INTRODUCTION:

A well-designed controlled drug delivery system can improve a particular medicine's therapeutic efficacy while resolving some of the issues with conventional therapy. The agent must be delivered to the target tissue in the ideal quantity and at the proper time in order to achieve optimum therapeutic efficiency while causing the least amount of toxicity and side effects possible. In order to deliver a medicinal chemical to the target region with a continuous regulated release, there are several different methods. Using microspheres as medication carriers is one such strategy.

Microspheres are naturally biodegradable powders made of proteins or synthetic polymers that flow freely and preferably have a particle size of less than 200m. The technique of microencapsulation involves very small droplets When a continuous polymeric film is applied on, or surrounds, liquid or solid substance particles. Solids, liquids, or even gases can be encased in minute particles to create thin walls of wall material around them through the process of microencapsulation. In general, a particle with a diameter of 1-1000m is considered a "microparticle," regardless of its exact internal or outer structure. Under the broad category of "microparticles," "microspheres" specifically refers to spherical microparticles, while the subcategory of "micro-capsules" refers to microparticles with a core encased in a substance that is noticeably different from the core. Gas, liquid, or even a solid could make up the core.

Classification:

Based on their morphology, microcapsules can be divided into three fundamental groups.

Fig. 1: Classification of Microcapsules

A. Mononuclear: In mononuclear (core-shell) microcapsules, the core is enclosed by a shell.

B. Polynuclear: Poly nuclear capsules include several cores that are encased in a shell.

C. Matrixtypes: With matrix encapsulation, the core substance is uniformly dispersed throughout the shell substance.

A microcapsule is atiny sphere with a nearly homogenous interior in its most basic form. wall enclosing some material. The enclosed material in the microcapsule is referred to as the core, While the wall is occasionally referred to as a shell, covering, ormembrane, the internal phase or fill is. Alginate is a polymer that can be combined with lipids and other substances to capture an object of interest². The pores in the majorityof microcapsules range in size from a few nanometers to a few micrometres. Typical materials for coating include:

Ethyl cellulose

Polyvinyl alcohol

Gelatin

Microcapsule structures:

Little spheres with dimensions between a few micrometres and a few millimetres make up the majority of microcapsules. But many of these microcapsules only have minor contents. similarity to these straightforward spheres.³ In actuality, the ingredients and procedures utilised to manufacture the micro particles affect their size and shape. A variety of wall materials, such as monomers and/or polymers, are used to create the various types of microcapsules and microspheres. Several types of particles can be produced depending on the physico-chemical characteristics of the core, the wall composition, and the microencapsulation technology employed straightforward sphere covered in a uniform-thickness covering; a particle with a centre of erratic form; Numerous implanted core particles.

Encapsulation's justifications:

There are many justifications for microencapsulation. Its primary uses include extending the stability and longevity of the substance being encapsulated, making product manipulation easier, and enabling the controlled release of the contents. It may be necessary to isolate the core from its surroundings in some circumstances, such as protecting vitamins from oxygen's deteriorating effects, delaying the evaporation of a volatile core, enhancing the handling characteristics of a sticky substance, or protecting a reactive core from chemical attack. In other situations, such the controlled-release of drugs or pesticides, the goal is to regulate how quickly the core releases its contents rather than entirely isolating it. The solution might be as straightforward as disguising the taste or odour. of the core, or as sophisticated as enhancing the selectivity of an adsorption or extraction process. A pesticide may be microencapsulated in environmental science to reduce the danger of leaching or volatilization. Self-healing polymer coatings can be designed using microencapsulated self-healing agents as well.

Methodology:

Materials:

The core material, which is the particular substance that will be coated, can either be a liquid or a solid. Due to the liquid core's ability to include dispersed and/or dissolved components, the composition of the core material might vary.⁴

Coating Materials:

The coating material must be able to create a cohesive layer with the core material, be chemically inert and nonreactive with the core material, and offer the appropriate coating attributes, such as strength, flexibility, impermeability, optical properties, and stability. There is some potential for in situ alteration of the coating materials employed in microencapsulation techniques.

Examples:

1. Water-soluble resin: Arabinogalactan, Carboxymethylcellulose, Hydroxyethylcellulose, Starch, Polyvinylpyrrolidone, Gelatine, Gum Arabic, Polyvinyl Alcohol, and Polyacrylic Acid.

