)2][2BF4] > [BisOct(BnIM)2][2Br]. Nonetheless, different tendencies were observed for the IL + API systems. The Cass is dependent upon the balance between various factors, such as binding strength of the cation with the anion and/or APIs and the electrostatic repulsion between IL cations. Furthermore, the Cass of pure ILs is modified in the API presence because the IL−IL intermolecular interactions were altered by the APIs because of IL−API interactions. Notably, the Cass of [BisOct(MIM)2][2Br] decreased in the presence of

Table 1. Concentration of Association (Cass), Enthalpy of Association (ΔHass), and Center of Mass Energy (Ecm,1/2) of Pure IL and IL + APIs [BisOct(MIM)2] [2Br]

pure +Ibu +Par +SA

[BisOct(BnIM)2] [2Br]

[BisOct(MIM)2] [2BF4]

Cass (mM)

ΔHass (kJ mol−1)

Cass (mM)

ΔHass (kJ mol−1)

Cass (mM)

ΔHass (kJ mol−1)

3.011 1.692 2.621 2.267

−1.612 0.142 −1.046 0.143

0.572 0.789 1.456 2.095

2.604 1.309 1.312 0.655

1.347 1.108 1.292

2.860 2.031 2.438

all APIs in this study. For [BisOct(BnIM)2][2Br], the Cass increased in the presence of APIs, and the Cass of [BisOct(MIM)2][2BF4] decreased in the presence of ibuprofen and paracetamol. Significant changes in Cass occurred in all systems, which indicates that each association is dependent on a particular IL + API combination. In addition, an important trend can be observed; for IL short side alkyl chain (methyl in [BisOct(MIM)2][2X], in which X = Br and BF4), the Cass decreases in the presence of APIs, indicating that IL + API interactions are favored. On the other hand, for [BisOct(BnIM)2][2Br], which has a bulky side alkyl chain, the Cass increases in the presence of APIs, which indicates that [BisOct(BnIM)2][2Br] + API interactions are delayed in relation to IL monomer interactions. In general, an increase was observed in the ΔHass for [BisOct(MIM)2][2Br] + API. However, a decrease of ΔHass was observed for [BisOct(BnIM)2][2Br] and [BisOct(MIM)2][2BF4] in the presence of APIs. These results indicate a complex balance of interactions between ILs and APIs because the ΔHass values show a distinct behavior according to the system observed. This is expected because the APIs in this study have different functional groups in their structures (SA: carboxylic acid and phenol; Par: amide and phenol; Ibu: carboxylic acid) that will interact with ILs in a particular way. Furthermore, ILs show different hydrophobicity degrees that ensure these differences in the ΔHass. By observing the results from the API point of view, it is possible to ascertain that the different ILs produce curves of different magnitudes of ΔHass versus C in the presence of API, although the order is always preserved (see the Supporting Information, Figure S1). As previously observed for pure IL systems, [BisOct(MIM)2][2Br] also demonstrates a more exothermic behavior, followed by [BisOct(BnIM)2][2Br] and [BisOct(MIM)2][2BF4] in the presence of different APIs. These tendencies denote important considerations: (i) all APIs used as models in this study exhibit intermolecular interactions with ILs of distinct hydrophobicity degrees because the presence of API promotes significant changes in ΔHass values; (ii) the IL−IL associations are broken to form new favored IL− API interactions; (iii) IL−API first interactions are driven by the IL structure because the IL order for ΔHass magnitude is the same for different APIs (see the Supporting Information, Figure S1). Nevertheless, it is necessary to consider that the APIs evaluated demonstrated an important role in modulating the IL−IL association properties. These results corroborate with the recent investigation by Pal and Yadav,16 which showed the pivotal role of lidocaine hydrochloride in modulating aggregation properties of monocationic ILs [DoDec(MIM)][Cl] and [TetDec(MIM)][Cl] (in which DoDec and TetDec correspond to the alkyl chain of 12 and 14 carbons, 2284


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ACS Omega respectively). However, this interaction can be quite different because this system is composed of a mixture of salts (both IL and API are charged). 2.2. Electrospray Ionization Tandem Mass Spectra. Electrospray ionization tandem mass spectra (ESI-MS-MS) was used to verify the relative abundance of IL−API associations as a function of the applied collision-induced dissociation (CID). Separation of the IL−API system, as the collision energy increases, produced different positively charged units. The percentage of fragment ion abundance in relation to the total ion abundance (I/∑I) was plotted versus the center-of-mass system (Ecm). The results were presented as breakdown curves.33 The Ecm values were calculated according to eq 1.34

