*4.2.2 In-situ polymerization*

This technique is very much like interfacial polymerization. The difference is that the polymerization occurs entirely in the one phase. This term includes suspension polymerization, emulsion polymerization, and dispersion polymerization. In a typical process, the wall forming monomer or pre-polymer is dissolved in the continuous phase and used to emulsify the external phase under high pressure homogenization. Thereafter, an initiator for polycondensation soluble in the continuous phase is added to initiate polycondensation. Acids are normally added to reduce pH and trigger polycondensation which leads to crosslinking and the deposition of crosslinked wall material round the oil drops [66]. Material used, stirring speed, pH, and curing temperature are some of the factors for optimization. Ureaformaldehyde and melamine—formaldehyde are well known examples developed with this method. Ishizuka and colleagues [67] recently prepared microcapsules by this technique with an amphiphilic macro RAFT wall material they synthesized. Their procedure eliminated the use of toxic solvents. The wall monomer was introduced into the rice bran oil continuous phase which was then emulsified with the aqueous phase containing sodium chloride in a shirasu porous glass membrane.

The crosslinkers, ethyleneglycoldimethacrylate, was added to the formed emulsion to bring about polymerization [67].

Emulsion polymerization: In this procedure, the core material is dissolved in a surfactant. The monomer solution is then added to it dropwise.

Dispersion polycondensation: In the category, all the components including the monomer, the dispersant and the initiator are present in a solvent in which the polymer to be formed is insoluble. Here, swelling of the polymer occur leading to growth of microcapsules which is sustained by continued addition of monomer and oligomer [68]. Jiang and colleagues [69] used this method to prepare a core shell for site specific delivery of a small molecule, doxorubicin and a protein drug, TRAIL, for cancer therapy.

Suspension polymerization: In this approach, the monomers used are insoluble in the continuous phase hence, they are dispersed as liquid droplets, in the aqueous phase, in the presence of a stabilizer using high pressure homogenization. The polymer is obtained as dispersed solid in the continuous phase. Racoti and coworkers [70] recently used suspension polymerization for the microencapsulation of ginger oil in polymethyl methacrylate shell using triethyleneglycol dimethachrylate as a monomer and Azobisisobutyronitrile (AIBN) as initiator. Their study showed that particle size increased with initiator concentration while encapsulation efficiency decreased with increasing oil concentration.

#### **4.3 Physicochemical techniques**

The physicochemical techniques discussed here are classified as chemical methods by some authors. However, they are classified as physicochemical techniques here because each technique involves one or two physical steps. Such techniques are solvent evaporation, coacervation, layer by layer deposition and liposomes.

#### *4.3.1 Solvent evaporation*

The first step is the dispersion of the core material in the coating solution to form an oil-in-water emulsion. The mixture is then homogenized in the presence of stabilizers such as polyvinyl alcohol (PVA), tween 80 and span 80 to obtain appropriately sized microcapsules. The last step is to evaporate the solvent off either at ambient or elevated temperatures depending on the solvent. For double emulsion solvent evaporation, the formed oil-in-water emulsion is emulsified again, homogenized before solvent evaporation [71]. The type of emulsion chosen will be dependent on the lipophilicity or hydrophilicity of the core material. Double emulsions of the w/o/w type are usually used for highly hydrophilic materials in order to improve their encapsulation efficiency and limit their diffusion out of the capsule into the continuous phase of oil-in-water emulsions [71]. Another approach that has been used for hydrophilic payloads is the suspension in organic phase template [72]. Solvent evaporation is the common method for preparing nanoparticles. Hoa and coworkers [73] prepared PVA stabilized ketoprofen loaded Eudragit E100-Eudragit RS nanoparticles using the solvent evaporation method. They studied effect of process and formulation parameters on the properties of the nanoparticles. They confirmed that the size and morphology of the particles depended on polymer and surfactant concentration, power and duration of applied energy, and volume ratio of water to oil phases. More recently, Jiang and colleagues [74] developed nanoparticles of Ginkoglide using solvent evaporation method. Likewise, Urbaniak and Musial [72], using solvent evaporation technique, prepared submicron sized capsules from lamivudine conjugated poly-ɛ-caprolactone polymer and studied the influencing parameters such as concentration and type, homogenization time and

