MICROENCAPSULATION

MICROENCAPSULATION

Definition:

It is the process by which individual particles or droplets of solid or liquid material (the core) are surrounded or coated with a continuous film of polymeric material (the shell) to produce capsules in the micrometer to millimeter range, known as microcapsules.

Fundamental Considerations:

·Nature of the core and coating materials.

·Stability and release characteristics of the coated materials.

·Microencapsulationmethods

Features of Microcapsule:                                                    

Microencapsulation is the packaging of small droplets of liquid or particles with a thin film.

Size:

It ranges in size from 1μm to 1mm. 

Shape:

The configuration of the core can be a spherical or irregular particle, liquid-phase suspended solid, solid matrix, dispersed solid and aggregates of solids or liquid forms.

Classification:

Microcapsules can be classified on three basic categories according to their morphology as follows,

1.      Mononuclear

Mononuclear (core-shell) microcapsules contain the shell around the core.

2.      Polynuclear

Polynuclear capsules have many cores enclosed within the shell.

3.      Matrix types

In matrix encapsulation, the core material is distributed homogeneously into the shell material.

In addition to these three basic morphologies, microcapsules can also be multiwalled i.e. mononuclear with multiple shells, or they may form clusters of microcapsules.

Composition:

Microcapsules consist of

·         Core material.

·         Coat or wall or shell material.

·         vehicle

Core materials:

The material to be coated. It may be liquid or solid or gas.

Composition of core material

Liquid core may be dissolved or dispersed material.

Solid core may contain drug, diluent, stabilizers and release rate inducers or inhibitors

Coating materials:

·         Gums; Gum Arabica, Sodium alginate, Carrageenan.

·         Carbohydrates;Starch, dextran, sucrose

·         Celluloses;Carboxymethylcellulose, methycellulose.

·         Lipids;Bees wax, stearic acid, phospholipids.

·         Proteins: Gelatin, albumin.

Chemical Classification of Polymers

REASONS FOR ENCAPSULATION:

This technique has been widely used;

1.      For masking the organoleptic properties like taste and odor of many drugs and thus improves patient compliance e.g. Nitrofurantoin for masking the bitter taste.

2.      For converting liquid drug in a free flowing powder.

3.      For protecting moisture, light and oxygen sensitive drugs such as Nifedipine is protected from photo instability, vitamin A palmitate is protected from oxidation etc.

4.      For preventing the incompatibility between different drugs

5.      The drugs which are volatile in nature may vaporize at room temperature like peppermint oil can be prevented by microencapsulation.

6.      For sustained, delayed orprolonged release ofthedrug.

7.      For targeted drug delivery andto increase thebioavailability ofdrug.

8.      Reduction in toxicity andGI irritation e.g., with KCland ferroussulphate.

9.      For changing the site of absorption of drugs that have high toxicity at lower pH.

Criteria for Microencapsulation:

Preparation of microspheres should satisfy certain criteria:

Ø      Should have ability toincorporate reasonably highconcentrations ofthe drug.

Ø      Should be stable after synthesiswith aclinically acceptable shelflife.

Ø      Should have controlled particle size anddispensability in aqueous vehiclesforinjection.

Ø      Should release active reagent with a goodcontrol over awide timescale.

Ø      Should be biocompatible with acontrollablebiodegradability.

Ø      Should be susceptible tochemical modification.

Mechanisms and Kinetics of Drug Release:

Major mechanisms of drug release from microcapsules include diffusion, dissolution, osmosis and erosion.

