Microspheres & Microcapsules (1) (1).ppt

24-01-2017
Milestone of Journey
Definition
Method of preparation
Microsphere
Microcapsule
Manufacturing variables
Characterization & Evaluation
Applications
Mechanism of Drug Release
References
L.M.College of Pharmacy

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Definition
• In simple means microsphere is sphere of
micron() size.
• Micro-particles are the polymeric entities
falling in the range of 1-1000 m.
• Microcapsules: micrometric reservoir
systems
• Microspheres: micrometric matrix systems.

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What is Microcapsule &
Microsphere?
Encapsulation involves surrounding drug molecules with a
solid polymer shell
Entrapment involves the suspension of drug molecules within
a polymer matrix.
drug
polymer
Drug
Polymer

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Microcapsule
Manufacturing of microcapsule is classified
in main two category according to
principle process involved.
Type A : Chemical Process
Type B : Mechanical Process

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1. Type A: Chemical Process
Coacervation phase separation
Simple Coacervation
Complex Coacervation
Polymer – Polymer interaction
Non solvent addition
Temperature change
Interfacial polymerization
In situ polymerization
Centrifugal force and Submerged nozzle
process

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2. Type B: Mechanical Process
Spray drying & spray congealing
Fluidized bed
Melt dispersion technique
Pan coating
Centrifugal extrusion
Rotation suspension separation
Multi orifice centrifugation technique

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Coacervation
Coacervation may be
Simple
Complex
Common out line of the process consists of
three steps
1. Formation of three-immiscible phase
2. Deposition of liquid polymeric coating material
3. Solidification/rigidization of the coating material

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Coacervation Technique
STEP #1:
Polymer dissolved in a solvent (or oil)
Drug dissolved in water
STEP #2:
2 liquids are rapidly mixed
water droplets form within the solvent
STEP #3:
Emulsion from step #2 is mixed rapidly with
fresh water
Oil droplets within the fresh water phase
Oil droplets contain original dispersed
water/drug phase
Oil diffuses into the fresh water phase
precipitating the polymer & entrapping the
drug
Drug/H20
Polymer/Oil
H20

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Simple Coacervation
Technique

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Complex Coacervation
Deals with system containing more than one
colloid.
It is a pH dependent process.
The system depending on its acidic or basic
nature may produce microencapsules. Below
that pH value they will not form.
Based on the ability of cationic & anionic
water-soluble polymers to interact in water to
form a liquid polymer rich phase called a
complex coacervate.

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Advantages
1. To encapsulate water immiscible liquids.
2. Microcapsules have size of 20-200 m
diameter that contains 80-90% wt of core
material.
Disadvantages
1. Physical properties of shell/barrier are
sensitive to environmental conditions.

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Polymer-Polymer Interaction
They essentially repel each other & form
two distinct phases. One phase is rich in
polymer designed to act as the capsule
shell.

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Polymer Polymer
Interaction
method

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Coating polymer
Ethyl cellulose
Cellulose nitrate
Cellulose acetate
Polymethyl
methacrylate
Polystyrene
Polymers used to
induce phase
separation
Polyethylene
Polybutadiene
Polymethyl siloxane

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By Non Solvent addition method
A liquid that is a Nonsolvent for a given
polymer can be added to a solution of the
polymer to induce phase separation.
The resulting immiscible liquid polymer
can be utilized to effect micro
encapsulation of an immiscible core
material.

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Nonsolvent Addition
Method

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Temperature Changing method
It involves a
polymer soluble in
a solvent at
elevated temp. but
insoluble in same
solvent at room
temp.

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 When certain polymers are insoluble in a
cold solvent with a core material present,
heating the mixture with an agitation to a
select temp and slowly cooling the
dispersion back to room temp can result in
Microencapsulation.

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As the temp of the
system is decreased
from point a along the
arrowed line aeb, the
phase boundary is
crossed at point e, and
the two-phase region
is entered.

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Interfacial Polymerization
A unique feature shell is formed at or on
the surface of droplets or particles by
polymerization of reactive monomers.
It can be used to encapsulate aqueous
solutions, water miscible liquids, & solids.

