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Microencapsulation
1. Guided by:
Dr. Mayur Patel
Department of pharmaceutics Institute of Pharmacy
Nirma University
Microencapsulation
Prepared By: Dhara Patel 14mph103 M Pharm Sem I Pharmaceutical Technology and Biopharmaceutics
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•Definition
•About
•Why???
•Classification
•Core material
•Coat material
• Mechanisms of drug release
•Techniques of preparation
•Evaluation parameters
•Applications
•Novel approaches
•Conclusion
•References
CONTENTS
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The process of
surrounding or enveloping
one substance (solid, liquid or gas)
within another substance (miniature capsule)
that can release their contents at
CONTROLLED RATES
under the influence of the specific conditions.
BIOENCAPSULATION:
Entrapment of a biologically active substance (from DNA to entire cell or group of cells) is known as bioencapsulation.
DEFINITION:
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•It is a process in which extremely tiny droplets, or particles of liquid or solid material, are packed within a second material or coated with a continuous film of polymeric material for the purpose of shielding the active ingredient from the surrounding environment.
•Size : one micron to several hundred microns.
•Shape : Spherical or variably shaped
ABOUT
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•Microencapsulation provides the means of converting liquids into solids, of altering colloidal & surface properties, of providing environmental protection, & of controlling the release characteristics or bioavailability of coated materials.
•Because of smallness of the particles, drug moieties can be widely distributed throughout the gastrointestinal tract.
improving drug sorption
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•For sustained or prolonged release.
•For taste masking and odour of many drugs to improve patient compliances.
•Converting oils or other liquid drugs in a free flowing powder.
•Drugs sensitive to oxygen, moisture or light, can be stabilized.
•Incompatibility among the drugs can be prevented.
•Vaporization of many drugs (methyl salicylate, peppermint oil) can be prevented.
Why???
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•To reduce toxicity and gastrointestinal irritation e.g. FeSO4 and KCL.
•Alteration in site of absorption can also be achieved.
•Improvement in flow properties.
•Microencapsulated drugs have enhanced stability.
•Aid in dispersion of water insoluble drugs in aqueous fluid.
•Production of sustained release, controlled release & targeted medication.
•Reduced dose dumping compared to high dose implants.
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•Solid and liquid can be coated.
•Liquid core include dispersed or dissolved material.
•Solid can be the mixture of API, diluents, excepients, release rate retardants or accelerators.
Core Material
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Core Material
Characteristic Technique
Purpose of Microencapsulation
Final product form
Acetaminophen
Slightly soluble solid
Taste masking
Tablet
Activated charcoal
Adsorbent
Selective sorption
Dry powder
Aspirin
Slightly water soluble solid
Taste masking, sustained release, reduced gastric irritation, separation of incompatibilities.
Tablet or Capsule
Isosorbide dinitrate
Water soluble drug
Sustained release
Capsule
Methanol/ methyl salicylate camphor mixture
Volatile solution
Reduction of volatility, sustained release.
Lotion
Vit A palmitate
Nonvolatile liquid
Stabilization to oxidation
Dry powder
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•Capable of forming a film.
•Compatible with core material.
•Non reactive to core material.
•Inert toward active ingredients.
•Controlled release under specific conditions.
•Film-forming, pliable, tasteless, stable, flexible, impermeable.
•Non-hygroscopic, less viscosity, economical.
•Soluble in an aqueous media or solvent.
Coat material
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Water soluble resins
Gelatin
Gum Arabic
Starch
PVP / PVA
CMC
MC/ HPC / HPMC
Water insoluble resins
EC
Polyethene
Nylon
Cellulose nitrate
Silicones
Waxes and lipids
Paraffin
Carnauba
Spermaceti
Beeswax
Stearic acid
Glyceryl stearate
Enteric resins
Shellac
CAP
zein
Examples of coat material
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•Major mechanisms of drug release from microcapsules are as follows:
1.Degradation controlled monolithic system
2.Diffusion controlled monolithic system
3.Diffusion controlled reservoir system
4.Erosion
MECHANISMS OF DRUG RELEASE
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The drug is dissolved in matrix and is distributed uniformly throughout. The drug is strongly attached to the matrix and is released on degradation of the matrix. The diffusion of the drug is slow as compared with degradation of the matrix.
1. Degradation controlled monolithic system
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•Here, the active agent is released by diffusion prior to, or concurrent with the degradation of the polymer matrix. Rate of release also depend upon where the polymer degrades by homogeneous or heterogeneous mechanism.
2. Diffusion controlled monolithic system
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Here, the active agent is encapsulated by a rate controlling membrane through which the agent diffuses and the membrane erodes only after its delivery is completed. In this case, drug release is unaffected by the degradation of the matrix.
