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Ind. Eng. Chem. Res. 2009, 48, 4844–4851
Synthesis of Monodisperse Glycerol Dimethacrylate-Based Microgel Particles by Precipitation Polymerization Berna Sarac¸ogˇlu,† Erdal Ug˘uzdog˘an,‡ C ¸ ig˘dem Go¨lgeliog˘lu,† and Ali Tuncel*,† Chemical Engineering Department, Hacettepe UniVersity, Ankara, Turkey, and Chemical Engineering Department, Pamukkale UniVersity, Ankara, Turkey
A new, single-stage precipitation polymerization was proposed for the synthesis of monodisperse crosslinked glycerol dimethacrylate (GDMA)-based microgel particles carrying hydroxyl and carboxyl functionalities, from nanometer to micrometer size range. The synthesis of monodisperse microgel spheres in the size range of 30-1500 nm was possible by the proposed method. In the polymerizations, glycerol dimethacrylate was copolymerized with methacrylic acid (MAA) in the medium containing toluene and acetonitrile without using a stabilizing agent. The effects of polymerization conditions on the final monomer conversion, polymerization kinetics, and MAA distribution in the microgel particles were investigated. The hydrodynamic size, the size distribution characteristics, and the mass charge density of microgel particles were also determined. Highly monodisperse and spherical microgel particles were obtained particularly with low GDMA feed concentrations. A marked increase in the hydrodynamic size was observed with the decreasing polarity (i.e., increasing toluene concentration) in the continuous medium. The distribution of MAA in the particles and the effect of pH on the swelling behavior in the aqueous medium indicated that the microgel particles contained a swellable shell and a nonswellable core. Most of the MAA charged was buried within the core part of the microgel particles. The swelling of microgel was controlled by the ionization of the carboxyl groups located on the shell layer. The swellable character, the presence of functional groups for surface derivatization, and the similarity of microgel to a biocompatible structure, poly(hydroxyethyl methacrylate), make the new microgel a promising material for biomedical applications. 1. Introduction Precipitation polymerization is a technique widely used for the preparation of monodisperse highly cross-linked polymer microspheres. Precipitation polymerization with acetonitrile as solvent was first proposed by Li and Stover for the preparation of highly cross-linked poly(divinylbenzene), poly(DVB), microspheres.1 A similar polymerization protocol for the production of monodisperse poly(DVB) microspheres was developed by El-Aasser et al. by using methanol or methanol-co-solvent mixtures.2 Poly(methacrylate-co-divinylbenzene), poly(divinylbenzene-co-maleic acid), and poly(chloromethyl-co-divinylbenzene) microspheres were also obtained by precipitation copolymerization of corresponding monomers.3-5 The precipitation copolymerizations of isobutyl maleate and 4,4-diphenylmethane diacrylate with DVB were successfully performed by Gawdzik and Maciejewska.6,7 The particle formation mechanism in the precipitation polymerization of DVB was investigated.8 The mechanistic studies of the precipitation copolymerization of styrene and DVB were also performed by Shim et al.9,10 Poly(DVB) particles were also used as a starting material for the preparation of methacrylic polymers and block copolymers tethered onto the particles by atom transfer radical polymerization.11 The precipitation polymerization was successfully utilized as a tool for the preparation of molecularly imprinted monodisperse polymer microspheres.12,13 Precipitation polymerization was also extensively used for the preparation of polymethacrylate-based copolymer microspheres. The mechanism of precipitation copolymerization of methacrylic acid and acrylamide in ethanol was investigated14 A relatively new * To whom correspondence should be addressed. Fax: +90-312299 21 24. E-mail:
[email protected]. † Hacettepe University. ‡ Pamukkale University.
method, the so-called distillation-precipitation polymerization, was developed for the production of highly cross-linked homopolymer or copolymer microspheres.15 Poly(DVB), poly(divinylbenzene-co-hydroxyethyl methacrylate), poly(ethylene glycol dimethacrylate), and poly(ethylene glycol dimethacrylateco-methacrylic acid) microspheres were obtained in the monodisperse form by using this technique.16-18 Until today, the precipitation polymerization studies were mostly focused on two relatively hydrophobic (i.e., apolar) crosslinking agents, DVB and ethylene glycol dimethacrylate. To the best of our knowledge, no report was found in the literature on the single-stage precipitation polymerization of relatively hydrophilic cross-linking agents. Only various two-stage precipitation polymerization methods were developed for the synthesis of core-shell microspheres with active hydroxyl groups by starting from DVB.11,16 In the present study, we proposed a single-stage precipitation method providing monodisperse cross-linked poly(glycerol dimethacrylate), poly(GDMA), microgel particles in the size range of 30-1500 nm. The chemical derivatization of poly(GDMA)-based microgel particles can be performed via their hydroxyl functionality, and the biochemical ligands can be covalently attached onto the particles. The ease of derivatization, the water swellability (i.e., hydrogel character), and the similarity of molecular structure to a biocompatible material, poly(2-hydroxyethyl methacrylate), make poly(GDMA) microspheres a promising material for various biotechnological and biomedical applications. Chromatographic separation of biomolecules, DNA diagnostic assays, drug targeting, and gene delivery are considered as some of the suitable potential areas where the poly(GDMA) microspheres can be evaluated as a sorbent or a microcarrier. Here, we wish to report the effect of polymerization conditions on the monomer conversion, average particle size, size distribution, and the surface charge of the poly(GDMA)-based microgel particles.
