Microspheres - Methods for Preparation of Microspheres

Microspheres are defined as solid, spherical particles ranging in size from 1- 1000 um, made up of polymeric, waxy or other protective materials.

1. 1Sagar Savale

2. CONTENT
 Definition
 History
 Material used
Criteria for selection of method
 Methods of preparation
 Applications
 References
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3. DEFINITION
Micro-particles are the polymeric entities falling in the range of
1-1000 mm, covering two types of the forms as follows:
Microcapsules: micrometric reservoir systems
Microspheres: micrometric matrix systems
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4. Microspheres are defined as solid, spherical particles ranging
in size from 1- 1000 um, made up of polymeric, waxy or other
protective materials.
Spherical drug carriers are preferred over rods, cylinder, slabs,
etc as they could be injected into body in a suitable vehicle
using hypodermic needle.
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5. HISTORY
The concept of packaging microscopic quantities materials
within microspheres dates to the 1930s: “the work of
Bungenberg de Jong and co-workers on the entrapment of
substances within coacervates”.
In the early 1950s Barrett K. Green developed the
microencapsulation that used the process of phase-separation-
coacervation.
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6. Material Used
1. Synthetic polymers
a. Non-biodegradable polymers
e.g. Poly methyl methacrylate (PMMA), Acrolein, Glycidyl
methacrylate, Epoxy polymers
b. Biodegradable polymers
e.g. Lactides, Glycolides & their co polymers, Poly alkyl cyano-
acrylates, Poly anhydrides
2.Natural polymers
Proteins: Albumin, Gelatin, and Collagen
Carbohydrates: Agarose, Carrageenan, Chitosan, Starch
Chemically modified carbohydrates: Poly dextran, Poly starch
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7. Criteria for selection of method of
preparation
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
Susceptibility to chemical modification
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8.  Single Emulsion method
 Double Emulsion method
 Polymerisation
 Phase Separation And Coacervation method
 Spray Drying And Spray congealing
 Wax Coating and Hot melt method
 Air Suspension
 Solvent Extraction
 Precipitation
 Freeze Drying

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9. Single Emulsion Method



agrS vlre vSvSvl
Aq. Sol./suspension of polymer vSSvS SvlSeSlvvv
Dispersion in organic phase oil / Chloroform
Microspheres in org. phase
Microspheres
Microspheres in org. phase
Heat
Denaturation
Chemical
crosslinking
Centrifugation, washing, separation
Stirring, Sonication
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10. Double Emulsion Method
Best suited for water soluble drugs, proteins and the vaccines.
Dispersion in organic phase
Homogenization or sonication
Addition of aq.sol. Of PVA


Addition of large aq.phase

Separation, washing ,drying
Microspheres
Aq.sol of polymer + drug
First emulsion
Multiple emulsion
Microsphere in solution
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Solvent evaporation
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11. Preparation of BSA loaded PLGA microspheres
Aq.sol. of BSA
PLGA in 10 ml Dichloromethane
Homogenization


Primary emulsion (w/o)

25 ml aq.sol. Of PVA (3%w/v)

Double emulsion (w/o/w)

stirred for 6hrs.
Centrifugation

Microspheres washed with D.W.

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Homogenization
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12. Polymerization
Mainly classified as :
1)Normal polymerisation
2) Interfacial polymerisation
1) Normal polymerisation
 Bulk :



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13. Suspension (Bead/pearl poly.)



Dispersed in water & stabilliser



Polymerisation Vigorous agitation
Heat



•Monomer
Bioactive
material
•Initiator
Droplets
Microspheres (>100um)
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14. 2) Interfacial Polymerisation
Involves reaction of monomers at interfaces
between two immiscible liquid phases, to form a film of
polymer, that essntially envelops the dispersed phase.
Two reacting monomers are employed.
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15. Monomer 1+drug+Neutraliser Monomer 2+ Surfactant (CMC)
in org. phase Stabilizer in aq. Phase

Emulsification

Emulsion of (monomer 1+drug sol.in oil)
in (aq. Phase containing monomer 2)
Polymerization
Microspheres in aq.media
Separation,washing,drying

