Surfactant Behavior of Ionic Liquids Involving a Drug: From Molecular

Article pubs.acs.org/Langmuir

Surfactant Behavior of Ionic Liquids Involving a Drug: From Molecular Interactions to Self-Assembly Corine Tourné-Péteilh,a Benoit Coasne,a,b,c,* Martin In,d,e David Brevet,a Jean-Marie Devoisselle,a André Vioux,a and Lydie Viau*,a,f a

Institut Charles Gerhardt Montpellier, UMR 5253, CNRS-UM2-ENSCM-UM1 Place Eugène Bataillon, CC1701, 34095 Montpellier, France. b MultiScale Material Science for Energy and Environment (UMI CNRS/MIT), Massachusetts Institute of Technology 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States c Department of Civil and Environmental Engineering, Massachusetts Institute of Technology 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States d Laboratoire Charles Coulomb, UMR 5221, CNRS-UM2 Place Eugène Bataillon, CC026, 34095 Montpellier, France e CNRS, Laboratoire Charles Coulomb UMR 5221, 34095 Montpellier, France f Institut UTINAM, UMR CNRS 6213, UFR des Sciences et Techniques, Equipe Matériaux et Surfaces Structurés, 16 route de Gray, 25030 Besançon, France S Supporting Information *

ABSTRACT: Aggregates formed in an aqueous medium by three ionic liquids CnMImIbu made up of 1-alkyl-3-methyl-imidazolium cation (n = 4, 6, 8) and ibuprofenate anion are investigated. Dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), 1H nuclear magnetic resonance measurements, and atom-scale molecular dynamics simulations are used to shed light on the main interactions governing the formation of the aggregates and their composition. At high concentration, mixed micelles are formed with a composition that depends on the imidazolium alkyl chain length. For the shortest alkyl chain, micelles are mainly composed of ibuprofenate anions with some imidazolium cations intercalated between the anions. Upon increasing the alkyl chain length, the composition of the aggregates gets enriched in imidazolium cations and aggregates of stoichiometric composition are obtained. Attractive interactions between these aggregates led to the formation of larger aggregates. As suggested by molecular simulations, these larger aggregates might constitute the early stage of phase separation. Transitions from micelles to vesicles or ribbons are observed due to dilution effects and changes in the chemical composition of the aggregates. We also show that aggregation can be probed using simple microscopic quantities such as radial distribution functions and average solvation numbers.

1. INTRODUCTION Ionic liquids (ILs) are used for many applications as an environmentally friendly alternative to traditional organic solvents because of their unique properties such as negligible vapor pressure, thermal stability, and nonflammability. They are also used as self-assembly media in nonaqueous systems such as microemulsions1 and in aqueous solutions.2 In the latter case, a strong correlation between the molecular structure of the IL and its ability to promote self-assembly of amphiphiles has been demonstrated. Since 2004, aggregation of ILs in water has been widely studied both experimentally3−9 and using computational studies.10−12 In particular, imidazolium cations with long alkyl chains and associated with halogenated counterions have been demonstrated to self-assemble to form micelles in aqueous solutions. As in classical surfactants, these counter-ions bind to the cationic interface only at the interfacial layer (Stern layer) and mitigate the headgroup repulsions. However, micelle © XXXX American Chemical Society

formation was also observed for imidazolium cation with short alkyl chain (n = 4) when associated with long alkyl chain anion such as octylsulfate.13,14 Recently, there has been a growing interest in the synthesis of such catanionic ILs. So far, only alkylsulfonate or alkylsulfate anions with long alkyl chains associated with medium alkyl chain imidazolium cations (n = 8)8,15,16 or ammonium cations have been reported.17−19 These authors pointed out that the ionic liquid nature confers no special properties in terms of surfactant properties. Anouti et al. have investigated the formation of vesicular structures of protic ionic liquids containing diisopropylammonium cation and longchain carbon carboxylate.20 Received: October 29, 2013 Revised: December 20, 2013

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dx.doi.org/10.1021/la404166y | Langmuir XXXX, XXX, XXX−XXX

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analyzed via the non-negative least-squares method (NNLS) to obtain the distribution of diffusion coefficients (D) of the solutes. The apparent equivalent hydrodynamic diameter (Dh) was then determined using the Stokes−Einstein equation. 1 H NMR. 1H NMR spectra were obtained at 27 °C using a Bruker AVANCE 400 NMR spectrometer operating at 400.13 MHz. The following parameters were used: spectral width = 12.5 ppm, pulse length = 8 μs, relaxation delay = 5 s, number of scans = 12. The chemical shifts were determined with respect to an external reference of 2,2,3,3-d(4)-3-(trimethylsilyl)propionic acid sodium salt (δ = 0.00 pm) in D2O. Experimental reproducibility of the chemical shifts is within ±0.01 ppm. 2.2. Molecular Simulations. Details can be found in the Supporting Information.

