MOJ Current Research & Reviews

Research Article Open Access

Review on micro-encapsulation with Chitosan for

pharmaceuticals applications
Abstract Volume 1 Issue 2 - 2018

There is evidence that several systematic researches recognized the importance

of using polymers in drugs manufacturing. Natural polymers are usually biocompatible, Abdelkader Hassani, Siti Aslina Hussain,
biodegradable and non-expensive like chitosan. Chitosan is one of the natural biodegradable Norhafizah Abdullah, Suryani Kmaruddin
groups of polymers that have been extensively used for microencapsulation of drugs like Department of Chemical and Environmental Engineering,
isoniazid, propranolol and aspirin. This natural polysaccharide has many pharmaceuticals Universiti Putra Malaysia, Malaysia
applications, such as oral and parenteral delivery of drugs. It is important for a wide range
of scientific and industrial processes to know the applications of chitosan microparticles Correspondence: Siti Aslina Hussain, Department of Chemical
loaded drugs in pharmaceuticals fields. Recently, this issue was the objective of many and Environmental Engineering, Faculty of Engineering, Universiti
Putra Malaysia, 43300 UPM Serdang, Selangor, Malaysia, Tel 03-
research papers in the literature. Chitosan can also be combined with other polymer to
89466292, Fax 86567120, Email [email protected]
encapsulate many drugs in order to achieve targets with performance delivery. Recent
advances in microencapsulation methods have facilitated investigation of chitosan usage Received: April 4, 2018 | Published: April 24, 2018
to load drugs. This review about the preparation of chitosan-based-micro and particles by
many fabrications methods of pharmaceutical applications including coacervation, drying
techniques, ionic cross-linking, ionotropic gelation and emulsion solvent diffusion method.

Keywords: Polymer, emulsion, chitosan, drug delivery systems, ionotropic gelation

Introduction of a microcapsule is generally made from polymer or wax. In order

to reach the adequate release kinetics of the core, many accuracy
Background controls of shell thickness and density can take place. Microcapsule is
As one of the most important forms of drugs and compounds used also with well-defined core material that contains reservoir-like
microencapsulation is disseminated in several industrial fields, structure and envelope/coat. There are many types of microcapsules
particularly in pharmaceutical industry with encapsulation of proteins that can be different in functions, compositions, and sizes. The final
drugs, it offers various advantages as drug delivery system. One of goal or site of microencapsulated product defines usually the type of
the benefits of this technique is the protection of active agent in order microcapsule. The entrapment of many substances such as solids,
to improve the effectiveness of medical treatment. The applications drugs, liquids, proteins, stem and bacterial cells can be made with
of microencapsulation augmented in many drugs form over the these small particles. With this variety of entrapment substances,
last two decades. Due its higher ratio of nitrogen (6.89%), chitosan microencapsulation has a large area of applications, like artificial
has a great economical interest as compared to other polymers like cell, tissue delivery, and drug delivery. Another significant use of
cellulose.1 Microencapsulation can also be used to increase the microencapsulation is microorganisms. In this area, vector systems
efficiency of many products in the industry. Moreover, it allows the can play an important role to deliver drugs into target cells. The
formulation of many pharmaceutical products, reforming and giving accumulation of bacteria such as clostridium salmonella in tumors in
them healthier and more properties as bioactive roles in the body.2 vivo can make them effective for cancer gene therapy vectors.5
Microencapsulation provides likely advantages for standard drug
delivery systems and is also recognized as unique transporter systems
for many pharmaceuticals. Even though important developments
have been made in the domain of microencapsulation techniques.
Microencapsulation has become increasingly important in the fields
of cell and pharmaceutical engineering. It helps to develop the drug
formulations and oral or parenteral delivery systems. At present, there
are many marketed microencapsulated products used for the delivery
of pharmaceutics.3 In this review, the term microencapsulation
includes microcapsules, microparticles, microspheres, and also
microemulsions. The term microsphere with small particles of solid
diffuse in a continuous polymer sell or matrix is used largely for a
homogeneous structure, which is made by one continuous phase, in
Figure 1 Microcapsule contained core and coat or shell.4
a solid matrix particle. Figure 1 shows microcapsule with core and
shell (coat). The active agent is usually melted or dissolved in the Definition of microencapsulation
same container as the active agent before accuracy article fabrication
treats into microspheres. On the other hand, microcapsule contains The term capsule states a solid structure of core and shell or
an inner core and an outer shell. The microcapsule core can be made core material and coating material as shown in Figure 2. The word
from liquid or solid and usually includes the active agent. The shell microcapsules imply the membrane surrounded particles or droplets