Microspheres


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16. Phase separation & coacervation
method
Specially designed for preparation of
reservoir type of the system, also used
for matrix type devices.
 Coacervation is induced by
subjecting the biphasic system to
conditions which brings coalescence
of the polymer by withdrawing the
solvent away from colloidal particles
under controlled conditions.
Schematic representation of
coacervation phase separation
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17. 1)Simple coacervation:
 Occurs in presence of only one macromolecule.
 E.g. water/gelatin
 Induced by- Non solvent addition
Salt addition
Temp. change
Incompatible polymer addition
2) Complex coacervation:
 Two or more macromolecules of opposite charges.
 E.g. Solution of positively charged Gelatin with
negatively charged Gum arabica.
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18. Phase Separation induced
by Solvent/ Heat
Hardening
Separation, Washing
Drying
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19. Spray drying and spray congealing
These methods are based on the drying of
mist of the polymer & drug in the air either
by removal of solvent (spray drying)or
cooling of the solution(spray congealing).
Advantages:
Feasibility of operation in aseptic
condition.
Suitable for both bath & bulk mfg.
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20. Polymer is dissolved in volatile organic solvents
Disperse solid drug in polymer solution
Homogenization
Atomization by hot air stream
Small droplets/fine mist
Evaporation of solvent
separation of microspheres & vacuum drying to remove
traces of solvent
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21. Preparation of 4-chlorocurcumin microsphere
Drug +EC
Dissolved in Chloroform(1%w/v)
Spraying the sol. Using Spray Gun
(Spray time 6-7s )
Evaporation of solvent
Microspheres
4-chlorocurcumin microsphere
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22. Wax coating & Hot melt technique
In this method, Wax is used to coat the core particles
Carnuba wax ,Bees wax.
Polyanhydrides
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23. Air Suspension
Prof. Dale E. Wurster.
It consist of dispersing the
solid particulate core material
in supporting air stream.
#Process variable parameter:-
1) Application rate of coating
material.
2) Coating material conc.
3) Core material properties.
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24. Solvent Extraction
Polymer and drug must be soluble in organic solvent.




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25. Precipitation
oAn emulsion is formed, which consists of polar droplets
dispersed in a non-polar medium. Solvent may be removed
from the droplets by the used of a co-solvent.
oThe resulting increase in the polymer-drug concentration
causes a precipitation forming a suspension.
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26. Freeze Drying
This method involves the freezing of emulsion.
The continuous-phase solvent is usually organic and is
removed by sublimation at low temperature and pressure.
Finally, the dispersed-phase solvent of the droplets is removed

by sublimation, leaving polymer-drug particles.
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27. Advantages as well as Applications of
Microsphere
APPLICATION EXAMPLES
Taste masking Fish oils, Sulfa drugs, Alkaloids and
salts
Enteric Coating Aspirin, Pancrelipase, Erythromycin
Sustained release & Controlled release KCL, Ibuprofen, Theophyllin
Instabillity to Environment and
volatillity
Vitamins, Aspirin, Volatile flavours
Separation of incompatible materialsDrugs, Excipient, Buffers
Administration in solid state & Dry
handling
Liquids , soft or sticky solids, oils,
Flavours, Vitamins A
Improvement of flow On conversion of powders to Spherical
shaped microspheres
Detoxification Vaccines, Safe handling of toxic
substances
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28. References
Vyas S P, Khar R K, Targeted & controlled Drug Delivery Novel
Carrier Systems, CBS Publishers, 1
st
ed;2004, 417-454.
Patrick B.Deasy, “Microencapsulation and related drug process”,
Marcell Dekkar, NewYork, 1985, p.no.61-71,155-160,255-265
James Swarbrick, James C.Boylan, Encyclopedia Of Pharmaceutical
Technology, vol.2, 2 ed, Marcel Dekker ,1783-1791.
R.S.R. Murthy, Vasicular & Particulate Drug Delivery Systems ,
1 ed;2010,Career Publication ,172 ,174, 184-190,196-201.
Microencapsulation , Marcel Dekker Publication By Benita. 35-57.
Leon L.; Herbert A.L.;Joseph K., The Theory and Practice of
Industrial Pharmacy, 3,Verghesepublishinghouse, Bombay,412-455
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29. P.K.Gogu, Preparation & invivo/ invitro characterisation of Spray Dried
Microspheres formulation Encapsulating 4- Chlorocurcumin , Indian
Journal of Pharmaceutical Sciences ,2010, vol.72, 346-352.
Review on Microspheres Technology & its application by Gunja
Chaturvedi.
N. Venkata Naga Jyothi, Microencapsulation Technique , Factors
Influencing Encapsulation Efficiency : A Review, The Internet Journal of
Nanotehnology , ISSN:1937-8262
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