Microencapsulation PDF

Pharmaceutics-3 PT 505 Pharmaceutics department Microencapsulation Asmaa Ashraf El-Kashef, PhD. ❖ Microencapsulation is the process or technique of applying thin solid coatings to microscopic size solid or liquid cores. ❖ Core The core may be a solid d...

Pharmaceutics-3 PT 505 Pharmaceutics department Microencapsulation Asmaa Ashraf El-Kashef, PhD. ❖ Microencapsulation is the process or technique of applying thin solid coatings to microscopic size solid or liquid cores. ❖ Core The core may be a solid drug or a liquid. The liquid core may be: 1. Drug solution. 2. A dispersion solution containing drug (suspensions, emulsions and colloids) 3. Drug melt. ❖ Coat The thickness of the coating film can be varied according to the physical characteristics of both the core and coating materials. ❖ Sizes 1. Nanocapsules: Capsules smaller than 1 m. 2. Microcapsules: Capsules size ranging from 1-1000 m. (most common) 3. Macrocapsules: Capsules larger than 1000 m. ❖ Classification of microcapsules. A. Core may be: 1. Continuous: one mass. 2. Multi-particulate: individual particles or droplets. B. Coat may be: a. Continuous: a film around the core. b. Matrix: a solid vehicle in which drug is embedded. (not used with continuous core) C. According to their structure, microcapsules can be classified into: Continuous core/ shell Multinuclear Multinuclear microcapsules microcapsules microspheres Having a continuous core A multiparticulate core A Matrix coat in which region surrounded by a surrounded by continuous multiparticulate core is continuous coat. coat. embedded. They usually have a spherical They usually have a They usually have an irregular geometry spherical geometry geometry. N.B.: Microcapsule has its coat as film, microsphere has its coat as matrix. ❖ Pharmaceutical applications 1. Masking the undesirable taste or odor of the drug. 2. Separation of incompatible ingredients in the same dosage form. 3. Sustaining or controlling the drug release. 4. Protection of the core material against: a. Chemical degradation by moisture/oxidation. b. Volatilization (volatile substances). 5. Altering surface and colloidal properties. 6. Conversion of liquids into solids. ❖ Non-pharmaceutical application Microencapsulation is applied to a wide range of core materials including adhesives, inks, pesticides, agrochemicals, flavors and fragrances. ❖ Formulation of microencapsulated drugs After completing the microencapsulation process, the material appears as free flowing powder which can be formulated in many dosage forms e.g.: tablets, filled in hard gelatin capsules or suspended in a suitable liquid for oral, topical or parenteral administration. ❖ Steps of microencapsulation 1. Liquefaction of the coating material. (must be liquid) Liquefaction of the coating material is achieved by either: a. Preparation of a solution of the coating material. The proper solvent is that dissolves the coating but not the core material. b. Melting the coating material, the core drug should be stable at the melting point of the coating material. (thermostable) 2. The droplet formation step It is converting the homogenously mixed dispersion of drug core in liquefied coat into small droplets. ❖ The core material may be a solid or a liquid, the coating material must be a liquid. ❖ Techniques for droplet formation: a. Spraying (atomization): where the bulk liquid in which core and coating materials are embedded is divided into small droplets by applying a strong air stream. b. Shearing: where vigorous agitation is applied to divide the bulk liquid containing the core and coating materials into small droplets. c. Centrifugation: the bulk liquid containing the core and coating material is centrifuged in a perforated vessel, it is divided into small droplets emerging from the pores of the vessel. 3. The coat deposition and solidification step The molecules of the coating material surround the core material forming a layer around it, when this layer solidifies the solid coat (or shell) is formed. ❖ Techniques for coat deposition: a. Solvent evaporation technique Getting rid of the solvent, which dissolves the coating material, by evaporation. b. Electrostatic attraction technique Charging the particles of core and coating materials with opposite electric charges  electrostatic attraction takes place between them leading to coat deposition. c. Phase separation “coacervation” technique Changing the physicochemical nature of the microenvironment within the droplet so that the molecules of the coating material deposit on the core. ❖ Classification of microencapsulation methods of formation ❖ According to the technique of coat deposition: 1. Solvent evaporation techniques. 