⎛ m ⎞ t ⎟⎟ Ecm = E lab⎜⎜ ⎝ mp + mt ⎠

Figure 3. Graphical representation of the sum of the 30 spectra in the CID range of 0−30 eV for [BisOct(MIM)2SA]+ (m/z 413). (1)

In eq 1, Elab, mt, and mp are the laboratory frame collision energy, mass of the target gas, and mass of the precursor ion, respectively.34,35 A decrease of the precursor ion abundance was observed as the Ecm increases. This indicates that the precursor ion tends to break up as the collision energy increases. Solutions of [BisOct(MIM)2][2Br], [BisOct(MIM)2][2BF4], and [BisOct(BnIM)2][2Br] with different APIs in ethanol− water solution (1:1, v/v) were evaluated in the positive ion mode using the scan mode. These data indicate that the ILs− APIs are preorganized in solutions where the interactions between them are maintained as the sample passes from the liquid to the gas phase. In this study, the analysis was carried out at a lower concentration (2 mM of each component in final solution), which is comparable with the concentration range evaluated by ITC. This is possible because of the high sensibility of the ESI-MS-MS equipment. The self-organization of dicationic ILs with different anions in solution was previously described by our research group in greater concentrations.24 Recently, we published a study in which the dicationic IL cation−anion interactions forces were evaluated by this technique.36 Currently, the objective is to use ESI-MS-MS to show the heteroassociation occurrence between dicationic ILs and APIs at very low concentrations and to estimate the interaction strength between these components. The positive ion mode mass spectra of the ILs demonstrated the precursor ion [BisOct(MIM)2API]+ (in which API corresponds to an anion of the pharmaceutical molecule). The association [BisOct(MIM)2API]+ was submitted to different E lab values until the complete dication-anion dissociation (eq 2) was observed. The anion corresponds to APIs evaluated in this study.

Figure 4. The breakdown curves of other IL + APIs species can be found in the Supporting Information. Figure 3 demonstrates that [BisOct(MIM)2SA]+ (m/z 413) and [BisOct(MIM)2]2+ (m/z 275) are abundant species of the [BisOct(MIM)2][2BF4] + SA solution. The peak in m/z 193 can be attributed to a monocation, i.e., dication without an imidazolium ring. Figure 4a demonstrates that the dication [BisOct(MIM) 2 ] 2+ is formed from [BisOct(MIM) 2 SA] + fragmentation because a decrease in the [BisOct(MIM)2SA]+ abundance is followed by an increase in the [BisOct(MIM)2]2+ abundance. In Ecm values over 0.5 eV, it becomes clear that the cation with 193 m/z is exclusively formed from [BisOct(MIM)2]2+ because its abundance increases with the decline of the dication m/z intensity. This can be related to the loss of an imidazole ring from dication [BisOct(MIM)2]2+. This behavior is an indication that the fragmentation process, in this case, occurs by the sequential loss of the pharmaceutical in the anionic form and then fragmentation of the cation. The breakdown curves of [BisOct(MIM)2][2BF4] + Ibu can be observed in Figure 4b, in which the fragmentation sequences are the same. However, the [BisOct(MIM)2Ibu]+ species is about 30% less abundant (less stable) than [BisOct(MIM)2SA]+. This indicates that the [BisOct(MIM)2][2BF4] has more affinity for SA than for Ibu in the ethanol−water solution. In both cases, the small abundance of 178 m/z can be attributed to a methyl unit loss from 193 m/z and may be observed in higher energy values (above 1.5 eV). The breakdown curve pattern for others systems showed a behavior analogous to [BisOct(MIM)2SA]+ and [BisOct(MIM)2Ibu]+ (see the Supporting Information, Figure S4). Fragmentations also occur initially in the cation−anion species and then in the dication, as the collision energy increases. The main fragments in the dication species were observed in all cases. Once again, when the I/∑I of dication reaches a maximum value, the loss of the imidazolium ring notably increases. From the breakdown graphs, the energy value corresponding to 50% of relative abundance of the precursor ion (Ecm,1/2) was obtained for all [BisOct(MIM)2X]+ species. The Ecm,1/2 can be used to measure the relative dissociation energy, in addition to being a well-established research strategy regarding the relative binding energies/stabilities of several systems.35,37,38 The Ecm,1/2 observed for the [BisOct(MIM)X]+ species is shown in Table 2. The Ecm,1/2 values for the species containing IL and Ibu (∼9 kJ mol−1) were lower than the IL−SA systems (∼20 kJ mol−1).

