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Microencapsulation techniques and its practices

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 Int J Pharma Sci Tech (© 2011)
Int J Pharma Sci Tech (© 2011)
Vol-6, Issue - 2, July - December-2011
ISSN : 0975-0525 (Print)
REVIEW ARTICLE
MICROENCAPSULATION TECHNIQUES AND ITS PRACTICE
Sanjoy Kumar Das1, 2*, Sheba Rani Nakka David 3, Rajan Rajabalaya3,
1 2 2 2
Hirak Kumar Mukhopadhyay , Tripti Halder , Mohanraj Palanisamy , Jasmina Khanam ,
21
Arunabha Nanda Institute of Pharmacy, Jalpaiguri, Pin: 735101, West Bengal, India
2
Department of Pharmaceutical Technology, Jadavpur University,
Kolkata 700032, West Bengal, India
3
School of Pharmacy & Health Sciences, International Medical University,
No.126, Jalan Jalil Perkasa 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
Received : 22/08/2011 ; Accepted : 17/11/2011 ; Published : 30/12/2011.
ABSTRACT
Microencapsulation is the enveloping of liquid droplets or fine solid particles to form
microcapsule, having an average diameter as small as 1 μm to several hundred micrometers.
Microencapsulation technology is of interest to a wide range of industries, including
pharmaceutical, food, agricultural, biotechnological, cosmetic and other industries with various
significant advantages, including: (i) an effective protection of the encapsulated active ingredient
against degradation, (ii) the possibility to control the release rate of the active ingredient. This
review paper will address the historical background of microencapsulation technology,
commonly used microencapsulation methods with its advantages and disadvantages and its
applications in pharmaceutical, food, agricultural, biotechnological and cosmetic field. It also
focuses on the influence of process parameters, residual solvent and cross linking agents as
described in the scientific journal and patent literature. Microencapsulation methods are divided
into two basic groups, namely chemical and physical. Each method has its own advantages as
well as disadvantages. However most of the commonly used methods have several disadvantages
such as unfavorable conditions for the core material, complexity in procedure and low
encapsulation efficiency. The results indicate that the number of process variables that should be
optimized during core material encapsulation. The dependence so many process variables may
become a problem in terms of reproducibility and scale-up process. Based on the existing results
and authors' reflection, this review gives rise to reasoning and suggested choices of process
parameters and microencapsulation procedure.

Key words: Applications, Capsule shell, Microcapsules, Microencapsulation technology,

Polymers.

Address for Correspondence: INTRODUCTION

Sanjoy Kumar Das*, Microencapsulation is defined as the application
Institute of Pharmacy, of a thin polymeric coating to individual core
Jalpaiguri, Pin: 735101, materials (tiny particles or droplets of liquids and
West Bengal, India. dispersions) that have an arbitrary particle size
Tel.: +91-3651-230057; range from 5-5000 μm to give small capsules with
Fax: +91-3651-221884. many useful properties (Bakan 1986; Onfrio et al.
E-mail address: sanjoydasju@gmail.com 1979; Radwick and Burgess 2002).

Vol-6, Issue - 2, July - December-2011 Page – 1


Microencapsulation is a modified form of film
coating, differing only in the size of the
particles to be coated and the method by which
this is produced (Bandi et al. 2004). Now a days
microencapsulation forms the basis of many
drug delivery systems which aim to give
control as to where and when a drug is
administered allowing it to degrade slowly
over a period of time, thus releasing its contents
at a controlled rate.
Microencapsulation of pharmaceuticals was
first investigated in 1931 by preparing gelatin
spheres using coacervation technique.
Processes and materials used for coating have
since been developed by the pharmaceutical
industry to aid in formulation of various dosage
forms such as tablets, capsules, injectables,
powders and topicals (Deasy 1984). The
resultant product of the microencapsulation
process is known as “microcapsule”. In a
relatively simpler form, a microcapsule is a
small sphere with a uniform wall around it. The
material inside the microcapsule is referred to
as the core, internal phase, or fill, where as the
wall is sometimes called a shell or coating.
Most microcapsules have diameters between a
few micrometers and a few millimeters.
Microcapsule ranges in size between 1 and
1000 μm. Capsules greater than 1000 μm (1
mm) can be called macrocapsules and those
smaller than 1μm are termed as nanocapsules.
The first truly successful commercial
development of a product using microcapsules
was carbonless copy paper by The National
Cash Register (NCR) of America in 1953, and
then microencapsulation technology was
further explored through encapsulation of
active ingredients in pharmaceutical industry.
Since then, microencapsulation technology has
been constantly improved, modified and
adapted for a variety of purposes and uses. A
wide range of core materials has been
encapsulated, including adhesives,
agrochemicals, live cells, active enzymes,
flavors, fragrances, vitamins, water and
pharmaceuticals. Most capsule shell or coating
materials are usually organic polymers but fats
and waxes are also used (Thies 1996; Chanda
Vol-6, Issue - 2, July - December-2011
Int J Pharma Sci Tech (© 2011)
and Roy 2007).This review is intended to give
a historical background of microencapsulation
tech n o lo g y, co mmo n ly u s ed
microencapsulation methods with its
advantages and disadvantages and its
applications in pharmaceutical, food,
agricultural, biotechnological and cosmetic
field.
Advantages of microencapsulation:
Microencapsulation offers great advantages
and the reasons for microencapsulations are
countless (Bakan 1986; Ghosh 2006;
Kamyshny and Magdassi 2006; Dubey et al.
2009). The main reasons for
microencapsulation can be summarized as
follows:
 Patients to consume lower doses for the
ame therapeutic effect;
 Lowers the risk of side effects;
 Masking of odor or taste for chewable
tablets, powders and suspensions for
children's medicines;
 Prolong action dosage form;
 Modify the physical characters of a
material which is required in certain
formulations;
 Protect chemicals against degradative
reactions such as oxidation,
dehydration;
 Controlled and targeted drug delivery;
 Diagnostic aids and medical
equipment design;
 Liquids can be handled as solids;
 Safe and convenient handling of toxic
substances;
Separation of incompatible components.
Morphology and types of microcapsules:
The morphology of microcapsules (Fig. 1)
depends mainly on the core material and the
deposition process of the shell. Microcapsules
may have regular or irregular shapes and, on
the basis of their morphology, can be classified
as mononuclear or continuous core/shell
microcapsule, multinuclear or polynuclear
microcapsule, and matrix microcapsule (Thies
1996; Ghosh 2006).
Mononuclear or Continuous core/shell
Page – 2

