Micellar transitions in catanionic ionic liquid–ibuprofen aqueous mixtures; effects of composition and dilution

Abstract

The present study aims to develop a basic understanding of the molecular interactions of an anti-inflammatory drug, ibuprofen (Ibu), with a surface active ionic liquid (IL), 1-dodecyl-3-methylimidazolium chloride (C₁₂mimCl), in aqueous medium, owing to their utility as the components of pharmaceutically active ionic liquids. Various techniques such as surface tension, steady-state fluorescence, UV-visible absorption, dynamic light scattering and ¹H NMR measurements have been employed to provide comprehensive knowledge of the C₁₂mimCl –Ibu interactions. The interactions between the ionic liquid and drug molecules have been found to be highly synergistic both in the mixed micelles as well as in the mixed monolayer due to the formation of catanionic mixtures. These mixtures are seen to display enhanced micellization and adsorption tendencies and varied aggregate assemblies in aqueous medium determined by the amphiphile mixing ratio and the total mixture concentration. The dilution induced transformation of smaller micelles to larger aggregates is ascribed to the solubility mismatch between the two components. Quantitative evaluation of the process of interaction between Ibu and the ILs has been done in terms of various quenching and binding parameters exploiting the fluorescence measurements. The formation of highly surface active catanionic complexes (C₁₂mim⁺Ibu⁻) of 1 : 1 stoichiometry stabilized largely by a combination of electrostatic, hydrophobic, cation–π and π–π interactions has been well established through spectroscopic investigations.

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1. Introduction

Ionic liquids (ILs) are being increasingly reported as multipurpose materials,^1–5 capturing the interest of the scientific fraternity even outside the discipline of chemistry. The credit for this lies in their ‘designer’ nature i.e. easily tunable behavior and especially in their ‘greener’ aspects.^6–9 The journey of these ILs started with the first generation ILs^9,10 possessing unique physical properties such as low vapor pressure and high thermal stability, progressing to the second stage with advanced functional materials called second generation ILs^11,12 produced through a modification of both physical and chemical properties. They are now heading towards the third generation where active pharmaceutical ingredients are being explored to produce ILs with biological activity.^13–15 One of the reasons for the deployment of ILs in this regard is the possibility of tailoring their physical, chemical and biological properties by developing specific features in the chemical structures of the cation or anion components that can offer unique attributes like the desired hydrophobicity/hydrophilicity, acidity/basicity, viscosity etc. These ILs generally employ a surface active ion like benzalkonium, alkyl imidazolium, docusate etc. along with a pharmaceutically active counterpart to provide the necessary dual functionality and also to control the solubility, stability and bioavailability of the drug. Such active pharmaceutical ingredient based ionic liquids (API-ILs) appear in the literature as lidocaine docusate, ranitidine docusate, didecyldimethylammonium ibuprofenate, benzalkonium saccharinate, benzalkonium ibuprofenate etc.^16,17 While these active ions may be pharmacologically independent, they may also act synergistically or antagonistically with one active ion counteracting the side effects of the other active ingredient. Hence, the appropriate combination of an anion/cation with a drug for a new pharmaceutical ingredient requires a fundamental understanding of the interactions between the cationic and anionic moieties at the molecular level.

With this in mind, we have tried to explore the interactions between the non-steroidal anti-inflammatory drug (NSAID),¹⁸ ibuprofen (Ibu) and an anti-film agent,¹⁹ 1-dodecyl-3-methyl imidazolium chloride (C₁₂mimCl), in aqueous medium. The knowledge of these interactions could be helpful in the development of an API-IL based on the above components providing us with a formulation that can facilitate the entry of an anti-inflammatory drug into biofilms. In addition, ibuprofen possesses antipyretic and analgesic properties while C₁₂mimCl possesses better surface active properties than conventional surfactants.²⁰ The interest in these interactions also stems from the fact that both the drug and the ionic liquid being amphiphilic are not only capable of forming micelle-like aggregates but are also oppositely charged and thus may interact electrostatically as well as hydrophobically to form ion pairs i.e. (C₁₂mim⁺Ibu⁻) in the solution giving rise to catanionic mixtures with their morphologies dependent on mixture composition. Such catanionic mixtures from oppositely charged surfactants^21–25 and oppositely charged ionic liquids and surfactants^26–28 have been shown to exhibit varied aggregate assemblies such as spheres, rods, disks, ribbons, bilayers, vesicles, etc. and particular phase behavior typically at equimolar ratios. However, similar catanionic drug–surfactant mixtures have been explored earlier for their use as drug delivery agents,^29–32 but hardly any studies addressing the issue of the physicochemical characterization of catanionic drug–IL mixtures appear in the literature. One such report by Viau and coworkers³³ discusses the surfactant-like behavior of salt-free catanionic ionic liquids composed of short alkyl chain imidazolium cations (chains containing 4,6 and 8 carbon atoms) and ibuprofenate anions, where catanionic pairing of Ibu has been observed only for ILs with 8 carbon atom chains. The role of alkyl chain length of the imidazolium moiety in modifying the micellar morphology has been well established earlier also.³⁴ However, we were more interested in the evaluation of the longer chain IL–drug interactions over the whole mixing range and that too in aqueous medium so as to mimic body fluids (where excess salts may be present) in order to meet the requirements for the use of these API–ILs in pharmaceutical applications.

Briefly, this paper takes into account a detailed analysis of interactions in the C₁₂mimCl–ibuprofen mixtures in aqueous solution, ranging from monomeric to micellar regions through an appraisal of both binding and micellar parameters employing surface tension, fluorescence, UV-visible, DLS and ¹H NMR measurements. Firstly, the formation and stoichiometry of the C₁₂mim⁺Ibu⁻ ion pair complexes has been judged and the extent of interactions in these complexes is quantitatively discussed in the light of the binding constant and Stern–Volmer quenching constant. Secondly, the interactions between the ionic liquid and drug molecules were evaluated in the bulk (mixed micelles) as well as at the air/water interface (mixed monolayer), for both of these properties are equally important in designing the composition of a mixture of the desired surface activity, optimal for a specific application. The structural transitions in these IL–drug mixtures have also been studied as a function of the mixture composition and the dilution. These pseudo-catanionic mixtures are seen to display interesting interfacial, micellar and phase behavior properties in aqueous medium, determined by the amphiphile mixing ratio and the total concentration of the mixture.