[BisOct(MIM)2API]+ → [BisOct(MIM)2 ]2 + + API− (2)

With the increase of the Ecm, several cationic units were observed for all ILs of this study. These units are produced by [BisOct(MIM)2API]+ fragmentation. The spectrum generated by combining all 30 spectra obtained in the CID range of 0−30 eV for [BisOct(MIM)2SA]+ (m/z 413) can be observed in Figure 3. This figure is a graphical representation of the relative abundance distribution of species observed in the [BisOct(MIM)2SA]+ fragmentation from the [BisOct(MIM)2][BF4] + SA system. The breakdown curves of the major ions observed in the spectrum of [BisOct(MIM) 2SA]+ and [BisOct(MIM)2Ibu]+ from [BisOct(MIM)2][BF4] + SA and [BisOct(MIM)2][BF4] + Ibu systems, respectively, are detailed in 2285


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Figure 4. Breakdown curves for several m/z ratios of associations formed from (a) [BisOct(MIM)2][2BF4] + SA and (b) [BisOct(MIM)2][2BF4] + Ibu.

Table 2. Ecm,1/2 Values for IL + API Systems system

Ecm,1/2 (kJ mol−1)

[BisOct(MIM)2][2Br] + Ibu [BisOct(MIM)2][2Br] + SA [BisOct(BnIM)2][2Br] + Ibu [BisOct(BnIM)2][2Br] + SA [BisOct(MIM)2][2BF4] + Ibu [BisOct(MIM)2][2BF4] + SA

9.301 21.401 8.857 20.532 8.877 18.487

These results indicate that dicationic ILs can interact more strongly with SA than Ibu. Despite [BisOct(BnIM)2][2Br] having demonstrated some hindrance to interact with API based on Cass and cac data, in this evaluation, this IL demonstrated an interaction energy comparable with [BisOct(MIM)2][2X] + SA (X = Br and BF4). It is reasonable to believe that this IL can interact better with SA than other APIs in this study. This result corroborates with cac values, in which the cac for [BisOct(BnIM)2][2Br] in the presence of SA is close to cac values of pure [BisOct(BnIM)2][2Br]. This indicates that the presence of SA does not promote significant delay in the aggregation process of [BisOct(BnIM)2][2Br] in solution than Ibu and Par, in which the cac is altered around 15 mM. Because the associations of dicationic ILs and paracetamol were observed by ESI-MS-MS only in low intensities, the CID evaluations, to construct breakdown curves, were not realized for these systems. 2.3. Conductivity. Aggregation parameters of ILs can be obtained both in the presence and the absence of APIs using electrical conductivity. The main parameter is the cac, which indicates the concentration in which the aggregates begin to form. The cac values of ILs were evaluated in the absence and the presence of Ibu, Par, and SA and were obtained by applying Carpena’s method32 in the conductivity (κ) versus IL concentration (C) plots (Figures 5 and S2 in the Supporting Information). The correlation coefficient (r) of the fitting obtained by this method demonstrated values close to 1. Figure 5 demonstrates the electrical conductivity curves of [BisOct(MIM)2][2Br] and [BisOct(MIM)2][2Br] + APIs in solution. Figure 5 demonstrates that the κ versus C curves for [BisOct(MIM)2][2Br] + Par and [BisOct(MIM)2][2Br] + Ibu are similar to [BisOct(MIM)2][2Br] in solution, while [BisOct(MIM)2][2Br] + SA has a distinct behavior. This can be attributed to a greater capacity of charge conduction of the

Figure 5. Conductivity vs concentration (C) for pure [BisOct(MIM)2][2Br] and systems with APIs.