10.1021/ie801572w CCC: $40.75 2009 American Chemical Society Published on Web 04/15/2009
Ind. Eng. Chem. Res., Vol. 48, No. 10, 2009 Table 1. Experimental Conditions for the Precipitation Copolymerizations Including GDMA and MAA code
GDMA (mM)
MAA (mM)
toluene (% v/v)
AcN (% v/v)
GM1 GM2a GM3 GM4 GM5 GM6 GM3 GM7 GM8 GM9 GM10 GM11 GM12 GM13 GM3 GM14 GM15 GM16 GM17 GM7 GM18 GM19 GM20 GM21 GM2 GM22 GM23
32.1 48.2 96.3 192.5 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 96.3 48.2 48.2 48.2 48.2 48.2
18.2 27.2 27.2 27.2 0.0 9.1 27.2 72.6 136.0 27.2 27.2 27.2 27.2 27.2 27.2 27.2 27.2 72.6 72.6 72.6 72.6 72.6 27.2 27.2 27.2 27.2 27.2
74.9 74.9 74.9 74.9 74.9 74.9 74.9 74.9 74.9 0.0 10.0 25.1 50.0 61.5 74.9 87.7 93.8 61.5 70.0 74.9 80.0 84.6 61.5 70.0 74.9 80.0 84.6
25.1 25.1 25.1 25.1 25.1 25.1 25.1 25.1 25.1 100.0 90.0 74.9 50.0 38.5 25.1 12.3 6.2 38.5 30.0 25.1 20.0 15.4 38.5 30.0 25.1 20.0 15.4
a Polymerization temperature: 70 °C, polymerization time: 24 h, shaking rate: 120 cpm, AIBN: 2.5 mg/mL continuous medium unless otherwise stated (AIBN: 1.4 mg/mL continuous medium). Total volume of continuous medium: 65 mL. GDMA and MAA feed concentrations are defined on the basis of the continuous medium.
2. Experimental Section 2.1. Materials. The monomers glycerol dimethacrylate (GDMA) and methacrylic acid (MAA) were supplied from Aldrich Chemical Co. and used without further purification. The solvents, acetonitrile (AcN, HPLC grade), toluene, and absolute ethanol (EtOH), were also obtained from Aldrich Chemical. The initiator, 2,2′-azobisizobutyronitrile (AIBN), was supplied from BDH Chemicals Ltd. and recystallized from methanol before use. 2.2. Preparation and Characterization of Poly(GDMA)Based Hydrogel Microspheres. A typical precipitation polymerization procedure followed for the production of poly(GDMAco-MAA) microspheres is given below. GDMA (1.5 mL), MAA (0.15 mL), and AIBN (0.16 g) were dissolved in an AcN/T mixture (65 mL, AcN/T, 25.1/74.9 (v/v)) in a cylindrical Pyrex reactor. The polymerization was performed at 70 ( 0.5 °C for 24 h in a temperature-controlled water bath shaken at 120 cpm. For both poly(GDMA) and poly(GDMA-co-MAA) microspheres, the dispersions including particles larger than 250 nm were extensively washed with ethanol by applying a successive centrifugation-decantation procedure. The microgel particles were then washed with DDI water again by the centrifugation-decantation protocol and finally dispersed in distilled water. No significant amount of coagulum was detected in all precipitation polymerizations performed. No cleaning was applied for the poly(GDMA)-based microgel dispersions including particles with an average size smaller than 250 nm. The experimental conditions are summarized in Table 1. The microgel particles in the form of GDMA-MAA copolymer (poly(GDMA-coMAA)) were obtained by varying GDMA and MAA feed concentrations and the composition of the dispersion medium. In the first and second sets, GDMA and MAA feed concentrations were changed between 32.1-192.5 and 0-136 mM,
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respectively, in a dispersion medium containing 25.1/74.9 v/v AcN/toluene. In the other sets, the composition of the continuous medium (i.e., AcN/toluene volume ratio) was changed at constant GDMA and MAA feed concentrations. The final overall monomer conversion at a polymerization period of 24 h was determined by a gravimetric procedure. For this purpose, the inhibitor solution (2.5 mL, 5 mg of pbenzoquinone/mL of ethanol) was mixed with the polymerization medium (5 mL) in a Petri dish and the solvent was evaporated in a vacuum oven at 40 °C for 48 h. The dry weight of the solid residue was determined by an electronic balance with a precision of (0.001 g. The kinetic experiments were performed at 70 °C by changing the MAA feed concentration and AcN/toluene volume ratio in the polymerization medium for a reaction period of 5 h. The samples (1-2 mL) were