2. Experimental

2.1 Materials

1-Alkyl-3-methylimidazolium chlorides (C₈mimCl and C₁₂mimCl) were synthesized in the laboratory according to the procedure mentioned elsewhere,³⁵ which involved alkylation of 1-methylimidazole with the corresponding 1-chloroalkanes. The products were then recrystallized from ethyl acetate and dried under vacuum. The purity of the products was ascertained by ¹H NMR spectrum in CDCl₃. Ibuprofen sodium salt (Ibu) was obtained from Fluka and 1-butyl-3-methylimidazolium chloride was a product of Sigma Aldrich. All chemicals were used as received and were of analytical grade. An analytical balance (Sartorius analytic) with a precision of ±0.0001 g was used for weighing the amount of different substances. The solutions were prepared by dissolving accurately weighed quantities in requisite volumes of deionised double distilled water. The structures of the ionic liquid (C₁₂mimCl) and the drug (Ibu) used in the present study are given in Fig. 1.

Fig. 1 Basic structures of the ionic liquid (C₁₂mimCl) and the drug (Ibu) used in the present study.

2.2 Methods

2.2.1 Surface tension measurements. The surface tension (γ) values were measured using a Du Nouy ring tensiometer (Kruss Easy Dyne tensiometer) from Kruss GmbH (Hamburg, Germany) equipped with thermostat, using a platinum ring at 298.15 ± 0.1 K. The platinum ring used in the measurements was thoroughly cleaned every time by washing with doubly distilled water followed by heating through an alcoholic flame. The surface tension of doubly distilled water (72.8 mNm⁻¹) was used for calibration. The γ values for pure C₁₂mimCl, Ibu and their mixtures were measured by adding concentrated stock solutions (at ten times their cmc) of pure amphiphiles and their mixtures in aqueous solutions. All measurements were performed after allowing the solutions to stabilize overnight. The accuracy in the measurement of surface tension with tensiometer is ± 0.15 mNm⁻¹.

2.2.2 Fluorescence measurements. The steady state fluorescence measurements were performed on a Hitachi Fluorescence spectrophotometer, F-4600 using a 10 mm path length quartz cuvette at 298.15 ± 0.1 K. The interactions between C₁₂mimCl and Ibu were studied using fluorescence spectroscopy in two ways. In one of the experiments we studied the micellar properties of the C₁₂mimCl + Ibu mixtures by employing an external probe, pyrene. For this, the concentration of pyrene used in all the measurements was approximately equal to 10⁻⁶ mol dm⁻³ with excitation at 335 nm and recording the emission spectra in the range of 350–500 nm using an excitation and emission slit width of 2.5 nm. The ratio of the intensity of pyrene emission, i.e. I₁/I₃ at 373 and 384 nm, respectively, was used for evaluating the polarity of the environment in which the pyrene was solubilised. Secondly, we studied the interactions between C₁₂mimCl and Ibu by considering the effect of varying amounts of C₁₂mimCl on the fluorescence emission spectra of Ibu recorded in the range of 250–400 nm at an excitation wavelength of 226 nm using an excitation and emission slit width of 2.5 nm. The titrations were performed by successive additions of stock solutions of C₁₂mimCl and Ibu directly into the quartz cuvette containing 2 mL of 0.1 mM Ibu solution. After every addition, the solution was equilibrated for 5 minutes to reach thermal equilibrium.

2.2.3 UV-visible measurements. The absorption spectra were recorded on a UV-1800, Shimadzu, UV-visible spectrophotometer with a quartz cuvette with a path length of 1 cm. The absorbance of pure C₁₂mimCl, Ibu and their aqueous mixtures at varying mole fractions of the two components were recorded at 298.15 K in the range of 200–400 nm.

2.2.4 Dynamic Light Scattering (DLS) measurements. DLS measurements were performed using a Malvern NanoZS zetasizer, equipped with a 532 nm laser beam. The samples of micellar solutions were properly filtered through 0.2 μm filters (Acrodisc) to avoid interference from dust particles. The scattered intensity for the various systems under study was obtained at an angle of 173° to the incident beam and data were collected at least five times for each independent sample. The apparent hydrodynamic diameters were then determined using the Stokes–Einstein equation. The ζ-potential measurements were also carried out with the same instrument.

2.2.5 NMR measurements. ¹H NMR experiments were performed on a 300 MHz JEOL-FT NMR-AL spectrometer using D₂O as solvent. The NMR titration experiments were performed by titrating 2 mM of C₁₂mimCl prepared in D₂O with increasing equivalents of Ibu. Chemical shifts were given on the δ scale. The center of the HDO signal (4.650 ppm) was used as the internal reference.

3. Results and discussion

Aqueous mixtures of two oppositely charged amphiphiles, the so-called catanionic mixtures, are pseudo-three component systems and known to exhibit interesting phase behavior particularly at equimolar ratios. Considering this, a series of solutions of pure C₁₂mimCl and pure Ibu with concentrations 0.1 mM, 1 mM, 10 mM, 50 mM and 100 mM were prepared. The equimolar solutions of both were then mixed in varying mole fractions ranging from 0.1 to 0.9. A visual inspection of these mixtures revealed interesting results as shown in Fig. 2 for 1 mM, 10 mM and 50 mM concentrations. The solutions with a total mixture concentration of 0.1 mM and 1 mM were clear and transparent throughout the entire mole fraction of C₁₂mimCl (x_IL = 0.1–0.9). In case of 10 mM total concentration, the solutions were turbid for the anionic mole fraction range i.e. x_IL = 0.1–0.5 and clear for x_IL = 0.6–0.9 (cationic rich mole fraction range). However, in solutions with a concentration of 50 mM, the turbidity appeared only in samples having 0.3–0.5 mole fraction of C₁₂mimCl. Further increase in the concentration also led to the disappearance of turbidity (and increase in viscosity) in samples having x_IL = 0.3, 0.4 and 0.5 at total mixture concentrations greater than 100 mM, 200 mM and 750 mM respectively. These observations indicated that the mixing of a cationic IL with an anionic drug did not lead to the precipitation of insoluble salts which might be due to the highly asymmetric chain lengths of the two components as is reported in the case of cetyltrimethylammonium octylsulfonate.^25,36

Fig. 2 (a) Phase behavior of C₁₂mimCl and Ibu mixtures in aqueous solution at varying mole fractions of C₁₂mimCl (x_IL) for total mixture concentration of 1 mM, 10 mM and 50 mM. (b) Phase behavior of C₁₂mimCl + Ibu aqueous mixtures at x_IL = 0.2 for total mixture concentration of 1 mM, 10 mM 20 mM, 30 mM, 40 mM and 50 mM.

Based on the above, we could differentiate two concentration regions as follows: firstly, at total mixture concentration ≤1 mM, where all the cationic (C₁₂mimCl) rich or anionic (Ibu) rich samples exhibited similar behavior. At such lower concentrations, the interactions between the monomeric forms of both the molecules could be speculated upon as discussed further below. Secondly, the regions at concentrations ≥1 mM in which the anionic dominated mole fractions were initially turbid followed by a gradual disappearance of turbidity at higher concentrations, while the cationic rich mixtures were clear throughout. As in the case of amphiphilic molecules, the changes in turbidity are generally considered to be associated with the change in size and scattering factor of aggregates in the solution, so the above observations can thus be visualized to be the result of the formation and the redissociation of some sort of C₁₂mimCl–Ibu aggregates, as both of the molecules being surface active can exhibit a tendency to undergo mixed micellization. Hence a complete analysis of the interaction phenomenon in the C₁₂mimCl–Ibu mixtures requires the evaluation of various changes associated with both the monomeric and micellar regions.

