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B: Biomaterials and Membranes

Structural Properties of SPAN 80/TWEEN 80 Reverse Micelles by Molecular Dynamics Simulations Ilia Vladimirovich Kopanichuk, Ekaterina Alexandrovna Vedenchuk, Alina S. Koneva, and Aleksandr Aleksandrovich Vanin J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b03945 • Publication Date (Web): 03 Aug 2018 Downloaded from http://pubs.acs.org on August 10, 2018

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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The Journal of Physical Chemistry

Structural Properties of SPAN 80/TWEEN 80 Reverse Micelles by Molecular Dynamics Simulations Ilia V. Kopanichuk, Ekaterina A. Vedenchuk, Alina S. Koneva, Aleksandr A. Vanin* Institute of Chemistry, St. Petersburg State University, 7-9 Universitetskaya nab., St. Petersburg, 199034, Russia *

E-mail: [email protected]

ABSTRACT The sorbitan monooleate (Span 80)/polyoxyethylene sorbitan monooleate (Tween 80) reverse micelles in the water-in-n-decane microemulsion were studied using the molecular dynamics (MD) simulation. The coexistence of the large RMs with the hydrodynamic radii Rh ~10 – 20 nm and small RMs with Rh ~1– 2 nm were previously specified for this system. Models of the both surfactants and decane were based on the united-atom approach to allow us describe the structural properties of the small RMs. The micelles have been self-assembled from an initially homogeneous mixture of surfactant, water and decane molecules. The dependence of the shape of the RMs on the relative content of surfactants has been established. The inner structure of Span 80, Tween 80 and Span 80/Tween 80 RMs was quantitatively described. Tween 80 molecules penetrate the water core while Span 80 molecules locate on the surface of the RM. The obtained data shows that the hydrogen bonds between surfactant molecules form on the surface of the RM and play an important role in the formation of RMs. The water hydrogen bonds density distribution in individual and mixed RMs explain advantages of mixed surfactants system than an individual surfactant.

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INTRODUCTION Water-in-oil (w/o) microemulsions are optically transparent, thermodynamically stable mixtures of water, oil, and surfactants. The structure of aggregates that form in a w/o microemulsion can be different: spherical or elongated droplets, worms or bicontinuous networks.1 Reverse micelles (RMs) are droplets formed in a w/o microemulsion and formed by surfactants. RMs attract attention due to their wide applications for various practical purposes. RMs are used as the template for the preparation of metallic nanoparticles,2, materials,4 ultra-dispersed inorganic salts powders,5,

6

3

polymeric

and drug nanocrystals.7 RMs are also

applied in drug-delivery8 and extraction processes.9 W/o microemulsions are useful in food, cosmetic, and fuel industries.10, 11 The structure and properties of a microemulsion depend on different parameters including temperature, concentration, type of surfactant, and water to oil ratio. The microstructure of w/o microemulsion plays a very important role in the synthesis of nanoparticles. It has been shown for manganese carbonate nanoparticles that the size of particles correlates with the size of RMs.12 Also the size of yttrium fluoride nanoparticles can be changed more than three times by varying the composition of w/o microemulsion.13 In microemulsions containing mixtures of different surfactants the composition of the mixture affects the structure of nanoparticles.5 The ability to determine the structure of a microemulsion and to predict it is very important. The most studied RMs are ones of the anionic surfactant Aerosol OT (AOT). They were widely investigated experimentally14 and theoretically.15 Computer simulations are very useful to study the shape, the inner structure, and fine structural details of RMs.16, 17, 18, 19 Nonionic surfactants have an advantage of being in most cases less toxic,20 more biocompatible21 and biodegradable22 that is particularly important in food, cosmetic, and pharmaceutical industries. Computer simulations have been successfully used to study the RMs of Span 80,23 C12E4,24 glycerol monooleate (GMO),25 and different phospholipids (DOPC, DPPC, and DSPC).26, 27, 28