periodically taken from the shaken reactor at different times, and the overall monomer conversions at different reaction periods were determined gravimetrically. A similar gravimetric procedure was also used to determine the soluble polymer content of the continuous medium. For this purpose, the particles were precipitated by centrifuging the polymerization mixture at 5000 rpm for 15 min and the supernatant was isolated. The soluble polymer content of the supernatant was found by the same method in terms of milligrams of solid residue per milliliter of supernatant. The percent of total monomer converted to the soluble polymer (% w/w) was calculated by using the soluble polymer content of the supernatant. The gravimetric procedure was also checked by including only unconverted monomers (i.e., GDMA and MAA) and the initiator (AIBN) in the AcN/toluene (25.1/74.9 v/v) mixture, and no significant amount of solid residue originating from the polymerization of monomers during the evaporation period was detected. The titratable acid content of the soluble polymer in the dispersion medium was determined by potentiometric titration. These determinations were only performed for the polymerization runs at which the MAA feed concentration was changed. In this set, the final overall monomer conversion values were higher than 96% w/w. For this reason, the titratable acid content of the soluble polymer in the continuous medium was assumed to be equal to that of the continuous medium by ignoring the contribution coming from unconverted MAA. The supernatant (2.5 mL) obtained by centrifuging the polymerization medium was mixed with distilled water (20 mL), and an excess amount of ethanol was added to obtain a homogeneous solution. The potentiometric titration of the resulting mixture was performed with 0.05 N NaOH solution. The titratable acid content of soluble polymer was expressed in terms of millimoles MAA per gram of polymer. The hydrodynamic size of poly(GDMA)-based microgel particles larger than 250 nm was measured in an aqueous medium at pH 7, at room temperature by dynamic light scattering (DLS) (NanoS, Malvern Instruments). DLS was applied with an angle of 170° by using a He-Ne laser (4 mW) operated at 633 nm.19 The polydispersity index (PDI) values for size distribution in aqueous medium were directly obtained from the software of hydrodynamic size distribution analysis in a NanoS system. The DLS measurements in the aqueous medium were also performed at different pH values between 2 and 10. The pH of latex was adjusted by aqueous HCl or NaOH solution to a prescribed value. Hydrodynamic size measurements of microgel particles smaller than 250 nm were performed within their polymerization media without applying any additional cleaning protocol.
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Ind. Eng. Chem. Res., Vol. 48, No. 10, 2009 Table 2. GDMA Feed Concentration on the Final Monomer Conversion, Conversions to Soluble Polymer and Microgel, and the Size Properties of Poly(GDMA-co-MAA) Microgel Particles
Figure 1. Molecular formula of glycerol dimethacrylate.
Poly(GDMA)-based microspheres were imaged in dry state by scanning electron microscope (Carl Zeiss, Inc.). For this purpose, poly(GDMA) dispersion was dropped onto a copper grid and dried at room temperature. The dried particles were then imaged with 10 000-25 000× magnification (mostly 15 000×), depending upon the average bead size. The diameters of individual beads were measured by a ruler on each photograph printed on an A4 page. All beads in each photo (mostly 200-400 beads) were measured and counted. The number average diameter of microgel particles (Dn) was calculated according to eq 1 by considering the length of scale bar on each photo, where Ni is the number of beads in a diameter of Di (in nanometers). The coefficient of variation for size distribution (CV) is calculated according to eq 2 where SD is the standard deviation for bead size (in nanometers).
