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Venkatesan P. et al /J. Pharm. Sci. & Res. Vol.1(4), 2009, 26-35.
26
MICROENCAPSULATION: A VITAL TECHNIQUE IN NOVEL DRUG DELIVERY
SYSTEM
P.Venkatesan, R.Manavalan and K.Valliappan
Department of Pharmacy, Faculty of Engineering & Technology, Annamalai University, Annamalai Nagar,
Tamilnadu, India 608 002
E-mail: venkatesan1978@gmail.com
___________________________________________________________________________
Abstract:
Novel drug delivery systems have several advantages over conventional multi dose therapy. Much research
effort in developing novel drug delivery system has been focused on controlled release and sustained release
dosage forms. Now considerable efforts are being made to deliver the drug in such a manner so as to get
optimum benefits. There are various approaches in delivering a therapeutic substance to the target site in a
sustained controlled release fashion. One such approach is using microspheres as carriers for drugs.
Microencapsulation is a process where by small discrete solid particles or small liquid droplets are surrounded
and enclosed by an intact shell. Microencapsulation is used to modify and delayed drug release form
pharmaceutical dosage forms. A well designed controlled drug delivery system can overcome some of the
problems of conventional therapy and enhance the therapeutic efficacy of a particular drug. It is the reliable
means to deliver the drug to the target site with specificity, if modified, and to maintain the desired concentration
at the site of interest without untoward effects. Microspheres received much attention not only for prolonged
release, but also for targeting of anticancer drugs to the tumor. The intent of the paper is to highlight the
potential of microencapsulation technique as a vital technique in novel drug delivery
Keywords: Microspheres, controlled release, sustained release, target site, therapeutic efficacy, novel drug
delivery.
___________________________________________________________________________
INTRODUCTION
Microencapsulation is a process by which
solids, liquids or even gases may be
enclosed in microscopic particles
formation of thin coatings of wall material
around the substances. The process had its
origin in the late 1930s as a cleaner
substitute for carbon paper and carbon
ribbons as sought by the business
machines industry. The ultimate
development in the 1950s of reproduction
paper and ribbons that contained dyes in
tiny gelatin capsules released on impact by
a typewriter key or the pressure of a pen or
pencil was the stimulus for the
development of a host of
microencapsulated materials, including
drugs [1].
The first research leading to the
development of microencapsulation
procedures for the Pharmaceuticals was
published by Bungen burg de Jong and
Kan in 1931 and dealt with the preparation
of gelatin spheres and the use of a gelatin
Coacervation process.
A well designed controlled drug delivery
system can overcome some of the
problems of conventional therapy and
enhance the therapeutic efficacy of a given
drug. To obtain maximum therapeutic
efficacy, it becomes necessary to deliver
the agent to the target tissue in the optimal
amount in the right period of time there by
causing little toxicity and minimal side
effects [2].
There are various approaches in delivering
a therapeutic substance to the target site in
a sustained controlled release fashion. One
such approach is using microspheres as
carriers for drugs.
Microspheres are characteristically free
flowing powders consisting of protiens or
synthetic polymers which are
biodegradable in nature and ideally having
particle size less than 200 μm [3].
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27
THE REASONS FOR
MICROENCAPSULATION
The reasons for microencapsulation are
countless. In some cases, the core must be
isolated from its surroundings, as in
isolating vitamins from the deteriorating
effects of oxygen, retarding evaporation of
a volatile core, improving the handling
properties of a sticky material, or isolating
a reactive core from chemical attack. In
other cases, the objective is not to isolate
the core completely but to control the rate
at which it leaves the microcapsule, as in
the controlled release of drugs or
pesticides. The problem may be as simple
as masking the taste or odor of the core, or
as complex as increasing the selectivity of
an adsorption or extraction process.
FUNDAMENTAL CONSIDERATIONS
The realization of the potential that
microencapsulation offers involves a basic
understanding of the general properties of
microcapsules, such as the nature of the
core and coating materials, the stability
and release characteristics of the coated
materials and the microencapsulation
methods [4].
