MICROENCAPSULATION

► Microencapsulation is defined as the application of

a thin coating to individual core materials that
have an arbitrary particle size range from 5 to
5000 µm (Nokhodchi and Farid 2002)
► 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.
► For solids, liquids and gases
 Microcapsules
Microcapsules are small particles (liquids,
solids, solutions, or dispersions) that can
contain an active substance coated by
natural or synthetic polymer of varying
thickness. Generally the active substance is
called CORE and the coating is called WALL
MATERIAL.
Microcapsules vs. Microspheres
A Microcapsule has a drug A Microsphere has its drug
located centrally within the dispersed throughout the
particle i.e. the internal
particle, where it is encased structure is a matrix of drug
within a unique polymeric and polymeric excipients
membrane
 Microspheres
► Microspheres are
defined as solid,
approximately
spherical particles
ranging in size from
about 1-1000 µm
(Burgess and Hickey
2002) and are widely
used as drug carriers
for controlled release
Reasons for microencapsulation
► To make the formulation sustained or controlled
release.
► To mask the taste & odor of bitter drugs
► A mean of separating incompatible materials
► To protect the drug from environmental conditions
(light, moisture & oxidation)
► For converting liquid into free-flowing powders
► To prevent the gastric irritation of certain drugs
► Water solubility or dispersibility
 Different Dosage Forms
The microencapsulated
drugs from different pharmacological classes
can be given in the form of free flowing
powders in hard & soft gelatin capsules,
tablets, suspensions, rectal & vaginal
suppositories, ointments, creams, aerosols,
plasters and dressings.
 General methods of preparation
Determined by some formulation ► Nature of polymer
and technology related factors
► Drug
► The particle size requirement.
► Intended use
► The drug or the protein
should not be, adversely ► Duration of therapy
affected by the process
► Reproducibility of the release
profile
► No stability problem.
► No toxic products associated
with the final product
► Solvent evaporation (Emulsification-Evaporation)
Oil-in-water emulsion (o/w)
Multiple emulsions: Water-in-oil-in-water (w/o/w):
Nonaqueous emulsions: Oil -in -oil (o/o)
► Polymerization techniques
Normal polymerization
► Bulkpolymerization
► Suspension polymerization
► Emulsion polymerization

Interfacial polymerization
► Phase separation coacervation technique
► Spray drying and spray congealing
 Solvent evaporation
(Emulsification-Evaporation)
► Fully developed at end of 1970
► Based on the evaporation of the internal phase of an emulsion
by agitation
DEFINITION : Process of microencapsulation in which
deposition of coating material or polymer around drug or core
material is carried out by the evaporation of volatile solvent in
which polymer is present. Actually creation of insufficiency of
solvent for polymer by evaporation of solvent results in
precipitation of polymer around core material & formation of
microcapsules. Aggitation is required during this process
 Method of preparations by
solvent evaporation process
Two major techniques are used for
microencapsulation by solvent evaporation.
► Single emulsion solvent evaporation
technique (O/W & O/O)
▪ Oil in water emulsion technique
▪ Oil in oil emulsion technique
► Multiple emulsion solvent evaporation
technique. (W/O/W)
 Oil-in-water (o/w) emulsion
► Water as nonsolvent to the polymer are in
general preferred.
► Extremely economical and negate the
recycling of the external phase
► Suitable for the encapsulation of lipophilic
active principles
► Microencapsulation of hydrophilic active
principles by this process can pose problems
 Multiple emulsions: Water-in-
oil-in-water (w/o/w)
► For the efficient encapsulation of water-soluble
active principles
► Organic phase acts as a barrier between the two
aqueous compartments preventing the diffusion of
the medicine toward the external aqueous phase
► This process proves much more effective when the
water solubility of the medicine is high (>900 mg/
mL) and prevent partioning of drug into organic
phase
► Sometimes viscosity of primary emulsion is
increased to prevent partioning
 Nonaqueous emulsions: Oil-in-
oil (o/o)
► Continuous & discontinuous phase are oil and
immiscible with each other
► For drugs having high hydrophilicity and gives
highest yield
► For drugs/polymers that are degraded in presence
of water
► More expensive than aqueous methods
► Difficult to recycle oil phase
► Traces of oil possesses problems
 Interfacial Polymerization
Definition; interfacial Polymerization is a
technique in which polymerization of two
monomers, one oil soluble and other water
soluble, takes place and a polymer is formed at
the interface of two immiscible substances.
This tech is mostly used for the encapsulation of
liquids rather than solids b/c penetration of
monomer to polymerization zone is much easy
from the liquid state rather than the solid state.
 General method of Preparation
► The process consists of bringing two reactants at the
interface of the dispersed phase and the continuous
phases in emulsion system
► This is usually accomplished by emulsifying the liquid
containing first reactant (dispersed phase) into continuous
phase, which is initially devoid of second reactant
► Additional continuous phase containing the second
reactant is then added. The interfacial polymerization
reaction produces a continuous film of the polymer around
the drug.
► Microcapsules can be recovered by spray drying or
filtration
Procedures adopted for interfacial
polymerization
► Procedure for water immiscible liquid core
► Procedure for water miscible liquid core
► Procedure for solid core
 Procedure for water
immiscible liquid core
When the core material is lipophilic liquid, the
monomer is dissolved in the liquid core.
Usually isocyanate or acid chloride is user as
monomer. Then this solution is disperesed
in aqueous phase (containing 2nd monomer)
this prpduces poolymerization of monomers
at the interface & results in formation of the
capsule wall
Procedure for water miscible
liquid core
Aqueous solution of water soluble drug (dispersed
phase) containing monomer is dispersed in to an
organic phase (continuous phase) which contain
the emulsifier to form W/O emulsion. When
additional oil containing 2nd monomer is added to
W/O emulsion, polymer membrane is formed.
Then microcapsules are separated by different
techniques
 Procedure for solid core

