Microencapsulation

Microencapsulation Dr. Asmaa Abdelaziz Mohamed PH.D of Pharmaceutics

Microencapsulation Microencapsulation is a means of applying thin uniform coatings to microparticles of solids dispersion or droplets of liquids.

Microcapsules • Microcapsules are small particles that contain an active agent (core material) surrounded by a shell orcoating. • Their diameters generally range from a few microns to a few millimetres. • Microcapsules can have many different types and structures: • a) simple droplets of liquid core material surrounded by a spherical shell (Microcapsules) • b) irregularly-shaped particles containing small particles of solid core material dispersed in a continuous polymer shell matrix )microspheres).

Microencapsulated solid Microencapsulated liquid microspheres

application of microencapsulation Four important areas of microencapsulation application are : • The stabilization of core materials • The control of release or availability of core materials • Separation of chemically reactive ingredients within a tablet or powder mixture. 4. Taste-masking.

Core Material • The core material is the material to be coated, which may be liquid or solid in nature. • The composition of the core material can be varied: • The liquid core can include dispersed and/or dissolved material. • The solid core can be a mixture of active constituents, stabilizers, diluents, excipients , and release-rate retardants or accelerators.

Some Microencapsulated Core Materials

Coating Materials The coating material should: • Be capable of forming a film that is cohesive with the core material • Be chemically compatible and non-reactive with the core material • Provide the desired coating properties, such as strength, flexibility, impermeability, optical properties, and stability. • Coating material selected from natural and synthetic film-forming polymers like: - carboxy methyl cellulose - ethyl cellulose - cellulose acetate phthalate - poly vinyl alcohol - gelatin, gelatin- gum arabic - poly hydroxy cellulose - waxes - chitosan

Microencapsulation methods • Air suspension • Coacervation-phase separation • Spray drying and spray Congealing • Pan coating

Air Suspension Principle • 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. • Within the coating chamber, particles are suspended on an upward moving air stream as indicated in the drawing.

3. The design of the chamber and its operating parameters provide a recirculating flow of the particles through the coating zone portion of the chamber, where a coating material, usually a polymer solution, is spray-applied to the moving particles. 4. During each pass through the coating zone, the core material receives an increment of coating material.

5. The cyclic process is repeated several times during processing, depending on the coating thickness desired. 6. The air stream also serves to dry the product while it is being encapsulated.

Pan Coating • In this method, the coating is applied as an atomized spray to the desired solid core material in the coating pan. To remove the coating solvent, a warm air is used in a process similar to that of tablet coating. • Pan Coating process is used for solid particles greater than 600 microns in size. • The coating is applied as a solution, or as an atomized spray, to the desired solid core material in the coating pan. • Warm air is passed over the coated materials as the coatings are being applied in the coating pans to remove the coating solvent.

Coacervation-Phase Separation Coating formation during coacervation phase-separation process consists of three steps carried out under continuous agitation: Step 1. formation of three immiscible chemical phases (vehicle ,Core and liquid coating). Step 2. Deposition of liquid coating material. Step 3. Rigidization of the coating

Step 1 Formation of three immiscible chemical phases: A liquid manufacturing vehicle phase, a core material phase, and a coating material phase. • is the formation of three immiscible phases which are the solvent phase, the liquid coating material phase and the core material phase. • To form the three phases, the coating polymer solution is mixed with immiscible solvent to form two immiscible liquids, then the core material is added to form the third phase.

Step 2 Depositing the liquid polymer coating upon the core material. • Step 2: it consists of depositing(استقرار او ترسب) the liquid coating material on the core material. Deposition of the liquid polymer coating around the core material occurs if the coating polymer is adsorbed at the interface between the core material and the immiscible solvent phase, and this adsorption phenomenon is a prerequisite (essential) to effective coating.

Step 3 Rigidizing the coating, it involves rigidizing the coating, usually by thermal techniques, to form the microcapsules.