In 2001, Paulsson and Edsman discovered that surface active drugs could form catanionic aggregates when mixed with oppositely charged single chain surfactants.21 Positively and negatively charged drugs can be used to form catanionic vesicles, catanionic micelles, or a mixture of both. When incorporated into gels, these catanionic aggregates show slower release when compared to the drug alone.22−24 This is an elegant approach because, in contrast to the use of classical vesicles in which the drug is encapsulated, the drug constitutes a building block of the carrier. Rico-lattes and collaborators have also reported the delivery of an anti-inflammatory drug by direct association with a sugar-derived amphiphile forming a catanionic surfactant.25 Recently, double chain surfactants and oppositely charged drugs were also studied.26 Ionic liquids have been used to design active pharmaceutical ingredients (APIs) in order to control solubility, stability, and bioavailability.27−29 However, to our knowledge, only one report has demonstrated the formation of catanionic ionic liquids containing a drug.30 These ILs are composed of ibuprofenate anions and imidazolium cations. Critical aggregation concentrations (CACs) of these CnMImIbu ILs (n = 4, 6, 8), which were determined by conductimetry and surface tension measurements, are very low compared to their parent imidazolium chloride. Thus, we demonstrated that association of ibuprofenate and imidazolium cation could be considered as an ion pair amphiphile showing very low interfacial activities. One of this IL (C4MImIbu) was also used in the synthesis of silica-based materials to act as drug release systems.31 The goal of this paper is to shed light on the interactions of ibuprofenate and imidazolium cation and to determine the structure and composition of the aggregates formed when they self-assemble in water. Both experimental data obtained from dynamic light scattering, cryogenic transmission electron microscopy, 1H NMR and atom-scale molecular dynamics simulations are reported.

3. RESULTS AND DISCUSSION 3.1. Phase Behavior. The chemical structures of the investigated 1-alkyl-3-methylimidazolium ibuprofenate ionic liquids are shown in Figure 1. The CACs, which were

2. EXPERIMENTAL AND COMPUTATIONAL DETAILS 2.1. Experimental Methods and Materials. Materials. The chemicals used in this study were obtained from the following commercial sources: 2,2,3,3-d(4)-3-(trimethylsilyl)propionic acid sodium salt 98 atom % D (Alfa Aesar), D2O 99 atom % (Aldrich). The following ILs 1-butyl-3-methylimidazolium ibuprofenate C4MImIbu (n = 4), 1-hexyl-3-methylimidazolium ibuprofenate C6MImIbu (n = 6) and 1-methyl-3octylimidazolium ibuprofenate C8MImIbu (n = 8) were prepared according to the procedure reported in our previous work.30 Distilled water was used as solvent except for NMR tests where D2O was used. Cryo-TEM Imaging. Samples were prepared by putting a drop of the IL aqueous solution on an electron microscopy grid coated with a perforated carbon film. After draining the excess liquid with a filter paper, the grid was quickly plunged into liquid ethane and stored under liquid nitrogen until use. Grids were mounted on a Gatan 626 cryoholder and transferred into a Tecnai F20 (FEI) microscope operated at 200 kV. Images were recorded at a 50000× magnification with an USC1000SSCCD camera (Gatan). Dynamic Light Scattering (DLS). DLS measurements were carried out at 25 °C using a NanoZS, Malvern Instruments, whose photospectrometer is equipped with a 532 nm laser beam. The detection angle was fixed to 173° to limit multiple scattering from the concentrated sample and to measure very small particles (down to 0.6 nm). The correlation function was

Figure 1. Chemical structures and labeling of the investigated 1-alkyl3-methylimidazolium ibuprofenate ionic liquids: CnMImIbu with n = 4, 6, and 8. The left structure is the CnMIm cation while the right structure is the ibuprofenate anion. The green and red circles identify the tail groups of the cation and anion, respectively.

determined previously, are equal to 75 mM for C4MImIbu, 45 mM for C6MImIbu, and 14 mM for C8MImIbu.30 We prepared solutions of CnMImIbu by dilution of concentrated solutions with final concentrations ranging from far below the CAC to at least five times the CAC. The aqueous solutions were investigated by dynamic light scattering and cryo-TEM, whereas solutions in D2O were used for 1H NMR measurements. The phase behavior of the ILs solutions has been first checked by visual observation. Above the CAC, the aqueous solutions were all transparent. Upon dilution, the samples get slightly turbid just below the CAC (Supporting Information Figure S1). The concentration range for which these turbidities are observed depends on the cation alkyl chain length and becomes broader upon decreasing the alkyl chain length. In the case of C8MImIbu in D2O, turbidity is also observed above the CAC and phase separation is also observed in the 84−100 mM concentration range. B


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Figure 2. Aggregate size distribution obtained from DLS at 25 °C and for different concentrations: IbuNa and C8MImCl (left); C4MImIbu, C6MImIbu and C8MImIbu (right) in aqueous solutions. For the sake of clarity, the amplitudes for C8MImCl and C6MImIbu have been shifted up by +25 and those of C8MImIbu by +50.

Figure 3. (top) Cryo-TEM images of C6MImIbu aqueous solutions at 14 mM (left and middle) and 28 mM (right). (bottom) Cryo-TEM images of C8MImIbu aqueous solutions at 8 mM.

