Simultaneous Cross Linking Polymerization

Simultaneous cross-linking polymerization allows one to prepare gel network in a single step in which polymerization as well as cross-linking processes occur simultaneously [144-148]. In these polymerizations, apart from monomer, a cross-linking agent (functionality >3) is used to allow three-dimensional network formation. In such polymerization process, the free radicals formed in the initiation step of the reaction tend to react with monomer and cross-linker molecules to obtain polymeric chains along with some cross-linking points. Intermolecular cross-linking leads to the formation of branched and highly network structure that ultimately is responsible for macroscopic gel product. The intramolecular cross-linking process is responsible for the formation internally cross-linked polymeric chain networks. Figure 6.12 illustrates the difference between inter- and intra-cross-linking behaviors in the simultaneous cross-linking polymerization process.

Micro- and nanogels can be successfully prepared by the cross-linking polymerizations employing (a) bulk polymerization, (b) solution polymerization, (c) emulsion polymerization, (d) suspension polymerization, and (e) nonconventional polymerization methods.

6.3.1.1 Bulk Polymerization. Bulk polymerization is rarely used preparative method for nanogels, but it is highly suitable to generate macroscopic gels [2-7]. Because of the auto-acceleration effect in the polymer reaction, the viscosity of the reaction mixture increases and it may not be possible to control the formation of macrogelation product [149,150]. Most of the simultaneous cross-linking polymerizations are not entirely homogeneous systems. Even before macrogelation, the system persists with different inhomogeneous density of cross-links, which can be separated at the molecular level. According to the classical gelation theory, homogeneous growth of linear polymeric chains and its cross-linking should not lead to individual microgels in the intermediate stage. However, recent investigations revealed that free-radical simultaneous bulk polymerization is effective in producing nanoscale gel particles [151,152]. Tetraethoxylated

Figure 6.12. Inter- and Intramolecular cross-linking modes in the simultaneous cross-linking polymerization.

bisphenol A dimethacrylate with styrene or divinyl benzene cross-linking polymerizations showed gel particles of 10-40 nm at different stages of the cross-linking process [151,152]. Simulation results of various multifunctional monomers demonstrated structural inhomogeneity in the microgel network formation [153-155]. Utilization of this type of polymerization still needs to be further explored for the synthesis of nanogels.

6.3.1.2 Solution Polymerization. Free-radical cross-linking polymerization is not adequate to produce nanogels, since it results in a broader size distribution than any other conventional polymerization techniques. However, this technique is versatile for understanding the gelation kinetics and there is no need of additional surfactants. The difficult part of the polymerization system is to control the propagation of linear polymeric chains and inter- and intramolecular cross-linking balance that may lead to macrogelation. Free-radical cross-linking polymerization mechanisms are documented in a few critical reviews [156,157]. According to these mechanisms, even much diluted systems can also result in the formation of macrogel. In order to avoid macrogelation, the concentration of polyfunctional precursors (co-monomers and multifunctional cross-linkers) is usually kept below its critical gelation concentration, and the solvent for each polymer system is critically selected to avoid macrogelation [84,158]. To obtain nanogels by solution cross-linking polymerization, one needs to balance the presence of dead chains, polymeric chains (active or propagating chains), and chain loops that act as good steric stabilizers. The polymerization reaction is conducted in a solvent in dilute condition, and the solvent solubility parameter (8) value is kept similar to that of the corresponding polymer. There is also a possibility of controlling the macrogelation in solution polymerization by using chain transfer agents (cobalt porphyrin) [159,160].

