Imidazolium Ionic Liquid Helps to Disperse ... - ACS Publications

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Imidazolium Ionic Liquid Helps to Disperse Fullerenes in Water Eudes Eterno Fileti*,† and Vitaly V. Chaban*,‡ †

Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, 12231-280 São José dos Campos, SP, Brazil MEMPHYS - Center for Biomembrane Physics, Odense M 5230, Kingdom of Denmark

‡

S Supporting Information *

ABSTRACT: Light fullerenes attract significant interest in pharmacy and medicine as drug vectors and antioxidants and to block AIDS virus enzyme. The progress of these applications is hindered by poor solubility of fullerenes in aqueous media. We propose a highly efficient hydrophilic system to disperse the C60 fullerene based on the accurate atomistic-resolution computer simulations. The introduced system is based on 1-butyl-3-methylimidazolium tetrafluoroborate, [C4C1IM][BF4]−water mixtures. The first component is used to form a corona around C60 while exhibiting a significant miscibility with water. Structural and dynamical peculiarities of the C60[C4C1IM][BF4]−water mixtures are discussed.

SECTION: Biomaterials, Surfactants, and Membranes

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very problematic for these applications to get out of chemical laboratory. Substitution of water with other solvents has not yet been sufficiently successful.22,23 To overcome a natural repulsion between fullerenes and water, we have implemented certain techniques. For instance, chemical functionalization of fullerenes is possible. Grafting functional groups increase hydrophilicity24 due to breakage of high molecular symmetry. Additional examples include encapsulation in specific carriers, such as cyclodextrins25 and liposomes,26 and suspension using cosolvents by saturating fullerenes in benzene solutions poured in tetrahydrofuran.27 In our recent works, we have shown that C60 can be efficiently dispersed in the imidazolium RTIL, 1-butyl-3methylimidazolium tetrafluoroborate [C4C1IM][BF4] at slightly elevated temperature. As suggested by quantum mechanical calculation, success of [C4C1IM][BF4] must be correlated by electron transfer between the imidazolium cation and the bucky-ball.28 We unveiled that the solubility of C60 in this RTIL at slightly elevated temperatures (T > 310 K) is higher than in most previously investigated solvents.28 This paper investigates a ternary system composed of water, [C4C1IM][BF4] RTIL, and C60. Five molar fractions of [C4C1IM][BF4] have been probed. We report that [C4C1IM][BF4]−water mixtures maintain highly concentration C60 solutions at 300 K. The investigated systems can be considered in future pharmaceutical and medical developments because none of the involved components are found to be toxic. Studies indicate that imidazolium RTILs with shorter lyophobic chains, such as butyl

anoscale drug delivery systems are currently receiving urgent attention from the communities of chemists, biologists, physicians, and nanotechnologists.1−5 The progress in this field promises significant advances in health care if the existing obstacles are circumvented. Poor water solubility of drugs is one of the most significant problems in the pharmaceutical industry and medicine. It has been recently estimated that 40% of all newly developed drugs are poorly soluble or totally insoluble in water.6 This constitutes an obvious obstacle, which requires an urgent attendance. Much has already been done for the development of strategies to solubilize hydrophobic pharmaceuticals to establish better drugdelivery systems.7−11 The majority of known methods involve manipulations with the structure or environment of the drug. However, conventional methods limit the solvation efficacy for solid drugs, which are prone to immediate, irreversible aggregation.11 A simple, drug-specific, and tunable strategy has been recently introduced to increase water solubility of amphiphilic drugs.12−14 This strategy largely relies on the peculiar properties of ionic liquids (RTILs). The mentioned approach can be useful to avoid many deficiencies of solid drugs, such as elimination of polymorphism, control of water solubility, and improvement of transdermal penetration.10,15,16 Furthermore, ionic liquids have been found to be useful to synthesize active pharmaceutical ingredients with modified solubility. RTIL can also enhance the efficacy of topical analgesia compared with initial materials and, particularly, to solubilize poorly soluble drugs.10,15−21 Light fullerenes, in particular, C60, exhibit several properties, suggesting their great potential for applications in biomedical fields.22 Unfortunately, their notorious hydrophobicity makes it © XXXX American Chemical Society

