Electrostatic Interactions and Osmotic Pressure of Counterions Control

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Electrostatic Interactions and Osmotic Pressure of Counterions Control the pH-Dependent Swelling and Collapse of Polyampholyte Microgels with Random Distribution of Ionizable Groups Ricarda Schroeder,§,‡ Andrey A. Rudov,⊥,§ L. Andrew Lyon,∥ Walter Richtering,# Andrij Pich,*,§,‡ and Igor I. Potemkin*,⊥,§ §

DWI−Leibniz Institute for Interactive Materials e.V., Aachen 52056, Germany Functional and Interactive Polymers, Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Aachen 52056, Germany ⊥ Physics Department, Lomonosov Moscow State University, Moscow 119991, Russian Federation ∥ Schmid College of Science and Technology, Chapman University, Orange, California 92866, United States # Institute of Physical Chemistry, RWTH Aachen University, Aachen 52056, Germany ‡

S Supporting Information *

ABSTRACT: In this work, different systems of colloidally stable, ampholytic microgels (μGs) based on poly(N-vinylcaprolactam) and poly(N-isopropylacrylamide), wherein the anionic and cationic groups are randomly distributed, were investigated. Fourier transmission infrared spectroscopy and transmission electron microscopy confirmed the quantitative incorporation and random distribution of ionizable groups in μGs, respectively. The control of hydrodynamic radii and mechanical properties of polyampholyte μGs at different pH values was studied with dynamic light scattering and in situ atomic force microscopy. We have proposed a model of pH-dependent polyampholyte μG, which correctly describes the experimental data and explains physical reasons for the swelling and collapse of the μG at different pHs. In the case of a balanced μG (equal numbers of cationic and anionic groups), the size as a function of pH has a symmetric, V-like shape. Swelling of purely cationic μG at low pH or purely anionic μG at high pH is due to electrostatic repulsion of similarly charged groups, which appears as a result of partial escape of counterions. Also, osmotically active counterions (the counterions that are trapped within the μG) contribute to the swelling of the μG. In contrast, electrostatic interactions are responsible for the collapse of the μG at intermediate pH when the numbers of anionic and cationic groups are equal (stoichiometric ratio). The multipole attraction of the charged groups is caused by thermodynamic fluctuations, similar to the those observed in Debye−Hückel plasma. We have demonstrated that the higher the fraction of cationic and anionic groups, the more pronounced the swelling and collapse of the μG at different pHs.

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aggregation. In contrast, collapsed μGs have smaller size as compared to swollen μGs and high polymer density because of effective attraction between monomer units. As a result, they have poor colloidal stability and can aggregate (precipitate). However, compared to macroscopic gels, μGs reveal much faster responses to stimuli, which are primarily controlled by their size. Water-soluble polyelectrolyte microgels23,24 represent a special class of soft particles that are considered to be excellent candidates for drug delivery carriers.14 In addition to neutral monomer units, they have charged groups, and counterions provide electric neutrality of the solution. However, counter-

INTRODUCTION Stimuli-responsive nano- and microgels (μGs) represent unique macromolecular objects, which are potentially useful for applications including biotechnology,1−8 drug delivery,9−15 semiconducting materials,16,17 sensor technology,18,19 and many others. It is believed that the internal structure of μGs resembles elements of macroscopic polymer networks: linear chains (subchains) are covalently linked with each other into a three-dimensional frame of size ranging between tens of nanometers and a few micrometers. As a result, μGs show some properties of macroscopic gels, like high elasticity as well as the ability to swell and collapse depending on the solvent quality and external stimuli20−22 (temperature, pH, etc.). Swollen μGs (good solvent conditions) are usually characterized by welldefined shape due to the swelling of each individual subchain, by low polymer volume fraction, and by high stability toward © XXXX American Chemical Society

Received: June 16, 2015 Revised: July 23, 2015

A

DOI: 10.1021/acs.macromol.5b01305 Macromolecules XXXX, XXX, XXX−XXX

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Macromolecules

Polyampholyte μGs have been synthesized by free-radical polymerization in emulsions21,46−49 or by precipitation polymerization.50−56 Ampholytic μGs were prepared by precipitation copolymerization of N-isopropylacrylamide (NIPAm) with acrylic acid and vinylimidazole.50−52,54 Kawaguchi and co-workers used acrylamide, methacrylic acid, and 2-(diethylamino)ethyl methacrylate to prepare polyampholyte μGs by semicontinuous precipitation polymerization in ethanol.55 Polyampholyte μGs with core−shell morphology were synthesized by two-step emulsion polymerization of 2(diethylamino)ethyl methacrylate and tert-butyl methacrylate.21 The acid hydrolysis of ester groups in tert-butyl methacrylate was carried out to generate the methacrylic acid moieties in μGs. Recently our group reported synthesis of polyampholyte μGs with core−shell distribution of ionizable groups. Synthesis of μGs was realized by copolymerization of N-vinylcaprolactam (VCL), itaconic acid dimethyl ester (IADME), and vinylimidazole (VIm) in the precipitation polymerization process.47 After hydrolysis of the ester groups of IADME, component μGs contained both acidic and basic groups in their structure. Due to the difference in monomer reactivity, itaconic acid groups and imidazole groups were localized in the core and corona, respectively. Some general trends in the synthesis of polyampholyte μGs by free-radical polymerization can be summarized as follows. To control the μG size, size distribution, and colloidal stability, surfactants are often used.21,46−48 The amount of the charged groups in the μGs can be controlled by varying the concentration of corresponding monomers in the reaction mixture50−52 or by postmodification reactions.21,47 However, precise control of the localization of ionizable groups of opposite charge in the μGs is difficult to achieve, and there is a limited amount of literature related to this topic. The aim of the current paper is a complementary experimental, theoretical, and computer simulation study of pH-controlled swelling and collapse of polyampholyte microgels where ionizable groups have homogeneous (random) distribution throughout the μG volume. Therefore, we optimize a synthetic method that allows flexible control of the amount of ionizable groups and ensures their random distribution inside of temperature-responsive μGs based on VCL and NIPAm. Itaconic acid and vinylimidazole are used as functional comonomers carrying negative and positive charges respectively in basic or acidic pH. We also manage to optimize the way that monodisperse colloidally stable μGs are synthesized in surfactant-free-conditions. They exhibit excellent colloidal stability in the whole pH range, which is unique among reported alternative μG systems. We develop a model of pHresponsive μG which correctly describes the experimental data for the pH-dependent swelling/deswelling of μGs with balanced (1:1) and unbalanced amounts of randomly distributed ionizable cationic and anionic groups and explains physical reasons for the observed behavior. Such model will serve as a basis for further studies of controlled uptake and release of polyelectrolytes by the polyampholyte microgels.

