RAHAT SHAMIM

Definition:
Suspensions are heterogeneous systems consisting of two

phases. The continuous or external phase is generally a liquid or semisolid, and the dispersed or internal phase is made up of particulate matter that is essentially insoluble in but dispersed throughout the continuous phase the insoluble matter may be intended for physiologic absorption or for internal or external coating functions. Preparations containing finely divided drug particles (suspensoid) distributed somewhat uniformly throughout a vehicle in which the drug exhibits the minimum degree of solubility. A coarse suspension is a dispersion of finely divided insoluble solid particles in a fluid.

 Systems with particles smaller than 0.1 to 0.2 micron are

generally considered to be colloidal and exhibit properties that lie between those of true molecular solutions and suspensions of visible particles do not exhibit all properties of colloid The suspended particles do not exhibit all properties o colloids, such as colligative properties but do have surface properties which enhances its adsorption power. Dispersed particles in the coarse dispersion have a greater tendency to separate from the dispersion medium because of their greater size than in fine dispersions. Most solids in dispersion tend to settle to the bottom of container due to greater density than dispersion medium. Complete and uniform redistribution of the dispersed phase is essential to the accurate administration of uniform doses.

Classification
Based On General Classes

Oral suspension Externally applied suspension Parenteral suspension Based On Proportion Of Solid Particles Dilute suspension (2 to 10% w/v solid) Concentrated suspension (50% w/v solid) Based On Electrokinetic Nature Of Solid Particles Flocculated suspension Deflocculated suspension Based On Size Of Solid Particles Colloidal suspension (< 1 micron) Coarse suspension (>1 micron) Nano suspension (10 ng)

Routes of Administration
Oral
Ocular Otic Rectal Parenteral Topical

Advantages
Suspension can improve chemical stability of certain drug.

E.g. Procaine penicillin G Drug in suspension exhibits higher rate of bioavailability than other dosage forms. bioavailability is in following order, Solution > Suspension > Capsule > Compressed Tablet > Coated tablet
Duration and onset of action can be controlled. e.g.

Protamine Zinc-Insulin suspension e.g. Chloramphenicol palmitate

Suspension can mask the unpleasant/ bitter taste of drug.

Disadvantages
Physical stability, sedimentation and compaction can causes problems.
It is bulky sufficient care must be taken during handling and transport. It is difficult to formulate Uniform and accurate dose can not be achieved unless suspension are packed in unit dosage form

Features Desired In Pharmaceutical Suspensions

The suspended particles should not settle rapidly and sediment

produced, must be easily re-suspended by the use of moderate amount of shaking. It should be easy to pour yet not watery and no grittiness. It should have pleasing odor, colour and palatability. Good syringe ability. It should be physically, chemically and microbiologically stable. Parenteral / ophthalmic suspension should be sterilizable. The characteristic of suspension should be such that the particle size of the suspensoid remain constant throughout long periods of undisturbed standing. the suspension should pour readily and evenly from its container.

FUNDAMENTAL PROPERTIES
A. Particle Properties
The most significant characteristics of a dispersion are the

size and shape of the dispersed particles. Both properties depend largely on the chemical and physical nature of the dispersed phase and on the method used to prepare the dispersion. The mean particle diameter as well as the particle size distribution of the dispersed phase have a profound effect on the properties of the dosage forms, such as product appearance, settling rate, drug solubility, resuspendability, and stability. Clinically important, the particle size can affect the drug release from the dosage forms that are administered orally, parenterally, rectally, and topically.

 Thus, these parameters have to be taken into account

when formulating pharmaceutical products with good physical stability and reproducible bioavailability. Particle Shape Insoluble particles of drugs or pharmaceutical excipients obtained from various sources and manufacturing processes are seldom uniform spheres even after size reduction and classification. For example, precipitation and mechanical comminution generally produce randomly shaped particles unless the solids possess pronounced crystal habits or the solids being ground possess strongly developed cleavage planes. Primary particles may exist in various shapes, ranging from simple to irregular geometries.