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RMs formed by the mixture of surfactants are of special interest. A combination of different surfactants provides better control over the behavior of the system than an individual surfactant.10 A wide range of possible values of hydrophilic-lipophilic balance (HLB) may be obtained using a mixture of two nonionic surfactants with different HLB values. It was found that the HLB value determines the phase behavior of a microemulsion,29 affects the size of obtained nanoparticles,4 and correlates with technologically important properties of microemulsion systems.10 In the present work we investigated the water-in-decane microemulsions formed with the mixture of nonionic surfactants Span 80 (sorbitane monooleate) and Tween 80 (polyoxyethylene sorbitan monooleate). Both Span and Tween types of surfactants are extensively used in food and pharmaceutical industries due to their low toxicity.30,

31, 32

Span 80/Tween 80 water-in-

decane microemulsion has been previously studied by experimental methods but the system was not considered on the molecular level.33 Data on the shape and on the inner structure of aggregates is important for the synthesis of nanoparticles. The size and shape of particles preparated in a w/o microemulsion correlates with the size and shape of the RMs, and the dependence between the composition of a certain type of RMs and its shape is hard to determine experimentally. The investigation of the formation of hydrogen bonds in RMs allows to predict the interactions with other molecules like biomolecules, polymers, and a coordinating metal complex which take part in reactions provided in RMs or which can be extracted via RMs. Reverse microemulsions are the model systems of bio-objects like cell-membrane or organelles, and the study of hydrogen bonds in such systems allows one to better understand the processes taking place in living organisms, where hydrogen bonds play an important role. The investigation of the influence of each surfactant on the structure and shape of the RM and also on the formation of hydrogen bonds in the RM will help to make better selection of composition of mixed RMs for a wide range of needs. We used molecular dynamics simulations to study the



shape and the inner structure of Span 80/Tween 80 RMs in dependence on the system composition. MODELS AND METHODS

Scheme 1. Structural formulas of surfactant molecules: Span 80 (a) and Tween 80 (b). Systems that contain sorbitan esters (Spans) and polysorbates (Tweens) were previously studied using coarse grained MARTINI force field,34 GAFF,35 GROMOS87,36 and GROMOS96 53a6OXY+D force fields.37 GROMOS96 force field was previously used for simulations of the mixture of Tween 80 and Span 80.37 We used the united atom approach to represent molecules of Tween 80, Span 80 (see Scheme 1) and n-decane (GROMOS96 53a6).38 Chirality of both surfactant molecules have not been taken into account because CH groups were represented as unified atoms. Mean stoichiometric structure was used for Tween 80.34, 37 SPC model was used for water.39 Atomic partial charges were derived from the CHELPG technique by the B3LYP/6-31G** calculations.36 Structure and topology files are attached in S. I. Molecular dynamics simulations were performed using GROMACS v. 5.05.40 Equations of motion were 4 ACS Paragon Plus Environment

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integrated by the leapfrog algorithm with a time step of 2 fs. For electrostatic interaction, the Particle Mesh Ewald method was used with interpolation of the fourth order and the maximum spacing of 0.12 for the fast Fourier transform grid.41 We truncated both the Lennard-Jones and the real part of the Coulombic interactions at 1.0 nm. Verlet cutoff scheme was used for the latter. The tolerance (ewald_rtol)40 was set to 10−5 for all systems. Software for creating the starting configuration was written using JGROMACS source code42 and the algorithm for calculating the center of mass (COM) for a set of point masses that are distributed in an unbounded environment.43 All configurations and trajectories were analyzed with the aid of VMD software.44 Table 1. Compositions of simulated systems by number of molecules (n) and their mass fractions (wt. %), size of the simulation box (L), and full time of simulations (τ).