CORE MATERIAL
The core material, defined as the specific
material to be coated, can be liquid or solid
in nature. The composition of the core
material can be varied as the liquid core
can include dispersed and/or dissolved
material. The solid core can be mixture of
active constituents, stabilizers, diluents,
excipients and release-rate retardants or
accelerators. The ability to vary the core
materials composition provides definite
flexibility and utilization of this
characteristic often allows effectual design
and development of the desired
microcapsules properties.
COATING MATERIAL
The selection of appropriate coating
material decides the physical and chemical
properties of the resultant
microcapsules/microspheres. While
selecting a polymer the product
requirements ie. stabilization, reduced
volatility, release characteristics,
environmental conditions, etc. should be
taken into consideration. The polymer
should be capable of forming a film that is
cohesive with the core material. It should
be chemically compatible, non-reactive
with the core material and provide the
desired coating properties such as strength,
flexibility, impermeability, optical
properties and stability.
Generally hydrophilic polymers,
hydrophobic polymers (or) a combination
of both are used for the
microencapsulation process. A number of
coating materials have been used
successfully; examples of these include
gelatin, polyvinyl alcohol, ethyl cellulose,
cellulose acetate phthalate and styrene
maleic anhydride. The film thickness can
be varied considerably depending on the
surface area of the material to be coated
and other physical characteristics of the
system. The microcapsules may consist of
a single particle or clusters of particles.
After isolation from the liquid
manufacturing vehicle and drying, the
material appears as a free flowing powder.
The powder is suitable for formulation as
compressed tablets, hard gelatin capsules,
suspensions, and other dosage forms [2].
RELEASE MECHANISMS
A variety of release mechanisms
have been proposed for microcapsules [6]:
A compressive force in terms of a
2 point or a 12 point force breaks
open the capsule by mechanical
means
The capsule is broken open in a
shear mode such as that in a waring
blender or a Z-blade type mixer
The wall is dissolved away from
around the core such as when a
liquid flavoring oil is used in a dry
powdered beverage mix
The wall melts away from the core
releasing the core in an
environment such as that occurring
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during baking
The core diffuses through the wall
at a slow rate due to the influence
of an exterior fluid such as water or
by an elevated temperature.
METHODS OF PREPARATION
Preparation of microspheres should satisfy
certain criteria:
The ability to incorporate
reasonably high concentrations of
the drug.
Stability of the preparation after
synthesis with a clinically
acceptable shelf life.
Controlled particle size and
dispersability in aqueous vehicles
for injection.
Release of active reagent with a
good control over a wide time
scale.
Biocompatibility with a controllable
biodegradability and
Susceptibility to chemical
modification.
MICROENCAPSULATION METHODS
[4]
Air suspension
Coacervation phase separation
Multiorifice-centrifugal process
Spray drying and congealing
Pan coating
Solvent evaporation techniques
Polymerization
AIR SUSPENSION
Microencapsulation by air suspension
technique consist of the dispersing of
solid, particulate core materials in a
supporting air stream and the spray coating
on the air suspended particles. Within the
coating chamber, particles are suspended
on an upward moving air stream. The
design of the chamber and its operating
parameters effect a recirculating flow of
the particles through the coating zone
portion of the chamber, where a coating
material, usually a polymer solution, is
spray applied to the moving particles.
During each pass through the coating
zone, the core material receives an
increment of coating material. The cyclic
process is repeated, perhaps several
hundred times during processing,
depending on the purpose of
microencapsulation the coating thickness
desired or whether the core material
particles are thoroughly encapsulated. The
supporting air stream also serves to dry the
product while it is being encapsulated.
Drying rates are directly related to the
volume temperature of the supporting air
stream.
COACERVATION PAHSE SEPARATION
Microencapsulation by coacervation phase
separation is generally attributed to The
National Cash Register (NCR)
Corporation and the patents of B.K. Green
et al. The process consists of three steps
[7]:
Formation of three immiscible
phases; a liquid manufacturing
phase, a core material phase and a
coating material phase.
Deposition of the liquid polymer
coating on the core material.
Rigidizing the coating usually by
thermal, cross linking or
desolvation techniques to form a
microcapsule.
In step 2, the deposition of the
liquid polymer around the interface formed
between the core material and the liquid
vehicle phase. In many cases physical or
chemical changes in the coating polymer
solution can be induced so that phase
separation of the polymer will occur.