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Review on micro-encapsulation with Chitosan for pharmaceuticals applications ©2018 Hassani et al. 78

distributed in solid matrix.6 Microencapsulation can be defined which can be put it in the way for the use in the pharmaceutical
as the process of surrounding or enveloping a continuous phase of and biopharmaceutical research areas like vaccine technology,
polymeric substance within very tiny solid or liquid particle, yielding mucoadhesion, and permeation enhancement. However, chitosan
microcapsules or microparticles which are small and are made properties, such as low solubility in water and organic solvents reduce
of natural or synthetic polymers. The diameters of these flowing its exploitation for special functions. The chemical modification of
free particles are ranging from 1 to 1000μm.7 Microencapsulation the chain is the best process to enhance and impart new properties
makes available the processes of converting liquids to solids, and to chitosan. This delicate process made usually by grafting of active
also providing environmental protection with the characteristic of groups, without variation of the original skeleton in order to save the
control release of coated material. Majority of these characteristics initial characteristics. The protonation process in acid environment to
can be reached by various techniques, though the distinction of neutral solution can take place due to the pKa value of amino group
microencapsulation is the small size of the covered microparticles in chitosan (~6.5). The reaction depends on pH and the %DA (The
and their following use and adoption to a wide selection of dosage degree of deacetylation)-value. Hence, chitosan become bioadhesive
samples and pharmaceutical formulations, which until now may not and binds easily to surfaces that negatively charges like mucosal
have been practicable technically. membranes.9 Due to its biodegradability and biocompatibility, chitosan
improves the role of polar drugs through epithelial surfaces. Even so,
the major inconvenient of chitosan is the poor solubility in water,
which can limit its usage for many drugs formulations.10 This polymer
is soluble in acetate buffer solutions under pH of 6.5.11 Moreover, the
positive charge of chitosan skeleton giving rises to be more soluble
in neutral and basic solutions. An increase in solubility of chitosan
can be made despite of the protonation of amino group in acidic
solution. The practice of this property has a great importance on
biomedical applications when the chitosan is used to deliver drugs
to acidic environment targets.12 With regards to its excellent film-
Figure 2 Fundamental consideration of microencapsulation. forming ability and cationic characters, chitosan can also react with
polyanions and produce polyelectrolyte complexes. In addition to
Chitosan properties and its usage as a pharmaceutical that, the biological properties of this polymer have paved the way
encapsulating agent of easy usage, mostly in the fields of biomedical and pharmaceutical
applications.13 It has been reported that chitosan is considered as a good
Chitosan is one of the most used polymers as an encapsulate agent candidate for wound dressing due its hemostatic properties.14 Despite
in pharmaceutical industry. It is a natural, biodegradable, and linear of its antibacterial property, chitosan helps to restrict the risk of local
polysaccharide that consists of distributed β-(1-4)-linked N-acetyl- infection.15 Consequently, using its intrinsic properties, chitosan has
D-glucosamine (acetylated unit) and D-glucosamine (deacetylated a great potential used in common applications for the preparation of
unit). This non-toxic polymer is prepared by the treating of shrimp’s microspheres/nanospheres and microcapsules in pharmaceutical field.
chitin shells, crabs and other sea crustaceans. Figure 3 shows the There are many techniques used to encapsulate drugs with chitosan
process of deacetylation of chitin, which is the simple process to such as coacervation, and ionotropic gelation.16 Table 1 shows
produce chitosan using sodium hydroxide and water. The reaction numerous biological and physicochemical properties of chitosan that
is made in two steps under high level activation energy.8 Previous influenced the usage in various applications and fields.
research has established that chitosan presents significant properties,

