Microencapsulation Final.

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 1. MICROENCAPSULATION
 2. INTRODUCTION TO MICROENCAPSULATION 2 ▶ Microencapsulation is
defined as the application of a thin polymeric coating to individual core materials
(tiny particles or droplets of liquids and dispersions) that have an particle size
range from 1-1000 μm to give small capsules with many useful properties. ▶
Generally, capsules can be classified according to their size: macrocapsules
(>1,000 µm), microcapsules (1 to 1,000 µm),and nanocapsules(<1 µm).
 3. INTRODUCTION TO MICROENCAPSULATION 3 ▶
Microspheres: micrometric matrix systems. ▶ 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. ▶ Microencapsulated
products (microparticles or microcapsules) are small entities that have an active
agent known as the core material surrounded by a shell known as the coating
material or embedded in a matrix structure. ▶ Microcapsules: micrometric
reservoir systems
 4. . Drug Core Polymer Coat = Polymer Matrix } = Entrapped Drug
MICROCAPSULES MICROSPHERES •According to some authors, microspheres are
essentially spherical in shape, whereas, microcapsules may be spherical or non-
spherical in shape. •Also, some authors classify microparticles, either
microcapsules or microspheres, as the same: ‘microcapsules’.
 5. INTRODUCTION TO MICROENCAPSULATION ▶ In terms of their shape and
construction, capsules can be divided into two groups: microcapsules and
microspheres. Microcapsules are particles consisting of an inner core,
substantially central, containing the active substance, which is covered with a
polymer layer constituting the capsule membrane. ▶ However, microspheres are
matrix systems in which the core is uniformly dispersed and/or dissolved in a
polymer network. 5
 6. COMPOSITION OF MICROCAPSULE ▶ Core Materials: The ingredients to be
coated are referred to as the core, internal phase (IP), encapsulate, or fill,
whereas terms applied to the coating of the microcapsules include the wall, shell,
external phase or membrane. ▶ All three states i.e., solid, liquid, and gases, may
be encapsulated and affect the size and shape of the capsules. ▶ If core material
is a solid or a crystalline material, the resultant capsule may be irregularly
shaped. However, if the core material is a liquid, the resultant capsule may be
spherical, containing a single droplet of encapsulate. 6
 7. COMPOSITION OF MICROCAPSULE ▶ Coating Materials/Wall
Materials/Polymer: The correct choice of the wall material/polymer is very
important because it influences the encapsulation efficiency and stability of the
microcapsule. ▶ The polymer should be capable of forming a film that is cohesive
with the core material. ▶ It should be chemically compatible, non-reactive with
the core material, and provide the desired coating properties such as strength,
flexibility, impermeability, optical properties, and stability. 7
 8. COMPOSITION OF MICROCAPSULE ▶ Generally, hydrophilic polymers,
hydrophobic polymers, or a combination of both are used for the
microencapsulation process. ▶ A number of coating materials have been used
successfully; examples of these include gelatin, polyvinyl ethylcellulose, cellulose
acetate phthalate, and alcohol, styrene- maleic anhydride. ▶ The film thickness
can be varied considerably depending on the surface area of the material to be
coated and other physical characteristics of the system. 8
 9. COMPOSITION OF MICROCAPSULE 9 Water-soluble Water- insoluble
Waxes and resins Enteric Gelatin Starch Hydroxyethylcell ulose
 Polyvinyl pyrrolidone Ethyl Cellulose Polyamide Polymethacry late
Polyethylene Paraffin Stearic acid Beeswax Stearyl alcohol Shellac Zein
Cellulose acetate phthalate Examples of coating polymers
 10. ADVANTAGES/ APPLICATIONS OF MICROENCAPSULATION
the incompatibility between drugs. ▶ The main advantage of microencapsulation
is to attain the sustained or prolonged release of the drug. ▶ This technique has
been widely used for masking the taste and odor of many drugs to improve
patient compliance. ▶ This technique can be used for converting liquid drugs into
a free-flowing powder. ▶ The drugs which are sensitive to moisture light and
oxygen can be protected by microencapsulation. ▶ The microencapsulation
technique is also helpful to prevent 10
 11. ADVANTAGES OF MICROENCAPSULATION 11 ▶ The drugs, which are
volatile in nature and vaporize at room temperature, can be prevented by
microencapsulation. ▶ Microencapsulation of drugs helps to reduce toxicity and
GI irritation. ▶ Microencapsulation can be done to change the site of absorption.
This application has been useful for those drugs which have toxicity at lower pH.
▶ Microencapsulation of vitamin A palmitate provides enhanced stability by
preventing it from oxidation.
 12. DISADVANTAGES OF MICROENCAPSULATION 12 ▶ It is very difficult to
achieve a continuous and uniform film. ▶ There may be a possibility of cross-
reaction between core and coating material. ▶ The Shelf life of hygroscopic drugs
is may get reduced by microencapsulation. ▶ The microencapsulation technique
leads to more production costs. ▶ The microencapsulation technique requires
more skill and knowledge.
 13. METHODS OF MICROENCAPSULATION 13 ▶ Polymerization process ▶
Physical Methods ▶ Air-suspension method ▶ Coacervation method ▶ Centrifugal
extrusion method ▶ Pan coating method ▶ Sprays drying - Spray congealing
method ▶ Single emulsion method ▶ Chemical Methods ▶ Solvent Evaporation
method
 14. Air suspension method ▶ Principle: A basic principle of the method is spray
coating the air suspended particles with a coating material. ▶ Construction: The
apparatus consists of a coating chamber, in which particles are suspended on an
upward-moving air stream (heated or not) as indicated in the figure. The inner
design of the chamber ensures the 14 circulating flow of particles.
 15. Air suspension method ▶ Working: At the base of the the pneumatic or
nozzle has been chamber , hydraulic placed, which sprays the coating material
(i.e. polymer). When particles pass through the coating area, it gains more and
more coating material, thus by controlling movement of the circulating a particle,
the desired coating thickness can be achieved. The upward stream can also be
used to dry the 15 particles by making it hot.
 16. Air suspension method 16 Factors that can affect the encapsulation
process and the thickness of the coating. ▶ Properties of core material (i.e.
particle): Density, surface area, melting point, solubility, flowability ▶ Properties
of coating material: Concentration, melting point (if not a solution), amount of
coating material ▶ Process Variables: Coating material application rate, the
volume of air, the inlet temperature of the air.
 17. Air suspension method 17 Advantages of Air Suspension Method: ▶ Low-
cost process ▶ It allows specific capsule porosities into the product size
distribution and low Disadvantages of Air Suspension Method: ▶ Degradation of
highly temperature-sensitive compounds
 18. Coacervation Method (Coacervation – Phase Separation) formation of a
coacervate phase via anion–cation interactions. ▶ Coacervation is the
 macromolecular aggregation process brought about by partial desolvation of fully
solvated macromolecules. ▶ Simple coacervation processes: It includes a simple
coacervation process in which microencapsulation is carried out by using water
as the solvent phase and a water-soluble polymer as the coating material.
Coacervation is induced by the addition of a soluble salt or alcohol, change in
temperature, or change in pH. ▶ Complex coacervation: In this method, an
oppositely charged polymer is added to the polymer solution leading to the 18
 19. Coacervation Method (Coacervation – Phase Separation) that The
coacervation process contains three main steps should be carried out under
continuous agitation. Step 1: Formation of three immiscible chemical phases Step
2: Deposition of coating Step 3: Rigidation of coating 19
 20. Coacervation Method (Coacervation – Phase Separation) 20 Step 1:
Formation of three immiscible chemical phases 1) Liquid manufacturing vehicle
phase 2) Core material phase 3) Coating material phase. The coating material
solution is prepared using a liquid manufacturing vehicle phase as a solvent, then
core material is dispersed in that solution.
 21. Coacervation Method (Coacervation – Phase Separation) Step 3:
Rigidation of coating It can be achieved by thermal, cross-linking, or non-solvent
addition techniques. 21 Step 2: Deposition of coating It is achieved by controlled,
physical mixing of coating material (in liquid state) and core material in the liquid
manufacturing vehicle. The coating material adsorbs on the surface of the core
material.
