NOVEL DRUG DELIVERY SYSTEMS

UNIT II
MICROENCAPSULATION

Dr. Amarjitsing Rajput

Assistant Professor
Department of Pharmaceutics
Poona College of Pharmacy,
Pune

BHARATI VIDYAPEETH DEEMED TO BE UNIVERSITY, POONA COLLEGE OF PHARMACY, PUNE 1

 CONTENT

➢ Introduction
➢ Reasons of microencapsulation
➢ Microencapsulation components
a) Core material
b) Coating material
➢ Drug release mechanisms
➢ Microencapsulation processes
➢ Applications of microencapsulation
➢ References

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 INTRODUCTION

Definition
❑ It a process of by which tiny droplets or particles of liquid or solid material
are surrounded or coated with a continuous film of polymeric material.

❑ It is also defined as the process of surrounding or enveloping one substance

within a another substance on a very small scale, yielding capsules ranging
from less than one micron to several hundred microns in size.

❑ It is a way of applying a thin coating to small particle of solid or droplet of

liquid or dispersion.

❑ It is a method by which solids, liquids, or even gases may be enclosed in

microscopic particles by formation of thin coatings of wall material around
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the substance.
❑ Particle size ranges- 50-500 micron.
❑ Mainly consists of 2 components- Core material
Coating material

❑ The product obtained by microencapsulation process is known as micro

particles, microcapsules, microspheres, coated granules, pellets etc.

❑ Particles with diameter ranging from 3- 800 micron are known as

microcapsules or microspheres.

❑ Particles larger than 1000 micron are known as “Microparticles.”

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❑ To obtain maximum therapeutic efficacy, drug is to be delivered,

✓ To target tissue.

✓ In optimum amount

✓ In a right period of time.

❑ Thereby causing little toxicity and minimum side effects.

❑ One of such approach is using microspheres as carrier of drugs.

❑ Microspheres are characteristics free flowing powder, comprise of synthetic

polymer or protein.

❑ It is biodegradable in nature.
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❑ The particle size is less than 200 micron.
 REASONS OF MICROENCAPSULATION

❑ To protect drug substances from the environment.

❑ To convert active liquid component into a dry solid system.

❑ To separate incompatible components for functional reasons.

❑ To protect immediate environment of the microcapsules from active components.

❑ To isolate core from the surrounding, isolating vitamins from deteriorating effects of

oxygen.

❑ It prevent evaporation of volatile core.

❑ It improve the handling properties of sticky material.

❑ It provide safe handling of toxic material.

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❑ It also provide targeted release of drug.
 REASONS OF MICROENCAPSULATION

❑ To control release of active components for delayed release or long acting

release.

❑ To mask taste or odour of core.

❑ To produce targeted drug delivery.

❑ To protect GIT from irritant effects of the drugs.

❑ To extend the duration of activity for an equal level of active agent.

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 MICROENCAPSULATION COMPONENTS

❑ Generally microparticles consist of 2 components,

1. Core material:

✓ Solid core can be mixture of active constituents, stabilizers, diluents,

excipients and release retardants or accelerators.

✓ It is a material to be coated. It may be liquid or solid or gas.

✓ Composition of core material:

➢ Drug or active constituent

➢ Additive like diluent

➢ Stabilizer 8
Properties of some microencapsulated core material
Core material Characteristic property Purpose of Final Product
encapsulation Form
Activated charcoal Adsorbent Selective sorption Dry powder

Aspirin Slightly water soluble solid • Taste masking Tablet or capsule

• Sustained
release
• Reduce gastric
irritation
Islet of Langerhans Viable cells Sustained Injectable
normalization of
diabetic condition

Isosorbide dinitrate Water soluble solid Sustained release Capsule

Menthol/methyl Volatile solution • Reduction of Lotion

salicylate camphor volatility
mixture • Sustained
release
Potassium chloride Highly water soluble solid Reduced gastric Capsule
irritation
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Vitamin A palmitate Non-volatile liquid Stabilization to Dry powder
oxidation
2. Coating material/coat/wall/shell material:

❑ Compatible, non reactive with core material.

❑ Provide desired coating properties like strength, flexibility, impermeability,

optical properties, non hygroscopicity, tasteless and stable.

❑ Inert substance which coats on core with desired thickness.

❑ Composition: Inert polymer
Plasticizer
Colouring agent
Resin, waxes and lipids
❑ Properties of coating material:
i. Stabilization of core material
ii. Inert toward active ingredients.
iii. Controlled release under specific conditions. 10

iv. Film-forming, tasteless, stable.

iv. Non-hygroscopic, less viscous, economical.
v. Soluble in an aqueous media or solvent.
vi. The coating can be flexible, brittle, hard, thin etc.