Ex: Ethyl cellulose (a water insoluble polymer) is applied to aminophenol powder (core material) by utilizing the temperature characteristics of the polymer in the cyclohexane(solvent). • The Ethyl cellulose is insoluble in cyclohexane at room temperature, but soluble at elevated temperature. • The ethyl cellulose and cyclohexane mixture is heated to form a homogeneous (one phase) solution. • The aminophenol is dispersed (as insoluble powder) in the solution with stirring. • Allowing the mixture to cool with continuous stirring results in coacervation-phase separation of the ethyl cellulose from cyclohexane and microencapsulation of the core material. Allowing the mixture to cool further to room temperature causes gelation and solidification of the coating. • The microencapsulated product is collected from by filtration.

Spray Drying and Spray Congealing • These methods can be used for both liquid and solid drugs. • Spray-drying and spray-congealing processes are similar in that both involve dispersing the core material in a liquid coating material and spraying the core-coating mixture into certain environmental condition, whereby rapid solidification of the coating is achieved. • The principal difference between the two methods is the means by which the solidification is achieved. • Coating solidification in the case of spray drying is achieved by • rapid evaporation of a solvent in which the coating material is • dissolved. • Coating solidification in spray congealing methods is accomplished by thermally congealing (cooling) • In practice, microencapsulation by spray drying is done by dispersing a core material in a coating solution, in which the core material is insoluble and then atomizing the mixture into an air stream

Cont. Spray Drying and Spray Congealing • The air (hot air) used for vaporization required to remove the solvent from the coating material • The equipment used for this purpose is the usual spray dryer. • Microencapsulation by spray congealing can be accomplished with spray drying device also. General process variables and conditions are quite similar to those of spray drying, except that the core material is dispersed in a coating material melt rather than the usual coating solution. Coating solidification (and microencapsulation) is accomplished by spraying the hot mixture into a cool air. • Ex:Waxes, fatty acids and certain polymers which are solids at room temperature but melt-able at high temperatures, are applicable to spray congealing technique.

Emulsions • ‘ thermodynamically unstable mixture of two essentially immiscible liquids

Theories of Emulsification: When two immiscible liquids are mechanically agitated, both phases initially tend to form droplets. When the agitation is stopped, the droplets quickly coalesce(cohere), and the two liquids separate. An explanation of this phenomenon is because of cohesive force between the molecules of each separate liquid exceeds adhesive force between two liquids. Due to interfacial energy or tension at boundary between the liquids.

Therefore, to prevent the coalescence and separation, • emulsifying agents have been used. • Usually, only one phase persists in droplet form for a prolonged period of time. This phase is called the internal (disperse or discontinuous) phase which is finely and uniformly dispersed as globules throughout the second phase (the continuous phase). • emulsion contains At least 2 phases: • Disperse or internal phase • or external phase. • pharmaceutical emulsions range from lotions (low viscosity) to creams (high viscosity). The particle size of the dispersed phase commonly ranges from 0.1 to 100 µm

Types of emulsion o/w emulsions. w/o emulsions. Multiple emulsions (e.g. w/o/w emulsions).

1- Oil in water emulsion: • Aqueousthe emulsionis termed oil-in-water (O/W) • They are non-greasy and are easily removable from the skin and they are used externally to provide cooling effect • internally to also mask the bitter taste of oil. • Water soluble drugs are more • quickly released from O/W emulsion. • O/W emulsion give a positive • conductivity test as water, the external • phase is a good conductor of electricity

2-Water in oil emulsion • Water is dispersed as globules in oil (continuous phase) is • termed water-in-oil emulsion (W/O) • have an occlusive effect by hydrating The stratum corneum • and inhibiting evaporation of sweating secretions • They are greasy and not water washable • and used externally to prevent evaporation • of the moisture from the surface of skin • e.g. cold cream. • e.g. Oil soluble drugs are more quickly • released from W/O emulsion. • W/O emulsion is not given a positive • conductivity tests because oil is the • external phase which is a poor conductor • of electricity.

3- Multiple emulsions • Multiple emulsions are complex systems. • They can be considered as emulsions of emulsions. • Is entirely feasible (can be made) to prepare a multiple emulsions with the characteristics oil-in-water-in oil (o/w/w) or of water-in oil-in water (w/o/w) emulsions. • Such emulsions also can invert however, during inversion they usually form "simple” emulsions. Thus, a w/o/w emulsion normally yields an o/w emulsion.