3.2. Dynamic Light Scattering. The aggregate size distributions obtained experimentally for CnMImIbu solutions at different concentrations C are shown in Figure 2. The results for IbuNa at 300 mM and C8MImCl at 500 mM are also shown for comparison. In qualitative agreement with previous work in which sodium ibuprofenate was demonstrated to form micelles,32 the solution of IbuNa at 300 mM is mainly composed of micelles with a hydrodynamic diameter Dh = 1.9 ± 0.3 nm about twice its molecular length and a polydispersity index PDI = 0.84. For C4MImIbu, at concentration above the CAC (125 mM), micelles with an average diameter Dh = 2.5 ± 0.5 nm (PDI = 0.480), which is slightly larger than that obtained for IbuNa, are observed. These micelles coexist with larger aggregates whose hydrodynamic diameters range from 100 to 400 nm. Upon dilution, these micelles disappear and only aggregates with hydrodynamic diameters ranging from 35 to 200 nm are observed. Similar observations were obtained for C6MImIbu; at a concentration about 5 times the CAC (223 mM), only micelles are observed with a hydrodynamic diameter Dh = 3.4 ± 0.7 nm (PDI = 0.146) which is slightly larger than that obtained for C4MImIbu. When the concentration is decreased to about twice the CAC (76 mM), micelles coexist with larger aggregates. In the turbid regime (C = 14 mM), only large aggregates were observed with hydrodynamic diameters

extending to 1000 nm. C8MImCl is also known to self-assemble in water; in particular, micelle-like oblate ellipsoids have been observed for this system at high concentration.33 Our experiments show that the solution of C8MImCl at 500 mM is composed of two populations with average hydrodynamic diameter Dh = 1.5 ± 0.2 nm and 1240 ± 1300 nm (Figure 2, left). DLS measurements for C8MImIbu show obvious monomodal distributions on both sides of the CAC (Figure 2 right). At a concentration ten times the CAC, only aggregates with Dh = 31 ± 7 nm (PDI = 0.016) were obtained. These aggregates are much larger than those obtained for IbuNa or C8MImCl and suggest that they do not remain spherical. Interestingly, upon dilution from 100 mM to 8 mM, the average size of the aggregate goes through a minimum at the CAC. The size distributions in Figure 2 are presented in percent of intensity. Because the intensity scattered by a single particle increases with the size to the power 6, it should be kept in mind that this representation enhances greatly the fraction of large aggregates compared to what it represents in terms of molar concentration in the sample. In terms of mass fraction, the bias is still very large; the size of the large aggregates is 2 orders of magnitude larger than the size of the small aggregates. If both populations scattered the same intensity, this would mean that C


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the chemical shifts δobs for the different protons of the ILs are summarized in Supporting Information Tables S1−S3. The difference in the chemical shifts obtained at the highest concentration δmax and those obtained at the lowest concentration δmin are shown in Figure 4 for C4MImIbu and

the large aggregates represent 1 ppm of the total mass of IL. The hydrodynamic diameter corresponds to the diameter of spheres characterized by the same diffusion coefficient. It cannot always be translated directly in terms of the size of the aggregates because attractive potential between particles is known to decrease the collective diffusion coefficient. This means that attracting particles can look much larger than what would be obtained by extrapolation to zero concentration. The decrease of diffusion coefficient could be interpreted either in term of an increase of size or as an increase in attraction.34 This is a classical ambiguity of scattering data, which cannot discriminate between an increase in mass and a negative second Virial coefficient under equilibrated aggregation condition. Cryo-TEM has been used to address this difficulty. 3.3. Cryogenic Transmission Electron Microscopy. Cryo-TEM measurements were also performed to investigate the structure of the large aggregates formed at the different concentrations. Micrographs obtained for C6MImIbu and C8MImbu in the turbid regime are shown in Figure 3. Aqueous solutions of C6MImIbu at a concentration of 14 mM present long twisted ribbons with some as long as 3 μm in contour length. At 28 mM, polydisperse unilamellar vesicles ranging from 30 to 200 nm are observed. These results are consistent with the DLS data described above. Aqueous solutions of C8MImIbu at 8 mM contain a mixture of unilamellar vesicles ranging from 70 to 80 nm and ribbon-like micelles. In this case, it should be emphasized that individual onion-like nanostructures and extended multilamellar structures were also obtained but to a lesser extent. The main diameter of individual structures is about 200 nm and the average distance between layers is 3.1 ± 0.3 nm. Interestingly, a similar onion phase has been observed by Hao and Liu in their studies on salt-free catanionic systems obtained by mixing trimethyltetradecylammonium hydroxide (TTAOH) and oleic acid (OA).35 However, contrary to them, our phases did not show any birefringence, as our IL was too diluted. The DLS and cryo-TEM measurements above show the formation of micelles for C4MImIbu and C6MImIbu at high concentration and a transition from micelles to vesicles or ribbon-like micelles, characterized by turbid solutions, upon dilution. The hydrodynamic diameter Dh of the micelles formed at high concentration follows the order IbuNa < C4MImIbu < C6MImIbu. The slight increase in the hydrodynamic diameter observed for C4MImIbu and C6MImIbu compared to IbuNa is due to the formation of mixed micelles. The much larger hydrodynamic diameter of the micelles obtained with C8MImIbu might be due to a sphere to rod transition. In order to confirm this interpretation, we measured the viscosity of our system since the formation of wormlike micelles is usually followed by a large increase of viscosity.36 The change in viscosity found for C8MImIbu solutions was too low to be ascribed to a sphere to rod transition. Another probable explanation of the results above is that attractive interaction between the aggregates led to the formation of spherical lumps of larger aggregates as observed by other authors.36,37 Below the CAC, large aggregates dominate, which can be premicellar aggregates as observed in some oligomeric surfactants.38 3.4. 1H NMR spectra. The aggregate compositions were determined from NMR chemical shifts which are sensitive to the environment of the nuclei. The 1H NMR spectra for C4MImIbu, C6MImIbu, and C8MImIbu in D2O as a function of concentration C are shown in Supporting Information Figure S2, S3, and S4. For all concentrations considered in this work,

