One of the important topics for Sem II M. Pharm (Pharmaceutics) students as per PCI Syllabus

1. Microcapsules and Microspheres
Types, Preparation & Evaluation
Dr. Atish S. Mundada
Associate Professor,
SNJB’s SSDJ College of Pharmacy,
Chandwad, Dist. Nashik

2. Background for Microcapsules & Microspheres:
Microcapsules:
• Microcapsules contain an active agent and surrounded polymeric
shell or and surrounded polymeric shell or dispersed in polymeric
matrix.
• Microcapsule size : 1 to 1000 micron
• Microcapsules can be of different structures.
Microspheres:
• Small spherical particles (also known as `Small spherical particles
(also known as micro particles)
• Diameter ranges from 1micron to 1000 micron (1 micron = 10-6
meters)
• Can be made using various materials. eg. Polymer, glass, ceramic.

3. • The principle of encapsulation is very old.
• If biochemistry is a principle of life, nothing would have been
possible without its integration in membrane bound structures
(cells, mitochondria...).
• By developing encapsulation methods, scientists and engineers
mimic nature to obtain innovative structures to isolate, protect,
release and functionalize active ingredients.
• However nature is not so easy to mimic, and what humans have
developed are still inferior to what biological cells offer.
• Encapsulation is used in many industrial and scientific domains.
• It is defined as “Entrapment of a compound or a system inside a
dispersed material for its immobilization, protection, controlled
release, structuration and functionalization.”
• This definition is more oriented to objectives than on the
structure of the microcapsules.

4. • The “true” microcapsule is a liquid core surrounded by a
membrane. However, many different structures are included under
the term “microcapsules” or “nanocapsules”.
• At the smallest scale, one could use hollow molecules inside of
which the active ingredient could be fixed.
• At a larger scale, more or less complex molecular assemblies could
form nanocapsules, or nanospheres, or lipidic structures like
liposomes.
• For sizes less than a few micrometers, one talks of nano-
encapsulation.
• For larger sizes, one finds hydrogel beads, solid microspheres and
microcapsules.
• For sizes greater than 1 mm, some talk about macroencapsulation.
• Parallel to the structural complexity, a large number of
technologies exist to produce microcapsules, which is a field unto
itself.

5. Why Encapsulation?
Five categories for the objectives of encapsulation-
• Immobilization or entrapment: To limit contact between certain
parts of a system.
• Protection: If some ingredients are fragile & need to be protected
from their environment. Most industrial enzymes are sold in an
encapsulated form to avoid allergic & health problems.
• Controlled release:
• Structuration: Homogeneous mixing of a small liquid volume with
large volume of powder Is a real challenge. Microencapsulation
allows converting this liquid in powder and facilitating this
operation.
• Fictionalization: Finally, microencapsulation may be used to
develop new functions such as regulating biocatalyst activity by
controlling the membrane permeability through pH changes.

6. How to Make MicroCapsules:
• Many applications from a variety of fields for diverse objectives
have led to many methods of encapsulation. Moreover,
terminology varies from domain to domain.
• The same technology may have different names in different fields.

7. An encapsulation process may be generally divided into three steps.
1. The first step consists of incorporating the active ingredients in
the matrix or microcapsule core. This may be in the form of a
solution, emulsion or suspension, resulting in a liquid or a
dispersed solid system. This could involve mixing or dispersing
processes, drying, grinding and/or sieving.
2. The second stage is a mechanical operation.
– For a liquid matrix, making a liquid–in-air (dropping or
spraying) or liquid dispersion (emulsification or micro-
emulsification).
– For a solid matrix, spraying a solution on particles under
agitation (fluid bed or pan coating or agglomeration).
3. The last step, is to stabilize/solidify droplets or the coating
solution by a chemical process (polymerization), physicochemical
process (gelation, coacervation) or physical process (drying,
solidification).
• These three steps may be repeated to reach the final structure.

