![Unit II
Microencapsulation
Akanksha Patel
Asst. prof.
produce a targeted drug delivery, 5. Protects the GIT from irritant effects of the drug, 6.
Extension of duration of activity for an equal level of active.agent. 7. To protect the immediate
environment of the microcapsules from the active components.
Mechanism and kinetics of drug release-
Diffusion
Diffusion is the most commonly involved mechanism wherein the dissolution fluid penetrates
the shell, dissolves the core and leak out through the interstitial channels or pores. Thus, the
overall release depends on, (a) the rate at which dissolution fluid penetrates the wall of
microcapsules, (b) the rate at which drug dissolves in the dissolution fluid, and (c) the rate at
which the dissolved drug leak out and disperse from the surface. The kinetics of such drug
release obeys Higuchi‟s equation as below:
Q = [D/J (2A - ε CS) CS t]1/2
Where, Q is the amount of drug released per unit area of exposed surface in time t; D is the
diffusion coefficient of the solute in the solution; A is the total amount of drug per unit volume;
CS is the solubility of drug in permeating dissolution fluid; ε is the porosity of the wall of
microcapsule; J is the tortuosity of the capillary system in the wall. The above equation can be
simplified to Q = vt where, v is the apparent release rate.
Dissolution
Dissolution rate of polymer coat determines the release rate of drug from the microcapsule
when the coat is soluble in the dissolution fluid. Thickness of coat and its solubility in the
dissolution fluid influence the release rate.
Osmosis
The polymer coat of microcapsule acts as semi permeable membrane and allows the creation
of an osmotic pressure difference between the inside and the outside of the microcapsule and
drives drug solution out of the microcapsule through small pores in the coat.
Erosion
Erosion of coat due to pH and/or enzymatic hydrolysis causes drug release with certain coat
materials like glyceryl monostearate, bees wax and stearyl alcohol.](https://image.slidesharecdn.com/2-240213173542-1720d24a/85/unit-2-various-approaches-on-Microencapsulation-pdf-4-320.jpg)
![Unit II
Microencapsulation
Akanksha Patel
Asst. prof.
I] Physical or Physico-mechanical methods
22
1.Air-suspension coating- Inventions of Professor Dale E. Wurster,
Basically the wurster process consists of the dispersing of solid, particulate core materials in a
supporting air stream and the spray-coating of the air suspended particles.
Equipment ranging in capacities from one pound to 990 pounds.
Micron or submicron particles can be effectively encapsulated by air suspension techniques.
Disadvantage- Agglomeration of the particles to some larger size is normally achieved.
Processing variables for efficient, effective encapsulation by air suspension techniques:
1.Density, surface area, melting point, solubility, friability, volatility, Crystallinity, and flow-
ability of core the core material.
2.Coating material concentration (or melting point if not a solution).
3.Coating material application rate.
4.Volume of air required to support and fluidizes the core material.
5.Amount of coating material required.
6.Inlet and outlet operating temperatures.](https://image.slidesharecdn.com/2-240213173542-1720d24a/85/unit-2-various-approaches-on-Microencapsulation-pdf-7-320.jpg)
![Unit II
Microencapsulation
Akanksha Patel
Asst. prof.
5. Vibrational Nozzle-
The process works very well for generating droplets between 100–5,000 μm
Units are deployed in industries and research mostly with capacities of 1–10,000 kg
per hour at working temperatures of 20–1500 °C.
Nozzles heads are available from one up to several hundred thousand are available.
II] Physico-chemical methods 39
1.Ionotropic gelation-
In this technique, the preparation of drug containing microparticles is based on the
principle of coalescence of colloidal polymer particles. Ionotropic gelation of the
anionic polysaccharide sodium alginate with oppositely charged calcium ions forms
microparticles.