Droplets of concentrated polymer solution
will form and coalesce to yield a two
phase liquid-liquid system. In cases in
which the coating material is an
immiscible polymer of insoluble liquid
polymer it may be added directly. Also
monomers can be dissolved in the liquid
vehicle phase and subsequently
polymerized at interface.
Equipment required for
microencapsulation this method is
relatively simple; it consists mainly of
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jacketed tanks with variable speed
agitators.
MULTIORIFIC-CENTRIFUGAL
PROCESS
The Southwest Research Institute (SWRI)
has developed a mechanical process for
producing microcapsules that utilizes
centrifugal forces to hurl a core material
particle trough an enveloping
microencapsulation membrane thereby
effecting mechanical microencapsulation.
Processing variables include the rotational
speed of the cylinder, the flow rate of the
core and coating materials, the
concentration and viscosity and surface
tension of the core material. The
multiorifice-centrifugal process is capable
for microencapsulating liquids and solids
of varied size ranges, with diverse coating
materials. The encapsulated product can be
supplied as slurry in the hardening media
or s a dry powder. Production rates of 50
to 75 pounds per our have been achieved
with the process.
PAN COATING
The microencapsulation of relatively large
particles by pan methods has become wide
spread in the pharmaceutical industry.
With respect to microencapsulation, solid
particles greater than 600 microns in size
are generally considered essential for
effective coating and there process has
been extensively employed for the
reparation of controlled release beads.
Medicaments are usually coated onto
various spherical substrates such as
nonpareil sugar seeds and the coated with
protective lagers of various polymers.
In practice, the coating is applied as a
solution or as 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 as the coatings are being applied
in the coating pans.
In some cases, final solvent removal is
accomplished in drying oven.
SPRAY DRYING AND SPRAY
CONGEALING
Spray drying and spray congealing
methods have been used for many years as
microencapsulation techniques. Because of
certain similarities of the two processes,
they are discussed together.
Spray drying and spray congealing
processes are similar in that both involve
dispersing the core material in a liquefied
coating substance and spraying or
introducing the core coating mixture into
some environmental condition, whereby
relatively rapid solidification of the
coating is effected. The principal
difference between the two methods, for
purpose of this discussion, is the means by
which coating solidification is
accomplished. Coating solidification in the
case of spray drying is effected by rapid
evaporation of a solvent in which the
coating material is dissolved. Coating
solidification in spray congealing method
however is accomplished by thermally
congealing a molten coating material or b
solidifying a dissolved coating b
introducing the coating core material
mixture into a nonsolvent. Removal of the
nonsolvent or solvent from the coated
product is ten accomplished by sorption
extraction or evaporation techniques.
SOLVENT EVAPORATION
Solvent evaporation techniques are carried
out in a liquid manufacturing vehicle
(O/W emulsion) which is prepared by
agitation of two immiscible liquids. The
process involves dissolving microcapsule
coating (polymer) in a volatile solvent
which is immiscible with the liquid
manufacturing vehicle phase. A core
material (drug) to be microencapsulated is
dissolved or dispersed in the coating
polymer solution. With agitation, the core
– coating material mixture is dispersed in
the liquid manufacturing vehicle phase to
obtain appropriate size microcapsules.
Agitation of system is continued until the
solvent partitions into the aqueous phase
and is removed by evaporation. This
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30
process results in hardened microspheres
which contain the active moiety. Several
methods can be used to achieve dispersion
of the oil phase in the continuous phase.
The most common method is the use of a
propeller style blade attached to a variable
speed motor.
Various process variables include methods
of forming dispersions, Evaporation rate of
the solvent for the coating polymer,
temperature cycles and agitation rates.
Important factors that must be considered
when preparing microcapsules by solvent
evaporation techniques include choice of
vehicle phase and solvent for the polymer
coating, as these choice greatly influence
microcapsule properties as well as the
choice of solvent recovery techniques.
The solvent evaporation technique to
produce microcapsules is applicable to a
wide variety of liquid and solid core
materials. The core materials may be either
water soluble or water insoluble materials.
A variety of film forming polymers can be
used as coatings.