microcapsules have a spherical geometry with
a continuous core region surrounded by a
continuous shell. Multinuclear or polynuclear
microcapsules have an irregular geometry and
contain a number of small droplets or particles
of core material. In matrix microcapsule, the
core material is distributed homogeneously
into the shell material. The term
“microcapsule” is usually preferred if the
entrapped substance is completely surrounded
by a distinct capsule shell and the terms “matrix
microcapsules” or “microspheres” are used if
the entrapped substance is dispersed
throughout the microsphere matrix (Torrado
and Augsburger 2008). In addition to these
three basic morphologies, microcapsules can
also be dual-core and multilayer microcapsules
with single core or they may form cluster of
microcapsules (Ghosh 2006; Kamyshny and
Magdassi 2006).
Equipment and processing of
microencapsulation:
The equipment required to produce
microencapsulation varies from complex to
simple processing equipment. Microcapsules
as bulk materials are available in either dry
powder or in dispersed form. Microcapsules
can be processed into final product by using
common equipment such as V-blender, tablet
machine, granulator, homogenizer, kneader,
hard gelatin capsule filling machine or coating
Table I. Methods of microencapsulation.
Chemical
Physico-chemical
• Polymerization • Coacervation
In-situ Emulsion, • Solvent evaporation,
Suspension, Solvent extraction
Dispersion • Layer-by-layer adsorption
• Interfacial polycondensation • Complex precipitation
• Ionic gelation
•Supercritical Fluid precipitation
Vol-6, Issue - 2, July - December-2011
Int J Pharma Sci Tech (© 2011)
equipment. Selection of processing equipment
depends on the final product form desired and
on the properties of the microcapsule (Bakan
1986).
Methodology for microencapsulation:
Microencapsulation is a multidisciplinary field
based on the knowledge and methods of colloid
chemistry, polymer chemistry, physical
c h e m i s t r y, b i o c h e m i s t r y, p h y s i c s ,
biotechnology, and material science
(Kamyshny and Magdassi 2006). A wide
number of methodologies available for the
encapsulation of core material have been
reported (Arshady 1999; Ranney 1969).
Generally, microencapsulation methods are
divided into two basic groups, namely
chemical and physical, with the latter being
further subdivided into physico-chemical and
physico-mechanical techniques. This article
describes the most generally accepted
classification of the microencapsulation
methods, summarized in Table I.
The present discussion focuses on the different
microencapsulation methodologies that are
more relevant to the pharmaceutical industries.
The microencapsulation methods and their
applicabilities are given in Table II.
The microencapsulation methods to be
discussed are polymerization, interfacial
polycondensation, coacervation, solvent
evaporation, supercritical fluid precipitation,
Physical
Physico-mechanical
• Spray-drying and congealing
• Electrostatic encapsulation
• Pan coating
•Vacuum encapsulation
• Extrusion
• Air suspension
• Multiorifice-centrifugal
Page – 3

air suspension, pan coating, spray-drying and
congealing, and multiorifice-centrifugal
techniques.
Chemical methods:
In-situ processes such as emulsion,
Int J Pharma Sci Tech (© 2011)
polymerized using either a free radical initiator
or high energy irradiation (Chen et al. 1994).
The most common type of emulsion
polymerization is oil-in-water emulsion, in
which droplets of monomer are emulsified in a
continuous phase of water. The main

Table II. Microencapsulation methods and their applicabilities.

Microencapsulation methods Physical nature of the core material Approximate
particle size(μm)
Polymerization solids and liquids 1-1000
Interfacial polycondensation solids and liquids 3-2000
Coacervation solids and liquids 2-5000*
Solvent evaporation solids and liquids 5-5000*
Air suspension solids 35-5000*
Pan coating solids 600-5000*
Spray-drying and congealing solids and liquids 600
Multiorifice centrifugal solids and liquids 1-5000*
*The 5000 μm size is not a particle limitation; the methods are also applicable to macrocoating (Bakan 1986;
Wurster 1990)
suspension, dispersion polymerization and advantage of emulsion polymerization is that
interfacial polycondensations are the most the final product can be used as it is and does
important chemical techniques used for not generally need to be altered. The main
microencapsulation. disadvantages of this technique are that
Polymerization techniques surfactant and other adjuvant may remain in
In situ polymerization technology is closely the polymer or are difficult to remove.
related to interfacial polymerization and is Suspension polymerization is a polymerization
used to encapsulate water-immiscible liquids process that uses mechanical agitation to mix
and solids. Capsule shell formation occurs the monomer or mixture of monomers in a
because of the polymerization of monomers liquid phase such as water, polymerizing the
added to the encapsulation reactor. monomer droplets while they are dispersed by
Polymerization occurs in the continuous phase continuous agitation. It is a well known process
and on continuous phase side of the interface for formation of polymer particles generally in
formed by the dispersed core material and a size range of about 200 to 600 microns. The
continuous phases. Polymerization of the advantages of this method are that the product
reagents located there produces a prepolymer, may easily recovered and direct application of
relatively low molecular weight, and then this final product. It is difficult to make small
prepolymer grows in size, it deposits onto the particles as the particles tend to coalesce
surface of the dispersed core material being during the polymerization process.
encapsulated. Most of cases capsules formed Dispersion polymerization is based on
by these techniques have a continuous core- precipitation polymerization in which
shell structure. polymerization begins with a monomer
Emulsion polymerization is a method most dissolved in dispersion medium and ends with
frequently employed for the preparation of an insoluble polymer in spherical form (Chen
nanoparticles (10 to 1000 nm) and involves et al. 1994). The system becomes
emulsification of a hydrophobic monomer in heterogeneous after nucleation and
an aqueous phase with the monomer stabilization of microspheres against