LIST OF COATING MATERIAL

Water soluble Water insoluble resin Wax & lipid Enteric resin
resin
Gelatin Ethyl cellulose Paraffin Shellac
Gum Arabic Polyethylene Carnauba wax Zein
Poly vinyl Polymethaacrylate Bees wax Cellulose acetate
pyrrolidone (PVP) phthalate

Carboxy Methyl Cellulose nitrate Stearic acid

cellulose [CMC]
Methyl cellulose Silicones Stearyl alcohol
Polyvinyl acrylate Polyamide Glyceryl
stearates
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Poly (lactide-co- Spermaceti

glycolide) [PLA]
 DRUG RELEASE MECHANISM

➢ The microencapsulation aim is the isolation of the core from its

surrounding, the wall must ruptured at the time of use.
➢ A different release mechanisms have been proposed for microcapsules. It
includes,
✓ By pressure or shear stress
✓ By melting the wall
✓ By dissolving under specific conditions as in enteric coating
✓ By solvent action
✓ By enzyme attack
✓ By chemical reaction
✓ By hydrolysis or slow disintegration
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 MICROENCAPSULATION PROCESSES

1. Coacervation phase separation

2. Air suspension (Wurster coating)
3. Multiorifice centrifugal
4. Solvent evaporation
5. Spray drying and congealing
6. Pan coating
7. Polymerization
8. Extrusion
9. Single and double emulsion techniques
10.Supercritical fluid anti-solvent method (SAS)
11.Nozzle vibration technology
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 MICROENCAPSULATION PROCESSES & APPLICATIONS

Microencapsulation process Applicable core Approximate

material Particle size (μm)

Air suspension (Wurster coating) Solids 35-5000*

Coacervation phase separation Solids & liquids 2-5000*

Multiorifice centrifugal Solids & liquids 1-5000*

Pan coating Solids 600-5000*

Solvent evaporation Solids & liquids 5-5000*

Spray drying and congealing Solids & liquids 600

* The 5000 μm is not a particle limitation. The methods are also applicable to
macrocoating i.e. particles greater than 5000 μm in size.
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 MICROENCAPSULATION PROCESSES

MICROENCAPSULATION PROCESSES

Physical or Physico-
Physio-chemical Chemical
mechanical

1. Air suspension 1. Solvent evaporation

1. Ionotropicgelation
2. Centrifugal Extrusion 2. Polymerization
2. Co-acervation
3. Pan coating 2.1 Interfacial polymer
4. Spray drying 2.2 In situ Polymerization
4.1 Co-current 2.3 Matrix polymer
4.2 Counter-current
4.3 Mixed flow
4.4 Vibrational nozzle

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 CO-ACERVATION PHASE SEPARATION METHOD

❑ Coacervation microencapsulation is the phase separation of one or many

hydrocolloids from the initial solution and the subsequent deposition of the newly
formed coacervate phase around the active ingredient suspended or emulsified in the
same reaction media.
❑ Coacervation is a unique microencapsulation technology because of the very high
payloads achievable up to 99%.
❑ Coacervation is typically used to encapsulate flavor oil and can also be adapted for the
encapsulation of fish oils, nutrients, vitamins, preservatives and enzymes.
❑ It is divided into 2 types,
A. Simple co-acervation
B. Complex co-acervation
❑ The mechanism of microcapsule formation for both processes is similar, except for the
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way in which the phase separation is carried out.
 SIMPLE CO-ACERVATION PHASE SEPARATION
❑ In case of simple co-acervation, desolvation agent is added in phase separation, while
complex co-acervation involves the complexation of oppositely charged polymers.
❑ It basically involves 3 steps,
Step 1: Formation of three immiscible phases
✓ It consists of following 3 phases
a) Liquid manufacturing vehicle phase (LMVP) [core material dissolved in coating]
b) Core material phase
c) Coating material phase
✓ In this coating material phase is formed by- Temperature change
By addition of incompatible polymer
By salt addition
By non solvent addition
Polymer-polymer interaction
Step 2: Deposition of liquid polymer coating upon the core material, the deposition of
the liquid polymer around the interface formed between the core material and the liquid vehicle
phase.
Step 3: Rigidization of coating :Usually takes place via thermal, crosslinking or
desolvation techniques. 17
SIMPLE CO-ACERVATION PHASE SEPARATION

18
COMPLEX CO-ACERVATION PHASE SEPARATION

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COMPLEX CO-ACERVATION PHASE SEPARATION

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 AIR SUSPENSION/WURSTER
COATING/FLUIDISED BED COATING
❑ This technique is invented by Prof. Dale E. Wurster, hence called as “Wurster coating.”