1.      Diffusion

Diffusion is the most common mechanism of drug release (core material) in which thedissolutionfluid penetrates the shell. When the core material comes intocontact with the dissolution fluidit leaks out through thepores. Basically, the release of core material depends on

·                  The rate of drug dissolution in thedissolution fluid

·                  The rate of penetration of dissolution fluid to the microcapsules

·                  Therate at which the dissolved drug escape from the microcapsule

2.      Dissolution:

In this mechanism first polymer coat gets dissolved followed by the release of drug. The release of core material depends on

·                  The solubility of polymer in the dissolutionfluid

·        Thickness of coat

3.     Osmosis:

The essential requirement of osmosis issemi permeable membrane andin microcapsule polymer coat serve the purpose.Asthe process progressesan osmotic pressure is created between the outsideand inside of membraneof microcapsulewhich results in release of drug through smallpores.

4.      Erosion:

Erosion of coat generally occur due to pH or enzymatic hydrolysis and causes drug release with  certain coat materials like bee’s wax, stearyl alcohol and glycerylmonostearate.

·         .

METHODS OF PREPARATION:

These depends on

DRUG FACTORS:

·         Physical properties

·         Chemical properties

·         Biological activity

·         Nature of drug

·         Stability of drug

PRODUCTION REQUIREMENT:

·         Entrapment efficiency

·         Percentage yield

PHYSICAL METHODS:

·         Spray drying

·         Spray congealing

·         Air suspension

·         Fluid bed coating

·         Pan coating

·         Centrifugal extrusion

·         Vibration nozzle

·         Multi orifice centrifugation  process

·         Spinning disk

1-SPRAY DRYING:

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.

2-SPRAY-CONGEALING:

This technique can be accomplished with spray drying equipment when the protective coating is applied as a melt.

1.      The core material is dispersed in a coating material melt.

2.      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.

3-AIR-SUSPENSION COATING

Microencapsulation by air suspension technique consist of the dispersing of solid, particulate core materials in a supporting air stream and the spray coating on the air suspended particles. Within the coating chamber, particles are suspended on an upward moving airstream.

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.

4-FLUID BED COATING

Fluid  bed  coating is  restricted  to encapsulation  of  solid  core  materials,  including liquids  absorbed  into  porous  solids. Solid  particles  to  be encapsulated are suspended on a jet of air and then  covered  by  a  spray  of  liquid  coating material.  The  capsules  are  then  moved  to  an area  where  their  shells  are  solidified  by  cooling or  solvent  vaporization.  The  process  of suspending,  spraying,  and  cooling  is  repeated until  the  capsules'  walls  are  of  the  desired thickness.

Different types of fluid-bed coaters include top spray, bottom spray, and tangential spray

(a) Top spray

(b) Bottom spray

(c) Tangential spray.

In the top spray system the coating material is sprayed downwards on to the fluid bed such that as the solid or porous particles move to the coating region they become encapsulated.

The bottom spray is also known as “Wurster’s coater”. This technique uses a coating chamber that has a cylindrical nozzle and a perforated bottom plate. The cylindrical nozzle is used for spraying the coating material. As the particles move upwards through the perforated bottom plate and pass the nozzle area, they are encapsulated by the coating material.

The tangential spray consists of a rotating disc at the bottom of the coating chamber, with the same diameter as the chamber. During the process the disc is raised to create a gap between the edge of the chamber and the disc. The tangential nozzle is placed

Above the rotating disc through which the coating material is released. The particles move through the gap into the spraying zone and are encapsulated. As they travel a minimum distance there is a higher yield of encapsulated particles.

5-SPINNING DISK:

§  Suspensions of core particles in liquid shell material are poured into a rotating disc.

§  Due to the spinning action of the disc, the core particles become coated with the shell material.

§  The coated particles are then cast from the edge of the disc by centrifugal force.

§  After that the shell material is solidified by external means (usually cooling).

§  This technologyis rapid, cost-effective, and relatively simple and has high production efficiencies.

6-PAN COATING:

When coating is liquid?

Coating is applied as a coating solution or atomized spray to the dried solid core particles in the coating pan.

To remove the coating solvent warm air is supplied to the coated materials while coatings are applied in the coating pan.

On some cases the solvent is removed by drying in the oven.

When coating is solid?