ions can violate the local electric neutrality of the μG (usually the case with monovalent counterions) and escape the network, moving to the outer solution for entropic reasons:24−26 the counterions try to occupy as large a volume as possible, which is opposed by electrostatic attraction to the corresponding coions of the μG. As a result, only some fraction of counterions is localized within the μG, whereas the others move freely between the μGs. This effect improves the colloidal stability of the system due to long-range electrostatic repulsion of similarly charged μGs (salt-free regime) and provides an opportunity to bind oppositely charged multivalent species27−29 (polyelectrolytes, particles, etc.) and form layer-by-layer assemblies.30 The oppositely charged species can be either absorbed or adsorbed on the surface, depending on the relative size of the μG’s subchain and bound objects. Such binding is usually accompanied by additional release of the counterions from the μG. The ultimate sign of the charge of the complex can be the same as that of the microgel (so-called undercharged μG) or the opposite (overcharged μG). The latter is a common effect valid for many oppositely charged objects. It is driven by physical reasons such as a release of counterions,29,31,32 gain in electrostatic energy,32−35 correlations in positions of charged units,36,37 and elasticity of macroions.29 Both under- and overcharged μGs are stable toward aggregation and can be used as delivery containers capable of releasing bound species as external conditions are changed. However, if the total charge of the μG complex is equal to zero (neutral or stoichiometric 1:1 complex), the complexes aggregate and precipitate.20−22 Such behavior is due to the duality of the electrostatic interactions. Short-range, fluctuation-induced attractions (similar to those in the Debye−Hückel plasma) dominate among oppositely and similarly charged units.38,39 Furthermore, this effect does not depend on the shape of macro-ions, and it is valid, for example, for rod-like macromolecules.40,41 Therefore, the presence of uncompensated charges in the complex is crucial for the delivery if additional routes of stabilization (like steric) are not used. In addition to the colloidal stability, the efficiency of delivery systems is determined by the time of loading and release of the charged species. Kinetics of binding of oppositely charged multivalent objects (like polyelectrolytes and microgels) is fast enough due to the strong long-range attraction of oppositely charged groups. On the other hand, in the case of pH-sensitive μGs, release of charged macromolecules upon variation of pH is hindered and proceeds via slow diffusion of the molecules into the outer solution. This process can be significantly accelerated if additional, preferably long-range microgel−polyelectrolyte repulsion can be induced. Such phenomena can be realized if we use polyampholyte μGs instead of polyelectrolyte ones. Polyampholyte μGs carry two types of ionizable groups, which can be switched “on” and “off” at different pH values. In other words, the μGs can be cationic at low pH and anionic at high pH. Thus, the release of loaded molecules from the μGs can be accelerated by similar (with respect to polyelectrolyte) charge of the subchains. Whereas polyelectrolyte μGs are well enough studied,23,24,42−45 the properties of polyampholyte μGs are less understood. The reasons for this are not only the complex internal structure of polyampholyte μGs and demanding analytical methods but also the complicated synthesis. It is a challenge to synthesize polyampholyte μGs with controlled size, narrow size distribution, high colloidal stability in aqueous phase, and controlled amount as well as localization of charges.

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EXPERIMENTAL SECTION

Materials. N-Vinylcaprolactam (VCL, 98%), itaconic acid (IA, ≥99%), 1-vinylimidazole (VIm, ≥99%), N-isopropylacrylamide (NIPAm, 97%), 2,2′-azobis[2-methylpropionamidine] dihydrochloride (AMPA, granular, 97%), and N,N′-methylene(bis)acrylamide (BIS, 99%) were purchased from Sigma-Aldrich. VCL and NIPAm were recrystallized from hexane and dried under vacuum before use. Water B


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Macromolecules Table 1. Reagents Used for the Synthesis of PVCL Microgels VIm:IA