2. Electrostatic attraction techniques. 3. Phase separation- coacervation techniques. 1. Solvent evaporation techniques. These methods have the following requirements: 1. The coating material must be in the form of solution (not a melt). 2. The used solvent a. Should dissolve the coating material not the core. b. Should have a suitable boiling point to be evaporated without drug decomposition. (volatile) 3. The core material must be non-volatile and thermostable at the solvent boiling point. 4. There must be cohesive forces & compatibility between the molecules of the core & coating material. ❖ The product of any solvent evaporation microencapsulation method is: a. Porous (of low bulk density). b. Low yield. ❖ These techniques include: A. Air suspension method. B. Spray drying method. C. Pan coating method.  A.Air suspension method The general features of this method are: a. It is used only for solid core materials (Liquid substances can be microencapsulated by air suspension method after being converted to solids), this can be achieved by the use of solid sorbents pretreated with the liquid sorbates.) b. The P.S. of the core ranges from 35 m to the range of macroencapsulation. ( ≥ 35 μm) c. The coating material is in the form of solution in a volatile solvent. ❖ The method depends on: 1-Suspending the particles of the solid core material in an air stream. 2-Spraying the solution of the coating material on the suspended particles. 3-Applying hot air to evaporate the volatile solvent leading to deposition of the molecules of the coating material on those of the core. ❖ The apparatus used for air suspension microencapsulation method is the Wurster Air Suspension Apparatus ❖Wurster Air Suspension Apparatus: Apparatus consists of: 1. Coating chamber [A] provided with two openings; One is for the core material [B] The other for collecting the microcapsules [C]. 2. These openings are closed by sliding sheets [D1 & D2]. 3. The level of the product opening is lower than that for the core opening. 4. Just below the level of the product opening, there is a screen -with a specified pore size- to lead the coated particles to the product outlet [E]. 5. The solution of the coating material is sprayed upwards from an inlet [F]. 6. The hot air stream is introduced from the bottom [G]. 7. Before reaching the coating solution inlet; the hot air passes through a rotating perforated plate [H] to be well- distributed 8. A transverse manifold [I] at the upper area of the coating chamber limits the coating area [J]. ❖ Process: ❖ Process variables that affect the properties of microcapsules prepared by air suspension method: 1. Particle size and surface area of the core particles. 2. Concentration of the solution of the coating material. 3. Spray rate of the solution of the coating material. 4. Velocity of the air stream. 5. Temperature of the air stream. B. Spray drying method ❖ The general features: 1. It is used for solid or liquid core materials. 2. It produces irregular multinuclear microspheres or microcapsules. 3. The hot air is used ONLY to evaporate the solvent. (not affect distribution, opposite to air suspension method) ❖ The spray dryer consists of: 1) Heating chamber [A], 2) Stream of hot air [B). 3) An inlet for feeding the dispersion of core in coating material [C]. 4) An outlet to harvest the microcapsules [D]. ❖Process 1. Prepare the concentrated solution of the coating material. 2. Disperse the core material in the prepared solution either in the form of suspension (for solid) or emulsion (for liquid). 3. Heat the heating chamber of the apparatus by applying a stream of hot air. 4. Introduce the prepared dispersion into the heating chamber. 5. When the droplets of the dispersion meet the hot air, the solvent will evaporate, coating material deposited on the core Advantages Limitations 1. Spray dryer is readily available. 1-The coating material must be sufficiently 2. Suitable for both solid and liquid cores. concentrated (40-60 % w/v) with adequate 3. Produce high yield and viscosity as the concentration ↑ →the microencapsulation efficiency. viscosity ↑ which makes the microencapsulation more difficult. 2-The solvent evaporation rate must be carefully controlled as rapid evaporation of the solvent → has poor microencapsulation efficiency. 3-The core should be 5-600 m  C. Pan coating ❖Process 1. Process depends on applying the solid core material [A] in the coating chamber along with the liquefied coating material [B]. 2. The coating material was liquefied by preparing a solution in a volatile solvent. 