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Hydrophobically Modified Responsive Polyelectrolytes† Tao Lu Lowe, Janne Virtanen, and Heikki Tenhu* Laboratory of Polymer Chemistry, University of Helsinki, P.O. Box 55, FIN-00014 Helsinki, Finland Received September 8, 1998. In Final Form: March 11, 1999 Thermally responsive latices composed of either linear or cross-linked copolymers, as well as macroscopic hydrogels, have been prepared by copolymerizing N-isopropylacrylamide (NIPAAM) with acidic monomers (methacrylic acid) and with nonsoluble hydrophobic monomers. The hydrophobic monomers include methyl methacrylate, as well as fluorinated methacrylates. The product polymers are polyelectrolytes showing thermal behavior typical of PNIPAAM. The dimensions of the latex particles have been studied by dynamic light scattering whereas the gels have been studied by swelling tests. The main topics of interest have been the effect of the chemical structure on the collapse of the polymers, on the one hand, and the effect of the topological structure of the network on the properties of the gels, on the other hand. It has been shown that the polyelectrolyte nature of the gels is to a certain degree dependent on the homogeneity of the network structure. Also, the binding of low molar mass substances into the polymers has been studied.
Introduction Poly(N-isopropylacrylamide) (PNIPAAM) is attracting interest in biomedical applications because it exhibits a well-defined lower critical solution temperature (LCST) in water around 32 °C, which is close to body temperature. PNIPAAM expands and swells when cooled below the LCST, and it shrinks and collapses when heated above the LCST.1 A further level of control of PNIPAAM properties arises from synthesis of PNIPAAM as latices, microgels, macroscopic gels, thin films, membranes, coatings, and fibers, as well as from the use of certain comonomers.1,2 When hydrophobic monomers are added into the PNIPAAM polymers, the critical temperature may be altered and hydrophobic domains may be induced. When ionic monomers are added into the polymer, PNIPAAM copolymer turns into a polyelectrolyte. The combination of both hydrophobic and ionic comonomers produces PNIPAAM-based hydrophobically modified polyelectrolytes. Through discovery of the right balance of hydrophobic and hydrophilic comonomers and adjustment of the number of electric charges in the chain as well as the degree of cross-linking, the structure and physical properties of PNIPAAM may be changed.3-12 The response of the polymer to physical or chemical stimuli, such as † Presented at Polyelectrolytes ’98, Inuyama, Japan, May 31June 3, 1998. * To whom correspondence should be addressed.
(1) Schild, H. G. Prog. Polym. Sci. 1992, 17, 163. (2) Laser Light Scattering in Biochemistry; Harding, S. E., Sattelle, D. B., Bloomfield, V. A., Eds.; The Royal Society of Chemistry: Cambridge, U.K., 1992. (3) Shibayama, M.; Tanaka, T.; Han, C. C. J. Chem. Phys. 1992, 97, 6842. (4) Yoshida, R.; Okuyama, Y.; Sakai, K.; Okano, T.; Sakurai, Y. J. Membr. Sci. 1994, 89, 267. (5) Yoshioka, H.; Mikami, M.; Mori, Y. J. Macromol. Sci., Pure Appl. Chem. 1994, A31, 121. (6) Brazel, C. S.; Peppas, N. A. Macromolecules 1995, 28, 8016. (7) Shibayama, M.; Mizutani, S. Y.; Nomura, S. Macromolecules 1996, 29, 2019. (8) Kawasaki, H.; Sasaki, S.; Maeda, H. J. Phys. Chem. B 1997, 101, 4184. (9) Lu, T.; Vesterinen, E.; Tenhu, H. Polymer 1998, 39, 641. (10) Lowe, T. L.; Tenhu, H. Macromolecules 1998, 31, 1590. (11) Lowe, T. L.; Benhaddou, M.; Tenhu, H. J. Polym. Sci., Part B: Polym. Phys. (in press). (12) Lowe, T. L.; Benhaddou, M.; Tenhu, H. Macromol. Chem. Phys. (in press).