 22. Coacervation Method (Coacervation – Phase Separation) Step 3:
Rigidation of coating It can be achieved by thermal, cross-linking, or non-solvent
addition techniques. 22 Step 2: Deposition of coating It is achieved by controlled,
physical mixing of coating material (in liquid state) and core material in the liquid
manufacturing vehicle. The coating material adsorbs on the surface of the core
material.
 23. Coacervation Method (Coacervation – Phase Separation) ▶ Thermal
change: When the temperature of the mixture is reduced at a definite rate, the
coating material phase from the deposited coating around the core material loses
solvent (i.e. liquid manufacturing vehicle phase) and hence rigidization or
solidification of coating material around microcapsule occurs. ▶ Non-solvent
addition: A liquid that is non-solvent for the given coating polymer can be added
to the polymer solution to induce phase separation. The resulting immiscible
liquid coating polymer can be utilized to form a coat around the core material.
The microencapsulated particles can be centrifuged and separated from the
vehicle phase. ▶ Cross-linking (Polymer addition): When any other polymer
having a solubility in the Liquid manufacturing vehicle phase is added to the
mixture, the polymer that has more strongly adsorbed to the surface to the core
material (normally earlier selected coating material phase) becomes the coating
23 material and solidifies.
 24. Coacervation Method (Coacervation – Phase Separation) Advantages of
Coacervation method: can be used to encapsulate heat-sensitive as the
procedure is carried out at room ▶ Coacervation ingredients temperature.
Disadvantages of Coacervation method: ▶ Toxic chemical agents are used ▶ The
complex coacervates are highly unstable ▶ There are residual solvents and
coacervating agents on the capsules surfaces ▶ Spheres obtained by the
technique are of a low size range ▶ An expensive and complex method 24
 25. Centrifugal extrusion method When the two-liquid column emerges from
the nozzle, it spontaneously breaks up into a stream of small droplets with liquid
cores surrounded by liquid coats. coating or shell material gets solidify Formation
 of Microcapsule 25 Centrifugal extrusion process requires two immiscible liquids
that are pumped into a spinning two-fluid nozzle. The core liquid is fed into the
center fluid channel and the coating or shell liquid is fed into the peripheral fluid
channel.
 26. Centrifugal extrusion method 26 ▶ The coating or shell material can
solidify by various means. ▶ If coating material is a melt it can be rapidly cooled
as the droplets fall away from the nozzle. ▶ If the coating material is formed in a
solution form the solvent can be evaporated by applying heat and forming a solid
coat. ▶ Alternatively, the droplets may fall into a gelling bath where the aqueous
shell is converted to a gel-like capsule. The method of solidification depends on
the properties of the polymer used as shell material.
 27. Centrifugal extrusion method 27 Advantages of Centrifugal extrusion
method: ▶ The material is totally surrounded by the wall material ▶ Any residual
core is washed from the outside ▶ It is a relatively low-temperature entrapping
method Disadvantages of Centrifugal extrusion method: ▶ The capsule must be
separated from the liquid bath and dried; ▶ It is difficult to obtain capsules in
extremely viscous carrier material melts
 28. Pan Coating Method ▶ The particles are tumbled in a pan or other device
while the coating material is applied slowly. 28
 29. Pan Coating Method 29 The particles are tumbled in a pan (solid particles
greater than 600 microns in size) The coating is applied as a solution or as an
atomized spray to the desired solid core material in the coating pan. Warm air is
passed over the coated materials to remove the coating solvent
 30. SPRAYS DRYING - SPRAY CONGEALING METHOD 30 Spray drying and spray
congealing processes are similar in that both involve dispersion of the core
material in a liquefied coating substance and spraying or introducing the core-
coating mixture into some environmental condition, whereby, relatively rapid
solidification and formation of the coating is affected.
 31. SPRAYS DRYING - SPRAY CONGEALING METHOD 31 Spray drying (Spray –
aqueous solution, Hot air) and spray congealing (Spray – Hot melt, Cold air)
 32. SPRAYS DRYING - SPRAY CONGEALING METHOD 32 ▶ The principal
difference between the two methods is the means by which coating solidification
is accomplished. ▶ Coating solidification in the case of spray drying is effected by
rapid evaporation of a solvent in which the coating material is dissolved. ▶ While
in spray congealing (cooling) coating solidification is accomplished by thermally
congealing a molten coating material or by solidifying a dissolved coating by
introducing the coating - core material mixture into a non-solvent.
 33. SPRAYS DRYING - SPRAY CONGEALING METHOD 33 Advantages of Spray
drying method: ▶ Low process cost ▶ Wide choice of coating material ▶ Good
encapsulation efficiency ▶ Good stability of the finished product ▶ Possibility of
large-scale production in continuous mode Disadvantages of Spray drying
method: ▶ It can degrade highly temperature-sensitive compounds ▶ Control of
the particle size is difficult ▶ Yields for small batches are moderate
 34. SPRAYS DRYING - SPRAY CONGEALING METHOD 34 Advantages of Spray
congealing method: ▶ Temperature-sensitive compounds can be encapsulated
Disadvantages of Spray congealing method: ▶ Control of the particle size is
difficult ▶ Yields for small batches are moderate ▶ Special handling and storage
conditions can be required
 35. Single Emulsion Method resulting in the formation of compact micro
particles.35 The solvent in the emulsion is removed by either evaporation at
elevated temperatures The polymer is dissolved in a water-immiscible, volatile
organic solvent such as dichloromethane and the drug is dissolved or suspended
 in the polymer solution. The resulting mixture is emulsified in a large volume of
water in the presence of an emulsifier.
 36. Single Emulsion method Advantages of Single Emulsion method: ▶ Polar,
non-polar (apolar), and amphiphilic can be incorporated ▶ Emulsions can either
be used directly in their “wet” state Disadvantages of Single Emulsion method: ▶
Instable when exposed to environmental stresses, such as heating, drying, etc ▶
A limited number of emulsifiers that can be used Applications Single Emulsion
method ▶ This method has been primarily used to encapsulate hydrophobic
drugs through the oil-in-water (o/w) emulsification process. ▶ In an attempt to
encapsulate hydrophilic drugs (e.g. Peptides and proteins), an oil-in-oil (o/o)
emulsification method 3 i6 s used.
 37. Solvent Evaporation Method The mixture is heated (if necessary) to
evaporate the solvent of the polymer Once all the solvent of the polymer is
evaporated, the liquid vehicle temperature is reduced to ambient temperature (if
required) with continued agitation if the core material is dispersed in the polymer
solution, polymer shrinks around the core and if the core material is dissolved in
the coa37ting polymer solution, a matrix - type microcapsule is formed. A core
material is dissolved or dispersed in the coating polymer solution. The coating
material is dissolved in a volatile solvent, which is immiscible with the liquid
manufacturing vehicle phase and
 38. Polymerization Process 38 Polymerization has the following three
types: ▶ In situ polymerization: ▶ Interfacial polymerization ▶ Matrix
polymerization
 39. Polymerization Process 39 In situ polymerization: the direct out on the ▶
In certain microencapsulation processes, polymerization of a single monomer is
carried particle surface ▶ e.g. Cellulose fibers are encapsulated in polyethylene
while immersed in dry toluene. ▶ The usual deposition rate is about 0.5μm/min.
▶ Coating thickness ranges from 0.2 to 75μm. ▶ The coating is uniform, even
over sharp projections.
 40. Polymerization Process 40 Interfacial polymerization: interface and
two reactants in a react ▶ In interfacial polymerization, the polycondensation
process meet at an rapidly. ▶ Under proper conditions, thin flexible walls form
rapidly at the interface. ▶ Condensed polymer walls form instantaneously at the
interface of the emulsion droplets.
 41. Polymerization Process 41 phase. Matrix polymerization: ▶ In the
number of processes a core material is embedded in a polymeric matrix during
the formation of the particles. ▶ A simple example of this type is spray-drying, in
which the particle is formed by evaporation of the solvent from the matrix
material. ▶ However, the solidification of the matrix can also be done by a
chemical change. ▶ Using this phenomenon prepares microcapsules containing
protein by incorporating the protein in the aqueous diamine
 42. Polymerization Process 42 Advantages of polymerization process: ▶
Micro-nanocapsules with narrow size distribution can be obtained Disadvantages
of polymerization process : ▶ Difficult control of the capsule formation
(polymerization)
Microencapsulation Unit 2 Novel Drug Delivery
System
 1. Ms. Shubhangi B Khade(M pharmacy) Sanjivani College of Pharmaceutical
Education & Research(Autonomous), Kopargaon, Ahmednagar.