∑ND /∑N
i
(1)
CV ) (SD/Dn) × 100
(2)
Dn )
i
i
code
CGDMA XT XSP XMP DH (mM) (% w/w) (% w/w) (% w/w) (nm)
PDI
GM1 GM2 GM3 GM4
32.1 48.2 96.3 192.5
0.020 563 MDb 0.024 769 MD 0.058 1028 6.3 0.240 609 15.3
86.1 97.9 QCa QC
36.8 10.7 11.8 6.0
49.3 87.2 88.2 94.0
647 825 1082 685
DD CV (nm) (%)
a QC: Quantitative conversion (final overall monomer conversion was determined as a value consistent with 100% w/w with a maximum deviation of (1% w/w). b MD: Monodisperse microgel particles (CV < 1.0%).
The carboxyl content of microgel particles was determined by potentiometric titration after applying the cleaning procedure described above. 3. Results and Discussion A new precipitation polymerization for the synthesis of monodisperse cross-linked poly(GDMA)-based microgel particles ranging between ca. 30 and 1500 nm in size was developed. In this method, poly(GDMA)-based microgel particles were obtained by a thermally initiated polymerization performed in a medium containing acetonitrile and toluene without using a stabilizer. The molecular structure of GDMA is given in Figure 1. As seen here, GDMA was obtained in the form of an isomer mixture. For this reason, the molar ratio of hydroxyl/methacrylate was determined as 0.258 by 1H NMR. 3.1. GDMA Feed Concentration. A set of polymerizations was performed to investigate the effect of GDMA feed concentration on the microgel size. Here, MAA was included as a comonomer and its feed concentration was fixed to 27.2 mM. A solvent mixture containing 25.1% ACN and 74.9% toluene was used as continuous medium. The polymerizations were performed at 70 °C for 24 h with the initiator concentration of 0.25% w/w. The effects of GDMA feed concentration on the final overall monomer conversion, conversion to microgel particles, and conversion to soluble polymer are given in Table 2. As seen here, the final overall monomer conversion increased and the conversion to the soluble polymer decreased with increasing GDMA feed concentration. Note that no significant amount of coagulum was observed in all polymerizations. For this reason, the difference between final overall monomer conversion and conversion to soluble polymer in the continuous medium was evaluated as the conversion of total monomer to the microgel particles. The results indicated that the yield of microgel particles increased with increasing GDMA feed concentration. SEM photographs of microgel particles obtained with different GDMA feed concentrations are given in Figure 2. As seen here, spherical and highly monodisperse microgel particles were obtained with lower GDMA feed concentrations (i.e., 32.1
Figure 2. SEM photographs of poly(GDMA-co-MAA) microgel particles obtained with different GDMA feed concentrations. Polymerization conditions: AcN/toluene volume ratio: 25.1/74.9 v/v. MAA feed concentration: 27.2 mM, temperature: 70 °C, polymerization time: 24 h. GDMA feed concentration based on dispersion medium (mM): (A) 32.1, (B) 48.2, (C) 96.3, (D) 192.5. AIBN concentration: 2.5 mg/mL for 48.2, 96.3, and 192.5 mM and 1.4 mg/mL for 32.1 mM of GDMA concentration.
and 48.2 mM). The GDMA feed concentration of 96.3 mM gave nonspherical particles with relatively broader size distribution (Figure 2C). The average size decreased, and the size distribution became broader with the highest GDMA feed concentration (Figure 2D). Note that the average microgel size was measured both by DLS in the aqueous medium at pH 7 and by SEM in the dry state. The effects of GDMA feed concentration on the size properties of poly(GDMA-co-MAA) microgel particles are given in Table 2. As seen here, slightly higher hydrodynamic size values were obtained in the aqueous medium with respect to the dry average diameters calculated from SEM photos. The difference between hydrodynamic size and dry average diameter values indicated limited swelling for the microgels synthesized with different GDMA feed concentrations. Note that the polydispersity index values showing the size distribution in the aqueous media obtained from DLS were reasonably consistent with the CV values calculated from SEM photos. The results in Table 2 also indicated that the hydrodynamic size increased with increasing GDMA feed concentration up to 96.3 mM. Note that the size increase was observed both by DLS for the swollen particles within the aqueous medium at pH 7 (Table 2) and by SEM for the dried microgel particles (Figure 2). In the precipitation polymerization of DVB, the average particle size also increased with increasing DVB feed concentration and is explained by the change in the solvency of the medium resulting from increased amount of monomer.9,15,20 However, the low-sized particles with relatively broader size distribution obtained with the highest GDMA concentration (i.e., 192.5 mM) did not obey this tendency.
