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Composition and concentration gradient induced structural transition from micelles to vesicles in the mixed system of Ionic Liquid–Diclofenac Sodium. Onkar Singh, Rajwinder Kaur, Vinod K. Aswal, and Rakesh Kumar Mahajan Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.6b01175 • Publication Date (Web): 06 Jun 2016 Downloaded from http://pubs.acs.org on June 12, 2016

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Composition and concentration gradient induced structural transition from micelles to vesicles in the mixed system of Ionic Liquid–Diclofenac Sodium. Onkar Singh1, Rajwinder Kaur1, Vinod Kumar Aswal2 and Rakesh Kumar Mahajan1* 1

Department of Chemistry, UGC-centre for Advanced Studies-II, Guru Nanak Dev University, Amritsar-143005, India 2

Solid State Physics Division, Bhabha Atomic Research Centre, Mumbai 400085, India

--------------------------------------------------------------------------------------------------------------------------------------*Corresponding author, Fax: +91 183 2258820 E-mail address: [email protected] (Rakesh Kumar Mahajan)

1 ACS Paragon Plus Environment

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Abstract Catanionic surfactant-hydrotrope mixtures are proved to be striking alternative to tune the microstructures over a wide range of composition and also to minimize the precipitation that is normally observed in catanionic mixtures at equimolar ratio. These mixtures are supposed to be of great relevance in biological systems when hydrotrope is a “drug”. Keeping this in view, here we report a composition- and dilution-induced structural changes in a catanionic mixture comprising ionic liquids (ILs) such as 1-dodecyl-3-methylimidazolium bromide (C12mimBr)/1-tetradecyl-3-methylimidazolium bromide (C14mimBr), and a drug diclofenac sodium (DFNa) in aqueous solution. The structural changes are probed by small angle neutron scattering (SANS), dynamic light scattering (DLS) and zeta potential measurements. SANS data and size distribution curves clearly depicts the formation of low curvatured structures on going from cationic rich to anionic rich composition upto 0.7 mole fractions of DFNa (XDFNa). The amphiphilic nature of DFNa is supposed to alter the surface charge density provoked by its incorporation in resulting aggregates as confirmed by modified zeta potential values. The modification of average packing parameter resultant of ILs and DFNa complexation equilibrium seems to play a vital role in bringing out structural transitions of mixed aggregates. We also focused our attention to study the effect of dilution in concentrations range from 100 mM to 25 mM. At XDFNa = 0.0 and 0.1, the size of prolate ellipsoids decreases on dilution mimicking the classic behaviour but opposite trend is observed at other XDFNa. Dilution induced transformation to larger aggregates is thought to be driven by the release of DFNa molecules from the mixed micelles on account of the cmc (solubility) mismatch between the two components. The role of other interactions such as cation–π and π-π in stabilizing the mixed aggregates in addition to hydrophobic interactions probed by 1H-NMR.


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1. Introduction Microscopic interactions between catanionic mixtures of two oppositely charged amphiphiles control the phase behavior and yield a variety of aggregate morphologies such as spheres, rods, disks, ribbons, bilayers, vesicles, etc. However, most of the catanionic mixtures turn out as thick precipitates at an equimolar concentration which limits their application. The appropriate selection of catanionic pairs can resolve such incompatibility in which they are not conducive for effective packing leading to weak interaction. Exploiting hydrotrope as one of the component of catanionic pair is proved to be remarkable option to minimize the precipitation and to tailor the microstructures over a wide composition range.1-3 Although hydrophobic part of hydrotropes is too small to form well defined assemblies, it can form diverse complex structures such as micelles, disks, vesicles, tubules in combination with surfactant molecules.3-10 Hassan et al. reported a dilution-induced morphological transition from long micelles to bilayers in a cationic–anionic mixture comprising a surfactant, cetyltrimethylammonium bromide (CTAB), and a hydrotrope, sodium salicylate (NaSal).11 In an another study, Hassan et al. reported the unusual concentration dependant rheology in a mixed micelle composition comprising cationic surfactant, cetyltrimethylammonium bromide (CTAB) and the hydrotropic salt sodium 3-hydroxynaphthalene 2-carboxylate (SHNC).4 Also significant growth of micelles and increase in viscosity upon dilution of CTAB-SHNC aqueous mixtures has been observed. Mixture of cationic surfactant erucyl bis-(hydroxyethyl)methylammonium chloride (EHAC) and SHNC showed anomalous temperature dependant phase behavior in a study by Kalur et al.12 In the phase diagram of EHAC–SHNC mixture, two phase region merged into single phase micellar region by the addition of excess salt. Chen et al. have studied the phase transition in the aqueous mixture solution of gemini surfactants and sodium


