**2.1 Microencapsulation**

*Nano- and Microencapsulation - Techniques and Applications*

Encapsulation, a process involving entrapment of an active ingredient or diagnostic tool within a carrier (capsule, shell, coating material or a matrix) is an old technology that has gained traction over the years with advances in polymer science and encapsulation technologies. The applications of encapsulation span pharmaceuticals, biotechnology, agrochemical, environmental, food and cosmetic spaces with immense benefits found in the pharmaceutical and biotechnology spaces. Encapsulation is used for immobilization of volatile compounds, enzymes, and microorganisms; protection and stabilization from environmental factors; safe handling of hazardous but useful materials; controlled release; taste, odor and color masking; site-specific delivery and solidifying of liquid droplets. Encapsulation improves on the challenges of conventional dosage forms in enhancing stability, taste, bioavailability and biodistribution. Some drugs such as insulin are not given orally because of degradation in the GIT before absorption. Encapsulation may be

an approach to change route of administration from intravenous to oral.

The parameters for encapsulation of active ingredients depend on the physicochemical properties of the active ingredient such as solubility, thermal and redox stability; however, the release of the active is then modulated by mechanical process, pH variations, enzymatic actions or other external stimuli [1]. The encapsulation methods classified as chemical, physicochemical and physicomechanical methods are used to encapsulate an active ingredient with the specific method chosen based on application and desired outcomes. The choice of materials to be used for encapsulation to accommodate the physicochemical behavior of the active in order to produce the desire encapsulation efficiency, shell or capsule size, surface morphology and functionalities of the capsule and the behavior of encapsulated active ingredient are fundamental preformulation studies before a new encapsulated product is developed. The bioavailability of existing poorly soluble drugs and those in the development pipeline can be significantly enhanced by encapsulation with the right encapsulating material(s). Natural polymers are choice materials for encapsulation. Natural polymers are macromolecules of large molecular weights obtained from nature and are preferred due to their flexibility to modification, biocompatibility, biodegradability, renewability, and low toxicity [2]. Being of natural origins such as plants, animals and microorganisms, they are able to interact with tissues and cells displaying some properties the body identifies with and as a result do not treat them as foreign bodies [3]. Natural polymers such as proteins, polysaccharides and lipids have been employed as encapsulation materials for encapsulating hydrophilic or hydrophobic active ingredients which may be in liquid, solid and gaseous states for transport and delivery to the sites they are needed. The chapter reviews fabrication techniques, lipids, and their applications in micro- and nanoencapsulation elucidating their functionalities which enable them to be utilized for encapsulation of therapeutics and diagnostics producing delivery systems with the desired outcomes. Polysaccharides and proteins are covered in part (II) of this chapter.

Encapsulation is the process of enclosing, entrapping, coating, or surrounding a liquid, solid or gas active compound within a material to achieve a more controlled/ sustained release, protect the active compound/active pharmaceutical ingredient from degradation before reaching the site of absorption or before reaching the site of action as well as reducing the associated adverse effects that go along with some non-encapsulated compounds like NSAIDS [4, 5]. Research on encapsulation utilizing natural polymers and their derivatives (semi-synthetic polymers) has evolved

**1. Introduction**

**4**

**2. Encapsulation**

Microencapsulation refers to the formulation process of encapsulating a bioactive compound in a particle size that is 1–1000 μm in diameter for the purpose of controlled and sustained delivery as well as protection of the encapsulated bioactive compound from the surrounding environment [7, 8]. Microencapsulation technology came into existence with the focus of achieving controlled and extended release profiles. Due to the size of micro carriers, encapsulation of macromolecules with large molecular weight such as proteins for controlled release can be encapsulated. Bochenek *et al.,* [9] utilized chemically modified alginate microsphere formulations to encapsulate allogeneic pancreatic islet cells for transient islet-graft function that have reached clinical trial stage for management insulin deficiency in diabetic populations. This was due to the fact that the immune-modulating alginate copolymer employed had controlled release profile that caused encapsulated islet cells to remain viable after transplantation into the general intraperitoneal (IP) space of human subjects, while also exhibiting lowered foreign-body reaction (FBR) compared to previous formulations. Chitosan-alginate microcapsules encapsulating biologically active compounds from aqueous extracts of *Garcinia kola* (GK) and *Hunteria umbellata* (HU) seeds, have also been shown to have selective release patterns depending on the pH of the medium [10]. Slower release of the GK and HU microcapsules of the active compounds was observed at pH 1.2, but increased controlled extended release profiles were observed to occur at pH 6.8 unlike conventional tablets that did not show controlled extended release profiles [10].