system 5_0 10_0 15_0 0_15 0_20 0_25 0_30 14_7 5_15 5_20 4_16

ntween80 5 10 15 0 0 0 0 14 5 5 4

nspan80 0 0 0 15 20 25 30 7 15 20 16

nwater 150 300 450 150 200 625 90 525 300 375 300

ndecane 525 1050 1575 375 500 625 1000 1575 750 938 750

wtsurf% 7.8 7.8 7.8 10.3 10.3 10.3 8.2 8.4 10.4 9.7 9.7

wtwater% 3.2 3.2 3.2 4.3 4.3 4.3 1.0 3.7 4.3 4.4 4.4

wtdecane% 89.0 89.0 89.0 85.4 85.4 85.4 90.8 87.9 85.3 85.9 85.9

L, nm 5.75 7.24 8.30 5.24 5.75 6.19 7.14 8.34 6.57 7.06 6.55

τ, ns 35 40 40 35 35 35 45 40 40 35 35

All obtained RMs were self-assembled. Firstly, we created the configuration with random locations of all molecules. Then we performed short simulation (80 to 160 ps) in the NpTensemble with T = 298.15 K and p = 1 bar to determine an average linear size of the box that corresponds to these conditions (see Table 1). In the NpT-ensemble the pressure was kept constant by the classical Berendsen barostat, and the temperature was constrained by canonical sampling through velocity rescaling.45. After that we created the new configuration of a given size and the same amount of every component. This configuration was used as the initial one for 5 ACS Paragon Plus Environment


the simulation in the NVT-ensemble with T = 298.15 K. The times of NVT simulation runs before the equilibration are shown in Table 1. A short 10 ns simulation was performed then to obtain average values of the local density, the radius of gyration, and the eccentricity. RESULTS AND DISCUSSION Considered systems Compositions of all simulated systems correspond to the microemulsion region of the pseudoternary phase diagram of Span 80/Tween 80/water/n-decane system.33 In ref.33 weight ratio between Span 80 and Tween 80 was close to 1:1 for all samples. We considered not only systems with equal mass fractions of the surfactants but also the systems with a prevalence of one of the surfactants. Three systems (5_0, 10_0, and 15_0) contain only Tween 80 without Span 80 (see Table 1). The next four systems (0_15, 0_20, 0_25, and 0_30) do not contain Tween 80, only Span 80. The last four systems (14_7, 5_15, 5_20, and 4_16) contain both surfactants with the different weight ratio of Tween 80 to Span 80 (6:1, 1:1, 3:4 and 1:1) respectively. The multimodal size distribution of Span 80/Tween 80 RMs observed by dynamic light scattering (DLS) and NMR is a problem because

33

the coexistence of small (Rh = 2-4 nm)

and large (Rh = 10-12 nm) RMs cannot be easily simulated by using an atomic approach. The systems containing large RMs are out of the range that is possible to simulate with available computer resources due to their size but the volume fraction of large RMs is lower than 2% for all studied systems, hence, simulations of only small RMs can be representative for the whole system. The size of the systems was chosen so that the hydrodynamic radii Rh of obtained RMs are close to the experimentally observed Rh for small RMs.33 Due to the lack of data about the composition of small RMs we performed NMR self-diffusion study for the binary Span 80–ndecane and for the ternary Span 80–Tween 80-n-decane. The self-diffusion coefficients D for dilute solutions of Span 80 (1 and 3.5 wt.%) and Span 80/Tween 80 mixture (3.5/3.5 wt.%) in ndecane were measured at 298 K. Experimental details are reported in S. I. For the system with 1 and 3.5 wt.% of Span 80, the only one diffusion mode was obtained with D value ~ 10-10 m2/s for 6 ACS Paragon Plus Environment

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surfactant molecules. The addition of Tween 80 to the system leads to an appearance of a second diffusion mode D ~ 10-11 m2/s (slow). The Tween 80 itself is insoluble in n-decane and the Span 80/Tween 80 mixture became heterogeneous at the total surfactant concentration less than 3.5 wt.%.33 We attributed the slow diffusion mode to Span 80/Tween 80 mixed reverse micelles and the fast diffusion mode to the free Span 80 molecules. Hence, the presence of both Span 80 and Tween 80 is necessary for the formation of aggregates. It is important to compare systems with different Tween 80/Span 80 ratio to find their roles in the process of formation of the RM. Shape Table. 2. Radii of gyration (Rg), semi-axes of respective ellipsoids (a, b, c), and eccentricities (e) of simulated RMs.