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deoxycholate induced by temperature change and pH. Sodium deoxycholate (bile salt) is also a hydrotrope having physiological importance.13 Thus synergistic interactions between catanionic pairs comprising hydrotropes have ability to tailor the aggregate geometry and resulting phase behavior found to be strongly dependent upon composition and concentration. Transformation among various selfassembled structures such as micelles, bilayers, vesicles, etc. upon external stimuli such as pH, temperature, ionic strength, etc. or by the addition of other ingredients is of great relevance in biological systems.14-17 Most of the studies on phase behavior of catanionic mixtures reported so far are focused on hydrotropic salts such as bile salts, NaSal, HNSC and p-toluidine hydrochloride (PTHC) etc.1-13 To the best of our knowledge, the phase behavior of catanionic mixtures comprising hydrotropic drug is less explored. Earlier our own research group has investigated 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.18 These mixtures are seen to display enhanced micellization, higher adsorption tendencies and various structural forms in aqueous medium determined by the amphiphile mixing ratio and the total mixture concentration. In the light of the above facts, it was thought worthwhile to study the phase behaviour of the hydrotropic drug and oppositely charged surfactant. Diclofenac sodium (DFNa), an analgesic and non-steroidal anti-inflammatory drug [NSAID] is known for its high biological activity and possesses high potential against pain and rheumatic inflammations.19 Ionic liquids (ILs) are reported as multipurpose materials, capturing the interest of the scientific fraternity even outside the discipline of chemistry. The credit for this lies in their ‘tailorable’ nature that results in easily tuneable properties and especially in their ‘greener’ aspects.20 Their applications in medicine and biology are just emerging as their potential for being used as pharmaceutical as well as biological ingredients. Briefly, this paper takes into account a


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detailed morphological analysis of surface active ionic liquid (ILs) 1-dodecyl-3methylimidazolium

bromide

(C12mimBr)/1-tetradecyl-3-methylimidazolium

bromide

(C14mimBr), and diclofenac sodium (DFNa) in aqueous solution. Here, we have used small angle neutron scattering (SANS), dynamic light scattering (DLS) and zeta potential measurements to identify and characterize the structural transitions in these IL–DFNa mixtures as a function of the mixture composition and the dilution. The size and shape of the resultant mixed aggregates in IL-DFNa catanionic mixtures are found to be strongly dependent on mixture composition as well as on dilution. DFNa and ILs being oppositely charged species interact electrostatically as well as hydrophobically to show various morphologies dependent on mixture composition. 1H NMR studies too clearly demonstrate the role of other interactions such as cation–π and π-π in stabilizing the mixed micelle. Similar catanionic drug–surfactant mixtures have been explored earlier for their use as drug delivery agents, but there are no studies addressing the issue of the physicochemical characterization of catanionic IL–DFNa mixtures.21 2. Experimental 2.1 Materials Diclofenac sodium (DFNa), 1-bromododecane, 1-bromotetradecane and 1-methylimidazole were purchased from Sigma Aldrich. The above mentioned reagents were of analytical grade with purities ≥99% and used as received without further purification. The ILs (1-dodecyl-3methylimidazolium

bromide

and

1-tetradecyl-3-methylimidazolium

bromide)

were

synthesized according to the procedure mentioned elsewhere.22 The synthesized ILs were characterized by 1H and

13

C NMR. The molecular structures of ILs and DFNa are given in

Scheme 1.


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Cl

g

2

10

8

18

16

14

12

20

N N

4

Br

A

h

5

Br

9

7

11

13

15

17

19

O Cl

e

C14mimBr

b

B d

C12mimBr

Na+

a

NH

g

N N

O-

f

6

c

DFNa

Scheme 1. Molecular structure of ILs and DFNa

2.2 Methods 2.2.1 SANS measurements and theoretical details. Small-angle neutron scattering (SANS) measurements were carried out using the SANS diffractometer operating at Dhruva reactor, Bhabha Atomic Research Centre (BARC), Mumbai, India. The mean incident neutron beam wavelength (λ) was 5.2 Å with a wavelength resolution (∆λ/λ) of approximately 15%. The scattered neutrons were detected in an angular range of 0.5−15° using a linear position-sensitive detector (PSD). The samples were held in quartz sample holder having thickness of 0.5 cm and temperature was kept constant at 30±0.1 °C during measurements. The scattered neutrons were measured for wave vector transfer, Q (Q = 4πsin(θ/2)/λ, where θ is the scattering angle) in the range of 0.015−0.3 Å−1. The measured SANS data were corrected for the background, empty cell contribution, and the transmission and were presented on an absolute scale using the standard protocols. For SANS measurements, samples were prepared in D2O in order to minimize the incoherent scattering and to increase the contrast.23 Theoretical details regarding SANS measurements are provided in Section S1 of Supporting information (SI). 2.2.2 Dynamic light scattering (DLS) measurements DLS measurements were performed using a Malvern Zetasizer Nano-ZS instrument employing a He–Ne laser (λ = 632 nm) at a scattering angle of 173°. The temperature of the measurements was maintained at 30±0.1 °C by built-in temperature controller having an accuracy of ±0.1°C and data were collected at least five times for each independent sample.


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The scattered data was processed using standard algorithm to hydrodynamic diameter (Dh) and is reported with an uncertainty of less than 5 %. For phase behavior and DLS measurements, samples were prepared in H2O. 2.2.3 1H NMR measurements 1