VCL

mol:mol

BIS

IA

VIm

g

mmol

g

mmol

g

mmol

0:20 5:15 10:10 15:5 20:0 5:5 15:15 20:20 25:25

0.803 0.803 0.803 0.802 0.802 0.806 0.805 0.800 0.802

5.769 5.769 5.769 5.762 5.762 5.791 5.783 5.750 5.762

0.039 0.040 0.040 0.041 0.041 0.030 0.038 0.044 0.053

0.253 0.260 0.260 0.266 0.266 0.195 0.246 0.285 0.344

0.187 0.140 0.093 0.047

1.437 1.076 0.715 0.361

0.042 0.160 0.249 0.374

0.323 1.230 1.914 2.875

reference

0.803

5.769

0.024

0.156

g 0.034 0.068 0.101 0.135 0.030 0.116 0.180 0.270

AMPA mmol

g

mmol

0.361 0.723 1.073 1.434 0.319 1.233 1.913 2.869

0.031 0.030 0.031 0.031 0.031 0.030 0.041 0.047 0.051

0.114 0.111 0.114 0.114 0.114 0.111 0.153 0.173 0.188

0.030

0.111

Table 2. Reagents Used for the Synthesis of PNIPAm Microgels VIm:IA

NIPAm

BIS

IA

VIm

mol:mol

g

mmol

g

mmol

g

mmol

0:20 5:15 10:10 15:5 20:0

0.8 0.8 0.8 0.8 0.8

7.070 7.070 7.070 7.070 7.070

0.041 0.042 0.041 0.041 0.041

0.266 0.272 0.266 0.266 0.266

0.230 0.173 0.115 0.058

1.768 1.330 0.884 0.446

used in the experiments was purified using a Millipore water purification system with a minimum resistivity of 18 MΩ·cm. Microgel Synthesis. Microgels were synthesized via precipitation polymerization in aqueous media. Appropriate amounts (see Tables 1 and 2) of NIPAm or VCL, IA, VIm, and BIS were dissolved in 80 mL of water and heated to 70 °C while purging with N2 in a stirred roundbottom flask. After 1 h, the initiator was added and the reaction carried out for 5 h under constant stirring. After synthesis, μG solutions were dialyzed for 4 d using a composite regenerated cellulose membrane from Millipore (NMWCO 30 000). Microgel Characterization. To obtain information about the incorporated amount of functional comonomers into the μG network, Fourier transmission infrared (FTIR) measurements were performed on dried μG samples at a Bruker Alpha-P apparatus at room temperature. The freeze-dried μG sample was mixed with KBr powder and then pressed to form a transparent KBr pellet. For potentiometric and conductometric titrations, 50 mg of the dry μG sample was dissolved in water. The pH was adjusted to 3 with HCl. The titration was done with 0.1 M NaOH in 0.002-mL steps at room temperature with a Metrohm 665 autotitrator. The hydrodynamic radius RH and the electrophoretic mobility of the μG particles in 1 mM NaCl were measured using a Zetasizer NanoZS (Malvern, UK). Unless otherwise noted, measurements were taken at 20 °C after equilibrating the samples for at least 15 min. Temperature trends were measured in a temperature range from 15 to 50 °C in 3-deg steps. pH trends were measured from 3 to 10 in 0.5unit steps using 0.1 M HCl and NaOH, respectively. Before all measurements, the samples were filtered with a 1.2 μm PTFE filter. For the atomic force microscopy (AFM) analysis, μGs were deposited on glass substrates. Therefore, cleaned glass substrates were put in 1 vol% APTMS solution in absolut ethanol and shaken for 2 h. Afterward, the glass substrates were put in well-plates, and buffer solution of pH 3, 6.2, or 10 was added. After shaking for 30 min, the buffer solutions were replaced by the μG sample solution. The wellplates were centrifuged at 3700 rpm for 10 min at room temperature. The glass substrates were taken out, rinsed thoroughly with water, and dried with N2. AFM images were taken in liquid (in buffer solutions of pH 3, 6.2, or 10) on an Asylum Research MFP-3D microscope (Santa Barbara, CA) in AC mode. Cantilevers of silicon nitride were purchased from

g 0.042 0.083 0.125 0.166

AMPA mmol

g

mmol

0.446 0.882 1.328 1.764

0.03 0.03 0.03 0.03 0.03

0.111 0.111 0.111 0.111 0.111

NanoWorld (Neuchatel, Switzerland) with a force constant of 42 N/ m. The force mapping was done in contact mode.

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COMPUTER SIMULATIONS We performed molecular dynamics simulations of single polyampholyte microgel with statistical distribution of charges and implicit solvent molecules. The μG was designed as follows. Fully stretched subchains of an ideal μG (all subchains have equal length) were connected through tetrafunctional cross-links57 and repeated a unit cell of the diamond crystal lattice (zoom-in in Figure 1). Then, we constructed a cubic frame consisting of 3×3×3 unit cells of the diamond crystal lattice (Figure 1). To provide a “spherical” shape of the μG, we

Figure 1. Algorithm of microgel preparation in computer simulations. Fully stretched subchains form a unit cell of the diamond crystal lattice (zoom-in). A cubic supercell consisting of 3×3×3 unit cells is constructed. A sphere, which is inscribed into the cube, cuts out the microgel from the supercell. C


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Figure 2. FTIR spectra of polyampholyte microgels: (a) Monomer spectra for comparison. (b) Spectra of microgel samples with the monomer ratio of VCL:VIm:IA and NIPAm:VIm:IA = 79:10:11 and 87:6:7, respectively.

inscribed a sphere into the cube and “cropped” all monomer units that were outside the sphere. As a result, we obtained a μG containing both subchains and dangling chains. Each subchain consisted of N = 13 particles (beads); the total number of the beads (including cross-linkers) in the μG was Ntotal = 3425. Let us denote by φ+ and φ− fractions of positively and negatively charged monovalent groups in the μG, 0 < φ+, φ− < 0.5, so that the total numbers of the cations and anions are φ+Ntotal and φ−Ntotal. They are randomly distributed in the μG. The corresponding counterions provide overall electric neutrality of the system. Computer simulations were based on a coarse-grained model. Both charged and uncharged monomer units of the system were modeled as Lennard-Jones particles of the diameter σ and of the mass m. The interactions between any pair of the particles (beads) were described through the truncated-shifted Lennard-Jones potential,

counterion and counterion−counterion interactions was set to εLJ = 1kBT. Electrostatic interactions between any two charged particles of charge valences qi = ±1 and qj = ±1, separated by a distance rij, were given by the Coulomb potential, UCoul(rij) =

rij

The solvent was treated implicitly as a medium with the dielectric constant ε = 81. The strength of the electrostatic interactions was quantified by the Bjerrum length, lb = e2/εkBT, where e is the elementary charge. In water at room-temperature the Bjerrum length is about 7 Å. In our simulations, the value of this parameter was fixed, lb = 3σ, which provided negligibly small fraction of condensed counterions (ionic pairs). Connectivity of the beads into polymer chains was maintained by the finite extension nonlinear elastic (FENE) potential,

⎧ ⎪ FLJ(rij) − FLJ(rcut) if rij ≤ rcut FLJSF(rij) = ⎨ ⎪ 0 if rij > rcut ⎩

⎡ ⎛ rij ⎞2 ⎤ UFENE(rij) = −0.5kspringR 0 2 ln⎢1 − ⎜ ⎟ ⎥ ⎢⎣ ⎝ R 0 ⎠ ⎥⎦

⎧U (r ) − U (r ) if rij ≤ rcut LJ ij LJ cut ⎪ ⎪ ULJSF(rij) = ⎨ + (rij − rcut)FLJ(rij) ⎪ ⎪ 0 if rij > rcut ⎩

where kspring is a spring constant, kspring = 7kBT/σ2, and the maximum extent of the bond is R0 = 2σ. The simulations were performed using the open source software LAMMPS.60 The simulation cell was a cubic box of the size Lx = Ly = Lz = 200σ. The calculations were carried out in NVT ensemble with periodic boundary conditions. The electrostatic interactions between the charges were calculated by the PPPM summation method61 with the accuracy of 10−5. The constant temperature was maintained by coupling the system to the Langevin thermostat. At each time step, all the particles were subjected to the action of a random force. Their velocities lowered using a constant friction. The average magnitude of the random and the friction forces were related in such a way to obey to the “fluctuation-dissipation” theorem. The friction coefficient ξ was set to ξ = 0,1m/τLJ, where τLJ = σ(m/kBT)1/2 is the standard LJ time. The velocity-Verlet algorithm with a time step Δt = 0.01τLJ was used for integration of the equations of motion.