2. Resins that are not soluble in water, such as cellulose nitrate, polyethylene, polymethacrylate, polyamide (Nylon), poly (ethylene-vinyl acetate), silicones, and poly (lactideco- glycolide).

3. Lipids and waxes, including paraffin, carnauba, spermaceti, beeswax, stearic acid, and stearyl alcohol.

4. Enteric resins, including Zein, Cellulose Acetate Phthalate, and Shellac.

Characteristics of the Coating Material:

1. Make the core material more stable.

2. Controlled release under predetermined circumstances.

3. Tasteless, flexible, film-forming, and stable.

4. Economical, non-hygroscopic, and low viscosity.

5. Melting or soluble in an aqueous medium or solvent.

6. The coating might be thin, hard, brittle, flexible, etc.

Manufacturing Methods for Microencapsulations:

The methods include:

· Physical and Chemical Spray drying

· Spray chilling

· Fluid bed coating

· Multi-orifice centrifugal

· Centrifugal extrusion:Pan coating

· Air suspension coating process

1. Pan coating:

The oldest and most popular industrial processes for creating small, coated particles or tablets are pan coating. Solid particles larger than 600 microns in size are typically considered essential for effective coating, and the process is extensively used for the preparation of controlled-release beads. ⁵. The particles are tumbled in a pan or other device while the coating material is slowly applied with respect to microencapsulation.

In actuality, the coating is applied to the chosen solid core material in the coating pans as a solution or as an atomized spray. Warm air is typically passed over the coated components as the coatings are being applied in the coating pans depicted in order to eliminate the coating solvent. Typically, medications are coated onto a variety of spherical substrates, such nonpareil sugar seeds, and then covered with layers of protective polymers.

Fig.2: Pan coating

2. Air suspension coating:

Coating that is air-suspended Compared to pan coating, air suspension coating offers better control and flexibility. It was first introduced by Professor Dale Erwin Wurster at the University of Wisconsin in 1959. The solid particulate core material is distributed into the supporting air stream during this process, and the suspended polymer-coated particles are then coated with a very thin coating of polymer after being coated with a volatile solvent.[6] The air suspension procedure is performed several hundred times until the necessary characteristics, such as coating. It succeeds in achieving thickness, etc. The air stream that supports the particles also aids in drying them, and the rate of drying is closely correlated with the air stream's temperature, which can be changed to further influence the coating's qualities.

Fig.3: Air suspension coating process

3. Centrifugal extrusion:

Using a revolving extrusion head with concentric nozzles, liquids are contained. In this procedure, a sheath of wall solution or melt surrounds a jet of core liquid. Due to Rayleigh instability, the jet breaks up into core droplets that are each coated with the wall solution as it travels through the air.The molten wall may solidify or a solvent may evaporate from the wall solution while the droplets are in flight [7].The majority of the droplets land in a small ring around the spray nozzle since their average diameter is less than 10%. As a result, the capsules can, if necessary, be hardened after formation by being caught in a ring-shaped hardening bath. This method works well to create particles with a diameter of 400–2,000 m (16–79 mils). The method only works with liquids or slurries since the droplets are created when a liquid jet breaks up. Up to 22.5 kg (50 lb) of microcapsules may be generated per nozzle every hour, which is a high production rate. There are 16-nozzle heads available.

Fig.4: Centrifugal extrusion

4. Spray-drying:

When an active substance is dissolved or suspended in a melt or polymer solution and becomes trapped in the dried particle, spray drying is used as a microencapsulation process. The key benefits include the operation's affordability as well as the capacity to handle labile materials due to the dryer's brief contact time. The viscosity of the solutions to be sprayed in contemporary spray dryers can reach 300mPa. In order to impact the relatively quick solidification (and creation) of the coating, spray drying andspray congealing techniques both entail dispersion the core material in a liquefied coating substance and spraying or introducing the core-coating mixture into some ambient condition. The process used to achieve coating solidification is the main distinction between the two approaches. The quick evaporation of a solvent in which the coating material is dissolved causes the coating to solidify in the case of spray drying. However, in spray congealing procedures, coating solidification is achieved either by thermally congealing a molten coating material or by solidifying a dissolved coating by dissolving the coating-core material mixture in a non-solvent. The non-solvent or solvent is subsequently removed from the coated product using a sorption, extraction, or evaporation procedure.

