Microparticulate Drug Delivery Systems Biology Essay

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Microencapsulation techniques is the process by which individual particles or droplets of liquid material are coated with a film of polymer material results in the formation of thin particles called spheres or capsules which are in the range of micrometer to millimeter .This is known as microspheres or microcapsules.

Bungsenberg de Jong and Kaes lead to the development of pharmaceuticals was published in the year 1931. Gelatin coacervation technique was employed for the preparation of gelatin spheres.

A well designed controlled drug delivery systems can overcome the problems of conventional theraphy and enhance the therapeutic efficacy of a given drug . For obtaining maximum therapeutic efficacy , it is necessary to deliver the agent to the target tissue , there by causing little toxicity and minimize side effects. In a sustained and controlled release fashion there are so many targeting approaches used for delivering a therapeutic substance to the target site. One of the major approach is using Microspheres as a carrier system for drugs.

Microencapsules can often be described by other terms such as coated granules ,pellets or seeds, microspherules ,and spansules. The most common type of microencapsule is mononuclear spherical structure.

The microencapsulate drug delivery systems which includes mainly pellets, microcapsules, microspheres, lipospheres, emulsions and multiple emulsions.

Microspheres are defined as solid, free flowing powders approximately spherical particles ranging in size from 1 to 1000µm. They are made up of polymeric ,waxy materials or other protective materials such as synthetic polymers (eg :-PLGA ,PLA) . Modified natural polymers include albumin,gelatin, chitosan, casein. The non -biodegradable polymers such as ethylcellulose, hydroxypropylmethylcellulose, celluloseacetate and polyvinylpyrollidone .

The term microcapsule should be used for reservoir type devices whereas microspheres are monolithic or matrix type microparticles. The particles can be embedded within a polymeric matrix in either a solid aggregate state or a molecular dispersion to form microspheres. The particles can be coated by a solidified polymeric envelope to form microcapsules.



Uniform distribution of particles or

A molecular dispersion.


Liquid contents , non permeable ,rigid membrane.

Aqueous contents ,semipermeable membrane

Solid core ,protective or release -controlling coating.


The microencapsulation reasons are enormous . In some cases , the core must be isolated from its surroundings. eg;- isolating vitamins from deteriorating effects of oxygen . In other cases, the main objective was not to isolate the core completely but to control the rate at which it leaves the microcapsule as in the controlled release rate fashion.

The process of microencapsulation enables us to achieve

Taste -masking

Selective sorption

Sustained release

Reduced gastric irritation

Conversion of liquid to solid form for stabilization

Reduction of volatility

Control of hygroscopy

Enhance flowability and dispersibility

Dust free powder

Enhance solubility

Stabilization to oxidation

Table No. 1: Product applications can be consolidated as






Shelf stability

Masking of active ingredients

Odor, color and taste masking

Unique release mechanism

Controlled, sustained, delayed, targeted release

Enteric,thermal ,pressure, osmotic ,ph induced ,

pulsatile release

Biodegradable or salt -induced release

Fundamental considerations

The microencapsulation technique involves a basic understanding of the general properties of the microspheres such as

Nature of the core

Coating materials

Stability and release characteristics of the coated materials and

Microencapsulation methods.


The core material which can be liquid or solid in nature . The liquid core material consists of dispersed or dissolved materials. The solid core can be a mixture of active constitutents ,stabilizers, diluents ,excipients and release rate retardents or accelerators. The core material composition varies and provides definite flexibility which enables design and development of desired microsphere properties.


Selection of the coating material applies to a major degree in the resultant physical and chemical properties of the microspheres. The coating material should be capable of forming a film which is cohesive , chemically compatible and non reactive with the core material to provide the desired coating properties such as



Brittleness, tender , thin


Optical properties and


Inert towards active ingredients

Proper selection of microcapsule coating material includes



Moisture sorption




The effective coating thickness varies from tenth of a micron to a few hundred microns depending on the coating to core ratio and the particle size of the core material.