Received: March 27, 2014 Accepted: May 6, 2014

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and ethyl, exhibit smaller toxicity in plants. The toxicity of tetrafluoroborate anion may come from hydrolysis in aqueous environments and generation of fluoride anions. However, this toxicity is not expected to be critical in the context of biomedical applications of the relatively RTIL-poor mixtures. The discussion is centered at C60. The solutions are characterized in terms of both structural and dynamic properties. Figure 1 reports mass densities for a set of [C4C1IM][BF4]− water mixtures solvating C60. Pure [C4C1IM][BF4] exhibits

Figure 2. Radial distribution functions derived for C60−water (solid red line), C60−cation (dashed green line), C60−anion (dashed-dotted blue line), and C60−C60 (dashed-dotted-dotted pink line). RDFs were calculated between centers-of-mass of the corresponding particles. The centers-of-mass were obtained dynamically (at each integration timestep).

Figure 1. Average density of system as a function of [C4C1IM][BF4] molar fraction at 300 K. The standard deviation does not exceed ±5 kg m−3 at any composition.

higher density than water (1221 vs 1000 kg m−3). Note that the applied RTIL model underestimates somewhat density of [C4C1IM][BF4].29 However, increase in molar fraction of RTIL decreases density of the system, although insignificantly. In general, high density of the system indicates favorable (attractive) interactions between the components. It should also be remembered that density of C60 fullerene molecules, per se, exceeds the densities of the RTIL and water. Radial distribution functions (Figure 2) were calculated between C60 molecules and all components of the systems to characterize the short-range structures. All RDFs are defined between centers-of-mass of the corresponding molecules or ions. Clearly, RTIL-20, RTIL-30, RTIL-40, and RTIL-50 systems exhibit very similar patterns, whereas RTIL-10 system significantly differs. Contact C60 pairs are detected exclusively in RTIL-poor system, whereas all other systems contain a welldefined peak at 1.35 nm corresponding to imidazolium ion separated C60 pair. The height of the cation separated peak exhibits an excellent correlation with the content of RTIL in the mixtures. The larger the number of RTIL ion pairs supplied, the smaller this peak becomes. This can be understood as the RTIL improves dispersion of fullerenes throughout the solution, and, consequently, more C60 molecules are not correlated with one another. The bucky-ball is a notoriously hydrophobic molecule with virtually zero solubility in water. The first peak for the water− fullerene interaction is smaller than unity. The peak is also poorly defined. No second peak is detected. Although water molecules are found in the proximity of the C60 surface, their approach to fullerene should be rather associated with thermal motion and favorable interactions with [C4C1IM][BF4]. The center-of-mass of imidazolium cation is located slightly closer to C60 than tetrafluoroborate anion. This observation confirms that the cation plays a principal role in the successful fullerene solvation due to π−π stacking.28 Certain amount of C60 molecules in [C4C1IM][BF4] RTIL exist in the form of solvent-separated solute pair. These

structures, as well as direct-contact solute pairs, that is, dimers, are very common in nonideal solutions. There are several principal differences of the observed structures from intercalation compounds. First, intercalation takes place in layered structures or in the host structures, providing a necessary matrix for such inclusions. Second, intercalated molecules or ions are always smaller than the host structure. On the contrary, the size of [C4C1IM]+ ion is quite similar to the size of C60 fullerene. Third, intercalation compounds are normally crystalline structures with very well-defined RDF peaks. In turn, the observed RDF peaks in the studied systems (Figure 2) are very broad. Being somewhat different in various simulated systems, they spread for 0.3 to 0.4 nm. The most probable distance between C60 molecules in the solvent separated pairs ranges from 1.2 to 1.6 nm. To provide an additional proof of our interpretation, we have computed mass density of C60 molecules along all three Cartesian directions in the simulated systems (Figure S1 in the Supporting Information). The additional structural analysis is given in Figures 2 and 3. Although ca. 70 mol % of fullerene molecules in the RTIL-10 system exists as lonely solute particles, there is a finite probability of larger aggregate formation. Nearly all simulated C60 molecules are excellently dispersed, and the fraction of dimers is negligible in other systems. Because the dispersion of C60 is triggered by RTIL (largely by [C4C1IM]+), we conclude that 10 mol % of [C4C1IM][BF4] is not enough to cover all bucky-balls. Practical applications of these systems require us to maximize percentage of water; therefore, the RTIL-20 system appears most attractive in this regard, whereas the systems with excessive content of [C4C1IM][BF4] are retained for the sake of fundamental interest. Figure 4 depicts how the largest C60 cluster in the MD system evolves in time. The shown part of trajectory is equilibrated. The observed maximum cluster sizes fluctuate 1796

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Figure 5. Shear viscosity versus [C4C1IM][BF4]−water mixture composition.