3.1 Formation of catanionic C₁₂mim⁺ Ibu⁻ complexes in monomeric regions

To have a detailed picture of the interactions between C₁₂mimCl and Ibu monomers in aqueous solution and to account for the formation of catanionic complexes (C₁₂mim⁺Ibu⁻), spectroscopic monitoring of their aqueous mixtures was carried out employing UV-visible and fluorescence measurements. The absorbance spectra of both pure C₁₂mimCl and Ibu at a concentration of 0.1 mM were recorded across the range 200–400 nm where Ibu is seen to exhibit an intense peak with maximum absorption wavelength (λ_max) at 226 nm and a smaller but broader peak at 254 nm while no such peaks were observed for C₁₂mimCl (Fig. S1, ESI†). This spectral characteristic of Ibu is consistent with previously reported data.³⁷ UV-visible measurements were employed to confirm the formation of catanionic C₁₂mim⁺Ibu⁻ complexes and to determine their stoichiometry by the method of continuous variation (Job’s method). This involves measuring the absorbances of various samples obtained by mixing equimolar solutions of both components (0.1 mM of aqueous mixtures each of Ibu and C₁₂mimCl were taken in the present study) in varying volume fractions. The corrected absorbances (ΔA) of these samples are then plotted against the volume fraction of the C₁₂mimCl as shown in Fig. 3. This corrected absorbance represents the difference between the measured absorbance (A_exp) and the theoretical absorbance (A_theo) of the samples as

ΔA = A_exp − A_theo (1)

where A_theo is calculated taking into account the Beer–Lambert law, i.e. the two components do not interact with each other and hence the total absorbance of the mixture is equal to the sum of their individual absorbances as per eqn (2):

A_theo = ε_ILC⁰_ILX_IL + ε_DC⁰_D(1 − X_IL) (2)

Fig. 3 Job plot depicting 1 : 1 stoichiometry for the catanionic C₁₂mim⁺Ibu⁻ complexes.

Here ε_IL and ε_D are the molar extinction coefficients and C⁰_IL and C⁰_D are the concentrations of the stock solutions of the ionic liquid (C₁₂mimCl) and the drug (Ibu) respectively, while X_IL represents the volume fraction of the ionic liquid. But the interaction between the two components leading to the formation of a new catanionic species (IL–D) makes the actual absorbance of the samples to be as in eqn (3):

A_exp = ε_ILC_IL + ε_DC_D + ε_IL-DC_IL-D (3)

where ε_IL-D is the molar extinction coefficient of the complex (C₁₂mim⁺Ibu⁻) and C_IL, C_D and C_IL-D are the concentrations of the respective species in the mixture. As depicted in Fig. 3, the presence of a maximum in the Job plot for the IL–drug mixtures at X_IL ≈ 0.5 corresponds to 1 : 1 stoichiometry for their binding. Further it also validates the presence of only one complex species i.e. C₁₂mim⁺Ibu⁻ in the solution.

A further quantitative evaluation of these interactions in terms of binding constants was taken care of by fluorescence spectroscopy as Ibu itself gave a fluorescence emission spectrum³⁸ when excited at 226 nm while the other component i.e. C₁₂mimCl showed no fluorescence in the region investigated. Moreover, the emission spectrum of a molecule is highly dependent on the polarity of the surrounding medium as compared to absorption measurements as the fluorophore stays for a longer time in the excited state and exposed to the relaxed environment with solvent molecules oriented around the dipole moment of the excited state.³⁹ Thus in fluorescence emission measurements, the amount of C₁₂mimCl was varied keeping the concentration of Ibu fixed at 0.1 mM and the corresponding changes in the fluorescence emission spectra for the peak maxima at 288.8 nm were noted and analyzed. The variation in the fluorescence emission spectrum of Ibu in its aqueous solution on addition of C₁₂mimCl is depicted in Fig. S2, ESI.† A decrease in the fluorescence emission of Ibu signified the reduced availability of the fluorophores i.e. Ibu monomers, arising out of the complexation with C₁₂mimCl molecules. This quenching of Ibu fluorescence can be dynamic or static resulting from collisions or complexation between the fluorophore (Ibu) and the quencher molecules (C₁₂mimCl) respectively. Hence the fluorescence intensity data of Ibu both in the absence (I₀) and presence (I) of varying amounts of C₁₂mimCl [Q] at 288.8 nm was fitted to the following Stern–Volmer equation:⁴⁰

A good linear relationship was obtained for the I₀/I vs. [Q] plots (Fig. S3(a), ESI†) from where Stern–Volmer quenching constant (k_SV), was calculated and is given in Table 1. Further, taking the average fluorescence life time (τ₀) of Ibu to be 10⁻⁸ s,⁴¹ the collisional quenching rate constant (k_q) for the binding between Ibu and C₁₂mimCl was found to be greater than the maximum diffusion collision quenching rate constant (2.0 × 10¹⁰ M⁻¹ s⁻¹) which signifies that the quenching was being mainly controlled by a static process rather than being a dynamic one. The corresponding free energies of quenching were evaluated employing eqn (5) and were found to be negative for the systems under study suggesting that the quenching of Ibu fluorescence by C₁₂mimCl is a spontaneous process.

ΔG_q = −RT ln k_SV (5)

Table 1 Stern–Volmer quenching constants (k_SV, k_q), binding constant (k_a), correlation coefficients (R_c), number of binding sites (n) and the corresponding free energy changes for quenching (ΔG_q) and binding (ΔG_a) for catanionic C_nmim⁺Ibu⁻ complexes

System	kSV (× 10^3 M^−1)	Rc	kq (× 10^10 M^−1 s^−1)	ka (× 10^3 M^−1)	n	Rc	ΔGq (kJ mol^−1)	ΔGa (kJ mol^−1)
Ibu + C12mimCl	3.62	0.9987	36.2	1.543	0.90	0.9989	−20.3	−18.2
Ibu + C8mimCl	1.65	0.9936	16.5	0.910	0.93	0.9953	−18.4	−16.9
Ibu + C4mimCl	1.41	0.9995	14.1	0.227	0.78	0.9956	−17.9	−13.4

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Further, as both UV-visible and static quenching measurements signify the formation of 1 : 1 catanionic complexes between Ibu and C₁₂mimCl, the complexation equilibria and hence the binding constant can be represented as