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Table 3. Effect of MAA Feed Concentration on the Initial and Final pH of the Polymerization Medium, Final Monomer Conversion, and Conversion to Microgel Particles code
CMAA (mM)
initial pH
final pH
XT (% w/w)
XMP (% w/w)
GM5 GM6 GM3 GM7 GM8
0 9.1 27.2 72.6 136.0
9.6 7.2 6.3 5.7 5.3
7.8 6.1 5.0 3.7 3.1
98.3 96.7 98.8 QCa QC
84.3 83.5 87.0 90.4 94.0
a QC: Quantitative conversion (final overall monomer conversion was determined as a value consistent with 100% w/w with a maximum deviation of (1% w/w).
Figure 4. Effect of MAA feed concentration on the soluble polymer in the continuous medium and the titratable acid content of the soluble polymer. Polymerization conditions are given in Figure 3.
Figure 3. SEM photographs of poly(GDMA-co-MAA) microgels synthesized with different MAA feed concentrations (MAA feed concentration (mM): (A) 0, (B) 27.2, (C) 72.6, (D) 136) and poly(GDMA-co-DMAEM) microgel (E) synthesized with the DMAEM feed concentration of 41.1 mM. Polymerization conditions: AcN/toluene volume ratio: 24.9/75.1 v/v, GDMA feed concentration: 96.3 mM, AIBN concentration: 2.5 mg/mL, temperature: 70 °C, polymerization time: 24 h.
3.2. MAA Feed Concentration. In a separate set of polymerization runs, the effects of MAA feed concentration on the behavior of the precipitation polymerization and the properties of microgel were investigated. The effects of MAA feed concentration on the initial and final pH of the polymerization medium and the final overall monomer conversion are given in Table 3. As expected, pH both before and after polymerization decreased with increasing MAA feed concentration. On the other hand, relatively lower pH values were obtained after polymerization with respect to the initial pH values. The pH decrease by polymerization should be attributed to the better ionization of carboxyl groups of soluble polymer and microgel particles in the final medium obtained by the complete consumption of GDMA. As seen in Table 3, no significant effect of MAA feed concentration on the final overall monomer conversion was observed. However, the conversion into the microgel particles slightly increased with increasing MAA feed concentration. The SEM photographs of poly(GDMA-co-MAA) microgel particles synthesized with different MAA concentrations are shown in Figure 3. The average sizes of poly(GDMA-co-MAA) microgel particles synthesized with the MAA feed concentrations of 27.2, 72.6, and 136 mM were determined as 1028, 1216, and 1247 nm, respectively, by SEM in the dry state. Hence, an increase in the average size was also observed with increasing MAA content for the dry particles. As seen in Figure 3, the particles in the nonspherical form were mostly obtained because of the use of relatively high GDMA feed concentration (i.e., 96.3 mM). However, the concentration of irregular-combined particles was higher in the precipitation polymerization of GDMA performed without using MAA as comonomer. A
decrease in the circularity of final particles with the increasing cross-linking agent concentration was also reported for the dispersion copolymerization of styrene and DVB and explained by the coagulation of fewer particles owing to the improved stability of individual particles at low monomer concentration.9 In our case, the decrease in the number density of irregularcombined particles in the presence of MAA should be attributed to the better stabilization of individual particles by the charged carboxyl groups coming from MAA units. In the precipitation polymerization runs, a cationic monomer, 2-dimethylaminoethyl methacrylate (DMAEM), was also used instead of MAA. A representative SEM photo of poly(GDMAco-DMAEM) microgel spheres is given in Figure 3E. As seen here, cationic poly(GDMA-co-DMAEM) microspheres with some irregularities were obtained with narrow size distribution. The hydrodynamic size at pH 7 by DLS and the dry particle size by SEM were determined as 1484 and 1363 nm, respectively. This run indicated that the precipitation polymerization of GDMA can be also used for the synthesis of cross-linked hydrogel spheres with different functionalities by changing the type of comonomer. The effect of MAA feed concentration on the conversion of total monomer into the soluble form is presented in Figure 4. The variation of titratable acid content of soluble polymer with the MAA feed concentration is also given in the same figure. As seen here, the conversion of monomer into the soluble polymer almost linearly decreased with the increasing MAA feed concentration. Then, the microgel yield increased since the final monomer conversion was almost constant (Table 3). In other words, the reactivity for particle formation increased under more acidic conditions. On the other hand, similar to the particles, the titratable acid content of soluble polymer increased with the increasing MAA feed concentration (Figure 4). The effect of MAA feed concentration on the distribution of MAA after polymerization is given in Table 4. Here, the weight percent values of MAA are given on the basis of the amount of MAA initially charged to the reactor. In Table 4, MAA buried in the particles was calculated by difference. For all polymerizations, most of the MAA initially charged is buried within the particles and is not available in the titration performed in the aqueous medium. One can conclude that there is a relatively hydrophobic, nonswellable core not allowing the diffusion of water molecules (also the hydroxyl ions in the titration) in the microgel particles. The percent of MAA in the nonswellable core exhibited an increase with the increasing MAA feed concentration. Oppositely, the weight percent of MAA located
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Table 4. Distribution of MAA in the Precipitation Copolymerization of GDMA and MAA as Weight Percent of MAA Initially Charged MAA in the MAA on the MAA feed soluble polymer particles found MAA buried concentration found by by titration in the particles code (mM) titration (% w/w) (% w/w) (% w/w) GM6 GM3 GM7 GM8
9.1 27.2 72.6 136.0
11.4 18.0 12.2 11.4
17.5 (0.069)a 9.9 (0.108) 8.2 (0.206) 8.1 (0.314)
71.1 (0.290)a 72.1 (0.801) 79.6 (2.107) 80.5 (2.980)
a The values in the parentheses show the MAA contents of microgels in terms of millimoles MAA per grams of microgel particles.