❑ Principle : In fluidized bed technique, hot air (gas) is passed at high pressure through
a perforated bottom of the container containing granules to be coated. The granules are
lifted from the bottom and suspended in the stream of air. This condition is called
fluidized state. The hot gas is surrounding every granule to completely coat them. Thus,
materials or granules are uniformly coated.
❑ Construction : Generally available in 2 types,
A. Vertical fluidized bed dryer
B. Horizontal fluidized bed dryer
The construction of vertical fluidized bed dryer is shown in Figure. It consists of following
parts,
a) Perforated bowl
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b) Fans
c) Filter bags
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❑ Working:
✓ The wet granules to be coated are placed in the detachable bowl on the top of
retaining screen.
✓ Fresh air is allowed to pass through a prefilter, which subsequently gets heated by
passing through a heat exchanger.
✓ The air velocity is gradually increased. When the velocity of the air is greater than
settling velocity of granules, the granules remain partially suspended in the gas
stream.
✓ The granules rise in the container because of high velocity gas (1.5 to 7.5 metres per
minute) and later fall back in a random boiling motion. This condition is said to be
fluidized state.
✓ The gas surrounds every granule to completely coat them. The air leaves the dryer
by passing through the bag filter. The coated particles remain adhered to the inside
surface of the bags. Periodically the bags are shaken to remove the coated
particles.
✓ Intense mixing between granules and hot gas provides uniform conditions of
temperature, composition and particle size distribution. Drying is achieved at
constant rate and falling rate period is very short. The residence time for drying is
about 40 minutes.
✓ The process parameters are optimized systematically,
a) Maximum, minimum, and optical air velocities
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b) Air temperature
c) Drying time
d) Tendency of cake and channel
❑ Uses:
✓ Used for drying of granules in the production of tablets.
✓ Used for three operations such as mixing, granulation and drying.
✓ It is modified for coating of granules.
❑ Advantages:
i) It requires less time to complete drying, i.e. 20 to 40 min compared to 24 h of tray dryer.
ii) Hot spots are not observed in the dryer, because of its excellent mixing and drying
capacities.
iii) Higher drying temperatures can be used that are not possible in tray dryer and truck
dryer.
iv) It facilitates the drying of thermolabile substances, since the contact time for drying
is short.
v) It can be used either as batch type or continuous type.
vi) It has a high output from a small floor space.

❑ Disadvantages:
i) Many organic powders develop electrostatic charges during drying.
ii) The turbulence of the fluidised state of granules may cause attrition of some materials
resulting in the production of fines. 24
 SOLVENT EVAPORATION METHOD
❑ In the case in which the core material is dispersed in the polymer solution, polymer

shrinks around the core.

❑ In the case in which core material is dissolved in the coating polymer solution, a matrix

- type microcapsule is formed.

❑ The core materials may be either

✓ Water - soluble or

✓ Water - insoluble materials.

❑ A variety of film forming polymers can be used as coatings.

❑ Used by various companies like NCR, Fuji Photo Film Co. Ltd.

❑ Example: Evaluation of sucrose esters as alternative surfactants in microencapsulation

of proteins by the solvent evaporation method. 25

Process:

Core material

Dissolved or dispersed

Coating polymer solution

With agitation

Liquid Manufacturing Vehicle Phase (LMVP)

Heating (If necessary)

Evaporation of polymer solvent

Microencapsulation
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Process:

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 as 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.
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 PAN COATING

❑ Oldest industrial procedures for forming small, coated particles or tablets.

❑ The particles are tumbled in a pan or other device while the coating
material is applied slowly.
❑ Solid particles greater than 600 microns in size are generally considered
essential for effective coating.
❑ Medicaments are usually coated onto various spherical substrates such as
nonpareil sugar seeds, and then coated with protective layers of various
polymers.
❑ It is used for preparation of controlled- release beads.
❑ Coating is applied as solution by automized spray to desired solid core
material in coating pan.
❑ Usually warm air is passed over the coated material as the coating are being
applied in the coating pan. 28
Steps
Step 1: Solid particles are mixed with a dry coating material.
Step 2: The temperature is raised so that the coating material melts and encloses the
core particles, and then is solidified by cooling or the coating material can be gradually
applied to core particles tumbling in a vessel rather than being wholly mixed with the
core particles from the start of encapsulation. Step 3: The particles are
tumbled in a pan or other device
while the coating material is
applied slowly.