Verapamil hydrochloride causes gastric irritation on sudden release. It is usually
administered as conventional tablets containing 40-120 mg, 3 times a day. Due to its
ready solubility in water and shorter half-life. Microparticulate system of verapamil
hydrochloride is prepared for prolonged release delivery system.](https://image.slidesharecdn.com/2-240213173542-1720d24a/85/unit-2-various-approaches-on-Microencapsulation-pdf-11-320.jpg)
![Unit II
Microencapsulation
Akanksha Patel
Asst. prof.
2. Coacervation-Phase Separation
The term coacervation is derived from Latin word acervus, which means a heap or aggregation.
The term coacervation was introduced in 1929 by Bungenberg de Jong and Kruyt, for a process
of phase separation in liquids containing colloidal solute.
Simple coacervation generally uses one colloid, which is precipitated out by salts or non
solvents or by increase or decrease in temperature.
Complex coacervation involves two or more than two colloids and salting out is carried out
by oppositely charged polymers, for example, Acaia and Gelatin
3 steps under continues agitation-
1) Formation of three immiscible chemical phases (Liquid phase, coating and core material
phase) 2)Deposition of the coating 3)Rigidization of the coating.
•Formation of three immiscible chemical Phases (Phase seperation)
• Temperature Change
•Incompatible Polymer addition
•Non Solvent addition
•Salt addition
•Polymer Polymer interaction
Schematic representation of the coacervation process.
(a) Core material dispersion in solution of shell polymer;
(b) separation of coacervate from solution;
(c) coating of core material by microdroplets of coacervate;
(d) coalescence of coacervate to form continuous shell around core particles.
III] Chemical process 45
1.Solvent Evaporation
In the case in which the core material is dispersed in the polymer solution, polymer shrinks
around the core. In the case in which core material is dissolved in the coating polymer solution,
a matrix - type microcapsule is formed.
The core materials may be either water - soluble or water - insoluble materials.
A variety of film - forming polymers can be used as coatings.](https://image.slidesharecdn.com/2-240213173542-1720d24a/85/unit-2-various-approaches-on-Microencapsulation-pdf-12-320.jpg)
unit 2. various approaches on Microencapsulation.pdf
- 1. Unit II Microencapsulation Akanksha Patel Asst. prof. Microencapsulation The first research leading to the development of microencapsulation procedures for the Pharmaceuticals was published by Bungen burg de Jong and Kan in 1931 and dealt with the preparation of gelatine spheres and the use of a gelatine Coacervation process. Definition:- MICROENCAPSULATION is a process by which very tiny droplets or particles of liquid or solid material are surrounded or coated with a continuous film of polymeric material. The product obtained by this process is called as Microcapsules. Microcapsules: “Microcapsules” refers to microparticles having a core surrounded by the coat or wall material(s) distinctly different from that of the core or pay-load or nucleus, which may be solid, liquid, or even gas. Microcapsules can be classified on three types: 1) Mononuclear: Containing the shell around the core. 2) Polynuclear: Having many cores enclosed with in shell. 3) Matrix type: Distributed homogeneously into the shell material. Microparticles‟ sizes range from 1 to 1000 μm and the well-known matrix or reservoir structure they exist in have various different structures. Microparticles,Microspheres, Microcapsules- The term “microcapsule” is defined, as a spherical particle with the size varying between 50 nm to 2 mm containing a core substance. Microspheres are in strict sense, spherically empty particles. In addition, some related terms are used as well. For example, “microbeads” and “beads” are used alternatively. Multiparticulate drug delivery systems (micropellets, microgranules, microspheres, microcapsules, microsponges, liposomal preparations). Microparticles, microspheres, and microcapsules are common constituents of multiparticulate drug delivery systems. Microparticles: “Microparticles” refers to the particles having the diameter range of 1-1000 μm, irrespective of the precise exterior and/or interior structures. Microspheres: “Microspheres” particularly refers to the spherically shaped microparticles within the broad category of microparticles.