Examples of shell materials






Natural synthetic polymers






The microcapsules consists of a single or cluster of particles . After isolation from the liquid manufacturing vehicle and drying the materials appears as a free flowing powders. The powders is suitable for formulation as compressed into tablets , hard gelatin capsules ,suspensions and other dosage forms.


Microencapsulation methods that have been or are being adapted to pharmaceutical use include,

1. Coacervation-phase separation

This technique of microencapsulation can be induced by

Temperature changes

Incompatible polymer addition

Non -solvent addition

Polymer - polymer addition

2. Air suspension

3. Spray drying and spray congealing

4.Pan coating

5. Solvent evaporation


7. Physical methods

Multi -orifice centrifugal process

Electrostatic encapsulation

South west Research Institute (SwRI) having more than 50 years of experience in microencapsulation and controlled release

has classified the methods of microencapsulation

Spray drying

Spray chilling

Rotary disk atomization

Stationary nozzle coextrusion

Fluidbed coating

Centrifugal head coextrusion

Submerged nozzle coextrusion

Pan coating

Phase separation

Solvent evaporation

Solvent extraction

Interfacial polymerization

Simple and complex coacervation

In-situ polymerization

Liposome technology


Air suspension

The air suspension technique consists of solid particulate of core materials dispersed in a supporting air stream .The spray solution (polymer) should be coated on the air suspended particles. Inside the coating chamber , suspended particles moves on an upward direction. The chamber design and its operating parameters bring about a recirculating flow of the particles through the coating zone portion of the chamber .During each time particles passes through the coating zone , the core materials receives an increase in the amount of coating materials .The cyclic process is repeated , for several times .The process depend on the purpose of microencapsulation , desired coating thickness, core particles are throughly encapsulated. The supporting air stream also serves to dry the product during encapsulation process.

Coacervation Phase Seperation

It consits of three steps

First step

Formation of three immiscible phases

Liquid manufacturing phase

Core material phase

Coating material phase

Second step

Deposition of the liquid polymer coating on the core material

Third step

Rigidization the coating usually by thermal ,cross linking or desolvation techniques to form a microcapsule.

In step two , the liquid polymer coating is deposited at the interface between the core material and the liquid manufacturing vehicle phase. While coating the polymer solution , physical or chemical changes will occur this will results in the phase separation of the polymer . The polymer solution in a droplet form will unite to yield a two phase system i.e liquid - liquid The coating material which is an immiscible polymer of insoluble liquid polymer may be added directly .The monomers were dissolved in the liquid vehicle phase and polymerized at interface. Simple method is required for doing the microencapsualtion techniques. In this method the equipment consist of mainly jacketed tanks with variable speed agitators.

Fig No .4: Schematic representation of coacervation process

Multi orifice Centrifugal process

The South West Research Institute (SWRI) has developed a mechanical methods for producing microspheres .In this method the centrifugal forces is used to throw a core material particle through an enveloping microencapsulation membrane thereby effective microencapsulation can be done.

Processing variables includes

rotational speed of the cylinder

flow rate of the core and

coating materials



surface tension of the core material

This process is capable for microencapsulating liquids and solids of various size ranges , with different types of coating materials .Finally the encapsulated product can be used as slurry in the hardening media or as in the form of dry powder.

Pan coating

The large particles can be microencapsulated by pan methods and it has become widely spread in the pharmaceutical Industry . Solid particles greater than 600µ in size are generally considered essential for effective coating and therefore process have been extensively employed for the preparation of controlled release beads.

Medicaments of various spherical substrates such as nanopareil sugar seeds coated with protective layers of various polymers. In this , the coating is applied as solution form or an atomized spray form to the desired solid core material in the coating pan. Usually , warm air is passed over the coated materials as the coatings are being applied in coating pans for removing the solvent from the material.In some cases , final solvent removal is accomplished in drying oven.

Spray drying and spray congealing

Spray drying and spray congealing process are similar in that both involve dispersing the core material in a liquefied coating substance and spraying (or) introducing the core mixture into some environmental conditions , where by relatively rapid solidifiacation of the coating effected .

Principal difference between two methods means by which coating solidification is accomplished .

