MICROENCAPSULATION

INTRODUCTION
Microencapsulation is a process by which very tiny droplets or particles of
liquid or solid material are surrounded or coated with a continuous film of
polymeric material.

The product obtained by this process is called as micro particles,

microcapsules.

Particles having diameter between 3 - 800m are known as micro

particles or

microcapsules or microspheres.

Particles larger than 1000m are known as Macroparticles .

CLASSIFICATION OF MICROPARTICLE
Generally Micro particles consist of two components
a) Core material
b) Coat or wall or shell material.

1.Microcapsules: The active agent forms a core surrounded by an inert

diffusion barrier.
2.Microspheres: The active agent is dispersed or dissolved in an inert
polymer.
ADVANTAGES:
To Increase bioavailability
To alter the drug release & separation of reactive core from other
materials.
To improve the patients compliance
To produce a targeted drug delivery
To reduce the reactivity of the core in relation to the outside
environment.
To decrease evaporation rate of the volatile core material.
To convert liquid to solid form & to mask the core taste.
Protects the GIT from irritant effects of the drug.
Prevents the oxidative degradation of drugs.
DISADVANTAGES
Its costly process, not economical.
More skill is required.
It is difficult to get continuous & uniform film.
Shelf life of hygroscopic drugs is reduced.
FUNDAMENTAL CONSIDERATION

CORE MATERIAL

The material to be coated

It may be liquid or solid or gas.
Liquid core may be dissolved or dispersed material

COMPOSITION OF CORE MATERIAL:

Drug or active constituent
Additive like diluents
Stabilizers
Release rate enhancers or retardants
COATING MATERIAL
Inert substance which coats on core with desired thickness
IDEAL CHARACTERISTICS:
Capable of forming a film cohesive with core material
Chemically compatible with the core material
Should be stable, non reactive & cheap
Provide desired
impermeability

coating

properties

like

strength,

flexibility&

COMPOSITION OF COATING
Inert polymer
Plasticizer
Coloring agent
Gelatin, gum Arabic, methyl cellulose, PVP, PVA , EC, beeswax, carnauba
wax.
Examples of Coating Materials
1. Water soluble resins- Gelatin, Gum Arabic, Starch, PVP, CMC, MC,
Arabinogalactan, Polyvinyl alcohol.
2. Water insoluble resins- EC, Polyethylene,
Polyamide (Nylon), Cellulose nitrate, Silicones.

Polymethacrylate,

3.Waxes and lipids- Paraffin, Carnauba, Beeswax, Stearic acid, Stearyl

alcohol, Glyceryl stearates.
4. Enteric resins- Shellac, Cellulose acetate phthalate, Zein
3

2. REASONS FOR ENCAPSULATION

1. To protect reactive substances from the environment,
2. To convert liquid active components into a dry solid system,
3. To separate incompatible components for functional reasons,
4. To protect the immediate environment of the microcapsules from the
active components.
To control the rate at which it leaves the microcapsule, as
1. To control release of the active components for delayed (timed) release
or long-acting (sustained) release,
2. The problem may be as simple as masking the taste or odor of the
core,
3. To Increase of bioavailability,
4. To produce a targeted drug delivery,
5. Protects the GIT from irritant effects of the drug,
6. Extension of duration of activity for an equal level of active agent.
3. Techniques to Manufacture Microcapsules
The technique of microencapsulation depends on the physical and
chemical properties of the material to be encapsulated.

The stability and the biological activity of the drug should not be
affected,

Yield and drug encapsulation efficiency should be high,

Microsphere quality and drug release profile should be reproducible

within specified limits,

Microsphere should not exhibit aggregation or adherence,

Process should be usable at an industrial scale.

The residual level of organic solvents should be lower than the limit
value.

ROLE OF POLYMERS :

Polymers are substances of high molecular weight made up by repeating

monomer units.

Polymer molecules may be linear or branched, and separate linear or

branched chains may be joined by crosslink's.

Polymers are used widely in pharmaceutical systems as adjuvant,

coating materials and, a components of controlled and site- specific drug
delivery systems
Fig. 3: Microencapsulation Techniques.