temperature, pH, ionic strength, solvent composition, and electric fields may thus be regulated. Hence, these polymers can be expected to act as intelligent materials in controlled or targeted drug release,13-16 immobilization of enzymes and cells,17-19 separation of aqueous proteins,20,21 and water treatment.9,22 This paper describes the synthesis and properties of a series of monodisperse aqueous latices and macroscopic hydrogels based on N-isopropylacrylamide (NIPAAM). The copolymers were hydrophobically modified with methyl methacrylate (MMA) or with a fluorinated comonomer, either hexafluoroisopropyl methacrylate (HFIPMA) or 2,2,3,3,4,4-hexafluorobutyl methacrylate (HFBMA). Methacrylic acid (MAA) was also incorporated into some of the polymers. By dynamic light scattering (DLS), the temperature dependence of the hydrodynamic radii of latex particles consisting of either linear or cross-linked copolymers, as well as the binding of two drugs, ibuprofen and ephedrine, to the polymer latices, was investigated. Rheological properties of the latices were studied to determine the effect of the comonomers on the behavior of the partially fluorinated particles. Gels with a constant cross-link density were prepared, and they were allowed to swell in equilibrium in pure water and in aqueous salt solutions with varying ionic strengths. By swelling measurements, the effects of the chemical composition and, correspondingly, the homogeneity of the gels, the added salt, and the two drugs on the critical temperature (13) Kaneko, Y.; Yoshida, R.; Sakai, K.; Sakurai, Y.; Okano, T. J. Membr. Sci. 1995, 101, 13. (14) Lim, Y. H.; Kim, D.; Lee, D. S. J. Appl. Polym. Sci. 1997, 64, 2647. (15) Winnik, F. M.; Adronov, A.; Kitano, H. Can. J. Chem. 1995, 73, 2030. (16) Wu, X. S.; Hoffman, A. S.; Yager, P. J. Polym. Sci., Part A: Polym. Chem. 1992, 30, 2121. (17) Cicek, H.; Tuncel, A. J. Polym. Sci., Part A: Polym. Chem. 1998, 36, 543. (18) Koopmann, J.; Hocke, J.; Gabius, H.-J. Biol. Chem. Hoppe-Seyler 1993, 374, 1029. (19) Galaev, I. Y.; Mattiasson, B. Enzyme Microb. Technol. 1993, 15, 354. (20) Wu, J. Z.; Sassi, A. P.; Blanch, H. W.; Prausnitz, J. M. Polymer 1996, 37, 4803. (21) Kawaguchi, H.; Fujimoto, K.; Mizuhara, Y. Colloid Polym. Sci. 1992, 270, 53. (22) Lehto, J.; Vaaramaa, K.; Vesterinen, E.; Tenhu, H. J. Appl. Polym. Sci. 1998, 68, 355.
10.1021/la981194n CCC: $18.00 © 1999 American Chemical Society Published on Web 05/01/1999
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Table 1. Summary of the Conditions Used To Prepare Linear Copolymer Latices and Microgelsa component (mol ratio) sample
NIPAAM
LN LNMM LNI LNIM MGNIM LNB LNBM MGNBM
100 80 90 80 80 90 80 80
MMA
hydrophobic comonomer HFIPMA HFBMA
MAA
reaction time (h)
BA
yield (%)
4 15
5 10 15 15 10 15 15
5 5
5.6
5 5
5.6
4 4 4 4 4 4
87.5 80.8 87.7 82.8 92.4
a L: latex of linear polymer. MG: microgel particles. M: methyl methacrylate (MMA) or methacrylic acid (MAA). B: 2,2,3,3,4,4hexafluorobutyl methacrylate (HFBMA). N: N-isopropylacrylamide (NIPAAM). I: hexafluoroisopropyl methacrylate (HFIPMA). BA: N,N′methylenebisacrylamide.