Vol-6, Issue - 2, July - December-2011 Page – 4

 Int J Pharma Sci Tech (© 2011)
Table III. Currently marketed protein based biodegradable microspheres (Tamilvanan 2008;
Siepmann and Siepmann 2006; Sinha and Trehan 2003).
Drug Trade name Company Route Application
Leuprolide acetate Lupron Depot® Takeda-Abbott 3 months depot Prostate cancer/
suspension endometriosis
Leuprolide acetate Trenantone® Takeda 3 months depot Prostate cancer/
suspension endometriosis
Leuprolide acetate Enantone® Takeda 3 months depot Prostate cancer/
suspension endometriosis
Recombinant Nutropin depot® Genentech- Subcutaneous injection Growth hormone
human growth Alkermes deficiency
hormone
Goserelin acetate Zoladex® I. C. I. Subcutaneous Implant Prostate cancer
Octreotide acetate Sandostatin® LAR Novartis Injectable Subcutaneous GH suppression,
Depot suspension anticancer
Triptorelin Decapeptyl® Debiopharm Injectable depot Cancer
Risperidone Risperdal® Consta® Janssen Intramuscular injection Schizophrenia
Recombinant Posilac® Monsanto Injectable depot, oil based To increase milk
bovine somatropin injection production in cattle
Bromocriptine Parlodel LAR® Novartis Monthly injection Parkinsonism

agglomeration and by the adequate selection of polycarbonate, or polyurethane are used to

stabilizer, solvent, concentration of initiator
and cross linker, microspheres with sizes in the
range of 0.4-5 mμ can be prepared (Dragan and
Vlad 2006). This technique can produce not
only nanoparticles but also microparticles with
size up to 15 μm (Chen et al. 1994). The
limitation of this technique is that the
covalently attached or adsorbed stabilizers are
considered undesirable contaminants for
certain applications (Dragan and Vlad 2006).
Interfacial polycondensation
Interfacial polymerization or
polycondensation technique has been applied
to the microencapsulation of a wide range of
core materials, including aqueous solutions,
water-immiscible liquids and solids (Kondo
1978; Thies 1996; Marison et al. 2004). Solids
can be encapsulated by interfacial
polymerization reactions, although the
polymerization chemistry differs from that
used to encapsulate liquids. This technique is
one in which two monomers, one oil-soluble
and other water-soluble, are used and a
polymer is formed on the droplet surface (Fig.
2). Two reactants are bringing together at the
interface of the dispersed and continuous
phases in emulsion system by this process. The
various polymeric material e.g., polyurea,
polyamide, polysulfonamide, polyester,
prepare microcapsules by this technique
(Beestman 1987). The recovery of the
microcapsules from the continuous phase can
be done by spray drying, flash evaporation,
filtration or any other suitable separation
techniques (Baxter 1974). The main
disadvantage of this technique is that the
reagent is dissolved in the core material
therefore reagent may chemically react with
core material (Marison et al. 2004).
When the core material is water-immiscible
liquid, the monomer is dissolved in the liquid
core and then this solution is dispersed into the
continuous phase of aqueous solution
containing an emulsifier and a coreactant. This
produces polymerization at the interface,
which later forms the solid polycondensate
capsule wall (Beestman 1987; Hincal et al.
2000).
An aqueous solution of a water-soluble liquid
is dispersed into an organic phase with the
application of an emulsifier to form a water-in-
oil emulsion and then water-insoluble reactant
is added to the water-in-oil emulsion to form
capsule wall on the surface of liquid droplets
(Hincal et al. 2000).
Solid cores are generally encapsulated by vinyl
monomers that polymerize by free radical
reactions. Interfacial polymerizations have

Vol-6, Issue - 2, July - December-2011 Page – 5


been used to encapsulate oils (Alexandridou et
al. 1994), dye precursors (Tan et al. 1993),
proteins (Yeo et al. 2001), peptides (Allémann
et al. 1998), enzymes (Mori et al. 1972),
antibodies (Wallace et al. 1992), and cells
(Park et al. 2000). The particle size of the
product by this method varies in accordance
with the particle diameter of the dispersed
phase (Wurster 1990). The methods of
encapsulation used for an enzyme depends on
the nature and the stability of enzyme under the
conditions of microcapsule formation and on
further applications of microcapsules (Aisina
1992).
Many factors influence the capsule properties,
including composition of the capsule shell or
wall, degree of cross-linking, the capsule
thickness, which is determined by the amount
Figure 1. Morphology of microcapsules: (A) Mononuclear or Continuous core/shell
microcapsule (Thies 1996); (B) Multinuclear or polynuclear microcapsule (Thies 1996); (C)
Matrix microcapsule (Vyas and Khar 2002).
of emulsifying agent and the degree of
agitation (Marison et al. 2004). Capsules
formed by the interfacial polymerization
technique often have a continuous core-shell
structure with a spherical geometry. The
exterior surface of many capsules formed by
interfacial polymerization is smooth and
uniform whereas the interior surface is
generally irregular. High temperature is not
favorable in interfacial polymerization,
generally interfacial polymerization reactions
о
are carried out at room temperature and 4 C is
Vol-6, Issue - 2, July - December-2011
Int J Pharma Sci Tech (© 2011)
preferred for enzymes, proteins, and peptides
(Whateley 1996). It is often hard to control the
polymerization reaction and the quality of the
membrane and yield obtained by interfacial
polymerization may be controlled by a number
of factors, such as chemical nature of the
monomers, and reaction conditions. The
concentrations of the monomers, temperature,
the mixing rate, and the reaction time are likely
to be important parameters in interfacial
polymerization. Interfacial polymerization
technique requires exhaustive washing to
remove monomers, by products, organic
solvents, and surfactants. Several washing
steps may lead to further loss of water soluble
drug (Yeo et al. 2001).
Physico-chemical methods:
Coacervation
Coacervation is a term used to describe the
basic process of capsule wall formation. The
process was discovered and developed by
Barrett K. Green of the National Cash Register
Corporation (NCR) in the 1940s and 1950s
(Green et al. 1957). Coacervation is a colloid
phenomenon which is carried out under
continuous agitation to encapsulate liquids and
solids (Versic 1988). Coacervations are of two
types, namely simple and complex
Page – 6