 2. Contents  Introduction  Definition  Advantages and disadvantages 
Microspheres/ microcapsules  Microparticles  Methods of Encapsulation 
Applications
 3. Introduction  Microencapsulation is defined as a process of enclosing or
enveloping solids, liquids within second material with a continuous coating of
polymeric materials yielding microscopic particles (ranging from less than 1
micron to several hundred microns in size).  In this process, small discrete solid
particles or small liquid droplets and dispersions are surrounded and enclosed by
applying thin coating for the purposes of providing environmental protection and
controlling the release characteristics or availability of coated active ingredients
 4.  Microencapsulation process is widely employed to modify and delayed
drug release form different pharmaceutical dosage forms.  The materials
enclosed or enveloped within the microcapsules are known as core materials or
pay-load materials or nucleus, and the enclosing materials are known as coating
materials or wall material or shell or membrane
 5. Advantages  To Increase of bioavailability.  To produce a targeted drug
delivery  To provide environmental protection of the core material from
moisture, light, and oxygen.  It enhances the solubility of poorly soluble drugs
and the safe handling of toxic medications.  It Masks the taste of bitter drugs to
make them more palatable and improving patient compliance.  To decrease
evaporation rate of the core material.(Reduction of volatility)
 6. Disadvantages  The cost of the materials used and the formulation process
might be higher than standard formulations.  Reproducibility is less  The effect
of the polymer matrix, polymer additives, and their degradation products on the
environment in response to heat, hydrolysis, or biological agents vary
significantly.  The core particle’s stability is affected by the change in the
process conditions like change in temperature, pH, solvent addition, or
evaporation of the solvent
 7.  Microparticles: “Microparticles” refers to the particles having the
diameter range of 1-1000 μm, irrespective of the precise exterior and/or interior
structures.  Microspheres: “Microspheres” particularly refers to the spherically
shaped microparticles within the broad category of microparticles. 
Microcapsules: “Microcapsules” refers to microparticles having a core surrounded
by the coat or wall material(s) distinctly different from that of the core or pay-
load or nucleus, which may be solid, liquid, or even gas.
 8.  Microcapsules can be classified on three types  i). Mononuclear:
Containing the shell around the core.  ii). Polynuclear: Having many cores
enclosed with in shell.  iii). Matrix type: Distributed homogeneously into the
shell material.
 9. Microspheres  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.  There are
two types of microspheres 1. Microcapsules are those in which entrapped
substance is distinctly surrounded by distinct capsule wall 2. Micromatrices in
which entrapped substance is dispersed throughout the matrix  Microspheres
are sometimes referred to as microparticles.
 10. Ideal characteristics of microspheres:  The ability to incorporate
reasonably high concentrations of the drug.  Stability of the preparation after
synthesis with a clinically acceptable shelf life.  Controlled particle size and
dispersability in aqueous vehicles for injection.  Release of active reagent with a
good control over a wide time scale.  Biocompatibility
 11. Advantages of microspheres: 1. Particle size reduction for enhancing
solubility of the poorly soluble drug. 2. provide constant and prolonged
therapeutic effect. 3. provide constant drug concentration in blood there by
increasing patent compliance, 4. Decrease dose and toxicity. 5. Protect the drug
from enzymatic and photolytic cleavage hence found to be best for drug delivery
of protein. 6. Reduce the dosing frequency and thereby improve the patient
compliance
 12. 7. Better drug utilization will improve the bioavailability and reduce the
incidence or intensity of adverse effects. 8. Microsphere morphology allows a
controllable variability in degradation and drug release. 9. Convert liquid to solid
form & to mask the bitter taste. 10. Protects the GIT from irritant effects of the
drug. 11. Biodegradable microspheres have the advantage over large polymer
implants in that they do not require surgical procedures for implantation and
removal. 12. Controlled release delivery biodegradable microspheres are used to
control drug release rates thereby decreasing toxic side effects, and eliminating
the inconvenience of repeated injections
 13. TYPES OF MICROSPHERES: 1. Bioadhesive microspheres 2. Magnetic
microspheres 3. Floating microspheres 4. Radioactive microspheres 5. Polymeric
microspheres i)Biodegradable polymeric microspheres ii)Synthetic polymeric
microspheres
 14. METHOD OF PREPARATION: 1. Spray Drying 2. Solvent Evaporation 3.
Single emulsion technique 4. Double emulsion technique 5. Phase separation
coacervation technique 6. Spray drying and spray congealing 7. Solvent
extraction 8. Quassi emulsion solvent diffusion
 15. MATERIALS USED IN THE PREPARATION OF MICROSPHERE:  1. Natural
polymers- Natural polymers obtained from different sources like carbohydrates
proteins and chemically modified Carbohydrates Carbohydrates: Agarose,
Carrageenan, Chitosan, Starch  Proteins: Albumin, Collagen and Gelatin
Chemically modified carbohydrates: Poly dextran, Poly starch.  2. Synthetic
Polymers Synthetic polymers are divided into two types. Biodegradable polymers
 E.g. Lactides, Glycolides & their co-polymers,Poly anhydrides,Poly alkyl cyano
acrylates Non-biodegradable polymers E.g. Poly methyl methacrylate (PMMA),
Glycidyl methacrylate, Acrolein, Epoxy polymers
 16. EVALUATION OF MICROSPHERES:  Particle size and shape  Electron
spectroscopy for chemical analysis:  Density determination  Angle of contact: 
In vitro methods:  Drug entrapment efficiency  Swelling index
 17. APPLICATION OF MICROSPHERES IN PHARMACEUTICAL INDUSTRY: 1.
Ophthalmic Drug Delivery 2. Oral drug delivery 3. Gene delivery 4. Nasal drug
delivery 5. Intratumoral and local drug delivery 6. Buccal drug delivery 7.
Gastrointestinal drug delivery 8. Transdermal drug delivery 9. Colonic drug
delivery 10. Vaginal drug delivery
 18. FUNDAMENTAL CONSIDERATION Microencapsulation Core material
Coating material Vehicle Solid Liquid Polymer Waxes Resins proteins
Aqueous Non aqueous
 19. MICROENCAPSULATION TECHNIQUES:  Physical Methods: • Air
suspension techniques (Wurster) • Coacervation Process • Pan Coating • Spray
Drying & Congealing • Fluidized bed technology • Solvent Evaporation •
 Polymerization • Single & Double Emulsion Techniques • Supercritical fluid Anti
Solvent method (SAS) • Nozzle Vibration Technology • Interfacial cross linking •
Multiorific-centrifugation
 20.  Chemical Methods: • Interfacial polymerization • In-situ polymerization •
Matrix polymerization
 21. Physical Methods  Air suspension • This process is also known as Wurster
Air Suspension and is based on Fluidized Bed coating process. •
Microencapsulation by air suspension method consists of the dispersing of solids,
particulate core materials in a supporting air stream and the spray coating on the
air suspended particles. • Solutions and suspensions of coating materials in both
water and volatile organic solvents are employed. • Within the coating chamber,
particulate core materials are suspended on an upward moving air stream.
 22. • The chamber design and its operating parameters influence a re-
circulating flow of the particles through the coating-zone portion of the coating-
chamber, where a coating material is sprayed to the moving particles. • During
each pass through the coating-zone, the core material receives a coat and this
cyclic process is repeated depending on the purpose of microencapsulation. •
The supporting air stream also serves to dry the product while it is being
encapsulated. • The drying of the coated particles is accomplished at either room
or elevated temperatures, depending on the solvent used. • The drying rate is
directly related to the temperature of the supporting air stream used.
 23. Fig. :Air suspension method for microencapsulation
 24. Coacervation phase separation • Coacervation may be initiated in a
number of different ways. Examples are changing the temperature, changing the
pH or adding a second substance such as a concentrated aqueous ionic salt
solution or a non-solvent. • As the coacervate forms, it must wet the suspended
core particles or core droplets and coalesce into a continuous coating for the
process of microencapsulation to occur.