Table 2. Summary of the Conditions Used To Prepare Hydrogels in Watera component (mol ratio) sample
NIPAAM
HGN HGNI HGNIM HGNB HGNBM
100 90 80 90 80
hydrophobic comonomer HFIPMA HFBMA 10 15 10 15
MAA
BA
reaction time (h)
yield (%)
5
4.9 5.4 5.6 5.4 5.6
4 4 4 4 4
79.8 80.2 88.0 87.2
5
a
N: N-isopropylacrylamide (NIPAAM). I: hexafluoroisopropyl methacrylate (HFIPMA). B: 2,2,3,3,4,4-hexafluorobutyl methacrylate (HFBMA). M: methacrylic acid (MAA). BA: N,N′-methylenebisacrylamide.
and the gel collapse were investigated. In addition, rheological measurements were conducted to study the elasticity of the gels. Experimental Section Materials. NIPAAM, purchased from Polysciences Inc., was purified by recrystallization in hexane. The comonomers, MMA (Fluka), HFIPMA (Polysciences), HFBMA (Polysciences), and MAA (Polysciences), were used without further purification, as were the initiator, potassium persulfate (KPS; Merck), crosslinker, N,N′-methylenebisacrylamide (BA; Serva), accelerator, N,N,N′,N′-tetramethylethylenediamine (TEMED; Aldrich) and surfactant, sodium dodecyl sulfate (SDS, Fluka). Low molar mass substances ephedrine and ibuprofen were from Sigma. Syntheses. (a) Syntheses of Polymer Latices. The latices composed of linear polymers, as well as the cross-linked latex particles, were prepared by emulsion polymerization with SDS as a surfactant and KPS as an initiator. The synthesis was carried out in a 1-L thermostated double-wall reactor fitted with a reflux condenser, a mechanical Teflon stirrer, and a nitrogen inlet/ outlet. A total of 3 g of monomers, either only NIPAAM or a mixture of NIPAAM, the hydrophobic comonomer MMA, HFIPMA, or HFBMA, and/or the hydrophilic comonomer MAA, was dissolved into 190 mL of deionized water together with SDS (0.2 g‚L-1). The solution was heated to 70 °C and stirred at 200 rpm for 30 min with a nitrogen purge to remove oxygen. Then, KPS (0.6 g‚L-1) dissolved in 10 mL of water was added to start the polymerization, and the reaction was carried out at 70 °C for 4 h. The synthesis method for the cross-linked particles was similar to that for the particles of linear polymer except that 1 g‚L-1 of cross-linker (BA) was added to the mixture of comonomers. After the copolymerization, the resulting products were purified by dialysis in cellulose tubings for 1 week. The polymers were dried at room temperature. The compositions and abbreviations for the polymers are shown in Table 1. (b) Syntheses of Hydrogels. The macroscopic hydrogels were prepared by radical polymerization in water at room temperature. The polymers were a cross-linked homopolymer of NIPAAM, as well as cross-linked PNIPAAM copolymers containing either HFIPMA or HFBMA as a hydrophobic monomer. Of five synthesized gels, two contained also MAA as a hydrophilic monomer. The homopolymer was polymerized in water, but the copolymers were prepared in aqueous solutions containing a few drops of ethanol. Monomer HFIPMA or HFBMA was first
dissolved in 2 mL of ethanol. In a 400 mL beaker, 3 g of the monomers and 0.2 g of cross-linker BA were dissolved into 20 mL of deionized water. The beaker was closed with Parafilm, and nitrogen was let into the solution through a syringe. After the solution was bubbled for 30 min, 0.12 g of KPS and 1 mol % TEMED with respect to monomers were added. The solution was bubbled for another 0.5 h, and then the syringe was removed. The polymerization was carried out for 4 h. The resulting gels were cut into disks with diameters of 14 mm and soaked in a mixture of ethanol and deionized water (50:50) for 1 day and in a 25:75 mixture for 6 h in order to remove all unreacted waterinsoluble compounds. The final wash was with deionized water for a period of 1 week. The gels were dried at room temperature. Table 2 summarizes the monomers used in the syntheses of various polymer networks, as well as the abbreviations used for the polymers. Polymer Characterization. (a) Dynamic Light Scattering. Dynamic light scattering measurements were conducted with a Brookhaven Instruments BI-200SM goniometer and a BI-9000AT multi-τ digital correlator with 522 time channels. The light source was a Spectra Physics 127 helium/neon laser (633 nm, 35 mW). Time-correlation functions were analyzed with a Laplace inversion program (CONTIN). The samples for dynamic light scattering were the pure aqueous latices, as well as the aqueous mixtures of LNMM and ibuprofen or ephedrine. The polymer concentration was 0.4 mg‚mL-1, except in the case of LNMM where the concentration was 0.08 mg‚mL-1. The concentration of ibuprofen or ephedrine was 0.04 mg‚mL-1, i.e., 50 wt % of the mass of the copolymer LNMM. The mixtures of the latex and the drugs were allowed to equilibrate at room temperature for 2 weeks before use. The intensity-intensity timecorrelation functions g2(t,q) in the self-beating mode were measured at the scattering angles 60° and 90° at temperatures ranging from 20 to 85 °C. At each temperature, the samples were allowed to equilibrate 20-60 min before the measurement. (b) Rheological Measurements. A Bohlin VOR rheometer with a concentric cylinder measuring geometry for the rheological measurements of the copolymer latices, LNI and LNIM, or a plate-plate PP 15 measuring head geometry for the macroscopic hydrogels was used. The viscosities of the copolymer latices were measured as functions of shear rate and temperature. The polymer concentration of the aqueous latices was 20 mg‚mL-1. The applied shear rates ranged from 0.232 to 5.81 s-1, and the measuring temperature was varied from 20 to 45 °C. The