POLYMERIZATION
A relatively new microencapsulation
method utilizes polymerization techniques
to from protective microcapsule coatings
in situ. The methods involve the reaction
of monomeric units located at the interface
existing between a core material substance
and a continuous phase in which the core
material is dispersed. The continuous or
core material supporting phase is usually a
liquid or gas, and therefore the
polymerization reaction occurs at a liquid-
liquid, liquid-gas, solid-liquid, or solid-gas
interface.
APPLICATION OF
MICROENCAPSULATION
There are many reasons why drugs and
related chemicals have been
microencapsulated [2, 4].
The technology has been used widely in
the design of controlled release and
sustained release dosage forms.
To mask the bitter taste of drugs
like Paracetamol, Nitrofurantoin
etc.
Many drugs have been
microencapsulated to reduce
gastric and other G.I. tract
irritations. Sustained release
Aspirin preparations have been
reported to cause significantly less
G.I. bleeding than conventional
preparations.
A liquid can be converted to a
pseudo-solid for easy handling
and storage. eg.Eprazinone.
Hygroscopic properties of core
materials may be reduced by
microencapsulation eg. Sodium
chloride.
Carbon tetra chlorides and a
number of other substances have
been microencapsulated to reduce
their odor and volatility.
Microencapsulation has been
employed to provide protection to
the core materials against
atmospheric effects, e.g.
Vit.A.Palmitate.
Separation of incompatible
substance has been achieved by
encapsulation.
PHYSICOCHEMICAL EVALUATION
CHARACTERIZATION
The characterization of the
microparticulate carrier is an important
phenomenon, which helps to design a
suitable carrier for the proteins, drug or
antigen delivery. These microspheres have
different microstructures. These
microstructures determine the release and
the stability of the carrier [8, 9].
SIEVE ANALYSIS
Separation of the microspheres into
various size fractions can be determined
by using a mechanical sieve shaker
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Venkatesan P. et al /J. Pharm. Sci. & Res. Vol.1(4), 2009, 26-35.
32
(Sieving machine, Retsch, Germany). A
series of five standard stainless steel sieves
(20, 30, 45, 60 and 80 mesh) are arranged
in the order of decreasing aperture size.
Five grams of drug loaded microspheres
are placed on the upper-most sieve. The
sieves are shaken for a period of about 10
min, and then the particles on the screen
are weighed [10].
MORPHOLOGY OF MICROSPHERES
The surface morphologies of microspheres
are examined by a scanning electron
microscope (XL 30 SEM Philips,
Eindhoven, and The Netherlands). The
microspheres are mounted onto a copper
cylinder (10 mm in diameter, 10 mm in
height) by using a double-sided adhesive
tape. The specimens are coated at a current
of 10 mA for 4 min using an ion sputtering
device (JFC-1100E, Jeol, Japan) [10, 11].
ATOMIC FORCE MICROSCOPY (AFM)
A Multimode Atomic Force Microscope
from Digital Instrument is used to study
the surface morphology of the
microspheres. The samples are mounted
on metal slabs using double-sided
adhesive tapes and observed under
microscope that is maintained in a
constant-temperature and vibration-free
environment [12].
PARTICLE SIZE
Particle size determination approximately
30 mg microparticles is redispersed in 2–3
ml distilled water, containing 0.1% (m
/m) Tween
20 for 3 min, using ultrasound
and then transferred into the small volume
recirculating unit, operating at 60 ml/ s.
The microparticle size can be determined
by laser diffractometry using a Malvern
Mastersizer X (Malvern Instruments, UK)
[13].
POLYMER SOLUBILITY IN THE
SOLVENTS
Solution turbidity is a strong indication of
solvent power [14]. The cloud point can be
used for the determination of the solubility
of the polymer in different organic
solvents [15].
VISCOSITY OF THE POLYMER
SOLUTIONS
The absolute viscosity, kinematic
viscosity, and the intrinsic viscosity of the
polymer solutions in different solvents can
be measured by a U-tube viscometer
(viscometer constant at 40 0C is 0.0038
mm2/s /s) at 25 ± 0.1 0C in a thermostatic
bath. The polymer solutions are allowed to
stand for 24 h prior to measurement to
ensure complete polymer dissolution [11].