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.

7-CENTRIFUGAL EXTRUSION:

As shown in Figure

§  The simple extrusion method utnizes a device consisting of two concentric tubes containing aligned fluid nozzles.

§  The liquid material to be coated is extruded through the nozzle of the inner tube into the coating fluid contained in the outer tube.

§  Initially. The fluid extrudes as a rod surrounded by the coating fluid, but the rod ultimately breaks up into droplets which are then immersed in the coating fluid.

§  As the extruded droplets pass through the nozzle orifice of the outer tube.

§  The coating fluid forms a surface coat which encases the extruded particle.

§  Spherically shaped particles are formed by the surface tension of the liquid.

§  By suitable means the formed coat is converted to a more rigid structure. Hardening baths are usually employed for this purpose.

8-MULTI ORIFICE-CENTRIFUGAL PROCESS:

Microencapsulation by the multi orifice-centrifugal process is the mechanical process in which the centrifugal force is applied to throw a core material particle through an enveloping microencapsulation membrane.

 The factors affect the Process include the rotational speed of the cylinder, the flow rate of the coating and core materials and the concentration, viscosity and surface tension of the core material.

It consists of a cylinder containing three circumferential grooves (coating material inlet)

Core material inlet

Counter rotating disc

Rotating cylinder

CHEMICAL METHODS:

1-SOLVENT EVAPORATION METHOD

Process

• Step I (Dispersion of Drug in Polymer Solution)

In this process microcapsule coating (polymer) is dissolved in a volatile solvent, which is immiscible with the liquid manufacturing vehicle phase.Methylene chloride is a preferred solvent because of its high volatility (boiling point 41C). Mixed solvents can also be used. The water immiscible solvent is the predominant component of the mixture.

Once the desired coating polymer is dissolved in the organic solvent, the drug to be encapsulated is added to this solution. The drug agent may be a solid (crystalline or amorphous) or a nonvolatile liquid. The added drug may completely dissolve in the polymer solution or it may be completely insoluble and simply form a dispersion, suspension, or suspension-emulsion.

• Step II (Emulsification)

To obtain the microcapsule of appropriate size the core and coating material mixture is dispersed in the liquid manufacturing vehicle phase (water) with agitation.

The drug/polymer/solvent mixture (i.e., the oil phase) is emulsified in water to form an oil-in-water emulsion.

In order to aid emulsification, a surfactant (PVA) is normally dissolved in the water phase before the oil-in-water emulsion is formed.

• Step III (Evaporation)

Evaporation is carried out by heating.

• Step IV (Separation)

Once solvent evaporation appears to be complete, the capsules are separated from the suspending medium by filtration, washed, and dried.

If the core material is dispersed in the polymer solution the polymer shrinks around the core. And if core material is dissolved in the coating solution matrix type microcapsules are formed.

POLYMERIZATION:

Microencapsulation by polymerization involved reaction of monomeric units located at interface between a core material substance and continuous phase in which the core material is dispersed. In polymerization a liquid or gaseous phase is used as continuous or core material and as a result the polymerization reaction occurs at a liquid-liquid, solid-liquid, Liquid-gas, or

solid-gas interface.

Interfacial polymerization (IFP)

In this technique the capsule shell will be formed on the surface of the droplet or particle by polymerization of the reactive monomers. The substances used are multifunctional monomers.

Generally used monomers include

• Multifunctional isocyanates
• Multifunctional acid chlorides

These will be used either individually or in combination.

Process

The multifunctional monomer (acid chlorides immiscible with water) dissolved in liquid core material and it will be dispersed in aqueous phase containing dispersing agent. A co reactant multifunctional amine will be added to the mixture. The polymerization depends on the fact that acid halides are water insoluble and diamines have partition coefficient toward the water immiscible organic phase and diffuse towards it and it results in rapid polymerization at interface and generation of capsule shell takes place.