Similar to shear viscosity, diffusion is known to be of major importance in controlled drug-delivery systems. A reliable and timely drug penetration through the biological membrane is directly related to its self-diffusion constant. Figure 6 shows the system’s self-diffusion constants decomposed into the components: C60 molecules, water molecules, cation [C4C1IM]+, and anion [BF4]− as functions of [C4C1IM][BF4] molar fraction. Being immersed in RTIL−water mixtures, C60 is surrounded by the network of strong electrostatic bonds, including hydrogen bonds. The mobility of the bucky-ball is, therefore, significantly decreased, as compared with dilute solutions in hydrophilic media.31 Ions and water exhibit significant mobility, which decreases with the increase in [C4C1IM][BF4] molar fraction. This trend is observed in the binary mixture of RTILs and water. The solute does not modify the trend. In the RTIL-20 system, the diffusion coefficient of the constituents is 10, 80, 100, and 500 μm s−1 for C60, [C4C1IM]+, [BF4]−, and water, respectively. Therefore, it is expected that the complex involving C60 molecule and its first solvation shell exhibits a greater mobility than pure C60. This favors faster translocation of C60 in the living systems. The interaction of C60 with biological systems has been recently attended a few times.32−34 The motivation of these studies covers such fundamental issues as solvation properties of C6028,31,35 as well as more practical issues such as toxicity and transport properties.32,36 On the basis of the results presented here, we anticipate the following mechanism for C 60 penetration into a biological membrane. In RTIL−water mixtures, C60 molecules are coated with a well-defined (Figure 2) monolayer of cations and anions forming a corona-like system. The systematically smaller amount of water is also detected in the first solvation shell due to a perfect miscibility of imidazolium RTIL with water. Considering reduced mobility of C60 in these mixtures, any appreciable diffusion of the buckyball occurs through the diffusion of the corona as a whole. The interaction of the corona with a biological membrane results in the insertion of the corona into the membrane. Because ionic liquids are able to incorporate into the structure of the biological membrane,37 ions are expected to be retained in the hydrophilic region of the membrane. In the meantime, C60 is dissolved in the hydrophobic region. This mechanism is obviously more energetically favorable than the insertion of pure C60. In summary, this work develops a system containing welldispersed fullerene molecules for applications in the emerging biomedical field. The proposed system is clearly hydrophilic, which removes previously existing barriers for fullerene penetration into the living organisms. Structural analysis indicates that solutions with molar content of RTIL between

Figure 3. Fullerene cluster size distributions in the systems containing 10, 20, 30, 40, and 50 molar percents of RTIL and 8 C60 molecules. If any atom of a C60 molecule touches any atom of another C60 molecule, these molecules are considered a cluster at a given time. The cutoff distance for the cluster analysis was determined from the experimental VDW diameters of the atoms.

Figure 4. Maximum cluster size fluctuations in the equilibrated RTILpoor system (RTIL-10).

from all individual fullerene molecules to seven fullerene molecules per cluster. The latter can be regarded as a nascent solid phase, although unstable. An ability of only 10 mol % [C4C1IM][BF4] to transform water-based system from totally segregated to a finely dispersed one is a dramatic structural change. A crucial property describing the dynamic of ILs is the zerofrequency shear viscosity. In particular, viscosity likely influences drug-delivery properties of a compound, affecting its application in the treatment of the affected site. The computed values for the viscosity of the ternary mixtures are presented in Figure 5. It is well known that the presence of small amounts of water dramatically decreases viscosity of ionic liquids.30 In particular, in water-rich mixtures (RTIL-10) the viscosity is reduced by 10 times as compared with pure [C4C1IM][BF4]. The viscosity of pure [C4C1IM][BF4] is very high, amounting to 98 cP.29 Note that fullerene molecules also significantly raise the viscosity of the system. 1797

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Figure 6. Self-diffusion constants computed separately for C60 molecules, cation, and anion of [C4C1IM][BF4], and water molecules.