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In Situ Polymerization
Capsule shell formation occurs because of
polymerization of monomers added to the
encapsulation reactor.
Polymerization occurs exclusively in the
continuous phase & on continuous phase-side
of the interface formed by the dispersed core
material & continuous phase.

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Centrifugal Force & Submerged
Nozzle Process
A cup, perforated with series of fine holes
is immersed in an oil bath.
It is rotated while immersed in oil thereby
extruding into the oil phase a stream of
droplets of an oil-in-water emulsion,
Produce Microcapsules.

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Submerged Nozzle Process
Capsules are produced by co extruding an
aqueous gelatin solution & oil to be
encapsulated through a two fluid nozzle into
a moving fluid stream of an oil solution.
The gelatin solution surrounds the oil drop to
be encapsulated at the point of extrusion & is
gelled thermally before the particles are
harvested & dried.

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Drug dissolved in oil
Gelatin

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Spray Drying & Spray Congealing
 In this core material, which is water
immiscible is dispersed in a solution of
shell material, which is a water-soluble
polymer like gum Arabic or modified
starch.

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 The mixture is then atomized into air stream.
The air usually heated supplies the latent
heat of vaporization required to remove the
solvent from the coating material.
 Capsules produced by this manner fall
between 10-300m in diameter.

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Fluidized Bed Coating
This method is limited to encapsulating
solid particles or porous particles into
which a liquid has been absorbed.
Three types of fluidized beds are available.
Ø Top spray
Ø Tangential spray
Ø Bottom spray(Wurster coater)

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Top Spray
This process consists of
the dispersing of solid
particulate core
materials in a
supporting air stream
& the spray coating of
air suspended particles.

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Bottom Spray
The bottom spray
(Wurster) coater is
the preferably used
unit to produce
encapsulated solids

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Melt dispersion method
This Technique involves dispersion of core
material into the melted coating material &
processing the dispersion into cold solvent.
Various coating material in different coat:
core ratio were tried.

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Pan Coating
This process has been employed for the
preparation of controlled release beads.
Solid particles >600m in size are considered
essential for effective coating.
The coating is applied as an atomized spray to
the desired solid core material in the coating
pan. To remove the coating solvent warm air is
passed over the coated materials as the coatings
are being applied in the coating pans.

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Centrifugal Extraction
The core & shell
material, two
mutually immiscible
liquids are pumped
through a spinning
two fluid nozzle.

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This produces a continuous two fluid columns
or rod liquid that spontaneous break up into a
stream of spherical droplets immediately after
it emerges from the nozzle.

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Rotational Suspension Separation
Core material dispersed in a liquid shell
formulation is fed into the rotating disk.
Individual core particles coated with a film
of shell formulation are flung off the edge
of the rotating disk along with droplets of
pure coating material.
When cooling solidifies shell formulation,
discrete microcapsules are produced.

24-01-2017 L.M.College of Pharmacy

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Multi-orifice Centrifugal Process
This process utilizes centrifugal forces to
hurl a core material particle through an
enveloping microencapsulation membrane,
thereby effecting mechanical
microencapsulation.

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MICROSPHERES

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Microsphere( Micromatrices)
Emulsion solvent evaporation method
Multiple emulsions
Solvent Extraction Technique
Chemical & Thermal cross-linking
Precipitation technique
Freeze drying
Melt method

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Emulsion solvent evaporation
method
This technique based on the evaporation of
the internal phase of an emulsion by
agitation.
 O/W Emulsion
 W/O Emulsion

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Solvent evaporation
technique

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Multiple emulsions
Active principle to be encapsulated is
incorporated in an aqueous solution, which is
poured into the casting organic solution of the
polymer to form the emulsion of type w/o.
The primary emulsion is itself emulsified in an
external aqueous phase leading to multiple
emulsion of the type (w/o/w)
The organic phase acts as a barrier between the
two aqueous compartment preventing diffusion
of drug towards the external aqueous phase.

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Multiple Emulsion
(W/O/W)
Solvent Evaporation
technique

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Solvent Extraction Technique
In the emulsification evaporation method,
the organic solvent of dispersed phase of the
emulsion is eliminated in two stages.
Diffusion of the solvent in the continuous
phase. (solvent extraction)
Elimination of solvent at the continuous
interphase.