MICROENCAPSULATION TECHNIQUES
Air suspension techniques( Wurster)

Coacervation process

Spray drying & congealing

Pan coating

Solvent evaporation

Interfacial Polymerization

Polymerization

Extrusion
5

Single & double emulsion techniques

Supercritical fluid anti solvent method (SAS)

Nozzle vibration technology

I] Physical or Physico-mechanical methods

1. Air-suspension coating

Inventions of Professor Dale E. Wurster

Basically the wurster process consists of the dispersing of solid,

particulate core materials in a supporting air stream and the spraycoating of the air suspended particles.

Equipment ranging in capacities from one pound to 990 pounds.

Micron or submicron particles can be effectively encapsulated by air

suspension techniques.

Disadvantage- Agglomeration of the particles to some larger size is

normally achieved.

PROCESSING VARIABLES IN WURSTER PROCESS

Core material: Density, S.A, M.P, Solubility, Friability, Volatility,
Crystallinity & Flowability.
Concentration of coating material.
Amount of coating material required.
Coating material application rate.
Inlet and outlet operating temperatures.
Volume of air required to support and fluidize the core material.
2. Centrifugal extrusion

Liquids are encapsulated using a rotating extrusion head containing

concentric nozzles.

This process is excellent for forming particles 4002,000 m in diameter.

Since the drops are formed by the breakup of a liquid jet, the process is
only suitable for liquid or slurry.

A high production rate can be achieved, i.e., up to 22.5 kg of

microcapsules can be produced per nozzle per hour per head.

Heads containing 16 nozzles are available.

3. PAN COATING

Oldest industrial procedures for forming small, coated particles or

tablets.

Coating pan is used for this operation

The particles are tumbled in a pan or other device while the coating
material is applied slowly.

Used for large size particles i.e 600-5000 m size

Solid particles greater than 600 microns in size are generally considered
essential for effective coating.

Coating solution is applied as a solution or atomized spray on sugar

pellets (Non-pareil sugar seeds)

Medicaments are usually coated onto various spherical substrates such

as nonpareil sugar seeds, and then coated with protective layers of
various polymers.

Warm air is passed to remove the coating solvent

Fig. 5: Representation of a typical pan coating

4. Spray-drying

In modern spray dryers the viscosity of the solutions to be sprayed can

be as high as 300mPa.s

Spray drying and spray congealing- dispersing the core material in a

liquefied coating substance and spraying.

Spray drying is effected by rapid evaporation of a solvent in which the

coating material is dissolved.

The equipment components of a standard spray dryer include

1. an air heater,
2. atomizer,
3. main spray chamber,
4. blower or fan,
5. cyclone and
6. product collector
PROCESSING VARIABLES
Rotational speed of Cylinder
Flow rate of Core & coating material
Concentration & viscosity of coating material
Viscosity & Surface tension of core material
5. Vibrational Nozzle

The process works very well for generating droplets between 1005,000
m

Units are deployed in industries and research mostly with capacities of

110,000 kg per hour at working temperatures of 201500 C.

Nozzles heads are available from one up to several hundred thousand are
available.
Formation of Droplets Using Vibrational Nozzle Technique
9

II] Physico-chemical methods

1. Ionotropic gelation

Chemical reaction between sodium alginate and calcium chloride or

other Counter ion solution such as barium chloride.

Verapamil hydrochloride causes gastric irritation on sudden release. It is

usually administered as conventional tablets containing 40-120 mg, 3
times a day. Due to its ready solubility in water and shorter half-life.

Microparticulate system of verapamil hydrochloride for prolonged release

delivery system.

2. Coacervation-Phase Separation

Patents of B.K. Green et al.

Three steps carried out under continuous agitation:

1) Formation of three immiscible chemical phases

2) Deposition of the coating
3) Rigidization of the coating

10

COACERVATION / PHASE SEPARATION

1.Formation of three immiscible phase

2.Deposition of coating
3.Rigidization of coating.
COACERVATION PHASE SEPARATION

11

1. TEMPERATURE CHANGE METHOD

Change in temperature causes separation of coating material from the
solvent
Useful when the solubility of the material depend on temperature
E.g. Coating material.: Ethyl cellulose in cyclohexane
( EC is insoluble in Cyclohexane at room temp.)
Core Material: N-Acetyl P-Amino Phenol
Temperature

Change

Method

2. INCOMPATIBLE POLYMER ADDITION

The polymer which is chemically not compatible will be added to the
coating solution .
The polymer which is to be added should have
More affinity towards solvents
No interaction with the core material
Incompatible with the coating material
E.g: Addition of liq. Polybutadiene (Incompatible polymer) to the EC
solution in toluene (Coating sol.). Core material: Methylene blue HCl.