Figure 3 Scheme of N-deacetylation of chitin into chitosan.1

Techniques of microencapsulation process in techniques commonly result in products including numerous types of
pharmaceutical applications coated particles. The precise numbers of particles required to make
a form of single administered dose which can vary functionally in
Many techniques of microencapsulation have been commonly the final particle product size and can be kept in either the micro-
used as a carrier of drug delivery and improved drugs. These or nanometer type range for micro and nanoparticulate drug delivery

Citation: Hassani A, Hussain SA, Abdullah N, et al. Review on micro-encapsulation with Chitosan for pharmaceuticals applications. MOJ Curr Res & Rev.
2018;1(2):77‒84. DOI: 10.15406/mojcrr.2018.01.00013
 Copyright:
Review on micro-encapsulation with Chitosan for pharmaceuticals applications ©2018 Hassani et al. 79

systems respectively. Table 2 mentions various techniques that have the efficacy of therapeutics. As aforementioned, microencapsulation
been selected for microencapsulation. Generally they can be divided reduces dosage requirements and prolongs the stability of drugs.5
into two main basic groups, namely chemical and physical processes. Table 3 mentions numerous pharmaceutical applications of many
Microencapsulation process has greatly improved researches of microencapsulation techniques.
pharmaceutics in terms of drug delivery systems; thus, has increased
Table 1 Physicochemical and biological properties of chitosan17

Physicochemical properties of chitosan Biological properties of chitosan

Fundamental as a biocompatible, immunoadjuvant, biodegradable natural polymer,

Frequently prescribed for acts as an antacid
safe, and non toxic
Linear polyamine with reactive amino and hydroxyl Binds to microbial cells with antitumoral activity Has a pivotal role in the
groups available regenerative circle on connective gum tissue

Absorption and binds fat Fundamental as a spermicidal, fungistatic, hemostatic, and anticholesterimic

Promotes weight loss and helps accelerate the formulation of osteoblast cells
responsible for bone formation
Frequently prescribed to promote wound healing and depressant on central
nervous system

Antifungal, antibacterial and reduces low-density lipoprotein (LDL) cholesterol

Table 2 Microencapsulation techniques18

Chemical process Physical process Physico-chemical processes

Interfacial polymerization Spray drying Polymer incompatibility

Poly condensation Air-suspension coating Ionotropic gelation

Polyelectrolyte complexation Vibration nozzle Sol-gel encapsulation

Cryogenic solvent extraction Pan coating Supercritical Co2 assisted microencapsulation

Phase separation (Coacervation) Centrifugal extrusion

Solvent evaporation and extraction

Interfacial polymerization

Suspension polymerization

Complex coacervation

In situ polymerization

Emulsion Polymerization

Coacervation and phase separation

Matrix polymerization

Liposome technology

Citation: Hassani A, Hussain SA, Abdullah N, et al. Review on micro-encapsulation with Chitosan for pharmaceuticals applications. MOJ Curr Res & Rev.
2018;1(2):77‒84. DOI: 10.15406/mojcrr.2018.01.00013
 Copyright:
Review on micro-encapsulation with Chitosan for pharmaceuticals applications ©2018 Hassani et al. 80

Table 3 Microencapsulation techniques and examples of its pharmaceutical applications18

Microencapsulation
Drug (core materials) Applications Coating materials
techniques

Drug delivery system (ex: oral Poly (alkyl cyanoacrylate),

Insulin, doxorubicin Emulsion Polymerization
administration of insulin) poly(butylcyanoacrylate)

Amino acid, enzymes,

Drug delivery system Polyamide microcapsules Interfacial polymerization
antibody

Chlorothiazide Drug delivery system Protein (Albumin), polysaccharides Suspension crosslinking

(Polycaprolactone) and PLGA Solvent evaporation/

BSA (bovine serum albumin) Drug delivery system
-(poly(DL-lactic-co-glycolic acid) extraction