Solid cores are encapsulated by vinyl monomers that

polymerizes by free radical reaction.
► Different solvents used
o CCl4
o Chloroform
o Methanol
o Water
► Different monomers used
Polyamines (hexamethylene diamine) polyphenol (hydroxy
phenol propane) polybasic acid halide (sebacoyl chloride)
 Applications of interfacial
polymerization
Some important applications are as follows;.
► Enzymes
► Proteins
► Artificial cells
► Pharmaceuticals
► Adsorbants
► Hormones and antibiotics
► Pigments, oily liquids & polyelectrolytes
Coacervation Or phase separation
technology
Coacervation is derived from Latin word
acervus means aggregation and the prefix
co indicates the preceding union of the
colloidal particles.
This term was first used to described the
phenomenon of phase separation in
colloidal system and thus it was defined as
A process in which aqueous colloidal solution
separate upon alteration of thermodynamic
condition of state into two liquid phases,
one rich in colloid i.e. the coacervate & the
other containing little colloide.
Deposition of this coacervate around drug or
core material form the embryonic capsule &
then appropriate gelling of coacervate
resulted in microcapsules.
 Core material
The core material or drug which can be
encapsulated by coacervation can be solid,
liquid, gas, liquid slurry, suspension or
emulsion and analgesics, antibiotics,
antihistamine, tranquillizers, iron salts and
vitamins
 Wall material
► The coating material can be selected from a variety of
natural and synthetic polymers depending on the core
material to be encapsulated and the desired
characteristics.
► The amount of coating material used ranges from 3%-
30%of the total weight.
► Both natural and synthetic colloids can be used,
Hydrophobic colloids are used for encapsulating water
soluble drugs whereas Hydrophobic colloids are used for
encapsulating water insoluble drugs.
 Methods employed for
coacervation
Following methods can be used for coacervation & the choice
of method depend upon the polymer and the set of
conditions which are being used;
► Temperature change
► Salt addition
► Nonsolvent addition
► Incompatible polymer addition
► polymer-polymer interaction
 Temperature change

By temp. change, phase separation of dissolved polymer

takes place in the form of immiscible liquid droplets, if drug
is present these droplets surround the core & form
microcapsules.
A system that utilizes ethyl cellulose & cyclohexane at high
temp. is an example of thermally induced
microencapsulation. Ethylcellulose is soluble in cyclohexane
elevated temp. but insoluble at room temp. first of all
ethylcellulose is dispersed in cyclohexane & then mixture is
heated to boiling point so that a homogenous polymer
solution is formed. Then core material is added in the
solution with continous stirring & mixture is allowed to
cool.
This results in phase separation of ethylcellulose &
microencapsulation of core material. Furthuf cooling of
mixture to room temp. causes gelation & solidification of
the coating.
 Salt addition
Soluble inorganic salts can be added to aqueous solution of
water soluble polymers to cause phase separation. A
gelation-water-sodium sulphate is an example. In this
system, phase separation/coacervation is induced by
adding dropwise 20% solution of sodium sulphate.
 Nonsolvent addition
A liquid that is a nonsolvent for a given polymer or does not
dissolve the given polymer can be added to a solution of
polymer to induce phase separation. The resulting
immiscible liquid polymer is used for encapsulation of an
immiscible core.
Fro example;
Cellulose acetate+ methyl ethyl ketone --------→ solution of
polymer---------→ addition of drug (scopolamine) -------
→addition of isopropyl ether (nonsolvent for polymer) -----
----→ phase separation & microencapsulation of suspended
drug occur.
Incompatible polymer interaction
Methylene blue-ethylcellulose-liquid polybutadiene is an
example of microencapsulation by incompatible polymer
addition.
Ethyl cellulose is dissolved in toluene to form polymer
solution. Then methylene blueis dispersed in polymer
solution. Phase separation is carried out by adding liquid
polybutadiene which is soluble in toluene but incompatible
with ethyl cellulose. Thus causes demixing of ethyl
cellulose & phase separation occur.
 Polymer-polymer interaction
Interaction of two oppositely charged polyelectrolyte can
result in the formation of a complex having such reduced
solubility that phase separation separation occur.
e.g. gelatin & acacia are examples of oppositely charged
polyelectrolyte because gelatin has positive charge
whereas acacia possess a negative charge. Gelatin-gelatin,
gelatin-CMC are examples of other oppositely chaeged
polyelectrolyte used in microencapsulatio.
 Description of coacervation
Coacervation method is divided into two main
groups
► Aqueous phase separation
▪ Simple coacervatio
▪ Complex coacervation
► Organic phase separation
 CHARACTERIZATION
► Recovery of formed microspheres
► Hydration of microspheres
► Drug loading
► Encapsulatipon efficiency
► Rheological properties
► Morphology (SEM,TEM)
► FTIR
► XRD
► TGA/DSC
► Drug release
► Drug release kinetics
 W ater immiscible liquid / O/W Emulsion
water insoluble particles
Or
Simple Coacervation +
Aqueous Suspension of Solid
Aqueous coating solution Particles
(gelatin in water)