#### **2.2 Nanoencapsulation**

Nanoencapsulation can be defined as the entrapment, enclosure, or coating of a bioactive compound within a carrier that is on the nanoscale dimension [5]. Nanoscale dimension is seen as particle sizes 1–100 nm [6]. However more recent definitions have given room for 1–300 nm and others 1–1000 nm [11]. The advancement of encapsulation from the micro scale to the nano scale was driven by the need for more site selective targeting purposes such as the use of chemotherapeutics in cancer. The main draw back in cancer chemotherapeutics has been that severe adverse effects occur due to toxicity caused by the non-selective action on both cancer cells and healthy cells at therapeutic doses. Hence, the inception of nanomedicines that could achieve active targeting was born. Nanoencapsulation in drug delivery has the merit of having a higher encapsulation efficiency, due to enhanced drug solubility of bioactive molecules in the core [12].

Silk fibroin nanoparticles encapsulating curcumin were found to demonstrate selective cytotoxicity for cancer therapy in neuroblastoma cells and hepatocarcinoma cells while not adversely affecting the healthy cells [13]. Diagnostics are also gaining from the merits of encapsulation. This was demonstrated in the simultaneous co-encapsulation of MRI contrast agent Gd-DTPA and fluorescent label ATTO488 in multimodal PEG – crosslinked hyaluronic acid nanoparticles (PEG-cHANPs) to formulate a probe for diagnostic purposes [14]. The PEG-cHANPs were observed to improve MR signals while concurrently magnifying the relaxation time, T1 5 times due to the presence of the ATTO 488 in the human glioma U87 MG cell line. Tammaro *et al.,* [14] implied that this could lead to the decrease in the administered dose of the probe, thereby resulting in a better resolution and higher quality images.

## **3. Merits and demerits of encapsulation**

The merits and demerits of encapsulation are viewed from the expected outcomes of encapsulation and are based on physicochemical properties of core materials (small molecules, biologics, or diagnostics), encapsulating techniques and materials. Encapsulating materials such as natural and semi-synthetic polymers have many advantages because they are obtained from natural sources. Immunogenicity issues when natural polymers are used as the encapsulating materials are greatly reduced compared to synthetic polymers. Encapsulation using natural polymers can be done without high temperatures thus preventing degradation due to high temperatures as seen in alginate–chitosan micro/nanoparticles which were successfully fabricated at room temperature excluding the utilization of organic solvents [4].

Encapsulation of an active compound using pegylated phospholipids also known as lipopolymers such as 2000 Da PEG-DSPE have demonstrated the merit of prolonging circulation time of active compounds when administered as nanoliposomes. This led to a reduction in the dosage frequency and reduction in uptake by the RES, thus leading to an increase in patient compliance as was observed in the first FDA approved nanomedicine; liposomal doxorubicin Doxil® in 1995 [15].

Efficacious poorly water-soluble drug candidates for therapeutics before now posed a challenge in formulation due to their low solubility profile and pharmacokinetic characteristics [16]. Micro- and nanoencapsulation technologies such as supramolecular hydrogels formulated with natural cyclic oligosaccharides also called cyclodextrins have successfully been able to encapsulate and deliver such drug candidates. This was demonstrated when lipophilic non-hydroxylated coumarins were encapsulated in the core of β-cyclodextrin hydrogels for trypanocidal activity via mitochondrial membrane potential studies for Chagas disease caused by the protozoan parasite, *Trypanosoma cruzi.* Trypanocidal activity was increased by 10% with the Supramolecular hydrogels of β-cyclodextrin linked to calcium homopoly-Lguluronate as compared to the free corresponding amidocoumarins [17, 18].

Demerits of natural and semi-synthetic polymers in micro- and nanoencapsulation mainly depends on the individual materials. However, a major drawback observed with natural polymers and their derivatives is batch to batch variation depending on regions/environments that these polymers were sourced from. Plant and animals of the same species have been found to have some slight differences in their composition based on factors such as type of soil or geographical regions [19, 20]. Low mechanical strength leading to weak wall formation, susceptibility to change in pH causing a reduction in stability, highly hygroscopic leading to denaturation are challenges that are observed with such polymers as alginate, gelatin and sodium hyaluronate [8].

To overcome the demerits of these polymers, physical and chemical modifications are undertaken. Extra care should be taken during storage of natural polymers to reduce degradation and denaturation that occur during storage. Despite any demerits that natural polymers and their derivatives may have, the application of natural polymers and their derivatives for micro- and nanoencapsulation will continue to increase because of their immense merits in therapeutics and diagnostics.

