-:CONTENTS OF SEMINAR :Introduction Advantage Polymar used for preparation General Method of Preparation Characterization of Microspheres.

Application of Microspheres

-: INTRODUCTION :

Microspheres are solid , approximately spherical particles ranging 1-1000m in size.

They are made up of polymeric substance in which the drug is dispersed through out the microspheres matrix.

ADVANTAGE OF MICROSPHERES:


They facilitate accurate delivery of small quantities of potent drug and reduced concentration of drug at site other than the target organ or tissue.

They

provide

protection

for

unstable

drug

before

and

after

administration, prior to their availability at the site of action.



They provide the ability to manipulate the in vivo action of the drug, pharmacokinetic profile, tissue distribution and cellular interaction of the drug.

They enable controlled release of drug. Ex: narcotic, antagonist, steroid hormones

POLYMER USED FOR MICROSPHERES PREPARATION:

Biodegradable Polyme:
Lactides&Glycolides and their copolymer

NON Biodegradable Polyme:

Poly methyl methacrylate Acrolein

Polyanhydrides Epoxy Polymer Polycynoacrylates Glycidyl methacrylate

THE ADMINISTRATION PARAMETERS THAT CAN BE SATISFACTORILY CONTROLLED ARE AS FOLLOW:

Taste and odour masking Conversion of oil and other liquids, facilitating ease of handling Protaction of the drug from the environment Delay of volatillisation Freedom from incompatibilities between drug and excipients,especially the buffers

Improvement of flow properties Safe handling of test masking Dispersion of water insoluble substance in aqueous media

GENERAL METHOD OF PREPARATION:

a) Single Emulsion Technique b) Double Emulsion Technique c) Polymerization Technique d) Phase Separation Coacervation e) Spray drying &spray coating f) Solvent Extraction

A) SINGLE EMULSION TECHNIQUE

Aqous solution /suspension of polymer(natural polymer) stirring / sonication dispersion in orgenic phase oil/chcl3 cross linking

Heat denaturation (by adding dispersion To heated oil)

chemical crosslinking (butanol,HCHO,Glutaraldehyde)

MICROSPHERES IN ORG.PHASE ORG.PHASE

MICROSPHERES IN

CENTRIFUGATION,WASHING,SEPARATION

MICROSPHERES

B) DOUBLE EMULSION TECHNIQUE

Aqueous solution of polymer
dispersion in oil/orgenic phase, vigorous homogenisation(sonication)

Primary emulsion(w/o)
addition of aqueous solution of PVA

W/O/W multipal emulsion

addition of large aq. Phase

MICROSPHERES in solution

SEPARATION,WASHING, DRYING

MICROSPHERES

C)POLYMERIZATION
A)Normal Polymerization:


Normal Polymerization is done by bulk, suspension, pption,emulsion and polymerization process.

1.

Bulk polymerization:
Monomer Bioactive material Initiator

Heated to initiate polymerization Initiator accelerate rate of raction

Polymer(Block) Moulded/fragmented MICROSPHERES

B)SUSPENSION POLYMERIZATION
Monomer Bioactive material Initiator

Dispersion in water and stebilizer Droplet

Vigorous ,Aggitation Polymerization by Heat

Hardened microspheres Separation&Drying

MICROSP HERES

3) EMULSION POLYMERISATION
Monomer/ Bioactive material Aq.Solution of NaOH, Initiator, Surfactant , Stabilizer

Dispersion with vigorous stirring Micellar sol. Of Polymer in aqueous medium Polymarization Microspheres formation

MICROSPHERES

D)PHASE SEPRATION COACERVATION

Aq./orgenic solution of polymer

Drug dispersed or dissolved in the polymer solution Phase sepration by salt addition, non solvent addition add. Incompatible polymer,etc Polymer rich globules Hardening microspheres in aqu./orgenic phase sepration/drying MICROSPHERES

E)SPRAY DRYING
Polymer dissolve in volatile organic solvent(acetone,dichloromethane) Drug dispersed in polymer solution under high speed homogenization Atomized in a stream of hot air Due to solvent evaporation small droplet or fine mist form Leads to formation of Microspheres Microspheres separated from hot air by cyclone separator,Trace of solvent are removed by vacuum drying

F)SOLVENT EXTRACTION
Drug is dispersed in organic solvent

(water miscible organic solvent such as Isopropanol)

Polymer in organic solvent

Organic phase is removed by extraction with water (This process decreasing hardening time for microspheres)

Hardened microspheres

CHARACTERIZATION PROPERTIES OF MICROSPHERES

1] Particle size analysis 2] Scanning electron microscopy (SEM) study 3] Flow properties 4] Thermal analysis 5] Determination of percentage yield 6] Drug content 7] Determination of drug loading
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8] Incorporation efficiency of microspheres 9] Determination of solubility 10] Dissolution studies of microspheres

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1] PARTICLE SIZE ANALYSIS

Particle size of recrystallized sample, pure samples, spays dried microspheres were determined by microscopic method using calibrated ocular micrometer. A microscopical image analysis technique for determination of particle size was applied. The morphology and particle sizes were determined in a Digital microscope equipped with a 1/3CCD camera imaging accessory The microspheres were dispersed on a microscope slide. A microscopical field was scanned by video camera. The images of the scanned field are analyzed by the softwar.