Step 4: The coating is applied

as a solution or as an atomized
spray to the desired solid core
material in the coating pan.
Step 5: Usually, to remove the
coating solvent, warm air is
passed over the coated materials as
the coatings are being applied in
the coating pans.
Step 6: In some cases, final
solvent removal is accomplished in
drying oven. 29
 POLYMERIZATION

❑ A relatively new microencapsulation method utilizes polymerization

techniques to form protective microcapsule coatings in situ.
❑ The method involve the reaction of monomeric unit located at the interface
existing between a core material substance and continuous phase in which
the core material is disperse.
❑ Example: In the formation of polyamide (nylon) polymeric reaction
occurring at liquid-liquid interface existing between aliphatic diamine &
dicarboxylic acid halide.
❑ 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.
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SINGLE EMULSION METHOD

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DOUBLE EMULSION METHOD

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 SPRAY DRYING
Principle : In spray dryer, the fluid to be dried is atomized into fine droplets, which
are thrown radially into a moving stream of hot gas. The heating medium (hot air) is in
contact with the material (direct drying). The temperature of the droplets is immediately
increased and fine droplets get dried instantaneously in the form of spherical particles.
Construction: ❑ It consists of a large cylindrical
drying chamber with a short
conical bottom, made up of
stainless steel.
❑ An inlet for hot air is placed in
the roof of the chamber. Another
inlet carrying spray-disk at
iomizer is set in the roof.
❑ The spray disk atomizer is about
300 m in diameter and rotates at
a speed of 3,000 to 50,000
revolutions per minute. Bottom
of the dryer is connected to a
cyclone separator.

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❑ Working: Drying of the material in spray dryer involves 4 stages.

(1) Atomization of the liquid

(2) Mixing of droplets

(3) Drying of the liquid droplets

(4) Recovery of the dried product

❑ Example:
❑ Solid dispersions of glibenclamide were prepared using a spray drying technique by
Chauhan et al.
❑ In this method, glibenclamide was dissolved in sufficient solvent to yield a clear
solution.
❑ Silicon dioxide was added and the resulting suspension was spray-dried using a spray
dryer under fixed conditions of inlet and outlet temperature, feed rate and
atomization air pressure.

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 SPRAY CONGEALING (SPRAY COOLING)

❑ In this method, molten lipid is sprayed into a cooling chamber and, on contact with
the cool air, congeals into spherical solid particles.
❑ Steps:
Step 1: Core particles are dispersed in a polymer solution and sprayed into a hot
chamber.
Step 2: The shell material solidifies onto the core particles as the solvent evaporates.
Step 3: The microcapsules obtained are of polynuclear or matrix type.
❑ It can be accomplished with spray drying equipment when the protective coating
is applied as a melt.
❑ Core material is dispersed in a coating material melt rather than a coating
solution.
❑ Coating solidification (and microencapsulation) is accomplished by spraying the
hot mixture into a cool air stream.
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Examples:

1. Microencapsulation of vitamins with digestible waxes for taste masking.

2. Praziquantel granules were prepared by melt granulation using PEG 4000 or

Poloxamer 188 as a meltable binder and lactose monohydrate as filler.

3. In another study by Cavallari et al. microparticles with narrow size

distribution were obtained when stearoyl polyoxylglycerides

(Gelucire® 50/13) were used as an excipient and significantly enhanced the

drug release of poorly water soluble drugs like Diclofenac.

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MULTIORIFICE CENTRIFUGAL METHOD

❑ The Southwest Research Institute (SWRI)

has developed a mechanical process for
producing microcapsules.
❑ Centrifugal forces to hurl a core material
particle through an enveloping
microencapsulation membrane thereby
effecting mechanical microencapsulation.
❑ 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 as a dry powder.
❑ For more details-Read from Lachman
book. 38
 CHARACTERIZATION OF MICROENCAPSULE
❑ Parameters:
1. Particle size: For size distribution analysis, different sizes in a batch were
separated by sieving by using a set of standard sieves. The amounts retained
on different sieves were weighed .

2. Percentage yield: The total amount of microcapsules obtained was weighed

and the percentage yield calculated taking into consideration the weight of
the drug and polymer.
Percentage yield = Amount of microcapsule obtained /Theoretical
amount × 100
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3. Entrapment efficiency: Encapsulation efficiency was calculated using the
formula:
Encapsulation efficiency =Actual Drug Content / Theoretical Drug Content
×100
4. Scanning Electron Microscopy (SEM): A small amount of microcapsules was
spread on gold stub and was placed in the scanning electron microscopy (SEM)
chamber. The SEM photomicrographs was taken at the acceleration voltage of
20 KV.
5. Drug content : Using suitable method i.e. UV or HPLC.
6. In vitro drug release: Using USP type II apparatus, phosphate buffer pH 7.4 at
37 °C and analyzed by UV or HPLC.
7. Atomic Force Microscopy
8. Viscosity
9. Bulk density
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APPLICATIONS OF MICROENCAPSULATION

41
 APPLICATIONS OF MICROENCAPSULES AND
MICROSPHERES

1. Agricultural Applications

❑ Reduce insect populations by disrupting their mating process.

