MICROENCAPSULATION

Definition :Microencapsulation is a process whereby tiny droplets of liquid or

particles of solid material are coated with a continuous film of
polymeric material.

In a relatively simplistic 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, whereas the wall is sometimes called a shell, coating, or membrane.

Most microcapsules have diameters between a few micrometers and a few

millimeters.
Particle size is a deciding factor when selecting the appropriate
microencapsulation technology for a given delivery route.

For example, most injectable particles are ideally 20 to 80 microns in

diameter.

Smaller particle sizes increase the surface area-to-volume ratio, making

them more readily soluble when encapsulated in smaller particle sizes,
and thus more easily assimilated by the human body

The uniqueness of microencapsulation is the smallness of coated particles

and their subsequent use, adaptation to wide variety of dosage forms and
product applications.
 Microencapsulation Applicable core material Approximate particle size
process (microns)
Air suspension coating Solids 35-5000

Coacervation-phase Solids and liquids 2-5000

separation
Multiorifice centrifugal Solids and liquids 1-5000

Pan coating Solids 600-5000

Solvent evaporation Solids and liquids 5-5000

Spray drying/congealing Solids and liquids 600

ADVANTAGES:

 Protection of active ingredient

 Controlled or sustained delivery of drugs

 Separation of incompatible materials

 Solidification of liquids

 Smaller in size

 Taste masking of active ingredients

 Ease of handling

 Applicable for variety of dosage forms

 Achieved by number of methods

 Elegant formulations

 Large surface area

LIMITATIONS:

Incomplete discontinuous coating may result

Inadequate stability

Non reproducible and unstable release characteristics may result

Not suitable for all compounds

BASIC COMPONENTS:

Core:

The core material is defined as the specific material to be coated, can be liquid or
solid in nature.

The composition of core material can be varied, as the liquid core can include
dispersed and/or dissolved material.

The solid core can be a mixture of active constituents, stabilizers, diluents, release
retardants or accelerators or other excipients.

Examples:
Drugs
Proteins and peptides
Flavours
Probiotics
Enzyme
Colours
Viable cells
Dyes
Nuclic acids
Food ingredients etc….
Coating materials:

The selection of appropriate coating material decides the resultant physical and
chemical properties of microcapsules.

The coating material should be capable of forming a film that is cohesive to the core
material, be chemically compatible and nonreactive with the core material.

The coating material should provide the desired coatin properties such as strength,
flexibility, impermeability and stability.

Examples
Polymers
Microorganisms
Resins (water soluble /insoluble)
Waxes
Lipids
Gums
Sugars etc….
EQUIPMENTS AND PROCESSING METHODS:

The processing methods for microencapsulation are basically divided into two
categories
Physical methods
Chemical methods

Physical methods:
Air suspension coating
Pan coating
Centrifugal extrusion
Spray drying
Spray congealing
Solvent evaporation

Chemical methods:
Coacervation – phase separation
In situ polymerization
Interfacial polycondensation
Emulsion stabilization
Air suspension coating

The technique is also called as Wurster process.

In this case the particles are coated while suspended in an upward-moving air stream.

They are supported by a perforated plate having different patterns of holes inside and
outside a cylindrical insert.

Just sufficient air is permitted to rise through the outer annular space to fluidize the
settling particles.

Most of the rising air (usually heated) flows inside the cylinder, causing the particles to
rise rapidly.

At the top, as the air stream diverges and slows, they settle back onto the outer bed and
move downward to repeat the cycle.

The particles pass through the inner cylinder many times in a few minutes.
Wurster Coating Process
Pan coating:

The pan coating process, widely used in the pharmaceutical industry, is among the
oldest industrial procedures for forming small, coated particles or tablets.

In this process the coating is applied as a solution or as a atomized spray to the desired
solid core material in the coating pan.

Warm air is passed over the coated material for drying and removal of solvent.
Spray drying:

Spray drying and Spray congealing methods are being used for microencapsulation
from many years.

Spray drying and spray congealing methods similar in that both involve dispersing the
core material inn liquefied coating substance and then spraying the core coating
mixture in desired environment condition, due to which relatively rapid solidification
of coating is achieved.

In case of spray drying coating solidification is effected by rapid evaporation of solvent

in which coating material is dissolved or suspended.