coacervation. The mechanism of microcapsule
formation for both coacervation processes is
same, except for the way in which the phase
separation is taken place. In simple
coacervation a single colloidal solute is
involved while complex coacervation requires
two or more colloidal solutes in the continuous
phase of the fluid system.
Simple coacervation is based on partial
polymer desolvation in binary or ternary
systems and this partial polymer desolvation
may be induced by changing the temperature of
polymer solution, by adding to the polymer
solution a poor solvent or nonsolvent for the
Figure 2. Microencapsulation by interfacial polymerization technique (Whateley 1996).
colloidal droplets. Gelatin (Okada et al. 1985;
Wang et al. 2008) and cellulose derivatives
(Weiss et al. 1995) are most widely used
polymers in simple coacervation, although
various other polymers have been used for the
production of microcapsule in pharmaceutical
practice. Simple coacervation with cellulose
derivatives has been used for
microencapsulating of various drugs, such as
Ibuprofen (Weiss et al. 1995), theophylline
(Wu et al. 1994) and indomethacin (41, Lu et
al. 2007). The objective of microencapsulation
of these drugs is to mask the bitter taste and
decrease their gastric irritation. The other
Vol-6, Issue - 2, July - December-2011
Int J Pharma Sci Tech (© 2011)
polymer, or by salting out by electrolytes
(Gander et al. 2002). A very commonly
employed simple coacervation technique
utilizes gelatin. Simple coacervation takes
place when a strongly hydrophilic substance,
such as sodium sulphate (Siddiqui and Taylor
1983) or ammonium sulphate or alcohol (Carter
1987; Gander et al. 2002), is added to a
colloidal solution (e.g. gelatin) and two phases,
one of which is rich in colloidal droplets, are
produced. If the colloidal solution contains
substances (e.g. liquid droplets or solid
particles) immiscible with the system before
coacervation then these liquid droplets or solid
particles may become encapsulated by the
polymers subjected to simple coacervation
technique include, poly(styrene) (Iso et al.
1985; Kondo 2001), poly(vinyl chloride) (Ishii
et al. 1995; Palomo et al. 1996), poly(vinyl
acetate) (Versic 1988; Yang et al. 2008),
poly(vinyl alcohol) (Bachtsi and Kiparissides
1996; Leimann et al. 2009), poly(acrylates)
(Friend 1992), chitosan (Chiang et al. 2009;
Lim and Wan 1998), albumin (Bayomi 2004;
Rahimnejad et al. 2009), casein (Yu and Lee
1997; Santinho et al. 1999), and also vegetable
proteins (Mauguet et al. 2002). Simple
coacervation offers additional flexibility of
operation over complex coacervation because
Page – 7

simple coacervation is relatively independent
of pH of the aqueous manufacturing vehicle as
compared with complex coacervation which is
very sensitive to even small changes in pH. The
main disadvantages of simple coacervation
process by salting-out are to control the
capsule size and the agglomeration of the
capsules. This agglomeration can be prevented
or minimized by adjusting the kinetics of the
salt addition or by decreasing the feed rate of
salt solution (Mauguet et al. 2002). The
microspheres tend to aggregate and
agglomeration occurs when the coacervate
droplets are sticky and adhere to each other
before the solvent is completely removed or
before the droplets are hardened. Addition of
non-solvent which does not induce
agglomeration but forms stable coacervates
Figure 3. Schematic diagram of O/W emulsion solvent evaporation method (O'Donnell
and McGinity 1997).
Vol-6, Issue - 2, July - December-2011
Int J Pharma Sci Tech (© 2011)
may solve this agglomeration problem (Yeo et
al. 2001).
In complex coacervation the oppositely
charged polyelectrolytes interact to form a
complex of reduced solubility, as in the case of
microencapsulation by coacervation process
induced by polymer-polymer interactions,
where two oppositely charged polymers (e.g.
gelatin and gum acacia) interact under the
proper temperature, pH, and concentrations to
bring about separation of the polymer rich
complex coacervate phase. Gelatin becomes
positively charged at pH values below its
isoelectric point and the gum acacia is a natural
anionic water soluble polymer. Neutralization
of the overall positively charges of one polymer
by the negative charge of another are used to
bring about separation of the polymer rich
Page – 8

complex-coacervate phase.
A complex coacervation using gelatin and gum
acacia is accomplished by emulsifying or
suspending the core material in the gelatin or
gum acacia solution. The aqueous solution of
both the polymer should each be 2% by weight.
The polymer solution which is not used to
disperse the core material is added into the
system. The pH is adjusted to 4-4.5 (Thies
1996). The temperature of the system is kept
higher (at 40-45оC) than the gel point of an
aqueous gelatin solution, mixing is carried out
continuously throughout the whole process.
Then the system is cooled to 25оC over a period
of one hour. The gelatin in the coacervate gels
thereby forming capsule shell which is then
о
further cooled to 10 C and treated with
glutaraldehyde (Lazko et al. 2004; Peters et al.
1992; Tiyaboonchai and Ritthidej 2003) or
formaldehyde (Kong et al. 2009) for
rigidization of the coating complex. The
microcapsules are then cooled, dried and
collected. The primary advantage of complex
Figure 4. The Wurster process (Hinkes 1977).
Vol-6, Issue - 2, July - December-2011
Int J Pharma Sci Tech (© 2011)
coacervation technique is that any core
material which can be dispersed in a liquid
phase can potentially be coated. This is a
significant advantage over interfacial
polymerization, which is limited only to liquid
or liquefiable materials (Muloueen 1998). On
the other hand naturally occurring enzymes are
good cross linking agents and most acceptable
because these are naturally occurring and
harmless.
Solvent evaporation
The solvent evaporation process to produce
microspheres is applicable to a wide variety of
liquid and solid core materials. The emulsion
solvent evaporation technique was fully
developed at the end of the 1970s. At first the
coating material is dissolved in a volatile
solvent, which is immiscible with the liquid
manufacturing vehicle phase. Then the core
material is dissolved or dispersed in the coating
polymer solution. The core coating material
mixture is then dispersed in the liquid
manufacturing vehicle phase with continuous
Page – 9