Spray drying

The spray drying process is accomplished by rapid evaporation of solvent in which the coating material is dissolved.

Fig No. 5: Microencapsulation technique by spray drying

Spray Congealing

The spray congealing process is accomplished by thermally congealing a molten coating material or solidifying a dissolved coating by introducing the coating core material mixture into a non solvent . Removal of the non solvent or solvent from the coated product is then by sorption extraction or evaporation techniques.

Solvent evaporation

This technique was carried out in a liquid manufacturing vehicle phase ( o/w emulsion) by simple agitation of two immiscible liquids. The process involves dissolving polymer in a volatile solvent which is immiscible with the liquid manufacturing vehicle phase. Adrug also dissolved or dispersed in the coating polymer solution. By the process of agitation , the core coating material mixture should dispersed in the liquid manufacturing vehicle phase to obtain microspheres.

Continuation of agitation takes place until the solvent partitions into the aqueous phase is removed by evaporation .Finally the process results in hardening the microspheres which contain the active moiety of the drug Several methods can be used to achieve dispersion of the oil phase in the continuous phase. The most common method is the use of propeller style blade attached to a variable speed motor.

Various process variables includes methods of forming substances

Evaporation rate of the solvent for the coating polymer

Temperature cycles

Agitation rates

Important factors to be considered when preparing microspheres by this method includes

choice of vehicle phase

solvent for the polymer coating as the choice greatly influence microcapsule properties

choice of solvent recovery techniques.

This techniques is applicable to a wide variety of liquid and solid core materials for producing microcapsules by using various polymers.


This methods involves the reaction of monomeric units at the interface existing between a core material substance and in a continuous phase the core material is dispersed. The core material is used as supporting phase consists of liquid or gas . The polymerization reaction occurs at liquid -liquid , liquid -gas ,solid -liquid or solid -gas interface.

Applications of microencapsulation

Technology have been used widely in the design of controlled release and sustained release dosage forms.

The bitter taste of drugs like paracetamol, nitrofurantoin can be minimized by using this technique.

To reduce gastric and other GI tract irritations the drugs have been microencapsulated

eg . Sustained release aspirin preparations have been reported to cause significantly less a GI bleeding than conventional preparations.

For easy handling and storage purpose , liquid can be converted to pseudo solid.

eg:- Eprazinone.

Hygroscopic properties of materials can be reduced by microencapsulation eg:- Nacl.

To reduce their odor and volatility the substances can be microencapsulated . eg:-CCl4

To provide protection to the core material against atmospheric effects microencapsulation technique has been employed eg:- Vit A.

Seperation of incompatible substances has been achieved by encapsulation .

Table No .2: Examples of some microencapsulated drugs

Drug/core material

Charcteristic property

Purpose of encapsualtion

Final pdt form


Slightly water soluble solid

Taste masking


Islet of Langherhans

Viable cells

Sustained normalization of diabetic condition



Slightly water soluble solid

Taste masking ,SR , reduced gastric irrtiation

Tablet or capsule

Isosorbide di nitrate

Water soluble solid




Volatile solution

Reduciton of volatility , SR



Slightly water soluble solid




Highly water soluble solid

Reduced gastric irritation



Water soluble enzyme

Permaeability of enzyme, substrate and rxn pdts.


Table No .3 : Microencapsulation process with their relative particle size ranges

Physico- mechanical process

Physico chemical process

Spray drying (5-5000µm)

Coacervation (2-1200µm)

Pan coating (600-5000µm)

Solvent evaporation (0.5-1000µm)

Fluid bed technology(20-1500µm)

Polymer -polymer incompatibility(0.5-1000µm


In these systems, the release rate is determined by its diffusion through the polymer matrix.. There are two types of diffusion devices.

Reservoir devices - in which a core of drug is surrounded by a polymeric membrane.

Matrix devices - in which drug distribution should be uniformly in an inert polymeric matrix.

Microspheres represent matrix type drug delivery systems whereas micropellets represent reservoir type systems.