When the protective coating is sprayed as a melt, spray drying equipment can achieve microencapsulation via spray congealing. The core material is dispersed in a coating material melt rather than a coating solution, but the general process variables and circumstances are relatively similar to those already discussed. Spraying the hot mixture into a cool air stream causes the coating to solidify (and microencapsulate).

Fig.5: Spray drying process

5. Fluidized-bed technology, or FBT Fluid bed coating:

Another mechanical encapsulation approach, is restricted to encapsulation of solid coresubstances, such as liquids absorbed into porous solids. Pharmaceuticals are frequently encapsulated using this method. A jet of air is used to suspend the solid particles that will be encapsulated, and a liquid coating material is then sprayed on top. The capsules are then brought to a location where the solvent is vaporised or cooled to solidify the capsules' outer shells. Iteratively suspending, spraying, and cooling are used to create capsules until the necessary thickness is reached for the walls. If the spray nozzle is at the bottom of the fluidized particle bed, the procedure is referred to as the Wurster process. The Wurster technique and fluidized bed coating are also variants of pan coating.

The liquid coating is sprayed onto the particles, and as it quickly evaporates, it helps the particles create an outer layer. You can get the coating in any desired thickness and formulation. [7]. Top spray, bottom spray, and tangential spray are three different varieties of fluid-bed coaters. The Multi-orifice Centrifugal Process, or 7. By using centrifugal forces to propel a core material particle through an encasing microencapsulation membrane, the Southwest Research Institute (SWRI) has created a mechanical approach for creating microcapsules. The cylinder's rotational speed, the rate at which the core and coating materials flow, the concentration, the viscosity, and the surface tension of the core material are all processing factors. The product that has been encapsulated may be delivered in the form of a dry powder or slurry in the hardening mediator. With this method, production rates of 50 to 75 pounds per hour have been attained.

Chemical Techniques:

· Coacervation Phase Separation

· Solvent Evaporation

· Solvent Extraction

· Interfacial Polymerization

· In-Situ Polymerization, and Matrix Polymerization are some examples of polymerization processes.

1. Coacervation-phase separation:

In general, the processes involve three steps that are completed while being continuously stirred,

Creation of Three Chemically Immiscible:

(a) A core material phase, a liquid production vehicle phase, and a coating material phase. The liquid production vehicle phase served as the solvent for the coating polymer, dispersing the core material in the solution to create the three phases⁸. One of the methods of phase separation-coacervation, such as changing the temperature of the polymer solution, adding a salt, non-solvent, or incompatible polymer to the polymer solution, or inducing a polymer-polymer interaction, is used to create the coating material phase, an immiscible polymer in a liquid state.

(b) Coating Deposition: This step entails coating the core material with a liquid polymer. This is achieved by physically and carefully combining the material in the manufacturing machine. Adsorption of the polymer at the interface produced between the core material and the liquid vehicle phase causes the liquid polymer to deposit around the core material, and this adsorption process is necessary for efficient coating⁹. A decrease in the system's total free interfacial energy, brought on by a reduction in the coating material's surface area during the clearance of the liquid polymer droplets, encourages the ongoing deposition of the coating material.

(c) Rigidizing the coating entails making it rigid, typically through heating, cross-linking, or desolvation to create a self-sustaining microcapsule using several ways. For instance, pressure-induced phase separation of CO2-expanded ethanol solutions can be used to coacervate the microencapsulation of talc particles with poly (methyl methacrylate).

Fig.6: Coacervation phase separation

2. Multilayer Interfacial Condensation:

The two reactants in a polycondensation meet at an interface and react quickly in an interfacial polycondensation. The fundamental step in this process is the Schotten-Baumann reaction, which takes place when an acid chloride reacts with a substance that contains an active hydrogen atom, such as an amine or alcohol, polyesters, polyurea, or polyurethane. At the interface, thin flexible walls quickly form when the correct circumstances are present¹⁰. An aqueous solution containing an amine and a polyfunctional isocyanate is added after a pesticide and a di-acid chloride solution have been emulsified in water. To counteract the acid that is produced during the reaction, base is present. Instantaneously, condensed polymer walls develop at the emulsion droplet contact.

Fig.7: Multilayer interfacial condensation

3. Interfacial Cross-Linking:

Also known as interfacial polycondensation, interfacial cross-linking was created to use of hazardous diamines in medicinal or cosmetic applications should be avoided. In this technique, the tiny bifunctional monomer containing active hydrogen atoms is substituted by a biosourced polymer, like a protein. When the reaction is carried out at the emulsion's interface, the acid chloride interacts with the protein's different functional groups to create a membrane. The technique is extremely flexible, and the characteristics of the microcapsules (size, porosity, degradability, mechanical resistance).