Encapsulation of liquid, solid Protein, Polysaccharides, Gelatin , Ethyl

Use gelatin and gum arabic
drug particles which have the cellulose, Gum arabic, Aqueous gelatin Coacervation/phase
(acacia) to encapsualte
ability to disperse in polymers solution, Gelatin–water–ethanol system, separation
pentobarbituric acid
solutions cellulose acetate phthalate solution

Microencapsulation of
Diphtheria toxoid Leuprorelin sensitive compounds and Polylactic acid (PLA, and poly(lactic-co- W/O/W-double emulsion
acetate Tetanus toxoid water-soluble (proteins, glycolic) acid (PLGA) technique
peptides, vaccines)
Recombinant hepatitis B
surface antigen Bromocriptine
Progesterone and To encapsulate sensitive
Poly(L-lactic acid), PLGA Stearylamine
theophylline Recombinant substances such as essential Spray drying
containing cationic microspheres
humane rythropoietin oils,vitamins and fragrance
(rhEPO) Recombinant human
growth hormone (rh-GH)

Allogenic and xenogenic Microencapsulation and AN-69 (copolymer of sodium methallyl

Co-extrusion
hepatocytes transplantation sulfonate and acrylonitrile)

Improve the dissolution rate

Felodipine (FLD) Poly-(ethylene glycol) PEG 4000 Supercritical fluid expansion
of drugs

Techniques of microencapsulation with Chitosan barriers at the emulsion interfaces droplet. To protect proteins during
the preparation of emulsion some approaches are available to stabilize
Many techniques have been used to encapsulate drugs with chitosan it against any damage of structure. The use of chitosan as a hydrophilic
such as ionotropic gelation, emulsion phase separation, cross-linking water-soluble polymer reduces the free energy of hydrophilic proteins.
with anions, emulsion solvent diffusion and coacervation.4 This employment need to know more about the type of hydrophilic
Emulsion cross-linking technique matrices which are used in this preparation. It has been demonstrated
that the type of cross-linking agent influenced the release rate. The
The formulation of polymeric microspheres and some final microspheres particles size can be affected by many factors such
microparticles based on emulsion method has recently become more as speed of stirring, cross-linking extent, and droplets size.21 Recent
useful. Hydrophobic biodegradable polymers, like (PLGA) poly study suggested a method which based on extrusion under pressure
(lactic-co-glycolic acid) are one of the most common groups used with aqueous solution of chitosan. This manufacturing method
on emulsions oil-in-water (O/W) or water-in-oil-in-water (W/O/W). used a membrane with systematic pores which incorporate inside a
Delivery system preparations based in water-soluble polymer need mixture of paraffin–petroleum ether. The final droplets dispersion of
the use of aqueous phase for dissolution of polymers. Consider chitosan was uniform in size and cross-linked with glutaraldehyde.
chitosan as an example. It dissolved in a weak acid solution like Tripolyphosphate (TPP) used to dissolve the peptidic drug in the
acid acetic despite of its pH-dependant solubility. Figure 4 shows chitosan solution and added the glutaraldehyde as a stabilizer. Using
the process of emulsion cross linking using suitable surfactants as soaking process bovine serum albumin (BSA) was adsorbed in this
emulsion stabilizers as well as the aqueous phase including the drug, case. By the same taken the membrane was emulsified with cross-
is dispersed in an oil phase like oil of paraffin.19 On the other hand, the linking process including tripolyphosphate (TPP) and glutaraldehyde
contact between proteins and water-oil interfaces caused deterioration as a stabilizer. The use of TPP prevent dehydration while the cross-
because of the interfacial tension and the close levels of energy linking step took place by glutaraldehyde.22

Citation: Hassani A, Hussain SA, Abdullah N, et al. Review on micro-encapsulation with Chitosan for pharmaceuticals applications. MOJ Curr Res & Rev.
2018;1(2):77‒84. DOI: 10.15406/mojcrr.2018.01.00013
 Copyright:
Review on micro-encapsulation with Chitosan for pharmaceuticals applications ©2018 Hassani et al. 81