H NMR measurements have been performed on Bruker Ascend 500 spectrometer

(AVANCE III HD console) in CDCl3 and 10% D2O−H2O mixtures. The NMR titration experiments were performed by titrating 5 mM of C14mimBr solution prepared in 10% D2O−H2O with increasing concentrations of DFNa. Chemical shifts were given on the δ scale. 3. Results and Discussion 3.1 Morphology of mixed aggregates 3.1.1 Phase behavior by visual inspection First of all, a preliminary qualitative evaluation of phase behavior of the aqueous mixture of ILs (CnmimBr, where n = 12 and 14) and DFNa was made by a visual inspection and the results were further evidenced by turbidity measurements. Oppositely charged ILs-DFNa aqueous mixtures, the so-called catanionic mixtures are known to exhibit interesting phase behavior arising from the electrostatic interactions between them. Considering this, a series of solutions of pure C14mimBr with concentrations ranging from 0.02 to 100 mM were prepared and the solutions were found to be clear (Figure 1a) consistent with small globular micelles. The transparency of the turbidity profiles for pure C14mimBr (Figure S1a) for the whole concentration range provides further evidence for the formation of relatively smaller micelles. IL and DFNa were then mixed in varying mole fractions of DFNa (XDFNa) ranging from 0.1 to 0.9 with different concentrations as shown in Figure 1(b-h). For total mixture concentration of 100 mM, the solutions were turbid at XDFNa = 0.5, 0.7 as shown in Figure S1b in SI and solutions were clear at all other studied mole fractions. A transition to greater


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turbidity at XDFNa = 0.5, 0.7 is consistent with larger aggregate structures such as vesicles (Figure S1b). At an equimolar concentration, most of the catanionic mixtures turn out as thick precipitates which limit their use in research and applications. In catanionic mixture, hydrophobic ion-pairs through electrostatic binding are formed and such ion-pair formation decreases the hydrophilicity of the ionic head groups generating sparingly soluble catanionic salt. However in the present case of IL-DFNa mixures such precipitation was not observed which is analogous to catianionic mixtures of certain polyelectrolytes or polypeptides. Weak interactions between catanionic mixtures of polypeptides lead to coacervation rather than precipitation.12 On similar ground, we believe that weak interaction between IL and DFNa as compared to other catanionic pairs does not lead to precipitation. Owing to specific structure of DFNa, it is not conducive for effective packing of cationic–anionic pairs, its packing can be different from conventional linear chain amphiphiles in catanionic mixture and this leads to weak interaction.

Figure 1. (a) Phase behavior of pure C14mimBr in aqueous solution at different concentrations. (b to h) Phase behavior of C14mimBr+DFNa mixtures in aqueous solution at varying mole fractions of DFNa (XDFNa) for total mixture concentration of 100mM, 50mM, 25mM, 5mM, 2mM, 1mM and 0.02mM.


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However, in solutions with a concentration of 50, 25, 5 and 2 mM, the turbidity also appeared in solutions at XDFNa = 0.9 as also evidenced by Figure S1b. Further decrease in the concentration (dilution) also led to the disappearance of turbidity. The solutions with a total mixture concentration of 0.02 mM and 1 mM were clear and transparent throughout the entire XDFNa with almost zero turbidity values as shown in Figure S1. These observations offer an important initial qualitative evaluation and the fine detail of these structures were obtained employing SANS and DLS measurements. 3.1.2 Effect of composition: Small angle neutron scattering (SANS) measurements SANS scattering curves for 100 mM of pure ILs (C12mimBr and C14mimBr) and their associated fits are shown in Figure 2. (a)

dΣ/ dΩ (cm-1)

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1

0.1

100 mM C12mimBr 100 mM C14mimBr 0.1 Q(Å-1)

Figure 2. Representative SANS data patterns for pure C14mimBr and C12mimBr. SANS data of both ILs show correlation peaks indicating the existence of interacting charged aggregates (Figure 2). Usually, this peak occurs at Qmax ≈ 2π/d, where d is the mean distance between the aggregates. Thus the quantitative analysis of scattering data takes into account both the form factor (equation 2, Section S1 of SI) and the structure factor as calculated by Hayter and Penfold analysis for charged macro-ions under a rescaled mean spherical approximation. The key model parameters obtained from fitted data are summarized in Table


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1. C12mimBr surfactant was found to form smaller micelles as compared to C14mimBr evidenced by the shift of peak position to higher Q value where the higher number density of smaller micelles gives rise to smaller mean distance between micelles. The smaller size of C12mimBr micelles can be understood from the shorter hydrophobic tail of C12mimBr as compared to C14mimBr (Table 1). Table 1. Various key model parameters: semimajor axis (a), semiminor axis (b) and fractional charge (αc) for pure C12mimBr and C14mimBr at a concentration of 100 mM. System

a

b

(nm)

(nm)

C12mimBr

3.59±0.10

1.47±0.04

0.20±0.02

C14mimBr

4.71±0.13

1.78±0.05

0.13±0.01

αc

SANS measurements have been employed to obtain more detailed information about the composition and concentration dependence of the phase behavior of ILs-DFNa system. SANS scattering curves obtained from C14mimBr+DFNa system at different XDFNa keeping total concentration constant at 100 mM are shown in Figure 3. The variation in the form of the scattering data of ILs illustrates that the shape as well as size of the aggregates is strongly dependent on the IL composition (Figure 3). As a function of XDFNa, three different regions are distinguished where prolate ellipsoids, rod like micelles and unilamellar vesicles (ULV) exist and these regions are discussed as below. XDFNa=0.1: For this IL rich composition, the scattering curve is typical of that of prolate ellipsoidal micelles as illustrated by the best fit curve (Figure 3a). There is an increase in the scattering cross section and shift of the peak position slightly to lower Q region (as compared to XDFNa= 0.0) indicating that the size of prolate ellipsoidal micelles increases. The micelles grow in size on the addition of DFNa as a consequence of decrease in fractional charge (αc) present on aggregates (Table 2). A broadening in correlation peak also evidenced the


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presence of synergistic interactions between the cationic and anionic mixed system.24 (b)