In case of spray congealing solidification is effected by thermally congealing a molten

coating material or by solidifying a dissolved coating by introducing the core-coating
mixture into nonsolvent.

The main advantages is the ability to handle thermo labile materials because of the
short contact time in the dryer, in addition, the operation is economical.

In modern spray dryers the viscosity of the solutions to be sprayed can be as high as
300mPa.s.
Solvent evaporation:

In this technique the microcapsule coating dissolved in volatile solvent which is

immiscible with the liquid manufacturing vehicle phase.

A core material to be microencapsulated is dissolved in coating polymer solution.

With agitation the core containing material mixture is dispersed in liquid manufacturing
vehicle phase to obtain the appropriate size of microcapsule.

The mixture is the heated to evaporate the solvent for the polymer.

Once all the solvent for the polymer is evaporated the liquid vehicle temperature is
reduced with continued agitation due to which there is formation of microencapsules
Chemical methods

Coacervation Phase separation:

Complex coacervation, (or phase separation), is the first large application of a

microencapsulation technology.

This chemical process of microencapsulation was developed in the 1950s by National

Cash Register (NCR, USA) to produce a two-component ink system for carbon less
copy paper.

The process is carried out in 3 steps

[Link] of three immiscible chemical phases

[Link] of the coating
[Link] of the coating
Step 1:

This step includes formation of three immiscible chemical phases i.e.

liquid manufacturing vehicle phase,
a core material phase and
a coating material phase.

To form the three phases the core material is dispersed in solution of coating polymer,
the solvent for the polymer being the liquid manufacturing vehicle phase.

The coating material phase, an immiscible polymer in liquid state, is formed by

utilizing one of the methods of phase separation coacervation that is

by changing the temperature of the polymer solution; or

adding a salt, nonsolvent or incompatible polymer to the polymer solution;

or by inducing the polymer polymer interaction.
Step 2:
The step includes the deposition of the liquid polymer coating upon the core material.

This is accomplished by controlled physical mixing of the coating material and the core
material in the manufacturing vehicle.

Deposition of the liquid polymer coating around the core material occurs if the polymer
is adsorbed at the interface formed between the core material and the liquid vehicle
phase.

The continued deposition of the coating material is promoted by a reduction in the total
free interfacial energy of the system, brought about by the decrease of the coating
material surface area during coalescence of the liquid polymer droplets.
Step 3:

This step involve the rigidizing of the coating usually by

thermal,
crosslinking, or
desolvation techniques, to form a self sustaining microcapsule.

The microcapsules are usually collected by filtration or centrifugation, washed with an

appropriate solvent and subsequently dried (air-dried or by standard techniques such as
by fluid bed or spray drying).
Methods:

1. Temperature change:
The following example illustrates the microencapsulation procedure using temperature
change as the principle of phase separation Coacervation.

Drug: paracetamol
Polymer: ethyl cellulose
Solvent: cyclohexane

Ethyl cellulose a water insoluble polymer is applied to the water soluble core material
paracetamol by using the temperature solubility characteristics of the polymer in the
hydrocarbon solvent cyclohexane.

Ethyl cellulose is insoluble in cyclohexane at room temperature but it is soluble at

elevated temperatures.

The ethyl cellulose(2%) is dispersed in cyclohexane at room temperature and then the
mixture is heated to the boiling point to form a homogeneous polymer solution.

The core material paracetamol is dispersed in the polymer solution at coating to core
ratio of 1:2.
Allowing the mixture to cool further to room temperature with continuous stirring
causes phase separation Coacervation of ethyl cellulose and microencapsulation of core
material.

The microencapsulated product is then collected by filtration, decantation, or

centrifugation technique

2. Incompatible polymer addition:

The following example illustrates the microencapsulation procedure using incompatible

polymer addition as the principle of phase separation Coacervation.
Drug/core: Methylene Blue
Polymer: Ethyl cellulose
Incompatible polymer: Polybutadiene
Solvent: Toluene

Ethyl cellulose is dissolved in toluene to achieve a polymer concentration of 2% by

weight.
Crystalline Methylene blue hydrochloride which is insoluble in toluene is dispersed
with stirring in the polymer solution at ratio of core to polymer 4:1.

Then slowly Polybutadiene is added in sufficient quantity to achieve ratio of

Polybutadiene to ethyl cellulose 25:1.