Figure 4. Amplitude of variation of chemical shifts Δδ for various protons for C4MImIbu in D2O at 25 °C: (■) C4MIm, (red ●) Ibu.

in Supporting Information Figures S5 for C6MImIbu and C8MImIbu. It has been demonstrated that the polarity decrease upon aggregation of classical long alkyl chains surfactants (going from aqueous solution to micelles core) commonly leads to a downshift of the 1H NMR chemical shift for alkyl groups.39 Upon incorporation of aromatic ions into surfactant micelles, two additional effects are observed. Aromatic protons move upfield upon intercalation into the micelles and the shift provides information on the average depth of the individual proton’s intercalation into the micelles.40 Additionally, protons of the surfactants in the proximity of the shielding cone of the aromatic ring move upfield. Figure 4 shows that all the protons of the cation and the anion undergo an upfield shift (Δδ < 0). This provides evidence for the close proximity of these two ions. For the ibuprofenate protons, two different groups can be observed. On the one hand, H14, H15, H16, and H17 undergo higher shielding which demonstrates that they are more deeply incorporated into the micelle. On the other hand, H11, H12, and H13 undergo less shielding, showing that the carboxylate function is pointing outward the micelles. The shielding effect on the anion is the same for the three ILs (see Figure S5, Supporting Information). Protons of the imidazolium ring as well as those of the alkyl chain shift upfield due to the presence of the aromatic group of ibuprofenate in their vicinity. Again, the shielding effect on the cation is the same for the different ILs. However, a larger difference is noticed for Δδ corresponding to H2 depending on the cation alkyl chain length: C4 (ΔδH2 = −0.151 ppm) > C6 (ΔδH2 = −0.096 ppm) > C8 (ΔδH2 = −0.032 ppm). This indicates a higher hydrogen bonding between the cation and the anion when increasing the alkyl chain length and the formation of strong ion pairs even at low concentration. These results highlight that, independent of the cation alkyl chain length, the ibuprofenate anion and the imidazolium cation are localized in the same environment when micelles are formed. It has been shown that 1H NMR chemical shifts can be used to determine the CAC of surfactants.41 Under fast exchange occurring on the NMR time scale, the observed chemical shift for a corresponding proton is a weight average of the monomer (δmono) and micelles (δmic) chemical shifts which can be expressed as D


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Figure 5. Chemical shift δobs as a function of 1/C for H7 of the cation (left) and H17 of the anion (right): C4MImIbu (■) C6MImIbu (red ●) and C8MImIbu (green ▲).

Table 1. Systems Investigated by Means of Molecular Dynamics Simulations concentration of IL (M)

number of ions pairs

number of water molecules

box length (nm) (C4/C8)

number density

volume fraction

0.20 0.76 1.39

18 68 125

5000 5000 5000

5.42/5.45 5.73/5.80 6.03/6.16

0.11/0.11 0.36/0.35 0.57/0.54

0.054/0.067 0.17/0.20 0.27/0.31

Figure 6. (top) Typical molecular configuration for C4MImIbu in water in which the different aggregates are distinguished (the concentration is C = 0.2 M). Each color corresponds to a set of anions (Ibu) and cations (C4MIm) that belong to the same cluster. The white spheres indicate the aggregate centers of mass. Water molecules have been removed for the sake of clarity. The box size is 5.42 nm. (bottom) Aggregate size distributions for C4MImIbu (left) and C8MImIbu (right) at different concentrations C. These distributions were estimated from the ensemble average over at least 1000 configurations taken along the MD trajectory. The numbers are the average number of molecules in the aggregates.

⎛C ⎞ ⎛C ⎞ δobs = δmon⎜ mon ⎟ + δmic⎜ mic ⎟ ⎝ C ⎠ ⎝ C ⎠

According to eq 2, the plot of δobs versus 1/C should give two straight lines with their intersection corresponding to the CAC. As an example, Figure 5 shows the variation of δobs as a function of the reciprocal of the concentration C for the different ILs. We choose to represent the chemical shifts for H7 of the cation and H17 of the anion. Only one break point was observed for C4MImIbu and C6MImIbu, whereas a second transition was noticed for C8MImIbu. This second transition corresponds to the concentration range where phase separation occurs. A similar change in the chemical shift direction was observed by Sominis and collaborators who ascribed it to a sphere-to-rod