 25. Aq/ organic solution phase dispersed or dissolved in the polymer solution
Microspheres in aq./ organic phase Drug Phase separation induced by different
means Polymer rich globules Polymer rich globules Hardening Separation, Drying
 26. • This process consists of three Steps-  Formation of three immiscible
phases; 1. a liquid manufacturing phase, 2. a core material phase and 3. a
coating material phase.  The core material is dispersed in a solution of the
coating polymer, the solvent for the polymer being the liquid manufacturing
vehicle phase.
 27.  The coating material phase, an immiscible polymer in a liquid state, is
formed by utilizing one of the methods of phase separation coacervation, that is,
• By changing the temperature of the polymer solution • By adding a salt • By
adding a non-solvent • By adding incompatible polymer to the polymer solution •
By inducing a polymer-polymer interaction.
 28. A) Temperature change  Core material: N-acetyl p-aminophenol 
Polymer:- ethyl cellulose  Solvent: cyclohexane. EC + Cyclohexane Polymer
solution + Nacetylp-aminophenol (1:2) Gelation & solidification of coating occur
Collected by filteration, decantation & centrifugal technique.
 29. B) Addition of incompatible polymer:  Core material: Crystalline methylene
blue HCl  Coating material: Ethyl cellulose  Solvent: Toluene  Incompatible
polymer: Polybutadiene EC + Toluene mixture methylene blue HCl (1:4) 55C EC
solidify by adding non-solvent hexane, Collected by titration & drying technique.
 30. C) By Non-solvent addition  Core material: Methyl scopolamine HBr 
Coating polymer: Cellulose acetate butyrate  Solvent: Methyl ethyl ketone 
Non-solvent: Isopropyl ether CA butyrate + Methyl ethyl ketone mixture methyl
 scopolamine 55C mixture + isopropyl ether (slowly cool at room temp., collected
by centrifugation & drying)
 31. D) By salt addition  Core material: oil soluble vitamin  Oil: corn oil  Aq.
phase: water  Polymer: gelatin  Salt: sodium sulphate Salt : emulsion ratio is
4:10. Oil soluble vitamin + corn oil mixture water +sodium sulphate (oil droplet
coated uniformly with gelation)
 32. E) By polymer-polymer interaction:  Core material: Methyl salicylate 
+ve charge polymer: Gelatin  -ve charge polymer: Gum Arabic  Aq. Gum arabic
+ Aq. Gelatin mixture + water  4.5 pH, 40-50 0C polymer interact to causes
phase separation warm mixture + methyl salicylate slowly cooled the mixture at
25 0C over 1 hr rigidization of coating is done by cooling microencapsule at 10
0C
 33.  Deposition of the liquid polymer coating on the core material • This is
done by controlled mixing of liquid coating material and the core material in the
manufacturing vehicle. • Deposition of the liquid polymer coating around the
core material occurs if the polymer is adsorbed at the interface formed between
the core material and the liquid vehicle phase.  Rigidizing of the coating
material by thermal, cross linking or dessolvation techniques to form
microcapsules.  Important equipments necessary for microencapsulation by
coacervation phase separation method are jacketed tanks with variable speed
agitators
 34. Fig.: Coacervation phase separation method for microencapsulation
 35. Pan coating  For relatively large particles, which are greater than 600 μ in
size, microencapsulation can be done by pan coating method,  In this method,
various spherical core materials, such as nonpareil sugar seeds are coated with a
variety of polymers  In practice, the coating is applied as a solution or 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 material.  By using this
technique larger sized particles will be coated effectively
 37. Spray Drying And Congealing  methods of microencapsulation are almost
similar  both the methods entail the dispersion of core material in a liquefied
coating agent and spraying or introducing the core coating mixture into some
environmental condition.  The main difference in-between these two
microencapsulation methods are the means by which the coating solidification is
carried out.  In spray drying method, the coating solidification is influenced by
the quick evaporation of a solvent, in which the coating material is dissolved
 38.  In spray congealing method, the coating solidification is accomplished by
the thermal congealing of molten coating material or solidifying a dissolved
coating by introducing the coating core material mixture into a non-solvent. 
Removal of non-solvent or solvent from the coated product is often done by
sorption extraction or evaporation.
 39. Fluidized-bed technology  used for the encapsulation of solid core
materials, including liquids absorbed into porous solids .  Solid particles to be
encapsulated are suspended on a jet of air and afterward, are covered by a spray
of liquid coating material.  The capsules are traveled to an area where their
shells are solidified by cooling or solvent vaporization .  The processes of
suspending, spraying, and cooling are repeated until the attainment of the
desired thickness of the capsule-wall.  This is known as Wurster process when
the spray nozzle is located at the bottom of the fluidized-bed of particles
 41. Solvent Evaporation  appropriate for liquid manufacturing vehicle (O/W
emulsion), which is prepared by agitation of two immiscible liquids.
  42.  The solvent evaporation method involves dissolving microcapsule coating
(polymer) in a volatile solvent, which is immiscible with the liquid manufacturing
vehicle phase.  A core material (drug) to be microencapsulated is dissolved or
dispersed in the coating polymer solution.  With agitation, the core–coating
material mixture is dispersed in the liquid manufacturing vehicle phase to obtain
the appropriate sized microcapsules.  Agitation of system is continued until the
solvent partitions into the aqueous phase and is removed by evaporation. This
process results in hardened microcapsules.  The most common method is the
use of a propeller style blade attached to a variable speed motor
 43. Process variables for solvent Evaporation  rate of solvent evaporation for
the coating polymer(s)  temperature cycles  agitation rates  The most
important factors that should be considered for the preparation of microcapsules
by solvent evaporation method include choice of vehicle phase and solvent for
the polymer coating, and solvent recovery systems.
 44.  utilizes the centrifugal forces to hurl a core particle trough an enveloping
membrane  Various processing variables of multiorific-centrifugation method
include  (i) rotational speed of the cylinder,  (ii) flow rate of the core and
coating materials, and  (iii) concentration, viscosity and surface tension of the
core material Multiorific-centrifugation
 46. Applications of Microencapsulation  can be used to formulate various
sustained controlled release dosage forms by modifying or delaying release of
encapsulated active agents or core materials  employed to formulate enteric-
coated dosage forms,  Gastric irritant drugs are being microencapsulated to
reduce the chances of gastric irritation.  The taste of bitter drug candidates can
be masked  liquids and gases can be changed into solid particles in the form of
microcapsules.  provides environmental protection to the encapsulated active
agents from various environmental issues, such as light, heat, humidity,
oxidation,

Microencapsulation
 1. Microencapsulation Dr. Gajanan S. Sanap M.Pharm.,Ph.D Department of
Pharmaceutics Ideal College of Pharmacy and Research Kalyan 421- 306
 2. CONTENTS • Introduction • Reasons for Microencapsulation • Release
Mechanisms • Coating Materials • Coating Material Properties • Techniques to
Manufacture • Application • References
 3. Defination 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. Microencapsulation may be defined as the process of
surrounding or enveloping one substance within another substance on a very
small scale, yielding capsules ranging from less than one micron to several
hundred microns in size.” It is mean of applying thin coating to small particle of
solid or droplet of liquid & dispersion. Microencapsulation is a process by which
solids, Liquids or even gases may be enclosed in microscopic particles by
formation of thin coatings of wall material around the substances INTRODUCTION
 4. • Particle size: 50-5000 micron. • 2 phases: a) Core material b) Coating
material The product obtained by this process is called as micro particles,
microcapsules, microsphere, coated granules, pellets..  Particles having
diameter between 3 - 800µm are known as micro particles or microcapsules or
microspheres.  Particles larger than 1000µm are known as Macroparticles .
 5. A well designed controlled drug delivery system - can overcome some of
the problems of conventional therapy. - enhance the therapeutic efficacy of a
given drug.
 6. To obtain maximum therapeutic efficacy, drug is to be delivered : -to the
target tissue -in the optimal amount -in the right period of time there by causing
little toxicity and minimal side effects. One such approach is using microspheres
as carriers for drugs. Microspheres are characteristically free flowing powders
consisting of proteins or synthetic polymers  biodegradable in nature particle
size less than 200 μm.