[BisOct(MIM)2][2Br] + SA system in relation to other systems in the study. Researchers have been studying IL interactions and aggregation properties in the presence of APIs in the salt form.16,39 It was showed that ILs can have several possible interactions with the APIs, hydrogen bonding, π···π staking, lone pair···π, dipolar, and ionic/charge−charge interactions.40,41 The APIs addressed herein are neutral to reduce the possibility of electrostatic interactions between ions and to maximize the probability of interactions of the noncovalent nature such as hydrogen bonding, π···π-staking, as well as to verify if these interactions can occur between charged ILs and neutral APIs. The ionization (α) degree of the aggregates can also be obtained using Carpena’s method.42,43 This parameter indicates the proportion of free ions in solution. The standard Gibbs free energy of aggregation (ΔG°agg) and the aggregation equilibrium constant (K) were acquired based on the mass-action model considering bolaform surfactants for calculation purposes,44 which is frequently used to elucidate the IL aggregation process. The parameters obtained from the conductivity measurements are summarized in Table 3. The following cac order was observed for pure ILs (Table 2): [BisOct(MIM)2][2Br] > [BisOct(MIM)2][2BF4] > [BisOct(BnIM)2][2Br]. This order follows the same one observed for ITC for the first IL−IL interactions. As previously published by our research group, the aggregation behavior of dicationic ILs is 2286


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ACS Omega Table 3. Conductivity Data of Pure ILs and Mixed IL and IL−APIs [BisOct(MIM)2][2Br] pure +Ibu +Par +SA

[BisOct(BnIM)2][2Br]

cac (mM)

ΔG°agg (kJ mol−1)

α

K

146.0 124.4 81.4 39.8

−6.125 −6.618 −8.599 −11.50

0.77 0.79 0.73 0.72

11.83 14.44 32.12 103.39

cac (mM) ΔG°agg (kJ mol−1) 26.7 40.6 41.7 29.3

−14.79 −12.12 −11.80 −16.25

[BisOct(MIM)2][2BF4]

α

K

cac (mM)

ΔG°agg (kJ mol−1)

α

K

0.60 0.66 0.68 0.46

286.55 133.10 116.90 752.64

81.7 28.6 39.6 39.9

−8.257 −15.82 −13.46 −11.99

0.77 0.50 0.56 0.68

27.96 591.72 228.38 126.04

Figure 6. Comparison between chemical shifts of [BisOct(MIM)2][2Br] + SA (red), [BisOct(MIM)2][2Br] (green), and SA (blue) in (a) aromatic and (b) aliphatic regions.

closely related to IL hydrophobicity.24 In this study, the [BisOct(BnIM)2][2Br] has the lower cac value that can be attributed to the additional hydrophobicity of the structure caused by the presence of benzyl rings bonded to N3 of imidazolium rings. In addition, these aromatic rings can act in π···π, CH···π, cation···π, or anion···π41,45,46 interactions at the aggregate interface, contributing to the reduced cac value. The degree of ionization is also reduced in comparison with [BisOct(MIM)2][2X] (in which X = Br and BF4). This indicates that a great proportion of anions are better stabilized on the aggregate surface. Ao et al.47 demonstrated from surface tension data that dicationic ILs with different size alkyl spacer chains (2, 4 and 6 carbons) and long side alkyl chains (12 carbons) present very low cac (0.75−0.78 mM). This can be attributed to the considerable hydrophobic character of ILs conferred by the side alkyl chain. When the side alkyl chain is short, the cac generally occurs at higher values.25 In general, pure ILs have greater cac values than IL + API systems. This indicates that the IL aggregation ability is improved with the presence of API (Table 3). The headgroup− headgroup repulsions in the IL aggregate formation are probably reduced because of the additional stabilization of APIs on the aggregate surface. This behavior has already been reported by Mahajan et al.11 and is related to the fact that these APIs are small polar organic compounds that adsorb mainly in the outer portion of the micelle, close to the water−aggregate interface. Adsorption of the additives in this manner decreases the energy required for aggregation. This assumption is supported by IL ΔGagg ° values that become smaller in the presence of pharmaceuticals, proving that aggregation is favored. The higher K values show that the equilibrium toward aggregation is also favored in the presence of API. Nevertheless, for [BisOct(BnIM)2][2Br] + API (Ibu, Par), K values were inferior (higher cac values) than the values for pure [BisOct(BnIM)2][2Br]. In this case, the presence of a benzyl unit bonded to the