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] SCANNING ELECTRON MICROSCOPY (SEM) STUDY

The morphology of microspheres was examined by scanning election microscopy. A small amount of powder was spread on an aluminum stub, which was placed latter gold sputtering in san SEM chamber. Photographs were taken at an acceleration voltages of 20 KV electron beam. Obtained photograph to identify and confirm spherical nature and Surface topography of the crystals.

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3] FLOW PROPERTIES
Flow properties of the microspheres were evaluated by determining the angle of repose and the compressibility index. a) The angle of repose of microsphere and commercial crystals was measured by fixed funnel method. Static angle of repose was measured according to the fixed funnel and free standing cone method of Banker and Anderson. A funnel with the end of the stem cut perpendicular to the axis of symmetry is secured with its tip at a given height (1 cm), H, above graph paper placed on a flat horizontal surface. The microspheres were carefully poured through the funnel until the apex of the conical pile so formed just reached the tip of the funnel.
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Thus, the R being the radius of the base of the microspheres conical pile: . tan = H/ R or = tan-1 (H/ R) where = the angle of repose

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b) Compressibility index (I): Carrs index was determined from powder volumes at the initial stage and after 1250 tappings to constant volume. Compressibility index (I) values of the microspheres were determined by measuring the initial volume (V0) and the final volume (V) after subjecting to 100 tapping in a graduated measuring cylinder using the equation. I = [1- (V/V0)] x 100 Apparent particle densities of microsphere were measured using a Pycnometer.
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4] THERMAL ANALYSIS
Differential scanning calorimeter (DSC) DSC study was carried out to detect possible polymorphic transition during the crystallization process. DSC measurements were performed on differential scanning calorimeter (DSC DuPont 9900) with a thermal analyzer. Differential scanning calorimetry (DSC) was performed on ketoprofen and ketoprofen loaded microspheres. DSC measurement were done on a Mettler Toledo DSC 822c C/ min over a temperature range of 30 to 30000 C under an inert atmosphere flushed with nitrogen at a rate of 20 ml/min.

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5] DETERMINATION OF PERCENTAGE YIELD

The yield of microspheres was determined by the formula, %Yield= Total Weight of Microspheres ------------------------------------------ x 100 Total Weight of Raw Material

The percentage yield of each formulation was determined according to the total recoverable finalweight of microsphere and the total original weight of Indomethacin.

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6] DRUG CONTENT
Microspheres in a particular quantity were dissolve in a solvent and at specified max of drug . The drug content of Microspheres is estimated. Microspheres (50 mg) were triturated with 10 ml of water. Allowed to stand for 10 min withoccasional swirling and methanol was added to produce 100 ml. After suitable dilution, sampleswere measured at particular max value of drug. Drug content was determined from standard plot.

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7] DETERMINATION OF DRUG LOADING

The drug loading was determined by UV Visible spectrophotometer. The microspheres were stirred with 100 ml particular solution as dissolution media (pH 7.40 phasphatebuffer )for 2hr. The drug concentration will be determin at particular max value of drug after suitable dilution. The readings were taken in triplicate. Drug loading (%) = M actual ------------------------------ x 100 Weighed quantity of powder of microspheres

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8] INCORPORATION EFFICIENCY OF MICROSPHERES

Incorporation efficiency (%) = M actual ---------------------- x 100 M theoretical

Where, M actual is the actual drug content in weighed quantity of powder of microspheres & M theoretical is the theoretical amount of drug in microspheres calculated from the quantity added in the fabrication process.

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9] DETERMINATION OF SOLUBILITY
The solubility of particular drug microspheres in specific solution as microspheres or microcapsule to be soluble in that particular environment (water and pH 7.4 phosphate buffer) was determined by taking excess quantity of microspheres in 50 ml to screw capped glass vials filled with water. The vials were shaken for two hours on mechanical shaker. The solution was filtered through Whatmann filter paper No.1 and drug concentration wasbe determined at particular max value of drug.

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10] DISSOLUTION STUDIES OF MICROSPHERES

The dissolution of microspheres is determined by using USP dissolution apparatus XXIV Type II. Dissolution medium was 900 ml 7.4 Phosphate buffer. The amount of dissolved drug was determined using UV spectrophotometric method at specified max of particular drug. The readings were taken in triplicate.

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APPLICATION OF MICROSPHERES


Microspheres in Vaccine delivery ,e.g. Mucosal Vaccine.

     

Targeting of Drug Magnetic Microspheres, e.g. MTX. Immunomicrospheres Microsponges: Topical Porous Microspheres Imaging Surface modifide Microspheres

REFERENCES
1] S. B. Gholap,International Journal of Pharmaceutical Sciences Review and Research, Issue: 1, Volume 1, March April 2010; Article 015,Page no.- 78 2] MUDIT DIXIT, International Journal of Drug Formulation & Research,ISSN: 2229-5054, Volume 2 (1),Jan-Feb. 2011, Page no.- 142-143 3] Deore B.V.,International Journal of ChemTech Research, ISSN: 0974-4290, Volume 1, No.3, July-Sept 2009,page no.- 635-636. 4] ASHWINI G KINI, International Journal of Pharmacy and Pharmaceutical Sciences,ISSN: 0975-1491,Volume 3, Suppl 2, 2011, Page no- 232.

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