By theoretically , the Ficks's law of diffusion were used to controlled release rate of drugs from both capsule and matrix type system which defines the flux of diffusion Jd across a plane surface of unit area.


Jd = - Ddc/dx

Where ,

D = diffusion of drug molecule in a medium of solid

dc/dx = concentration gradient of the drug molecules across a diffusion path of thickness dx

The negative sign indicates the flux of the drug in the decreasing concentration. In the matrix type of drug delivery systems , the concentration gradient is dependent on time and decreases progressively in response to the growing thickness of diffusional path, dx as times goes on. In these systems , the drug molecules can elute out of matrix through dissolution and then by diffusion through the polymer structure. The dry solid which is close to the surface of the device are first elute and then followed by that in the next layer. This is as shown in the figure 6.


Fig No.6: Schematic illustration of Controlled release of Drug molecules from matrix type drug delivery system


A = intial amount of drug solid impregnated in a unit volume of polymer matrix.

Cp = Solubility of drug in polymer phase

Cb = Concentration of the drug at the polymer -solution interface

C = Concentration of the solution in bulk of the elution solution

∂p = Thickness of drug depletion zone in matrix

∂d = Thickness of hydrodynamic diffusion layer device on the immediate surface

∂(∂p) = Differential thickness of depletion zone formed after more drug solid elutes out

The drug which is solid in nature dissolves first from the surface layer , when this layer becomes exhausted of the drug .The next layer starts to be depleted by dissolution and diffuses through the matrix to the external solution. In this fashion, the interface between the region containing the dissolved drug and that containing the dispersed drug moves into the interior as a front.

Higuchi equation

This equation can be used to express the release rate of the drug .

Q = DE/ T(2A-ECS)Cst x1/2

Q = Drug released in g/unit surface area

D = Diffusion coefficient of the drug

E = Porosity of the polymer matrix

T = Tortousity of the polymer matrix

Cs = Solubility of the drug (g/ml)

A = Concentration of the drug in the dosage form

Keeping all the parameters constant , Higuchi equation can be reduced to

M = kt â…“

Where , k is a constant.

The assumptions made in deriving the mathematical model are

During the release process a pseudo steady state is maintained .

The total volume of the drug present in the matrix is substantially greater than the saturation solubility of the drug in matrix ie , excess solute is present

Drug particles should be smaller in diameter then the average distance of diffusion.

The diffusion coefficient should be remains constant.

There is no interaction occurs between the drug and the matrix.


Drug release from degradable microspheres should based on the microstructure of particles and mechanism of erosion. The drug release is influenced by

Structure of microparticles

Properties of the biodegradable polymer itself.

The drug delivery through microparticles should exhibit a matrix type of internal solid dispersion of morphology structure. The drug may be insoluble in the solid matrix , and the drugs are released by two mechanism that involves both pore diffusion and polymer erosion. First water diffuses into the matrix dissolving the drug particles adjacent to the surface. The resulting osmotic pressure is take over charge by forming a tarteous channel to the surface and releasing a defined amount of drug in the initial drug burst .


Fig No. 7: Mechanism of drug release from microparticles

The burst effect is controlled by three factors

Drug polymer ratio

Particle size of dispersed drug

Particle size of the microspheres

The water should be penetrated in front continues diffusion takes place into the microparticulate core, the dispersed drug particles are dissolved by creating a network of water filled pores through which the drug diffused in a controlled manner and hence the pore diffusion mechanism takes place.

For example from gel beads , leakage of drug can occur is influenced by polymer concentration and mechanical treatment of beads. In physical shaking it produces more leakage when compared to packed beads in column.


In the open lattice structure , by allowing small leakage of proteins it provide high porosity for large substrates and efficient exchange of substrates and products. The crosslinking polymer such as chitosan ,polyacrylic acid, polyvinylalchol, protein and polyethylamine which are used to produce more stable, lower porosity complexes with improved leakage characteristics.

Delivery system for microspheres

For commercial use , microspheres should be placed in pharmaceutically acceptable oral delivery systems.

1.12. Microspheres - Parental Administrations

Microspheres have been used for intra venous and intra arterial targeting and drug delivery system.

