*3.2.1 Dispersion/precipitation polymerization*

In this technique, polymerization generally starts in a homogenous solution of monomers and cross-linkers [49, 50]; as polymerization progresses, the monomer and the developed oligomers remain soluble; after achieving the critical length phase, separation takes place by enthalpic precipitation leading to particle nuclei formation. The nuclei aggregate to form large particles that carry on growing resulting into microgel formation. In dispersion polymerization stabilizers can be added to regulate the particle size and to keep particles in narrow size distribution [51]. The described method is schematically presented in **Figure 2**.

Dispersion polymerization technique was employed for the synthesis of pHsensitive poly((2-dimethylamino)ethyl methacrylate) microgels with diameter of about 100–200 nm in dry sate [52]. The microgels exhibited volume phase change at about pH 8, with 32 times decrease in diameter. Dispersion polymerization was involved in the preparation of hydrophilic microparticles of poly(2-hydroxyethyl methacrylate) [53].

Duracher et al. [54] synthesized thermoresponsive microgels by precipitation polymerization of N-isopropylmethacrylamide. The prepared microgels were

**89**

*pH-Responsive Microgels: Promising Carriers for Controlled Drug Delivery*

found to be temperature sensitive. Moreover, with the modifications in the synthetic protocol, more complex microgel structures can be synthesized. Examples include temperature- and pH-sensitive microgels prepared by copolymerization of N-isopropylmethacrylamide with acrylic acid [55], vinyl acetic acid [56, 57], or

*Precipitation polymerization (a) initiation of polymerization and chain growth, (b) precipitation and nuclei* 

One approach to synthesize complex structures, e.g., core-shell microgels or hollow microgels, involves polymerization of different monomers and/or already formed seed particle. Core-shell microgels have structurally separated zones of different polymers. Zhou et al. [59] synthesized temperature sensitive microgels based on oligo(ethylene glycol). The microgels were stable across the important

In general, microemulsions can be prepared as direct oil-in-water (O/W) or inverse water-in-oil (W/O) emulsions. The inverse emulsions are widely investigated for the formulation of hydrogel nanoparticles. In this approach, dispersed phase consists of either monomer having ability to polymerize or prepolymers with ability of cross-linking dissolved in water is added to a continuous phase of organic medium having large amount of oil-soluble surfactant. The mixture is stirred to achieve thermodynamically stable microemulsion. Synthesis of microgels takes place inside the droplets, e.g., via free radical polymerization. Initiation of polymerization takes place either from the interior of droplets or from the continuous phase

Shen et al. [61] synthesized poly(acrylamide-co-acrylic acid) microgels by polymerization in inverse microemulsion. The effect of chemical constitution on size, morphology, swelling behavior, thermal properties, and pH-sensitivity was explored. The size of p(AM-co-AA) microgels was larger in comparison to PAM microgels. The microgels exhibited pH-responsive behavior and have higher swell-

In another study, microemulsion polymerization phenomenon was employed for the copolymerization of methacrylic acid and 2-ethylhexyl acrylate to demonstrate colon-specific delivery of drug. An anticancer drug (5-fluorouracil) was entrapped inside the copolymer through solvent evaporation method. In vitro drug release studies performed at different pH levels revealed pH-dependent release of 5-fluoro-

Miniemulsions in general are kinetically stable emulsions; considerably less surfactant is required for the droplet stabilization [63]. This approach is versatile

physiological temperature range with adjustable volume phase changes.

[60]. **Figure 3** illustrates the microgel synthesis in W/O emulsion.

ing ratio, with an increase in acrylic acid content.

uracil in a sustained manner [62].

*3.2.3 Microgel synthesis in miniemulsions*

*DOI: http://dx.doi.org/10.5772/intechopen.82972*

**Figure 2.**

2-aminoethyl methacrylate hydrochloride [58].

*formation, (c) particle growth, and (d) microgels.*

*3.2.2 Synthesis of microgels in microemulsions*

**Figure 1.** *Schematic presentation of coacervation technique.*

*pH-Responsive Microgels: Promising Carriers for Controlled Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.82972*

#### **Figure 2.**

*Pharmaceutical Formulation Design - Recent Practices*

**3.2 Synthesis of microgel in heterogeneous phase**

• Dispersion/precipitation polymerization

ous solution can be distinguished as:

• Miniemulsion polymerization

• Microemulsion polymerization

*3.2.1 Dispersion/precipitation polymerization*

The described method is schematically presented in **Figure 2**.

Other techniques include coacervation and desolvation. In both techniques phase separation of readily formed polymers takes place, resulting in micro-/nanoparticles which are then cross-linked. **Figure 1** represents typical steps involved in coacervation method. Phase separation is usually induced by changing temperature, adding salt, nonsolvent addition, non-compatible polymer addition, or polymer-polymer interaction. The resulting coacervate (polymer droplet) is then solidified and stabilized forming microgel particle. This technique is usually employed in synthesis of microgels from biopolymers such as (modified) gelatin or chitosan. For example, pHresponsive chitosan nanoparticles were synthesized by complex coacervation [47] and two-step desolvation route was involved in synthesis of gelatin nanoparticles [48].