The Polybutadiene is soluble in toluene and incompatible with ethyl cellulose causes
the demixing of ethyl cellulose from solution and subsequent microencapsulation of the
core material results.

The ethyl cellulose coating is solidified by adding a nonsolvent like hexane.

The resultant product crystalline Methylene blue coated with ethyl cellulose is collected
by filtration and drying techniques.
3. Non solvent addition:
The following example illustrates the microencapsulation procedure using non solvent
addition as the principle of phase separation Coacervation.

Drug: Methyl scopolamine

Polymer: Cellulose acetate butyrate
Nonsolvent: Isopropyl ether
Solvent: Methyl ethyl ketone

A liquid that is nonsolvent for a given polymer can be added to a solution of polymer to
induce phase separation.

A 5% weight to volume methyl ethyl ketone solution of cellulose acetate butyrate is

prepared and in it micronised methylscopolamine hydrobromide is dispersed with
stirring (core to coating 2:1).

The resulting mixture is heated to 55 oC and isopropyl ether a nonsolvent for coating
polymer is added slowly to achieve phase separation/Coacervation and
microencapsulation of the core material.

The system is cooled to room temperature and microcapsule are separated by

centrifugation, washed with isopropyl ether and dried.
4. Salt addition:
The following example illustrates the microencapsulation procedure using salt addition
as the principle of phase separation Coacervation.

Drug: Vitamin – A
Polymer: Gelatin
Salt: Sodium sulphate
Solvent: Corn oil and water

An oil soluble vitamin A is dissolved in corn oil and then it is emulsified in high quality
pigskin gelatin having an isoelectric point at about pH 8.9.

Twenty parts of oil to 100 parts of water by weight are used for the oil/water emulsion.

The emulsion process is carried out at 50 oC.

Phase separation Coacervation is achieved by slowly adding a 20% solution of sodium

sulfate (emulsion to salt 10:4). This causes microencapsulation of core by gelatin.

The resultant vitamin microcapsules are rigidized by transferring them to sodium

sulfate solution (7% at 19 oC).
5. Polymer- polymer interaction:
The following example illustrates the microencapsulation procedure using polymer-
polymer interaction as the principle of phase separation Coacervation.

Drug: Methyl salicylate

Polymer 1: Gelatin
Polymer 2: Gum arebic
Solvent: Water

Gelatin and gum arebic are polyelectrolytes that can be caused to interact. Gelatin at pH
conditions below its isoelectric point possesses a net positive charge, where as gum
arebic possesses a net negative charge.

Under the proper conditions of temperature and pH the two polymers can interact
through their opposite electrical charges and causes phase separation/Coacervation.

Aqueous solution of gum arebic and gelatin are prepared (2%).

The homogenous polymer solutions are mixed together in equal amounts diluted to
twice their amount with water adjusted to pH 4.5 and warmed to 40 to 45 oC.
While maintaining the warm temperature conditions the liquid core material methyl
salicylate is added to a ratio of 25 parts of core to 1 part of coating material (dry).

The core material is emulsified and then the system is slowly cooled with stirring over
a period of one hour.

During the cooling the phase separation/Coacervation occurs and core is get coated
with the gelatin-gum arebic complex.
Interfacial polymerization:

In Interfacial polymerization, the two reactants in a polycondensation meet at an

interface and react rapidly.

The basis of this method is the classical Schotten Baumann reaction between an acid
chloride and a compound containing an active hydrogen atom, such as an amine or
alcohol, polyesters, polyurea, polyurethane.

Under the right conditions, thin flexible walls form rapidly at the interface.

A solution of the pesticide and a diacid chloride are emulsified in water and an aqueous
solution containing an amine and a polyfunctional isocyanate is added.

Base is present to neutralize the acid formed during the reaction. Condensed polymer
walls form instantaneously at the interface of the emulsion droplets.
Insitu polymerization

In a few microencapsulation processes, the direct polymerization of a single monomer

is carried out on the particle surface.

In one process, e.g. Cellulose fibers are encapsulated in polyethylene while immersed
in dry toluene.

Usual deposition rates are about 0.5μm/min. Coating thickness ranges 0.2-75μm.

The coating is uniform, even over sharp projections.

Emulsion stabilization:

Preparation of protein- and polysaccharide-based microcapsules and microspheres

using the “emulsion crosslinking” or “emulsion stabilization” technology is very
frequent.