12

3. SALT ADDITION
Soluble inorganic salts can be added to aqueous solutions of certain
polymers
The salt added should
Be soluble in water
Should precipitate the polymer from the solution
Not have any interactions with a core material
Eg: Addition of 20% Sod. Sulfate to the gelatin solution.
Core Mat.: Oil soluble vitamin in corn oil.

13

4. NON SOLVENT ADDITION

Phase separation can be induced by addition of non-solvent for given
polymer
The non-solvent used should
Have more affinity towards solvent which is used
Precipitate the coating polymer
Not have any affinity towards core materia
Eg: Addition of Isopropyl ether to Cellulose acetate butyrate (CAB)
dissolved in Methyl ethyl ketone.
Core Mat: Methyl Scopolamine HBr.

5. POLYMER- POLYMER INTERACTION (COMPLEX COACERVATION):

Based on the ability of cationic and anionic water soluble polymers to
interact in water to form a liq, polymer rich phase complex coaservate
Eg: gelatin below its isoelectric pH possess + ve charge, gum Arabic
is ve ly charged.
Core mat: Methyl Salicylate.
Microcapsules of 20-800m size will be obtained
The microcapsule shells are moisture sensitive
14

COMPLEX COACERVATION:

MULTIORIFICE CENTRIFUGATION
By using centrifugal forces for encapsulating liquids & solids
Rotating cylinder
3 Circumferential Grooves
Intermediate groove with orifice
Tubes to carry coating material to upper & lower groove.
Counter rotating disc- Atomizes/Disperses cores.

15

SOLVENT

EVAPORATIONS

Step 1:
Formation of a solution/dispersion of the drug into an organic polymer
phase.
Step 2:
Emulsification of the polymer phase into an aqueous phase
containing a suitable stabilizer, thus, forming a o/w emulsion.
Step 3:
Removal of the organic solvent from the dispersed phase by
extraction or evaporation leading to polymer precipitation and formation of the
microspheres.

16

SPRAY DRYING & CONGEALING (COOLING)

Spray drying: spray = aqueous solution / Hot air

Spray congealing : spray = hot melt/cold air
SPRAY DRYING & CONGEALING (COOLING)
Approximate size range : 5-600 m
Applicable for both : Solids & Liquids
In both the processes dispersing the core material in coating material solution
& then treating the core-coating mixture to environmental condition where
relatively rapid solidification of the coating solution is done.
The main difference between two processes is :Spray drying : Here the coating solidification is effected by rapid evaporation of
a solvent in which coating material is dissolved.
Spray congealing : Here the coating solidification is effected by thermally
congealing a molten coating material.

17

POLYMERIZATION:

Monodisperse microgels in the micron or submicron size range.

Precipitation polymerization starts from a homogeneous monomer
solution in which the synthesized polymer is insoluble.
The particle size of the resulting microspheres depends on the
polymerization conditions, including the monomer/co monomer
composition, the amount of initiator and the total monomer
concentration
18

 INTERFACIAL POLYMERIZATION

Interfacial polymerization ( IFP)

-The shell form over the droplet or particle by reactive monomer.
- The multifunctional monomer dissolved in liquid core material & it is
dispersed in
aqueous phase containing dispersing agent.
- The co-reactant amide is added which result
at interface & microcapsule is generated.

in rapid polymerization

In-situ polymerization
-Similar to interfacial polymerization that shell form by polymerization.
- But in this process no reactive agent added to core material.
- The polymerization starts in continuous phase & is deposited at
interface.
- As the time progress the pre-polymer grows in size.
EXTRUSION:
This method was first patented in 1957.
The advantage of extrusion is that it completely surrounds the core
material with wall material.

19

 The process involves forcing a core material dispersed in a molten

carbohydrate mass through a series of dies, into a bath of dehydrating
liquid.
When contact with the liquid is made, the carbohydrate case hardens to
entrap the core material.
The extruded filaments are separated from the liquid bath, dried using
an anti-caking agent such as calcium tripolyphosphate and sized .
This process is particularly useful for heat labile substances such as
flavours, vitamin C and colours.
APPLICATION OF MICROENCAPSULATION TECHNIQUES

KINETICS OF DRUG RELEASE FROM MICROCAPSULES

Major mechanisms of drug release from microcapsules includes

Diffusion

Dissolution

Osmosis

Erosion

20

 Diffusion
- Most common mechanism of drug release.
- In this, dissolution fluid penetrates the shell & then the core material
comes in contact with the dissolution
fluid & then leak out through the interstitial channels or pores.
- Basically, the release of core material depends on the rate of drug
dissolution, rate of penetration, etc.