system

R , nm

5_0 10_0 15_0 0_15 0_20 0_25 0_30 14_7 5_15 5_20 4_16

1.3 1.6 1.9 1.4 1.5 1.6 1.6 1.9 1.6 1.7 1.6

a, b, c, nm

g

2.1 2.6 3.4 2.0 2.1 2.2 2.3 3.1 2.4 2.4 2.3

1.4 1.7 2.0 1.8 1.9 2.0 2.0 2.0 2.0 2.2 2.1

e 1.2 1.6 1.6 1.5 1.7 1.8 1.7 2.0 1.8 2.0 1.8

0.8 0.8 0.9 0.7 0.8 0.6 0.7 0.8 0.7 0.5 0.6

11 systems of different composition were simulated by the molecular dynamics technique. The RM formed in every system from the initially homogeneous mixture of water, ndecane, and surfactants. To characterize the size of the RM we calculated the radius of gyration for each RM (see Table 2). In experimental studies the hydrodynamic radius is usually calculated in an assumption that the RM is spherical. The systems 5_15 and 4_16 have the Tween 80/Span 80 ratio that is the closest one to the experimental systems. We estimated Rh for the system 5_15 and 4_16 from their radius of gyration Rg 26

= ,

(1)



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to be sure that our RMs are similar to experimentally observed ones. Both experimental and calculated RH = 2 nm. The shape of the RM was approximated by the ellipsoid of uniform density. The eccentricity of the ellipsoid can be found by the equation:

= 1 ,

(2)

where a, b, and c are semi-axes of the ellipsoid. Semi-axes are calculated from the diagonalized tensor of inertia of the RM.46 The eccentricity shows the distortion of the shape of the RM from the ideal sphere (e = 0 for a sphere and 1 for a rod). All calculated parameters are given in Table 2.

Figure 1. Snapshots of Tween 80 RMs configurations in the systems: (a) 5_0, (b) 10_0, (c) 15_0. Tween 80 headgroups are yellow, tailgroups are green, and water molecules are blue. Tween 80 and Span 80 RMs were considered to find the contribution of each type of a surfactant to the properties of Span 80/Tween 80 RM. We focused on Tween 80 RM that has quiet a complex shape. These RMs look like a heart (Figure 1a), a kidney (Figure 1b), or a liver (Figure 1c). The eccentricity of Tween 80 RMs ranges from 0.8 to 0.9 and slightly increases with an increase in their size. This value of e means that they are significantly elongated. Tween 80 is a moderately heavy molecule; its mass is 73 times larger than the mass of a water molecule. Hence, 4 wt. % of water for system containing 8 wt. % of Tween 80 as the only surfactant correspond to the water to surfactant ratio w0 = 30. This water to surfactant ratio seems large but 8 ACS Paragon Plus Environment

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the headgroup of Tween 80 is so big that there is actually a lack of water in the system. Tween 80 headgroups cannot cover the surface of the RM; they only penetrate the core. The whole aggregate looks like a hive where walls are built of polyethylene oxide groups and tunnels are filled by water.

Figure 2. Snapshots of Span 80 RMs configurations in the systems: (a) 0_15, (b) 0_10, (c) 0_25. Span 80 headgroups are red, tailgroups are magenta, and water molecules are blue. Span 80 RMs are closer to spherical shape in all considered cases; e ranges from 0.6 to 0.7. Figures 2a, 2b, and 2c show that the increase in the size of Span 80 RMs does not significantly affect its shape. The eccentricity nonmonotonically changes with the change of the size of the system. The eccentricity of the low-water Span 80 RM is equal to 0.7 that is in a range of e of high-water Span 80 RMs. Comparison of all three types of RMs show the influence of each surfactant on the shape of the RM. A reduction of concentration of Tween 80 in comparison to Span 80 leads to a decrease in eccentricity of the RM. This dependence is clearly seen in Figures 3a, 3b, and 3c. The most elliptical RM (e = 0.8) forms in the system 14_7 shown in Figure 3a and Tween 80 to Span 80 weight ratio in this system is equal to 6:1. The RM in the system 5_15 (see Figure 3b) is significantly more spherical (e = 0.7); weight ratio of Tween 80 to Span 80 is equal to 1:1. Figure 3c shows the Span 80/Tween 80 RM that corresponds to the system 5_20. This RM is even more spherical (e = 0.5) than any of pure Span 80 RMs. The reason for the decrease in the eccentricity may be an increase in the amount of water compared to Span 80 RMs. 9 ACS Paragon Plus Environment