Maitra's group [161,162] reported NIPAM-based copolymer gel (~50nm) using solution polymerization employing ammonium persulfate/ferrous ammonium sulfate (APS/FAS) as the initiating system at room temperature for delivery of nonsteroidal anti-inflammatory drugs. We have recently developed poly(N-isopropylacrylamide-covinyl pyrrolidone) [poly(NIPAM-co-VP)] nanogels with an average size of 40 nm for the delivery of anticancer drugs (Figure 6.13). Other research groups have explored novel methods to form smart core-shell polymeric gels of PNIPAM/PEI and PNIPAM/PEI/chitosan using the same polymerization technique [62,63]. Similarly, well-defined amphiphilic core-shell polymer nanospheres are obtained (60-160 nm) via graft copolymerization of methyl methacrylate (MMA) from water-soluble polymer chains containing amino groups and casein [39,40]. Furthermore, the temperature-sensitive liposomes bearing or modified with poly(N-isopropylacrylamide) are possible to obtain by solution polymerization in dioxane or organic solvent using 4,41-azobisisobutyronitrile (AIBN) initiator [87,106]. Molecularly imprinted, soluble, highly cross-linked acrylamide-arginine-tyrosine nanogels have been prepared in dimethylsul-foxide (DMSO) [163]. Highly cross-linked microgels based on ethylene dimethacrylate-methyl methacrylate-trimethylolpropane trimethacrylate (EDMA-MMA-TRIM) have been successfully prepared in different solvent systems using free-radical solution polymerization [85]. A facile and direct homogeneous solution polymerization approach for hydroxyethyl methacrylate and methacrylic acid nanogels was developed in a single step without the use of oleophilic surfactants [164]. It is possible to produce more complex

NIPAM pendent group v Vinyl pyrrol idone pendent group

Figure 6.13. Transmission electron microscope (TEM) image of nanogel and nanogel internal cross-linking network structure.

NIPAM pendent group v Vinyl pyrrol idone pendent group

Figure 6.13. Transmission electron microscope (TEM) image of nanogel and nanogel internal cross-linking network structure.

architectural nanogels using anionic polymerization in solution and as small as 3-30 nm in size [165-167].

6.3.1.3 Emulsion Polymerization. Emulsion polymerization is widely used method to synthesize both micro- and nanogels. To prepare nanogels using this method, the droplets of monomer solution are added to a stable emulsion (Figure 6.14) in which the system contains initiator molecules that generate free radicals in the liquid phase (usually water) to start the polymerization reaction. In this manner, the polymer chains grow in the surfactant protected layers and then the surrounding solvent is removed by evaporation, extraction, or dialysis. Using this method of polymerization, the size of gel or nanoparticles can be controlled effectively by maintaining the size of the droplets in the water-oil emulsions [168,169]. In this method of polymerization, monofunctional monomers can give polymer nanoparticles where multifunctional monomers form internally cross-linked network polymers or gels. In the case of a monofunctional monomer system, polymerization can be readily terminated but multifunctional system restricts this behavior and the propagation and cross-linking steps of polymerization process leads to the formation of gel networks. The prepared nanogels/microgels employing this method are generally incompatible with biological macromolecules. To obtain better compatibility with biomacromolecules, water-water emulsions could be employed for the preparation of nanoparticles or gels, but controlling the size of gels to lower nanometers is difficult [170,171].

Microemulsion, inverse emulsion, and surfactant-free emulsion polymerization techniques are modified methods of emulsion polymerization from which nearly

Hydrophilic head

Hydrophilic head

Low surfactant High surfactant Critical micelle concentration concentration concentration

Hydrophobic tail

Hydrophobic tail mmu

Low surfactant High surfactant Critical micelle concentration concentration concentration

micelle

Figure 6.14. Classical emulsion polymerization technique for nanogel preparation. See insert for color representation of this figure.

Figure 6.14. Classical emulsion polymerization technique for nanogel preparation. See insert for color representation of this figure.

monodispersed microgels can be obtained [172-179]. These methods differ in the selection of particular conditions, but the main principle is the same as emulsion polymerization. The major variations in these methods are as follows:

Microemulsion. Constructed with a critical concentration of emulsifier where all the monomer molecules are present in micelles and not in the form of monomer droplets, and the polymerization is initiated under such condition.

Inverse Emulsion. This technique is just opposite to the emulsion polymerization, that is, polymerization of hydrophilic monomers is carried out in organic hy-drophobic phase instead of in an aqueous phase.

Surfactant-Free Emulsion Polymerization. This method of polymerization is carried out without any surfactant but monomer and the formed polymer chains themselves act as emulsifier.

Various authors have studied extensively the kinetics, mechanism, and size distribution of gel particle formation using these methods.