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oscillation measurements were carried out for the hydrogels. The hydrogels were swollen with pure water and with a 0.01 M aqueous NaCl solution at room temperature. The polymer content of the gels was kept constant, 40 wt %. The frequency was initially fixed at 5 Hz, and the rheological parameters were measured as a function of the strain amplitude in order to find out the linear region where the complex modulus (G*) and the storage modulus (G′) were independent of applied strain at any frequency. The storage moduli (G′) of the gels were measured using a fixed strain (0.0015), with frequencies in the range 0.06-6 Hz at 20 °C. (c) Swelling Measurements. Dry cross-linked polymers were immersed in water and 0.01 and 0.1 M aqueous NaCl solutions, and allowed to swell in equilibrium at 10 °C. Then, temperature was stepwise increased up to 50 °C. Gel samples containing 30 wt % of ephedrine or ibuprofen were prepared by first dissolving the drugs in a few drops of ethanol and then adding the ethanol solutions to the dry polymers. After ethanol was evaporated in a vacuum, the polymers loaded with drugs were swollen in pure water, and the swelling ratios were measured against temperature. All of the samples were equilibrated at a certain fixed temperature for 1 day, removed from the solvent, and weighed quickly after being wiped with filter paper to remove excess water on the gel surface. The swelling ratio was defined as the mass of swollen gel per mass of dry polymer.
Results and Discussion In general, macroporous PNIPAAM hydrogels may be obtained by polymerization in water above the LCST. However, in the present study it has been observed that the topological structure of copolymeric PNIPAAM hydrogels can also be affected by the choice of the hydrophobic comonomers, even though the hydrogels are synthesized below the LCST. The surfaces of PNIPAAM gels containing hexafluoroisopropyl methacrylate, HGNI and HGNIM, are even, and the polymers are transparent, homogeneous in both dry and swollen states at room temperature. However, the surfaces of PNIPAAM gels containing hexafluorobutyl methacrylate, HGNB and HGNBM, are turbid and rough, and the swollen gels are opaque, heterogeneous. The difference in the homogeneity of the gels most probably is due to different solubilities of the hydrophobes which affect their spatial distribution in the network. The swelling ratios of the gels HGNI and HGNIM, both containing HFIPMA as a comonomer, are shown in Figure 1a against temperature. The swelling ratios have been measured in pure water and in aqueous NaCl solutions. Both gels behave as expected. The acidic gel HGNIM swells more than the neutral one although the difference is small. Addition of NaCl decreases the swelling, as well as the critical temperatures of both gels, and the swelling degree is dependent on the concentration of salt. These observations indicate that the salt not only screens the charges of the polyelectrolyte but also increases the tendency of the uncharged polymer chains to aggregate. Further, from the fairly small difference between the swelling ratios of the neutral and the acidic polymer, it may be concluded that the hydrophobic parts of the polymers are aggregated and hinder the swelling. The swelling ratios of the hydrogels containing HFBMA are shown against temperature in Figure 1b. Surprisingly, at T < LCST the nonionic gel swells more than the ionic one. In this case, the swelling of the neutral polymer is not affected by the addition of salt. It should also be noted that in pure water the degree of swelling of neutral HGNB is higher than that of the neutral polymer HGNI. The finding is important because it shows that the heterogeneity of the network affects not only the degree of swelling but also the polyelectrolytic nature of the polymer. In Figure 1b it may be seen that the addition of NaCl
Figure 1. Swelling ratios against temperature for the homogeneous HGNI and HGNIM hydrogels (a) and the heterogeneous HGNB and HGNBM hydrogels (b) in pure water and 0.01 and 0.1 M aqueous NaCl solutions.