- 2. Unit II Microencapsulation Akanksha Patel Asst. prof. Microspheres can be characterized as matrix systems in which the drug is homogeneously dispersed, either dissolved or homogenously suspended. Microcapsules are heterogenous particles where a membrane shell is surrounding the core forming a reservoir Microparticles 7 Microcapsules Microspheres Size varies from 1-2000um or depends on the type of microencapsulation technique Fundamental Consideration Generally Micro particles consist of two components; a) Core material. b) Coat or wall or shell material Core Material The material to be coated. It may be liquid or solid or gas. Liquid core may be dissolved or dispersed material. Composition of core material: Drug or active constituent, Additive like diluents, Stabilizers. Coating Material Inert substance which coats on core with desired thickness. Composition of coating: Inert polymer, Plasticizer, Colouring agent, Resins, waxes and lipids, Release rate enhancers or retardants Examples of Coating Materials 1. Water soluble resins- Gelatin, Gum Arabic, Starch, PVP, CMC,.MC, Arabinogalactan, Polyvinyl alcohol. 2. Water insoluble resins- EC, Polyethylene, Polymethacrylate, Polyamide (Nylon), Cellulose nitrate, Silicones. 3. Waxes and lipids- Paraffin, Carnauba, Beeswax, Stearic acid, Stearyl alcohol, Glyceryl stearates. 4. Enteric resins- Shellac, Cellulose acetate phthalate, Zein.
- 3. Unit II Microencapsulation Akanksha Patel Asst. prof. Type of Core materials, Coting materials and Vehicles used in Microencapsulation. Core Material Characteristic Property Purpose of Encapsulation Final Product Form Aspirin Slightly water- soluble solid Taste-masking; sustained release; reduced gastric irritation; separation of incompatibles Tablet or capsule Vitamin A Palmitate Nonvolatile liquid Stabilization to oxidation Dry powder Isosorbide dinitrate Water soluble solid sustained release Capsule REASONS FOR ENCAPSULATION The core must be isolated from its surroundings, as 1. To protect reactive substances from the environment, 2. To convert liquid active components into a dry solid system, 3. To separate incompatible components for functional reasons, 4. To protect the immediate environment of the microcapsules from the active components. To control the rate at which it leaves the microcapsule, as 1. To control release of the active components for delayed (timed) release or long-acting (sustained) release, 2. The problem may be as simple as masking the taste or odor of the core, 3. To Increase of bioavailability, 4. To
- 4. Unit II Microencapsulation Akanksha Patel Asst. prof. produce a targeted drug delivery, 5. Protects the GIT from irritant effects of the drug, 6. Extension of duration of activity for an equal level of active.agent. 7. To protect the immediate environment of the microcapsules from the active components. Mechanism and kinetics of drug release- Diffusion Diffusion is the most commonly involved mechanism wherein the dissolution fluid penetrates the shell, dissolves the core and leak out through the interstitial channels or pores. Thus, the overall release depends on, (a) the rate at which dissolution fluid penetrates the wall of microcapsules, (b) the rate at which drug dissolves in the dissolution fluid, and (c) the rate at which the dissolved drug leak out and disperse from the surface. The kinetics of such drug release obeys Higuchi‟s equation as below: Q = [D/J (2A - ε CS) CS t]1/2 Where, Q is the amount of drug released per unit area of exposed surface in time t; D is the diffusion coefficient of the solute in the solution; A is the total amount of drug per unit volume; CS is the solubility of drug in permeating dissolution fluid; ε is the porosity of the wall of microcapsule; J is the tortuosity of the capillary system in the wall. The above equation can be simplified to Q = vt where, v is the apparent release rate. Dissolution Dissolution rate of polymer coat determines the release rate of drug from the microcapsule when the coat is soluble in the dissolution fluid. Thickness of coat and its solubility in the dissolution fluid influence the release rate. Osmosis The polymer coat of microcapsule acts as semi permeable membrane and allows the creation of an osmotic pressure difference between the inside and the outside of the microcapsule and drives drug solution out of the microcapsule through small pores in the coat. Erosion Erosion of coat due to pH and/or enzymatic hydrolysis causes drug release with certain coat materials like glyceryl monostearate, bees wax and stearyl alcohol.