where ⎡⎛ ⎞12 ⎛ ⎞6 ⎤ σ σ ULJ(rij) = 4εLJ⎢⎢⎜⎜ ⎟⎟ − ⎜⎜ ⎟⎟ ⎥⎥ , r r ⎝ ij ⎠ ⎦ ⎣⎝ ij ⎠

kBTlbqiqj

′ (rij) FLJ(rij) = ULJ

rij is the distance between two interacting beads, and rcut is a cutoff radius. Similarly to the model reported recently58,59 we set the cutoff distance rcut = 2.5σ for monomer−monomer interactions, and rcut = 21/6σ for monomer−counterion and counterion−counterion pairwise interactions. The value of the Lennard-Jones interaction parameter was fixed for the monomer−monomer interactions, εLJ = 0.15 kBT, which corresponds to the case of good solvent quality. Here kB is the Boltzmann constant, and T is the absolute temperature. The value of the Lennard-Jones parameter for the monomer−

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RESULTS AND DISCUSSION Determination of Amount of Charged Groups in Microgel Particles. Poly(N-vinylcaprolactam) (PVCL) and D


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The amounts of ionizable groups obtained from analysis of the FTIR data are in good agreement with the values used during synthesis. The integration of large amount of ionizable groups (up to 22 mol%) is possible for both PVCL and PNIPAm μGs. The experimentally determined values will be used for sample naming in the following. Determination of Charge Distribution in Microgels. Samples were stained with uranyl acetate and analyzed via TEM microscopy to obtain information about the distribution of IA and VIm groups in the μG network. Uranyl acetate binds to the carboxylic groups in the μG network and enhances the contrast.68 Figure 3 shows the stained sample VCL:VIm:IA = 58:16:16. The close-up image shows clearly the uranyl acetate as black dots that are randomly distributed over the whole μG network.

poly(N-isopropylacrylamide) (PNIPAm) microgels with various ratios of ionizable groups have been synthesized by precipitation polymerization under surfactant-free conditions. FTIR spectroscopy, conductometric and potentiometric titration were used to analyze the chemical composition and amounts of incorporated imidazole and carboxylic acid groups. A typical FTIR spectrum of polyampholyte PVCL μG is shown in Figure 2b. The peak at 1722 cm−1, corresponding to CO stretching modes of itaconic acid,62,63 and at 1231 cm−1, corresponding to the ring vibration modes of 1-vinylimidazole,63 were used to identify the amount of charged groups in the μG particle by comparing them to the peak at 1654 cm−1 corresponding to the CO stretching of PVCL.65,66 In the case of PNIPAm μGs, the vibrational band at 1638 cm−1, corresponding to the CO stretching of PNIPAm,67 was considered. The peaks were compared to the monomer peaks (Figure 2a). Prominent peaks of VCL are at 2860 cm−1(C−Hstretching), 1654 cm−1 (amide I), 1487 cm−1 (C−Nstretching), and 1430 and 1407 cm−1 (C−Hdeformation bands). Peaks at 1657 cm−1 (amide I), 1548 cm−1 (amide II), and 1246 cm−1 (amide III) were assigned to NIPAm. Characteristic peaks for IA peak are at 3066 cm−1 (OHstretching), 1670 cm−1 (COstretching), 1515 cm−1 (CH3,symmetric deformation mode), 1361 cm−1 (C−O−Hin‑plane bending), and 1212 cm−1 (C−Ostretching). VIm shows peaks at 3106 cm−1 (CCH, NCHstretching), 1647 cm−1 (off-ring vinyl), 1498 cm−1 (CC, CNstretching), 1286 and 1224 cm−1 (C−H, C− Nring), 1075 cm−1 (CHin‑plane bending), and 652 cm−1 (ring torsion). By integration and setting them in proportion to each other, the amounts of incorporated groups into the microgel network could be calculated and compared to the amounts used during synthesis (see Tables 3 and 4).

Figure 3. TEM images of stained microgel sample with monomer ratio of VCL:VIm:IA = 58:16:16.

Electrophoretic Mobility and Hydrodynamic Radii of Microgels at Different pH Values. To study the behavior of μGs in aqueous solution dynamic light scattering (DLS) and electrophotetic mobility measurements were performed at 20 °C. At this temperature both PVCL and PNIPAm μGs with various amounts of VIm and IA groups are in swollen state below the volume phase transition temperature (VPTT) (see Figure S1, Supporting Information). The change of the electrophoretic mobility by varying the pH can further provide important information about surface charge and give some additional insights into charge distribution inside the particle (Figure 4). The isoelectric points (IEPs) for μGs with unbalanced ratio of ionizable groups are summarized in Table 5. For μGs with an unbalanced ratio of VIm:IA, it can be observed that with increasing amount of itaconic acid, the electrophoretic mobility is shifted to more negative values resulting in increasing values for the IEP (Table 5). An IEP can be observed for pure VIm μGs due to the presence of charge resulting from the initiator. Experimental data in Figure 4a indicate that PVCL and PNIPAm μGs show very symmetric behavior. Taking the sample with a ratio of VCL:VIm:IA = 82:4:14 as an example, the electrophoretic mobility is 0.25 and −0.89 μmcm/V·s at pH 3 and 10, respectively, indicating that the number of anionic groups present in the μGs is a factor of 3 larger than the number of positive charges. PNIPAm μGs exhibit lower electrophoretic mobility in the acidic region indicating that more IA and less VIm, respectively, are incorporated. For polyampholyte μGs with balanced ratio of ionizable groups, a change in EM is expected to be similar but differently pronounced in dependence on the amount of charged groups

Table 3. Amounts of Ionizable Groups in PVCL Microgels As Obtained from FTIRa VIm, mol%

IA, mol%

VCL, mol%

feed

FTIR

feed

FTIR

80 80 80 80 80 90 70 60 50

0 5 10 15 20 5 15 20 25

0 4 10 13 18 6 14 16 21

20 15 10 5 0 5 15 20 25

16 14 11 6 0 4 15 16 22

a

Uncertainties of each measurement due to errors in weighing and inhomogeneous mixing are read from the calibration curve and average to ±8%.