Microspheres is injected into the veins to ensure passive targeting of drugs. The drug released is controlled by diffusion through the polymer matrix and by the erosion of polymer . The microspheres depends on their size and site of injection in playing the role

In order to target the RES microparticles of diameter smaller than 2µm can be injected in an intra -venous ,intrarterial and intra peritoneal manner. Intra venous injection of microspheres size from 3 to 12µm is intended to block the capillary of the lungs , liver and spleen .

Vessels can be hyper selectively embolized with drug loaded particulate materials of more than 10µm. These are used as particulate agents for the embolization of tumors and a steroids venous malformations. In these delivery systems, microspheres have two fold action as embolic agents and drug carriers.Microsphers of 100to 300µm size are the most appropriate embolic agents.They reach the intra lesional precapillary arteries and cause reduction

of blood flow.


Microspheres intended for parentral administration should be

Sterile &

Pyrogen free.

Most of the polymers degrade upon sterilization which can be inferred through a decrease in molecular weight , changes in viscosity and mechanical properties.Thus for the preparation of microspheres, aseptic processing is the most acceptable method .The polymer solution in methylene chloride can be easily filtered through 0.22µm filters and the final compounding of the product may be carried out in a sterile environment . It is important to establish sterility of the microspheres , not only on the surface , but also internally by dissolving microspheres in mild non- toxic solvents as DMSO or DMA and further subjecting to sterility testing .
















Aliphatic polyesters

Poly(malic acid)

Poly(glycolic acid)

Poly(hydroxyl butyrate)

Poly(lactic acid)

Cross linked proteins and Hydrogels

Poly Vinyl Alchol(PVA)

Cross linked Poly Vinyl Pyrollidone (PVP)


Hydroxy Propyl Methyl Cellulose(HPMC)

Ethyl cellulose


Cellulose acetate

Polyethyl Vinyl Acetate(PVA)

Poly Ether Urethane(PEU)

Poly Vinyl Chloride (PVC).




Aceclofenac is a Non Steroid Anti Inflammatory Drug (NSAID ) which is a phenyl acetic acid derivative . It shows effective anti inflammatory effect and analgesic properties . It is mainly used in Rheumatoid arthritis, Osteo arthritis and ankylosing agents.

After oral administration it is rapidly and effectively absorbed with 100% bioavailability.But its biological half- life is only 3-4 hours . Therefore it requires multiple dosing of drug for maintaining therapeutic effect throughout the day .The normal dose of aceclofenac is 100mg b.i.d. The frequent adverse side effects occurring with aceclofenac are GI disturbances , GI bleeding and peptic ulceration . To minimize the gastric erosion side effect , it is essential to provide an enteric coated dosage form . The short half -life and multiple administration makes aceclofenac a good candidate for the formulation of delayed release microspheres. The main aim of the study was to formulate the delayed release of microspheres of aceclofenac .In our studies we have adopted emulsion solvent evaporation technique to formulate the delayed release dosage forms.

The preparation and invitro evaluation of aceclofenac microspheres using Seven different polymers where carried out in the following stages.

Standard graph of aceclofenac

Preformulation studies

Preparation of microspheres by emulsion slovent evaporation technique

Compatibility studies

Micrometric properties

Morphology of microsphere (SEM)

Drug entrapment efficiency or incorporation efficiency

Percentage yield

Invitro drug release




Parul Trivedi .et al17 ( 2008) in their "Preparation and characterization of Aceclofenac microspheres'' reported that microspheres by solvent evaporation technique using eudragit (S100 , RL100 and RS100) to provide controlled release and local side effects by can be minimized by avoiding the drug release in the upper GIT. The microspheres were prepared and subjected to micrometric evaluation, drug loading studies, and invitro drug release studies. The drug -polymer concentration in the dispersed phase will influence the particle size and drug release particulate of all the formulation are at higher pH values follows matrix Higuchi Model.