- 5. Unit II Microencapsulation Akanksha Patel Asst. prof. Figure 4. Release mechanisms in microencapsulated products Advantages of microencapsulation: 1. Providing environmental protection to the encapsulated active agents or core materials. 2. Liquids and gases can be changed into solid particles in the form of microcapsules. 3. Surface as well as colloidal characteristics of various active agents can be changed. 4. modify and delayed drug release form different pharmaceutical dosage forms 5. Formulation of sustained controlled release dosage forms can be done by modifying or delaying release of encapsulated active agents or core materials. 6. particle size reduction for enhancing stability of the poorly soluble drug. 7. provide constant and prolonged theraperutic effect. 8. Decrese dose and toxicity. 9. protects the GIT irritant effect of the drug. 10. reduce the dosing frequency and thereby improve the patient compliance.
- 6. Unit II Microencapsulation Akanksha Patel Asst. prof. Disadvantages of microencapsulation: 1. Expensive techniques. 2. This causes reduction in shelf-life of hygroscopic agents. 3. Microencapsulation coating may not be uniform and this can influence the release of encapsulated materials. 4. The costs of thematerialsand processing of thecontrolled release preparation, aresubstantiallyhigher than thos eofstandardformul ations. 5. The fate ofpolyn1erma trixanditseffectontheenvironment. 6. Thefateofpolymer additivessuc hasplasticizers ,stabilizers,antioxidants andfillers 7. Reprodudbili tyisless. 8. P rocess conditions like change in temperature,pH,solvent addition, and evaporation/agitationmayinf luencethestabilityofcor eparticlestobe encapsulated. 9. Theenv ironmental impact of thedegradationproductsof thepolymer 10. matrixproduced inresponsetoheat,hydrolysis,oxidation,so lar radiation orbiologicalagents. Techniques to Manufacture Microcapsules 19 The technique of microencapsulation depends on the physical and chemical properties of the material to be encapsulated. The stability and the biological activity of the drug should not be affected, Yield and drug encapsulation efficiency should be high, Microsphere quality and drug release profile should be reproducible within specified limits, Microsphere should not exhibit aggregation or adherence, Process should be usable at an industrial scale, The residual level of organic solvents should be lower than the limit value.
- 7. Unit II Microencapsulation Akanksha Patel Asst. prof. I] Physical or Physico-mechanical methods 22 1.Air-suspension coating- Inventions of Professor Dale E. Wurster, Basically the wurster process consists of the dispersing of solid, particulate core materials in a supporting air stream and the spray-coating of the air suspended particles. Equipment ranging in capacities from one pound to 990 pounds. Micron or submicron particles can be effectively encapsulated by air suspension techniques. Disadvantage- Agglomeration of the particles to some larger size is normally achieved. Processing variables for efficient, effective encapsulation by air suspension techniques: 1.Density, surface area, melting point, solubility, friability, volatility, Crystallinity, and flow- ability of core the core material. 2.Coating material concentration (or melting point if not a solution). 3.Coating material application rate. 4.Volume of air required to support and fluidizes the core material. 5.Amount of coating material required. 6.Inlet and outlet operating temperatures.
- 8. Unit II Microencapsulation Akanksha Patel Asst. prof. 2. Centrifugal extrusion Liquids are encapsulated using a rotating extrusion head containing concentric nozzles. This process is excellent for forming particles 400–2,000 μm in diameter. Since the drops are formed by the breakup of a liquid jet, the process is only suitable for liquid or slurry. A high production rate can be achieved, i.e., up to 22.5 kg of microcapsules can be produced per nozzle per hour per head. Heads containing 16 nozzles are available. 3. Pan coating Oldest industrial procedures for forming small, coated particles or tablets. The particles are tumbled in a pan or other device while the coating material is applied slowly. Solid particles greater than 600 microns in size are generally considered essential for effective coating. Medicaments are usually coated onto various spherical substrates such as nonpareil sugar seeds, and then coated with protective layers of various polymers.