(1)

where Cmon, Cmic, and C are the concentrations of surfactant monomers, surfactant in micelles and total surfactants in solution, respectively. Above the CAC, it was assumed that the free monomer concentration remains constant so that Cmic = C − CAC . Inserting this relation in eq 1 gives δobs = δmic −

CAC (δmic − δmon) C

(2) E


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transition and micelle growth.42 The CACs obtained from the plot of δobs vs 1/C are given in Supporting Information Table S4 for the different ILs. These CACs are in good agreement with those obtained previously by conductimetry and surface tension (Supporting Information Table S4).30 Furthermore, as expected from our previous diffusion measurements,30 the CACs for the different ILs are identical for the cation and the anion, which confirms the formation of mixed micelles. 3.5. Molecular Dynamics. Molecular dynamics simulations were used to investigate the composition of CnMImIbu aggregates and to determine the factors governing aggregation. Two different systems were considered to determine the effect of the alkyl chain length, C4MImIbu and C8MImIbu. We considered different concentrations: C = 0.2 M, 0.76 M, and 1.39 M. Details of the systems which were investigated are summarized in Table 1. Significant aggregation was observed for both C4MImIbu and C8MImIbu upon increasing the concentration C. Figure 6 shows a typical molecular configuration for C4MImIbu in water in which the different aggregates are distinguished (C = 0.2 M). Although only solubilized ions and small ion clusters were observed for very low concentrations, large supramolecular aggregates were observed for larger concentrations. In order to determine the effect of concentration on aggregation for C4MImIbu and C8MImIbu, we estimated the aggregate size distribution as follows. Two ions A and B (that is, cations and anions) were considered as belonging to the same aggregate if A possesses at least one atom at a distance r < 0.36 nm from any atom of B. This cutoff was chosen based on the g(r) functions discussed below as it corresponds to the largest physical bond formed by atoms in physical interaction. Although any choice in the cutoff is necessarily arbitrary, it does not affect the validity of the results below but shifts up or down the aggregate size distributions and, hence, the average value. Figure 6 shows the aggregate size distributions for C4MImIbu and C8MImIbu upon increasing the concentration. We distinguished in Figure 6 the solubilized anions (Ibu) or cations (CnMIm), the ion pairs and the aggregates. These latter were separated into three categories depending on their residual charges: anionic [Agg]−, cationic [Agg]+, or neutral [Agg]. The numbers in the rectangles represent the average aggregation numbers N. Supporting Information Table S4 summarizes the composition of anionic and cationic aggregates depending on the concentration. At the lowest concentration, both C4MImIbu and C8MImIbu already form small clusters of a size smaller than 20 ions. At this concentration the solutions are, however, mainly composed of isolated cations or anions. The number of isolated cations is always larger than the number of isolated anions and is highest for C4MImIbu. This results from the tendency of ibuprofenate anions to micellize on its own. Upon increasing the concentration to 0.76 M, the C4MImIbu solution is mainly composed of isolated cations. No isolated anions are present, and the number of molecules composing anionic aggregates increases from 7 to 38. At the same concentration, C8MImIbu solution is mainly composed of neutral aggregates. Upon further increasing concentration, C4MImIbu solution is still mainly composed of isolated cations and of anionic aggregates (N = 225), whereas C8MImIbu solution exhibits a single aggregate that percolates through the simulation box. This behavior can be interpreted as a phase separation as observed during our experimental work. As suggested from our experimental results, C4MImIbu solutions are, thus, mainly composed of anionic aggregates due to the

ability of ibuprofenate to micellize by itself. The differences observed by increasing the alkyl chain length are due to a change of the aggregates composition. We now discuss the main interactions involved in the aggregate formation in C4MImIbu and C8MImIbu. For the sake of clarity, only the results obtained for C = 0.76 M are discussed in what follows (similar conclusions were reached for the other concentrations). Radial distribution functions (RDFs), also known as pair correlation functions g(r), are a powerful statistical mechanic tool to investigate the microscopic structure of liquids and solids. In particular, partial radial distribution functions gαβ(r) between two types of atoms, α and β, allow probing the correlation between the positions of these two atoms as they are related to the probability to find an atom β at a distance r from an atom α. The g(r) functions are related to the inverse Fourier transform of the structure factor S(q) that is measured in diffraction experiments. When probed between atomic sites of different molecules (as in the present work), the gαβ(r) functions provide crucial information about the interactions that are responsible for the cohesion of liquids and solids and the driving forces of self-assembly. The RDFs between the terminal H atoms of the cation alkyl chain (H10/ H10 for C4MImIbu and H23/H23 for C8MImIbu), between H atoms of the anion alkyl chain (H17/H17), and those between cation and anion alkyl chains (H10/H17 for C4MImIbu and H23/ H17 for C8MImIbu) are represented in Figure 7A, B, and C respectively. The RDFs obtained in Figure 7A are similar to those reported by Bhargava and Klein for CnMImBr ionic liquids with a first maximum located at around 0.4 nm.10 The amplitude of this peak is very small (around unity) for C4MImIbu, which suggests that there is no specific organization of the cations alkyl tails around each other. This result shows that C4MIm cations do not micellize on their own. This is consistent with the fact that entropic effects prevent aggregation in solution of very small chain. In other words, hydrophobic interactions between C4MIm molecules are not strong enough to get H10 atoms close to each other. On the contrary, the anion/anion RDFs for C4MImIbu present an intense peak at 0.4 nm with an amplitude of ∼7.0. This means that Ibu anions attract each other, which was expected since they micellize by their own, even when they are associated with a simple cation like sodium. More interestingly, the cation/anion RDFs (Figure 7C) for C4MImIbu has a maximum located at 0.4 nm with an amplitude of ∼3.0, which indicates close proximity between C4MIm and Ibu alkyl tails. The strong attractive ionic interactions that exist between C4MIm and Ibu bring the cation and the anion close to each other. This suggests the formation of mixed micelles, which are mainly composed of ibuprofenate anions. The behavior for C8MImIbu is quite different. The amplitude of the cation/cation RDFs (Figure 7A) is much larger (∼6.4), which suggests the formation of aggregates through strong interactions between the H23 atoms. This simulation result is consistent with the fact that C8MImCl does micellize in water as a result of strong hydrophobic interactions. The anion− anion RDFs (Figure 7B) for C8MImIbu is comparable to the one obtained for C4MImIbu, but its amplitude is lower meaning that Ibu anions are more homogeneously distributed in mixed micelles with C8MIm than in mixed micelles with C4MIm. This suggests that the composition of the C8MImIbu micelles are closer to stoichiometry than C4MImIbu micelles. The H23/H17 anion/cation RDFs (Figure 7C) has a maximum located at 0.4 nm with an amplitude that is much larger for F