3. The coating chamber is a large pan rotating around its axis [C]. 4. Hot air is introduced through the hot air inlet [D], where it evaporates the volatile solvent and exits through the air outlet [E]. 5. This leads to deposition of the coating material on the particles of the core material and microcapsules are then produced ❖ Limitations ❖ The core material must be Solid and of large particle size (> 600 µm “600-5000 µm”). ❖ To increase the diameter of the core material particles they may be carried on sugar seeds. 2-Electrostatic deposition techniques. ❖ The method depends on: 1. Introducing the core material [A] (as solid particles or liquid droplets) to the coating chamber [B] through an ion discharger [C] so that the core material acquires certain electric charge. 2. At the same time, the liquefied coating material is introduced through another ion discharger [E] so that its droplets acquire the opposite electric charge. 3. When the droplets of the coating & core material meet, deposition of the coat occurs. 4. Mainly for Small particles (1-50 µm)  3- Phase separation-coacervation techniques. Coacervation: Piling or heaping things together = accumulation. ❖ The process of coacervation consists of three steps: 1) Formation of three components 2 phases system. Liquid vehicle. Phase 1: solution of the coating Core material. material in the liquid vehicle. Coating material. Phase 2: The dispersed core. 2) Using a de-solvation agent: Separation of the dissolved coating material from the solution with the formation of 3 phases system (core, coat and liquid vehicle) "phase separation". 3) Accumulation of the separated coating material around the dispersed core drug. "Coacervation" N.B.: The accumulated coating material is called coacervate. 4) Under certain conditions the coacervate solidifies forming a coat around the core drug producing microcapsules. N.B.: Phase separation- coacervation methods differ according to the used de-solvation agent used to cause the phase separation (step number 2). ❖ Accordingly, phase separation-coacervation methods are: a. Temperature change method b. Addition of incompatible substances methods: i. Incompatible polymer method ii. Salt addition method iii. Non- solvent method c. Polymer- polymer interaction method. a. Temperature change method ❖ Mechanism: In this method, the coating material is soluble in the vehicle while hot and deposits around the core material on cooling. N.B.: the coating material may be melted, then the core drug is dispersed in the melted coat, by cooling the coat is caused to solidify around the core. The de-solvation agent is lowering the temperature (cooling) b. Incompatible substance method ❖ Mechanism: The coating material is soluble in the used solvent. On addition of an incompatible substance, phase separation of the dissolved coating material, coacervation around the dispersed core drug, solidification producing microcapsules. i. incompatible The ii. incompatible incompatiblesalt substanceiii.mayincompatible be solvent method polymer method method (salting out) (non-solvent) 1. The coating material is soluble in the used solvent when alone. 2. A solution of the 2. A solution of the 2. A solvent that doesn’t dissolve the incompatible polymer (in incompatible salt (in the coating material (non- solvent) is the same solvent of the same solvent of the coating added → The addition of the non- coating material solution) material solution) is added. solvent changes the nature of the is added. Solvent: mostly water→ original solvent (DEC)→ decrease to prefer salt solubility to the solubility of the coating material coating material solubility in the original solvent 3. Phase separation of the dissolved coating material, coacervation around the dispersed core drug, solidification. ❖ The used incompatible substance: 1. Not interact with the coating material or the core drug. 2. Has high affinity to solvent (preferably dissolved by solvent in case of salt or polymer) → to cause coating material precipitation. N.B.: These 3 methods are called “Simple phase separation coacervation methods”.  c. Polymer - Polymer interaction method ❖ Mechanism: Drug is dispersed in a solution of a certain polymer. A solution of the anther polymer (in the same solvent of the original polymer) is added. The 2 polymers interact producing a new polymer that is insoluble in the used solvent → phase separation of the produced polymer → coacervate around the dispersed core drug → solidification. ❖ The used incompatible polymer 1. Should be preferably dissolved in the solvent compared to the coating material. 