 7. Microspheres Formulated Microsphere Red one’s are R.B.C Purple one’s
are microspheres
 8. REASONS FOR MICROENCAPSULATION 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. 5. Isolation of core from its surroundings, as in isolating vitamins
from the deteriorating effects of oxygen. 6. retarding evaporation of a volatile
core. 7. improving the handling properties of a sticky material. 8. isolating a
reactive core from chemical attack. 9. for safe handling of the toxic materials. 10.
to get targeted release of the drug 11. To control release of the active
components for delayed (timed) release or long-acting (sustained) release, 12.
The problem may be as simple as masking the taste or odor of the core, 13. To
Increase of bioavailability, 14. To produce a targeted drug delivery, 15. Protects
the GIT from irritant effects of the drug, 16. Extension of duration of activity for
an equal level of active agent.
 9. Generally Micro particles consist of two components a) Core material. The
solid core can be mixture of active constituents, stabilizers, diluents, excipients
and release-rate retardants or accelerators. b) Coat or wall or shell material
•Compatible, non reactive with core material •Provide desired coating properties
like strength, flexibility, impermeability, optical properties, non hygroscopicity,
tasteless and stable Fundamental Consideration /Formulation considerations
 10. 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
 11. Coating Material Inert substance which coats on core with desired
thickness. Composition of coating:  Inert polymer  Plasticizer  Coloring agent
 Resins, waxes and lipids  Release rate enhancers or retardants 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 crosslinks. Polymers are
used widely in pharmaceutical systems as adjuvants, coating materials and, a
components of controlled and site- specific drug delivery systems
 12. 1. Stabilization of core material. 2. Inert toward active ingredients. 3.
Controlled release under specific conditions. 4. Film-forming, pliable, tasteless,
stable. 5. Non-hygroscopic, no high viscosity, economical. 6. Soluble in an
aqueous media or solvent, or melting. 7. The coating can be flexible, brittle, hard,
thin etc. Coating Material Properties
 13. List of coating material Water soluble resin Water insoluble resin Wax &
lipid Enteric resin Gelatin, Gum arabic, PVP, CMC, Methyl cellulose,
Arabinogalactan, Polyvinyl acrylate, Polyacrylic acid. Ethyl cellulose,
Polyethylene, Polymethacrylate, Cellulose nitrate, Silicones. Paraffin, Carnauba
wax, Bees wax, Stearic acid, Stearyl alcohol. Shellac, Zein, Cellulose acetate
phthalate.
 14. Core Material Characteristic Property Purpose of Encapsulation Final
Product Form Aspirin Slightly water- soluble solid Taste-masking; sustained
release; reduced gastric irritation; separation of incompatibles Tablet or capsule
Vitamin A Palmitate Nonvolatile liquid Stabilization to oxidation Dry powder
Isosorbide dinitrate Water soluble solid sustained release Capsule Table:
Properties of Some Microencapsulated Core Materials.
 15. ADVANTAGES:  To Increase of bioavailability  To alter the drug release 
To improve the patient’s 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 core material.  To convert liquid to solid form &
To mask the core taste. Disadvantages • It is an expensive process • Requires
skill • Difficult to obtain continuous and uniform film
 16. Morphology of Microcapsules The morphology of microcapsules depends
mainly on the core material and the deposition process of the shell. 1-
Mononuclear (core-shell) microcapsules contain the shell around the core. 2-
Polynuclear capsules have many cores enclosed within the shell. 3- Matrix
encapsulation in which the core material is distributed homogeneously into the
shell material. - In addition to these three basic morphologies, microcapsules can
also be mononuclear with multiple shells, or they may form clusters of
microcapsules.
 18. RELEASE MECHANISMS Even when the aim of a microencapsulation
application is the isolation of the core from its surrounding, the wall must be
ruptured at the time of use. A variety of release mechanisms have been
proposed for microcapsules : by pressure or shear stress. by melting the wall.
 by dissolving it under particular conditions, as in the case of an enteric drug
coating. by solvent action by enzyme attack by chemical reaction by
hydrolysis or slow disintegration.
 19. MICROENCAPSULATION TECHNIQUES: 1. Air suspension
techniques( Wurster) 2. Coacervation process 3. Spray drying & congealing 4.
Pan coating 5. Solvent evaporation 6. Polymerization 7. Multiorific-centrifugal 8.
Extrusion 9. Single & double emulsion techniques 10. Supercritical fluid anti
solvent method (SAS) 11. Nozzle vibration technology
 21. Coacervation 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% and the controlled release possibilities based on mechanical stress,
temperature or sustained release. Coacervation is typically used to encapsulate
flavour oil and can also be adapted for the encapsulation of fish oils, nutrients,
vitamins, preservatives and enzymes. There are two methods for coacervation
are available, namely simple and complex processes. The mechanism of
microcapsule formation for both processes is identical, except for the way in
which the phase separation is carried out. •-
 22. The general process consist of 3 steps under continuous agitation: 1.
Formation of 3 immiscible chemical phase 2. Deposition of coating 3. Rigidization
 of coating. Step: 1) Three immiscible phases are as: a) Liquid manufacturing
vehicle phase b) Core material phase c) Coating material phase. Coating material
phase formed by utilizing following methods: A) Temperature change. B) By
addition of incompatible polymer C) By non-solvent addition D) By salt addition E)
Polymer-polymer interaction. •In simple coacervation : a desolvation agent is
added for phase separation. • whereas complex coacervation involves
complexation between two oppositely charged polymers
 23. In step 2, the deposition of the liquid polymer around the interface formed
between the core material and the liquid vehicle phase. In many cases physical
or chemical changes in the coating polymer solution can be induced so that
phase separation of the polymer will occur. Finally : the prepared microcapsules
are stabilized by crosslinking, desolvation or thermal treatment. Equipment
required for microencapsulation this method is relatively simple; it consists
mainly of jacketed tank with variable speed agitator.
 24. COACERVATION / PHASE SEPARATION Polymeric Membrane Droplets
Homogeneous Polymer Solution Coacervate Droplets PHASE SEPARATION
MEMBRANE FORMATION 1.Formation of three immiscible phase 2.Deposition of
coating 3.Rigidization of coating.
 25. COMPLEX COACERVATION :
 26. Coacervation Formation
 27. 27  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 spray-coating 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. Air Suspension Techniques (Wurster) (FLUIDISED BED COATING )
 28.  Within the coating chamber, particles are suspended on an upward
moving air stream. The design of the chamber and its operating parameters
effect a recalculating flow of the particles through the coating zone portion of the
chamber, where a coating material, usually a polymer solution, is spray applied
to the moving particles.
 29. The Wruster Process This technology is characterized by the location of a
spray nozzle at the bottom of a fluidized bed of solid particles. The particles are
suspended in the fluidizing air stream that is designed to induce a cyclic flow of
the particles past the spray nozzle. The nozzle sprays an atomized flow of coating
solution, suspension, or other coating vehicle. The technology can be used to
encapsulate solid materials with diameters ranging from near 50µm to several
centimeters. Wruster Process can be used to encapsulate vitamins, minerals, and
functional food ingredients.
 30. Air suspension techniques (WURSTER PROCESS):
 31. • It consist of dispersing the solid particulate core material in supporting air
stream and being coated with coating material (usually polymeric solution) • In
this, the fine core materials are suspended in a vertical current of air and
sprayed with the coating material • After evaporation of solvent, a layer of
encapsulating material is deposited on core • Gives improved control and
flexibility as compared to pan coating. • During each pass through the coating
zone, the core material receives an increment of coating material. • The cyclic
process is repeated, perhaps several hundred times during processing,
depending on the purpose of microencapsulation the coating thickness desired or
whether the core material particles are thoroughly encapsulated. • The
supporting air stream also serves to dry the product while it is being
 encapsulated. • Drying rates are directly related to the volume temperature of
the supporting air stream. 31
 32. 32  Disadvantage- Agglomeration of the particles to some larger size is
normally achieved. variables for efficient, effective encapsulation by air
suspension techniques: 1.Density, surface area, melting point, solubility,
friability, volatility, Crystallinity and flow-ability of core the core material.