Dissolution

- The release rate of drug from the microcapsule depends on the

dissolution rate of polymer coat & the
solubility of the coat in the dissolution fluid.
- Generally, the solubility in the dissolution fluid & thickness of coat
influence the release rate.
Osmosis
- Another method drug release is through osmosis.
- The essential requirement of osmosis is semi-permeable membrane.
- As the process progresses an osmotic pressure is created between the
outside & inside membrane of
microcapsule which results in the release of drug through small pores.
Erosion
- Erosion of coat generally occurs due to the pH or enzymatic hydrolysis &
causes the release of drug with
certain
coat
materials
gycerylmonostrearate.

like

beeswax,

stearyl

alcohol

&

- The drug release from microcapsules has become complicated because of

the diversity in the physical
forms of microcapsules with shape, size & arrangement of the coat & core
materials.
21

Evaluation of microencapsules
Following parameters are carried out for evaluation of microencapsules
1. Morphology ( shape )
2. Drug content
3. Encapsulation efficiency
4. % yield
5. Bulk density
6. Angle of repose
7. Particle size determination
8. In-vitro dissolution / drug release
9. Stability studies
10. Assay
1. Morphology (shape) - Optical microscope helps us to diagnose the shape of microspheres.
- Shape & surface morphology study also carried out by SEM.
- It gives idea regarding the surface before coating & after coating.
- It also help in determining uniformity & the nature of the coating shell.

22

2. Drug content
- Microcapsules selected randomly from various batches.
- The specific quantity of microcapsules are taken & mechanically powdered.
- These powdered microcapsules are then dissolved in dissolution media of
specific quantity & then filtered through whatmann filter paper.
- Then 1ml of this solution is diluted & analyzed by using sophisticated
technique.
- From this techniques we know the concentration 7 the none can determine
the drug release by following formula
Drug release = conc. 1000 dilution factor
Wt. of drug
% Drug release = Drug release 100
3. Encapsulation efficiency It is determined by using formulaEncapsulation Efficiency = Actual drug content

100

Theoretical drug content

4. % yield It is determined by using formula

Where M is wt. of microcapsule & Mo is the theoretical wt. of drug plus polymer
5. Bulk density - Bulk density can be determined by 3-tap method.
- Bulk density is defined as the mass of powder divided by the bulk volume.
Bulk density = wt. of sample (gm.)
Final volume after taping
23

6. Angle of repose The angle of repose is determined by funnel method.

Tan = h
r
Where,
= Angle of repose
h = Height of pile
r = Radius
7. Particle size determination - Size distribution plays a very important role in determining the release
characteristics of the microcapsules.
- It also determines the variation in coating.
- The size of the coated particle is one of the techniques to checked batch to
batch variation.
- Particle size can be determined by optical microscopy method.
- The new technique SEM is also used to determine the particle size.
8. In-vitro dissolution / drug release - Depending upon the type of micro capsule select suitable USP dissolution
apparatus.
- Then as per the dissolution medium given in pharmacopoeia prepared the
buffer.
- Then at specified condition of temperature, RPM & interval withdrawn the
sample, filter through whatmann filter paper of size 0.45 micron.
- Then by suitable method estimate the drug content at that time interval.
- The data validate by ANOVA & standard deviation by at least 6 times

24

9. Stability studies - Short term 3-6 months, Long term 1-2 years
- This studies are performed as per ICH guidelines.
- Parameters considered are temperature & relative humidity.
Temperature
Relative humidity
25c
55%
30c
60%
40c
70%
-If not possible then storing the sample at 45c for 45 days & then the drug
content is determined.
-If there is no change in drug release pattern, then the prepared
microencapsules are stable & vice-versa.
10. Assay
-The assay of microcapsule is carried out by dissolving the specified weight of
microcapsule into methanol or any other
suitable solvent.
- Then filter through 0.45 micron filter.
- Then by appropriate method estimate the drug content.
- The assay carried out on each batch in at least 6 times in order to checked
batch to batch variation.

25