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Figure 3. Snapshots of Span 80/Tween 80 RMs configurations in the systems: (a) 14_7, (b) 5_15, (c) 5_20. Tween 80 headgroups are yellow, tailgroups are green; Span 80 headgroups are red, tailgroups are magenta, and water molecules are blue. Inner structure The radial profiles (which is the best choice for the description of the structure of spherically symmetric body) were calculated to study the inner structure of RMs. The shapes of all studied aggregates deviate significantly from that of a sphere. It leads to broadening of peaks of radial profiles of components of the RM and to an increase of deviations of these profiles. Intrinsic density profiles were calculated to solve the problem because intrinsic surface properties are not affected by the choice of the coordinate system, the position of the viewer relative to the surface, and the particular parameterization of the surface.47 Hence, the intrinsic profiles directly take into account the surface and automatically delete all the shape fluctuations from the density of the components.48 The intrinsic surface was defined as a figure so shaped that for every point on its surface d(int) = 0, and d(int) was calculated using this formula:49

=

% ∑ ! "#$ & % ∑ ! "#$

,

(3)

where d(int)j is the distance between the current particle j and the intrinsic surface, N is the number of anchor points on the surface, θ is the angle in radians between the vectors from center of mass of the RM to the anchor point si and to the current particle rj, and λ is a surface


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smoothness. In this work carbon atoms from ester groups (CO1 in Span 80 and C in Tween 80, see S.I.) were used as anchor points, and λ was taken equal to 15.49

Figure 4. Radial (a, c) and intrinsic (b, d) density profiles for systems 0_15 (a, b) and 10_0 (c, d); r is the distance to the center of mass of the RM; d is the distance to the intrinsic surface of the RM. Radial profiles of Span 80 RMs seem more usual (see Figure 4a) compared to those of Tween 80 RMs (see Figure 4c). Profiles of a headgroup of Span 80 have only one peak. The density of water inside Span 80 RMs reaches the density of bulk water ρbulk = 33.5 nm-3 at the center of mass of the RM. Intrinsic density of tailgroups of Span 80 raises faster near the surface of the RM than the radial density of those groups (see Figures 4a and 4c) The radial profile of a headgroup of Tween 80 reaches an anomalous value at the center of mass of the RM where the density of water is significantly suppressed (Figure 4c). These anomalies are typical artifacts of a spherical symmetry of radial profiles. Intrinsic profiles of these groups show a normal value of 11 ACS Paragon Plus Environment


the water density and suppressed density of Tween 80 inside the RM. The intrinsic profile of Tween 80 tailgroups density shows that Tween 80 tailgroups do not penetrate surface as it is shown by radial profile. However, Tween 80 headgroups34 penetrate the core of the RM deep and form the network hidden on the inside of the RM. Their local density grows nonmonotonically from the surface towards the center of the RM.