3. Diffusion controlled reservoir system
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Erosion of the coat due to pH and enzymatic hydrolysis causes drug release with certain coat material like glyceryl mono stearate, beeswax and steryl alcohol, etc.
4. Erosion
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PHYSICAL METHODS
Coacervation –Phase separation Coacervation Process Air-suspension Centrifugal extrusion Pan-coating Spray-drying Rapid expansion of supercritical fluids (RESS) Gas anti-solvent Particles from gas- saturated solution
CHEMICAL METHODS
Solvent evaporation
Interfacial polymerization
In-situ polymerization
Matrix polymer
TECHNIQUES OF PREPARATION:
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Polymeric Membrane
Droplets
Homogeneous
Polymer Solution
Coacervate Droplets
PHASE
SEPARATION
MEMBRANE
FORMATION
•Coacervation is based on separation of a solution of hydrophilic polymer(s)into two phases, which are small droplets of a dense polymer-rich phase and a dilute liquid phase.
–Simple Coacervation.
–Complex Coacervation.
Coacervation
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Simple Coacervation
•Involves only one polymer and the phase separation can be induced by conditions that result in desolvation (or dehydration) of the polymer phase.
•These conditions include addition of a water-miscible non-solvent, or addition of inorganic salts.
Complex Coacervation
•It involves two hydrophilic polymers of opposite charges.
•When one charge get neutralized by the opposite charge the polymer gets separated and deposits on the droplet.
•Once coacervates form, these polymer complexes are stabilized by cross-linking using gluteraldehyde.
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•Microparticles can be produced from emulsion of two or more immiscible liquids.
•solution of hydrophobic drug and polymer in an organic solvent is emulsified in an aqueous solution containing an emulsifying agent to produce oil in-water (o/w) emulsion.
•Depending on the solubility of the drug the type of emulsion can be modified.
Emulsion solidification
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SOLVENT EVAPORATION
•Polymer is dissolved in volatile organic solvent
•Drug is solubilized or dispersed in polymer solution
•Emulsified in aq solution containing emulsifying agent.
•Stirred till all solvent get evaporated
•Washed and freeze dried.
•Sometimes emulsion is heated to evaporate organic phase.
SOLVENT EXTRACTION
•Volatile solvents used otherwise it results in irregular morphology, high porosity of the microspheres, loss of payload, polydispersed
•Relatively non volatile solvent can be removed by extraction in continuous phase
•This is done by using solvent that has significant solubility in continuous phase, increasing the concentration difference between continuous phase and dispersed phase or by adding third solvent in continuous phase to facilitate extraction of solvent.
CROSS LINKING
•The hydrophilic polymers from natural origin such as gelatin, albumin, starch, dextran and chitosan can be solidified by a chemical or thermal cross-linking process. A w/o emulsion is prepared by emulsifying the polymer solution in an oil phase containing an emulsifying agent such as Span 80.
•Heating and adding counter polyions or cross-linking reagents are alternative crosslinking methods.
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•The polymer is first melted and then mixed with solid drug particles or liquid drug.
•This mixture is suspended in an immiscible solvent and heated to 5˚C above the melting point of the polymer under continuous stirring.
• The emulsion is then cooled below the melting point until the droplets solidify.
Hot-Melt Microencapsulation
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•Ionic gelation involves cross-linking of polyelectrolyte's in the presence of multivalent counter ions.
•Ionic gelation is often followed by polyelectrolyte complexation with oppositely charged polyelectrolyte's.
•This complexation forms a membrane of polyelectrolyte complex on the surface of the gel particles, which increases the mechanical strength of the particles.
•Nowadays, it has widely been used for both cell and drug encapsulation.
Ionic Gelation/Polyelectrolyte Complexation
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Interfacial Polymerization
Polymerization can be terminated by adding excess non-aqueous phase.
Then additional non-aqueous phase containing acid chloride is added to the emulsion to allow interfacial polymerization.
A non-aqueous phase containing surfactant and an aqueous phase containing drugs and diamine are mixed to form a w/o emulsion.
Monomers can be polymerized at the interface of two immiscible substances to form a membrane.
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•Spray drying is a single-step, closed-system process applicable to a wide variety of materials.
•The drug is dissolved or suspended in a suitable solvent containing polymer materials.
•The solution or suspension is atomized into a drying chamber.
•Microparticles form as the atomized droplets are dried by heated carrier gas.
Spray Drying
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•Spray desolvation involves spraying a polymer solution onto a desolvating liquid.
•For example, microparticles can be made by spraying a PVA solution onto an acetone bath. Here, the polymer solvent (water) is extracted into acetone, and PVA precipitates to form solid microparticles.
Spray Desolvation
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•In spray coating, the coating material is sprayed onto solid drug core particles that are rotated in a coating chamber.
a.Fluid bed coating (air suspension technique)
b.Pan coating
Spray Coating
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•It consists of dispersing of solid, particulate core materials are suspended in upward moving air stream and then spray- coating of the air suspended particles.
a. Fluid bed coating
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•Relatively large particles can be encapsulated by pan coating.