imidazolium ring can promote an additional steric hindrance between the IL monomers and API molecules at aggregate interfaces, thus slowing the aggregation process. Pal et al.16 recently evaluated binding interactions of the anesthetic drug lidocaine hydrochloride with SAILs and found that cac decreases as the concentration of the drug increases. The authors attributed this cac reduction to the presence of cation−π interactions between the imidazolium ring of the SAIL and the drug molecules. In our study, the benzyl group bonded with the imidazolium ring in [BisOct(BnIM)2][2Br] hinders this type of interaction. 2.4. 1H NMR. The interactions of APIs (SA, Ibu, and Par) with the dicationic ILs were also visible from the 1H NMR spectra. The changes in the chemical shift values (δ) in the IL + API spectra in relation to separated compounds, under the same conditions, allow us to establish the nature of IL and API interactions in the different systems evaluated.11,39 The changes in the 1H δ of IL and API are shown in Figure 6a fand Figure 6b for the BisOct(MIM)2][2Br] + SA system in aromatic and aliphatic 1H resonance regions, respectively. The signals in δ close to 7.3 and 3.3 are attributed to CDCl3 and CD3OD residual peaks, respectively. In the 1H NMR of the IL + API systems, changes can be observed in the chemical shift of the API and cationic heads of the IL 1H signals. This indicates that the API probably interacts with the polar portion of dicationic ILs. This observation suggests that in the aggregate phase formed by these ILs, the APIs (SA, Par, and Ibu) should interact on the aggregate surface, as already reported in the literature for other IL + API systems.11,18 The Δδ (δbonded − δfree) represents the variation in the chemical shifts of the analyzed nuclei. The APIs signals were attributed according to refs.48−50 The presence of SA greatly effects the environment of surfactant protons, especially the hydrogen close or directly bonded to the head group. The deshielding effect of H4 and H5 may result from hydrogen-bonding interactions between 2287


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more difficult to be detected by NMR, and only stronger Hbonds were observed in the concentration evaluated.

these H with SA, probably with a carbonyl group of SA. The H2 of the imidazolium ring shows a high field shift (shielding effect), which is likely due to the breaking of the H2···A− interactions in the presence of SA. Furthermore, H2 can be shielded by magnetic effects from aromatic rings (from IL and/ or API). These IL Δδ values confirm the interaction between IL and API molecules that lead to the heteroassembly of IL and API molecules in solution. Mehta et al.39 have found that the presence of diclofenac sodium greatly effects the environment of ammonium surfactant (DDAB and DTAC) protons, especially the protons in close proximity to the head group. Moreover, the significant changes in δ confirmed the interaction between the drug and surfactant molecules at the micelles surface in solution. In a recent study, our research group observed the effect of the IL anion in the interactions on the surface of aggregates in a solution of 4.75% of ethanol in water (v/v). The study showed that [BisOct(MIM)2][2X] (in which X = Br and BF4) forms spherical aggregates. Furthermore, it was found that alkyl chains are folded and cationic heads interact by CH···π at the aggregate surface.23 We expect dicationic IL aggregates in an ethanol−water solution (1−1, v/v) to be organized in a similar way, including [BisOct(BnIM)2][2Br]. Therewithal, it can be concluded that API molecules can strongly affect the interactions between cationic heads when compared with selfassembly, in which the head groups organize themselves to interact effectively with APIs. The hydrogens of the alkyl chain (H12, H13, and H14) were omitted for better visualization of the affected signals because of the insignificant Δδ in the presence of SA. The signal in 3.9 ppm in the SA spectra can be attributed to the exchange reaction between CD3OD and hydrogen of SA carboxylic acid. The signal in 4.9 ppm in the [BisOct(MIM)2][2Br] + SA spectra can be attributed to the same exchange reaction or residual water present in the sample. H11 shows upfield shift because of the increased shielding effect from the imidazolium ring. In this case, the API interacts with cationic heads, making more compact the IL alkyl spacer chain, thus generating the shielding effect. Nevertheless, the shielding in H31 can be related to CH···π interactions, in which H31 is the hydrogen donor of the interaction. The same chemical shift behavior was observed for [BisOct(MIM)2][2Br] + Ibu and [BisOct(MIM)2][2BF4] + Par systems. On the other hand, in the [BisOct(MIM)2][2Br] + Par, [BisOct(MIM)2][2BF4] + SA, and [BisOct(MIM)2][2BF4] + Ibu systems, the H4 and H5 shift upfield, as does H2. In this case, all hydrogen atoms of imidazolium rings are in the shielding cone of API and are not H-bond donors. This behavior shows that the interactions in these systems are complex and dependent on both IL and API, as previously observed in ITC and conductivity measurements. The spectra of other IL + API systems are depicted in the Supporting Information. Notably, the 1H spectra of [BisOct(BnIM)2][2Br] + API demonstrate minor δ changes in relation to separated compounds, with the exception of H2 of ILs. As previously observed from ITC and conductivity results, the presence of a benzyl unit bonded in the imidazolium ring confers a greater hydrophobic character to [BisOct(BnIM)2][2Br], thus promoting lower Cass and cac self-assembly values. On the other hand, in heteroassembly, the benzyl group on the surface of the aggregate can hinder interactions between the IL monomers and the API molecules, delaying the aggregation process. For this reason, [BisOct(BnIM)2][2Br] + API interactions may be