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Chemical & Thermal cross-linking
Microspheres made from natural polymers
are made by cross-linking process
§ Gelatin
§ Albumin
§ Starch
§ Dextran etc.

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As the desired emulsion obtained, cross-
linking process solidifies water-soluble
polymer.
This involves thermal treatment in addition
of a cross-linking agent such as
glutaraldehyde to form stable cross-linking.

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Precipitation technique
The emulsion consists of polar droplets
dispersed in a non-polar medium.
Solvent may be removed from the droplets
by use of a co solvent.
The resultant increase in the polymer drug
conc. causes a precipitation forming a
suspension.

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Freeze drying
This technique involves freezing the suspension
of the emulsion, the relative freezing points of
continuous & dispersed phases are important.
The continuous phase solvent is usually organic
& is removed by sublimation at low temp &
pressure.
Finally the dispersed phase solvent of the
droplets is removed by sublimation, leaving
polymer drug particles.

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Melt method
The polypeptide or protein drugs are very
fine micro particles by freeze drying
followed by spray drying of an aqueous
solution with or without appropriate
excipients & stabilizers.
The protein drug is then intimately
admixed into a block copolymer at temp.
above the melting point of block polymer.

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The drug powder may be suspended into a
copolymer melt or the drug powder &
particles of copolymer are admixed first &
then melted together in either events or
substantially fluid melted homogeneous
mixture of drug & copolymer is formed
having a suitable low viscosity that micro
droplet of the molten mixture can be formed.

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Excipients
Microspheres are made of polymeric, waxy,
or other protective materials.
If the polymer used to prepare microspheres
is biodegradable then the microspheres are
“BIODEGRADABLE MICROSPHERES”

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The Biodegradable Microspheres
Natural source
 Protein
(albumin & gelatin)
 Polysaccharides
(starch, alginate,
& chitosan)
Synthetic polymers
 Polylactides (PLA)
 Polyglycolides (PGA)
 Poly (lactide-co-
glycolides)(PLGA)
 Polyanhydrides
 Polyorthoesters
 Poly (alkyl carbonates)
 Polyacrylamides

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From production point of view
synthetic polymers are more preferable,
because of purity & less batch-to-batch
variations.

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Manufacturing Variables in the
production of microspheres
The most important physicochemical characteristics
that may be controlled in microsphere-
manufacture are:
Particle Size and Distribution
Molecular Weight of Polymer
Ratio of Drug to Polymer
Ratio of Organic:Aq.
Total Mass of Drug and Polymer
Drug loading

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Characterization & Evaluation
Polymer Characterization
Microsphere Characterization

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Polymer Characterization
Molecular weight by
 Gel permeation
 Viscosity
 Colligative
properties
 Refractometry

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Purity & Polymorphism
 Gas chromatography
 Karl fisher & thermogravimetry
analysis
 Differential photoelectron
spectroscopy
 X ray spectroscopy

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Misc.
 Density
 Crystallinity
 Film forming properties
etc..

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Microsphere Characterization
Particle size & size
distribution
Surface
characterization
Surface charge analysis
Surface area
Porosity
Hardness &
Friability
Density
Flow properties
Drug content
Drug release
profiles

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Particle size & size distribution
 Sieving
 Microscopy
 Coulter counter analysis
 L.A.S.E.R. diffraction analysis
 Photon correlation techniques

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Surface characterization
 High-resolution microscopy
 Scanning electron microscopy
 Scanning tunneling microscopy
Surface charge analysis
 Micro electrophoresis
 L.A.S.E.R Doppler
anemometry

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Density
 Bulk density
 Tapped density
Flow properties
 Angle of repose
 Hausner ratio
Drug release profiles
 In Vitro
 In Vivo

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Drug release by diffusion
Early encapsulation and entrapment systems released the
drug from within the polymer via molecular diffusion
 When the polymer absorbs water it swells in size
 Swelling created voids throughout the interior polymer
 Smaller molecule drugs can escape via the voids at a
known rate controlled by molecular diffusion (a function
of temperature and drug size)
Add
water
Add
time