Tamizharasi S.etal23 ; (2007) in their work "Formulation , characterization and invitro release kinetics of aceclofenac loaded poly(€caprolactone ) microspheres" reported that drug to carrier ratio(1:4) showed high drug entrapment efficiency and drug released upto 15 hr were found to be sustained. There was no interaction between the drug and polymer.

Gohel MC. etal 33; (2005) in their work " Preparation and formulations of optimization of sugar cross linked gelation microspheres of Diclofenac sodium reported that sugar/ e.g glucose ,fructose can be used as cross linking agent of gelation for the preparation of modified release microspheres . The microspheres which are prepared by emulsion cross linking method revealed that ,the parameters such as drug to carrier ratio, volume of light paraffin and stirring rate were found to affect the morphology and drug release of microspheres.

Choudhary K.P.R. etal (59) 2000. The ethyl vinyl acetate of nifedipine microcapsules were prepared by emulsion solvent evaporation method using chloroform as solvent. The prepared microcapsules were subjected to SEM shows spherical discrete and free flowing . Drug content was uniform and microencapsulation efficieny was in the range of 79-99%. The release from the microcapsule was slow and extended release over more than 12 hours.

Latha S.etal .(47) ,2004 .The magnetic microspheres of ranitidine hydrochloride were prepared by emulsion solvent evaporation and reported its invitro characterization.

Mohammadi R.etal (48),2003. The microscopic method was used for the determination of contact angle of microspheres and it was reported .

Al-Helw .A.A. etal (68) . The cross linked chitosan microspheres had sustained release effect was reported.

A.P. Kakkar etal reported that Ibuprofen microspheres were prepared and evaluated. The prepared microspheres were subjected to SEM having good spherical geometry and smooth surface. Ibuprofen was selected as model drug for anti inflammatory because of shorter half life . Invitro release studies suggested that drug release from microspheres is above 60% after eight hours.

D.Perumal etal studied on The Microencapsualtion of Ibuprofen microspheres and Eudragit RS100 by the emulsion solvent evaporation method in 2001.

Nagoji K.E.V.etal (89) 2000. Compare the release profiles of Nifidipine form ethylcellulose matrices and microcapsules and reported that the drug release will be sustained .

Nath B.S etal (94) ,1995 . The Nitrofurantoin microspheres were prepared by extrusion congealing technique and the release kinetics of the drug from the microspheres was studied.

Gowthamarajan K.etal (35) 2003. The Microspheres of Eudragit L100 and S100 containing Insulin Protease Inhibitor and Bile salts by using solvent diffusion technique . The drug, polymers and adjuvants showed no interaction subjected to FTIR spectroscopy .Invitro release studies of the microspheres showed a prolonged hypoglycemic effect for three hours when compared with the i.v injection of bovine insulin.

Dandagi P.M.etal (43) 2004. The study has been carried out on the design and evaluation of micropellets of verampil hydrochloride by ionotorpic gelation technique using sodium alginate , HPMC and HPC of the nine formulations prepared. Only three formulations showed good results for flow behaviour ,drug entrapment efficiency , invitro dissolution, and stability studies . It was concluded that the prolonged release micropellets of verampil hydrochloride could be achieved with success by employing ionotropic gelation.

Dharmadhikari N.B.etal (95) 1994. The microparticulate drug delivery system for salbutamol sulphate were prepared by melt dispersion technique and its invitro characterization were reported.

Sandra kokisch etal (50) 2003. The polymeric microspheres were prepared for drug delivery to the oral cavity and invitro mucoadhesive potential were studied .

Hassan etal (78) 1992. A site specific delivery of anti cancer agents such as oxantrazole and 5-fluoro uracil were developed.

Jameela S.R. etal (64) 1995. Reported that glutraldehyde cross linked chitosan microspheres acts as a biodegradable drug delivery vehicle using mitoxantrone as the model drug.

Muzzarelli R.etal (71) 1999. The ampicillin loaded chitosan microspheres were prepared and showed a controlled release of the drug .

Jameela S.R .etal (66) 1998. The progesterone loaded chitosan microspheres were prepared and act as a long acting biodegradable controlled drug delivery system.