DENSITY DETERMINATION
The density of the microspheres can be
measured by using a multi volume
pychnometer. Accurately weighed sample
in a cup is placed into the multi volume
pychnometer. Helium is introduced at a
constant pressure in the chamber and
allowed to expand. This expansion results in
a decrease in pressure within the chamber.
Two consecutive readings of reduction in
pressure at different initial pressure are
noted. From two pressure readings the
volume and density of the microsphere
carrier is determined.
BULK DENSITY
The microspheres fabricated are weighed
and transferred to a 10-ml glass graduated
cylinder. The cylinder is tapped using an
autotrap (Quantach- rome, FL, USA) until
the microsphere bed volume is stabilised.
The bulk density is estimated by the ratio
of microsphere weight to the final volume
of the tapped microsphere bed [12].
CAPTURE EFFICIENCY
The capture efficiency of the microspheres
or the percent entrapment can be
determined by allowing washed
microspheres to lyse. The lysate is then
Venkatesan P. et al /J. Pharm. Sci. & Res. Vol.1(4), 2009, 26-35.
33
subjected to the determination of active
constituents as per monograph requirement
[9]. The percent encapsulation efficiency is
calculated using following equation:
% Entrapment = Actual
content/Theoretical content x 100
ANGLE OF CONTACT
The angle of contact is measured to
determine the wetting property of a micro
particulate carrier. It determines the nature
of microspheres in terms of hydrophilicity
or hydrophobicity. This thermodynamic
property is specific to solid and affected by
the presence of the adsorbed component.
The angle of contact is measured at the
solid/air/water interface. The advancing and
receding angle of contact are measured by
placing a droplet in a circular cell mounted
above objective of inverted microscope.
Contact angle is measured at 200C within a
minute of deposition of microspheres [9].
IN VITRO METHODS
There is a need for experimental methods
which allow the release characteristics and
permeability of a drug through membrane
to be determined. For this purpose, a
number of in vitro and in vivo techniques
have been reported. In vitro drug release
studies have been employed as a quality
control procedure in pharmaceutical
production, in product development etc.
Sensitive and reproducible release data
derived from physico chemically and hydro
dynamically defined conditions are
necessary. The influence of technologically
defined conditions and difficulty in
simulating in vivo conditions has led to
development of a number of in vitro release
methods for buccal formulations; however
no standard in vitro method has yet been
developed. Different workers have used
apparatus of varying designs and under
varying conditions, depending on the shape
and application of the dosage form
developed[25,2627,28].
BEAKER METHOD
The dosage form in this method is made to
adhere at the bottom of the beaker containing
the medium and stirred uniformly using over
head stirrer. Volume of the medium used in
the literature for the studies varies from 50-
500 ml and the stirrer speed form 60-300
rpm [9, 16, 17, 18, 19].
DISSOLUTION APPARATUS
Standard USP or BP dissolution apparatus
have been used to study in vitro release
profiles using both rotating elements,
paddle [20, 21, 22 and basket 23, 24].
Dissolution medium used for the study
varied from 100-500 ml and speed of
rotation from 50-100 rpm.
ADVANTAGES
Reliable means to deliver the drug
to the target site with specificity, if
modified, and to maintain the
desired concentration at the site of
interest without untoward effects.
Solid biodegradable microspheres
have the potential throughout the
particle matrix for the controlled
release of drug.
Microspheres received much
attention not only for prolonged
release, but also for targeting of
anticancer drugs to the tumour.
The size, surface charge and
surface hydrophilicity of
microspheres have been found to be
important in determining the fate of
particles in vivo.
Studies on the macrophage uptake
of microspheres have demonstrated
their potential in targeting drugs to
pathogens residing intracellularly
[9].
CONCLUSION
The microencapsulation technique offers a
variety of opportunities such as protection
and masking, reduced dissolution rate,
facilitation of handling, and spatial
targeting of the active ingredient. This
approach facilitates accurate delivery of
small quantities of potent drugs; reduced
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34
drug concentrations at sites other than the
target organ or tissue; and protection of
labile compounds before and after
administration and prior to appearance at
the site of action. In future by combining
various other approaches,
microencapsulation technique will find the
vital place in novel drug delivery system.
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