Pelton and co-workers [16,58,180-183] have systematically developed PNIPAM latexes (gel particles) in water. These gel particles were prepared using NIPAM with potassium persulfate as an initiator, sodium dodecyl sulfate (SDS) as a surfactant, and N,N'-methlylenebisacrylamide (MBA) as a cross-linker in aqueous media. The authors reported that under these conditions, the gel particles are formed only above the critical temperature (i.e., 55°C). Using similar procedure, Murray et al. [15,80] have tailored various colloidal microgels from NIPAM, NIPAM with acrylic acid, and/or other vinyl monomers. Antonietti et al. [184] disclosed the critical values of microgel cross-link density for gel transition in microemulsion polymerization, where the gels are stabilized with polymeric chains itself.

Recently, nanogels composed of NIPAM, AAc, and N-vinylimidazole have been reported [15,60]. Ito et al. [60] adopted an oil-free (surfactant-free) redox emulsion polymerization for NIPAM-based anionic and cationic polyelectrolyte nanogels in the presence of sodium dodecylbenzenesulfonate (NaDBS). Ishii et al. [185] employed surfactants other than NaDBS to obtain nanogels with longer self-life. Ramanan et al. [186] described in their studies in-depth the information about how the particle size of polyNIPAM gel changes with change in concentration of SDS. Lyon's group [75,76] prepared core-shell cross-linked gels with PNIPAM as core and NIPAM/acrylic acid polymeric arms using seed and feed precipitation emulsion polymerization.

6.3.1.4 Suspension Polymerization. This method is less suitable for producing nanogels or nanoparticles [149,156,187]. The nanogel preparation using this method follows different steps. Usually, suspension polymerization proceeds with a suitable initiator with a dilute system of monomers; the cross-linker is dispersed by mechanical agitation in the above liquid phase to obtain macromolecular chains. However, as these chains reach a critical length, they collapse to form precursor gel particles. These precursor particles continue to increase in their size due to aggregation of macromolecular chains. The particles formed in this way possess good colloidal stability; however, the main deficiency of this method is the difficulty in controlling the particle size because the colloidal stability is dependent on monomer to cross-linker composition, initiator, and temperature.

6.3.1.5 Nonconventional Polymerization Methods. It is widely speculated that the conventional simultaneous cross-linking polymerization methods followed by initiation with thermally decomposed initiators to give fragments (free radicals) are responsible for activation of polymerization and subsequent cross-linking reactions to acquire cross-linked network for nanogels [149,150]. These techniques produce end polymeric gels that contains unreacted species including cross-linker, initiator, reactive intermediates, and surfactants. The unreacted or active species are physically entrapped in their polymeric networks and are chemically bound. The presence of unreacted species in the final product can cause an adverse effect and hence is a concern. Furthermore, the existence of cross-linker can lead to structural nonhomogeneity that can harm the phase transition of gels [58,188-190].

Alternative cross-linking polymerization paths such as UV polymerization, radiation polymerization, and ultrasound/microwave polymerizations are other convenient

Reaction Between Mba And Pnipam
Figure 6.15. Formation of cross-linked PNIPAM nanogels under UV irradiation. (Reproduced with permission from Ref. 198, Figure 6.5. Copyright 2006, Elsevier, Ltd.)

methods to prepare nanogels [191-195]. To achieve highly homogeneous cross-linked gels, the UV-curing polymerization is considered quite appropriate. The benefit of this method is that monomers employed are multifunctional in which photosensitive initiators are introduced to obtain highly cross-linked polymers [196]. Gao and Frisken [197] reported a convenient way to prepare cross-linker free poly(N-isopropylacrylamide) nanospheres. Initially, linear poly(N-isopropylacrylamide) is prepared using a potassium persulfate/N,N'-tetramethylethylenediamine (KPS/TMEDA) initiating system, which is then exposed to He-Ne laser beam irradiation at high temperature (70°C) to form intramolecular cross-linked PNIPAM gel networks. Nanogels can also be prepared using this method with monomers encapsulated/entrapped in liposomes [65]. Figure 6.15 demonstrates the mechanism of formation of nanogels from monomer/polymeric chains through photopolymerization [198]. The yield was higher at pH 2 media, where the polymerization reaction accelerates with H+ ions. Another convenient UV-polymerization method, is based on double layer. In this method, the upper layer contains droplets and UV is exposed to the lower layer that gives internally cross-linked PEG nanogels [199].

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