8. Techniques of Microencapsulation:
• Although a variety of techniques have been reported for
microencapsulation, they can broadly be divided into two main
categories.
• The first category includes those methods in which starting
materials are monomers/pre-polymers. In these methods chemical
reactions are also involved along with microsphere formation.
• The second category consists of those methods in which starting
materials are polymers. Hence, in these methods no chemical
reactions are involved and only shape fabrication takes place.
• Generally the choice of the microencapsulation method depends
on the nature of the polymeric/monomeric material used.
• Thus appropriate combination of starting materials and synthesis
methods can be chosen to produce microencapsulated products
with a wide variety of compositional and morphological
characteristics.

10. Emulsion polymerisation:
• According to this technique the monomer (alkyl acrylates) is added
dropwise to the stirred aqueous polymerisation medium
containing the material to be encapsulated (core material) and a
suitable emulsifier.
• The polymerisation begins and initially produced polymer
molecules precipitate in the aqueous medium to form primary
nuclei. As the polymerisation proceeds, these nuclei grow
gradually and simultaneously entrap the core material to form the
final microcapsules.
• Generally lipophilic materials (insoluble or scarcely soluble in
water) are more suitable for encapsulation by this technique.
• In addition to the entrapment of drug during microcapsule
formation, drug loading can also be accomplished by incubation of
cyanoacrylate nanocapsules (empty nanocapsules) with the
dissolved or finely dispersed drug.

11. Interfacial polycondensation:
• As the term "interfacial" implies, this technique involves the
polycondensation (condensation polymerization) of two
complementary monomers at the interface of a two phase system.
• For the preparation of microcapsules, this two-phase system is
mixed under carefully-controlled conditions to form small droplets
of one phase (dispersed phase) in the other one (continuous
phase/suspension medium).
• The material to be encapsulated must be chosen in such a way as
to be present (dissolved or dispersed) in the droplets.
• It is also necessary to use a small amount of a suitable stabilizer to
prevent droplet coalescence or particle coagulation during the
poly-condensation process and capsule formation.

12. • Interfacial polycondensation can be utilized to produce both
monocore type or matrix type microcapsules, depending on the
solubility of the polycondensate in the droplet phase.
• If the polymer is soluble in the droplets, matrix type microcapsules
are formed. On the other hand, if the polymer is not soluble, it
precipitates around the droplets and leads to the formation of
monocore type microcapsules.
• Preparation of microcapsules by interfacial polycondensation is
applicable to a large number of polymers including polyamides,
polyureas, polyurethanes and polyesters.
• In either case, the process can be adopted to produce micrometer
or nanometer size particles.

13. Suspension crosslinking:
• Suspension crosslinking is the method of choice for the
preparation of protein and polysaccharide micro-capsules.
• Microcapsule formation by this technique involves dispersion of an
aqueous solution of the polymer containing core material in an
immiscible organic solvent (suspension/dispersion medium) in the
form of small droplets.
• The suspension medium contains a suitable stabilizer to maintain
the individuality of the droplet/microcapsules. The droplets are
subsequently hardened by covalent crosslinking and are directly
converted to the corresponding microcapsules.
• The crosslinking process is accomplished either thermally (at
>500C) or by the use of a crosslinking agent (formaldehyde,
terephthaloyl chloride, etc).
• Suspension crosslinking is a versatile method and can be adopted
for microencapsulation of soluble, insoluble, liquid or solid
materials, and for the production of both micro and nanocapsules.