XDFNa = 0.0 XDFNa = 0.1 XDFNa = 0.3

(a)

1

0.1

XDFNa = 0.5 XDFNa = 0.7 XDFNa = 0.9

10

dΣ/ dΩ (cm-1 )

10

dΣ/ dΩ (cm-1)

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0.01

1

0.1

0.01

-1

0.1 Q(Å-1)

0.1

Q(Å )

Figure 3. Representative SANS data patterns for C14mimBr+DFNa (100 mM) mixed system at various mole fractions of DFNa (XDFNa) (a) XDFNa = 0.0, 0.1, 0.3 (b) XDFNa = 0.5, 0.7, 0.9. XDFNa=0.3: At this composition with further incorporation of DFNa into IL micelles, the scattering pattern is modified significantly in the low-Q region. The shift of peak position to lower Q values with increase in scattering cross section is observed (Figure 3a) which is characteristics of a structural transition from prolate ellipsoidal micelles to rod-like micelles with rod length, l = 12.96 nm and radius, r = 1.69 nm (Table 2). The insertion of DFNa into IL micelles modifies the surface charge density of the aggregates and also modifies the effective area of headgroups. Simultaneously, the effective packing parameter in the aggregate increases and this ultimately induces a transition to elongated micelles. Thus, at a certain threshold they are elongated (rod like), is a consequence of the low charge density of the aggregates. This observation is further supported by results on the microstructural changes in the catanionic mixture of cetylpyridinium chloride (CPC) and sodium deoxycholate (NaDC) at the mole fractions of CPC in the mixtures (XCPC), 0.8 and 0.7.25 The scattering pattern of pure CPC micelles at total surfactant concentration of 400 mM gets modified significantly in the low-Q region with the incorporation of NaDC into CPC


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micelles. Similar observations are reported as a function of composition or concentration in which disk-like or oblate micelles are often observed in many mixed surfactant systems. Disk- and ribbon-like micelles in mixture of sodium dodecylsulfate (SDS) and dodecyltrimethylammonium bromide (DTAB) surfactant solutions with changes in surfactant composition have been reported by Bergstrom and Pedersen.26-28 Table 2: Various key model parameters: semimajor axis (a), semiminor axis (b), vesicle thickness (t), factional charge (αc ), length (l) and radius (r) calculated from SANS for C14mimBr+DFNa at three different concentrations. XDFNa 0.0

0.1

Conc. (mM) 100 50 25 100 50 25 100

a (nm) 4.71±0.13 4.28±0.12 3.70±0.10 5.63±0.15 5.02±0.14 4.31±0.12 -

b (nm) 1.78±0.05 1.78±0.05 1.78±0.05 1.75±0.05 1.75±0.05 1.75±0.05 -

50

-

-

25

-

-

0.3

0.5

0.7

0.9

100 50 25 100 50 25 100 50 25

3.08±0.10 1.29±0.04 -

-

l and r (nm) -

t (nm) -

l=12.96±0.40 r=1.64±0.05 l =15.78±0.48 r=1.64±0.05 l= 19.53±0.55 r=1.64±0.05 l=14.18±0.45 r=1.30±0.04 l=17.00±0.52 r=1.30±0.04

-

αc 0.13±0.01 0.14±0.01 0.15±0.01 0.08±0.01 0.09±0.01 0.11±0.01 -

1.73±0.05 1.73±0.05 1.73±0.05 1.30±0.04 1.30±0.04 1.30±0.04 1.30±0.04

-

1.30±0.04

-

-

XDFNa=0.5, 0.7: The scattering intensity is consistent with the formation of unilamellar vesicles (ULVs) where the solution undergoes phase transition. The absence of any correlation peak and scattering on a log-log scale at low Q indicates the formation of ULVs (Figure 3b). The ULVs are seen as a bilayer in the limited Q window of SANS measurements and therefore would show a linear scattering pattern having a slope of −2 on a log−log scale, which is also seen in the present case. Moreover, because no Bragg peak coming from the 12 ACS Paragon Plus Environment

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repetition of lamella is observed in the SANS data, the multilamellar structure of the vesicles is ruled out.29 The cutoff in the higher-Q region in the SANS spectra decides the thickness of the vesicles and the corresponding thicknesses of vesicles at XDFNa = 0.5 and 0.7 are 1.73 and 1.30 nm, respectively. It is to be mentioned here that the calculated thickness of vesicles is much smaller than twice the extended length of the hydrophobic tail of C14mimBr, which is about 1.92 nm. The penetration of DFNa in between the positively charged headgroups of C14mimBr decreases the contrast, reducing the apparent bilayer thickness measured by SANS.30 Israelachvili et al. have developed the concept of molecular packing parameter denoted by P to elucidate, and to predict the shape of molecular self-assembly of surfactants. It is defined as P = v/al, where ‘v’ and ‘l’ are the volume and length of the hydrophobic alkyl chain of surfactant respectively and ‘a’ is the area of the surfactant headgroup.31 According to this concept, vesicles are favoured microstructures when the value of P is between 1/2 and 1. Therefore, the micelle-to-vesicle transition of the ILs in presence of DFNa may be attributed to modified packing parameter resultant of decrease in area of head group due to the interactions of contact ion pairs. According to Collin’s law, contact ion pairs without intermediate water molecules are formed when a chaotropic ion interacts with another chaotropic ion.32,33 Surfactant headgroups (ILs in our study) are considered to be chaotropic due to large surface area. Similarly, DFNa is also considered as amphiphile (like surfactants) having carboxylate ion as headgroup and aromatic rings as hydrophobic part. Thus the oppositely charged headgroups ILs and DFNa are interacted via. electrostatic interactions and at the same time the hydrophobic interactions further facilitates the binding. Thus the average packing parameter is resultant of ILs and DFNa complexation equilibrium to form ion-pairs and a mixed micelle is formed comprising ion-pairs and uncomplexed components. Overall these interactions would result in decrease of ‘a’ and increase of P, which facilitates the