C₁₂mimCl + NaIbu ↔ C₁₂mim⁺Ibu⁻

k_a = [C₁₂mim⁺Ibu⁻]/[C₁₂mimCl][NaIbu] (6)

The corresponding association constants for the complexation between IL and Ibu molecules can be determined from the spectral ratio between the fluorescence intensity of the bound (I) and the free ibuprofen (I₀) as per eqn (7):⁴²

log[(I₀ − I)/I] = log k_a + n log[IL] (7)

where n represents the number of binding sites and k_a is the apparent binding constant. A linear regression of the fitting curve of log(I₀ − I)/I vs. log of C₁₂mimCl concentration (Fig. S3(b), ESI†) provides the values of k_a and n as listed in Table 1. It is clear from the values of the binding constant that C₁₂mimCl exhibits a larger binding affinity for the Ibu molecule as compared to its shorter chain analogues i.e. C₈mimCl and C₄mimCl. This increase in the k_a values with increasing chain length clearly emphasizes the role of hydrophobic forces in the formation of catanionic IL–Ibu complexes. The binding capacity (n) is found to be almost unity for all C_nmimCl + Ibu mixtures in accordance with UV-visible measurements. Further, from the values of k_a, the free energy change for the complexation between ILs and Ibu can be evaluated from the following equation:

ΔG_a = −RT ln k_a (8)

The values of ΔG_a as listed in Table 1 have been found to be negative indicating the feasibility of formation of C₁₂mim⁺Ibu⁻ catanionic complexes under the given conditions. Both k_a and ΔG_a are higher in magnitude in the C₁₂mimCl–Ibu mixtures as compared to C₈mimCl–Ibu and C₄mimCl–Ibu which suggests the greater feasibility and stability of the complex in the case of the former.

Hence on the basis of spectroscopic investigations we can conclude that the interaction between monomers of C₁₂mimCl and Ibu leads to the spontaneous formation of C₁₂mim⁺Ibu⁻ catanionic complexes stabilized largely by a combination of electrostatic as well as hydrophobic forces.

3.2 Formation of mixed micelles in catanionic C₁₂mimCl–Ibu (IL–drug) mixtures

As the cmc of a surface active substance is best regarded as a measure of its industrial utility, we herein investigated the behavior of aqueous mixtures of C₁₂mimCl and Ibu at varying mole fractions both in the bulk as mixed micelles and at the interface as mixed monolayers using fluorescence and surface tension measurements. For this, the propensity of both substances to form micelles individually was explored with conductivity and surface tension measurements, [Fig. 4(a) and (b)] where the cmc values for both C₁₂mimCl and Ibu were found to be 14.22 mM and 187.63 mM respectively, being in good agreement with the literature values.^43,44 Ibu displays rather less capacity to form aggregates than C₁₂mimCl as revealed from its comparatively much higher cmc. This could also be due to the presence of a long alkyl chain in C₁₂mimCl giving it a high hydrophobicity.

Fig. 4 Plots showing variation of surface tension (γ) vs. log of amphiphile concentration and variation of specific conductivity (κ) with molar concentration of amphiphile [inset] for (a) C₁₂mimCl and (b) Ibu.

Further conductivity, surface tension and fluorescence measurements were performed for C₁₂mimCl + Ibu mixtures at various mole fractions to deduce the mixed micellization behavior. The conductivity techniques were unable to detect the mixed micelle formation in these mixtures due to the much smaller difference in pre-micellar and post-micellar slopes making the break at cmc indistinguishable. However, sharp breaks in the plots of both γ vs. log of concentration and I₁/I₃ ratio of pyrene emission spectrum vs. the concentration were obtained for all the mixtures [Fig. 5(a) and (b)].

Fig. 5 Plots showing (a) variation of surface tension (γ) vs. log of total mixture concentration and (b) variation in the pyrene I₁/I₃ ratio with total mixture concentration for catanionic C₁₂mimCl + Ibu aqueous mixtures (For clarity reasons, the values of γ for x_IL = 0.70, 0.59, 0.20 and 0.10 have been shifted by +3, +6, +9 and +12 mN m⁻¹ respectively).

For surface tension measurements, the anionic rich mole fractions displayed a single break while the cationic rich mole fractions exhibited two breaks in the plots of γ vs. log of concentration. As per Table 2, the first break in all these mixtures coincided well with the point corresponding to the onset of aggregation (C_onset) from fluorescence measurements. Moreover in fluorescence measurements, the anionic dominated mixtures exhibited turbidity at their respective cmcs, but no turbidity was obtained in the case of surface tension measurements corresponding to the first break. Hence the first break obtained from the surface tension measurements was ascribed to the saturation concentration (C_s) corresponding to the formation of surface aggregates in all these mixtures. The second break coincided well with those of fluorescence measurements and was identified to be the critical micellar concentration (cmc) for the mixtures. The cmc values of anionic dominated mixtures were also determined from turbidity measurements (τ vs. concentration plots given in Fig. S4, ESI†) and were found to be in good agreement with the fluorescence measurements. The information in Table 2 clearly shows the very high micellization tendency of C₁₂mimCl + Ibu mixtures in aqueous solution on account of quite low cmc values in comparison to those of the individual components. This is as expected as the mixtures of oppositely charged amphiphiles exhibit great synergistic activity owing to the strong electrostatic and hydrophobic interactions.

Table 2 Micellar parameters for C₁₂mimCl + Ibu aqueous mixtures at varying mole fractions of C₁₂mimCl (x_IL); saturation concentration (C_S), critical micellar concentration experimental (cmc) and ideal (cmc*), micellar mole fraction of C₁₂mimCl experimental (X₁) and ideal (X_ideal), interaction parameter (β^m) and activity coefficients of C₁₂mimCl (f₁) and Ibu (f₂) in the mixed micelles

xIL	ST^a		Flu^b		cmc* (mM)	X1	X ideal	β^m	f1	f2
	Cs (mM)	cmc (mM)	Conset (mM)	cmc (mM)
a cmc determined by surface tension (error limit ± 0.04 mM).b cmc determined by fluorescence (error limit ± 0.05 mM).
0.10	2.34	—	2.36	3.61	84.54	0.52	0.59	−13.106	0.049	0.029
0.20	2.18	—	2.05	2.83	54.56	0.55	0.77	−12.968	0.072	0.020
0.59	1.44	2.14	1.42	2.32	22.90	0.61	0.95	−12.140	0.158	0.010
0.70	1.09	1.65	1.13	1.75	19.68	0.62	0.97	−13.668	0.139	0.005
0.79	0.98	1.40	0.84	1.46	17.64	0.63	0.98	−14.974	0.129	0.003

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3.2.1 Micellar parameters to deduce interactions between the components in mixed micelles. Considering the phase separation model, the ideality in the mixed micelle formation for these catanionic mixtures was evaluated in terms of ideal cmc (cmc*) using Clint’s model⁴⁵ as per eqn (9):where x₁ represents the mole fraction of the C₁₂mimCl, and cmc₁ and cmc₂ are the critical micellar concentrations of the pure C₁₂mimCl and Ibu respectively. It is to be mentioned here that in exploring various micellar parameters for the mixtures, we considered the cmc values obtained from fluorescence measurements to maintain consistency in the results. As per Table 2, non-ideal behavior has been found for the mixtures in the whole mixing range as indicated by the much higher ideal cmc values than the experimental ones. Since the structure of the head groups of the ionic liquid and the drug molecule are quite different, this non-ideality on mixing seems to be justified. These observations were then further confirmed employing Rubingh’s theory,⁴⁶ which not only provides the mole fraction of the components in the micellar form (X₁), but also measures the nature and strength of the interaction between the two amphiphiles in terms of the interaction parameter (β^m), as per eqn (10) and (11).