Figure 4 Emulsion cross-linking method.20

Drying techniques efficiency. For nasal delivery of vaccines, BSA also was encapsulated
in chitosan microspheres in order to induce Immunoglobulin G
These techniques include spray drying and supercritical fluid (IgG) as an antigen-specific. These microspheres is then loaded with
drying. cetylpyridinium chloride used as an anti infective agent, followed
Spray drying by the addition of cross-linking agent.25 In terms of nanosystem
applications by spray drying, chitosan nanoparticle loaded mannitol
This process is the most commonly drying method used to prepare microspheres in order to transport therapeutic protein drug to the
microparticles based on chitosan and chitosan derivatives. After the lungs. Nanoparticles were cross-linked with trypolyphosphate
dissolution of chitosan in an aqueous medium the drug is dispersed in and loaded with BSA using ionic gelation process. The suspension
this solution. Tripolyphosphate solvent used to overcome the problem result was spray-dried to produce dry powders of BSA-chitosan-
of poor solubility of non-cross-linked chitosan in aqueous media. The TPP nanoparticles. The characterization of the dispersion chitosan
addition of natural cross-linking agents improves biocompatibility nanoparticles and mannitol in microspheres was made using time-
and performance of drugs. Hence, free-flowing particles can be of-flight secondary ion mass spectroscopy, X-ray photoelectron
produced after the solvent evaporation and atomization of small spectroscopy, and confocal laser scanning microscopy (CLSM).
droplets.23 To obtain the suitable particle size many parameters should Mannitol used as a stabilizer of protein structure enhanced the
be controlled, such as extent of cross-linking, atomization pressure, aerosolization of protein drugs into lungs.26
the spray flow rate, size of the nozzle, and inlet air temperature. The
use of adequate excipient reduces the risk of thermal degradation Supercritical fluid drying
during the spray drying process. Polysorbate 20 can be used as Usually, supercritical fluid process with carbon dioxide (CO2)
protective agent of proteins from denaturation due to high shear rates used to prepare diverse pharmaceutical applications despite of the low
during atomization step.24 Previously, bovine serum albumin (BSA) pressure and temperature. The process is nontoxic, nonflammable,
was loaded as a protein type in microparticles using spray drying and ensures the minimal decomposition of drugs like proteins. It
process. The characterization of physicochemical properties and provides also the possibility to prepare microparticles especially
integrity of protein encapsulated was made by circular dichroism and which are oriented for inhalation. As an example of loading drug or
sodium dodecyl sulphate–polyacrylamide gel electrophoresis . The biopharmaceuticals into chitosan or chitosan derivatives, N-trimethyl-
incorporation of BSA at high loading levels retained the integrity of chitosan (TMC) microparticles were produced by spray drying process
protein entrapped. In consequence, the use of spray drying process using the solution of albumin polymer including water, dimethyl
to prepare chitosan microparticles including proteins has a good sulfoxide DMSO, and supercritical CO2 (SC-CO2 ) as an antisolvent.

Citation: Hassani A, Hussain SA, Abdullah N, et al. Review on micro-encapsulation with Chitosan for pharmaceuticals applications. MOJ Curr Res & Rev.
2018;1(2):77‒84. DOI: 10.15406/mojcrr.2018.01.00013
 Copyright:
Review on micro-encapsulation with Chitosan for pharmaceuticals applications ©2018 Hassani et al. 82

After that, DMSO water solution was added to the mixture in order of chitosan naoparticles to deliver polypeptides such as diphtheria
to dissolve albumin and TMC. Thus they obtained spherical non and tetanus toxoid.29 In previous research, chitosan microparticles
agglomerated microspheres suitable for inhalation.27 were formulated by ionotropic gelation and emulsification modified
using tripolyphosphate, calcium and citrate as anions. As a result, an
Ionic cross-linking method electrostatic interaction between chitosan and anions was carried out
Ionic cross-linking are one of the most widely used methods for by various solutions. Among these approaches, various formulations
the preparation of chitosan microparticles. It have been extensively of nanoparticles based on chitosan and Arabic gum were prepared
used for loading biopharmaceuticals. Moreover, this method does using ionic gelation method for oral delivery of insulin. The solubility
not support the use of organic solvent especially solvents with high of chitosan and the pH values influenced the release of insulin. Hence,
temperatures. The ionic interactions between anionic charged of the diffusion of polymer affect the release controlled released of
molecules and the positively charged of chitosan amino groups has a protein.29
pivotal role in the formation of microparticles. Two main groups have
been used as anionic cross-linkers: anionic low-MW molecules, like
cyclodextrin derivatives or TPP; and anionic macromolecules, such
as poly-y-glutamic acid, dextran sulfate, hyaluronic acid, and sodium
alginate.20