• A poly urea shell will be formed when isocyanate reacts with amine
• A polynylon or polyamide shell will be formed when acid chloride reacts with amine.

1.      In situ polymerization (ISP)

In this process no reactive agents are added to the core material, polymerization occurs exclusively in the continuous phase. Initially a low molecular weight pre polymer will be formed, as time goes on the pre polymer grows in size, it deposits on the surface of the dispersed core material there by generating a solid capsule shell.

PHYSICOCHEMICAL METHOD:

1- COESERVATION

“A coacervate is a tiny spherical droplet of assorted organic molecules (specifically, lipid molecules) which is held together by hydrophobic forces from a surrounding liquid.”

Their name derives from the Latin “coacervare”, meaning “to assemble together or cluster.”

PROCESS

The general outline of the processes consists of three steps carried under continuous agitation:

Step 1: Formation of three immiscible chemical phases

The immiscible chemical phases are

(i)                 A liquid manufacturing vehicle phase

(ii)               A core material phase

(iii)             A coating material phase

To form the three phases, the core material is dispersed in a solution of the coating polymer, the solvent for the polymer being the liquid manufacturing vehicle phase.

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 incompatible polymer to the polymer solution
• By inducing a polymer-polymer interaction

Step 2: Depositing the liquid polymer coating upon the core material

This is accomplished by controlled, physical mixing of the coating material (while liquid) 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, and this adsorption phenomenon is a prerequisite to effective coating. The continued deposition of the coating material is promoted by a reduction in the total free interfacial energy of the system, brought about by the decrease of the coating material surface area during coalescence of the liquid polymer droplets.

Step 3: Rigidizing the coating

This is usually done by

·         Thermal Technique

·         Cross linking Technique

·         Desolvation Technique, to form a self-sustaining microcapsule.

1-TEMPERATURE CHANGE METHOD:

Change in temperature causes separation of coating material from the solventUseful when the

solubility of the material depend on temperature

  E.g. Coating mat.: Ethyl cellulose in cyclohexane (EC is insoluble in Cyclohexane at room temp.)

        Core Material: N-Acetyl P-Amino Phenol

The EC is insoluble in cyclohexane at room temperature but is soluble at elevated temperatures. The mixture is heated to the boiling point to form a homogeneous polymer solution. The finely divided core material is dispersed in the solution with stirring. Allowing the mixture to cool with continued stirring, and microencapsulation of the core material occurs.

2- INCOMPATIBLE POLYMER ADDITION:

The polymer which is chemically not compatible will be added to the coating solution

The polymer which is to be added should have

§  More affinity towards solvents

§  No interaction with the core material.

E.g: Addition of liq. Polybutadiene (Incompatible polymer) to the EC solution in toluene (Coating sol.).

   Core material: Methylene blue HCl.

Dissolves EC in toluene              disperse methylene blue with stirring               slowly add liq polybutadiene               solidification by addition of hexane                  filtration and drying of microcapsules.

3- SALT ADDITION:

§  Soluble inorganic salts can be added to aqueous solutions of certain polymers

§  Should be soluble in water

§  Should precipitate the polymer from the solution.

Eg: Addition of 20% Sod. Sulfate to the gelatin solution.

Core Mat.: Oil soluble vitamin in corn oil.

4- NON-SOLVENT ADDITION

Phase separation can be induced by addition of non-solvent for given polymer.Have more affinity towards solvent which is usedPrecipitate the coating polymer

•      Eg:  Addition of Isopropyl ether to Cellulose acetate butyrate (CAB) dissolved in Methyl ethyl ketone.

•      Core Mat: Methyl Scopolamine HBr

ENCAPSULATION BY RAPID EXPANSION OF SUPERCRITICAL FLUIDS

Supercritical fluids are highly compressed gasses.