agitation to obtain the desired size
microcapsule. When the desired emulsion
droplet size is formed, the stirring rate is
reduced and evaporation of the solvent for the
polymer is done under atmospheric or reduced
pressure at an appropriate temperature.
Subsequent evaporation of the solvent for the
polymer yields solid polymeric microcapsules
entrapping the core. Polymer shrinks around
the core if the core material is dispersed in the
polymer solution and matrix-type
microcapsules are formed when the core
material is dissolved in the coating polymer
solution. The prepared microspheres are
collected by centrifugation or filtration and
then freeze-dried.
Schematic diagram of O/W emulsion solvent
evaporation method is shown in Fig. 3. The use
of a propeller style blade attached to a variable
speed motor is most commonly used. As the
motor speed is increased, the size of the
dispersed droplets decreases as a result of the
high shear induced by the propeller (O'Donnell
and McGinity 1997). Palanishmy et al.,
prepared the metoprolol succinate
microspheres by emulsion solvent evaporation
technique and characterized the structure,
surface morphology by scanning electron
microscopy (SEM) and found that the surface
morphology was uneven, porous in nature and
matrix type (Palanisamy et al. 2009).
There are several process and formulation
parameters that may affect the properties of
microcapsules prepared by solvent
evaporation method. The parameters would
include, but not limited to, the aqueous
solubility of the core material to be
encapsulated, the types and concentration of
the dispersing agent, the polymer/drug ratio,
and the agitation rates (Horoz et al. 2004).
Agitation is one of the important parameter for
controlling the size of microspheres and many
other factors (the geometry of the reactor, the
number of the impellers and their position and
the ratio of impeller's diameter compared to
the reactor's diameter) linked to the agitation
have also an effect on the size of microspheres
(Maa and Hsu 1996). The solvent evaporation
Vol-6, Issue - 2, July - December-2011
Int J Pharma Sci Tech (© 2011)
is a simple method and has been used to prepare
microspheres of various compounds using
different polymeric materials (Chiao and Price
1994; Soppimath et al. 2001; Pérez et al. 2000).
Solvent evaporation technique offers several
advantages and is preferable to the other
preparation methods such as spray drying,
sonication and homogenization, etc, because it
requires only mild conditions such as constant
stirring and ambient temperature (Kim et al.
2002). The emulsion solvent evaporation
technique has been used successfully in the
preparation of microspheres made from several
biocompatible polymers such as poly(D,L-
lactide-co-glycolide) (O'Donnell and
McGinity 1997; Viswanathan et al. 1999;
Kawashima et al. 1998; Mandal et al. 1996),
poly(Є-caprolactone) (Pérez et al. 2000;
Benoit et al. 1999; Palanisamy et al. 2009), and
Eudragit (Perumal 2001; Behera et al. 2008;
Basu and Adhiyaman 2008; Das and Das
1998).
Solvent evaporation has several problems and
limitations. The solvent evaporation methods
require use of toxic organic solvents, such as
dichloromethane and ethyl acetate, as a solvent
for dissolving biodegradable polymers.
Therefore the use of toxic organic solvent
should be minimized or avoided to meet the
regulatory requirement regarding the residual
solvent in the final products. Another limitation
is the drug encapsulation efficiency into the
microspheres is not high. Maintenance of
internal aqueous phase pH close to the iso-
electric point of the protein and osmotic
balance between the internal aqueous phase
and the external aqueous phase during solvent
evaporation method helped in better
encapsulation of the protein drug (Srinivasan et
al. 2005). Solvents commonly used in this
method, such as methylene chloride or
chloroform, may be retained in the
microspheres as organic volatile impurity or
residual solvents. For methylene chloride the
limit is 500 ppm and for chloroform the limit is
50 ppm, as per USP XXIII (The United States
of Pharmacopoeia 1995). Methylene chloride
is still used solvents because it evaporates fast,
Page – 10

produces microspheres with spherical and
more uniform form with high drug
e n c a p s u l a t i o n e f f i c i e n c y. A n o t h e r
disadvantage of any kind of solvent
evaporation method includes solvent residues
in polymer and the polymer degradation
(Brunner and Göpferich 1996). Presence of
residual solvents may alter the polymer
properties which directly leads to different
release patterns. They can have a negative
influence on drug stability and also cause
tissue irritation after subcutaneous or
intramuscular injection of microspheres.
Therefore, during the development of a
parenteral depot system based on
biodegradable microspheres, requires
evaluation of solvent-elimination and drying
techniques to eliminate residual organic
solvents as far as possible (Kissel et al. 1997).
Residual solvents are not desirable in the final
pharmaceutical product and their acceptable
limits have been published in pharmacopoeias
and ICH guidelines. Grodowska and
Parczewski reviewed and discussed some of
current analytical procedures including gas
chromatographic (GC) and other alternative
techniques which are used for residual solvents
determination (Grodowska and Parczewski
2010). Freitas et al., reviewed the current state
of the art in solvent extraction/evaporation-
based microencapsulation technologies
(Freitas et al. 2005). The solvents used in this
method should meet up the requirements of
high volatility, low boiling point, poor
solubility in the continuous phase, reduced
toxicity and the ability to dissolve the chosen
polymer.
Supercritical fluid precipitation
Strict regulations on the use of organic
solvents and their residual level in the end
products form a major issue to the traditional
processing techniques. Supercritical fluid
technology is an outcome of such research
with special emphasis in the green synthesis
and particle formation. Supercritical fluid is
defined as a fluid of which temperature and
pressure are simultaneously higher than at the
critical point, i.e. critical temperature and
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critical pressure, at which the density of a gas is
equal to that of the remaining liquid and the
surface between the two phases disappears.
Most widely used supercritical fluids are
supercritical CO2, alkanes (C2 to C4) and nitrous
oxide (N2O). Particle formation with this
technology involves minimal or no use of
organic solvents, while the processing
conditions are relatively mild. Two main routes
to particle formation with supercritical fluids
are the rapid expansion of supercritical
solutions (RESS), and supercritical antisolvent
crystallization (SAS) (Vamavarapu et al. 2005;
Yeo et al. 2001; Dubey et al. 2009).
Rapid expansion of supercritical solutions
(RESS): In RESS, the drug and the polymer are
dissolved in a supercritical fluid at high
pressure and precipitated by reducing the
solvent's density through a rapid
decompression. As the supercritical fluid is a
gas after decompression, the solid product is
recovered in pure, solvent-free form (Yeo et al.
2001). Supercritical CO2 is widely used for its
low critical temperature value in addition to its
non-toxic, environmentally benign, non-
inflammable, readily available, highly pure and
cost effective (Yeo et al. 2001; Dubey et al.
2009). A wide variety of wall or shell materials
that either dissolve (paraffin wax, acrylates,
polyethylene glycol) or do not dissolve
(proteins, polysaccharides) in supercritical CO2
are used for encapsulating core substances
(Dubey et al. 2009). In this method solvent free
solids in a single processing step. Moreover,
many process variables affect the morphology
of RESS powders, and thus it is difficult to
control and predict the morphology of the
precipitate (Yeo et al. 2001). Different core
materials (pesticide, pigments, pharmaceutical
ingredients, vitamins, flavors, and dyes) have
been encapsulated by this method (Yeo et al.
2001; Ghosh 2006).
SAS (supercritical antisolvent crystallization):
The method is also known as ASES (aerosol
solvent extraction system) or PCA
(precipitation with a compressed fluid anti
solvent). In this process, supercritical fluid is
Page – 11