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Figure 8. RDFs for (A) H2 of CnMIm around the oxygen atoms of Ibu and (B) H2 of CnMIm around the oxygen atoms of water at C = 0.76 M for C4MImIbu (black data) and C8MImIbu (red data).

C8MIm than C4MIm. These results show that stronger interactions exist between the cation and the anion when the alkyl chain length increases as a result of stronger hydrophobic interactions as discussed above. This result is fully consistent with our NMR measurements above. The amplitudes of the RDFs between H2 and water are very low so that water can be considered as being weakly coordinated to the imidazolium cation. This confirms that imidazolium cations are incorporated in between ibuprofenate anions, in the micellar core, and not present at the micelle interface. The desolvation concomitant to the self-assembling process can be probed by calculating the average number of water molecules NH2O solvating a cation or anion as a function of the concentration C. A water molecule is considered as solvating an ion if it is located at a distance r < 0.5 nm from any of its atom. Again, this cutoff was chosen as it corresponds to the typical distance between two nonbonded atoms. It should be noted that the qualitative results discussed below do not depend on the choice made for the cutoff. As usually done for classical ions such as sodium halides,44 NH2O was normalized to the accessible surface Sacc of the cation and anion (i.e., nH2O = NH2O/Sacc). Following previous works on adsorption in porous media,45,46 Sacc can be estimated using the following Monte Carlo procedure. Let us consider a simulation box of volume V containing the cation or anion. Many random lines l = {l1, l2, l3, ..., ln) are thrown within the simulation box. Each line li intersects pi times with the cation or anion surface, p = {p1, p2, p3, ..., pn). The accessible surface area is given by

Figure 7. RDFs for (A) cation/cation, (B) anion/anion and (C) cation/anion tails groups at C = 0.76 M for C4MImIbu (black data) and C8MImIbu (red data).

C8MImIbu (∼6.5) than for C4MImIbu and that is close to that obtained for the cation/cation RDFs. This means that the hydrophobic and electrostatic interactions between C8MIm cations are the same as those between C8MIm cations and Ibu anions. Because electrostatic interactions are about the same for C4MImIbu and C8MImIbu this evidence the strongest hydrophobic interactions in C8MImIbu. We also compared the RDFs obtained between the most acidic hydrogen atom of the imidazolium ring (localized between the two nitrogen atoms) and the oxygen atoms of the anion and water for C4MImIbu and C8MImIbu (Figure 8). These RDFs are consistent with those reported by Kirchner and co-workers for CnMImOAc, although the amplitudes reported in the present work are higher.43 Ibuprofenate exhibits more pronounced correlations with the imidazolium ring for G


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Figure 9. Number of water molecules nH2O solvating CnMIm (left) and Ibu (right) per unit of surface area as a function of the concentration C. The blue and red data are for C4MImIbu and C8MImIbu, respectively. A water molecule is considered as solvating an ion if it is located at a distance r < 0.5 nm from any of the ion atoms. n

Sacc(δ) = 2V

some amounts of cations intercalated between the anions. When increasing the imidazolium alkyl chain length, stronger hydrophobic interactions are present between alkyl chains of the imidazolium and the ibuprofenate, and the number of imidazolium incorporated into the micelle increases. As the number of imidazolium incorporated into the aggregates increases, the composition of the aggregates becomes close to equimolar. TEM, DLS, and viscosity measurements suggest the formation of larger aggregates which are spherical lumps of aggregates, and phase separation is observed by simulation. These spherical lumps of aggregates might constitute the beginning of phase separation. The observation of phase separation is quite common for stoichiometric mixtures of catanionic surfactants.55 As the concentration decreases, strong ion pairs are formed between the cation and the anion. These ion pairs behave as double tail amphiphile and start forming vesicles. All theses studies were performed at room temperature. Studying the effect of the temperature on the observed phases and aggregates would be interesting to better understand the properties of the system. Such an investigation, which would provide a more complete description of the phase behavior of the system, is out of the scope of the present paper.