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vesicle formation. A similar explanation for micelle-to-vesicle transitions of sodium dodecylbenzenesulfonates by addition of tetraalkylammonium chloride was reported by Ismail et al.34 The aromatic rings of DFNa are twisted in relation to each other as a consequence of the presence of two chlorine atoms in the ortho positions.35 However, the chlorine atoms are not too bulky to restrict the rotation of these twisted aromatic rings and thus the spatial arrangement of the rings can be modified. This suggests that the DFNa can be encapsulated into the bilayer of vesicles where dichlorophenyl ring of DFNa is likely to be oriented towards the hydrophobic core of the vesicles. At the same time, oppositely charged headgroups (ILs and DFNa) are interacted via. electrostatic interactions. The above proposed mechanism of formation of vesicles is consistent with results from investigations of the molecular associations of anti-inflammatory drugs with phospholipids.36 XDFNa=0.9: For this DFNa rich composition, a broad correlation peak with decrease in the scattering cross section is observed indicating the return of prolate ellipsoids with dominated content of DFNa (Figure 3b). When high concentration of DFNa associate to bilayer of vesicles the packing parameter can be modified leading to phase transformation. Similar results depending on the drug concentration in which the decrease in the size of structures due to formation of mixed micellar solution from liposomes were observed.36 Our further interest is in exploring the effect of hydrophobic chain length of ILs on the morphology of mixed aggregates and to do so, we have carried out SANS measurements for C12mimBr+DFNa mixed system. SANS curves for C12mimBr+DFNa mixtures at different mole fractions of DFNa (XDFNa) keeping the total concentration constant at 100 mM are shown in Figure S2. A perusal of the various aggregate parameters as listed in Table 3 reveals that the shape and morphology of aggregates remains the same but the structural parameters decreases due to the decrease in the length of the alkyl chain of C12mimBr.


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Table 3: Various key model parameters: semimajor axis (a), semiminor axis (b), vesicle thickness (t), factional charge (αc), length (l) and radius (r) calculated from SANS for C12mimBr+DFNa at 100 mM concentrations. XDFNa

l and r (nm)

t (nm)

0.0

3.59±0.10 1.47±0.04

a (nm)

b (nm)

-

-

0.20±0.02

0.1 0.3

4.51±0.12 1.47±0.04 -

-

0.13±0.01 -

0.5 0.7 0.9

2.96±0.10 1.06±0.03

l=16.80±0.50 r=1.46±0.04 -

1.46±0.04 1.10±0.03 -

-

αc

-

3.1.3 Effect of dilution: SANS measurements We now focus our attention on the aggregation behavior at low concentrations, i.e. from 100 mM to 25 mM for C12mimBr+DFNa system. Broadly speaking one can see that (Table 2 and Scheme 2): (i) at XDFNa = 0.0 and 0.1, the size of prolate ellipsoids decreases on dilution, thus mimicking the classic behavior of single chained ionic surfactants (ii) at XDFNa = 0.3, the rod shaped micelles grow on dilution (iii) at XDFNa = 0.5 and 0.7, the size of structures with zero curvature i.e. vesicles remain unchanged (iv) at XDFNa = 0.9, the size of prolate ellipsoids increases ultimately leading to the formation of vesicles and rod like micelles on dilution, thus opposing the classic behavior. At XDFNa = 0.0 and 0.1 i.e. IL rich composition, the peak position is shifted to higher Q values upon dilution as shown in Figure S3 revealing the formation of prolate ellipsoids in all the cases. The smaller size of micelles are found on dilution (Table 2).25,37 It has been commonly observed among organized assemblies that on increasing the temperature or upon dilution, structure with a near zero spontaneous curvature transforms into one with higher curvature called vesicle to a micelle transitions. However, studies on the reverse behavior, i.e. the transition from micelle to vesicle/bilayers upon dilution are scarce. There are a few reports which show such reverse transitions. Verma et al. have observed a dilution induced change in the microstructure and rheological behavior of mixed micelles


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formed by cetyltrimethylammonium bromide (CTAB) and sodium 3-hydroxy naphthalene 2carboxylate (SHNC), in the hydrotrope-rich region.38 They have reported a significant growth of the micelles upon dilution from 10% w/w to 3% w/w of CTAB–SHNC mixtures and upon further dilution, the micellar phase transforms to a vesicular dispersion. Effect of Size dilution

decreases

Length of rod ULVs

ULVs

Rod

increases

remain

remain

formed

unchanged

unchanged

→

IL

+ULVs

DFNa

25

50

100

↑Conc. (mM)

0.0

0.1

0.3

0.5

0.7

0.9

XDFNa→

Scheme 2. Proposed schematic illustrations of variation of ILs+DFNa mixed aggregates tunable by the mole fraction of DFNa (XDFNa) and the total concentration. Although there are numerous studies that enhance the knowledge on the structural transitions in catanionic mixtures as a function of composition of the mixture, the mechanism of dilution induced transformations is still not conclusively determined. However various research groups proposed the mechanism of solubility mismatch between the two 16 ACS Paragon Plus Environment