Table 4. Amounts of Ionizable Groups in PNIPAm Microgels As Obtained from FTIR VIm, mol%

IA, mol%

NIPAm, mol%

feed

FTIR

feed

FTIR

80 80 80 80 80

0 5 10 15 20

0 5 6 17 21

20 15 10 5

16 13 7 6

E


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Figure 4. Electrophoretic mobility of microgels with varying pH. (a) PVCL and PNIPAm microgels with unbalanced ratio of ionizable groups. (b) PVCL microgels with balanced ratio of ionizable groups.

Microgels that have both VIm and IA groups are swollen at both pH 3 and 10. Additionally, they show a minimum in particle size at their respective IEP. Notable is the good colloidal stability of the particles at this point. No aggregation was found for any of the samples for months of storage. To investigate the aggregation phenomena and colloidal stability for polyampholyte μGs at different pHs in more detail, sedimentation analysis was employed. In this method the μG dispersions are subjected to the centrifugal force and demixing process can be followed as a function of time. Weakly stabilized μGs form aggregates upon centrifugation and consequently the sedimentation velocity of weakly stabilized μGs is larger as compared to well-stabilized μGs in water. Based on this assumption the sedimentation velocity values determined with LUMiSizer at different pHs should provide information about colloidal stability of polyampholyte μGs. Figure 6 gives the different sedimentation velocities for μG samples with different compositions in different pHs. The PVCL μG exhibiling RH = 201.8 nm, PDI = 0.084 at 20 °C (reference sample, Table 1) synthesized without ionizable groups is well stabilized in water by steric mechanism and shows the lowest sedimentation velocity. The polyelectrolyte PVCL μGs prepared with itaconic acid or imidazole groups exhibit much higher sedimentation velocities at different pHs. Microgel sample with itaconic acid as the only charged monomer (VCL:VIm:IA = 84:0:16) shows the lowest sedimentation velocity at pH 10. Here, the colloidal stability is higher than at lower pH due to the negative charges of the itaconic acid. The opposite can be seen for the sample VCL:VIm:IA = 82:18:0. Here, the colloidal stability is highest at pH 3. From this we conclude that, for polyelectrolyte μGs, stronger charge leads to better colloidal stabilization effect. The sedimentation velocity values for three polyampholyte μGs presented in Figure 6 show remarkably different behavior compared to polyelectrolyte μGs with just acidic or basic ionizable groups. For the selected polyelectrolyte μGs, measurements were performed at pH 3 and different IEPs, and at pH 10. The samples with unequal amounts of VIm and IA exhibit the highest colloidal stability depending on which monomer predominates. For instance, the sample VCL:VIm:IA = 81:13:6 is more stable at pH 3 than at pH 10 due to the higher amount of positive charges that stabilize the particle. Microgel sample VCL:VIm:IA = 82:4:14 shows just the opposite trend. The polyampholyte μG with the monomer

Table 5. Isoelectric Points for PVCL and PNIPAm Microgels with Unbalanced Ratiso of Ionizable Groups IEP PVCL/PNIPAm:Vim:IA

PVCL

PNIPAm

84:0:16 82:4:14/82:5:13 79:10:11/87:6:7a 81:13:6/76:17:6 82:18:0/79:21:0

− 4.8 5.9 6.3 7.8 (initiator)

− 4.0 4.9 5.8 6.8 (initiator)

a

Same IEPs for VCL:Vim:IA = 90:6:4, 71:14:15, 58:16:16, and 52:21:22.

that are incorporated. Thus, the significant points such as the IEP and the minimum in particle size are expected not to change dramatically from sample to sample. Indeed it can be seen that all samples have an IEP of around 6.2, while the value of the EM is increasing with increasing amount of charged groups. The fact that the curves are very symmetric can be taken as an indication that the charges are distributed homogeneously inside the μG particle. If charges would only be located in the shell of the particles, the degree of swelling would be more pronounced than when the charges are located in the core of the particles. Charges in the loosely cross-linked shell lead to a stronger swelling than in the highly cross-linked core. It is expected that particles become smaller in size when positive and negative charges compensate each other at the IEP. At lower and higher pH, charges lead to a swelling of the particles due to the increased osmotic pressure induced by the diffusion of the counterions into μG network and due to electrostatic repulsion of non-compensated charged groups. Figure 5 shows the change of the hydrodynamic radius RH for μGs with various charge ratios at different pHs. The electrophoretic mobility is shown again for better comparison. The measurements show that μGs with only VIm as a comonomer swell at pH 3 and are collapsed at pH 10. The particle size of PVCL μGs with 21 mol% VIm decreases from 225 to 111 nm, PNIPAm μGs deswell from 198 to 154 nm. The opposite behavior can be observed for PVCL and PNIPAm μGs with 16 mol% IA. They are collapsed at pH 3 and swell at pH 10. PVCL μGs swell from 99 nm at pH 3 to 178 nm at pH 10, while PNIPAm μGs swell from 113 nm at pH 3 to 150 nm at pH 10. F


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Figure 5. pH dependence of electrophoretic mobility (circles) and hydrodynamic radius RH (squares) for microgels with variable amounts of ionizable groups (T = 20 °C).

The swelling behavior of all balanced PVCL μGs is shown in Figure 7. As expected, all samples have the same IEP at around

Figure 7. pH dependence of hydrodynamic radius for polyampholyte PVCL microgels with equal amounts of VIm and IA groups (T = 20 °C).

Figure 6. Sedimentation velocities of PVCL microgels with different charge distributions at various pH and 20 °C. The numbers on the xaxis give the ratio VCL:VIm:IA.