2.Coating material concentration (or melting point if not a solution). 3.Coating
material application rate. 4.Volume of air required to support and fluidizes the
core material. 5.Amount of coating material required. 6.Inlet and outlet operating
temperatures.
 33. Solvent Evaporation (Chemical process) 33  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.
 34. 34  Used by companies including the NCR Company, Gavaert Photo -
Production NV, and Fuji Photo Film Co., Ltd. eg. Evaluation of Sucrose Esters as
Alternative Surfactants in Microencapsulation of Proteins by the Solvent
Evaporation Method.
 35. 35 Core material Dissolved Or Dispersed Coating polymer solution With
Agitation Liquid Manufacturing Vehicle Phase Heating (If necessary) Evaporation
of Polymer solvent Microencapsulation Solvent Evaporation process…..
 36. Polymer + Volatile organic solvent Organic Polymeric Phase Formation of
Oil-in-Water Emulsion Solvent Evaporation Particle Formation by Polymer
Precipitation RECOVERY OF POLYMERIC MICROPARTICLES Temperature increase
Active Ingredient Addition into an aqueous phase (+o/w stabilizer) 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.
 37. Solvent evaporation 37
 38. 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.
 39. Figure Pan coater 1. Solid particles are mixed with a dry coating material.
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.
 40.  The particles are tumbled in a pan or other device while the coating
material is applied slowly  The coating is applied as a solution or as an atomized
spray to the desired solid core material in the coating pan  Usually, to remove
the coating solvent, warm air is passed over the coated materials as the coatings
 are being applied in the coating pans.  In some cases, final solvent removal is
accomplished in drying oven.
 42. 42 Polymerization  A relatively new microencapsulation method utilizes
polymerization techniques to from 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.  The core material supporting phase is usually a liquid or
gas, and therefore polymerization reaction occur at liquid-liquid, liquid-gas, solid-
liquid, or solid-gas interface.  E.g. In the formation of polyamide (Nylon)
polymeric reaction occurring at liquid-liquid interface existing between aliphatic
diamine & dicarboxylic acid halide.
 43. Drug Addition of the alcoholic solution of the initiator (e.g., AIBN) 8 hrs
Reaction time Monomer(s) (e.g. acrylamide, methacrylic acid) + Cross-linker (e.g.
methylenebisacrylamide) Alcohol T (reaction) = 60 °C Nitrogen Atmosphere
Preparation of the Polymerization Mixture Initiation of Polymerization
Monodisoerse Latex Formation by Polymer Precipitation RECOVERY OF
POLYMERIC MICROPARTICLES 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. POLYMERIZATION:
 44. Polymerization 1) Interfacial polymer In Interfacial polymerization, the
two reactants in a …..polycondensation meet at an interface and react rapidly. 2)
In-situ polymerization In a few microencapsulation processes, the direct
…..polymerization of a single monomer is carried out on the …..particle surface.
e.g. Cellulose fibers are encapsulated in polyethylene while . immersed in dry
toluene. Usual deposition rates are about …..0.5μm/min. Coating thickness
ranges 0.2-75μm. 3) Matrix polymer In a number of processes, a core material is
imbedded in a …..polymeric matrix during formation of the particles.  Prepares
microcapsules containing protein solutions by incorporating the protein in the
aqueous diamine phase.  National Lead Corporation- utilizing polymerization
techniques
 45. Interfacial polymerisation In- situ polymerisation The multifunctional
monomer dissolved in liquid core material which will be then dispersed in
aqueous phase containing dispersing agent.  A co reactant multifunctional
amine will be added to the mixture.  This results in rapid polymerization at
interface and generation of capsule shell takes place. A polyurea shell will be
formed when isocyanate reacts with amine, polynylon or polyamide shell will be
formed when acid chloride reacts with amine. In this process no reactive agents
are added to the core material.  polymerization occurs exclusively in the
continuous phase and on the continuous phase side of the interface formed by
the dispersed core material and continuous phase. Initially a low molecular
weight prepolymer will be formed, as time goes on the prepolymer grows in size.
 it deposits on the surface of the dispersed core material thereby generating
solid capsule shell. 45
 46. Polymerization Single emulsion method 46
 47. Double emulsion method 47
 48. 48 Spray Drying and Spray Congealing Spray Drying: The coating
solidification effected by rapid evaporating of solvent in which coating material is
dissolved. Spray Congealing: The coating solidification is effected by thermally
 congealing a molten coating material. The removal of solvent is done by sorption,
extraction or evaporation technique. Figure Schematic diagram of a Spray Dryer
 49. 49  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.
 50. - Microencapsulation by spray-drying is a low-cost commercial process
which is mostly used for the encapsulation of fragrances, oils and flavors. Steps:
1- Core particles are dispersed in a polymer solution and sprayed into a hot
chamber. 2- The shell material solidifies onto the core particles as the solvent
evaporates. - The microcapsules obtained are of polynuclear or matrix type.
 51. Spray congealing 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. - e.g. microencapsulation of vitamins with digestible waxes for taste
masking.
 52. Spray drying and congealing 52 Dispersing the core material in a liquefied
coating Substance /spraying or introducing the coating mixture on to core
material. Coating solidification in spray drying is effected by rapid evaporation
of a solvent in which the coating material is dissolved.  Coating solidification in
spray congealing method is accomplished by thermally congealing a molten
coating material or by solidifying a dissolved coating by introducing the coating
core material mixture into a non-solvent.
 53. Spray Drying Spray Drying is the most commonly used encapsulation
method in the food industry. The process is economical and flexible uses
equipment that is readily available, and produces particles of good quality. The
process involves three basic steps: Preparation of a dispersion or emulsion to be
processed Homogenization of the dispersion and Atomization of the mass into
the drying chamber. Spray dried ingredients typically have a very small particle
size (generally less than 100µm) which makes them highly soluble. Typical shell
materials include gum acacia, maltodextrins, hydrophobically modified starch
and mixtures. Other polysaccharides like alginate, carboxymethylcellulose and
guar gum. Proteins like whey proteins, soy proteins, sodium caseinate can be
used as the wall material in spray drying.
 54. Spray-Drying
 55. SPRAY DRYING & CONGEALING ( COOLING) Spray drying : spray = aqueous
solution / Hot air Spray congealing : spray = hot melt/cold air
 56. Spray cooling/chilling is the least expensive encapsulation technology. It is
used for the encapsulation of organic and inorganic salts, textural ingredients,
enzymes, flavors and other functional ingredients. It improves heat stability,
delay release in wet environments, and/or convert liquid hydrophilic ingredient
into free flowing powders. Spray cooling/chilling is typically referred to as ‘matrix’
encapsulation because the particles are more adequately described as
aggregates of active ingredient particles buried in the fat matrix. Spray Cooling/
Chilling
 57. The Southwest Research Institute (SWRI) has developed a mechanical
process for producing microcapsules that utilizes. centrifugal forces to hurl a
core material particle trough an enveloping microencapsulation membrane
 thereby effecting mechanical microencapsulation. Processing variables include
the rotational speed of the cylinder, the flow rate of the core and coating
materials, the concentration and viscosity and surface tension of the core
material. 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. Production rates of 50 to 75 pounds per our have been achieved
with the process. MULTIORIFIC-CENTRIFUGAL PROCESS
 58. 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 Scanning electron microscopy •Scanning electron
photomicrographs of drug loaded ethyl cellulose microcapsules were taken. 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. EVALUATION OF MICROCAPSULES
 59. Particle size analysis 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 . Encapsulation efficiency [8]
Encapsulation efficiency was calculated using the formula: Encapsulation
efficiency = Actual Drug Content / Theoretical Drug Content ×100
 60. Cefotaxime sodium drug content in the microcapsules was calculated by
UV spectrophotometric (Elico SL159 Mumbai India) method.  The method was
validated for linearity, accuracy and precision. A sample of microcapsules
equivalent to 100 mg was dissolved in 25 ml ethanol and the volume was
adjusted upto 100 ml using phosphate buffer of pH 7.4. The solution was filtered
through Whatman filter paper. Then the filtrate was assayed for drug content
by measuring the absorbance at 254 nm after suitable dilution. Estimation of
Drug Content
 61. Drug release was studied by using USP type II dissolution test apparatus
(Electrolab TDT 08L) in Phosphate buffer of pH 7.4 (900 ml). The paddle speed at
100 rpm and bath temperature at 37 ± 0.5°c were maintained through out the
experiment. A sample of microcapsules equivalent to 100 mg of cefotaxime
sodium was used in each test. Aliquot equal to 5ml of dissolution medium was
withdrawn at specific time interval and replaced with fresh medium to maintain
sink condition. Sample was filtered through Whatman No. 1 filter paper and after
suitable dilution with medium; the absorbance was determined by UV
spectrophotometer (Elico SL159) at 254 nm. All studies were conducted in
triplicate (n=3). The release of drug from marketed sustained release tablet was
also studied to compare with release from microcapsules. Invitro Drug release
Studies
 62. APPLICATION OF MICROENCAPSULATION TECHNIQUES:
 63. Applications of Microcapsules and Microspheres 63 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.
 64. 64 3. Food Industry  Adding ingredients to food products to improve
nutritional value can compromise their taste, colour, 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, tumors, 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.