Eqn (10) is solved iteratively for X₁, the mole fraction of C₁₂mimCl in the mixed micelle whose value is then substituted into eqn (11) to obtain the value of β^m, a measure of the interaction between two different amphiphiles, relative to their self interaction under the same conditions before mixing. The β^m values were then further utilized to account for the deviation of the mixtures from ideal behavior in terms of the activity coefficients for C₁₂mimCl (f₁) and Ibu (f₂) using relations (12) and (13):

f₁ = exp{β^m(1 − X₁)²} (12)

f₂ = exp{β^m(X₁)²} (13)

A perusal of Table 2 indicates that the value of β^m comes out to be highly negative at all the mole fractions of C₁₂mimCl + Ibu mixtures, which indicates that the interactions between the two components being investigated are more attractive or less repulsive than the self interactions of the two amphiphiles before mixing. These highly synergistic interactions between the oppositely charged IL and drug molecules arise due to the lessening of the electrostatic repulsion between the charged heads as well as strengthening of the hydrophobic interactions among the tails in a mixed micelle, thus favoring micellization at much reduced cmc values. This synergism in mixtures is generally a goal from both the fundamental and applied points of view. Similar evidence of strong synergism has previously been reported in several catanionic surfactant systems.^47–49

However, in the anionic rich mole fractions, β^m tends to become less negative as the concentration of Ibu is being increased, while for the cationic dominated mixtures, the synergism is found to be enhanced with increase in drug concentration. This might be the result of different types of molecular interactions coming into play on the mixing of two amphiphiles having different structures and different properties.⁵⁰ These could be electrostatic repulsive interactions between ionic hydrophilic head groups, ion–dipole attractions between the ionic hydrophilic groups, steric repulsion between bulky hydrophilic or hydrophobic groups, attractive van der Waals interactions depending on the length, degree of branching and the closeness of packing of the hydrophobic groups, and hydrogen bonding between hydrogen acceptor and donor groups in the two amphiphilic molecules. The values of both f₁ and f₂ (Table 2) have been worked out to be much less than unity confirming that the mixtures are behaving non-ideally. As the concentration of the IL in the mixture increases, the activity of the Ibu molecules should decrease while that of C₁₂mimCl should increase in the mixed micelles; however, contrary to the above, a decrease of the activity coefficient of C₁₂mimCl in the cationic rich region is observed. This might indicate some sort of hindrance being offered to IL molecules in the cationic dominated mixed micelles.

Further from Motomura’s approximation,⁵¹ the deviation of the micellar mole fraction (X₁) values from that in the ideal state, X_ideal, have been computed as per eqn (14):

Higher values of X_ideal than X₁ in both anionic and cationic dominated mixtures indicate that the micelles are richer in the Ibu component again hinting at the lesser capacity of the C₁₂mimCl molecules to intercalate in the mixed micelles, which might be due to the bulkiness of the imidazolium head group.

3.2.2 Interfacial parameters to deduce interactions between the components in mixed monolayer. When a surfactant mixture is added to water, it first gets absorbed at the interface to form a mixed monolayer, which on further increasing the concentration eventually leads to the formation of mixed micelles in the solution. The composition of the adsorbed monolayer of the binary mixtures and interactions between the components have been evaluated using Rosen’s approach⁵² [eqn (15) and (16)], in analogy with the derivation of Rubingh’s equation for mixed micelles, where X₁, cmc₁, cmc₂ and cmc [in eqn (10) and (11)] are replaced by X^σ₁, C^σ₁, C^σ₂ and C^σ₁₂ respectively. The symbols C^σ₁, C^σ₂ and C^σ₁₂ represent the molar concentrations of pure C₁₂mimCl, pure Ibu and their mixtures at different mole fractions of C₁₂mimCl (x_IL), required to produce a surface tension reduction (γ = 45 mN m⁻¹) at the air–water interface.

As can be seen in Table 3 this provides negative values of β^σ indicating that there is synergism between the components in the mixed monolayer too. However as expected, β^σ is more negative than β^m since the reduction of electrostatic repulsion between the charged head groups has a greater effect at the planar air/water interface as compared to the convex micellar surface.⁵² Also, the accommodation of the two hydrophobic groups of the mixtures is easier at the planar interface than in the interior of a spherical micelle. This high synergism between the C₁₂mimCl and Ibu molecules makes their catanionic mixtures behave non-ideally as indicated by the values of the activity coefficients for C₁₂mimCl (f^σ₁) and Ibu (f^σ₂) at the air/water interface in Table 3 [f^σ₁ and f^σ₂ have been derived in analogy with eqn (12) and (13) replacing X₁ and β^m by X^σ₁and β^σ respectively].

Table 3 Interfacial parameters for C₁₂mimCl + Ibu aqueous mixtures at varying mole fractions of C₁₂mimCl (x_IL); interaction parameter (β^σ) and activity coefficients of C₁₂mimCl (f^σ₁) and Ibu (f^σ₂) in the mixed monolayer, surface excess (Γ_max), minimum area per molecule experimental (A_min) and ideal (A_ideal), surface pressure (π_cmc) and pC₂₀^a

xIL	β^σ	f^σ1	f^σ2	Γmax (× 10^−6) (mol m^−2)	Amin (nm)^2	Aideal (nm)^2	πcmc (mN)	pC20
a Maximum uncertainity limits in Γmax, Amin and πcmc are ±0.03, ±0.02 and ±0.2 respectively.
0.00				4.14	0.40		41.6	1.670
0.10	−15.705	0.027	0.014	2.17	0.76	0.43	45.5	3.692
0.20	−14.991	0.048	0.011	2.14	0.78	0.46	45.3	3.721
0.59	−13.994	0.106	0.006	2.09	0.79	0.59	45.2	3.793
0.70	−14.608	0.108	0.004	2.07	0.80	0.62	45.1	3.854
0.79	−15.225	0.111	0.003	2.03	0.82	0.65	44.9	3.907
1.00				2.31	0.70		39.0	2.761