6.2, while their degree of swelling at pH 3 and 10 compared to their size in collapsed state at pH 6.2 is increasing with increasing amount of charged groups. For example when VIm and IA are present in μGs in roughly equal amounts (10:11). PVCL μGs swell around 77% at pH 3 (compared to their size at pH 6.2) and around 90% at pH 10 (compared to their size at pH 6.2). PNIPAm μGs swell around 71% at pH 3 (compared to their size at pH 6.2) and around 79% at pH 10 (compared to

ratio VCL:VIm:IA = 79:10:11 (balanced amount of charges) is equally stable at pH 3 and 10, but less stable at pH close to IEP. Therefore, from the experimental data presented in Figure 6, we can conclude that the colloidal stability of polyampholyte μGs with balanced or unbalanced amounts of ionizable groups is reduced considerably at the isoelectric point. G


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result. Though there is no real core−shell structure in investigated μG samples, both parts were analyzed separately and two values are given for the Young’s Modulus: for the “core” and the “shell”, respectively. Figure 9 shows the Young’s modulus for PVCL and PNIPAm particles for different pHs (3, 6.2, and 10). PVCL μGs show an unexpected behavior. The particles are stiffer at pH 3 and 10 while being softer at pH 6.2. Furthermore, at pH 3 and 10, strong differences in mechanical properties between the inner and the outer parts of one μG particle can be observed. On the other hand, PNIPAm μGs show expected behavior. The μG at pH 6.2 is about 8 times stiffer than at pH 3 or pH 10. The differences between inner and outer parts of one μG are less pronounced. This difference between PVCL and PNIPAm μGs between the center and the shell of the particles can be explained by looking at to which degree the particles spread on the glass substrate (Figure 10). Comparing both PVCL and PNIPAm, it is striking that PNIPAm μGs seem to be much softer due to higher spreading of the particle. PVCL μGs on the other hand are able to retain their shape better and are thus stiffer. The ratio between the length and the height of the particle is 2.3 for PVCL and 6.1 for PNIPAm particles indicating that PNIPAM particles are deformed thrice as much as PVCL particles. Thus, the difference between the outer and the inner parts of one particle is less pronounced for PNIPAm μGs. All sizes obtained from AFM measurements are shown in Figure 11. Here, both PVCL and PNIPAm particles are swollen at pH 3 and 10, while being in a collapsed state at pH 6.2. These data coincide with values obtained from DLS (Figure 5). Computer Simulation and Theoretical Results. In order to explain the swelling and the collapse of the polyampholyte μGs in aqueous solutions at different pH values, we address to computer simulations (see Computer Simulations for details) and theoretical estimates. After annealing of the μG depicted in Figure 1 under good solvent conditions, we get the structures shown in Figure 12. The snapshots differ by the fraction of cationic and anionic groups depicted by blue and red dots, respectively. Purely cationic and anionic μGs (Figure 12a,g) reveal swollen states. Their swelling is primarily controlled by charged groups and counterions rather than excluded volume effect (short-range repulsion of monomer units) like in neutral systems. If we deal with a small enough μG (small number of subchains) and dilute solution of them, most of the counterions leave the particle due to entropic reasons.24−26 In this case, long-range repulsion of bare (non-screened) charged monomer units is responsible for the μG swelling which is opposed by elasticity of the subchains. The linear swelling coefficient α, which is convenient to define as the ratio of the size of the swollen subchain to the size of the Gaussian subchain in thetasolvent (in contrast to the swelling ratio defined in Table 5), can be estimated as α ≈ n1/2(φ±)2/3p2/9(lB/σ)1/3, where n and p are the number of monomer units per subchain and the number of the subchains in the μG, respectively. In this regime, the swelling coefficient is mainly controlled by the length of the subchain, n, and by the fraction of the charged units, φ±. In the opposite limit of high number of the subchains, p ≫ 1 (microgels of a micron size), most of the counterions are localized inside the particle to compensate high electrostatic energy which overcomes the entropic penalty of the counterions caused by their localization. In this regime, the swelling occurs because of high exerting osmotic pressure of the

their size at pH 6.2). This is in agreement with FTIR measurements (Figure 2) where PVCL μGs have slightly higher incorporation of IA than VIm. PNIPAm μGs on the other hand have a lower incorporation of both IA and VIm which might explain the lower swelling degree than for PVCL μGs. For truly polyampholyte μGs, the difference in swelling between PVCL and PNIPAm μGs is not as pronounced as in μGs with only VIm or IA. Table 6 shows the swelling degree at different pHs for all samples. Table 6. Swelling Ratio of Polyampholyte PVCL Microgels at pH 3 and 10, Compared to the Minimum in Size at pH 6.2a VIm:IA mol:mol

RH(pH 3)3/RH(pH 6.2)3

RH(pH 10)3/RH(pH 6.2)3

6:4 10:11 14:15 16:16 21:22

4.1 5.5 7.6 7.3 20.9

4.3 6.9 6.9 8.3 19.3

a

Swelling ratios were calculated as follows: a = RH(pH 3)3/RH(pH 6.2)3 and b = RH(pH 10)3/RH(pH 6.2)3.

Apart from the sample with VIm:IA ratio of 16:16, the swelling ratio is steadily increasing and is quite similar for acidic and basic pH. Again, this can be considered as an additional indication that charges are homogeneously distributed in the microgel particle. The relatively low swelling degree of the sample with the ratio of VIm: IA 21:22 can be explained by the low amounts of both functional groups, that are only slightly higher than the sample with a ratio of VIm:IA 14:15 as detected by FTIR spectroscopy. Mechanical Properties of Microgels. AFM was used to obtain information about height and spreading of μGs adsorbed on a surface. In addition, we measured the force constants for μGs to determine the Young’s modulus (YM) and evaluate mechanical properties of μGs in swollen state at different pHs. For this, PVCL and PNIPAm μGs were deposited on a glass surface and measured in swollen state in buffer solution at pH 3, 6.2, or 10. While the particles are shrunken at pH 6.2 (i.e. at IEP), they are expected to be denser and thus stiffer. On the other hand, at pH 3 and 10, particles are swollen due to positive or negative charges and are thus expected to be softer. Figure 8 shows AFM images for PVCL and PNIPAm μGs samples with a VIm:IA ratio of 4:14 measured in a buffer at pH 3. The overview of AFM images in Figure 8a shows that at pH 3 PVCL μGs have a more homogeneous coating than PNIPAm μGs. This behavior could be observed for pH 6.2 and 10 as well (see Figure S3, Supporting Information). AFM images in Figure 7b show that PNIPAm μGs are smaller in size than PVCL μGs what is in a good agreement with DLS data. Furthermore, PNIPAm μGs seem to be more homogeneous in size than PVCL μGs. The mechanical properties of μGs can be evaluated by determining the force constants from AFM measurements (Figure 8d). The darker a spot in those images, the softer this spot is. White spots indicate the glass substrate. It can be seen for both particles that there are two different areas in a particle: while the shell seems to be soft (darker color), the core is stiffer (lighter color). This is not surprising since the μG is “thicker” in the middle and more polymer is “sensed” by indenting with the AFM cantilever at this point making the core stiffer. In addition, more cross-links in the μG core contribute to this H