∑i = 1 pi n ∑i = 1 li

(3)

We found that Sacc = 4.1 nm2, 5.4 nm2, and 4.7 nm2 for C4MIm, C8MIm, and Ibu, respectively. These results can be considered satisfactory as they scale with the size and mass of the ions; as expected, C4MIm has a smaller accessible surface area than C8MIm and Ibu has an accessible surface area in between those for C4MIm and C8MIm owing to its intermediate size. Figure 9 shows nH2O solvating C4MIm, C8MIm, and Ibu as a function of the concentration C. For both C4MImIbu and C8MImIbu, nH2O decreases upon increasing C. This result confirms that aggregation becomes more pronounced as C increases so that, on average, the anion and cation surface in contact with water decreases. The difference in the aggregates composition is also reflected in Figure 9. Although nH2O solvating Ibu is nearly the same for C4MImIbu and C8MImIbu, a clear difference is noticed for nH2O solvating C4MIm and C8MIm. The amount of water molecules solvating the cation is higher for C4MIm than for C8MIm because of the presence in the solution of a larger amount of isolated cations (see above). The formation of stoichiometric aggregates is clearly demonstrated by the fact that nH2O solvating Ibu or C8MIm are the same. To summarize, our experimental and theoretical results can be related to previously published works on a mixture of anionic and cationic surfactants where transition from vesicles to micelles were obtained by increasing the temperature,47 by adding organic additives48 or by varying the ratio between the two components.49−52 In the latter case, the transition was triggered by the change in the ratio of cationic to anionic surfactant with vesicles being formed as equimolar composition is approached. Transition from micelles to vesicles upon dilution has been also observed by Hassan and co-workers for mixed micelles made up of cetytrimethylammonium bromide (CTAB) and sodium 3-hydroxynaphthalene-2-carboxylate and more recently for cationic−anionic mixture of CTAB and a hydrotrope, sodium salicylate (NaSal).53,54 This transition was ascribed to a solubility disparity between the surfactant and the hydrotrope. Our DLS results demonstrated that concentrated solutions of C4MImIbu and C6MImIbu are mainly composed of micelles with hydrodynamic diameters slightly higher than that of ibuprofenate. Our molecular simulations show that, for C4MImIbu, the aggregates present strong hydrophobic interactions between anions and, to a lesser extent, between cation and anion. This suggests that micelles of C4MImIbu and C6MImIbu are mainly composed of ibuprofenate anions with

4. CONCLUSION In this study, we demonstrated that aggregate structures of ionic liquids containing surface active pharmaceutical ingredients such as ibuprofenate can be modulated by tuning the cation alkyl chain length. Both experimental measurements and atom-scale molecular simulations were used to gain insights into the aggregate structure and composition. For imidazolium cations with a short alkyl chain, spherical micelles are obtained. These micelles are mainly composed of ibuprofenate anions with small amount of imidazolium cations incorporated between the ibuprofenate anions. Upon increasing the alkyl chain length, the number of imidazolium cations incorporated into the micelles increases so that an increase of the micelle mean hydrodynamic diameter is observed. Upon increasing further the alkyl chain length, aggregates of stoichiometric composition are obtained. Attractive interactions between the aggregates lead to the transition to large globular aggregates, which might constitute the beginning of phase separation. At low concentration, strongly correlated ion pairs between imidazolium and ibuprofenate form and act as double tail amphiphiles leading to the formation of vesicles. Our molecular simulations indicate that the formation of ion clusters between the imidazolium cation and the ibuprofenate anion, which arises because of the hydrophobic nature of these ions and the change H