Properties

• Possess properties of both liquids and gases
• Miscible with common gases such as hydrogen (H₂) and nitrogen

Supercritical CO₂ is widely used for its following properties: -

Properties

• Nontoxic
• Nonflammable
• Readily available
• Highly pure 
• Cost-effective

Applications:

It has found applications in encapsulating active ingredients by polymers.

Core Materials Different core materials such as pesticides, pharmaceutical ingredients, vitamins, and dyes are encapsulated using this method.

Shell Materials A wide variety of shell materials that either dissolve (acrylates, polyethylene glycol) or do not dissolve (proteins, polysaccharides) in supercritical CO₂ are used for encapsulating core substances.

Methods:

The most widely used methods are as follows:

• Rapid expansion of supercritical solution (RESS)
• Gas anti-solvent (GAS)
• Particles from gas-saturated solution (PGSS)

I Rapid expansion of supercritical solution (RESS):

In this process, supercritical fluid containing the active ingredient and the shell material are maintained at high pressure and then released at atmospheric pressure through a small nozzle. The sudden drop in pressure causes desolvation of the shell material, which is then deposited around the active ingredient (core) and forms a coating layer.

Disadvantage

• The disadvantage of this process is that both the active ingredient and the shell material must be very soluble in supercritical fluids.
• The solubility of polymers can be enhanced by using co-solvents and non-solvents.

A schematic of the microencapsulation process using supercritical CO2

II GAS ANTI-SOLVENT (GAS) PROCESS:

This process is also called supercritical fluid anti-solvent (SAS). Here, supercritical fluid is added to a solution of shell material andthe active ingredients and maintained at high pressure. This leads to  super saturationsuch that precipitation of the solute occurs. Thus, the solute must be soluble in the liquid solvent, but should not dissolve in themixture of solvent and supercritical fluid.

 On the other hand, the liquid solvent must be miscible with the supercritical fluid.

Advantage

• It is alsopossible to produce submicron particles using this method.

Disadvantage

• Thisprocess is unsuitable for the encapsulation of water-soluble ingredients as water has low solubility in supercritical fluids.

IIIPARTICLES FROM A GAS-SATURATED SOLUTION (PGSS):

This process is carried out by mixing core and shell materials in supercritical fluid at high pressure. During this process supercritical fluid penetrates the shell material, causing swelling. When the mixture is heated above the glass transition temperature the polymer liquefies. Upon releasing the pressure, the shell material is allowed to deposit onto the active ingredient. In this process, the core and shell materials may not be soluble in the supercritical fluid.

LOADING OF DRUG IN MICROENCAPSULE

Mechanisms For Loading Drug:

Drug can be loaded by

Ø  physical entrapment

Ø  chemical linkage

Ø  surface adsorption 

The active components are loaded over the microsphere principally at two points

Ø  During the preparation of microsphere

Ø  After the formation of microsphere by incubating them with the drug or protein.

Maximum loading can be achieved by incorporating drug during the time of preparation.

Loading during preparation is avoided because during prep loading is effected by

1)      Method of preparation.

2)      Presence of additives e.g. crosslinking agent, surfactant stabilizer.

3)      Heat of polymerization.

4)      Agitation intensity.

KINETICS OF DRUG RELEASE:

In some cases, the release rateis zero-order, i.e. the release rate is constant. In this case, the microcapsules deliver a fixed amount of drug per minute or hour during the period of their effectiveness. This can occur as long as a solid reservoir or dissolving drug is maintained in the microcapsule.

A more typical release pattern is first-order in which the rate decreases exponentially with time until the drug source is exhausted. In this situation, a fixed amount of drug is in solution inside the microcapsule. The concentration difference between the inside and the outside of the capsule decreases continually as the drug diffuses.