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Next, to have a comprehensive assessment of the interfacial behavior of these IL–drug aqueous mixtures in comparison to the individual components, certain other surface active parameters like surface excess (Γ_max), minimum area per molecule (A_min) and the surface pressure (π_cmc) need to be evaluated. The adsorption efficiency of the amphiphiles at the air/water interface is often discussed in terms of their bulk concentration which generates a surface tension reduction of 20 mNm⁻¹ (C₂₀) from pure solvent i.e. water. The higher the value of the negative logarithm of this concentration (pC₂₀), the more efficient is the amphiphile. It is clear from Table 3 that the adsorption efficiency increases in the order Ibu < C₁₂mimCl < Ibu + C₁₂mimCl aqueous mixtures. The presence of a longer alkyl chain and hence greater hydrophobicity in C₁₂mimCl is responsible for its being more surface active than the Ibu molecules. However as the mixtures involve the adsorption of a catanionic pair containing both surface active ions, they are expected to be more active at the air/water interface than their individual counterparts. This adsorption efficiency among mixtures is found to be enhanced slightly with an increase in the concentration of the IL.

Further applying the Gibbs adsorption isotherm to the tensiometric profiles, the maximum surface excess concentration, Γ_max, representing the amount of the amphiphile adsorbed at the interface and the minimum area occupied by a amphiphilic molecule, A_min, at the air/water interface were evaluated as per eqn (17) and (18)

where n, R and N_A represent the number of species at the air/solution interface, the gas constant and Avogadro’s number respectively at a temperature T. The Γ_max and A_min values for pure C₁₂mimCl have been found to be in conformity with the literature values.⁴³ In accordance with the larger size of the hydrophilic head group of the C₁₂mimCl molecule as compared to Ibu, the respective A_min values have been found to be larger in the case of the former. For the catanionic mixtures, the Γ_max values decrease and the corresponding A_min values increase in comparison to those of the pure components. But with the change in mole fraction of the mixtures, neither Γ_max and A_min exhibits an appreciable change. This signifies that these mixtures involve the adsorption of bulkier catanionic C₁₂mim⁺Ibu⁻ pairs, which are expected to be more hydrophobic than both components. This is also manifested by the corresponding larger values of A_min in comparison to A_ideal for the mixtures over the whole mixing range. These results signifying the formation of ion-pairs in mixtures are in corroboration with our earlier results from spectroscopic measurements.

Another parameter that directly proves the effectiveness of surface tension reduction is the surface pressure at the cmc i.e. π_cmc. It indicates the maximum reduction of surface tension caused by the dissolution of the amphiphilic molecules and is usually defined by relation (19)

π_cmc = γ₀ − γ_cmc (19)

where γ₀ and γ_cmc represent the surface tension of the pure solvent and the surface tension of the solution at the cmc respectively. As per Table 3, the aqueous IL–drug mixtures display higher values of π_cmc than their individual counterparts in accordance with their higher surface activity as mentioned earlier, although their efficiency to bring about a reduction in the surface tension of water varies only slightly with the mixture composition.

3.2.3 Thermodynamic evaluation of catanionic mixtures. Further, the thermodynamic evaluation of these catanionic IL–drug mixtures was done to reveal the spontaneity of the micellization and the adsorption phenomenon in terms of the standard free energy of micellization (ΔG⁰_m) and adsorption (ΔG⁰_ads) as per eqn (20) and (21), where X_cmc represents the cmc in mole fraction units.

ΔG⁰_m = RT ln X_cmc (20)

Negative values of ΔG⁰_m and ΔG⁰_ads (Table 4) clearly indicate the feasibility of both the micellization as well as adsorption processes for all the catanionic mixtures, however more negative values of ΔG⁰_ads than ΔG⁰_m show that the adsorption of these mixtures at the air/water interface is a more favorable phenomenon and work needs to be done to transfer an amphiphilic molecule from the air/water interface to the micelle through the solvent medium. Moreover higher values of ΔG⁰_ads and ΔG⁰_m for the mixtures in comparison to the pure components signify an increased adsorption and enhanced micellization because of newer stronger electrostatic and hydrophobic interactions among the oppositely charged components in a catanionic mixture. These adsorption and micellization tendencies are also found to be enhanced with increase in the concentration of the more surface active (C₁₂mimCl) component. Further the thermodynamic stability of the surfaces can be judged from the free energy change (G_min) accompanying the transport of the solution components from the bulk phase to the surface phase from eqn (22):

G_min = A_minN_aγ_cmc (22)

Table 4 Thermodynamics of micellization and adsorption for C₁₂mimCl, Ibu and their aqueous mixtures at varying mole fractions of C₁₂mimCl (x_IL)

xIL	ΔG^0ex (kJ mol^−1)	ΔG^0m (kJ mol^−1)	ΔG^0ads (kJ mol^−1)	Gmin (kJ mol^−1)
0.00		−14.106	−24.154	72.209
0.10	−8.109	−23.899	−44.867	119.79
0.20	−7.956	−24.503	−45.671	122.41
0.59	−7.159	−24.995	−46.622	125.81
0.70	−7.982	−25.694	−47.481	127.51
0.79	−8.652	−26.143	−48.261	131.01
1.00		−20.501	−37.384	140.67

---

Our observed values of G_min are higher for the mixtures reflecting the formation of thermodynamically more stable surfaces and the enhancement in surface activity. Similarly the stability of the mixed micelles is being confirmed by the negative values of excess free energy of mixing (ΔG⁰_ex), obtained by using the values of activity coefficients f₁ and f₂ as per relation (23):

ΔG⁰_ex = RT(X₁ ln f₁ + X₂ ln f₂) (23)

Thus in the micellar regions, the interaction of the IL with the drug molecules in aqueous medium leads to the formation of catanionic mixtures displaying more surface active properties and enhanced micellization tendencies at all compositions, hence being industrially and economically as well as environmentally beneficial.