Fig.8: Interfacial cross-linking method

4. In-situ polymerization:

In a few microencapsulation procedures, a single monomer is directly polymerized on the surface of the particle. Cellulose fibres, for instance, are encapsulated in polyethylene in one procedure while submerged in dry toluene. The average deposition rate is 0.5m/min. Layer thickness) spans 0.2 to 75m (0.0079–2.9528mils). Even over sharp projections, the coating remains consistent. Protein microcapsules are biocompatible and biodegradable, and the membrane is more robust and elastic thanks to the protein backbone than those made via interfacial polycondensation.

Fig.9: In-situ polymerization process

5. Matrix Polymerization:

During the creation of the particles, a core material is embedded in a polymeric matrix in a number of processes. Spray-drying, in which the particle is created by the evaporation of the solvent from the matrix material, is a straightforward process of this kind. Yet, a chemical process can also be to blame for the matrix's solidification.

In this method, the material to be encapsulated (core material) and an appropriate emulsifier are introduced to a stirred aqueous polymerization solution together with the monomer (alkyl acrylate). The polymerisation commences and initially generated polymer molecules precipitate in the aqueous media to form primary nuclei. These nuclei gradually expand as the polymerization process continues, encasing the core substance to create the finished microcapsules.

6. Solvent Extraction and Evaporation:

Similar to suspension cross linking, solvent evaporation/solvent extraction creates microcapsules, however in this instance the polymer is often hydrophobic polyester. The core material is additionally dissolved or distributed in the volatile organic solvent used to dissolve the polymer, such as dichloromethane or chloroform. The resulting mixture is then dropped in. to create tiny polymer droplets containing encapsulated material in a swirling aqueous solution that contains an appropriate stabiliser, such as poly (vinyl alcohol) or polyvinylpyrrolidone, etc. The droplets eventually solidify to form the matching polymer microcapsules. ¹¹. Compared to microcapsules made using solvent evaporation, those made through solvent extraction have larger porosities for the creation of drug-loaded microcapsules made of biodegradable polyesters such polylactide, poly (lactideco- glycolide), and polyhydroxybutyrate, solvent evaporation/extraction techniques are appropriate.

Fig. 10: Solvent evaporation process

Evaluation of Microcapsules:

Percentage Yield:

The measured weight was divided by total amount of all non‐volatile components which

were used for the preparation of microcapsule.

% yield = (Actual weight of product/Total weight of excipient and drug) x 100

Incorporation Efficiency:

In 100ml volumetric flask 25mg of crushed microcapsules were taken and dissolved with small quantity of ethanol of the volume is made up to mark with pH 6.8 and stirred for 12 hours. After stirring the solution was filtered through Whatman filter paper and from the filtrate appropriate dilutions were made and absorbance was measured at nm by using UV‐ spectrophotometer (Shimadzu).

Micromeritic Properties:

Particle Size: Determination of average particle size of the Trihexyphenidyl microcapsules was carried out by the optical microscopy method. A minute quantity of microcapsules was dispersed in glycerin and then spread on clean glass slide and average sizes of 100 microcapsules were determined in each batch.

Angle of Repose: Determination of angle of repose, the microcapsules were carried out byemploying fixed funnel method.

Angle of repose θ = tan-1(H/R)

Where, H = Height of the pile; R = Radius of the pile.

Scanning Electron Microscopy:

The samples for SEManalysis were prepared by following method. Theshape and surface morphology of the microcapsulewas studied by using scanning electron microscope. Microcapsules weremounted directly onto the SEM sample stub usingdouble-sided sticking tape and coated with gold film (thickness 200nm) under reduced pressure (0.001mm of Hg). The microcapsules were viewed at anaccelerating voltage of 10KV.

Drug Release:

In vitro release studies:

In vitrodissolution profile of each formulation was determinedby employing g USP XXII type 2 basket method (900ml of pH 6.8‐phosphate buffer, 100rpm, 37±0.5^OC).