#### **4. Encapsulation techniques**

The process of enclosing vesicles in a thin continuous film of a natural or semi synthetic polymer has been accomplished using a variety of both physical and chemical methods or a combination of both depending on the size of the targeted

**7**

**Figure 1.**

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

capsules either in the nanometer, micrometer or millimeter range. Over the years and as a result of continuous innovation, these techniques have evolved from the earliest relatively simple coacervation phase separation used for making only microcapsules to current comparatively complex techniques capable of making both microcapsules and nanocapsules with a careful tuning of process parameters. The choice of a technique not only determines the size but also the morphology and probably the stability expected of the targeted capsules [21]. The choice of technique stems from other parameters such as the physicochemical fingerprint of both shell and core material, the objective of the encapsulation process, the expected release profile/mechanism, the intended application of the final capsules, need for scale up, and of course, processing cost for large scale manufacture. An ideal technique aims at achieving monodispersed capsules with great stability to aggregation, adherence and other destabilizing factors, and high loading and encapsulation efficiency for the cargo. The changing landscape of expectations for drug delivery and other applications is driving the application of more than one encapsulation technique towards achieving goals such as in theragnostic applications. Bazylińska and colleagues [22] combined two encapsulation techniques (**Figure 1**), emulsion solvent evaporation and Layer by layer assembly (LbL) to engineer nanocapsules

Encapsulation processes have been classified broadly into physical and chemical techniques. There is no consensus over the third class, physicochemical techniques, and may be because the techniques only take the mechanism of capsule formation into consideration. However, each encapsulation technique involves processing that may involve mechanism not inherent in the name. For instance, emulsion solvent evaporation or in situ polymerization techniques are core chemical techniques but may involve physical processes such as mechanical stirring, homogenization, and sonication in achieving solvent evaporation. **Table 1** outlines the different

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

for dual fluorescence bioimaging and drug delivery.

classification of encapsulation techniques.

*Combination of two encapsulation techniques for microcapsule formation [22].*

#### *Natural Polymers in Micro- and Nanoencapsulation for Therapeutic and Diagnostic… DOI: http://dx.doi.org/10.5772/intechopen.94856*

capsules either in the nanometer, micrometer or millimeter range. Over the years and as a result of continuous innovation, these techniques have evolved from the earliest relatively simple coacervation phase separation used for making only microcapsules to current comparatively complex techniques capable of making both microcapsules and nanocapsules with a careful tuning of process parameters. The choice of a technique not only determines the size but also the morphology and probably the stability expected of the targeted capsules [21]. The choice of technique stems from other parameters such as the physicochemical fingerprint of both shell and core material, the objective of the encapsulation process, the expected release profile/mechanism, the intended application of the final capsules, need for scale up, and of course, processing cost for large scale manufacture. An ideal technique aims at achieving monodispersed capsules with great stability to aggregation, adherence and other destabilizing factors, and high loading and encapsulation efficiency for the cargo. The changing landscape of expectations for drug delivery and other applications is driving the application of more than one encapsulation technique towards achieving goals such as in theragnostic applications. Bazylińska and colleagues [22] combined two encapsulation techniques (**Figure 1**), emulsion solvent evaporation and Layer by layer assembly (LbL) to engineer nanocapsules for dual fluorescence bioimaging and drug delivery.

Encapsulation processes have been classified broadly into physical and chemical techniques. There is no consensus over the third class, physicochemical techniques, and may be because the techniques only take the mechanism of capsule formation into consideration. However, each encapsulation technique involves processing that may involve mechanism not inherent in the name. For instance, emulsion solvent evaporation or in situ polymerization techniques are core chemical techniques but may involve physical processes such as mechanical stirring, homogenization, and sonication in achieving solvent evaporation. **Table 1** outlines the different classification of encapsulation techniques.

*Nano- and Microencapsulation - Techniques and Applications*

The merits and demerits of encapsulation are viewed from the expected outcomes of encapsulation and are based on physicochemical properties of core materials (small molecules, biologics, or diagnostics), encapsulating techniques and materials. Encapsulating materials such as natural and semi-synthetic polymers have many advantages because they are obtained from natural sources. Immunogenicity issues when natural polymers are used as the encapsulating materials are greatly reduced compared to synthetic polymers. Encapsulation using natural polymers can be done without high temperatures thus preventing degradation due to high temperatures as seen in alginate–chitosan micro/nanoparticles which were successfully fabricated at room temperature excluding the utilization

Encapsulation of an active compound using pegylated phospholipids also known as lipopolymers such as 2000 Da PEG-DSPE have demonstrated the merit of prolonging circulation time of active compounds when administered as nanoliposomes. This led to a reduction in the dosage frequency and reduction in uptake by the RES, thus leading to an increase in patient compliance as was observed in the first FDA approved nanomedicine; liposomal doxorubicin Doxil® in 1995 [15]. Efficacious poorly water-soluble drug candidates for therapeutics before now posed a challenge in formulation due to their low solubility profile and pharmacokinetic characteristics [16]. Micro- and nanoencapsulation technologies such as supramolecular hydrogels formulated with natural cyclic oligosaccharides also called cyclodextrins have successfully been able to encapsulate and deliver such drug candidates. This was demonstrated when lipophilic non-hydroxylated coumarins were encapsulated in the core of β-cyclodextrin hydrogels for trypanocidal activity via mitochondrial membrane potential studies for Chagas disease caused by the protozoan parasite, *Trypanosoma cruzi.* Trypanocidal activity was increased by 10% with the Supramolecular hydrogels of β-cyclodextrin linked to calcium homopoly-L-

guluronate as compared to the free corresponding amidocoumarins [17, 18].