Gel colloid by pouring Then add 20% w/w Na 2SO4

Filter and wash coacervate coacervate solution with continuous
with cold water to remove salt M ix in to 70 % w/w Na 2SO4 stirring to produce
solution Cacervation

Treat filtered material with Filter and wash particles with

Dry to remove remaining
formaldehyde to harden cold water to remove
solvent
coacervate hardening agent
 Complex
W ater immiscible liquid /
Cacervation water insoluble particles
O/W Emulsion
Or
+
Aqueous Suspension of Solid
Aqueos coating solution
Particles
(accacia in water)

Pour coacervate mixture in to Add warn water until Then add gelatin solution
cold water coacervate is produced with stirring

Remove aggregates of
Then treat coacervate with Dry and comminute
encapsulated material and
formaldehyde solution aggregated material
wash with water
 W ater immiscible liquid /
W /O Emulsion
water insoluble particles
Organic Phase +
Or
Separation Polymer in organic solvent
Suspension of Solid Particles
(in solid particles)
(PLA in methylene chloride)

Cooling of microcapsules to Phase separation Then addition of non solvent

solidify PLA coating (microcapsule are produced) for polymer (mineral oil)

Then further treatment with

W ash and dry
non solvent for hardening
 Applications of coacervation
► Antibiotics;amoxicillin, ampicillin,
bacampacillin, cephalexin, cephradine,
erythromycin, clarithromycin,
chloramphenicol
► Anti-inflammatory drugs; diclofenac sodium,
ibuprofen, naproxen, mefenamic acid &
flufenamic acid.
► Bronchodilators; theophylline & terbutaline
sulphate.
 Applications of coacervation
► Sulfa drugs; sulfadiazine, sulfamerizine &
sulfamethoxazole
► Diuretics; furosemide, chlorothiazide &
sulfonamide
► Urinary antiseptics; nitrofurantoin & nalidixic
acid
► Antiepileptic drugs; phenytoin sodium,
beclamide
 Applications of coacervation
► Antihypertensive;isosorbide mononitrate,
captopril, propranolol &nicardipine

► Analgesics; acetyl salicylic acid

► Anticancers; mitomycin, bleomycin &

mercaptopurine.
► Tranquilizers; diazepam & oxazepam.
 Applications of coacervation
► Electrolyte replenisher; sodium chloride &
potassium chloride.
► Vitamins & metal salts; A, B1, B2, B6, B12,
C & D and mineral salts like Zinc sulphate.
► Converting liquids into free flowing
powders; Cod liver oil, benzaldehyde &
other citrus essential oils.
► Recovery of formed ► Hydrationof
microspheres microspheres
► Rheological studies
► Drug loading

► Encapsulation efficiency
Ethylene Glycol Dimethacrylate co-
vinyl acetate microspheres
► Polyhydroxybutyrate-
co-valerate (PHB-HV)
FTIR & XRD of PCL-PVP
microspheres
 DSC
► 5-FU microspheres
Drug release
Equation for drug release kinetics
• Zero order release Qt = k0 t
• First order log Qt = log Q0 − k1 t
• Higuchi,s model Qt = k H t 1/ 2

− Qt = k HC t
1/ 3 1/ 3
• Hixson-Crowell Q0
• Korsmeyer-Peppas Mt
= k KP t n
M0
Application
 Potential applications of
microspheres
► Taste and odor masking
► Conversion of oils and other liquids to solids for ease of
handling
► Protection of drugs against the environment as moisture ,
light ,heat , oxidation etc and vice versa i.e. prevention of
pain of injection
► Delay of volatilization
► Separation of incompatible materials
► Improvement of flow properties of powders
► Safe handling of toxic substances
► Aid in dispersion of water insoluble substances in aqueous
media
► Production of sustained release, controlled release and
targeted medications
► Reducing dose dumping potential compared to large
implantable devices (Burgess and Hickey 2002).
► If you stand for a reason, be prepared to
stand alone like a tree and if you fall on the
ground , fall as seed that grows back to
fight again

► Whenever you get really attached to some

one more than anyone else, then that
person is surely going to hurt you more
than any one else