added to a solution of shell material and the
active ingredients and maintained at high
pressure and this leads to a volume expansion
of the solution that causes supersaturation such
that precipitation of the solute occurs. One of
the disadvantages of SAS is that as a result of
polymer plasticization by CO2, polymers with
low glass transition temperatures often
agglomerate even at low temperatures. SAS, as
compared with RESS, is more flexible in
solvent selection (Yeo et al. 2001; Ghosh
2006).
The processing vessel where the supercritical
fluid is brought in contact with the material(s)
to be processed is also known as pressure
vessel or a reaction vessel. Controlled
conditions of temperature and pressure in the
processing vessel or reaction vessel are
important to get reproducible results and can
be achieved through the use of a backpressure
regulator, sensitive transducers and
temperature measuring instruments
(Vamavarapu et al. 2005).
Physico-mechanical methods:
Air suspension
The Air Suspension Coating Process was
invented by Professor Dale E. Wurster while at
the Department of Pharmacy, University of
Wisconsin. The Wurster Process has been in
commercial use since 1959, and is now used by
Wisconsin Alumni Research Foundation
licensees in the United States, Canada, Europe
and Japan (Hinkes 1977). Air suspension
apparatus consists of different sections such as
control panel, coating chamber, air distribution
plate, nozzle for applying film coatings.
Within the coating chamber of air suspension
apparatus particles are suspended on an
upward moving air stream. In the coating zone,
coating material is applied by spraying to the
moving core particles. The design and
operating parameters of the chamber affect the
recirculating flow of the core particles through
the coating zone. The core material receives an
increment of coating material, usually a
polymer solution during each pass through the
coating zone. The cyclic process is repeated
until desired coating thickness is achieved. The
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supporting air stream helps to dry the product
during encapsulation.
A schematic diagram of the Wurster apparatus
is presented in Figure 4. In the Wurster Process,
drying conditions are a function of the
humidity, temperature, and flow volume of the
processing air stream (Hall and Hinkes 1973).
For efficient and effective encapsulation by this
technique processing variables that receive
considerable attention include the following:
1. Density, Hygroscopicity, Surface area,
Particle Size/Shape, Melting point, Solubility,
Wettability, Volatility, Compressibility,
Crystallinity, Hardness, Cohesiveness,
Adsorption, Friability and flowability of the
core material.
2. Concentration, application rate and the
amount of the coating material.
3. Volume of air stream required to support and
fluidized the core material.
4. Inlet and outlet operating temperatures.
Air suspension techniques are generally
applicable only to encapsulate the solid core
materials. The rate of drug release from the
microcapsules was highly dependent on the
encapsulating materials (Hideki et al. 2001).
The small sized Wurster equipment has been
able to encapsulate small particles in the size
range of 74-250μm using the spraying systems
air atomizing nozzles (Hinkes 1977). The air
suspension process has the capability of
applying coatings in the form of organic
solutions, aqueous solutions, emulsions,
dispersions or hot melts. In regard to the
particle size; this Wurster process is applicable
both for microencapsulation and
macroencapsulation coating processes.
Pan coating
Pan coating is an older method developed in the
1880s. Pan coating method is useful for coating
solids and to obtain final particles of a size
between micrometers and a few millimeters
and these microcapsules can be defined as
pellets (Torrado and Augsburger 2008). Solid
particles generally greater than 600 microns in
size are considered essential for effective
coating in microencapsulation. In this
technique, coating is applied as a solution, or as
Page – 12

an atomized spray, to the desired solid core
material in the coating pan. Usually to remove
the coating solvent, warm air is passed over the
coated materials in the coating pans (Bakan
1986). In pan coating, a coating material is
sprayed onto a particulate mass tumbled in a
mixer and forming coated particles and this
process is used by pharmaceutical industry to
produce controlled-release products. In some
cases final removal of solvent is accomplished
in drying oven (Venkatesan et al. 2009).
Puranik and coworkers prepared abietic acid-
sorbitol derivatives as material for
microencapsulation by pan coating technique,
using salicylic acid as a model drug. They
isolated abietic acid from rosin N Grade. The
coated microcapsules were evaluated for
moisture absorption, flow properties, friability
and release characteristics. The result showed
that the materials having lower acid values
with moisture protection properties and also
prolong the release of the salicylic acid
(Puranik et al. 1992).This method is useful for
forming small, coated particles or tablets. The
disadvantage of this method is that it requires
rather large particles on the order of several
millimeters to several centimeters in size
(Versic 1995). Usually the coating material is
sprayed at an angle from the side into the pan.
The process is continued until an even coating
is completed (Burgess and Hickey 2007).
Spray-drying
Spray-drying is a low-cost commercial process
which is mostly used for the encapsulation of
fragrances, oils and flavors. The spray drying
process for the production of microcapsules is
useful for a variety of materials and can be used
to encapsulate both liquids and solids (Bakan
1986). Spray drying is probably the oldest
encapsulation technique and it has been used
since 1930s. Spray dried lactose was
introduced to the pharmaceutical market in the
1960s and used as an excipient for direct
compression (Gunsel and Lachman 1963),
solid dispersions (Takahashi et al. 2005), and
more recently to manufacture dry powders
containing insulin for inhalation (White et al.
2005). Other applications of spray drying in
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pharmaceutical practice include the production
of active pharmaceutical ingredient (API)
when control of particle properties is desired.
In practice, microencapsulation by spray
drying is conducted by dispersing a core
material in a coating solution, in which the
coating substance is dissolved and in which the
core material is insoluble. Then atomizing the
mixture into the hot air stream to remove the
solvent from the coating material and thus
coating solidification is accomplished. A
standard spray dryer consists of different
components such as an air heater, atomizer,
spray chamber, fan or blower, cyclone and
product collector. Microcapsules are separated
from the hot air with the help of cyclone
separator while the traces of solvent are
removed by vacuum drying. However
microcapsules produced by spray drying
techniques tend to be very porous because of
rapid solvent evaporation (Vyas and Khar
2002). The spray drying process produces
microcapsules approaching a spherical
structure in the range of 5 to 600 microns
(Bakan 1986). The rounded or generally
spherical shape of the spray dried particles
promotes good flow characteristics and good
tableting characteristics. Therefore spray-
drying microencapsulation techniques are
frequently used for oral administration
(Torrado and Augsburger 2008). The spray
drying process usually produces coated
aggregates rather than coated single particles
(Wurster 1990). The control of the processing
conditions during drying has a significant
influence on the physical properties of the final
powder microcapsule (Sanguansri and
Augustin 2007). Spray-drying encapsulation is
capable of producing a wide range of
microcapsules in good yield. Water-soluble
polymers (e.g. Gum arabic, maltodextrins,
starch derivatives, and hydrolyzed gelatin) are
mainly used as shell or wall materials (Teixeira
et al. 2004; Krishnan et al. 2005; Adachi et al.
2004). Water-soluble polymers like gum
Arabic or modified starch do not form high-
viscosity solutions and therefore favored for
spray drying. Water is the preferred solvent for
Page – 13