Demerits of natural and semi-synthetic polymers in micro- and nanoencapsulation mainly depends on the individual materials. However, a major drawback observed with natural polymers and their derivatives is batch to batch variation depending on regions/environments that these polymers were sourced from. Plant and animals of the same species have been found to have some slight differences in their composition based on factors such as type of soil or geographical regions [19, 20]. Low mechanical strength leading to weak wall formation, susceptibility to change in pH causing a reduction in stability, highly hygroscopic leading to denaturation are challenges that are observed with such polymers as alginate, gelatin and

To overcome the demerits of these polymers, physical and chemical modifications are undertaken. Extra care should be taken during storage of natural polymers to reduce degradation and denaturation that occur during storage. Despite any demerits that natural polymers and their derivatives may have, the application of natural polymers and their derivatives for micro- and nanoencapsulation will continue to increase because of their immense merits in therapeutics and diagnostics.

The process of enclosing vesicles in a thin continuous film of a natural or semi synthetic polymer has been accomplished using a variety of both physical and chemical methods or a combination of both depending on the size of the targeted

**3. Merits and demerits of encapsulation**

of organic solvents [4].

sodium hyaluronate [8].

**4. Encapsulation techniques**

**6**


**9**

personalizing each process.

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

below are common to most physical encapsulation techniques.

spinning disc atomizers. There are a variety of archetypes for each.

Physical/mechanical encapsulation techniques involve formation of micro or nanocapsules by a transformation in the physical attributes of a droplet such as its size or a change from a liquid droplet to a solid droplet. Some steps as discussed

Atomization: This a process whereby tiny droplets are created from a liquid by dispersion in a gas phase. A range of atomization methods are available and can be adapted to various techniques. These are pressure nozzles, vibrating nozzles, and

Spray drying is a widely used encapsulation method that dates to the early

fifties. It also serves as a means of microcapsule recovery for many other encapsulation methods. The process involves dispersion of the core material in a solution of the shell material (most commonly water or cosolvents) to form a dispersion, emulsion or suspension [23]. The resulting liquid is fed into the drying chamber at the same time atomized with hot air (nitrogen in rare gases) coming from sonic energy, pressure nozzle, two-fluid nozzle or veined wheel. The solvent is flash evaporated in the hot air stream leaving a free flowing solid of core encapsulated in the shell. It is a simple, flexible encapsulation method that yields consistently distributed particles size between 10 and 40 μm range and is amenable to automation [24]. The first step in the process is to dissolve the shell material in a solvent, most commonly water, and homogenize with the core active ingredient, most commonly hydrophobic. The film forming materials predominantly used in spray drying are hydrophilic natural polymers such as modified starch, gelatin, gum Arabic and maltodextrin. It is not uncommon to use blends of these polymers. The second step is to feed this dispersion into the drying chamber using a sprayer that atomizes it to droplets. Hot air fed into the chamber quickly evaporates the solvent leaving a deposit of the shell forming material around the core droplet. The encapsulated material is then collected through a separator that separates the product from the exhaust air. Even though spray coating is one of the most common and industrialized encapsulation methods particularly for lipids, flavors, aromas and pigment, the process is beset with low thermal efficiency, nozzle clogging, high maintenance cost and product loss [21]. Optimization of process parameters such as inlet temperature, nozzle diameter, liquid feed viscosity and flow rate, gas flow rate, atomization pressure, temperature distribution efficiency and drying rate can minimize negative outcomes in terms of morphology, size and size distribution of the product [25]. Zang and coworkers [26] explored the influence of process parameters on the physical characteristics of tea tree oil microcapsules. They found that there is a need to strike a balance in inlet temperature as an extremely high temperature cracked the microcapsules while an extremely low temperature led to the formation of droplets instead of microcapsules. More recently, Wei and colleagues [27] studied the influence of inlet temperature and precursor concentration among other parameters on the physicochemical properties of theophylline loaded chitosan-triphosphate particles prepared by spray drying. They showed that particle size increased with precursor concentration. In their study, the optimum temperature for making the targeted size of microcapsules was 130° C. Zhang and coworkers [26] found the optimum temperature for their targeted application in the range of 210°C - 215° C buttressing the need for

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

**4.1 Physical encapsulation techniques**

*4.1.1 Spray drying*

#### **4.1 Physical encapsulation techniques**

Physical/mechanical encapsulation techniques involve formation of micro or nanocapsules by a transformation in the physical attributes of a droplet such as its size or a change from a liquid droplet to a solid droplet. Some steps as discussed below are common to most physical encapsulation techniques.