decreases the critical temperature, but the effect is not as clear as in the case of HGNI and HGNIM. The elastic moduli G′ of the hydrogels, swollen in pure water and in 0.01 M aqueous NaCl solution at 20 °C, are shown in Figure 2a,b. The storage moduli are independent of frequency, as is expected for solidlike materials that do not flow. The elastic moduli G′ against frequency are shown in Figure 2a, for the hexafluoroisopropyl-substituted homogeneous gels. The storage modulus of the neutral gel HGNI swollen either in water or aqueous NaCl is on the order of 1 kPa. The modulus of the sample swollen in aqueous NaCl is slightly higher than the modulus of the gel in pure water. The difference may be due to the association of the chains upon addition of salt. The G′ of the acidic gel HGNIM is 500 kPa in pure water and decreases to 10 kPa when the polymer is swollen in the aqueous salt solution.
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Figure 3. Temperature dependence of the particle size of the latices of linear polymers: b, LN; 9, LNI; 0, LNIM; 2, LNB; 4, LNBM.
Figure 2. Storage modulus G′ against frequency for the gels HGNI and HGNIM (a) and the gels HGNB and HGNBM (b).
This indicates that HGNIM combines favorably the properties of polyelectrolytes and hydrophobically associating polymers. The high storage modulus evidently results from the association of the hexafluoroisopropyl side chains, as well as the extension of the charged polymer chains. The storage moduli of the heterogeneous gels partially substituted with hexafluorobutyl side chains are shown against frequency in Figure 2b. The properties of these gels differ totally from those shown in Figure 2a. G′ for a water-swollen neutral gel composed of NIPAAM and hexafluorobutyl methacrylate is of the order of 1 kPa and almost an order of magnitude less for a gel also containing methacrylic acid. The addition of salt decreases the G′ of the neutral gel but increases the G′ of the acidic gel. This type of behavior is due to the heterogeneity of the network structure, where a great number of the polymer chains are held in dense clusters distributed along the network. The results are in accordance with the observed swelling
behavior and indicate that the heterogeneous gels with fluorinated butyl substituents do not behave as might be expected for polyelectrolyte gels. Latex particles with chemical composition similar to that of the macroscopic gels have been prepared by emulsion polymerization. Figure 3 shows the temperature dependence of the average hydrodynamic radii of the latex particles composed of linear polymers, measured by dynamic light scattering. All of the samples in Figure 3 show a discontinuous volume transition with increasing temperature. The homopolymer LN undergoes a sharp change at 34 °C. At temperatures above the LCST (34 °C), LN is colloidally stable because of the electrostatic repulsive forces between the anionic charges of residual SDS on the surface of the particles. However, as will be shown below, the stability of the various polymer latices is affected not only by SDS but also by the chemical structure (i.e., the hydrophobicity) of the polymers. When hexafluoroisopropyl acrylamide, HFIPMA, is copolymerized with NIPAAM, the average hydrodynamic radius of the copolymer particles LNI is smaller than that of homopolymer LN at room temperature. When temperature is increased to 32 °C, LNI starts to coagulate, but the average hydrodynamic radius of LNI is still smaller than that of LN. However, above 34 °C the average radius of LNI is larger than that of LN because of extensive coagulation. This implies that the fluorocarbon side groups of HFIPMA increase the tendency of the polymer to form intra- and intermolecular associations to such an extent that the SDS molecules on the particle surface cannot totally prevent the particle-particle contacts. When hydrophilic methacrylic acid is copolymerized into the associating copolymer LNI, the average hydrodynamic radius of the product particles (LNIM) is larger than that of LNI at T e 35 °C and no coagulation takes place in the temperature range from 20 to 45 °C. This is a consequence of the electrostatic repulsion between the carboxylic groups. As is shown in Figure 3, the average hydrodynamic radius of LNB copolymer particles (NIPAAM and HFBMA) is larger than that of LN and LNI. This may be due to the larger size and flexibility of the partially fluorinated n-butyl side chains when compared to the protonated or
Hydrophobically Modified Responsive Polyelectrolytes