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components in catanionic mixtures. They showed that upon dilution, the micelles grow due to release of the component which have poor solubility (or higher cmc) from the mixed micelles to maintain the external monomer concentration.12,39,40 As a result of this, the overall composition of the aggregates varied ensuing in micellar growth and upon reaching a limit, the aggregates transform into vesicles or bilayer sheets. A similar type of explanation on this unusual behavior has also been reported by Egelhaaf and Schurtenberger in bile salt and lecithin mixed micelles, where on dilution a micelle to vesicle transition takes place due to their different solubilities.12 On dilution the bile salt to lecithin ratio in the aggregates decreases lowering the average spontaneous curvature of the mixed micelles. A similar mechanism has been applied to mixed micelles of CTAB, and a hydrotrope, sodium salicylate (NaSal); catanionic surfactant systems such as hexadecyltrimethylammonium octylsulfonate (TASo), alkyltrimethylammonium alkylsulfonates of the type Cm+Cn-.12,39,40 On similar grounds, the structural transitions in the present studied system can be predicted. Thus at XDFNa = 0.3, lowering of the average spontaneous curvature of the mixed micelles facilitates the growth of the rod like micelles (Table 2). Moreover the role of counter-ions comes into play when the mixed micelles are rich in ILs. Because now the mixed micelles rich in ILs, are positively charged and more bromide ions bind to micelles due to their poor hydration as compared to sodium ions. Binding of bromide ions decreases the surface charge density which further facilitates the growth of micelles. At XDFNa= 0.9, due to similar reasons, lowering of the average spontaneous curvature of the prolate ellipsoids facilitates their growth to form rod like micelles. Moreover along with formation of rod like micelles, the vesicle formation is also induced resulting in their coexistence with rod like micelles (Table 2). It may be concluded here that the effective packing parameter of the mixed micelles changes upon dilution and it facilitates structural


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transitions. However at XDFNa 0.5 and 0.7, already low curvatured structures (vesicles) are formed and dilution has no effect on these structures. 3.1.4 Hydrodynamic diameter and zeta potential The samples prepared at various compositions as well as concentrations were found to be stable for several months and hence it is presumed that they are equilibrium structures. The transformation of aggregate size in terms of hydrodynamic diameter (Dh) and surface charge (zeta potential) with changes in the composition of the mixture was also tracked by DLS and zeta potential (ζ) measurements. DLS, a light scattering technique measures the translational diffusion coefficient of particles which are subjected to Brownian motions and size expressed as hydrodynamic diameter is computed by analysis of the intensity fluctuations in the scattered light.41 This analysis is done by using Stokes−Einstein relationship and it is assumed that there is no effect of interparticle interaction on diffusion of the particles. However when interparticle interactions are present between the particles then diffusion of one particle is affected by the presence of neighboring particles and the particles should be dilute enough to neglect the effect of any interparticle interactions. Or in other way, to determine the infinite dilution diffusion coefficient, (Do) it is enviable to perform the experiments at different electrolyte (say NaCl) concentrations to reduce the effect of particle interactions.41 However, in practice, electrolytes are not inert spectators and change micelle size, micelle shape, and the extent of counterion binding and hence mask the actual results of study.42 Thus in present study, use of electrolytes is avoided and, the discussions on variations in Dh rests on the values obtained in H2O only. ζ values are a measure of the electric field potential at the micelle’s plane of zero shear and are influenced by the size, shape and surface charge of the structure. The normalized correlation function and Zeta potential of the representative compositions are shown in Figure 4 and thus the evaluated hydrodynamic diameter of various


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aggregates are given in Table S1 and S2. At XDFNa = 0.0, a small size distribution of aggregates of C14mimBr with Dh of 1.0 nm (Table 1) exists with ζ value of +43.6 mV as illustrated by DLS and zeta potential measurements respectively. SANS results illustrate that the aggregates are small micelles with prolate ellipsoidal shape which is in accordance with the transparent solution as mentioned above. At XDFNa = 0.1, prolate ellipsoidal micelles as indicated by SANS were formed with Dh of 1.8 nm and ζ value of +32.7 mV. Such a decrease in ζ value from +43.6 mV to +32.7 mV clearly indicate that DFNa get physically intercalated in micelles of IL resulting in partial charge neutralization. At XDFNa = 0.3, results shows the existence of aggregates with Dh of 13.5 nm and ζ value of +20.9 mV, obviously larger than that of prolate ellipsoids and found to be rod shaped as predicted by SANS. Thus adding more oppositely charged DFNa molecules into the mixed solutions leads to the growth and structural transition of aggregates due to further decrease in surface charge density. When the mixing ratio gets close to 1:1 i.e. XDFNa = 0.5 and 0.7, the rod like micelles transform into aggregates with Dh of 190.0 nm and 122.3 nm at XDFNa=0.5 and 0.7 respectively. These larger aggregates are stated to be ULVs by SANS. However the ζ values are -3.25 and -13.47 mV at XDFNa=0.5 and 0.7 respectively. There is a clear correlation between vesicle size and surface potential: large vesicles have small surface potentials and vice versa.43 Moreover the negative ζ values indicated the predominance of DFNa in the resultant mixed aggregates. Finally at XDFNa = 0.9, the anionic rich composition, a small size distribution of aggregates with Dh of 4.8 nm exists with ζ value of -26.2 mV indicating the return of prolate ellipsoids with dominated content of DFNa as revealed by negative ζ value. It is to be mentioned here that micellar size at XDFNa = 0.9 is larger than XDFNa = 0.1 which is an opposite result obtained from SANS measurements. As the mixtures investigated here also involve the presence of salt (sodium and bromide ions as counterions), the observed Dh for