Atomization: This a process whereby tiny droplets are created from a liquid by dispersion in a gas phase. A range of atomization methods are available and can be adapted to various techniques. These are pressure nozzles, vibrating nozzles, and spinning disc atomizers. There are a variety of archetypes for each.

#### *4.1.1 Spray drying*

*Nano- and Microencapsulation - Techniques and Applications*

**Physicochemical techniques**

**Chemical techniques**

**Polymerization**

**Physical/mechanical/thermal techniques**

**Coating**

• Pan

•

Spinning disc

• • • • • •

**Table 1.**

*Classification of encapsulation techniques.*

Single or twin screwed extrusion

Microextrusion

Electrohydrodynamics

Vibrating nozzle/annular jet (Coextrusion)

Centrifugal extrusion

Stationary nozzle

Coating

•

Fluid bed coating

**Atomization**

**Extrusion**

**Thermal**

> •

• • •

Phase inversion

• •

Sol–gel

Molecular inclusion

Spray congealing

•

Solvent extraction

Spray chilling

•

Solvent evaporation

Spray drying

•

Layer by Layer deposition

• • •

Interfacial

Emulsion

Suspension

**Coacervation**

**8**

Spray drying is a widely used encapsulation method that dates to the early fifties. It also serves as a means of microcapsule recovery for many other encapsulation methods. The process involves dispersion of the core material in a solution of the shell material (most commonly water or cosolvents) to form a dispersion, emulsion or suspension [23]. The resulting liquid is fed into the drying chamber at the same time atomized with hot air (nitrogen in rare gases) coming from sonic energy, pressure nozzle, two-fluid nozzle or veined wheel. The solvent is flash evaporated in the hot air stream leaving a free flowing solid of core encapsulated in the shell. It is a simple, flexible encapsulation method that yields consistently distributed particles size between 10 and 40 μm range and is amenable to automation [24]. The first step in the process is to dissolve the shell material in a solvent, most commonly water, and homogenize with the core active ingredient, most commonly hydrophobic. The film forming materials predominantly used in spray drying are hydrophilic natural polymers such as modified starch, gelatin, gum Arabic and maltodextrin. It is not uncommon to use blends of these polymers. The second step is to feed this dispersion into the drying chamber using a sprayer that atomizes it to droplets. Hot air fed into the chamber quickly evaporates the solvent leaving a deposit of the shell forming material around the core droplet. The encapsulated material is then collected through a separator that separates the product from the exhaust air. Even though spray coating is one of the most common and industrialized encapsulation methods particularly for lipids, flavors, aromas and pigment, the process is beset with low thermal efficiency, nozzle clogging, high maintenance cost and product loss [21]. Optimization of process parameters such as inlet temperature, nozzle diameter, liquid feed viscosity and flow rate, gas flow rate, atomization pressure, temperature distribution efficiency and drying rate can minimize negative outcomes in terms of morphology, size and size distribution of the product [25]. Zang and coworkers [26] explored the influence of process parameters on the physical characteristics of tea tree oil microcapsules. They found that there is a need to strike a balance in inlet temperature as an extremely high temperature cracked the microcapsules while an extremely low temperature led to the formation of droplets instead of microcapsules. More recently, Wei and colleagues [27] studied the influence of inlet temperature and precursor concentration among other parameters on the physicochemical properties of theophylline loaded chitosan-triphosphate particles prepared by spray drying. They showed that particle size increased with precursor concentration. In their study, the optimum temperature for making the targeted size of microcapsules was 130° C. Zhang and coworkers [26] found the optimum temperature for their targeted application in the range of 210°C - 215° C buttressing the need for personalizing each process.

#### *4.1.2 Prilling (spray congealing/spray chilling/spray cooling)*

This is an encapsulation technique in which a homogenized dispersion of core material in a molten shell material (spray congealing, Prilling) or thermally gelling matrix (spray chilling) is atomized by suspension in a gas phase at ambient or low temperature (usually air or nitrogen (gas or liquid) that causes rapid solidification of the shell material around the core material [28, 29]. When the melting point of the lipophilic matrix is above 45° C, solidification is brought about at ambient temperature in a spray cooling process but for matrixes with lower melting point, frozen gases are used, and the process known as two major steps are involved firstly of which is creating free falling drops from molten solid, strong solutions or slurries using spinning discs and baskets. The second is solidifying the drops individually in a countercurrent of cold air. The size of each droplet determines the final size of each sphere. The resulting encapsulates of this high productivity, grossly monodispersity technique are microspheres with sizes in the range of 60 to 2000 μm [28]. Prilling is a high throughput, relatively inexpensive, easy-to-operate technique that has found extensive use in the fertilizer industry. When used for food encapsulation, the process is limited by the possibility of granule agglomeration due to high temperatures. Most used shell materials are lipids, waxes, fats and gelling hydrocolloids. Russo and colleagues [30] recently explored the possibility of combining Zn and Ca cations as an ionic gelation agents for prednisolone encapsulated alginate beads developed with the Prilling technique. The calcium carbonate decomposed internally in the acidic environment releasing a gas that increased porosity of the microcapsules ultimately translating to buoyancy in the gastrointestinal fluid and extended hours of anti-inflammatory effect.