Coacervation and precipitation method

This process is particularly useful to study the insolubility of
chitosan in alkaline solution. Sodium hydroxide used to blow chitosan
solution in order to prepare particles as shown in Figure 6. Drops was
synthesised using air nozzle and ethanediamine or sodium hydroxide
solutions. Blowing chitosan solution is one of the most common
procedures for preparing drops. Recombinant interleukin-2 (rIL-
2) encapsulated into microparticles using sodium sulfate and acidic
chitosan. Microparticles separation was carried out by centrifugation Figure 6 Representation of ionic gelation method.26
and freeze dried. The loaded process was made by adding protein to
sodium sulfate. The control of chitosan concentration, protein amount Emulsion solvent diffusion
and volume of sodium sulphate solution were carried out in this study.
Recently, the use of biodegradable polymers in microparticles
As a result, the encapsulated amount of rIL-2 was increased when the
and nanoparticles has increased in spite of their adequate properties
protein amount increased Figure 5.28
and potential pharmaceutical applications. Numerous of processes
have been reported for the preparation of nanoparticles drug delivery
systems. Therefore, the efficacy of simple emulsion process remains
to be identified. It may expect that emulsification solvent diffusion
could be considered as a suitable process to formulate chitosan-based
micro- and nanoparticles. Ethyl acetate and chitosan solution were
used to prepare water-in-oil emulsion using Gentamicin sulfate as
encapsulated drug. Chitosan was used as a coated material as well as
Tripolyphosphate was added as a cross-inker agent. The result obtained
did not mention any influence of the cross liker agent on shape and
size of microparticles. The most important relevant finding was the
decrease of drug release rates as well as the increase of cross linker
amount.30 There are relatively few studies in the process of emulsion
solvent diffusion. This method was developed to prepare poly (lactic-
Figure 5 Process of coacervation and precipitation.20
co-glycolic) acid PLGA nanoparticles. The partial miscibility of the
Ionotropic gelation method organic solvent is a common condition which has a considerable
impact on the procedure. There is a growing body of literature
This process is one of the most common procedures for preparing that recognizes the importance of this process in pharmaceutical
chitosan nanoparticles using tripolyphosphate as a crosslinking applications based on chitosan. The process-based on the addition
agent as shows in Figure 6. A major advantage of this method was of hydrophobic drug dissolved in an organic solvent to an aqueous
related to its mild conditions attained. It was selected for its reliability phase contained chitosan using stabilizer ingredient like lecithin.
and validity for sensitive proteins without using harmful organic As a result, the simple water-in-oil O/W emulsion was formed upon
solvent and heat or agitation vigorous. Therefore, it has the ability high-pressure homogenisation. The addition of acetone decreased the
to retain bioactive molecules such as proteins, DNA, etc. it has solubility of chitosan. Hence, the isolation of nanoparticles was made
been established that chitosan nanoparticles have a good efficacy to using centrifugation process Figure 7.26
associate with proteins. More recent attention has focused on the use

Citation: Hassani A, Hussain SA, Abdullah N, et al. Review on micro-encapsulation with Chitosan for pharmaceuticals applications. MOJ Curr Res & Rev.
2018;1(2):77‒84. DOI: 10.15406/mojcrr.2018.01.00013
 Copyright:
Review on micro-encapsulation with Chitosan for pharmaceuticals applications ©2018 Hassani et al. 83

Figure 7 Representation of emulsion solvent diffusion.26

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