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the mixtures might be somewhat different than the actual ones. At XDFNa = 0.9, prolate ellipsoids rich in DFNa exits with ζ value of -26.2 mV and thus to counter this negative surface charge: sodium ions in preference to bromide ions will bind to micellar surface. Larger value of Dh is resultant of high degree of hydration of sodium ions owing to its smaller size.

(a)

XDFNa = 0.0 XDFNa = 0.1 XDFNa = 0.3 XDFNa = 0.5

0.6

XDFNa = 0.7 XDFNa = 0.9

g-1(t)

0.8

Zeta potential / mV

1.0

0.4 0.2 0.0 1

1.0

g-1(t)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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10

100 1000 τ (µS)

(b)

10000

100000


0.8


0.6


45 40 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 -30 -35 -40 -45

(c)

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

XDFNa

45 40 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 -30 -35 -40 -45

0.4 0.2 0.0 1

10

100 1000 τ (µS)

10000

100000

Figure 4. Normalized correlation function of various aggregates formed in (a) C14mimBr+DFNa (100 mM) (b) C12mimBr+DFNa (100 mM ) and (c) zeta potential of C14mimBr+DFNa of mixed system at various mole fractions of DFNa (XDFNa). We have also performed DLS measurements to assess the structural changes in the aggregates with the dilution. Similar to SANS measurements, the aggregate structures of mixed system (C14mimBr+DFNa) are examined at three fixed concentrations of 100, 50, 25 mM (Figure S4). The apparent Dh of the micelles show an increase with decreasing concentration at each studied mole fraction of DFNa except at XDFNa = 0.5 and 0.7 in which size remained constant (Table S1). At XDFNa = 0.9, the anionic rich composition with concentration of 50 and 25 mM, two size distributions of aggregates showed the coexistence 20 ACS Paragon Plus Environment

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of both the rod like micelles (Dh = 22–32 nm) and the larger aggregates i.e. ULVs (Dh = 100– 200 nm). Thus these structural transitions on dilution further support the mechanism of solubility mismatch between the two components in catanionic mixtures. We have also performed DLS measurements in D2O in order to study the effect of solvent on size and structural changes of aggregates. It is observed that size of the aggregates remains the same in D2O as well. 3.2 1H NMR measurements 1

H NMR measurements have been carried out to develop a basic understanding of the IL-

DFNa interactions and to probe the location and orientation of DFNa molecules in micellar interfaces by means of the chemical shift changes. For this, 1H NMR spectrum for C14mimBr (at fixed concentration of 5 mM which is at least twice as large as its cmc value i.e. the mixture are present in the form of aggregates) and pure DFNa were recorded. To ascertain that observed chemical shift changes of the C14mimBr protons arise from C14mimBr-DFNa interactions and not from changes in IL concentrations, C14mimBr concentrations were kept constant at 5 mM, and solely the DFNa concentrations were varied. For better clarity and understanding, the protons of C14mimBr have been assigned from H1 to H20 and the marking of different proton on DFNa is done from Ha to Hf as shown in Scheme 1. The discussion is divided into two parts: 3.2.1 1H NMR of C14mimBr The spectra showing the changes in the 1H NMR signals for the various aromatic and aliphatic protons of C14mimBr with increasing concentrations of DFNa (at 0.2 and 0.4 mM) have been given in Figure 5 and Figure S5 and observed chemical shift values (δ) are summarized in Table S3.


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(b)

(a)

δ (ppm)

δ (ppm)

Figure 5. 1H NMR titrations of C14mimBr with increasing concentrations of DFNa. The concentrations of DFNa are indicated above each spectrum. As can be seen from Figure 5 and Figure S5, with the addition of DFNa the protons around the headgroup IL (H2-H8) showed upfield shift, whereas the protons in aliphatic chain (H20) show a downfield shift. The remarkable changes observed in δ values in aromatic region cannot be solely explained by the hydrophobic interactions and hence, the 1H NMR titrations also predicted some other types of interactions between C14mimBr and DFNa. The significant chemical shifts in aromatic region demonstrate that the aromatic ring current of imidazolium ring due to circulating π electrons experience change upon increasing the concentration of negatively charged DFNa molecules during 1H NMR titrations. This indicates clear possibility of presence of π-π interactions between the imidazolium moiety of the C14mimBr and the benzene ring of DFNa, in addition to possibility of H-bonding between H-atoms of imidazolium ring of IL and negatively charged carboxyl group of DFNa.25 Both the π−π stacking interaction and electrostatic attraction in addition to hydrobhobic interactions between the oppositely charged moieties can contribute to synergic effect between the ILs and DFNa. These interactions provide a clue for the close proximity of IL and DFNa or in other words DFNa molecules get intercalated in the hydrophobic microdomain of micelles near headgroup as upfield shift is observed only in H1-H9 protons. Benefitting from this penetration, the electrostatic repulsion between ILs headgroups is significantly screened resulting in decrease in the mean area of surfactant headgroup which 22 ACS Paragon Plus Environment