14. Solvent Evaporation/Solvent Extraction:
• Microcapsule formation by solvent evaporation/solvent extraction
is very similar to suspension crosslinking, but in this case the
polymer is usually hydrophobic polyester.
• The polymer is dissolved in a water immiscible volatile organic
solvent like dichloromethane or chloroform, into which the core
material is also dissolved or dispersed.
• The resulting solution is added dropwise to a stirring aqueous
solution having a suitable stabilizer like poly (vinyl alcohol) or PVP,
etc. to form small polymer droplets containing encapsulated
material.
• With time, the droplets are hardened to produce the
corresponding polymer microcapsules.
• This hardening process is accomplished by the removal of the
solvent from the polymer droplets either by solvent evaporation
(by heat or reduced pressure), or by solvent extraction (with a
third liquid which is a precipitant for the polymer and miscible
with both water and solvent).

15. Coacervation/Phase separation:
• Coacervation (or phase separation) is widely employed for the
preparation of gelatin and gelatin-acacia microcapsules, as well as
for a large number of products based on cellulose derivatives and
synthetic polymers.
• Phase separation processes are divided into simple and complex
coacervation.
– Simple coacervation involves the use of a single polymer such
as gelatin or ethyl cellulose, in aqueous or organic media,
respectively.
– Complex coacervation involves two oppositely charged
polymeric materials such as gelatin and acacia, both of which
are soluble in aqueous media.
• In both the cases, coacervation is brought about by gradual
desolvation of the fully solvated polymer molecules.

16. • Microencapsulation by coacervation is carried out by preparing an
aqueous polymer solution (1-10 %) at 40-50°C into which the core
material (hydrophobic) is also dispersed.
• A suitable stabilizer may also be added to the mixture to maintain
the individuality of the final microcapsules.
• A suitable desolvating agent (coacervating agent) is gradually
introduced to the mixture, which leads to the formation of partially
desolvated polymer molecules and hence their precipitation on the
surface of the core particles.
• The coacervation mixture is cooled to about 5-20°C, followed by
the addition of a crosslinking agent to harden the microcapsule
wall formed around the core particles.

17. Other Techniques:
• Microencapsulation can also be carried out by spray drying,
fluidised bed coating, melt solidification, polymer precipitation, co-
extrusion, layer-by-layer deposition, supercritical fluid expansion,
and spinning disk.
• Microencapsulation by spray drying is a low cost commercial
process, which is mostly used for the encapsulation of fragrances,
oils and flavors.
• In this process, an emulsion is prepared by dispersing the core
material, usually an oil or active ingredient immiscible with water,
into a concentrated solution of wall material.
• The resultant emulsion is atomized into a spray of droplets by
pumping the slurry through a rotating disc into the heated
compartment of a spray drier.
• There the water portion of emulsion is evaporated, yielding dried
capsules containing core material. Lycopene has been
microencapsulated inside gelatin microcapsules by using this
technique.

18. • Fluidised bed coating is used for encapsulation of solid core
materials including liquids absorbed into porous solids.
• This technique is used extensively to encapsulate pharmaceuticals.
• Solid particles to be encapsulated are suspended in a jet of air and
then covered by a spray of liquid coating material.
• The capsules are then moved to an area where their shells are
solidified by cooling or solvent vaporization.
• The process of suspending, spraying and cooling is repeated until
the capsule walls are of the desired thickness.
• Ascorbic acid has been microencapsulated in polymethacrylate as
well as ethyl cellulose by using this technique

19. • Biodegradable microcapsules are also produced by the solidification
of molten polymer droplets or by polymer precipitation.
• A dispersion of the drug in molten polymer is stirred in silicone oil
to produce small droplets of the polymer drug mixture.
• The suspension mixture is then cooled and the resulting solidified
microcapsules are separated from the oil.
• Insulin has been microencapsulated in polyanhydride by using this
technique.
• In the polymer precipitation process, an aqueous solution of the
polymer containing the drug is dropped into a stirred solution,
which acts as the precipitating medium.
• Here, the polymer droplets precipitate immediately and are thus
converted into the drug loaded microcapsules.
• Enzymes have been encapsulated in conjugated phenolic polymers
by using this technique.