most spray-drying encapsulations because the
use of organic solvents produces toxicity and
environmental problem. The spray drying
method for preparation of microspheres from
biodegradable polymers presents a number of
advantages compared to other techniques.
Water-soluble and water-insoluble drugs can
be encapsulated into hydrophilic or
hydrophobic polymers with relatively high
encapsulation efficiencies. The spray drying
process is a rapid and reproducible method
with good potential for scale-up (Kissel et al.
1997). Spray drying is useful for
encapsulation of heat sensitive drugs, such as
proteins or peptides, because it requires mild
temperatures (Giunchedi and Conte 1995).
The main disadvantages of spray drying
process is the high capital investment
necessary for spraying equipment allowing
both processing under aseptic conditions and
the possible high working temperature, which
could alter highly thermostatic drugs, and
recovery of organic solvents for ecological
reasons. Residual solvents in microspheres
can be eliminated by additional drying
methods (Kissel et al. 1997). There are a
number of process variables ( for e.g. feed
material properties, such as viscosity,
uniformity, and the concentration of drug and
polymer mixtures, feed rate, method of
atomization, and the inlet and outlet
temperatures) that should be optimized during
drug encapsulation (Bakan 1986). The
dependence so many process variables may
become a problem in terms of reproducibility
and scale-up process (Yeo et al. 2001). Spray-
drying encapsulation has several limitations.
Water-soluble shell or wall materials are
limited and most of the cases these wall
materials form aqueous solutions that are too
viscous to spray. The core loading carried out
by most spray-dried capsules is a great matter
of concern. During the process, the active
ingredient is exposed to harsh conditions like
high temperatures and organic solvents that
could considerably damage the activity of the
proteins. Other limitations consist of the
losses in the final product and difficulties to
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control the particle size. During spray-drying
there may be a significant loss of the product
due to the adhesion of the microparticles to the
inner wall of the drying chamber, or to
agglomeration of the microparticles. A novel
technique has been developed to solve these
problems using two injection devices of which
one nozzle was used to spray the polymer-drug
solution and additional nozzle simultaneously
sprayed an aqueous manitol solution as an
antiadherent (Tewes et al. 2006).
Spray-congealing (chilling)
Microencapsulation by spray-congealing
method can be accomplished with spray drying
equipment and the protective coating is applied
as a melt. In this process, the core material is
dispersed in a coating material melt. Here the
air stream is usually cool as the polymer is a
melt and the resulting polymer solidifies
around the core to form a microcapsule.
Various waxes, fatty acids and alcohols which
are solids at room temperature but meltable at
reasonable temperatures are applicable to
spray-congealing techniques (Adeyeye and
Price 1991; Albertini et al. 2008; Cavallari et al.
2007). Spray-congealing method is similar to
spray drying except that no solvent is used for
the coating material. Higher concentrations of
coatings are required for spray congealing than
spray drying, because molten coating forms the
coat of the liquid phase. Spray congealing
coatings are less porous as compared to spray
drying because of the absence of solvent
evaporation during most spray-congealing
processes. The particle size of spray-
congealing products can be accurately
controlled when spray drying equipment is
used. Spray-congealing is an interesting and
potentially highly useful means of preparing
solid dosage forms, having the advantages of
simplicity, speed, and reasonably low cost once
the equipment is established. Frozen liquids,
heat sensitive substances and those not soluble
in the usual solvents can be encapsulated by
spray-congealing method (Gibbs et al. 1999).
Multiorifice-centrifugal
The Southwest Research Institute (SWRI) has
developed this process for producing
Page – 14

microcapsules that utilizes centrifugal forces
to hurl a core material particle through an
enveloping microencapsulation membrane,
thereby effecting mechanical
microencapsulation. The apparatus consists of
a rotating cylinder within it three
circumferential grooves are present. The upper
and lower grooves located circumferentially
around the cylinder, carry the polymer or
coating material in molten or solution form via
inlet tubes to the respective grooves. The
intermediate groove, are a plurality of orifices
spaces closely and circumferentially around
the cylinder. The ridges of the coating material
grooves, upper and lower, serve as a weir over
which the coating or polymer material
overflows when the volume of the upper and
lower grooves is exceeded by the volume of the
material pumped into the system. Under
centrifugal force the coating material imparted
by the cylinder rotation flows outward along
the countersunk portion and forms a film
across the orifice. A counter rotating disc
atomizes or disperses the core material fed
through the centrally located inlet. The counter
rotating disc flings the particulate core
material toward the orifices. Then the core
material arrives at the orifices and encounters
the coating material membrane and the impact
and centrifugal force hurls the core material
through the enveloping coating membrane.
The embryonic microcapsules are then
hardened, congealed, or voided of coating
solution by a variety of means (Bakan 1986).
Processing variables include the rotational
speed of the cylinder, the flow rate of the
coating and core materials, the concentration
and viscosity and surface tension of the core
material. Production rates of 50 to 75 pounds
per hour have been achieved with the process.
The process is capable for microencapsulating
liquids and solids of varied size ranges, with
diverse coating or polymer materials
(Venkatesan et al. 2009).
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Applications:
Applications in pharmaceutical industry
A major application of microencapsulation
technique in pharmaceutical field is controlled
or sustained drug delivery. A wide number of
pharmaceutical microencapsulated products
are currently on the market, such as aspirin
®
controlled release tablets (ZORprin CR) are
used to treat pain and fever, to relieve pain and
inflammation associated with arthritis and
other inflammatory conditions, Cephalexin
(Ceff-ER) and Cefadroxil (Odoxil OD)
antibiotic for bacterial infections.
Microencapsulation of proteins and peptides
has recently become a relevant alternative to
develop novel drug delivery system (Saez et al.
2007). The number of commercially available
microsphere does not reflect the amount of
research that has been carried out in this field,
nor did the benefits that can achieve using this
technology. Microspheres have also been
found potential applications as inhalation or
injection products (Burgess and Hickey 2007).
Several protein based biodegradable
microspheres have already been marketed, as
shown in Table III.
Applications in food industry
Currently food industry uses more and more
purified natural synthetic fragile substances
and there is an increased need to protect them.
Consumers are more aware regarding what
they eat and what benefits certain ingredients
has maintaining good health. Functional food
ingredients (for e.g. flavors, vitamins or
antioxidants etc.) are sensitive to
environmental stress during manufacturing,
storage and consumption of the food product.
Sometimes these food ingredients slowly
degrade and lose their bioactivity during
digestion in the stomach and intestine. Most of
the “functional foods” are augmented with
ingredients to improve nutritional value can
compromise their taste, color, texture and
aroma. Microencapsulation is a useful
Page – 15