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ultimately increases the molecular packing parameter and induces the transformation from micelles to vesicles. In this studied concentration range of DFNa (0.2 and 0.4 mM), its signals are of little investigative value, since the signal intensity is low due to the small concentrations in the micelles. 3.2.2 1H NMR of DFNa Further to probe the location and orientation of DFNa molecules in IL micelles, the concentration of DFNa is increased from 0.4 to 1.2 mM. The signals of DFNa and C14mimBr in aromatic region i.e. from δ 6.3 to δ 7.5 ppm merge together and therefore were not further analyzed to probe the orientation and, simply taken as evidence that the DFNa are embedded in the C14mimBr micelles (Figure S6).44 However, observing the changes in chemical shifts for Ha, He, Hh and Hf protons (Scheme 1) on DFNa in pure and embedded in micelles, an attempt is made to probe the orientation of drug in C14mimBr micelles. The magnitude and nature (upfield/downfield) change in chemical shift (∆δppm = δDFNa(pure) – δDFNa (in micelles)) at 1.2 mM concentration of DFNa in micelles is used as an indicator of discussion. In case of Ha protons on acetyl group, a small upfield shift (∆δppm =0.14 ppm) is observed and thus it can be inferred that the effect of imidazolium ring currents is negligible here. This also suggests that these protons reside in the Stern layer of micelle.45 But relatively large upfield shift with ∆δppm ≈0.30 ppm, is observed for He protons indicating the parallel orientation of aromatic ring A of DFNa with respect to the imidazolium ring of C14mimBr.46 The parallel orientation is further evidenced by upfield shift of imidazoilium ring protons. A remarkable downfield shift (∆δppm =1.68 ppm) of Hf proton present on N atom of DFNa suggests that these protons are deshielded due to interaction with an electron-capturing group. Taking into account the interactions, it seems possible that the NH group of DFNa can interacts with the positively charged nitrogen atom of imidazolium ring influencing the electronic density of NH modifying the NMR spectrum. As already discussed, the aromatic


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rings of DFNa are twisted in relation and chlorine atoms are not too bulky to block the rotation of the linkage between the nitrogen atom and the aromatic rings. Therefore, it is assumed that the spatial position of the rings can be modified when they get embedded in micelles and electronic density of nitrogen atom gets changed.36 Moreover an upfield shift of comparatively lower magnitude (∆δppm ≈ 0.20 ppm), for Hh proton on aromatic ring B indicates that this part of DFNa is deeply buried into the palisade layer. This positioning of aromatic ring B of DFNa with tilted orientation towards palisade layer is further corroborated by upfield shifts of ≈0.20 ppm for H7 and ≈0.15 ppm for H8 proton of akyl chains of C14mimBr relative to that of in absence of DFNa. 4. Conclusions This report investigates the composition- and dilution-induced structural changes from micelles-vesicles-micelles in a catanionic IL-DFNa mixture comprising surface active ionic liquids

(ILs)

1-dodecyl-3-methylimidazolium

bromide

(C12mimBr)/1-tetradecyl-3-

methylimidazolium bromide (C14mimBr), and diclofenac sodium (DFNa) in aqueous solution. The prolate ellipsoids formed in IL-rich composition (XDFNa = 0.0 and 0.1) examined by SANS, DLS and zeta potential were transformed to rod shaped micelles at XDFNa = 0.3 followed by vesicle formation at XDFNa 0.5 and 0.7. Being amphiphilic in nature, DFNa get physically intercalated in the resulting aggregates leading to change in surface charge density as inferred by zeta potential values. This modification leads to decrease in area of surfactant headgroup ultimately increasing average packing parameter, a necessary condition required for formation of larger aggregate. Finally XDFNa = 0.9, being anionic rich composition, experiences the return of prolate ellipsoids with dominated content of DFNa. Dilution of all the studied mole fractions of DFNa further results in interesting structural transitions. At XDFNa = 0.0 and 0.1, the size of prolate ellipsoids follows the classical trend of decrease in size upon dilution. Contrary to classical behavior at XDFNa = 0.3 growth of rod


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like micelles and at XDFNa = 0.9, transition from prolate ellipsoids to larger aggregates (vesicles + rod like micelles) was observed. These exceptional transformations at XDFNa = 0.3 and 0.9 are thought to be driven by the release of DFNa molecules from the mixed micelles on account of the cmc (solubility) mismatch between the two components. A decrease in ratio of DFNa in the mixed aggregates lowers the average spontaneous curvature of the mixed micelles forcing them to grow. However at XDFNa 0.5 and 0.7, already low curvatured structures (vesicles) were present and dilution has no effect on these structures. NMR measurements confirm that the DFNa intercalated in to IL micelles via. cation–π and π-π interaction in addition of hydrophobic interaction. Acknowledgements Onkar Singh is thankful to University Grants Commission (UGC), New Delhi as a part of research project [F. No. 42-278/2013 (SR)] for providing financial support. The Authors gratefully acknowledge Department of Science and Technology (DST, New Delhi) for funding instrumental facilities. Supporting information Supporting information is available free of charge via the Internet at ACS Publication website. Theoretical details of the SANS measurements, 3 table (Tables S1 to S3) and 6 figures (Figures S1 to S6). 5. References (1)

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6. Table of Content (TOC)

IL DFNa


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