APPLICATIONS OF MICROENCAPSULATION

Microencapsulation has many applications in pharmaceutical industry especially for the drugs with poor bioavailability. This method is usedin variousways to improve drugdelivery to targetsites:

1-    Sustained drugdelivery:

By encapsulating a drug in a polymer matrix, which limits accessof the biologicalfluid into the drug until the time of degradation, micro particles maintain the blood level of the drug within a therapeuticwindow for a prolonged period. Toxic side effects can be improved by reducing the frequency of administration. For example novel sustained release microspheres of Glipizide are quite beneficial for diabetic patient.

2-      Mixing of Incompatible Compounds:

Microencapsulation allows mixing of incompatible compounds like for easy addition of oily ingredients in formulations.

3-      Controlled drugdelivery:

Using this technique, CR dosage forms can be made through which the drug can be delivered at a predetermined rate, locally or systemically for a specified period of time. Depot formulation of shortacting peptide have been successfully developed usingmicro particle technology e.g.  Leuprorelin acetate and triptoreline, both areluteinizing   hormone releasinghormone agonists.

4- Improved Shelf Life and Protection Against Environmental Harms:Microencapsulation of drugs enhances their shelf life by preventing degradativereactions (dehydrationand oxidation).  Microencapsulation protects the drugs againstenvironmental effects of uv-rays, heat, oxidation, acids and bases.e.g.: microencapsulation of vitamin Apalmitate and vitamin K.

 

 

5-      Taste and OdourMasking:

Microencapsulation is used tomaskthe bittertasteof drugs like paracetamoland nitrofurantoin etc. It also decreases the odour and volatility of certain compounds like carbon tetrachloride.

6-      ImprovedProcessing:

Microencapsulation of ingredients results in better controlof hygroscopye.g.  of  NaCl,enhanced solubility, flowability and dispersibility, e.g. microencapsulation of non-flowing multicomponent solid  mixture  of  thiamine,  riboflavin, niacin  and  ironphosphate  foreasy tableting.

Oils can be encapsulated and tablets can be made thereof.

7-      Pulsatile drugdelivery:

Pulsatile release of antibiotics can alleviate evolution of the bacterial resistance.  In the vaccinedelivery, initial burst followed by delayed release pulsed can mimic an initial and boost injection respectively. Potential application of this drug delivery system isreplacement of therapeutic agents, gene therapy, and in use of vaccine for treating AIDS, tumors, cancer, and diabetes. The spheres are engineered to stick tightly to and even penetrate linings inthe GITbefore transferring their contents overtime into circulatorysystem

Based on this novel drug delivery technique, Quinidine gluconate CR tablets are used for treating and preventing abnormal heart rhythm. Glucotrol  (Glipizide SR)  is  an  ant  diabetic  drug  used  to  control high  blood  sugar levels.

8-      Targeted drug delivery :

·         Antitumor  microparticles  are  administered intraarterially   and target an organor

·         Body cavity i.e.,peritoneum.

·         Therapeutic drug delivery of anti cancer drugs.  e.g.  .doxorubicinand 5-fluorouracil. 

c. Markers for analysis/detection. E.g.  Detect tumours;  infected  cells; 

Intracellular  delivery:

a.  Gene  delivery e.g. delivery  of plasmid DNA

b.     Anti-sense therapy e.g. Closing production of certain proteins by delivery of anti-sense oligonucleotides   to bind  ribosomal mRNA

c.  Intracellular toxins   for cancer therapy

d.  Ribozyme delivery

e.  Drug delivery to  cell organelles  e.g.mitochondria

f.      Vaccine adjuvant i.e. biodegradable polylactic  acid  and  polylactic  acid  co-glycolic  acid microspheres also act as immune  adjuvant  by providing  a  depot  formulation of  the  antigen  at the  site of administration.   The antigenis thus continuouslyreleased to antigen presentingcells.

9-      Recombinant Gene Therapy:

Corrective gene sequence in the form of plasmids is microencapsulated to be incorporated in the body for the treatment of genetic disorders.

10-  Enzyme and Microbes Immobilization:

Enzymes have been encapsulated in cheese to accelerate ripening and flavor development. The encapsulated enzymes are protected from low pH and high ionic strength in cheese.