Heterophase copolymerization of monomers with cross-linking agents in aque-

In this technique, polymerization generally starts in a homogenous solution of monomers and cross-linkers [49, 50]; as polymerization progresses, the monomer and the developed oligomers remain soluble; after achieving the critical length phase, separation takes place by enthalpic precipitation leading to particle nuclei formation. The nuclei aggregate to form large particles that carry on growing resulting into microgel formation. In dispersion polymerization stabilizers can be added to regulate the particle size and to keep particles in narrow size distribution [51].

Dispersion polymerization technique was employed for the synthesis of pHsensitive poly((2-dimethylamino)ethyl methacrylate) microgels with diameter of about 100–200 nm in dry sate [52]. The microgels exhibited volume phase change at about pH 8, with 32 times decrease in diameter. Dispersion polymerization was involved in the preparation of hydrophilic microparticles of poly(2-hydroxyethyl methacrylate) [53]. Duracher et al. [54] synthesized thermoresponsive microgels by precipitation polymerization of N-isopropylmethacrylamide. The prepared microgels were

**88**

**Figure 1.**

*Schematic presentation of coacervation technique.*

*Precipitation polymerization (a) initiation of polymerization and chain growth, (b) precipitation and nuclei formation, (c) particle growth, and (d) microgels.*

found to be temperature sensitive. Moreover, with the modifications in the synthetic protocol, more complex microgel structures can be synthesized. Examples include temperature- and pH-sensitive microgels prepared by copolymerization of N-isopropylmethacrylamide with acrylic acid [55], vinyl acetic acid [56, 57], or 2-aminoethyl methacrylate hydrochloride [58].

One approach to synthesize complex structures, e.g., core-shell microgels or hollow microgels, involves polymerization of different monomers and/or already formed seed particle. Core-shell microgels have structurally separated zones of different polymers. Zhou et al. [59] synthesized temperature sensitive microgels based on oligo(ethylene glycol). The microgels were stable across the important physiological temperature range with adjustable volume phase changes.

#### *3.2.2 Synthesis of microgels in microemulsions*

In general, microemulsions can be prepared as direct oil-in-water (O/W) or inverse water-in-oil (W/O) emulsions. The inverse emulsions are widely investigated for the formulation of hydrogel nanoparticles. In this approach, dispersed phase consists of either monomer having ability to polymerize or prepolymers with ability of cross-linking dissolved in water is added to a continuous phase of organic medium having large amount of oil-soluble surfactant. The mixture is stirred to achieve thermodynamically stable microemulsion. Synthesis of microgels takes place inside the droplets, e.g., via free radical polymerization. Initiation of polymerization takes place either from the interior of droplets or from the continuous phase [60]. **Figure 3** illustrates the microgel synthesis in W/O emulsion.

Shen et al. [61] synthesized poly(acrylamide-co-acrylic acid) microgels by polymerization in inverse microemulsion. The effect of chemical constitution on size, morphology, swelling behavior, thermal properties, and pH-sensitivity was explored. The size of p(AM-co-AA) microgels was larger in comparison to PAM microgels. The microgels exhibited pH-responsive behavior and have higher swelling ratio, with an increase in acrylic acid content.

In another study, microemulsion polymerization phenomenon was employed for the copolymerization of methacrylic acid and 2-ethylhexyl acrylate to demonstrate colon-specific delivery of drug. An anticancer drug (5-fluorouracil) was entrapped inside the copolymer through solvent evaporation method. In vitro drug release studies performed at different pH levels revealed pH-dependent release of 5-fluorouracil in a sustained manner [62].

#### *3.2.3 Microgel synthesis in miniemulsions*

Miniemulsions in general are kinetically stable emulsions; considerably less surfactant is required for the droplet stabilization [63]. This approach is versatile

**Figure 3.** *Illustration of microgel preparation via inverse emulsion polymerization.*

and allows utilization of different monomers, functional compounds incorporation, and the accurate adaptation of droplets and particles size [64, 65]. In general, high deformation forces are applied to pre-emulsion of droplet leading to uniform distribution of well-defined nanodroplets (50–500 nm). The surfactant present in the system obstructs the coalescence of these nanodroplets; in addition, the costablizer added to dispersed phase prevents Ostwald ripening leading to kinetically stable miniemulsion [66].

Miniemulsions can be classified as direct (oil-in-water) or inverse (water-in-oil) systems. Oil-in-water miniemulsification is a well-established approach for the polymerization of hydrophobic monomers for the formulation of polymeric latexes [63]; on the other hand, the inverse method involves diverse synthetic pathways for the formation of nanohydrogels [67]. One approach involves the free radical copolymerization of hydrophilic monomers with cross-linking agents in dispersed droplets

**91**

**Table 1.**

*pH-Responsive Microgels: Promising Carriers for Controlled Drug Delivery*

**4. Pharmaceutical applications of pH-responsive microgels**

(**Table 1**). Few examples from the literature are demonstrated here.

of either aqueous solutions of these compounds or their mixture without additional solvent. The monomers must be immiscible with the continuous phase. Examples include the formation of polyacrylamide (PAAm)- [68] and PHEMA-based [65] microgels. **Figure 4** schematically represents the described synthetic pathway.