#### *4.1.3 Coating*

Coating as an encapsulation technique involves the deposition of a thin film of membrane around a solid particle or a liquid adsorbed onto a solid. Two approaches have been used. The traditional older pan coating and the air suspension coating or fluid bed coating.

Pan coating: Pan coating is old coating technique that dates to the 18th century and traditionally used for applying sugar and film coats to tablets and pellets measuring several millimeters. In encapsulation, it is generally used for core material measuring above 600 μm [31]. The process involves the application of a coating solution through a spray unto the granule bed in a rotating coating pan inclined at an angle and fitted on the inside with anti-slip bars or angled blade that enable circulation of the core material. Warm or room temperature air is continually introduced and removed through exhaust pipes to facilitate the drying of the coating solution. Coating pans can be conventional or vented with perforations that allow for the escape of the drying air through the powder bed [32].

Air suspension technique: This technique also known as fluid bed coating is the gold standard in coating. The core material is suspended in a stream of hot or ambient air (depending on the coating solution) in relation to a coating spray that can be applied in the same direction as the fluidized air, tangentially or in opposite direction. **Figure 2** shows the application from the bottom of the chamber also known as the Wurster set up. The air suspension technique has also been used for both drying and granulation. For encapsulation purposes, a powder bed is initially fluidized by a jet of hot or ambient air. Subsequently, a coating solution of the shell material is sprayed through an atomizing nozzle onto the fluidized particles depositing a coat, consequent to the evaporation of the solvent, on individual particles

**11**

**Figure 2.**

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

as they get to the top of the chamber. The exhaust air passes through a filter to the outside while the particles recycle to the base of the chamber and the coating cycle continues till adequately coated. Almost any type of wall material can be applied in the Wurster process [33]. The particle size ranges from less than 100 μm to 150 μm [24]. Uniformity of the coat and the size of the capsules depend on the size and type of spraying nozzle. The viscosity of the coating liquid, air inlet temperature and

flow rate must be optimized for each application.

*Schematic representation of the Wurster set up [34].*

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

*Natural Polymers in Micro- and Nanoencapsulation for Therapeutic and Diagnostic… DOI: http://dx.doi.org/10.5772/intechopen.94856*

**Figure 2.** *Schematic representation of the Wurster set up [34].*

as they get to the top of the chamber. The exhaust air passes through a filter to the outside while the particles recycle to the base of the chamber and the coating cycle continues till adequately coated. Almost any type of wall material can be applied in the Wurster process [33]. The particle size ranges from less than 100 μm to 150 μm [24]. Uniformity of the coat and the size of the capsules depend on the size and type of spraying nozzle. The viscosity of the coating liquid, air inlet temperature and flow rate must be optimized for each application.

*Nano- and Microencapsulation - Techniques and Applications*

anti-inflammatory effect.

*4.1.3 Coating*

fluid bed coating.

*4.1.2 Prilling (spray congealing/spray chilling/spray cooling)*

This is an encapsulation technique in which a homogenized dispersion of core material in a molten shell material (spray congealing, Prilling) or thermally gelling matrix (spray chilling) is atomized by suspension in a gas phase at ambient or low temperature (usually air or nitrogen (gas or liquid) that causes rapid solidification of the shell material around the core material [28, 29]. When the melting point of the lipophilic matrix is above 45° C, solidification is brought about at ambient temperature in a spray cooling process but for matrixes with lower melting point, frozen gases are used, and the process known as two major steps are involved firstly of which is creating free falling drops from molten solid, strong solutions or slurries using spinning discs and baskets. The second is solidifying the drops individually in a countercurrent of cold air. The size of each droplet determines the final size of each sphere. The resulting encapsulates of this high productivity, grossly monodispersity technique are microspheres with sizes in the range of 60 to 2000 μm [28]. Prilling is a high throughput, relatively inexpensive, easy-to-operate technique that has found extensive use in the fertilizer industry. When used for food encapsulation, the process is limited by the possibility of granule agglomeration due to high temperatures. Most used shell materials are lipids, waxes, fats and gelling hydrocolloids. Russo and colleagues [30] recently explored the possibility of combining Zn and Ca cations as an ionic gelation agents for prednisolone encapsulated alginate beads developed with the Prilling technique. The calcium carbonate decomposed internally in the acidic environment releasing a gas that increased porosity of the microcapsules ultimately translating to buoyancy in the gastrointestinal fluid and extended hours of

Coating as an encapsulation technique involves the deposition of a thin film of membrane around a solid particle or a liquid adsorbed onto a solid. Two approaches have been used. The traditional older pan coating and the air suspension coating or