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Drug release by erosion
Modern delivery systems employ biodegradable polymers
 When the polymer is exposed to water, hydrolysis occurs
 Hydrolysis degrades the large polymers into smaller
biocompatible compounds
– Bulk erosion process – Surface erosion process
mer
Polymer
mer mer mer mer mer mer mer mer
Water attacks bond
mer mer mer mer mer mer mer mer mer
mer mer mer mer mer mer mer mer mer

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Bulk erosion
(e.g. poly lactide, polyglycolic acid)
 These small compound diffuse out of the matrix through
the voids caused by swelling
 Loss of the small compounds accelerates the formation of
voids thus the exit of drug molecules
Add
water
Add
time

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Surface erosion
(e.g., polyanhydrides)
 These small compound diffuse from the interface of the
polymer
 Loss of the small compounds reveals drug trapped within
 Note these polymer do not swell.
Add
water
Add
time

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Applications
1. It is used to mask bitter or unpleasant taste
of the drug. E.g. quinidine, clofibrate, &
paracetamol.
2. Conversion of oils & other liquids to solids
for ease of handling. e.g. liquids such as
eprazine can be converted to a pseudo solid
by microspheres as an aid to handling and
storage.

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3. It is used to protect reactive materials
against environment. (& Visa Versa) E.g.
vitamins, aspirin.
4. To facilitate handling of toxic materials.
E.g. microspheres has been used to
decrease potential danger in handling toxic
substances like pesticides, fertilizers, and
certain pharmaceuticals.

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5. To alter the residence time and to improve the
bioavailability. e.g. albumin and gelatin
microspheres containing pilocarpine nitrate for
delivery to eye increase residence time of drug in
the eye and provide improved bioavalibility.
6. To separate incompatible substances. e.g. the
stability of incompatible drugs like aspirin and
chlorpheniramine maleate mixture was increased
by microspheres of individual components.

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7. For production of Sustained release &
Controlled release medicaments.
e.g. drugs like Riboflavin, Indomethacin,
Aspirin, and steroids like Progesterone;
Testosterone, etc. can be incorporated in it to
control their release.
Release of drug is controlled by
Molecular structure of drug & polymer
Surface area
Porosity of microspheres

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8. It is used in enteric release dosage form &
to decrease irritation.
e.g. drugs like Aspirin, Paracetamol,
Salbutamol sulphate etc. which irritant
to the stomach and other side effects can
be incorporated in microspheres for their
selective release in intestine

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9. Used as Organ Targeting
Active targeting
By attachment of site-specific vector
agents such as Monoclonal Antibody, lectins
etc.
Diversional targeting
By blocking natural distribution of
microspheres, impairing the cells of R.E.S.
which would other wise take up
microspheres.

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Physical Targeting
 Magnetically responsive drug carrier systems.
Addition of Matrix filler like Fe3
So4
Improved anti tumor activity by casein and
gelatin microspheres containing Adriamycin
were magnetically delivered to the tumor site.
It is a highly efficient method of site-specific
delivery

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Market products
Arestin (Minocycline HCl) microspheres 1
mg
ImavistTM
, Imavist (perflexane lipid
microsphers)
PulmospheresTM
PROMAX inhalation microcapsules

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References
Encyclopedia of pharmaceutical Technology.10,1-29.
‘Microencapsulation’ Marcel Dekkar publications
J Pharm Sci 93(4) 831-837.
J Pharm Sci 93(4) 943-955.
J Pharm Sci 93(5) 1100-1109.
J Pharm Sci 93(10) 2573-2584.
J Pharm Sci 93(10) 2624-2634.

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1. www.artecoll.com/ microspheres.jpg
2. www.kubiatowicz.com/.../
Albumin_Microspheres.jpg
3. www.indiamart.com/tureen/
4. www.tlchm.bris.ac.uk/.../ rob/RobAtkin.htm
5. www.siigroup.com/.../ micro_intro.htm
Web Sites @

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STUDY QUESTIONS:-
Define Microcapsules and microspheres
Enlist various techniques used for production of
microcapsules. Describe any one in details
Classify the techniques used for the manufacture of
microcapsules. Describe any one in details.
Give the analytical methods for the analysis of
microparticles.
What are the common advantages as well as application
of microcapsules and microspheres
Describe in details the mechanism of drugs release from
microcapsules

Microspheres & Microcapsules (1) (1).ppt

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