2. Interacts with the original polymer producing insoluble product →the actual coating material. 3. The interaction occurs because the 2 polymers carry opposite charges. 4. Not interact with the core drug. N.B.: This method is called “Complex coacervation method”. (Coat is prepared in situ) Common advantage of all phase separation coacervation method: simple, unsophisticated and has low cost. 4- Spray congealing method ❖ This method is a combination between Spray drying method (droplet formation) and Phase separation- coacervation method. ❖ (Coat deposition) “Temperature change method” 1. The drug is dispersed in a melted coating material. 2. The dispersion is sprayed into the coating chamber (as in spray drying) 3. Coat deposition occurs by cooling (as in the temperature change method) using a cold air stream. 4. Particle size: 5-600 µm (as spray drying method) 1. Choice of microencapsulation techniques. No microencapsulation techniques developed to date is suitable for all types and sizes of core materials. ❖ The nature of the coating material In all microencapsulation methods, the coating material should be liquefied either by being melted or dissolved in a suitable solvent. For melted coating Only temperature change and spray congealing methods can be used. materials ❖ If core particle size 5-600 m so choose spray congealing or (Core must be heat temperature change (1-5000 m) stable) ❖ If core particle size > 600 m so choose temperature change only. For solutions of 1. If solvent is volatile and thermostable so choose any of the solvent the coating evaporation methods (air suspension, spray drying & pan coating). materials: a. If core p.s < 50 m so choose spray drying b. 50 m < core p.s < 600 m so choose Air suspension or spray drying c. If core p.s > 600 m so choose Air suspension or pan coating 2. If solvent is non-volatile or thermolabile so choose electrostatic attraction method or phase separation method (except Temperature change) a. If core p.s < 50 m so choose electrostatic deposition method b. If core p.s > 50 m so choose phase separation coacervation ❖ The nature of the core material 1. For liquid core materials, air suspension and pan coating methods can NOT be used. 2. For solid core materials, all methods can be used (selected according to particle size) 3. For heat labile core drug, don't use a method that makes use of heat as: a. Solvent evaporation techniques (air suspension, spray drying and pan coating methods), b. Phase separation- coacervation technique depends on temperature change. c. Spray congealing technique. ❖ History The 1st microencapsulation product was prepared by complex coacervation. ❖ Future considerations A. Microencapsulation of drugs in red blood cells Where the cell membrane is composed of phospholipids and proteins, which were found to be ideal coating materials for many drugs. In addition, encapsulation of drugs in the red blood cells results in drug targeting to certain the liver and spleen, where the red blood cells are destructed normally in the body. B. Microencapsulation of living cells Microencapsulated living cells offer an alternative to organ transplantation. The microencapsulated cells can be implanted into the patient’s body with minimal immune rejection. This is particularly important for liver cells (used in case of liver dysfunction), pancreatic cells (used in case of type I diabetes) and thyroid cells (used in case of thyroid dysfunction).  ❖ Evaluation of microcapsules 1. Morphology by scanning electron microscopy (SEM). 2. Micrometric study (particle size, particle size distribution). 3. Flow properties. 4. Drug content & microencapsulation efficiency. 5. Drug release and dissolution. 6. Analysis of residual solvents/chemicals should not exceed the stated safety limits. ❖ The efficiency of any microencapsulation process Wt of drug in core % Microencapsulation efficiency = x 100 total Wt of drug to be encapsulated Yield value = Weight of prepared microcapsules N.B.: Efficient microencapsulation produce microcapsules containing 10 - 90% (w/w) drug. Example: 50 g of n-acetyl p-amino phenol was suspended in 1 liter of 20 % w/v solution of ethyl cellulose in warm cyclohexane (50C0), The suspension was sprayed in the coating chamber where it met a stream of cold air (15 C0) a) 40 g of microcapsules were produced. When analyzed they contained 27 g n-acetyl p-amino phenol, 12 g ethyl cellulose and 1 g cyclohexane. b) The core drug is …… (n-acetyl p-amino phenol) c) The coating material is …….. (ethyl cellulose) d) The microencapsulation method is ……….. (spray congealing) e) The microencapsulation efficiency = ……………… (27*100/50 = 54%) f) The yield = ……….. (40 g )