Figure 5. Radial (a, c) and intrinsic (b, d) density profiles for systems 14_7 (a, b) and 4_16 (c, d); r is the distance to the center of mass of the RM; d is the distance to the intrinsic surface of the RM. RMs made of both type of surfactants are of special interest in this study (see Figures 3 and 5). Their inner structure is very close to a superposition of structures of RMs containing only one type of surfactant. The size of Tween 80 headgroup does not allow Span 80/Tween 80 RMs to make a water core; water molecules are distributed among Tween 80 headgroups. Figures 5b and 5d show the compression of Span 80 headgroups with an increase in the concentration of the 12 ACS Paragon Plus Environment

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surfactant as for the pure Span 80 RMs. The same effect for Tween 80 headgroups has not been observed. In contrast, the headgroups expand with an increase in the concentration. Tailgroups of both surfactants do not penetrate the core and reside in the oil phase entirely. The hydrogen bonding

Figure 6. Radial distribution functions between an oxygen atom of water (O-water) and oxygen atoms of surfactants (a); r is the distance between atoms. Distributions of orientations between the water dipole vector and vectors from oxygen atoms of surfactants to an oxygen atom of water (b). The network made of Tween 80 headgroups is evident in the system with a prevalence of Tween 80, see Figure 5. We suggest that the only way to assemble such a complex structure is via the formation of hydrogen bonds between the molecules of the surfactant. We calculated the radial distribution function g(r) for all oxygen-oxygen pairs in the systems and the distribution of a cosine of an angle between the water dipole moment and the vector from a target oxygen atom to an oxygen atom of water to choose the best geometric criterion for the formation of a hydrogen bond. All oxygen atoms in the system were united into different groups by their location in the molecule. O-water is an oxygen atom of water molecule. O-hydroxy, O-ring, and O-ester groups contain oxygen atoms of hydroxyl groups, sorbitane 5-ring, and ester groups of Tween 80 and Span 80, respectively. O-polyetoxy group contains oxygen atoms of etoxyl groups of Tween 80. It was found that the distance between the O-water and its first coordination sphere 13 ACS Paragon Plus Environment


of oxygen atoms of surfactants is less than 0.3 nm (see Figure 6a). The preferred angle between the water dipole vector and O–O-water vector inside this sphere is equal to θ0 = π - 0.5* (cosθ0 = -0.58) for all oxygen atoms of surfactants (see Figure 6b). O-hydroxy and O-polyetoxy atoms also slightly prefer θ = 0 and θ = π, respectively, because these groups contain different oxygen atoms placed near each other (see Scheme 1). The radial distribution functions between all oxygen atoms in the system and oxygen atoms of hydroxyl groups of surfactants are shown in Figure 7. The distance between oxygen atoms in all cases is less than 0.3 nm, except for the Oring atom that is located at a constant distance from O-hydroxy atoms in Span 80 5-ring (see Scheme 1). All this confirms that water and surfactants actively form hydrogen bonds between each other and between themselves. As the length of the O-H bond in our model is equal to 0.1 nm, we decided that the simple distance criterion O…H < 0.25 nm from ref.50 is adequate for the considered systems.

Figure 7. Radial distribution functions between oxygen atoms of hydroxyl groups of Tween 80 and Span 80 (O-hydroxyl) and oxygen atoms of surfactants or water; r is the distance between atoms. Figure 8a shows the radial density profile of water-water hydrogen bonds from the center of mass of the RM. The number of hydrogen bonds is divided by the number of water molecules to show the relative differences between the systems. The density of hydrogen bonds of water in the system 15_0 (Tween 80 only) never reaches the maximum value 2.0 nm-3 bonds per water molecule but it decreases very slowly with an increase in the distance from the center of the RM. 14 ACS Paragon Plus Environment

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The density of hydrogen bonds in the system 0_25 (Span 80 only) demonstrates the opposite behavior. It reaches maximum value in the center of the RM but decreases much faster than in the previous system. The density of hydrogen bonds in the system 5_15 containing both surfactants shows a superposition of the behavior of the density of hydrogen bonds in Span 80 and Tween 80 RMs. It almost reaches maximum value 2.0 nm-3 in the center of the RM and decreases slower than in the Span 80 RM. Comparison with literature data for ionic RMs formed by Aerosol-OT shows that the hydrogen bonds distribution in the RM formed by only Tween 80 is significantly different that for the ionic RM. Distributions in Span 80 and mixed RMs seems more similar to AOT RMs with higher water to surfactant ratio than to the AOT RMs with equal water to surfactant ratio.48