Pan coating: Pan coating is old coating technique that dates to the 18th century

Air suspension technique: This technique also known as fluid bed coating is the gold standard in coating. The core material is suspended in a stream of hot or ambient air (depending on the coating solution) in relation to a coating spray that can be applied in the same direction as the fluidized air, tangentially or in opposite direction. **Figure 2** shows the application from the bottom of the chamber also known as the Wurster set up. The air suspension technique has also been used for both drying and granulation. For encapsulation purposes, a powder bed is initially fluidized by a jet of hot or ambient air. Subsequently, a coating solution of the shell material is sprayed through an atomizing nozzle onto the fluidized particles depositing a coat, consequent to the evaporation of the solvent, on individual particles

and traditionally used for applying sugar and film coats to tablets and pellets measuring several millimeters. In encapsulation, it is generally used for core material measuring above 600 μm [31]. The process involves the application of a coating solution through a spray unto the granule bed in a rotating coating pan inclined at an angle and fitted on the inside with anti-slip bars or angled blade that enable circulation of the core material. Warm or room temperature air is continually introduced and removed through exhaust pipes to facilitate the drying of the coating solution. Coating pans can be conventional or vented with perforations that

allow for the escape of the drying air through the powder bed [32].

**10**

#### *4.1.4 Extrusion*

Generally, extrusion is a process in which a material is subjected to some form of compression that bring about a change in its physical properties as it is pushed through the orifice or die of an extruder, that is made up of one or two screws, under controlled conditions [35]. The core material is blended with the polymeric shell material in a molecular mixing to form a solid dispersion or solution. The solid dispersion is then passed through extruders to produce submicron capsules. A variety of extruders and nozzles configuration exists for different applications.

Extrusion-spheronisation: In this technique, the core material is intimately combined with the shell material and extruded into cylindrical mass that is subsequently broken up and rounded into spheres [36]. Muley and coworkers [36] described a variety of extruders to include sieve, basket, ram, screw and roll extruders.

Hot melt extrusion (HME): This continuous process technique originated for the food, plastic and rubber industries in the early nineteenth century but was applied much later in the pharmaceutical industry for product development and manufacturing of poorly soluble drugs. It involves pumping polymeric material that serves as the shell and the API through screw extruders at temperatures above their glass transition or gelling (and sometimes, melting) temperature to achieve molecular mixing of the component as shown in **Figure 3** [37].

The rotating screw pushes the feed towards the orifice whilst generating frictional heat that increases the viscosity of the feed as it melts. The extrudate is shaped by passing through a flake forming calendar roll or a pellet forming rotary knives, traveling shears or saws as it leaves the orifice. Materials capable of HME processing must be capable of deformation inside the extruder and individually capable of physically and chemically withstanding high temperatures. Waxes find extensive use as inert carrier materials for HME process. Starches, sugars, and sugar alcohols have also been used. Plasticizers such as acetic acid, stearic acid, citric acid, salicylic acid and triethyl citrate are used to alleviate the temperature effects in the HME process.

**Figure 3.**

*A schematic diagram of the hot melt extrusion process used in the encapsulation of Angelica gigas Nakai (AGN) [38].*

**13**

**Figure 4.**

*Schematic representation of the co-extrusion technique.*

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

Gately and colleague [39] explored the possibility of using a natural polymer, shellac as a low temperature extrudable polymer in the encapsulation of a probiotic powder. They found that not only was it possible, but the probiotic powder had an additional plasticizing effect on the extrudates. Melt extrusion and its earlier variant, melt injection has found extensive use as an encapsulation technique especially for fragrances and flavors due to the lower energy requirement, minimal emission of odor fouled exhaust, no requirement for solvent, and possibility for large volume encapsulation [40]. In addition, extrusion encapsulations impart longer stability on flavors and lower degradation for enzymes, when compared to other encapsulation methods like spray drying [39]. Glassy carbohydrates, polysaccharides, proteins and their blends have all been used as carrier polymers for melt extrusion encapsulated flavors [41]. Carnauba wax was also recently used for melt encapsulation of Quercetin [42].

Coextrusion is a variation of the extrusion technique that involves two concentric nozzles through which the core and shell material are extruded individually and exiting the nozzle as a single drop of core material encapsulated in the shell. It is designed primarily for liquid materials and the process schematically represented in **Figure 4**. The core material and the shell material do not mix unlike in the extrusion technique. The liquid shell material is pumped through the outer nozzle while the core material is extruded through the inner nozzle. The stream of liquid forms a laminar that is broken into discrete drops of the core enveloped by the shell. The drops are received in a curing liquid that hardens the encapsulated product [43]. It has been shown that coextrusion encapsulation technique offers better protection against instability in encapsulated aroma oils than extrusion technique [44].