Encapsulation of microbes has been used to improve stability of starter culture.

11-  Protection against Environmental Effects:

Microencapsulation protects the drugs against environmental effects of UV rays, heat, oxidation, acids and bases. E.g: microencapsulation of vitamin A palmitate and vitamin K.

12-  Improved Processing, Texture and Less Wastage of Ingredients:

Ø  Control of hygroscopy (NaCl)

Ø  Enhanced flowability and dispersibility

Ø  Microencapsulation of non-flowing multicomponent solid mixture of thiamine, riboflavin, niacin and iron phosphate for easy tableting.

Ø  Enhanced solubility

13-  Microencapsulation of Inslin and Pancreatic Islets:

Ø  For better and prolonged therapeutic effects of insulin.

Ø  For the improvement of compromised pancreatic function.

 

Advantages of Microencapsulation:

1.     Taste and odor masking.  e.g.: Fish oils, sulfadrugs.

2.     Protection of drugs fromenvironment.

3.        Particle size reduction for enhancing solubility of the Sustained or controlled drug delivery e.g.:  KCl,Ibuprofen.

5.     Targeted release of encapsulated material.

6.     Live cellencapsulation.  e.g.: Resealederythrocytes.

7.     Conversion ofliquid   to free flowing solids.

8.     Delay of volatilization.

10. Separation of incompatible   components eg: Excipients, buffers and other drugs.

9.            Improvement of flow ofpowder.

10.     Safe handling oftoxic  substances.

11.     Aid in dispersion ofwater insoluble substancein aqueousmedia.

 

Disadvantages of Microencapsulation:

 

1. Possible cross reaction that may occur between the core and wall material selected.

2. Difficult to achieve continuous and uniform film.

3. Shelf life of hygroscopic drug is reduced.

4. More skills and knowledge required to use this advanced and complex technique.

5. Production costs.

 

Evaluation of Microparticles:

The parameters, methods andtechniquesused for theevaluation ofmicrocapsulesare given in the following passages.

Note that the terms microspheres and microcapsules are sometimes used interchangeably.

1       Microsphererecovery/yield:

These studies involve determination of the amount of microsphere obtainedat the endof preparationand the amount of polymer and drug consumed in its preparation. It can be calculated as follow: Percentage Yield = (Practical yield)/ (Theoretical yield) ×100

Practical yield of microspheres = Amount of encapsulated drug /Amount ofadded drug

2       Drug Entrapment Efficiency Determination of UntrappedDrug

The amount of drugpresent at the surfaceis measuredby digesting the microsphere withsaline (0.9%w/v) at room temperature, sonicating the solution in an ultrasonic bath for 5  min  and centrifuging it at 3000 rpm for 2 min. The supernatant is filtered through 0.45μm filter and the drug is quantified bya suitable analytical method.

It is calculated by:

Percentage loading of microsphere =Quantity of free drug present/ Weight of    microsphere

Entrapped drug  in microsphere:

The residue left over from the extraction of the free and adsorbed drug is mixedwith 5ml of 0.1mglacial acetic acid. The sample is centrifuged at 5000rpm for 10 minutes. The supernatant is filtered through 0.45μm filter andthe amountof drug entrappedis quantified bysuitable analyticalmethod.

Percentage of the encapsulated drug = Quantity of drug encapsulated (g) /Quantity of drug added for encapsulation

3-SurfaceMorphology:

It provides vital information about the porosity and microstructure of these drug delivery systems. The most common technique usedis scanning electronmicroscopy(SEM). The sample prepared for this method should be dehydrated as vacuum field is necessary for image generation in SEM. Prior to loading the samples  are  coated with  electron dense  coating  materials  such as gold,  palladium  or  a combination  of both  to take photomicrograph..