20. • The co-extrusion process also possess a number of commercial
applications.
• In this process a dual fluid stream of liquid core and shell
materials is pumped through concentric tubes and forms droplets
under the influence of vibration.
• The shell is then hardened by chemical crosslinking, cooling or
solvent evaporation.
• Hepatocytes have been encapsulated in polyacrylonitrile by using
this technique.
• One important method of microencapsulation is layerby-layer
deposition.
• In this process polyelectrolyte multilayers are prepared by
sequentially immersing a substrate in positively and negatively
charged polyelectrolyte solutions in a cyclic procedure.
• Core shell particles with tailored size and properties are prepared
using colloidal particles as the core material that serves as a
template onto which multilayers are fabricated.

21. • Hollow capsules of organic, inorganic or hybrid particles can be
obtained by dissolving the core material.
• This technique is both versatile and simple, with the multiplayer
film thickness being controlled precisely by varying the total
number of layers deposited.
• In this way the final properties can be tuned. Glucose oxidase has
been microencapsulated by alternate deposition of polyallylamine
and polystyrene sulfonate layers.
• Microencapsulation has also been carried out by rapid expansion
of supercritical fluid.
• Supercritical fluids are highly compressed gases that possess
several advantageous properties of both liquids and gases.
• Most widely used ones are supercritical CO2, alkanes (C2 to C4) and
nitrous oxide (N2O).
• Supercritical CO2 is widely used for its low critical temperature
value in addition to its non-toxic and non-flammable properties.
• It is also readily available, highly pure and cost effective.

22. • It has found applications in encapsulating active ingredients by
polymers. Different core materials such as pesticides, pigments,
pharmaceutical ingredients, vitamins, flavors and dyes have been
encapsulated by using this method.
• A wide variety of shell materials that either dissolve (paraffin wax,
acrylates, polyethylene glycol) or do not dissolve (proteins,
polysaccharides) in supercritical CO2 are used for encapsulating
core substances.
• In this process, supercritical fluid containing the active ingredient
and the shell material are maintained at high pressure and then
released at atmospheric pressure through a small nozzle.
• The sudden drop in pressure causes desolvation of the shell
material, which is then deposited around the active ingredient
(core) and forms a coating layer.
• Felodipine has been encapsulated in poly(ethylene glycol) by using
this technique.

23. • In the spinning disc method the microencapsulation of suspended
core materials is carried out by using a rotating disc.
• Suspensions of core particles in liquid shell material are poured
into a rotating disc and due to the spinning action of the disc, the
core particles become coated with the shell material.
• The coated particles along with the excess shell material are then
cast from the edge of the disc by centrifugal force, after which the
shell material is solidified by external means (usually cooling).
• This technology is rapid, cost effective, simple and has high
production efficiencies.
• Paraffin microbeads have been synthesized by using this
technique

24. Evaluation of the Microcapsules:
• A variety of analytical and physical methods is used to characterize
particles and encapsulated ingredients.
– Particle size
– Payload
– Content uniformity and stability
– Active ingredient release profiles and activity
– Colloid stability
– Particle stability
– Drug release study

25. Microspheres & its Types:
• Microspheres are small spherical particles, with diameters 1 μm to
1000 μm.
• They are spherical free flowing particles consisting of proteins or
synthetic polymers which are biodegradable in nature.
• Microspheres are sometimes referred to as microparticles.
Types of Microspheres:
1. Bioadhesive microspheres
2. Magnetic microspheres
– i)Therapeutic magnetic microspheres
– ii)Diagnostic magnetic microspheres
3. Floating microspheres
4. Radioactive microspheres
5. Polymeric microspheres
– i)Biodegradable polymeric microspheres
– ii)Synthetic polymeric microspheres

26. Methods of Preparation:
1. Spray Drying and spray congealing
2. Solvent Evaporation
3. Single emulsion technique
4. Double emulsion technique
5. Phase separation coacervation technique
6. Solvent extraction
7. Quassi emulsion solvent diffusion
8. Polymerization techniques