3. CONCLUSIONS From the several techniques applied in this investigation, it was possible to demonstrate that dicationic ILs of different hydrophobicities can effectively interact with APIs of different natures. From ITC, we were able to show that the Cass (initial IL + API associations) is reduced for [BisOct(MIM)2][2X] (in which X = Br and BF4) in the presence of APIs, whereas it is increased for [BisOct(BnIM)2][2Br]. Different tendencies were observed for ΔHass depending on the IL + API combination. These results indicate a complex balance of interactions between ILs and APIs. Nevertheless, IL + API first interactions are driven by the IL structure because the ILs maintain the same order of ΔHass magnitude for different APIs. The conductivity data provided information about the aggregation behavior of ILs in the absence and the presence of APIs. Furthermore, cac decreased in the presence of APIs for [BisOct(MIM)2][2X] (in which X = Br and BF4) and increased for [BisOct(BnIM)2][2Br], revealing the same tendency of the Cass data. When the cac decreased, the ΔGagg ° and K presented lower and higher values, respectively, demonstrating that heteroassembly IL−API is favored when compared with IL self-assembly. From ESI-MS-MS, the species [BisOct(MIM)2X]+ (in which X = API) were detected in the positive ion mode. Breakdown curves of these species were constructed, and dication−API interaction strength values were provided based on the Ecm,1/2 data. This is the first time that IL + API systems were detected in an equimolar mixture and the strength of dication−API interactions were quantitatively characterized. Results evidenced that, in general, dicationic ILs interact more strongly with SA (∼21 kJ mol−1) than with Ibu (∼8 kJ mol−1). 1 H NMR spectral data proves the occurrence of interactions between IL and API because of the considerable changes in the chemical shifts of the systems related to separate compounds. Because of the great δ changes of 1H IL cationic heads, it is suggested that the different APIs interact with IL cationic heads in ethanol−water solution. The [BisOct(BnIM)2][2Br] demonstrates more changes in δ for H2 of ILs (H acid) and OH of APIs, thus indicating that [BisOct(BnIM)2][2Br] + API interactions occur mainly in these sites. The complementary techniques provided very important insights regarding IL + API heteroassembly. 4. MATERIALS AND METHODS 4.1. Materials. 1,8-Dibromooctane, 1-methylimidazole, 1benzylimidazole, and sodium tetrafluoroborate were purchased from Sigma-Aldrich (St. Louis, MO, USA). Acetonitrile, ethyl ether, and absolute ethanol were purchased from Tedia (Rio de Janeiro, RJ, Brazil). All chemical products were of high-grade purity and used without further purification. 4.2. Synthesis. The ILs were synthesized in accordance with methodologies previously described in the literature.24,51 The structures of all products were confirmed by NMR and mass spectra. The characterization data of [BisOct(MIM)2][2X], in which X = Br and BF4, are depicted in the refs 24 and 51. Characterization data of [BisOct(BnIM)2][2Br] in DMSOd6 are depicted in the Supporting Information. 4.3. Solution Preparation. IL solutions were prepared by weighing the compound (IL or API) in a volumetric flask and 2288