4.      Particle SizeAnalysis:

It is done study to whether the particle size of formulation lies in the optimal range. A wide variety of methods which employ different physical principles   for the determination of size include:

(A)  Manual

a)  OpticalMicroscopy

b)  ElectronMicroscopy

Transmission Electron Microscopy or Scanning Electron Microscopy can be used.

c)  Sieving

d)  Sedimentation  (Andreason Pipette Method)

(B)   Automated

a)  Particle counters e.g.  Optical particle  counting and Impaction  &inertial techniques

b)  Light  Scattering  techniques e.g   Dynamic  light  scattering or Enhanced laserdiffraction

c)  Flow cytometry

d)  Field  flow fractionation

5.      In-vitro ReleaseStudies:

These studies aid in understanding the behavior of these system in terms of drug release and their efficacy.

Since microsphere is heterogeneous system, the drug release form the polymer takes placethrough a diffusion process, in an in vitro environment. As a result, the drug and polymer matrix are phase separated and form a biphasic system. The release of the drug is determined by the extent of degradation of polymericmicrosphere.The in vitro release experiment can be performed using the dialysis method.  In  this  method,  a  weighed quantity of  the  microsphere  is  placed in  a  dialysis  bag, which  is  immersed in a larger volume of continuous phase acceptor fluid. The compartment is stirred and the drug which diffuses out of the microspheres into the continuous phaseis periodicallysampled andassayed.

Dissolution can also be done to check in vitro release profile of microcapsules. Standard USP or BP Dissolution apparatus is used.

6.      Differential Scanning Calorimetry (DSC) Analysis:

The DSC technique can provide qualitative and quantitative information about  the  physicochemical status of the drug in the microcapsule. This involves an endothermic or  exothermic  process  and the related  thermal  transitions  include   melting,  recrystallisation,  decomposition,  out  gassing  or  a  change in the heat capacity of the listed material. DSC is used to monitor different samples of the  same  materials  to assess  their  similarities/differences, or the effects of additives on the thermal properties of  thematerial.

7.      In-vivo Tissue  DistributionStudies:

Such studies are done to understand the functional characteristics of formulationin a biologicalsystem. To examine the appropriate properties of the formulation in vivo, adult albino mice, rats or rabbits, etc. of certain specified weight are used.

A calculated dose of the drug is administered to each animal as dispersion in saline with 1% of tween 80 at predetermined time.  Tail vein is usedas route of administration and animals are sacrificed by cervical dislocation.  The organs like lungs,liver, kidneys, heart and spleen are extracted and studied for target action. The tissue samples are stored for 24hat specified temperatures. Then the concentration of drug localized in each organ is determined quantitatively   using the HPLCmethod.

In vivo tissue distribution  studies  in  animal models  are  carried out  to prove  the hypothesis  of targeting of microsphere/formulation to the organs and compare them  with  conventional  dosage  forms  of the drug.

Along with these methods, polymersolubility in the solvents, viscosity of polymersolutions anddensity of microcapsules are also checked. To determine the nature of microcapsules as hydrophilic or hydrophobic,   wettability byangle ofcontact is measured.

  Examples of Microencapsulated Drugs:

Following are some examples of microencapsulated drugs.

Active moiety	Characteristic Property	Purpose                             of Encapsulation	Final product Form
Aspirin	Slightly   soluble  in  water	Taste      masking,     sustained release,      reduced      gastric irritation	Tablet   or capsule
Paracetamol	Slightly   soluble  in  water	Taste masking	Tablet
Islet of Langerhans	Viable  cells	Sustained    normalization   of diabetic condition	Injection
Progesterone	Slightly   soluble  in  water	Sustained  release	Varied
Menthol	Volatile  solution	Reduction       in           volatility, Sustained release	Lotion
Potassium chloride	Highly  soluble   in water	Reduction  in  gastric irritation	Capsule
Nifedipine	Practically insoluble   in Water	Prevention      from      photo- Instability	Dry powder