- 9. Unit II Microencapsulation Akanksha Patel Asst. prof. 4. Spray-drying In modern spray dryers the viscosity of the solutions to be sprayed can be as high as 300mPa.s Spray drying and spray congealing- dispersing the core material in a liquefied coating substance and spraying. Spray drying is effected by rapid evaporation of a solvent in which the coating material is dissolved. The equipment components of a standard spray dryer include 1.an air heater, 2.atomizer, 3.main spray chamber, 4.blower or fan, 5.cyclone and 6.product collector Spray congealing- can be accomplished with spray drying equipment when the protective coating is applied as a melt Core material is dispersed in a coating material melt rather than a coating solution. Coating solidification (and microencapsulation) is accomplished by spraying the hot mixture into a cool air stream. Airflow There are three modes of contact: A. Co-current B.Counter-current C.Mixed-flow
- 11. Unit II Microencapsulation Akanksha Patel Asst. prof. 5. Vibrational Nozzle- The process works very well for generating droplets between 100–5,000 μm Units are deployed in industries and research mostly with capacities of 1–10,000 kg per hour at working temperatures of 20–1500 °C. Nozzles heads are available from one up to several hundred thousand are available. II] Physico-chemical methods 39 1.Ionotropic gelation- In this technique, the preparation of drug containing microparticles is based on the principle of coalescence of colloidal polymer particles. Ionotropic gelation of the anionic polysaccharide sodium alginate with oppositely charged calcium ions forms microparticles. Verapamil hydrochloride causes gastric irritation on sudden release. It is usually administered as conventional tablets containing 40-120 mg, 3 times a day. Due to its ready solubility in water and shorter half-life. Microparticulate system of verapamil hydrochloride is prepared for prolonged release delivery system.
- 12. Unit II Microencapsulation Akanksha Patel Asst. prof. 2. Coacervation-Phase Separation The term coacervation is derived from Latin word acervus, which means a heap or aggregation. The term coacervation was introduced in 1929 by Bungenberg de Jong and Kruyt, for a process of phase separation in liquids containing colloidal solute. Simple coacervation generally uses one colloid, which is precipitated out by salts or non solvents or by increase or decrease in temperature. Complex coacervation involves two or more than two colloids and salting out is carried out by oppositely charged polymers, for example, Acaia and Gelatin 3 steps under continues agitation- 1) Formation of three immiscible chemical phases (Liquid phase, coating and core material phase) 2)Deposition of the coating 3)Rigidization of the coating. •Formation of three immiscible chemical Phases (Phase seperation) • Temperature Change •Incompatible Polymer addition •Non Solvent addition •Salt addition •Polymer Polymer interaction Schematic representation of the coacervation process. (a) Core material dispersion in solution of shell polymer; (b) separation of coacervate from solution; (c) coating of core material by microdroplets of coacervate; (d) coalescence of coacervate to form continuous shell around core particles. III] Chemical process 45 1.Solvent Evaporation In the case in which the core material is dispersed in the polymer solution, polymer shrinks around the core. In the case in which core material is dissolved in the coating polymer solution, a matrix - type microcapsule is formed. The core materials may be either water - soluble or water - insoluble materials. A variety of film - forming polymers can be used as coatings.