Figure 7. Schematical representation of conceptual model describing the core-shell structure of poly(GDMA-co-MAA) microgel particles synthesized with the MAA feed concentrations of 72.6 and 136 mM.
Figure 5. Effect of MAA mole percent in feed on the hydrodynamic size and the surface MAA content of poly(GDMA-co-MAA) microgel particles.
Figure 6. Effect of pH on the hydrodynamic size of poly(GDMA-co-MAA) microgels synthesized with different MAA feed concentrations. Polymerization conditions are given in Figure 3.
in the surface layer (i.e., determined by aqueous titration) exhibited higher values with the lower MAA feed concentrations. However, a clear increase was observed in the MAA content of surface layer when it was expressed as millimoles MAA per gram of microgel particles (Table 4, fourth column). The effect of mole percent of MAA in feed on the surface MAA content of poly(GDMA-co-MAA) particles is sketched in Figure 5 together with the hydrodynamic size values determined at pH 7. As seen here, both the surface MAA content and the hydrodynamic size of microgel almost linearly increased with increasing MAA feed concentration in the aqueous medium at pH 7. The behavior in Figure 5 may be attributed to the fact that the swelling is related to the ionization of carboxyl groups located on the surface layer of microgel particles. The stimuli-responsive behavior of poly(GDMA-co-MAA) microspheres is shown in Figure 6. Here, the variation of hydrodynamic diameter with pH is shown for the poly(GDMAco-MAA) microspheres obtained with different MAA feed concentrations. No significant change was observed in the
average size for the poly(GDMA) microspheres synthesized without using MAA. The effect of pH on the hydrodynamic size became more appreciable with increasing MAA feed concentration. As expected, the most appreciable size increase was observed for the poly(GDMA-co-MAA) microspheres synthesized with the highest MAA feed concentration (i.e., 136 mM). The hydrodynamic size values in Figure 6 indicated that appreciable swelling was observed with the particles synthesized with MAA feed concentrations of 72.6 and 136 mM. By considering the distribution of MAA in the microgel particles given in Table 4 and the behavior observed in Figure 6, the conceptual model described in Figure 7 was proposed for the structure of poly(MAA-co-GDMA) microgel particles synthesized with the MAA feed concentrations of 72.6 and 136 mM. As seen here, the microgel particles synthesized with relatively high MAA feed concentrations should probably have a highly cross-linked, nonswellable core and a loosely cross-linked (MAA-rich) swellable surface layer. At the basic pH, the hydrodynamic size increase should probably occur due to the ionization of MAA units located in the shell layer. In other words, the radial thickness of the surface layer gradually increases by the diffusion of water into this region while no significant size change occurred in the highly cross-linked core not allowing the diffusion of water molecules. Although the concentration of titratable MAA units based on the weight of microgel particles seemed relatively low in Table 4, the local concentration of MAA on the surface layer should be higher with respect to the core region for obtaining an efficient swelling in the surface region of the microgel particles. The effect of MAA feed concentration on the polymerization kinetics is shown in Figure 8. In this plot, the zero polymerization time was defined as the time at which the reactor temperature reached the prescribed value (i.e., 70 °C). As seen in Figure 8, the monomer conversion at zero reaction time was higher than 40% w/w in all runs, due to the polymerization taking place during the heating period of the reactor. The polymerization rate in the initial polymerization period was only slightly higher in the absence of MAA. As shown in Figure 3, the average size in the dried form was determined as 1051 nm for the particles synthesized in the absence of MAA. The particle size values obtained with the other MAA feed concentrations were also reasonably close to this value (Figure 3). On the basis of this result, no significant change in the polymerization rate
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Figure 8. Variation of overall monomer conversion with time in the precipitation polymerizations performed with different MAA feed concentrations. Polymerization conditions: MAA concentration: variable, AcN/ toluene volume ratio: 24.9/75.1 v/v, GDMA feed concentration: 96.3 mM, AIBN concentration: 2.5 mg/mL, temperature: 70 °C, polymerization time: 5 h.