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Figure 8. AFM studies for microgels with a VIm:IA ratio 4:14 measured at pH 3 and 20 °C (left, PVCL μGs; right, PNIPAm μGs). (a) Overview picture of microgel monolayer adsorbed on glass substrate. (b) Adsorbed microgels at higher magnification. (c) Cross sections from images (b) represented by a red line. (d) Force constants for microgels shown in (b). Force constant images are slightly shifted to the left compared to images in (b) due to adjustments between measurement modes.

counterions. The swelling coefficient is estimated as α ≈ (nφ±)1/2; i.e., it does not depend on the number of the subchains like in the case of macroscopic gels.24−26 The

crossover between the regimes occurs when the number of the subchains approaches a value p0 ≈ (φ±)−3/4(lB/σ)−3/2: the electrostatic and the osmotic regimes prevail at p < p0 and I


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Figure 9. Young’s modulus as measured with AFM for PVCL (a) and PNIPAm (b) microgels with VIm:IA ratio 4:14 at 20 °C. Error bars were determined by evaluating a representable number of data points in Figure 7. Note the different scales of the ordinates.

Figure 10. Sizes of PVCL and PNIPAm microgels on glass substrate and in water.

p > p0, respectively. In both cases α is proportional to the square root of the number of monomer units in the subchain, α ∼ n1/2, and the end-to-end distance of the subchain r is proportional to n, r ∼ n. Taking into account the space-filling condition for the μG of the radius R, R3 ∼ pr3, one can obtain that the radius of the swollen μG is also proportional to the contour length of the subchain n, R ∼ np1/3. Therefore, elongation of the subchain is a much more efficient way to increase the size of the swollen μG in comparison with the increase of the number of the subchains. It has to be mentioned that in the collapsed state of the μG (polymer volume fraction inside the μG, ϕ ≈ 1), both elongation of the subchains and increase of their number equivalently contribute to the size of the μG, R ∼ σ(np/ϕ)1/3. This estimate is a consequence of the space-filling condition, R3ϕ ∼ npσ3. With the increase of the fraction of anionic groups and decrease of φ+, the swelling degree of the polyampholyte μG decreases (Figure 12b,c) reaching minimum value at stoichiometric ratio (Figure 12d). Gradual decrease of α is related to

Figure 11. Particle radii for PVCL and PNIPAm microgels in buffer (pH 3, 6.2, or 10) as obtained from AFM measurements.

Figure 12. Equilibrium structures of the microgel depending on the fraction of positively (blue) and negatively (red) charged groups φ+ and φ−: (a) 20%−0%, (b) 16%−4%, (c) 12%−8%, (d) 10%−10%, (e) 8%−12%, (f) 4%−16%, and (g) 0%−20%. Counterions are not shown. J


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Macromolecules partial compensation of charged units: the total charge of monomer units of the μG goes down and becomes zero at the stoichiometric ratio. Most of counterions escape the μG because the oppositely charged monomer units play a role of “immobile” counterions. Therefore, the μG cannot swell neither due to electrostatics nor osmotic pressure of counterions. Furthermore, the μG becomes collapsed because of effective attraction among the charged monomer units (Figure 12d). This attraction has the same nature as that in plasma: thermodynamic fluctuations of charged species form virtual dipoles which induce multipole (dipole, quadropole, etc.) attraction.69 However, in contrast to the conventional, roomtemperature Debye−Hückel plasma, where attraction between the charges does not lead to their condensation due to the high mobility of the low-molecular-weight ions, polymers are known to be poor in entropy and the weak charge fluctuations result in their condensation (globule formation or precipitation). The presence of cross-links in the μG weakly impacts the collapse of each individual subchain, because it contains both cationic and anionic groups. Furthermore, the cross-links do not prohibit aggregation of neighbor subchains and density of the resulted interchain globulae is primarily determined by the fraction of charged groups rather than their sequence along the subchain. Therefore, the correlation free energy for interpolyelectrolyte 1:1 complex of linear chains can be used for the description of attraction between charged units in the μG,29,35 Fcoor/kBTV ≈ (φ±)3/2(lBϕ/σ5)3/4. Here, V is the volume of the μG. The attraction is opposed by excluded volume repulsion of monomer units. In the case of theta-solvent, it can be described within a virial expansion approach taking into account triple interactions of monomer units. The free energy per unit volume can be written as Fint/kBTV ≈ (Cϕ3/σ3), where the dimensionless third virial coefficient C ≈ 1. The equilibrium polymer volume fraction in the μG ϕ is calculated from the condition of equality of the osmotic pressure of the monomer units to zero,35 ϕ ≈ (φ±)2/3(lB/σ)1/3. Therefore, the higher the fraction of oppositely charged units in the μG at stoichiometric ratio, the denser the μG. This theoretical result is supported by computer simulations (see Figure 14). In order to propose a model for the effect of pH in computer simulations of the μGs with a balanced charge ratio, let us address to the experimental results on electrophoretic mobility of the PVCL μGs (Figure 4b). A linear fit of the curves seems to be a quite accurate. Velocity v of the μG is determined by a balance between the electrostatic force ∼QE applied to the particle, where Q and E are the total charge of the μG (without counterions) and intensity of the external field, respectively, and the friction force varies with v, so that the mobility v/E ∼ Q. Therefore, if the maximum of absolute values of the mobility is observed at pH 3 and 10 (Figure 4), where the μG is purely cationic or anionic, the Q−pH dependence should also have the linear form (Figure 13). The stoichiometric condition is achieved at pH 6.5, which is close to the experimental data (pH 6.2 in Figure 4b). The straights in Figure 13 allow calculating variation of the number of charged groups with pH: the number of the cationic groups decreases with pH linearly from the maximum value at pH 3 to 0 at pH 10, whereas the number of the anionic groups linearly increases from 0 at pH 3 to the maximum value at pH 10. Thus, in order to determine the size of the μG at certain pH, the number of charged units is calculated from Figure 13 (all charges have random distribution throughout the volume). The hydrodynamic radius of the μG