 65. 65  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.65 
Some of the applications of microencapsulation can be described in detail as
given below: 1. Prolonged release dosage forms. 2. Prepare enteric-coated
dosage forms selectively absorbed in the intestine rather than the stomach. 3. It
can be used to mask the taste of bitter drugs. 4. To reduce gastric irritation.
 66. 66 5. Used to aid in the addition of oily medicines to tableted dosage forms.
To overcome problems inherent in producing tablets from otherwise tacky
granulations. This was accomplished through improved flow properties. eg. The
non-flowable multicomponent solid mixture of niacin, riboflavin, and thiamine
hydrochloride and iron phosphate may be encapsulated and made directly into
tablets. 6. To protect drugs from environmental hazards such as humidity, light,
oxygen or heat. eg. vitamin A and K have been shown to be protected from
moisture and oxygen through microencapsulation. 7. The separations of
incompatible substances, eg. pharmaceutical eutectics. The stability
enhancement of incompatible aspirin- chlorpheniramine maleate mixture was
accomplished by microencapsulating both of them before mixing.
 67. 6767 Pharmaceutical Application  To improve the flow properties. e.g.
Thiamine, Riboflavine  To enhance the stability. e.g. Vitamins  To reduce the
volatility of materials. e.g. Peppermint oil, Methyl salicylate  To avoid
incompatibilities. e.g. Aspirin and Chloramphenicol  To mask the unpeasant
taste and odour. e.g. Aminophylline, castor oil  To convert liquids into solids.
e.g. Castor oil, Eprazinone,  To reduce gastric irritation. e.g. Nitrofurantoin,
Indomethacin
 68.  Microencapsulation has been employed to provide protection to the core
materials against atmospheric effects, e.g., Vitamin A Palmitate.  Separation of
incompatible substance has been achieved by encapsulation  To mask the bitter
taste of drugs like Paracetamol, Nitrofurantoin etc.  To reduce gastric and other
gastro intestinal (G.I) tract irritations, For eg, sustained release Aspirin
preparations have been reported to cause significantly less G.I. bleeding than
conventional preparations.  A liquid can be converted to a pseudo-solid for easy
handling and storage. eg.Eprazinone.  Hygroscopic properties of core materials
may be reduced by microencapsulation e.g. Sodium chloride.  Carbon tetra
chlorides and a number of other substances have been microencapsulated to
reduce their odour and volatility  To reduce volatality of liquids like peppermint
oil  Helps to prepare SRDF and enteric coated products, controlled release
products  Used to improve flow properties before compression into tablets 68
 69. Brand name API Manufacturer OROS CT (osmotically active tablets) Colon
specific drugs Alza corp. ReGel (oncogel) Paclitaxel Macro Med Inc. Clopigrel
 clopidogrel+ Aspirin Lupin pinnacle Clobitab clopidogrel+ Aspirin Lupin pinnacle
Atoplus Atorvastatin Triton (calyx) 69
 70. 70  Jackson L. S.; Lee K. (1991-01-01). "Microencapsulation and the food
industry". Lebensmittle–WissenschaftTechnologie. http://cat.inist.ft/?
aModele=afficheN&cpsidt=5014466. Retrieved 1991-02-02.
Editor's Notes
1. Air

Ndds 4 MICROENCAPSULATION DRUG DELIVERY

SYSTEM
 1. PREPARED BY: PROF. SHASHANK CHAURASIYA BANSAL COLLEGE OF
PHARMAY, BHOPAL MICROENCAPSULATION
 2. MICROENCAPSULATION : METHODS & THEIR APPLICATIONS
 3. Defination 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. Microencapsulation may be defined as the process of
surrounding or enveloping one substance within another substance on a very
small scale, yielding capsules ranging from less than one micron to several
hundred microns in size.” It is mean of applying thin coating to small particle of
solid or droplet of liquid & dispersion. Microencapsulation is a process by which
solids, Liquids or even gases may be enclosed in microscopic particles by
formation of thin coatings of wall material around the substances INTRODUCTION
 4. • Particle size: 50-5000 micron. • 2 phases: a) Core material b) Coating
material The product obtained by this process is called as micro particles,
microcapsules, microsphere, coated granules, pellets.. Particles having diameter
between 3 - 800µm are known as micro particles or microcapsules or
microspheres.  Particles larger than 1000µm are known as Macroparticles .
 5. A well designed controlled drug deliverysystem - can overcome some of
the problems of conventional therapy. - enhance the therapeutic efficacy of a
given drug.
 6. To obtain maximum therapeutic efficacy, drug is to be delivered : -to the
target tissue -in the optimal amount -in the right period of time there by causing
little toxicity and minimal side effects. One such approach is using microspheres
as carriers for drugs. Microspheres are characteristically free flowing powders
consisting of proteins or synthetic polymers  biodegradable in nature particle
size less than 200 μm.
 7. Microspheres Formulated Microsphere Red one’s are R.B.C Purple one’s
are microspheres
 8. REASONS FOR MICROENCAPSULATION 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. as in isolating vitamins from the5. Isolation of core from its
surroundings, deteriorating effects of oxygen. 6. retarding evaporation of a
volatile core. 7. improving the handling properties of a sticky material. 8.
 isolating a reactive core from chemical attack. 9. for safe handling of the toxic
materials. 10. to get targeted release of the drug 11. To control release of the
active components for delayed (timed) release or long-acting (sustained) release,
12. The problem may be as simple as masking the taste or odor of the core, 13.
To Increase of bioavailability, 14. To produce a targeted drug delivery, 15.
Protects the GIT from irritant effects of the drug, 16. Extension of duration of
activity for an equal level of active agent.
 9. Generally Micro particles consist of two components a) Core material. The
solid core can be mixture of active constituents, stabilizers, diluents, excipients
and release-rate retardants or accelerators. b) Coat or wall or shell material
•Compatible, non reactive with core material •Provide desired coating properties
like strength, flexibility, impermeability, optical properties, non hygroscopicity,
tasteless and stable Fundamental Consideration /Formulation considerations
 10. 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
 11. Coating Material Inert substance which coats on core with desired
thickness. Composition of coating:  Inert polymer  Plasticizer  Coloring agent
 Resins, waxes and lipids  Release rate enhancers or retardants 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 crosslinks. Polymers are
used widely in pharmaceutical systems as adjuvants, coating materials and, a
components of controlled and site- specific drug delivery systems
 12. 1. Stabilization of core material. 2. Inert toward active ingredients. 3.
Controlled release under specific conditions. 4. Film-forming, pliable, tasteless,
stable. 5. Non-hygroscopic, no high viscosity, economical. 6. Soluble in an
aqueous media or solvent, or melting. 7. The coating can be flexible, brittle, hard,
thin etc. Coating Material Properties
 13. List of coating material Water soluble resin Water insoluble resin Wax &
lipid Enteric resin Gelatin, Ethyl cellulose, Paraffin, Shellac, Gum arabic,
Polyethylene, Carnauba wax, Zein, PVP, CMC, Polymethacrylate, Cellulose nitrate,
Bees wax, Stearic acid, Cellulose acetate phthalate. Methyl cellulose, Silicones.
Stearyl alcohol. Arabinogalactan, Polyvinyl acrylate, Polyacrylic acid.