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Figure 9. SEM photographs of poly(GDMA-co-MAA) particles obtained with different toluene concentrations. Toluene concentration (% v/v): (A) 61.5, (B) 70.0, (C) 75.0, (D) 80.0, (E) 84.6. GDMA feed concentration: 48.2 mM, MAA concentration: 27.2 mM, AIBN concentration: 2.5 mg/ mL, temperature: 70 °C, polymerization time: 24 h.
Table 5. Effect of Toluene Concentration on the Final Monomer Conversion, Conversions to Soluble Polymer and Microgel Particles, and the Titratable Acid Content of the Continuous Medium code
CTol (% v/v)
XT (% w/w)
XSP (% w/w)
XMP (% w/w)
QMAA (% w/w)
GM20 GM21 GM2 GM22 GM23
61.5 70.0 75.0 80.0 84.6
90.3 91.6 97.9 97.9 QCa
40.9 23.7 10.8 17.0 16.0
49.4 67.9 87.1 80.9 84.0
50.0 37.3 27.7 29.1 25.4
a QC: Quantitative conversion (final overall monomer conversion was determined as a value consistent with 100% w/w with a maximum deviation of (1% w/w).
is expected with the MAA feed concentration since the polymerization rate should be proportional to the particle size. 3.3. Composition of the Continuous Medium. As seen in Table 1, the polymerization runs related to the effect of composition of the continuous medium were performed in the form of three separate sets. In the first one of these (i.e., the third set in Table 1), the toluene concentration was changed by using a relatively high GDMA feed concentration (i.e., 96.3 mM). When studying the effect of MAA feed concentration with the GDMA feed concentration of 96.3 mM, it was shown that the sphericity of microgel particles was improved by increasing the MAA feed concentration up to 72.6 mM (Figure 3C). For this reason, the effect of composition of the continuous medium was studied with the GDMA and MAA feed concentrations of 96.3 and 72.6 mM, respectively, in the fourth set. On the other hand, the polymerization runs performed to test the effect of GDMA feed concentration showed that the microgel particles with good sphericity were obtained with the low GDMA feed concentrations. By considering this finding, the effect of composition of the continuous medium was also studied with the low GDMA feed concentration (i.e., 48.2 mM) in the last set in Table 1. The variation of overall monomer conversion, conversion to soluble polymer, and titratable acid content of continuous medium with the toluene concentration are given in Table 5. As seen here, the overall monomer conversion increased with increasing toluene concentration. The conversion to soluble polymer decreased, and the conversion to microgel particles increased with increasing toluene concentration. All these results
Figure 10. Variation of hydrodynamic size with the toluene concentration for the poly(GDMA-co-MAA) microgel particles synthesized with different polymerization conditions. AIBN concentration: 2.5 mg/mL, temperature: 70 °C, polymerization time: 24 h.
should be probably related to the decrease in the solvency of the medium for the poly(MAA-co-GDMA) copolymer with the increasing toluene concentration. Depending upon the change occurred in the solvency, the weight percent of initially charged MAA (i.e., XMAA) found in the continuous medium also markedly decreased. Representative SEM photographs showing the variation of dry particle diameter with the toluene feed concentration are given in Figure 9. The effect of toluene feed concentration on the hydrodynamic diameter of microgel particles is given in Figure 10. Here, the particle diameters calculated from the SEM photos in Figure 9 were also included for comparison with the hydrodynamic size values. As seen in Figure 10, both the hydrodynamic size and dry particle size increased with increasing toluene feed concentration. The same tendency was also obtained for different GDMA feed concentrations. The increase in the particle size is clearer particularly for the toluene feed concentrations higher than 60% v/v. The proposed precipitation polymerization provided monodisperse cross-linked and reactive microgel particles in a broad size range between 30 and 1500 nm by changing the polarity of the polymerization medium. There was a similar tendency for the effect of toluene concentration on the average size poly(DVB) particles in the
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Figure 11. Variation of overall monomer conversion with the time in the precipitation polymerizations performed with different toluene concentrations. GDMA feed concentration: 48.2 mM, MAA concentration: 27.2 mM, AIBN concentration: 2.5 mg/mL, temperature: 70 °C, polymerization time: 5 h.