technique to preserve the beneficial properties
of these food ingredients and to control their
release at both the right place and the right time.
Spray drying techniques is generally used in
food industry to decrease water content and
thereby ensure a microbiological stability of
products. Spray drying techniques has been for
decades to encapsulate food ingredients such as
flavors, lipids, and carotenoids (Gharsallaoui et
al. 2007). Zhang et al. treated grape seeds with
supercritical fluid extraction to remove the oils
and extracted the procyanidins from the waste
of grape juice during wine production. In order
to extend the shelf life of procyanidins they
prepared microcapsules by spray drying with
gum arabic and maltodextrin as wall materials
(Zhang et al. 2007). The food industry is thus
challenged to develop delivery systems for
incorporating nutraceutical compounds into
food without reducing their bioavailability
(Chen et al. 2009). Microencapsulation
technology is used to encapsulate liquid flavor
compounds in a carrier matrix to provide dry
free-flowing materials protected against
degradative reaction and the loss of flavors
during food processing. Two encapsulation
techniques such as microencapsulation in
cyclodextrin and spray drying were reported for
flavor encapsulation (Takeshi et al. 2001).
Applications in agricultural industry
One of the most important applications of
microencapsulated products in pesticide
industry is to improve handling safety of the
pesticides by hazard and exposure reduction
(Tsuji 2001). Microencapsulation technology
satisfies many of the drivers towards the safer
use of pesticides (Shirley et al. 2001). The
heavy use of herbicides has given rise to serious
environmental and public health problems. It is
therefore important to develop new herbicide
formulations that are highly effective, safer for
the worker and for the environment. Controlled
release formulations of herbicides have become
necessary in recent years, since they often
increase herbicide efficacy at reduced doses
(Sopeña et al. 2009). Pesticide is widely used
throughout the world in the area of crop
protection. Aldicarb is a carbamate pesticide,
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Int J Pharma Sci Tech (© 2011)
highly toxic to mammals. In order to overcome
these problems, microspheres of aldicarb by
using carboxymethyl cellulose (CMC) as the
biodegradable support material cross-linked
with aluminium chloride (Kök et al. 1999).
Endosulfan, a known pesticide has been
identified as an important environmental
pollutant. Controlled release formulation of
endosulfan microspheres prepared by Roy et
al. by cross linking sodium alginate with
calcium ions in the presence of gelatin serve for
reducing environmental impact of pesticides
(Roy et al. 2009).
Applications in biotechnological industry
Polymeric micro spheres are used for the
separation and purification of biomaterials.
Effective separation depends on the micron
size of microspheres with high porosity to
obtain high load capacities (Puskas et al. 2004).
Magnetic supports have found application in
increasingly diverse areas of biotechnology,
including purification of proteins, viruses and
nucleic acids, cell sorting and isolation,
enzyme immobilization, and biosensors.
Artificial cell microencapsulation technology
retains bioactive materials inside the capsules
has shown promise in the treatment of a
number of diseases (Chen et al. 2007).
Microsphere-based assays represent a new
generation of diagnostics in this field and
provide substantial quantitative and qualitative
information from gene expression profiling.
However, for gene expression profiling is still
in the demonstration phase (Lawrie et al.
2006).
Applications in cosmetic industry
In the field of Cosmetics microencapsulation
technology has been used for making products
like deodorants, shampoos, sprays, to improve
their stability or bioavailability (Saez et al.
2007). The particulate delivery systems used in
cosmetics include microparticulates, porous
polymeric systems, nanoparticulates,
cyclodextrin complexes. Generally
microparticles are used in cosmetics to avoid
incompatibility of substance, reduce odor of
actives and for protection of substances prone
to oxidation or action by atmospheric moisture.
Page – 16

Nylon microspheres are being used in
cosmetic make-up and skin care products
because of the feel and skin adhesion they
impart. Chemical inertia of nylon
microspheres allows them to hold hydrophilic
and lipophilic ingredients including vitamins,
sun filters, moisturizers, fragrances and many
other actives (Patravale and Mandawgade
2008). The use of vitamin E, a natural
antioxidant, in skin care products protects
tissue from the effects of UV radiation, delays
the photoaging process and exhibits
moisturizing properties. Alencastre et al.,
prepared Carboxymethylcellulose
(CMC)/chitosan microparticles containing
vitamin E by a complex coacervation method
and evaluated their potential use as a topical
delivery system. In vitro permeation and
retention studies showed a higher penetration
rate of vitamin E in the free and encapsulated
forms, from the W/O emulsion (Alencastre et
al. 2006).
Conclusions
Since the concept of controlled drug delivery
was introduced in 1970s, great progresses
have been made in microencapsulation areas
as microencapsulation offers a variety of
opportunities such as protection and masking,
reduced dissolution rate, facilitation of
handling, and spatial targeting of the core
material. A single microencapsulation method
cannot be universally applied for a variety of
drug materials. In developing a new
microparticle system for a given drug, it is
important to understand the physicochemical
properties of the drug and polymers that best
match the properties and find an encapsulation
method. However most of the commonly used
methods have several disadvantages such as
unfavorable conditions for the core material,
complexity in procedure and low
encapsulation efficiency. Organic solvents,
such as dichloromethane, chloroform, ethyl
acetate or acetone are used to dissolve the
biodegradable polymers but the toxicity of the
solvent is a great matter of concern. Trace
amounts of these solvents may remain in the
final product as residual solvents. Therefore it
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is preferable to minimize the exposure to toxic
organic solvents. Additional drying
procedures, such as vacuum drying at elevated
temperatures or lyophilization, may produce
microspheres with low content of residual
solvent. Cross-linking agents such as
formaldehyde or glutaraldehyde are toxic,
therefore cannot be used as the product may be
applied to or ingested within a mammalian
body. Naturally-occurring enzymes with good
cross-linking property may solve this problem.
Most of the work is in lab-scale setups;
therefore the manufacturing process requires
enough knowledge to scale up to the
commercial scale.
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