 14. Core Material Characteristic Property Purpose of Encapsulation Final
Product Form Aspirin Slightly water- soluble solid Taste-masking; sustained
release; reduced gastric irritation; separation of incompatibles Tablet or capsule
Vitamin A Palmitate Nonvolatile liquid Stabilization to oxidation Dry powder
Isosorbide dinitrate Water soluble solid sustained release Capsule Table:
Properties of Some Microencapsulated Core Materials.
 15. ADVANTAGES:  To Increase of bioavailability  To alter the drug release 
To improve the patient’s compliance  To produce a targeted drug delivery the
outside To reduce the reactivity of the core in relation to environment  To
decrease evaporation rate of the core material.  To convert liquid to solid form &
To mask the core taste. Disadvantages • It is an expensive process • Requires
skill • Difficult to obtain continuous and uniform film
 16. Morphology of Microcapsules The morphology of microcapsules depends
mainly on the core material and the deposition process of the shell.
1Mononuclear (core-shell) microcapsules contain the shell around the core. 2
Polynuclear capsules have many cores enclosed within the shell. 3Matrix
encapsulation in which the core material is distributed homogeneously into the
shell material. - In addition to these three basic morphologies, microcapsules can
 also be mononuclear with multiple shells, or they may form clusters of
microcapsules.
 18. RELEASE MECHANISMS Even when the aim of a microencapsulation
application is the isolation of the core from its surrounding, the wall must be
ruptured at the time of use. A variety of release mechanisms have been
proposed for microcapsules : by pressure or shear stress. by melting the wall.
by dissolving it under particular conditions, as in the case of an enteric drug
coating. by solvent action by enzyme attack by chemical reaction by
hydrolysis or slow disintegration.
 19. MICROENCAPSULATION TECHNIQUES: 1. Air suspension
techniques(Wurster) 2. Coacervation process 3. Spray drying & congealing 4. Pan
coating 5. Solvent evaporation 6. Polymerization 7. Multiorific-centrifugal 8.
Extrusion 9. Single & double emulsion techniques 10. Supercritical fluid anti
solvent method (SAS) 11. Nozzle vibration technology
 21. I] Physical or Physico-mechanical methods 16 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 spray-coating 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 tosome larger size is normally achieved
 22. 18 Processing variables for efficient, effective encapsulation by air
suspension techniques: 1.Density, surface area, melting point, solubility,
friability, volatility, Crystallinity, and flow-ability of core the core material.
2.Coating material concentration (or melting point if not a solution). 3.Coating
material application rate. 4.Volume of air required to support and fluidizes the
core material. 5.Amount of coating material required. 6.Inlet and outlet operating
temperatures.
 23. 19 Fig. 4: Air SuspensionApparatus.
 24. 20 2. Centrifugal extrusion  Liquids are encapsulated using a rotating
extrusion head containing concentric nozzles.  This process is excellent for
forming particles 400–2,000 μm 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.
 25. 21 3. 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.
 26. 22 Fig. 5: Representation of a typical pan coating
 27. 23 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.
 28. 24 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.
 29. 25  Spray congealing 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.
 30. 26 Airflow There are three modes of contact: 1. Co-current 2. Counter-
current 3. Mixed-flow
 31. 27 5. Vibrational Nozzle  The process works very well for generating
droplets between 100–5,000 µm  Units are deployed in industries and research
mostly with capacities of 1–10,000 kg per hour at working temperatures of 20–
1500 C.  Nozzles heads are available from one up to several hundred thousand
are available.
 32. 28 Fig. 7: Formation of Droplets Using Vibrational Nozzle Technique.
 33. II] Physico-chemical methods 29 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.
 34. 30 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
 35. 31 Fig. 8: Schematic representation of the coacervation process. (a) Core
material dispersion in solution of shell polymer; (b) separation of coacervate from
solution; (c) coating of core material by microdroplets of coacervate;
(d)coalescence of coacervate to form continuous shell around core particles.
 36. III] Chemical process 32 1. Solvent Evaporation  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.
 37. 33  Used by companies including the NCR Company, Gavaert Photo -
Production NV, and Fuji Photo Film Co., Ltd. eg. Evaluation of Sucrose Esters as
Alternative Surfactants in Microencapsulation of Proteins by the Solvent
Evaporation Method.
 38. 34 2. Polymerization 1) Interfacial polymer In Interfacial polymerization,
the two reactants in a polycondensation meet at an interface and react rapidly.
2) In-situ polymerization In a few microencapsulation processes, the direct
polymerization of a single monomer is carried out on the particle surface.
 39. Continue… 35 e.g. Cellulose fibers are encapsulated in polyethylene
while immersed in dry toluene. Usual deposition rates are about 0.5μm/min.
Coating thickness ranges 0.2-75μm. 3) Matrix polymer In a number of processes,
a core material is imbedded in a polymeric matrix during formation of the
particles.  Prepares microcapsules containing protein solutions by incorporating
the protein in the aqueous diamine phase.  National Lead Corporation- utilizing
polymerization techniques
 40. APPLICATION OFMICROENCAPSULATION TECHNIQUES:
 41. Applications of Microcapsules and Microspheres 1.
AgriculturalApplications  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.
 42. 3. Food Industry  Adding ingredients to food products to improve
nutritional value can compromise their taste, colour, 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. PharmaceuticalApplications 
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, tumors, 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. 
Some of the applications of microencapsulation can be described in detail as
given below: 1. Prolonged release dosage forms. selectively2.Prepare enteric-
coated dosage forms absorbed in the intestine rather than the stomach. 3. It can
be used to mask the taste of bitter drugs. 4. To reduce gastric irritation.
 44. 5. Used to aid in the addition of oily medicines to tableted dosage forms. To
overcome problems inherent in producing tablets from otherwise tacky
granulations. This was accomplished through improved flow properties. eg. The
non-flowable multicomponent solid mixture of niacin, riboflavin, and thiamine
hydrochloride and iron phosphate may be encapsulated and made directly into
tablets. 6.To protect drugs from environmental hazards such as humidity, light,
oxygen or heat. eg. vitamin A and K have been shown to be protected from
moisture and oxygen through microencapsulation. 7.The separations of
incompatible substances, eg. pharmaceutical eutectics. The stability
enhancement of incompatible aspirin- accomplished bychlorpheniramine maleate
mixture was microencapsulating both of them before mixing.
 45. 67 Pharmaceutical Application  To improve the flow properties. e.g.
Thiamine, Riboflavine  To enhance the stability. e.g. Vitamins  To reduce the
volatility of materials. e.g. Peppermint oil, Methyl salicylate  To avoid
incompatibilities. e.g. Aspirin and Chloramphenicol  To mask the unpeasant
taste and odour. e.g. Aminophylline, castor oil  To convert liquids into solids.
e.g. Castor oil, Eprazinone,  To reduce gastric irritation. e.g. Nitrofurantoin,
Indomethacin
 46.  Microencapsulation has been employed to provide protection to the core
materials against atmospheric effects, e.g., Vitamin APalmitate.  Separation of
incompatible substance has been achieved by encapsulation  To mask the bitter
taste of drugs like Paracetamol, Nitrofurantoin etc.  To reduce gastric and other
gastro intestinal (G.I) tract irritations, For eg, sustained release Aspirin
preparations have been reported to cause significantly less G.I. bleeding than
conventional preparations  A liquid can be converted to a pseudo-solid for easy
handling and storage. eg.Eprazinone.  Hygroscopic properties of core materials
 may be reduced by microencapsulation e.g. Sodium chloride.  Carbon tetra
chlorides and a number of other substances have been microencapsulated to
reduce their odour and volatility  To reduce volatality of liquids like peppermint
oil  Helps to prepare SRDF and enteric coated products, controlled release
products  Used to improve flow properties before compression into tablets 68
 47. Brand name API Manufacturer OROS CT (osmotically active tablets) Colon
specific drugs Alza corp. ReGel (oncogel) Paclitaxel Macro Med Inc. Clopigrel
clopidogrel+ Aspirin Lupin pinnacle Clobitab clopidogrel+ Aspirin Lupin pinnacle
Atoplus Atorvastatin Triton (calyx) 69
 48. . THANK YOU…