3.3 Morphology of C₁₂mimCl–Ibu mixed aggregates

In further exploring the nature of the species present in the aqueous solutions of these catanionic IL–drug mixtures, DLS measurements were undertaken to illustrate the changes in the morphology of the mixed aggregates from anionic rich to being cationic dominated ones and also to study the effect of dilution/concentration on the size of mixed micelles so as to associate it with the turbidity changes as discussed previously. It is worthwhile mentioning that as the mixtures investigated here involve the presence of salt (sodium and chloride ions as counterions), the observed hydrodynamic diameters for the mixtures might be somewhat smaller than the actual ones because of the salt effect.⁵³

The aggregate size distributions for both pure C₁₂mimCl and Ibu in aqueous solutions at varied concentrations of 10 mM of each and at concentrations pertaining to five times cmc (70 mM for C₁₂mimCl and 900 mM for Ibu) are given in Fig. S5, ESI.† As observed at higher concentrations, both C₁₂mimCl and Ibu revealed the presence of two types of aggregates i.e. small micelles with hydrodynamic diameter (D_h) of 1–2 nm and larger aggregates with D_h in the range of 100–300 nm. For C₁₂mimCl, these larger aggregates have been stated to be unilamellar vesicles by Wang et al.⁵⁴ But the larger aggregates for Ibu molecules have not yet been characterised and the presence of small micelles is in accordance with the earlier reports.^44,55 However at a concentration of 10 mM of each, only large aggregates with D_h of 157.5 ± 5.7 nm for C₁₂mimCl and 187.1 ± 8.3 nm for Ibu were obtained. This behavior is peculiar to ionic surfactants and has been illustrated previously⁵³ where the hydrodynamic diameters are observed to go through a minimum at their respective cmcs.

3.3.1 Effect of mixture composition. From the aggregate size distributions for the various catanionic mixtures at a fixed total mixture concentration of 250 mM, the hydrodynamic diameters were obtained for varying mole fractions as listed in Table 5. An appraisal of these D_h values showed a clear dependence on the mixture composition. The anionic dominated mole fractions revealed the existence of only small micelles with D_h between 3–20 nm, showing a micellar growth in mixtures with larger IL fractions, due to intercalation of more of C₁₂mimCl molecules in the micelles. As the mole fraction of IL exceeded equimolarity, a clear transition was observed with the cationic dominated mole fractions showing the coexistence of small micelles (D_h = 1–2nm) and larger aggregates (D_h increased with increasing IL mole fraction). On the whole, it can be assumed that the mixed micelles which are dominated by Ibu molecules (as highlighted earlier) first grow to a particular size by the intercalation of C₁₂mimCl molecules due to the decrease of electrostatic repulsions between the head groups, allowing the amphiphilic molecules to approach each other more closely and hence forming bigger micelles needing greater space for the hydrophobic chains. But further increase in the concentration of these IL molecules with bulky head groups and relative lessening of the Ibu concentration lead to the generation of steric and electrostatic repulsion, hence causing the breakdown of micelles to smaller sizes and the excess IL molecules rearranging in the form of unilamellar vesicles, either alone or in mixed form with Ibu molecules. This behavior is in concordance with our earlier discussions on the values of the interaction parameters. A similar coexistence of two types of aggregates has also been reported recently by Viau et al. for salt free catanionic complexes of short chain imidazolium ILs with ibuprofen.⁵⁵

Table 5 Hydrodynamic diameters (D_h) for C₁₂mimCl, Ibu and their mixtures at varying mole fractions of C₁₂mimCl (x_IL)

xIL	0.00	0.10	0.20	0.30	0.59	0.70	0.79	1.00
Dh (nm)	1.59 ± 0.22	3.34 ± 0.85	7.08 ± 1.66	19.63 ± 5.82	10.38 ± 2.05	2.58 ± 0.41	1.95 ± 0.25	1.34 ± 0.19
	269.9 ± 22.7	—	—	—	34.89 ± 6.45	52.9 ± 8.3	169.4 ± 17.9	155.7 ± 25.6

---

3.3.2 Effect of dilution. Further analysis of these catanionic mixtures in aqueous solution was performed to illustrate the effect of dilution on the mixed micellar size by studying the aggregate distributions for x_IL = 0.79 and x_IL = 0.20 at varying total mixture concentrations as shown in Fig. 6. Here, the cationic dominated mixture (x_IL = 0.79) showed the coexistence of both the small micelles (D_h = 1–5nm) and the larger aggregates (D_h = 100–400 nm) at all concentrations, with the size of the small micelles remaining almost the same and that of the larger ones increasing (Table S1, ESI†). This might indicate that the larger aggregates which are unilamellar vesicles are not purely formed by IL molecules but rather are of mixed nature with Ibu molecules solubilised in them. However, prominent transitions in the size of the micelles were observed for the Ibu rich mole fraction (x_IL = 0.20), where only large aggregates with D_h extending up to 3000 nm (which might be multilamellar vesicles) appeared at 10 mM, the two types of aggregates (corresponding to size of unilamellar vesicles) coexisted at concentrations of 50 mM and 100 mM followed by a population of only smaller micelles at 250 mM concentration. This could provide a reasonable answer for the disappearance of turbidity in anionic dominated mole fractions at higher concentrations as the increase in concentration leads to the transformation of larger aggregates into smaller micelles.

Fig. 6 Aggregate size distributions for catanionic IL–drug mixtures with increasing total mixture concentrations at (a) x_IL = 0.20 and (b) x_IL = 0.79. The amplitudes for 50 mM, 100 mM and 250 mM mixture concentrations have been shifted upwards by +20, +40 and +60 units respectively.

This transition from micelle to vesicle/bilayers upon dilution in catanionic mixtures has been reported by many workers. Egelhaaf and Schurtenberger⁵⁶ have observed that in bile salt and lecithin mixed micelles, the monodisperse spherical micelles change to elongated, flexible cylindrical polymer-like micelles upon dilution. They have attributed this to the difference in the solubilities, i.e., cmc values of bile salt and lecithin where on dilution the bile salt to lecithin ratio in the aggregates decreases which eventually lowers the average spontaneous curvature of the mixed micelles forcing them to grow. In another recent report on catanionic surfactant–hydrotrope mixtures, Hassan and coworkers⁵⁷ have ascribed this dilution induced transition from micelles to vesicles to be driven by the release of hydrotropes from the mixed micelles on account of the solubility mismatch between the two components. In our case too, since there is a big difference between the cmc of C₁₂mimCl and Ibu, the same reason seems to be valid here also. At high concentrations, the micelles are dominated by Ibu molecules and the corresponding repulsion between the charges favours the formation of smaller micelles. But on dilution, the release of Ibu molecules from the mixed micelles will be much larger in comparison to its cationic counterpart (having much lower cmc) forcing Ibu molecules to partition in the bulk, lowering the surface charge density of the micelle. This ultimately leads to micellar growth to higher aggregates because of the decreased average spontaneous curvature of the mixed micelles. The lowering of surface charge density for anionic dominated catanionic mixtures (x_IL = 0.20) has also been verified from ζ-potential measurements at total mixture concentrations of 100 mM, 50 mM and 10 mM and found to be −21.5, −11.0 and −10.2 respectively. However, to be more sure about the mechanism of these transitions a detailed study using SANS and rheological measurements needs to be carried out and will thus constitute a part of our further studies.