Additionally, extrusion yields matrix spheres in which there is an intimate mixture between the shell and the core. Whereas in coextrusion, the core is separated from and covered by the shell. Sodium alginate has extensively been used as a shell

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

*4.1.5 Coextrusion*

#### *Natural Polymers in Micro- and Nanoencapsulation for Therapeutic and Diagnostic… DOI: http://dx.doi.org/10.5772/intechopen.94856*

Gately and colleague [39] explored the possibility of using a natural polymer, shellac as a low temperature extrudable polymer in the encapsulation of a probiotic powder. They found that not only was it possible, but the probiotic powder had an additional plasticizing effect on the extrudates. Melt extrusion and its earlier variant, melt injection has found extensive use as an encapsulation technique especially for fragrances and flavors due to the lower energy requirement, minimal emission of odor fouled exhaust, no requirement for solvent, and possibility for large volume encapsulation [40]. In addition, extrusion encapsulations impart longer stability on flavors and lower degradation for enzymes, when compared to other encapsulation methods like spray drying [39]. Glassy carbohydrates, polysaccharides, proteins and their blends have all been used as carrier polymers for melt extrusion encapsulated flavors [41]. Carnauba wax was also recently used for melt encapsulation of Quercetin [42].

## *4.1.5 Coextrusion*

*Nano- and Microencapsulation - Techniques and Applications*

mixing of the component as shown in **Figure 3** [37].

Generally, extrusion is a process in which a material is subjected to some form of compression that bring about a change in its physical properties as it is pushed through the orifice or die of an extruder, that is made up of one or two screws, under controlled conditions [35]. The core material is blended with the polymeric shell material in a molecular mixing to form a solid dispersion or solution. The solid dispersion is then passed through extruders to produce submicron capsules. A variety of extruders and nozzles configuration exists for different applications. Extrusion-spheronisation: In this technique, the core material is intimately combined with the shell material and extruded into cylindrical mass that is subsequently broken up and rounded into spheres [36]. Muley and coworkers [36] described a variety of extruders to include sieve, basket, ram, screw and roll

Hot melt extrusion (HME): This continuous process technique originated for the food, plastic and rubber industries in the early nineteenth century but was applied much later in the pharmaceutical industry for product development and manufacturing of poorly soluble drugs. It involves pumping polymeric material that serves as the shell and the API through screw extruders at temperatures above their glass transition or gelling (and sometimes, melting) temperature to achieve molecular

The rotating screw pushes the feed towards the orifice whilst generating frictional heat that increases the viscosity of the feed as it melts. The extrudate is shaped by passing through a flake forming calendar roll or a pellet forming rotary knives, traveling shears or saws as it leaves the orifice. Materials capable of HME processing must be capable of deformation inside the extruder and individually capable of physically and chemically withstanding high temperatures. Waxes find extensive use as inert carrier materials for HME process. Starches, sugars, and sugar alcohols have also been used. Plasticizers such as acetic acid, stearic acid, citric acid, salicylic acid and triethyl citrate are used to alleviate the temperature effects in the HME process.

*A schematic diagram of the hot melt extrusion process used in the encapsulation of Angelica gigas Nakai* 

*4.1.4 Extrusion*

extruders.

**12**

**Figure 3.**

*(AGN) [38].*

Coextrusion is a variation of the extrusion technique that involves two concentric nozzles through which the core and shell material are extruded individually and exiting the nozzle as a single drop of core material encapsulated in the shell. It is designed primarily for liquid materials and the process schematically represented in **Figure 4**. The core material and the shell material do not mix unlike in the extrusion technique. The liquid shell material is pumped through the outer nozzle while the core material is extruded through the inner nozzle. The stream of liquid forms a laminar that is broken into discrete drops of the core enveloped by the shell. The drops are received in a curing liquid that hardens the encapsulated product [43]. It has been shown that coextrusion encapsulation technique offers better protection against instability in encapsulated aroma oils than extrusion technique [44].

Additionally, extrusion yields matrix spheres in which there is an intimate mixture between the shell and the core. Whereas in coextrusion, the core is separated from and covered by the shell. Sodium alginate has extensively been used as a shell

**Figure 4.** *Schematic representation of the co-extrusion technique.*

forming polymer which is usually cured by ionic interactions with divalent cations. Silva and colleagues [44] compared the extrusion technique with co-extrusion for the encapsulation of probiotic, *Lactobacillus acidophilus* LA3 using a blend of alginate and shellac. They found that co-extrusion using sunflower oil as a carrier for the probiotic provided additional stability.

Centrifugal extrusion: This variation of co-extrusion is a liquid extrusion technique that makes use of a spinning extrusion head that carries the concentric nozzles. The concentric feeding tube serves as a tributary to the many concentric nozzles located at the surface of the device. As the spinning head rotates, the inner core and the outer shell material are extruded in flow that break into droplets as it makes its way from the nozzles (**Figure 5**). The particle size of extrudates can be as small as 150 μm. The particles harden by solvent evaporation as they take flight from the device.