The water molecule was represented using the three-site TIP3P38 nonpolarizable model. The ionic liquid, [C4C1IM][BF4], was simulated using the empirical potential with scaled electrostatic charges introduced by Chaban et al.39 The fullerene force-field model treats each uncharged carbon atom by means of pairwise Lennard-Jones (12,6) equation. This force field has proven its reliability for the investigation of structure, dynamics, and solubility of C60 in ionic, organic, and aqueous environments.35,40,41 The parameters for each molecule were obtained using a physically equivalent procedure to map potential energy surfaces around these particles. Therefore, the models can be safely combined in a single molecular dynamics (MD) simulation. All electrostatic charges were kept fixed (nonpolarizable approach) during the MD simulations. The interactions between [C4C1IM][BF4] and C60 have been adjusted, as justified in our recent methodological work.28 The solutions were pre-equilibrated during 20 ns. After that, a set of equilibrium properties was determined from production runs of 120 ns each. The integration time step of 2.0 fs was used. All bonds involving hydrogen atoms were kept fixed by the LINCS algorithm.42 The coordinates were collected every 25 ps for the analysis of structure and every 0.2 ps for the analysis of dynamics. The pressure tensor was saved every 0.5 ps for the calculation of shear viscosity using the Einstein-type equation. The systems were immersed into the external heat bath for weak temperature coupling. The velocity-rescaling thermostat (time constant of 1.0 ps) by Bussi, Donadio, and Parrinello was applied.43 The total pressure was maintained constant using the Parrinello−Rahman44 barostat (time constant of 4.0 ps). The electrostatic interactions were computed using direct pairwise Coulomb potential at the separations smaller than 1.4 nm and using particle mesh Ewald scheme45 for all distances beyond the real-space cutoff. The neighbor list was updated every 0.02 ps within 1.4 nm. Domain decomposition scheme was used to parallelize force calculation at every time step employing 16 processors. All simulations of MD trajectories were performed using the GROMACS 4.6 program.46,47

10 and 20% are optimal to generate a complete surface coverage of C60 using imidazolium cations. The overall content of the RTIL is, therefore, minimized, eliminating potential toxicity-related problems. Our mathematical modeling also indicates that problems related to high viscosity of many imidazolium-based ionic liquids and relatively low mobility of C60 can be overcome or reduced by the use of binary hydrophilic solvents. Eight C60 molecules were randomly inserted into the previously equilibrated mixtures of water and [C4C1IM][BF4]. All systems (Figure 7) were simulated under normal conditions

Figure 7. Representation of the [C4C1IM][BF4]-poor mixture (left) and the [C4C1IM][BF4]-rich mixture (right). The systems are located in their corresponding free-energy minima at 300 K and 1 bar.

(temperature of 300 K and pressure of 1 atm) using five different [C4C1IM][BF4]−water mixture compositions and constant number of bucky-balls. Table 1 presents the compositions of all investigated mixtures. Table 1. Composition of the Mixtures of Water and [C4C1IM][BF4] at the Different RTIL Molar Fractions system

no. ion pairs

no. water

no. interact. sites

density (kg m−3)

RTIL-10 RTIL-20 RTIL-30 RTIL-40 RTIL-50

50 100 150 200 250

450 400 350 300 250

3330 4680 6030 7380 8730

1195 1193 1189 1186 1184

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ASSOCIATED CONTENT

S Supporting Information *

Mass density of C60 molecules in X, Y, and Z directions of the simulated system containing 20 mol % of [C4C1IM][BF4] 1798

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RTIL. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: fi[email protected] (E.E.F.) *E-mail: [email protected], [email protected] (V.V.C.) Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS E.E.F. thanks Brazilian agencies FAPESP and CNPq for support. MEMPHYS is the Danish National Center of Excellence for Biomembrane Physics. The Center is supported by the Danish National Research Foundation.

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