Microemulsions: • Microemulsions are systems consisting of water, oil and surfactant, which constitute a single optically isotropic متماثلand thermodynamically stable liquid solution. • Such emulsions appear transparent to the human eye in daylight. • In a microemulsions, disperse globules having a radius below the range of 10 to 75 nm

Formation of Emulsions emulsion preparation by the commonly employed dispersion method requires a sequence of processes for breaking up the internal phase into droplets. The requirement in the design of any emulsification process that the variable physical and chemical parameters are selected and controlled to favor emulsion formation.

Physical Parameters • The application of energy as heat, mechanical agitation,ultrasonic vibration, or electricity is required to reduce the internal phase into small droplet. • The amount of work input depends on the length of time during which energy is supplied; thus, timing (scheduling of work input) becomes another important physical parameter. • Heat • -Vaporization is an effective way of breaking almost all the bonds between the molecules of a liquid. It is possible to prepare emulsions by passing the vapor of a liquid into an external phase that contains suitable emulsifying agents This process of emulsification, called the condensation method but limited to the preparation of dilute emulsions of materials having low vapor pressure. The more practical emulsification by dispersion is affected by temperature changes. The interactions are complex, and it is almost impossible to predict whether a raise in temperature will favor emulsification or coalescence.

Heat -Vaporization is an effective way of breaking almost all the bonds between the molecules of a liquid. It is possible to prepare emulsions by passing the vapor of a liquid into an external phase that contains suitable emulsifying agents This process of emulsification, called condensation method but limited to the preparation of dilute emulsions of materials having relatively low vapor pressure. The more practical emulsification by dispersion is affected by heat—or better, changes in temperature. The interactions are complex, and it is almost impossible to predict whether a raise in temperature will favor emulsification or coalescence. -An increase in temperature decreases interfacial tension as well as viscosity. that emulsification is favoured by an increase in temperature. however, an increase in temperature raises the kinetic energy of droplets and thereby facilitates their coalescence. This type of instability is normally observed when emulsions are stored at elevated temperatures for long periods of time. -Changes in temperature alter the distribution of emulsifier between the two phases and cause emulsifier migration. The distribution of the emulsifier as a function of temperature cannot be correlated directly with either emulsion formation or stability

Phase Inversion Temperature The most important influence of temperature on emulsion is inversion. -It was observed that w/o emulsions of benzene in water that were stabilized with sodium stearate (emulsifier) invert to o/w emulsions upon heating and reform w/o emulsions upon cooling. -The temperature at which the inversion occurs depends on emulsifier concentration and is called phase inversion temperature (PIT). -Emulsions formed by a phase inversion technique are generally considered quite stable and are believed to contain a finely dispersed internal phase. -It may be made by the addition of an electrolyte or by changing the phase volume ratio or by temperature changes. Phase inversion by using the proper emulsifying agent in adequate concentration, keeping the concentration of dispersed phase between 30 to 60 percent. And by storing the emulsion in a cool place.

Timing During the initial period of agitation required for emulsification, droplets are formed; however, as agitation continues, the Chance for collision between droplets becomes more frequent,and coalescence can occur. It is generally advisable to avoid excessive periods of agitation during and after the formation of an emulsion.

Formulation of emulsion The smaller the globules of the disperse phase, the slower will be the rate of creaming in an emulsion. The size of these globules can also affect the viscosity of the product, i.e, the smaller the globules, the higher viscosity. equipment Mechanical stirrers: by impellers, turbine mixers (2) Homogenizers: (such as the Silverson mixer-homogenizer) can also be used to reduce globule size still further (3) Ultrasonifiers,

(4)Colloid mills: Colloid mills are also suitable for the preparation of emulsions. The extensive shearing of the product they produce emulsions of very small globule size.

Cont. formation of emulsion • In many cases simple blending of the oil and water phases with a suitable emulgent system sufficient to produce good emulsions. • small scale by the use of a pestle and mortar or by using a mixer fitted with an impeller type of agitator, the size and type of which will depend primarily on the volume and viscosity of the product. • Fat or oil drugs for oral administration are formulated as o/w emulsions. In this form, the presence of a flavor in the aqueous phase will mask any unpleasant taste. • Emulsions for intravenous administration must be of o/w type, although intramuscular injections can also be formulated as w/o products if a water-soluble drug is required for depot therapy (S.R). • Emulsions are most widely used for external application. Semisolid emulsions are such as creams and more fluid-containing preparations are called either lotions or liniments (liniments are intended for skin massage).