Figure 8. Local densities of hydrogen bonds between water molecules per one oxygen atom of water in systems 15_0, 0_25, and 5_15 (a); local densities of hydrogen bonds between molecules of surfactants in systems 15_0, 0_25, and 5_15 (b); r is the distance to the center of mass of the RM. Then we calculated the radial density of surfactant-surfactant hydrogen bonds. It was surprising that there are no hydrogen bonds between the surfactant molecules in the core of the RM (see Figure 8b). Span 80 hydrogen bonds form a tall and narrow peak of the density on the surface of RM 0_25. Tween 80 molecules form more dispersed hydrogen bonds network due to their longer headgroups. On the one hand, we suggest that the ability to form this network makes 15 ACS Paragon Plus Environment


Tween 80 such good agent for the microemulsion formation. On the other hand, an addition of Span 80 to Tween 80 microemulsion increases the density of hydrogen bonds on the surface of the RM (see Figure 8b, system 5_20). Hence, Tween 80 and Span 80 cover the weak sides and intensify the strong sides of one another in the process of the formation of the mixed RM. This can explain the increase of water uptake by w/o microemulsions formed by Span 80/Tween 80 mixture compared to a microemulsions formed by only one surfactant.51 On the one hand, the investigation of the inner structure of small RMs shows that it is possible for small RMs to be formed by the mixture of Span 80 and Tween 80, not only by Span 80 as it was suggested previously.33 On the other hand, NMR studies show that large RMs appear in the systems immediately with adding of Tween 80 to the systems. The coarse-grained simulation is required to answer the question of how the formation of two types of aggregated with significant difference in size is possible. CONCLUSIONS This paper presents the results of MD simulations of model RMs formed by nonionic surfactants Span 80 and Tween 80 in the water-in-decane microemulsion. We simulated small RMs because their volume fraction is about 98%, hence, these simulations are representative for the whole system. The Rh of our simulated RMs was taken from the experimental data. The role of Tween 80 and Span 80 in the process of the formation of aggregates was established. The shape of RMs with a prevalence of Span 80 is close to ellipsoid with the eccentricity ranged from 0.5 to 0.7; RMs with a prevalence of Tween 80 tend to be even more elliptical with e in the range from 0.8 to 0.9. The distortion of the shape of Span 80 RMs does not increase with an increase in the amount of components or with a decrease in the water to surfactant ratio w0. Comparison of intrinsic density profiles with radial density profiles shows that radial profiles hide some details of the inner structure of the RMs and may lead to wrong conclusions about the distribution of the components in case of the RMs with a distorted shape. Intrinsic 16 ACS Paragon Plus Environment

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density profiles shows that Span 80 molecules stay on the surface of the RM and Tween 80 molecules deeply penetrate the core of the RM. An increase in the concentration of Tween 80 leads to the destruction of the inner water pool and to the formation of the surfactant-surfactant network inside the RM. The hydrogen bonding analyses show that the nature of the surfactant significantly affects the water-water hydrogen bonds distribution. Water in the Span 80 RM forms dense hydrogen bond network in the core and sparse network on the surface of the RM. Water-water hydrogen bonding in the core of Tween 80 RM is not as dense as it is in the Span 80 RM but the number of hydrogen bonds per molecule slightly decreases towards the surface of the RM. The density of water-water hydrogen bond network in the Tween 80/Span 80 mixed RM is higher in the core of the RM and slightly decreases towards the surface of the RM. Surfactant-surfactant hydrogen bonds predominantly form on the surface of the RM and are not observed in the core of the RM in all considered systems. Span 80 molecules forms a tall and narrow peak of the hydrogen bonds density on the surface of the RM. Tween 80 molecules form wide and dispersed hydrogen bond network due to the shape of Tween 80 headgroups. Hydrogen bond network in Tween 80/Span 80 mixed RM is extended but it is also dense. Hence, Tween 80 and Span 80 cover weak sides of each other and work together to build a mixed microemulsion. The investigation of the inner structure of small RMs does not directly answer the phenomenon of the coexistence of two types of aggregates with significant difference in size. The answer could be found by performing the coarse-grained simulation of large RMs. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: PGSTE NMR measurements; structure and topology files: SPAN80.gro, TWEEN80.gro, span80.itp, tween80.itp.



AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] ACKNOWLEDGMENTS This work was supported by the grant of Russian Science Foundation № 16-13-10042. We thank Dr. Vladimir Sizov (SPSU, St. Petersburg) for the help with calculations of the atomic charges. The NMR studies were performed at the Center for Magnetic Resonance, St. Petersburg State University. REFERENCES (1) Krauel, K.; Girvan, L.; Hook, S.; Rades, T. Characterisation of Colloidal Drug Delivery Systems from the Naked Eye to Cryo-FESEM. Micron 2007, 38, 796-803. (2) Podhorska, L.; Delcassian, D.; Goode, A. E.; Agyei, M.; McComb, D. W.; Ryan, M. P.; Dunlop, I. E. Mechanisms of Polymer-Templated Nanoparticle Synthesis: Contrasting Zns and Au. Langmuir 2016, 32, 9216-9222. (3) Quinlan, F. T.; Kuther, J.; Tremel, W.; Knoll, W.; Risbud, S.; Stroeve, P. Reverse Micelle Synthesis and Characterization of ZnSe Nanoparticles. Langmuir 2000, 16, 4049-4051. (4) Goncalves, V. S. S.; Gurikov, P.; Poejo, J.; Matias, A. A.; Heinrich, S.; Duarte, C. M. M.; Smirnova, I. Alginate-Based Hybrid Aerogel Microparticles for Mucosal Drug Delivery. Eur. J. Pharm. Biopharm. 2016, 107, 160-170. (5) Bulavchenko, A. I.; Deinidova, M. G.; Beketova, D. I. Preparation of Ultradispersed KNO3 Powders in Mixed Reverse Micelles of Tergitol NP-4+AOT by Isothermal Evaporation Crystallization. Cryst. Growth & Design 2013, 13, 485-490. (6) Bulavchenko, A. I.; Beketova, D. I.; Podlipskaya, T. Y.; Demidova, M. G. Composition and Size of Reverse Micelles of Tergitol NP-4 and Tergitol NP-4+AOT in NDecane During Evaporation Crystallization of KNO3. Cryst. Growth & Design 2014, 14, 11421148. (7) Rozner, S.; Popov, I.; Uvarov, V.; Aserin, A.; Garti, N. Templated Cocrystallization of Cholesterol and Phytosterols from Microemulsions. J. Cryst. Growth 2009, 311, 4022-4033. (8) Chatzidaki, M. D.; Papavasileiou, K. D.; Papadopoulos, M. G.; Xenakis, A. Reverse Micelles as Antioxidant Carriers: An Experimental and Molecular Dynamics Study. Langmuir 2017, 33, 5077-5085. (9) Vasudevan, M.; Wiencek, J. M. Mechanism of the Extraction of Proteins into Tween 85 Nonionic Microemulsions. Ind. Eng. Chem. Res. 1996, 35, 1085-1089. (10) Lin, B. J.; Chen, W. H.; Budzianowski, W. M.; Hsieh, C. T.; Lin, P. H. Emulsification Analysis of Bio-Oil and Diesel under Various Combinations of Emulsifiers. Appl. Energy 2016, 178, 746-757. (11) Flanagan, J.; Singh, H. Microemulsions: A Potential Delivery System for Bioactives in Food. Crit. Rev. Food Sci. Nutr. 2006, 46, 221-237. (12) Granata, G.; Pagnanelli, F.; Nishio-Hamane, D.; Sasaki, T. Effect of Surfactant/Water Ratio and Reagents' Concentration on Size Distribution of Manganese 18 ACS Paragon Plus Environment

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