precipitation polymerization of DVB conducted in an AcN/ toluene medium.9 However, the precipitation polymerization of GDMA is more sensitive to the effect of cosolvent concentration since the average size exhibited a change in a wider range by changing the medium polarity. The solubility parameters of toluene and AcN are 8.9 and 11.9 (cal/cm3)0.5, respectively.21 The polarity of polymerization medium decreased with increasing toluene concentration, and larger poly(GDMA-co-MAA) particles were formed in the apolar media. The solubility parameter of GDMA could not be found in the literature. However, the solubility parameter of GDMA should be close to that of ethylene glycol dimethacrylate (EGDMA, 8.9 (cal/cm3)0.5) since its molecular structure is similar.22 The solubility parameter of MAA is 11.1 (cal/cm3)1/2 and very close to that of AcN.23 Therefore, the solvency of the medium increases with increasing toluene feed concentration in the precipitation polymerization of GDMA. In the case of a good solvent system, the critical chain length increases and the adsorption rate of the oligomers onto the particles is suppressed. The decrease in the rates of nuclei formation and adsorption of the oligomers leads to the formation of larger particles.24 The effect of medium polarity on the polymerization kinetics is shown in Figure 11. As seen here, higher polymerization rates were obtained with the decreasing toluene concentration. In Figure 11, the first-order derivative of overall monomer conversion with respect to time was evaluated as a measure of polymerization rate. This derivative was calculated by assuming linear variation of overall monomer conversion with the time in the first 90 min of the monitoring period. The variation of first-order derivative with the toluene concentration is shown in Figure 12. As seen here, the polymerization rate almost linearly decreased with increasing toluene concentration in the range of 61.5-84.6% v/v. This decrease should be probably related to the increase of the average microgel size. The variation of polydispersity index of the particles with the toluene feed concentration is also given in Figure 12. The polydispersity index values calculated by the software of the DLS system used were lower than 0.10 in all cases. In our case, “zero polydispersity index” corresponds to “excellent monodisperse sample”. Hence, the polydispersity index values close to zero showed that the size distribution was not so broad in the toluene concentration range studied. This result is also confirmed by the SEM photos in Figure 9. This makes it possible to establish a relationship between the average microgel size and particle number density and polymerization rate.
Figure 12. Effect of toluene feed concentration on the polymerization rate and polydispersity index of the final microgel particles. Effect of particle number density on the polymerization rate is given in the inset. The polymerization conditions are described in Figure 10.
As seen in Table 5, the overall monomer conversion exhibited a slight increase with increasing toluene concentration. Hence, a significant increase in the average microgel size with approximately constant overall monomer conversion means a significant decrease in the particle number density. The variation of polymerization rate with the particle number density is shown in the inset in Figure 12. As seen here, almost a linear increase in the polymerization rate with the increasing particle number density is obtained in the logarithmic coordinates. The slope of this change determined as 0.10038 showed that the polymerization rate was not directly proportional to the number of forming particles as stated for the emulsion polymerization.25 4. Conclusions A new precipitation polymerization protocol for the synthesis of monodisperse and reactive microgel particles was proposed. The average microgel size was changed in a reasonably wider range with respect to the similar precipitation polymerizations particularly proposed with hydrophobic cross-linking agents. The presence of dual functionality (i.e., carboxyl and hydroxyl groups) also makes easier the chemical derivatization (i.e., tailoring) of proposed microgel particles. The hydrogel character and the similarity of molecular structure to a biocompatible material, poly(2-hydroxyethyl methacrylate), make poly(GDMA) microspheres a promising material for biotechnological and biomedical applications. Nomenclature AIBN ) 2,2′-azobisizobutyronitrile CGDMA ) GDMA feed concentration (mM) CMAA ) MAA feed concentration (mM) CTol ) toluene concentration in the continuous medium (% v/v) CV ) coefficient of variation for size distribution (%) DD ) dry average microgel diameter (nm) DH ) hydrodynamic diameter of microgel (nm) GDMA ) glycerol dimethacrylate MAA ) methacrylic acid PDI ) polydispersity index obtained from the size distribution algorithm of DLS QMAA ) titratable acid content in the continuous medium (% w/w of MAA initially charged) XMP ) percent of total monomer converted to microgel particles (% w/w of total monomer)
Ind. Eng. Chem. Res., Vol. 48, No. 10, 2009 XSP ) percent of total monomer converted to soluble polymer (% w/w of total monomer) XT ) final overall monomer conversion (% w/w of total monomer)
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ReceiVed for reView October 18, 2008 ReVised manuscript receiVed March 14, 2009 Accepted March 20, 2009 IE801572W