fluorinated isopropyl groups. Although the particles prepared in an emulsion probably differ in their structure from the gels synthesized in solution, it may be of interest to note that the effect of the hydrophobic comonomer on the particle size is similar to its effect on the swelling of the gel. The particles of LNBM (with methacrylic acid added) are larger than LNB particles at all studied temperatures, and in LNBM the decrease of the radius with temperature is more gradual than that in LNB. This again shows the effect of the carboxylic groups on the temperature-induced conformational changes of the polymer. In some cases shown in Figure 3, the values of the average radius scatter below the LCST. This may be due to a balance between hydrophobic and electrostatic forces but may also simply reflect changes in the shape of the size distribution function. Thermal behavior of the latice particles containing hexafluoroisopropyl substituents was studied also by measuring the dynamic viscosities of the latices at various temperatures. Figure 4a shows the shear rate dependence of the viscosity of aqueous LNI at temperatures between 20 and 40 °C. LNI shows shear thinning behavior at all temperatures. The viscosity drops considerably when the solution is heated above the room temperature, because of shrinking of the particles. At 30 °C e T e 40 °C, the viscosity increases gradually upon increasing temperature. This is in accordance with the observed coagulation of the LNI latex above 30 °C (Figure 3) caused by the high hydrophobicity of HFIPMA. The latex of the polymer LNIM which contains methacrylic acid has approximately the same viscosity at 20 °C as the latex LNI does. Also in this case, the viscosity suddenly drops with increasing temperature from 20 to 30 °C. The difference between LNIM and LNI can be seen at temperatures above 30 °C (cf. Figure 4b). LNIM does not coagulate and the viscosity decreases steadily with increasing temperature. Cross-linking of the latex particles was studied as a method to regulate their size. Addition of multifunctional monomers into the emulsion polymerization reaction results in the formation of microgel particles. Figure 5 shows the average hydrodynamic radii of the methacrylic acid containing latex particles composed of the linear copolymers, LNIM and LNBM, and those of the crosslinked copolymers, MGNIM and MGNBM, against temperature. Below the LCST the microgel particles are smaller than the particles consisting of linear copolymers. Cross-linking not only reduces the size of the particles but also rigidifies them. Thus, the linear polymers show a discontinuous volume transition, but the change in the size of the cross-linked particles is only moderate, and more gradual. When the volume changes of the macroscopic gels are compared with those of the nanoparticles prepared in emulsions, an interesting conclusion can be drawn. The volumes of the polyelectrolytic gel samples HGNIM and HGNBM decrease about 8-fold during the gel collapse, when the gels are heated from room temperature up to 45 °C (see Figure 1). The volume changes of the latex particles are of the same order of magnitude as the changes of the gels; the ratio of the volumes below and above the LCST varies between 6 and 10 depending on the fluorinated monomer. This demonstrates that the chemical composition, and consequently the topological structure of the polymer, determines the swelling degree, no matter whether the polymers are in the physical form of macroscopic gels or nanoparticles prepared in emulsions. The interactions of the polymers with low molar mass
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Figure 4. Viscosity versus shear rate for LNI (a) and LNIM (b) latices at various temperatures: [, 20 °C; 9, 30 °C; 2, 35 °C; ×, 40 °C.
compounds have been studied using both latices and macroscopic gels. The purpose has been to evaluate the applicability of the polymers in certain drug-delivery applications. Two low molar mass substances, ibuprofen and ephedrine, were chosen mainly because of their different solubilities in water. A hydrophobic drug, ibuprofen (2-(4-isobutylphenyl)propionic acid), is a weak acid only slightly soluble in water and is widely used for acute relief of pain and for treatment of chronic diseases such as rheumatoid arthritis and other rheumatoid conditions.23 Figure 6 shows the temperature dependence of the average hydrodynamic radii of the latex particles composed of NIPAAM, methyl methacrylate, and methacrylic acid (LNMM). The upper curve in Figure 6 is the radius of a pure particle in water. Below that, the radius of the particle containing ibuprofen, 50 wt % of the (23) Sen, S. E.; Anliker, K. S. J. Chem. Educ. 1996, 73, 569.