Microcapsules equivalent to 100mg of microcapsules was loaded into the basket of the dissolutionapparatus. Aliquot of 5 mL was withdrawn from the dissolution media at suitable time intervals and thewithdrawn volume was replenished with the samevolume of dissolution medium in order to keep thetotal volume constant. The absorbance of the sampleswas measured at λmax nm after suitable dilution ifnecessary, using phosphate buffer of pH 6.8 as blank. Results of in vitro drug release studies obtained fromabsorbance data were tabulated and shown graphicallyas Cumulative % drug released Vs Time.

Release Procedures among the drug release mechanisms:

1. Degradation controlled monolithic system:

The medication is evenly dispersed throughout the matrix after it has been dissolved. The medication has a tight bond with the matrix and is released when the matrix breaks down. In comparison to the rate of material degradation, drug dispersion is slow.

2. Diffusion controlled monolithic system:

In this system, the active drug is released by diffusion either before or at the same time as the polymer matrix breaks down. The homogeneous or heterogeneous method used to breakdown the polymer will also affect the rate of release.

3. Diffusion-controlled reservoir system:

In this system, the active ingredient is enclosed by a membrane that regulates the rate at which it diffuses, and the membrane only starts to erode once the active ingredient has been delivered. In this instance, matrix degradation has no impact on drug release.

4. Erosion:

Some coat materials, such as glyceryl mono stearate, beeswax, and stearyl alcohol, among others, promote medication release by causing the coat to erode due to pH and enzymatic hydrolysis. the following factors can be considered: The zero order is followed by the drug release rate from microcapsules. The first half of the total drug release is dependent on the release rate of monolithic microcapsules, after which the rate exponentially declines.

Monolithic microcapsules that contain more dissolved medication and have a t1/2 dependent release rate practically the entire time the medication is released.

Applications:

Microencapsulation has a wide range of applications. Some of the most typical ones are those listed below.

A. AgricultureCrop protection: By preventing insects from mating, pheromones can lower insect populations.

B. Pharmaceutics: Pharmaceutical and biomedical applications for controlled/sustained encapsulation: drug delivery is one of the main application areas of the method.

C. Food Business: Increasing a food's nutritional value may damage its flavour, appearance, texture, and scent. Occasionally they gradually deteriorate and lose their functionality or turn dangerous due to oxidation reactions.

D. Energy production: To harness nuclear fusion for the purpose of generating electrical energy, hollow plastic microspheres that are filled with gaseous deuterium (a fusion fuel) are employed. The capsules have several layers. Self-healing composites and polymers are a significant use of microencapsulation technology in the field of defence

Advantages and disadvantages:

Advantages of Microencapsulating Drugs:

To make bitter medications more pleasant and increase patient compliance, it masks their taste. The most popular coating substance for this use is Eudragit E100. Because they are insoluble in the mouth, medicines that are microencapsulated do not interact with taste receptors. Such as ofloxacin. Transforming a liquid dose form into a powder that is semi-solid or free-flowing. such as eprazinone. Result for the term microencapsulation

To offer the core material environmental protection from oxygen, light, and moisture. such as nifedipine.

To avoid aspirin's volatilization at room temperature and to stop the physical and chemical incompatibilities between medications.

To create dosage forms for sustained or prolonged release that continually release the medications at a specific pace for a predetermined amount of time.

It makes a substance more soluble. medicines that are poorly soluble and the safe administration of hazardous pharmaceuticals.

In order to deliver the enclosed substance precisely where it is needed.

To change a drug's surface and physical characteristics. Changing sodium chloride's hygroscopicity, for instance.

Disadvantages of Microencapsulating Drugs:

The price of the ingredients and the formulation procedure may be more expensive than with ordinary formulations.

Less replication is possible.

In reaction to heat, hydrolysis, or biological agents, the impact of the polymer matrix, polymer additives, and their degradation products on the environment varies greatly.

Changes in process variables like temperature, pH, solvent addition, or solvent evaporation have an impact on how stable the core particle is.

CONCLUSION:

The microencapsulation technology has a number of advantages, including protection and masking, a slower rate of dissolution, handling ease, and spatial targeting of the active ingredient. This method makes it easier to administer powerful medications in small doses accurately, lower drug concentrations at locations other than the target organ or tissue, and safeguard labile substances before, after, and before they manifest at the site of action. Future developments in innovative drug delivery systems will incorporate the microencapsulation process with a number of other methods.

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Received on 11.03.2023 Modified on 03.05.2023

Res. J. Pharma. Dosage Forms and Tech.2023; 15(3):203-210.

DOI: 10.52711/0975-4377.2023.00033