27. 1. Spray Drying and spray congealing:
• These methods are based on the drying of the mist of the
polymer and drug in the air.
• Depending upon the removal of the solvent or cooling of the
solution, the two processes are named spray drying and spray
congealing respectively.
• The polymer is first dissolved in a suitable volatile organic solvent
such as dichloromethane, acetone, etc.
• The drug in the solid form is then dispersed in the polymer
solution under high speed homogenization.
• This dispersion is then atomized in a stream of hot air. The
atomization leads to the formation of the small droplets or the
fine mist from which the solvent evaporates instantaneously
leading the formation of the microspheres in a size range 1-100
μm.
• Microparticles are separated from the hot air by means of the
cyclone separator while the traces of solvent are removed by
vacuum drying.

28. 2. Solvent Evaporation:
• This process is carried out in a liquid manufacturing vehicle
phase.
• The microcapsule coating is dispersed in a volatile solvent which
is immiscible with the liquid manufacturing vehicle phase.
• A core material to be microencapsulated is dissolved or dispersed
in the coating polymer solution.
• With agitation the core material mixture is dispersed in the liquid
manufacturing vehicle phase to obtain the appropriate size
microcapsule.
• The mixture is then heated if necessary to evaporate the solvent
for the polymer of the core material to disperse in the polymer
solution, polymer shrinks around the core.
• If the core material is dissolved in the coating polymer solution,
matrix – type microcapsules are formed.
• The core materials may be either water soluble or water in
soluble materials.

29. 3. Single emulsion technique:
• The natural polymers are dissolved or dispersed in aqueous
medium followed by dispersion in non-aqueous medium like oil.
• In the next step, the cross linking of the dispersed globule is
carried out. The cross linking can be achieved either by means of
heat or by using the chemical cross linkers.
• The chemical cross linking agents used are glutaraldehyde,
formaldehyde, acid chloride etc.
• Heat denaturation is not suitable for thermolabile substances.
• Chemical cross linking suffers the disadvantage of excessive
exposure of active ingredient to chemicals if added at the time of
preparation and then subjected to centrifugation, washing,
separation.
• The nature of the surfactants used to stabilize the emulsion
phases can greatly influence the size, size distribution, surface
morphology, loading, drug release, and bio performance of the
final multiparticulate product.

30. 4. Double emulsion technique:
• Double emulsion method of microspheres preparation involves
the formation of the multiple emulsions or the double emulsion of
type w/o/w and is best suited to water soluble drugs, peptides,
proteins and the vaccines.
• The aqueous protein solution is dispersed in a lipophilic organic
continuous phase. This protein solution may contain the active
constituents.
• The continuous phase is generally consisted of the polymer
solution that eventually encapsulates of the protein contained in
dispersed aqueous phase.
• The primary emulsion is subjected then to the homogenization or
the sonication before addition to the aqueous solution of the poly
vinyl alcohol (PVA). This results in the formation of a double
emulsion.
• The emulsion is then subjected to solvent removal either by
solvent evaporation or by solvent extraction.

31. 5. Phase separation coacervation technique:
• This process is based on the principle of decreasing the solubility
of the polymer in organic phase to affect the formation of polymer
rich phase called the coacervates.
• In this method, the drug particles are dispersed in a solution of
the polymer and an incompatible polymer is added to the system
which makes first polymer to phase separate and engulf the drug
particles.
• Addition of non-solvent results in the solidification of polymer.
• The process variables are very important since the rate of
achieving the coacervates determines the distribution of the
polymer film, the particle size and agglomeration of the formed
particles.
• The process variables are critical as they control the kinetic of the
formed particles.

32. 6. Solvent extraction:
• Solvent evaporation method is used for the preparation of
microparticles, involves removal of the organic phase by
extraction of the organic solvent.
• The method involves water miscible organic solvents such as
isopropanol. Organic phase is removed by extraction with water.
• This process decreases the hardening time for the microspheres.
• One variation of the process involves direct addition of the drug
or protein to polymer organic solution.
• The rate of solvent removal by extraction method depends on the
temperature of water, ratio of emulsion volume to the water and
the solubility profile of the polymer.