Article

ACS Omega using an analytical scale with ±0.001 g (Marte AL 500, Brazil). The volumetric flask was filled with an ethanol−water solution (1:1, v/v). The water used to prepare the solutions was doubledistilled and deionized using Millipore quality water (Elix-03, Barueri, Brazil; and Milli-Q, Molsheim, France). The absolute ethanol HPLC grade was acquired from Tedia Brazil. 4.4. Electrical Conductivity. Conductivity was measured using a Digimed DM-3P conductivity meter (DMC-100M) operating with a cell constant of 10 cm−1. The conductivity meter was calibrated with KCl solution (0.1 mol L−1). The solutions of pure IL and IL + API were thermostated in the cell at 25 ± 0.1 °C. In the mixtures, the API concentration was kept constant at 3 g L−1. The stock solution of IL (1000 mM) in ethanol−water solution (1:1, v/v) was progressively added into an API solution in ethanol−water solution (1:1, v/v) at 3 g L−1 to obtain the desired IL concentration. After each addition of IL, the mixture was homogenized and the conductivity measured after the temperature was stabilized. The conductivity of the solutions was measured in a large concentration range of IL to clearly observe the cac. 4.5. ESI-MS-MS Measurements. ESI-MS-MS were acquired with an Agilent Technologies 6460 triple quadruple mass spectrometer (Santa Clara, CA, USA) operating in the positive ion mode. The gas temperature was 300 °C, the flow of the drying gas was 5 L min−1, and the nebulizer was set to 45 psi. The voltage of the capillary was 3500 V, whereas the voltage of the fragmentor was 0 V. The injection volume of the IL + API (2 mM) solutions was 5 μL. Nitrogen was used as both nebulization gas and collision gas. A tetrahydrofuran− methanol (1:1, v/v) solution was used as the mobile phase. The mass spectra were recorded in a range of CID values to promote the dissociation of the species. The intensity of the precursor ion as a function of the CID values provides the collision−energy−dissociation profiles. 4.6. Isothermal Titration Calorimetry. Calorimetric measurements were carried out using a MicroCal iTC 200 from GE Healthcare Life Sciences (Fairfield, Connecticut, EUA) at 25 °C (±0.1). The syringe was filled (38 μM) with IL (50 mM) in an ethanol−water (1:1, v/v) solution. Aliquots of 2 μM were added into the sample cell filled with 200 μL of solvent (pure ethanol−water solution1:1, v/v) or API solution (3 g L−1) to observe the enthalpy behavior versus the concentration of IL in the absence and the presence of API, respectively. The measurements were carried out with an initial delay of 60 s and a spacing time (between each injection) of 150 s. 4.7. NMR. 1H spectra were recorded on Bruker AVANCE III (1H at 600.13 MHz) equipped with a BCU II unit as a cooling/heating system for the probe (temperature of 25 °C). The IL + API systems for 1H NMR analysis were synthesized by solubilizing IL and API in an equimolar ratio in 4 mL of ethanol−water solution (1:1, v/v). The samples were stirred at 40 °C until complete solvent evaporation and maintained under high vacuum at 25 °C for 3 days. Then, the samples were placed in 5 mm tubes with a 10% solution of CD3OD in CDCl3 (50 mM). This CDCl3 solution was used to minimize the possibility of interaction breaking by polar protic solvents. The amount of CD3OD used to solubilize the samples was minimal.

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ITC, conductivity and ESI-MS-MS curves, and 1H NMR spectra (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (C.P.F.). *E-mail: [email protected] (M.A.P.M.). ORCID

Clarissa P. Frizzo: 0000-0002-1175-7880 Caroline R. Bender: 0000-0002-5791-4730 Paulo R. S. Salbego: 0000-0001-7774-6327 Marcos A. Villetti: 0000-0002-5138-7343 Marcos A. P. Martins: 0000-0003-2379-220X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge the financial support from CNPq, CAPES, and FAPERGS, also the research fellowships from CNPq (C.P.F., C.R.B., P.R.S.S., M.A.V., and M.A.P.M.) and FAPERGS (C.A.A.F.). The authors acknowledge the Central ́ of Federal University of Paraná (UFPR) and Professor Analitica Marcos R. Mafra for the access to the ITC equipment and Andrea B. G. Bonassoli and Patricia K. Iwankiw for the kind support in the measurements.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b02097. 2289


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Heteroassembly Ability of Dicationic Ionic Liquids and Neutral Active

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