❑ Protects the pheromone from oxidation and light during storage and release.

2. Catalysis
❑ Safe handling, easy recovery, reuse and disposal at an acceptable economic
cost.
❑ Metal species such as palladium (II) acetate and osmium tetroxide have
been encapsulated in polyurea microcapsules and used successfully as
recoverable and reusable catalysts without significant leaching and loss of
activity.

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3. Food Industry
❑ Adding ingredients to food products to improve nutritional value can
compromise their taste, color, texture and aroma.
❑ Sometimes they slowly degrade and lose their activity or become hazardous
by oxidation reactions.
❑ Ingredients can also react with components present in the food system, which
may limit bioavailability.

4. Pharmaceutical Applications
❑ Potential applications of this drug delivery system are replacement of
therapeutic agents (not taken orally today like insulin), gene therapy and in use
of vaccines for treating AIDS, tumours, cancer and diabetes.
❑ The delivery of corrective gene sequences in the form of plasmid DNA could
provide convenient therapy for a number of genetic diseases such as cystic
fibrosis and hemophilia. 43
❑ Lupin has already launched in the market worlds first Cephalexin (Ceff-ER)
and Cefadroxil (Odoxil OD) antibiotic tablets for treatment of bacterial
infections.
❑ Aspirin controlled release version ZORprin CR tablets are used for relieving
arthritis symptoms.
❑ Quinidine gluconate CR tablets are used for treating and preventing
abnormal heart rhythms.
❑ Niaspan CR tablet is used for improving cholesterol levels and thus reducing
the risk for a heart attack.
❑ Prepare enteric-coated dosage forms selectively absorbed in the intestine
rather than the stomach.
❑ Used to aid in the addition of oily medicines to tablet dosage form.
❑ To protect drugs from environmental hazards such as humidity, light,
oxygen or heat. Example: Vitamin A and K have been shown to be protected
from moisture and oxygen through microencapsulation. 44
❑ To improve the flow properties. Example: Thiamine, Riboflavine.
❑ To enhance the stability. Example: Vitamins.
❑ To reduce the volatility of materials.
Example: Peppermint oil, Methyl salicylate.
❑ To mask the unpleasant taste and odor. Example: Aminophylline, Castor oil.
❑ To convert liquids into solids. Example: Castor oil, Eprazinone.
❑ To reduce gastric and other gastro intestinal (G.I) tract irritations. For
example sustained release aspirin preparations have been reported to cause
significantly decrease G.I. bleeding than conventional preparations.
❑ Hygroscopic properties of core materials may be reduced by
microencapsulation
Example: Sodium chloride.
❑ To reduce volatility of liquids like peppermint oil.
❑ Used to improve flow properties before compression into tablets
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 MARKETED PRODUCTS

Brand Name API Manufacture

OROS CT Colon specific drugs Alza corporation

(osmotically active
tablets)

ReGel Paclitaxel Macro Med Inc.

(oncogel)

Clopigrel Clopidogrel+ Aspirin Lupin pinnacle

Clobitab Clopidogrel+ Aspirin Lupin pinnacle

Atoplus Atorvastatin Triton (calyx)

69

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 REFERENCES

❑ llen LV, Popovich NG, Ansel HC. Pharmaceutical Dosage Forms and Drug
Delivery Systems. Delhi, India: BI Pubication;2005;8:265.
❑ N.K.Jain, Controlled and Novel drug delivery, 04 Edition, 236-237, 21. 3.
S.P.Vyas and R.K.Khar, Targeted and Controlled drug delivery, 07 Edition, 418.
❑ Lachman LA, Liberman HA, Kanig JL. The Theory and Practice of Industrial
Pharmacy. Mumbai, India: Varghese Publishng House;3:414-415.
❑ Remington GA. The Science and Practice of Pharmacy. Delhi, India: BI
publication;2006, 21st Edition, Volume I:924.
❑ https://www.youtube.com/watch?v=WIjCQivGn2g, accessed date May 19,
2021.
❑ https://www.slideshare.net/GajananSanap/microencapsulation-58778836

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