3.4 ¹H NMR measurements

¹H NMR measurements have been carried out to predict the changes in the environment of various protons of C₁₂mimCl and Ibu on interacting with each other. For this, the ¹H NMR spectrum of both pure C₁₂mimCl and Ibu were recorded in D₂O at a concentration of 2 mM each. The corresponding spectrum obtained and the peaks assigned to various protons for both are given in the Fig. S6 and S7 (ESI†). It has been observed that the peak due to H2 of C₁₂mimCl did not appear in the spectrum probably due to its rapid H–D exchange as reported earlier.⁵⁸ Further addition of increasing equivalents of Ibu was made to the C₁₂mimCl solution (2 mM) so as to get catanionic mixtures with varying mole fractions and the corresponding ¹H NMR spectra were recorded for each mixture. The spectra showing the changes in the ¹H NMR signals for the various aromatic as well as aliphatic protons at different mixture compositions have been given in Fig. 7(a) and (b) respectively and the chemical shift (δ) values for the different protons of both the IL and Ibu have been summarized in ESI Tables S2 and S3.†

Fig. 7 ¹H NMR spectra for pure C₁₂mimCl, pure Ibu and their catanionic mixtures at varying mole fractions in the (a) aromatic region and (b) aliphatic region.

The remarkable changes observed in the position of the ¹H NMR signals (δ values) for the mixtures with respect to that of the pure components provide direct evidence of the existence of interactions between C₁₂mimCl and Ibu molecules. It should be mentioned here that a definite assignment of the proton peaks and the actual phenomenon of the conformational changes occurring in the mixtures are difficult to predict on the basis of chemical shifts alone; the observations made here are predictive but well suffice to develop a basic understanding of the interaction between the IL and drug moieties. Fig. 7(a) shows that the aromatic protons (H4 and H5) of C₁₂mimCl resonate at almost similar frequency but are well separated and shifted upfield in the presence of Ibu molecules indicating a change in the environment for the two protons. Similar behavior was observed for the aromatic protons (Hf, Hg, Hi, Hj) of the Ibu molecules which provides clue for the close proximity of these two molecules. Zheng et al.³⁴ have also reported the upfield shifting of aromatic protons upon intercalation into the micelles. Here in our case too, although the concentrations of the pure components are well below their cmc, the mixtures tend to show aggregation at these concentrations as revealed earlier from surface tension measurements. Hence the separation of the ¹H NMR signals (in these catanionic mixtures) of similar protons could be the result of conformational changes (more restricted environment) in both the molecules when in a mixed micelle. The restricted molecular motion of aggregates in comparison to IL monomers has also been established by Zhao and coworkers.⁵⁹ In accordance with our previous discussion and earlier reports,^59–61 there is a clear possibility of the existence of cation–π and π–π interactions between the imidazolium moiety of the IL and the benzene ring of the Ibu, in addition to the possibility of H-bonding between the cationic and anionic moieties with H2 of the imidazolium ring bonding with the carboxyl group of the Ibu molecules. Also from Fig. 7(b), prominent upfield and downfield chemical shifts in the ¹H NMR signals of both the cationic and anionic moieties are an indication of the hydrophobic interactions between the aliphatic protons on the alkyl chains. The shielding of the aliphatic protons (H8, H9-17 and H18) also supports the presence of π–π stacking interactions. However more prominent shifts in the aromatic region are observed in comparison to the aliphatic ones as the head groups point towards the exterior of the micelle, being more exposed and less shielded than the alkyl protons.⁵⁹ A clear indication of the change in the micelle characteristics from being cationic rich (smaller micelles) to anionic dominated (larger aggregates) is also provided by the downfield shifting of the signals on comparison of the ¹H NMR of mixtures from x_IL = 0.60 to 0.30. It can be observed that the peaks due to H4 and H5 appear split in cationic dominated mixtures while they become merged in anionic rich mixtures. This behavior is an indication of the change in the micelle morphology from micelles to vesicles as reported by Kumar et al.⁶² Hence the results from ¹H NMR measurements highlight the interplay of cation–π, π–π and H-bonding interactions between the IL and IBu molecules within a mixed micelle.

Hence, the present study establishes the formation of highly surface active catanionic C₁₂mim⁺Ibu⁻ complexes, which when aggregating in the form of mixed micelles provide a diverse morphological behavior depending on the mixture composition and the dilution.

4. Conclusions

In the course of the above study we looked at understanding the interactions between the surface active ionic liquid C₁₂mimCl and the NSAID ibuprofen molecules in aqueous solution, from varied concentration regimes of monomers to micelles using a multi-technique approach. Fluorescence and surface tension measurements reveal the existence of highly synergistic interactions between the oppositely charged components both in the mixed micelle and in the mixed monolayer, with greater effect at the air/water interface on account of its planar geometry. The aggregate morphology is seen to vary from anionic dominated to cationic rich mixtures with former being larger than the latter. An assembly of molecules in the form of unilamellar vesicles in mixed form has also been predicted for cationic rich mixtures through DLS measurements. The appearance of turbidity in anionic dominated mole fractions at lower concentrations has been ascribed to the dilution induced transformation of smaller micelles to larger aggregates. This structural transition is thought to be driven by the release of Ibu molecules from the mixed micelles on account of the cmc (solubility) mismatch between the two components.

The formation of highly surface active catanionic complexes (C₁₂mim⁺Ibu⁻) of 1 : 1 stoichiometry is well established through UV-visible spectroscopy although the complexes are pseudo-catanionic due to the presence of counterions as salts in aqueous solution. The fluorescence emission measurements provide quantitative evaluation of this complex formation in terms of binding constant and quenching constant values where an increase in alkyl chain length of the imidazolium moiety is observed to produce significant changes. We conclude that hydrophobic interactions also play a very important role along with electrostatic interactions in the formation of these complexes. ¹H NMR studies too clearly demonstrate the role of other interactions such as cation–π, π–π, H-bonding etc. in stabilising the mixed micelles. Hence, a comprehensive view of the interactions between C₁₂mimCl and Ibu molecules presented here will surely be of benefit in enhancing our understanding for the development of ionic liquids with pharmaceutically active ingredients, thus enriching the field of third generation ionic liquids. In addition, the knowledge of these transitions from vesicles to micelles is of particular interest for they provide an easy way of encapsulating active agents by dissolving them in a micellar phase prior to vesicle formation.

Acknowledgements

Reshu Sanan thanks the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for the award of a Senior Research Fellowship.

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Footnote

† Electronic supplementary information (ESI) available: Fig. S1–S6 contain supporting plots of UV-visible, fluorescence, turbidity, DLS and ¹H NMR spectra. Results from DLS measurements illustrating the effect of dilution on the anionic and cationic dominated mole fractions are given in Table S1 while Tables S2 and S3 provide the values of chemical shifts from ¹H NMR measurements of C₁₂mimCl + Ibu mixtures. See DOI: 10.1039/c4ra10840j

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