- 13. Unit II Microencapsulation Akanksha Patel Asst. prof. Solvent Evaporation Method 2. Polymerization 1)Interfacial polymer In Interfacial polymerization, the two reactants in a …..polycondensation meet at an interface and react rapidly. Examples of wall materials are polyamide, polyurea, polyurethane epoxy resin. Common pharmaceuticals that can be encapsulated are vitamins, flavoring materials and adhesives. An advantage of this process is that the properties of microcapsules can be modified by combination of monomers. This process is used for encapsulating both oily and aqueous substances. Size of microcapsules formed by this method is generally some milimeters. Disadvantage: i) drug degradation due to harsh condition like temperature, reactive monomers concentration ii)toxicity associated with monomers, (iii) high permeability of coating (iv) fragility, and (v) lack of biodegradability of products
- 14. Unit II Microencapsulation Akanksha Patel Asst. prof. Interfacial Polymerization APPLICATIONS OF MICROCAPSULES AND MICROSPHERES General Application 1. Cell immobilization: In plant cell cultures, Human tissue is turned into bio-artificial organs, in continuous fermentation processes. 2. Beverage production 3. Protection of molecules from other compounds: 4. Quality and safety in food, agricultural and environmental sectors. 5. Soil inoculation. 6. In textiles: means of imparting finishes. 7. Protection of liquid crystals 8. Most flavoring is volatile; therefore encapsulation of these components extends the shelf- life of products by retaining within the food flavours that would otherwise evaporate out and be lost. Some ingredients are encapsulated to mask taste, such as nutrients added to fortify a product without compromising the product‟s intended taste 2. Controlled Release and Sustained Release Dosage Forms 1. To mask the bitter taste of drugs like Paracetamol, Nitrofurantoin etc. 2. To reduce gastric and other gastro intestinal (G.I) tract irritations, e.g., sustained release Aspirin preparations have been reported to cause significantly less G.I. bleeding than conventional preparations. 3. A liquid can be converted to a pseudo-solid for easy handling and storage e.g. eprazinone. 4. Hygroscopic properties of core materials may be reduced by microencapsulation e.g., Sodium chloride. 5. Carbon tetrachloride and a number of other substances have been microencapsulated to reduce their odor and volatility. 6. Microencapsulation has been employed to provide protection to the core materials against atmospheric effects, e.g., Vitamin-A Palmitate. 7. Separation of incompatible substance has been achieved by encapsulation
- 15. Unit II Microencapsulation Akanksha Patel Asst. prof. 8. Physicochemical evaluation characterization: The characterization of the microparticulate carrier is an important phenomenon, which helps to design a suitable carrier for the proteins, drug or antigen delivery. These microspheres have different microstructures. These microstructures determine the release and the stability of the carrier. 2. Medical application 1. Release of proteins, hormones and peptides over extended period of time. 2. Gene therapy with DNA plasmids and also delivery of insulin. 3. Vaccine delivery for treatment of diseases like hepatitis, influenza, pertusis, ricin toxoid, diphtheria, birth control. 4. Passive targeting of leaky tumour vessels, active targeting of tumour cells, antigens, by intraarterial/ intravenous application. 5. Tumour targeting with doxorubicin and also treatments of leishmaniasis. Magnetic microspheres can be used for stem cell extraction and bone marrow purging. 6. Used in isolation of antibodies, cell separation, and toxin extraction by affinity chromatography. 7. Used for various diagnostic tests for infectious diseases like bacterial, viral, and fungal. 3. Radioactive microsphere’s application 1. Can be used for radioembolisation of liver and spleen tumours. 2. Used for radiosynvectomy of arthiritis joint, local radiotherapy, interactivity treatement 4. Cosmetics : For cosmetic applications, organic acids are usually good solvents; chitin and chitosan have fungicidal and fungistatic properties. Chitosan is the only natural cationic gum that becomes viscous on being neutralized with acid. These materials are used in creams, lotions and permanent waving lotions and several derivatives have also been reported as nail lacquers. 5. Photography: Chitosan has important applications in photography due to its resistance to abrasion, its optical characteristics, and film forming ability. Silver complexes are not appreciably retained by chitosan and therefore can easily be penetrated from one layer to another of a film by diffusion.