33. 7. Quassi emulsion solvent diffusion:
• A novel quasi-emulsion solvent diffusion method to manufacture
the controlled release microspheres of drugs with acrylic polymers
has been reported in the literature.
• Microsponges can be manufactured by a quasi emulsion solvent
diffusion method using an external phase containing distilled
water and polyvinyl alcohol.
• The internal phase consists of drug, ethanol and polymer. The
concentration of polymer is in order to enhance plasticity.
• At first, the internal phase is manufactured at 600C and then
added to the external phase at room temperature.
• After emulsification process, the mixture is continuously stirred
for 2 hours. Then the mixture can be filtered to separate the
microsponges.
• The product is then washed and dried by vacuum oven at 400C for
a day.

34. 8. Polymerization techniques:
• The polymerization techniques conventionally used for the
preparation of the microspheres are mainly classified as:
I. Normal polymerization
II. Interfacial polymerization.
• Both are carried out in liquid phase.
I. Normal polymerization:
• It is carried out by using different techniques as bulk, suspension,
precipitation, emulsion and micellar polymerization methods. In
bulk, a monomer or a combination of monomers along with the
initiator or catalyst is usually heated to initiate polymerization.
• Polymer so obtained may be moulded as microspheres.

35. • Suspension polymerization also referred as bead or pearl
polymerization. It is carried out by heating the monomer or
composition of monomers as droplets dispersion in a continuous
aqueous phase.
II. Interfacial polymerization:
• This involves the reaction of various monomers at the interface
between the two immiscible liquids to form a film of polymer that
essentially envelops the dispersed phase.

36. Preparation of Microspheres by Thermal cross-linking:
• Citric acid, as a cross-linking agent was added to 30 mL of an
aqueous acetic acid solution of chitosan (2.5% wt/vol)
maintaining a constant molar ratio between chitosan and citric
acid (6.90 × 10−3 mol chitosan: 1 mol citric acid).
• The chitosan cross-linker solution was cooled to 0°C and then
added to 25 mL of corn oil previously maintained at 0°C, with
stirring for 2 minutes.
• This emulsion was then added to 175 mL of corn oil maintained at
120°C, and cross-linking was performed in a glass beaker under
vigorous stirring (1000 rpm) for 40 minutes.
• The microspheres obtained were filtered and then washed with
diethyl ether, dried and sieved.

37. Preparation of Microspheres by Glutaraldehyde cross linking:
• A 2.5% (w/v) chitosan solution in aqueous acetic acid was
prepared. This dispersed phase was added to continuous phase
(125 mL) consisting of light liquid paraffin and heavy liquid
paraffin in the ratio of 1:1 containing 0.5%w/v Span 85 to form a
water in oil (w/o) emulsion.
• Stirring was continued at 2000 rpm using a 3- blade propeller
stirrer).
• A drop-by-drop solution of a measured quantity (2.5 mL each) of
aqueous glutaraldehyde (25% v/v) was added at 15, 30, 45, and
60 minutes.
• Stirring was continued for 2.5 hours and microspheres are
separated by filtration under vacuum and washed, first with
petroleum ether (60°C-80°C) and then with distilled water to
remove the adhered liquid paraffin and glutaraldehyde, resp.
• The microspheres were then finally dried in vacuum desiccators.

38. Evaluation of Microspheres:
1. Particle size and shape
2. surface chemistry
3. Density determination
4. Isoelectric point: The micro electrophoresis is an
apparatus used to measure the electrophoretic mobility
of microspheres from which the isoelectric point can be
determined.
5. Angle of contact for wetting ability
6. In vitro methods
7. Drug entrapment efficiency
8. Swelling index