Figure 13. Total charge of the microgel, Q, as a function of pH for the balanced composition of cationic and anionic groups, φ+max−φ−max: (a) 5%−5% (black), (b) 10%−10% (red), and (c) 20%−20% (green).

as a function of pH is plotted in Figure 14. It has V-like shape with the minimum at equal numbers of cationic and anionic

Figure 14. Dependence of hydrodynamic radius of the microgel on pH for the balanced cases φ+max−φ−max: (a) 5%−5% (black), (b) 10%− 10% (red), and (c) 20%−20% (green). Blue squares and circles correspond to 30−30 and 40−40 compositions, respectively. Dashed line depicts hydrodynamic radius of the microgel where charged monomer units are substituted by neutral ones.

groups (1:1 μG). These curves clearly demonstrate duality of the electrostatic forces. Long-range repulsion of similarly charged monomer units (pH 3 and 10) together with osmotic pressure of counterions are responsible for the swelling of the μG in comparison with equivalent μG, where charged monomer units are substituted by neutral ones (dashed line in Figure 14). Short-range attraction of equal numbers of cations and anions leads to collapse of the μG. In both cases, the higher the number of charged groups, the more pronounced the swelling or collapse (Figure 14), which underlines the electrostatic character of the phenomenon. The curves in Figure 14 qualitatively repeat experimental observations summarized in Figure 7. The polymer volume fraction profiles in swollen, collapsed and intermediate states are shown in Figure 15. The average density of the μG in the swollen state (pH 3 and 10) is K


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Figure 15. Polymer volume fraction inside the microgel (yellow bar), fractions of positively (blue) and negatively (red) charged monomer units as functions of radial coordinate (a distance from the center of mass of the μG) at different ratios of φ+−φ− (pH in parentheses): (a) 20%−0% (3), (b) 16%−4% (4.4), (c) 12%−8% (5.8), (d) 10%−10% (6.5), (e) 8%−12% (7.2), (f) 4%−16% (8.6), and (g) 0%−20% (10).

approximately five times smaller than in the collapsed state at pH 6.5 which is also manifestation of the electrostatic attraction at stoichiometric conditions. Non-monotonic behavior of the density profile70 can be attributed to the finite size effect: the μG is cut from the 3×3×3 supercell with the center of mass being in the middle of the unit cell (diamond crystal lattice) (Figure 1). In other words, the center of mass and centers of another unit cells correspond to “empty” spaces of the μG particle before annealing. That is why the density profile has local minima in these places after annealing. The distribution of charged groups in the μG (blue and red curves in Figure 15) roughly repeats the distribution of monomer units. In the unbalanced case, when the maximum numbers of cations and anions are different, the linear plot for electrophoretic mobility (total charge of the μG) vs pH is quite acceptable as well (see Figure 5). Figures 16 compares the unbalanced 5%−15% μG with the balanced (10%−10%) and purely anionic (0%−20%) ones. One can see that the excess of anionic groups in the μG shifts the stoichiometric ratio (collapsed state) to lower pH values and makes the V-like RH− pH dependence asymmetric. These results are qualitatively consistent with the experimental data obtained for PVCL and PNIPAm μGs, see Figure 5.

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CONCLUSIONS We have synthesized polyampholyte microgels on the basis of poly(N-vinylcaprolactam) and poly(N-isopropylacrylamide) with random distribution of anionic and cationic groups. The main experimental result comprises reproducible one-step synthesis that allows obtaining monodisperse and colloidally stable μGs. The quantitative incorporation and statistical distribution of ionizable groups in μGs was achieved due to the comparable copolymerization parameters of functional monomers and was confirmed by FTIR spectroscopy and transmission electron microscopy. Our synthesis method allows flexible control over the chemical structure of polyampholyte μGs and variation of the ratio between ionizable groups in μGs as shown by electrophoretic mobility measurements. The hydrodynamic radii and mechanical properties of polyampholyte μGs at different pH values were experimentally determined by dynamic light scattering and in situ atomic force microscopy.

Figure 16. pH dependence of the hydrodynamic radius RH (black curve) and the total charge of the microgel (electrophoretic mobility, red curve) at different composition of charged groups: (a) purely anionic μG with maximum fraction of charged groups 20%; (b) unbalanced polyampholyte μG with maximum fractions of anionic and cationic groups 5% and 15%, respectively; and (c) balanced polyampholyte μG with 10% of anionic and cationic groups.

L


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Macromolecules We have proposed a model of pH-dependent μG that correctly describes the experimental data. In the case of balanced μGs (equal number of cationic and anionic groups), the size as a function of pH has a symmetric, V-like shape. Both, the swelling of purely cationic (pH 3) or anionic (pH 10) μG as well as collapse at stoichiometric 1:1 ratio (pH 6.5) are fully controlled by electrostatic interactions: the higher the fraction of cationic and anionic groups, the more pronounced the swelling and collapse. In the case of unbalanced μG (different numbers of cations and anions), the stoichiometric ratio can be shifted toward lower pH (excess of anions) or higher pH (lack of anions). Therefore, the pH value, which induces collapse of the polyampholyte μG, can finely be tuned via proper design of the primary structure. By a combination of experiment and theoretical calculations, we developed a model that allows precise description of the internal structure (polymer mass fraction, amount of charges) and pH-dependent swelling of aqueous microgels with variable amounts and ratios between ionizable groups.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.5b01305. Analysis of the dependence of μG size on temperature, and AFM images of μGs adsorbed on glass at pH 6.2 and 10 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Deutsche Forschungsgemeinschaft (DFG) within Collabolative Research Center SFB 985 “Functional Microgels and Microgel Systems” and the Russian Foundation for Basic Research within projects 13-03-00728 (I.I.P.) and 15-33-21151 (A.A.R.) is gratefully acknowledged. R.S. and A.P. thank the VolkswagenStiftung for financial support. Simulations were performed on multiteraflop supercomputers Lomonosov and Chebyshev at Moscow State University.

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Electrostatic Interactions and Osmotic Pressure of Counterions Control

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