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Figure 5. Average hydrodynamic radii as a function of temperature in pure water for latices of linear polymers (0, LNIM; 4, LNBM) and microgel copolymers ([, MGNIM; *, MGNBM).
Figure 6. Hydrodynamic radii of the latex particles LNMM against temperature for the pure aqueous copolymer ([) and for the one containing 50 wt % added ibuprofen (0).
mass of the copolymer, is shown. Ibuprofen added to the aqueous latex dissolves in the polymer particles and decreases their dimensions below the LCST, as well as makes the volume transition of the copolymer sharp, occurring between 31 and 35 °C. A hydrophilic, weakly basic drug, ephedrine (β-hydroxyphenylethylamine), dissolves in water and is known as both R- and β-adrenergic agonists.24,25 The interaction of ephedrine with the latex particles has been studied by dynamic light scattering. When ephedrine is added into the aqueous copolymer latices, the normalized correlation functions g1(t) are bimodal with a constant relaxation time (24) Aturki, Z.; Fanali, S. J. Chromatogr. A 1994, 680, 137. (25) Sevcik, J.; Stransky, Z.; Ingelse, B. A.; Lemr, K. J. Pharm. Biomed. Anal. 1996, 14, 1089.
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Figure 7. Normalized correlation functions g1(t) measured at various temperatures for the LNMM latex with added ephedrine.
of the fast decay and the amplitude of the slow process increasing with increasing temperature at temperatures e35 °C, as shown in Figure 7. However, at temperatures above 35 °C, only one relaxation mode is apparent and the relaxation time starts to decrease with increasing temperature. The correlation functions of the pure aqueous copolymer latices are monomodal over the entire temperature range from 25 to 70 °C, and the relaxation time decreases with increasing temperature. The observations indicate that below the LCST ephedrine is bound to the acidic polymer particles because of acid-base interactions, resulting in the aggregation of the copolymer particles. However, above the LCST (T g 45 °C), the aggregates break down while the particles start to shrink and ephedrine is cleaved from the polymer to water. The process is reversible: when temperature is lowered to room temperature, the aggregates start to form. Kawasaki et al.26 have shown that carboxylic groups of a gel of NIPAAM and acrylic acid protonate upon the gel collapse; this may explain the observed release of ephedrine from the latex particles at T > LCST. The interaction of ibuprofen and ephedrine with various gels has been studied by swelling tests. The swelling ratios of the gels swollen in pure water are plotted against temperature in Figure 8 and compared with the swelling ratios of the samples containing ephedrine and ibuprofen. Below the LCST, ephedrine does not affect the swelling of the nonionic gels HGN, HGNI, and HGNB but decreases the swelling ratios of anionic gels HGNIM and HGNBM regardless of the differences in the homogeneity of the networks. When added into the acidic gels, ephedrine obviously binds to the polymer by interaction with the carboxylic groups. The binding of ephedrine thus reduces the repulsion between the negative charges of the chain, and the swelling ratio decreases. Polymers containing ibuprofen show very limited swelling in water, if any. Because of the hydrophobic interaction between ibuprofen and the polymers, the polymer chains are highly aggregated, thus preventing the diffusion of water into the gels. (26) Kawasaki, H.; Sasaki, S.; Maeda, H. J. Phys. Chem. B 1997, 101, 5089.
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Figure 8. Effect of ephedrine and ibuprofen on the swelling of the gels. Top curves: pure polymers. Middle curves: polymers containing ephedrine. Lowest curves: polymers containing ibuprofen.
To conclude, the noticeable effect of the choice of the hydrophobe on the properties of the gels and latices has been shown. The difference in the solubilities of the hydrophobes affects the homogeneity of the polymer networks, as well as that of the nanoparticles. Properties of the nanoparticles have been shown to resemble closely those of the macroscopic gels. An important finding has
been the effect of the network heterogeneity on the polyelectrolytic properties of the polymers. The application of the polymers in drug delivery is subject to further studies. LA981194N