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liquids, [C(n)H(2n+1)mim][CkH2k+1SO3]: synthesis and physicochemical properties. Phys. Chem. Chem. Phys. 2009, 11, 8939−8948. (9) Singh, T.; Drechsler, M.; Mueeller, A. H. E.; Mukhopadhyay, I.; Kumar, A. Micellar transitions in the aqueous solutions of a surfactantlike ionic liquid: 1-butyl-3-methylimidazolium octylsulfate. Phys. Chem. Chem. Phys. 2010, 12, 11728−11735. (10) Bhargava, B. L.; Klein, M. L. Aqueous solutions of imidazolium ionic liquids: molecular dynamics studies. Soft Matter 2009, 5, 3475− 3480. (11) Bhargava, B. L.; Klein, M. L. Molecular Dynamics Studies of Cation Aggregation in the Room Temperature Ionic Liquid [C(10)mim][Br] in Aqueous Solution. J. Phys. Chem. A 2009, 113, 1898− 1904. (12) Bhargava, B. L.; Yasaka, Y.; Klein, M. L. Computational studies of room temperature ionic liquid-water mixtures. Chem. Commun. 2011, 47, 6228−6241. (13) Miskolczy, Z.; Sebok-Nagy, K.; Biczok, L.; Gokturk, S. Aggregation and micelle formation of ionic liquids in aqueous solution. Chem. Phys. Lett. 2004, 400, 296−300. (14) Singh, T.; Drechsler, M.; Mueeller, A. H. E.; Mukhopadhyay, I.; Kumar, A. Micellar transitions in the aqueous solutions of a surfactantlike ionic liquid: 1-butyl-3-methylimidazolium octylsulfate. Phys. Chem. Chem. Phys. 2010, 12, 11728−11735. (15) Brown, P.; Butts, C. P.; Eastoe, J.; Fermin, D.; Grillo, I.; Lee, H.C.; Parker, D.; Plana, D.; Richardson, R. M. Anionic Surfactant Ionic Liquids with 1-Butyl-3-methyl-imidazolium Cations: Characterization and Application. Langmuir 2012, 28, 2502−2509. (16) Rao, K. S.; Trivedi, T. J.; Kumar, A. Aqueous-Biamphiphilic Ionic Liquid Systems: Self-Assembly and Synthesis of Gold Nanocrystals/Microplates. J. Phys. Chem. B 2012, 116, 14363−14374. (17) Brown, P.; Butts, C.; Dyer, R.; Eastoe, J.; Grillo, I.; Guittard, F.; Rogers, S.; Heenan, R. Anionic Surfactants and Surfactant Ionic Liquids with Quaternary Ammonium Counterions. Langmuir 2011, 27, 4563−4571. (18) Villa, C. C.; Moyano, F.; Ceolin, M.; Silber, J. J.; Dario Falcone, R.; Mariano Correa, N. A Unique Ionic Liquid with Amphiphilic Properties That Can Form Reverse Micelles and Spontaneous Unilamellar Vesicles. Chem.Eur. J. 2012, 18, 15598−15601. (19) Brown, P.; Butts, C. P.; Eastoe, J.; Grillo, I.; James, C.; Khan, A. New catanionic surfactants with ionic liquid properties. J. Colloid Interface Sci. 2013, 395, 185−189. (20) Anouti, M.; Sizaret, P.-Y.; Ghimbeu, C.; Galiano, H.; Lemordant, D. Physicochemical characterization of vesicles systems formed in mixtures of protic ionic liquids and water. Colloids Surf., A 2012, 395, 190−198. (21) Paulsson, M.; Edsman, K. Controlled drug release from gels using surfactant aggregates. II. Vesicles formed from mixtures of amphiphilic drugs and oppositely charged surfactants. Pharm. Res. 2001, 18, 1586−1592. (22) Bramer, T.; Dew, N.; Edsman, K. Catanionic mixtures involving a drug: A rather general concept that can be utilized for prolonged drug release from gels. J. Pharm. Sci. 2006, 95, 769−780. (23) Bramer, T.; Dew, N.; Edsman, K. Pharmaceutical applications for catanionic mixtures. J. Pharm. Pharmacol. 2007, 59, 1319−1334. (24) Dew, N.; Bramer, T.; Edsman, K. Catanionic aggregates formed from drugs and lauric or capric acids enable prolonged release from gels. J. Colloid Interface Sci. 2008, 323, 386−394. (25) Consola, S.; Blanzat, M.; Perez, E.; Garrigues, J.-C.; Bordat, P.; Rico-Lattes, I. Design of original bioactive formulations based on sugar-surfactant/non-steroidal anti-inflammatory catanionic self-assemblies: A new way of dermal drug delivery. Chem.Eur. J. 2007, 13, 3039−3047. (26) Jiang, Y.; Li, F.; Luan, Y.; Cao, W.; Ji, X.; Zhao, L.; Zhang, L.; Li, Z. Formation of drug/surfactant catanionic vesicles and their application in sustained drug release. Int. J. Pharm. 2012, 436, 806− 814. (27) Hough, W. L.; Smiglak, M.; Rodriguez, H.; Swatloski, R. P.; Spear, S. K.; Daly, D. T.; Pernak, J.; Grisel, J. E.; Carliss, R. D.; Soutullo, M. D.; Davis, J. H., Jr.; Rogers, R. D. The third evolution of

in the screening of the electrostatic interactions (Debye length) upon increasing the ion concentration, is responsible for the formation of the aggregates. We also show that aggregation can be studied in terms of simple functions such as radial distribution functions and average solvation numbers. This preliminary study opens up perspectives for the use of ILs based on pharmaceutical ingredients for drug delivery and materials synthesis.

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ASSOCIATED CONTENT

S Supporting Information *

Additional information on molecular simulations, chemical shifts, and NMR spectra (Figures S1−S6 and Tables S1−S5). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*L. Viau. E-mail: [email protected]. Fax: + (33) 03 81 66 62 88. Tel: + (33) 03 81 66 62 93. Author Contributions

All authors have contributed to the work and have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by The Agence Nationale de la Recherche ANR-10-JCJC-0802. The authors thank Ms. Karine Parra from the Laboratoire de Mesures Physiques of the Université de Montpellier 2 for her help with NMR experiments. Pr. Alain Brisson from the team Chimie Moléculaire et NanoBioTechnologie of the Université de Bordeaux is gratefully acknowledged for the cryo-TEM images reported here.

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REFERENCES

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