Cont. formation of emulsion • In most cases, the oil phase of an emulsion is the active agent, and therefore its concentration in the product is predetermined. Castor oil and cod liver oil are examples of medicaments which are formulated as emulsions for oral administration. • A high viscosity is necessary in order to maintain a physically stable emulsion. It is important, however, that these products should be shaken and poured easily from the container. On the other hand, the main disadvantage with low-viscosity emulsions is their tendency to cream easily.

Emulsifing agent choice: The final choice will depend on the properties and use of the final product and the other materials required to be present. The HLB balance The inclusion of an emulsifying agent(s) is necessary for the emulsification process during manufacture, and also to ensure emulsion stability during the shelf-life of the product. A useful method has been suggested for calculating the quantities of these emulsifying agents necessary to produce physically stable emulsion. This is called the hydrophile-lipophile balance (HLB) method. Each surfactant has an HLB number representing the relative proportions of the lipophilic and hydrophilic parts of the molecule. High numbers (e.g., 20, 30, 33, etc.) indicate a surfactant exhibiting mainly hydrophilic or polar properties, whereas low numbers represent lipophilic or non-polar characteristics.

The phase inversion temperature • An o/w emulsion stabilized by non-ionic emulgents will invert to form a w/o product on heating. This is because, as the temperature increases, the HLB value of a non-ionic surfactant will decrease as it becomes more hydrophobic. • At a temperature at which the emulgent has equal hydrophilic and hydrophobic tendencies the emulsion will invert. This temperature is called the phase inversion temperature. • The stability of an emulsion is related to the phase inversion temperature of its emulsifying agent.

CLASSIFICATION OF EMULSIFYING AGENTS There are different classes of emulsifying agents (also called emulsifiers or emulgents). classified as shown below. I. Synthetic emulgents 1. Anionic surfactants: in aqueous solutions, these compounds dissociate to form negatively charged anions that are responsible for their emulsifying ability. They are widely used because of their cheapness, but because of their toxicity are only used for externally applied preparations. Example is sodium stearate. 2. Cationic surfactants: these materials dissociate to form positively charged cations in water that provide the emulsifying properties. The most important group of cationic emulgents consists of the quaternary ammonium compounds. Like many anionic emulgents, if used on their own they will produce only poor emulsions, but if used with non-ionic emulgents (auxiliary) they will form stable preparations. Example is Tween.

3. Amphoteric surfactants: this type possesses both positively and negatively charged groups, depending on the pH of the system. They are cationic at low pH and anionic at high pH. They are not widely used as emulsifying agents. Example is lecithin. II. Natural emulgents Naturally occurring materials often suffer from two main disadvantages: they show batch-to-batch variation in composition and hence in emulsifying properties, and are susceptible to bacterial growth. For these reasons they are not widely used in manufactured products requiring a long shelf-life, but rather for extemporaneously prepared emulsions designed for use within a few days of manufacture. Example is acacia. III. Semisynthetic emulgents In order to reduce the problems associated with natural emulgents, semisynthetic derivatives are available. Several grades of methylcellulose and carmellose sodium are available. Methylcellulose, for example, is used to stabilize Liquid Paraffin Oral Emulsion.

Other formulation additives In addition to the emulgents, other additives such as buffers, preservatives, thickening agents, flavors, colors and sweeteners are also used.

PHYSICAL STABILITY PROBLEMS some cases of physical instability. I.Creaming It is the separation of an emulsion into two regions, one of which is richer in the disperse phase than the other. Ex: the creaming of milk, when fat globules slowly rise to the top of the product. This is not a serious instability problem that can be reformed by shaking the product (reversible case). It is, however, undesirable because of the increased risk of coalescence and is also inelegant and, if the emulsion is not shaken adequately, there is a risk of the patient obtaining an incorrect dosage. According to Stokes' law, to slow the rate of creaming the following methods can be used: 1. Production of an emulsion of small droplet size. 2. Increase in the viscosity of the continuous phase. 3. Control of disperse phase concentration: It is not easy to stabilize an emulsion containing less than 25% disperse phase, as creaming will readily occur. A higher disperse phase concentration would result in a hindrance of movement of the droplets and reduction in rate of creaming. theoretically possible to include as much as 75% of an internal phase, it is found (practically) that at about 60% concentration phase inversion occurs.