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*Natural Polymers in Micro- and Nanoencapsulation for Therapeutic and Diagnostic…*

rate on the particle size. Surfactant concentration and homogenization rate were identified as the most important factors affecting particle size. Solvent evaporation method is advantageous in that it limits the use of toxic solvents, proceeds rapidly

This technique also known as solvent displacement technique was patented by Fessi in 1989 [75] for making nanospheres and nanocapsules. It has close resemblance to solvent evaporation technique. Here, the solvent phase containing the film forming polymer, and the drug to be encapsulated is a water miscible solvent such as acetone or methanol, and the non-solvent phase which is a water immiscible solvent such as chloroform or dichloromethane, also called the oil phase, are mixed under stirring. Thereafter, the solvent is removed to yield nanoparticles suspension or nanocapsules if a mineral oil was added. Centrifuging and freeze drying will yield the powder. Chitosan, starch, and gelatin are among the commonly used natural polymer film formers. Many studies have tried to analyze the difference in nanoparticles generated by solvent evaporation and solvent displacement. Hernández-Giottonini and colleagues [76] evaluated the effect of process parameters and formulation parameters on polylactic-co-glycolic acid (PLGA) nanoparticles prepared by both techniques. While particle size was dominantly affected by PLGA and PVA concentrations for the nanoprecipitation method, solvent fraction had the most effect of the particle size for the solvent evaporation technique. However, the influence of agitation speed in both techniques was the

This technique involves the phase separation of one or more hydrocolloids from its initial solution brought about by changes such as pH, ionic strength, temperature, solvent type or polarity and the subsequent deposition of the separated coacervate on the core droplets in the solution [77]. The lower particle diameter obtainable from simple coacervation is 20 μm while that for complex coacervation is 1 μm; and 500 μm capsules are also possible from both [33]. Generally, the first step in any coacervation process is the dispersion of the oil phase in the solution of the hydrocolloid (formation of oil-in-water emulsion). The next step involves the precipitation of the hydrocolloid by temperature, polarity, pH, or ionic strength change (polyelectrolyte complex formation). This is usually achieved by addition of a salt such as sodium sulphate, or desolvation with water miscible non-solvent, in simple coacervation [78]. Induction of polymer-polymer gelling by addition of a second oppositely charged hydrocolloid happens only in complex coacervation. The resulting complex is stabilized by crosslinking (usually glutaraldehyde, transglutaminase, calcium ions or tripolyphosphate) and the harvested microcapsules washed and dried. Complex coacervation is advantageous due to the high loading of payload up to 99%. From the relatively simple and early use of pork skin gelatin and gum arabic, many other variations have emerged including patented deviations. Majority of the polymers used are natural polysaccharides such as starches, maltodextrins, and gum arabic; and proteins such as albumin,

Brito de Souza and coworkers [79] used complex coacervation as a tool to protect the phenolic compounds and mask the astringent taste of spray dried hydrophilic proanthocyanidins-rich cinnamon using a combination of various polysaccharides and gelatin as the coacervate wall material. They also evaluated the stability of the microcapsules under various storage conditions. Their study showed that

*DOI: http://dx.doi.org/10.5772/intechopen.94856*

*4.3.2 Nanoprecipitation*

*4.3.3 Coacervation*

yielding particles in the size range of 10–100 nm.

same- a decrease in average particle diameter [76].

gelatin, and casein; and lipids such as diglycerides [77].

rate on the particle size. Surfactant concentration and homogenization rate were identified as the most important factors affecting particle size. Solvent evaporation method is advantageous in that it limits the use of toxic solvents, proceeds rapidly yielding particles in the size range of 10–100 nm.