• Size of solid particles should be greater than 600 mm to achieve effective coating using this method.
b. Pan coating
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•The supercritical fluid method is a relatively new method, which can minimize the use of organic solvent and harsh manufacturing conditions taking advantage of two distinctive properties of supercritical fluids.
Supercritical Fluid
•Utilizes the supercritical fluid (e.g., carbon dioxide) a solvent for the polymer
Rapid Expansion of Supercritical Solutions (RESS)
•Using the fluid as an antisolvent that causes polymer precipitation.
Supercritical antisolvent crystallization (SAS)
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•Here, supercritical fluid containing the active ingredient and the shell material are maintained at high pressure.
•These are then released at atmospheric pressure through a small nozzle.
•Due to the sudden drop in pressure, desolvation of the shell material takes place leading to its deposition surrounding the active ingredient (core) and forms a coating layer.
RAPID EXPANSION OF SUPERCRTICAL SOLUTION (RESS)
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•This process is also called supercritical fluid antisolvent (SAS).
•Here SCF is added to a solution of shell material + active ingredients maintained at high pressure.
•This leads to volume expansion of the solution causing super saturation causing precipitation of the solute occurs.
•The liquid solvent must be miscible in with SCF.
•And solute should be soluble in liquid solvent, but not dissolve in solvent + SCF.
•This process is not suitable for encapsulation of water soluble substances due to its low solubility in SCF.
Supercritical antisolvent crystallization (SAS)
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EVALUATION PARAMETERS
Production Yield
Drug Content and Loading Efficiency
Particle Size Measurement
Surface Characterization of the Microcapsules
Determination of Bulk Density
Angle of Repose
Zeta Potential Study
Swelling Property
Infrared Absorption Study
X-ray Diffraction
Thermal Analysis
In vitro Drug Release
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Production Yield:
•%production yield= (W1 / W2) * 100
•W1 = weight of dried microcapsules
•W2 = sum of initial dry weight of starting materials.
Drug Content and Loading Efficiency
•Drug Content can be measured through dissolution and assay.
•Loading Efficiency = ( actual amount of drug loaded/ theoretical amount ) * 100
Particle Size Measurement:
•Microcapsules are suspended in suitable solvents and measured by laser particle size distribution analyzer or microscopic method.
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Surface Characterization of the Microcapsules:
•scanning electron microscope (SEM)
•electron microscopy
•scanning tunneling microscopy (STM)
Determination of Bulk Density :
•Average weight of microcapsules taken in 100 ml graduated cylinder
•apparent volume (v) = 50 – 100 ml
•Bulk density = mass / volume
•Unit = gm/ ml
Angle of repose:
•tan Ө = h/r
Zeta Potential Study:-
•determined by Zeta Meter.
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In Vitro Drug Release Study:
• Franz diffusion cell
• USP dissolution apparatus (Basket)
Thermal Analysis:
•Differential Scanning Calorimetry (DSC)
•Thermo Gravimetric Analysis(TGA)
•Differential Thermometric Analysis (DTA)
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Prolonged release dosage form.
Enteric coated dosage form.
Masking of taste.
Encapsulating volatile substances.
Oily medicines can be tableted.
Protect drugs from environmental conditions.
Reduction in hygroscopic nature.
Reduce gastric irritation of many drugs.
Prepare intrauterine contraceptive device.
For preparing multilayer tablet.
applications
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Self emulsifying oral lipid based formulation to improve oral bioavailability of poorly water soluble drugs. E.g. Cyclosporine A
Advances in Heparin delivery.
Vesicles as tool for dermal and transdermal delivery to enhance the penetration rate and acts as depot for sustained release of dermal active compounds.
Lipid and polymeric colloidal carriers for ocular drug delivery.
Novel approaches
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•Microencapsulation technology can protect active materials against environment, stabilize them, prevent or suppress volatilization.
•Microencapsulation technology can provide new forms and features, thus, it can create whole new fields of applications.
• Drug delivery has become increasingly important mainly due to the awareness of the difficulties associated with a variety of old and new drugs Of the many polymeric drug delivery systems, biodegradable polymers have been used widely as drug delivery systems because of their biocompatibility and biodegradability.
conclusion
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1.“Encyclopedia of Pharmaceutical Technology” by James Swarbrick; 3rd edition; Vol-4; Pg – 2315
2.The theory and practice of industrial pharmacy; by Leon Lachman, Herbert A. Liberman; 2009; Pg – 412.
3.“ Microencapsulation – Methods and Industrial Applications” Drugs and The Pharmaceutical Sciences; by Simon Benita Vol– 158; 2nd edition.
References