Flocculation • Flocculation involves the aggregation of the dispersed globules into loose clusters within the emulsion. • The individual droplets retain their identities but each cluster behaves physically as a single unit. This would increase the rate of creaming. • As flocculation must precede coalescence, any factor preventing or retarding flocculation would therefore maintain the stability of the emulsion.

Coalescence(breaking): • The coalescence (breaking) of oil globules in an o/w emulsion is resisted by the presence of a mechanically strong adsorbed layer of emulsifier around each globule. Coalescence results in separation of the two phases and emulsion failure (irreversible case). • Coalescence is usually attributed to the failure of the emulsifying agent in doing its job. It is necessary therefore, to ensure that any emulgent system used is not only physically but also chemically compatible with the active agent and with the other emulsion ingredients. Ionic emulsifying agents, for example, are usually incompatible with materials of opposite charge. Anionic and cationic emulgents are thus mutually incompatible.

how to enhance stability (to prevent creaming and cracking)? • 1-Globule size: • Smaller particles have slower creaming or sedimentation than larger particles (Stoke’s law). • Stable emulsions require a maximal number of small sized (1-3 µm) globules and as few as possible larger (>15 µm) diameter globules. • A homogenizer will efficiently reduce droplet size by forcing the emulsion through a small aperture to reduce the size of the globules. • Additionally, reducing droplet size may additionally increase the viscosity if more than 30% of disperse phase is present. • .

2-Viscosity of the continuous phase: Increasing the viscosity of the continuous phase will reduce the potential for globule creaming and hence coalescence as this reduces the movement of globules. How to increase viscosity? Viscosity enhancing agents, which increase the viscosity of the continuous phase, may be used in o/w emulsions. e.g tragacanth, sodium alginate and methylcellulose. Higher percentages of oil phase (o/w). Decreasing the particle size of the internal phase. Higher amounts of solid fats in the oily phase (i.e. high ratios of solid fat to liquid fats)

2-Using emulsifying agents (hydrocolloids, surfactants and other) : Forming interfacial film mechanical barrier which decreases the potential for coalescence (more important). Surfactants may reduce the interfacial tension between the two phases (less important). Hydrocolloids enhance the viscosity of the medium. 3-Storage temperature: Extremes of temperature can lead to an emulsion cracking. When water freezes it expands, so undue pressure is exerted on dispersed globules and the emulsifying agent film, which may lead to cracking. Conversely, an increased temperature decreases the viscosity of the continuous phase and disrupts the integrity of the interfacial film. An increasing number of collisions between droplets will also occur, leading to increased creaming and cracking.

Application of emulsions Oral route: Oral administration of oil-soluble drugs (o/w emulsions). To enhance palatability of oils when given orally by masking both taste and oiliness. Increasing absorption of oils and oil-soluble drugs through intestinal walls. Ex: griseofulvin in oil in an oil-in-water emulsion. IM route: IM depot therapy: Intramuscular injections of some water-soluble vaccines (w/o emulsions) provide slow release and therefore a greater antibody response and longer-Lasting immunity. IV route: IV (o/w) emulsions for hydrophobic drugs. Total parenteral nutrition (TPN) makes use of a sterile oil-in water emulsion to deliver oily nutrients intravenously to patients, using non-toxic emulsifying agents, such as lecithin. Topical applications Transdermal route Rectal route

Identification of emulsion type Miscibility test: An emulsion will only mix with a liquid that is miscible with its continuous phase. Therefore an o/w emulsion is miscible with water. a w/o emulsion with an oil. Conductivity measurement: Systems with an aqueous continuous phase will conduct electricity, whilst systems with an oily continuous phase will not. Staining test: A dry filter paper impregnated with cobalt chloride turns from blue to pink on exposure to stable o/w emulsions. Dye test: If an oil-soluble dye is used, o/w emulsions are paler in colour than w/o emulsions and vice versa. If examined microscopically. an o/w emulsion will appear as coloured globules on a colourless background whilst a w/o emulsion will appear as colourless globules against a coloured background

Microencapsulation