This method can be used for the encapsulation of soluble or insoluble liquids, or solid
agents to be released by diffusion, erosion or dissolution.

Emulsion stabilization is a technique based on single or double emulsions.

Since many biopolymers are generally water-soluble, two systems can be distinguished
when biopolymers are used as wall material :
1. Hydrophilic active ingredients:

Single water-in-oil (W/O)-emulsions are employed if the active ingredient is

water-soluble.

In this case an aqueous biopolymer solution containing the active ingredient is

emulsified in a hydrophobic phase like vegetable oil or organic solvent.

When the desired droplet size is obtained, the matrix material is stabilized by
crosslinking.

Then, the oil phase is removed by washing with solvents like hexane and the
particles are isolated.

The particles can either be dried to obtain a powder, or used as a slurry.

2. Hydrophobic active ingredients :

Double oil-water-oil (O/W/O)-emulsions can be used if the active ingredient is

hydrophobic.

The active ingredient is first added to an oil phase.

This oil phase is then emulsified in the aqueous biopolymer phase to form an O/W-
emulsion.

Then the O/W-emulsion is added to a hydrophobic phase to form the double O/W/O-
emulsion.

Common challenge with emulsion stabilisation for hydrophobic ingredients is retention

of the core ; often losses occur during the encapsulation process
APPLICATIONS OF MICROENCAPSULATION:

Drug delivery:
Microencapsulated APIs in tablets often achieve the desired release profile in
combination with a solid matrix or enteric coating that slows the exposure of API to the
digestive tract.

A fine example of an orally administered microencapsulated drug is Cipro XR. Bayer

submitted a New Drug Application (NDA) in October 2002 to market Cipro XR
(extended release) as a once-daily tablet to treat urinary tract infections (UTIs). The
new 24-hour formulation uses a bi-layer matrix of active ingredients. In addition, Bayer
jointly developed a once-daily form of Cipro-OD with Ranbaxy Laboratories of India.
Because the drug was scheduled to lose patent protection in December 2003, Cipro
XR's upgraded performance not only extends the product life, but also provides Bayer
with additional exclusivity for the same molecule.
Vaccines:
Advances in injectable drug delivery have made for smarter molecules that can stay in
the bloodstream longer with fewer side effects.

Microencapsulation allows for less-frequent injections, longer-lasting half-lives of

drugs, more sophisticated site targeting, and reduced toxicity.

Example ; in case of vaccines like hepatitis B or protein/ peptide drugs the harsh
conditions in the stomach denature most of them rendering some conventional oral
delivery routes useless for them. Consequently, they must be injected, and in order to
achieve reasonable patient compliance, they require some sort of depot or extended
release, which can be achieved by microencapsulation.
Probiotics delivery:
Microencapsulation of probiotics allows their safe and effective delivery to human
beings. Microencapsulated lactobacilli and other probiotics proving their effectiveness
worldwide.

Enzyme immobilization:
Microencapsulation is one of the best methods for immobilization of enzymes. Such
immobilized enzymes are used in chemical, textile, food and fermentation industries as
a catalyst. Enzymes also used as a drug for human beings but their peptide/protein
nature causes their degradation in GIT.

Microencapsulated enzymes can be successfully given by oral route without

degradation in GIT.
E.g. urease
Flavour delivery:
Microencapsulation of flavours is a well-known process in food industry such
microencapsulation protects the flavours from high temperature, effect of light
and other environmental conditions

Example the yeast microencapsulated mustered flavour which is stable up to

250oc during processing in food industry

Bioencapsulation:
Microencapsulation includes BIOENCAPSULATION which is more restricted to the
entrapment of a biologically active substance (from DNA to entire cell or group of cells
for example) generally to improve its performance &/or enhance its shelf life.
E.g. Microencapsulated viable cells like Islet of langerhans for sustained normalization
of diabetes
Agrochemicals:
Microencapsulated agrochemicals like pesticide are proved to be more effective and
less toxic.

So the leading agrochemical industries worldwide are developing novel pesticide based
up on microencapsulation technique to reduce their toxic effects and to improve their
efficiency.

Other applications:
Microencapsulation shows many other applications like improvement of drug
properties like solubility, bioavailability. It also has wide number of applications in dye
industries and textile industries