Another approach is cross-linking of preformed polymers in inverse miniemulsion. In this method mixture of two W/O emulsions (A and B) are ultrasonicated. Emulsion A constitutes the solution of already formed polymer, and emulsion B constitutes solution of cross-linker. Ultrasonication leads to mixing of the components of both emulsions, inducing the cross-linking reaction. This method has been employed for the synthesis of covalently cross-linked gelatin microgels [69]. In another study, temperature-responsive nanogels poly(N-isopropylacrylamide) nanogels were fabricated by nanoemulsion polymerization as smart delivery

pH-responsive microgels have demonstrated a number of medical applications

pH-responsive p(NIPAAm/AA) microgels were fabricated for transferrin-based targeting of cancer [71]. These microgels were able for specific delivery to human cervical carcinoma cell line (HeLa) cells. In another study methacrylic-based copolymeric pH-sensitive nanogels were prepared for targeted delivery of 5-fluorouracil to the colon [62]. Recently, Eswaramma et al. [72] developed pH-sensitive interpenetrating polymer network (IPN) microgels of chitosan and guar gum*g*-poly((2-dimethylamino)ethyl methacrylate) (GG-*g*-PDMAEMA) and treated as responsive drug carriers for an anticancer agent, 5-fluorouracil (5-FU). The microgels showed encapsulation efficiency up to 81%, and the release kinetics showed pH-dependent drug release with an excellent controlled release pattern for 5-FU

Dadsetan et al. [73] used a copolymer of oligo(poly(ethylene glycol) fumarate) (OPF) and sodium methacrylate (SMA) to fabricate the pH-responsive microgels for the delivery of doxorubicin (DOX) in order to optimize its antitumor activity

**Drug Application Reference**

[72]

[73]

[82]

[83]

[84]

activity

activity

delivery

targeted delivery

insulin delivery

5 fluorouracil Antitumor

Ketoprofen For colon-

Microgels Protein drug For oral delivery [85]

Microgels Insulin Self-regulated

*DOI: http://dx.doi.org/10.5772/intechopen.82972*

systems [70].

over a period of more than 24 h.

**Polymers Polymeric** 

GG-*g*-PDMAEMA IPN-

P(AM)-g-carrageenan and

Methacrylate derivatives of dextran and concanavalin

Alg and chemically modified carboxymethyl CS

sodium alginate

**DDSs**

Microgels

Hydrogel beads

*Examples of various applications of microgels as drug delivery carriers.*

OPF-SMA microgels Microgels Doxorubicin Antitumor

P(MMA-*g*-EG) Microgels Insulin Oral peptide

MEMA-co-IA Microgels Esomeprazole Intestinal delivery [76]

**Figure 4.** *Schematic illustration of radical cross-linking in inverse miniemulsion.*

*pH-Responsive Microgels: Promising Carriers for Controlled Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.82972*

*Pharmaceutical Formulation Design - Recent Practices*

and allows utilization of different monomers, functional compounds incorporation, and the accurate adaptation of droplets and particles size [64, 65]. In general, high deformation forces are applied to pre-emulsion of droplet leading to uniform distribution of well-defined nanodroplets (50–500 nm). The surfactant present in the system obstructs the coalescence of these nanodroplets; in addition, the costablizer added to dispersed phase prevents Ostwald ripening leading to kinetically

*Illustration of microgel preparation via inverse emulsion polymerization.*

Miniemulsions can be classified as direct (oil-in-water) or inverse (water-in-oil)

systems. Oil-in-water miniemulsification is a well-established approach for the polymerization of hydrophobic monomers for the formulation of polymeric latexes [63]; on the other hand, the inverse method involves diverse synthetic pathways for the formation of nanohydrogels [67]. One approach involves the free radical copolymerization of hydrophilic monomers with cross-linking agents in dispersed droplets

**90**

**Figure 4.**

stable miniemulsion [66].

**Figure 3.**

*Schematic illustration of radical cross-linking in inverse miniemulsion.*

of either aqueous solutions of these compounds or their mixture without additional solvent. The monomers must be immiscible with the continuous phase. Examples include the formation of polyacrylamide (PAAm)- [68] and PHEMA-based [65] microgels. **Figure 4** schematically represents the described synthetic pathway.

Another approach is cross-linking of preformed polymers in inverse miniemulsion. In this method mixture of two W/O emulsions (A and B) are ultrasonicated. Emulsion A constitutes the solution of already formed polymer, and emulsion B constitutes solution of cross-linker. Ultrasonication leads to mixing of the components of both emulsions, inducing the cross-linking reaction. This method has been employed for the synthesis of covalently cross-linked gelatin microgels [69]. In another study, temperature-responsive nanogels poly(N-isopropylacrylamide) nanogels were fabricated by nanoemulsion polymerization as smart delivery systems [70].