 Their aggregation behavior produces an even greater variety

of shapes and structures. Most common shapes found with pharmaceutical solids are spheres, cylinders, rods, needles, and various crystalline shapes. Various pharmaceutical excipients exhibit characteristic particle morphologies determined by their molecular structure and the arrangement of the molecules. Some clay particles have plate-like structures possessing straight edges and hexagonal angles, e.g., bentonite and kaolin, while other clays may have rod-shaped particles. The information on particle shape is particularly important for the understanding of the behavior of suspensions during storage.

 The particle shape of the suspended particles

(suspensoids) may have an impact on the packing of sediment (e.g., packing density and settling characteristics) and thus the product's re-suspendability and stability. Packing density is defined as the weight-to-volume ratio of the sediment at equilibrium. A wide particle size distribution often results in a highdensity suspension, whereas widely differing particle shapes (e.g., plates, needles, filaments, and prisms) often produce low-density slurries. Symmetrical barrel-shaped particles were found to produce stable suspensions without caking upon storage, while asymmetrical needle-shaped particles formed a tenacious sediment cake, which could not be easily redispersed .

 The viscosity of colloidal dispersions is affected by the shape

of the dispersed phases. The relationship of particle shape and viscosity reflects the degree of solvation of the particles. Particle Size and Size Distribution The particle size and size distribution of the dispersed phase is important for a thorough understanding of any disperse system. The particle size can significantly affect the absorption behavior of a drug . Certain types of dosage forms require specific size ranges, for example, suspension aerosols delivering drugs into the respiratory tract should contain particles in the order of 1-5 um and no particles larger than 10 urn.

B. Surface Properties and Interfacial Phenomena

One of the most obvious properties of a disperse system is

the vast interfacial area that exists between the dispersed phase and the dispersion medium. When considering the surface and interfacial properties of the dispersed particles, two factors must be taken into account: the first relates to an increase in the surface free energy as the particle size is reduced and the specific surface increased; the second deals with the presence of an electrical charge on the particle surface.

The Interface
An interface is defined as a boundary between two phases.
The solid/liquid and the liquid/liquid interfaces are of

primary interest in suspensions and emulsion, respectively. Other types of interfaces such as liquid/gas (foams) or solid/gas interfaces also p1ay a major role in certain pharmaceutical dosage forms, e.g., aerosols. A large surface area of the dispersed particles is associated with a high surface free energy that renders the system thermodynamically unstable. The surface free energy, AG, can be calculated from the total surface area, AA, as follows: AG = ysL AA or AG = yLL AA (1)

 where ySL and yLL are the interfacial tension between the

solid particles and the liquid medium and the liquid/liquid interfacial tension, respectively. Very small dispersed particles are highly energetic. In order to approach a stable state, they tend to regroup themselves in order to reduce the surface free energy of the system. An equilibrium will be reached when AG = 0. This condition may be accomplished either by a reduction of the interfacial tension or by a decrease of the total surface area.

Particle Interactions
The interactions between similar particles, dissimilar

particles, and the dispersion medium constitute a complex but essential part of dispersion technology. Such inter-particle interactions include both attractive and repulsive forces. These forces depend upon the nature, size, and orientation of the species, as well as on the distance of separation between and among the particles of the dispersed phase and the dispersion medium, respectively. The balance between these forces determines the overall characteristics of the system.

 The particles in a disperse system with a liquid or gas being

the dispersion medium are thermally mobile and occasionally collide as a result of the Brownian motion. Between particles both attractive and repulsive forces are operative. Attractive forces agglomerates instability of system. Repulsive forces dominate homogeneous stable dispersion Various types of attractive interaction are operating: (a) dipole-dipole forces, (b) dipole-induced dipole or Debye induction forces, (c) induced dipole-induced dipole or London dispersion forces, and (d) electrostatic forces between charged particles.

 The strongest forces are the electrostatic interactions

between charged particles. These forces, either attractive or repulsive, are effective and dependent on the ionic charge and size of the particle. Vander Waals forces coupled with hydrogen bond interactions are significant various types of attractive inter-particulate forces can lead to the instabilities of disperse systems

Electrical Properties of the Interfaces

Most insoluble materials, either solids or liquids, develop a

surface charge when dispersed within an aqueous medium. For example, the ionization of functional groups present at the surface of the particle, such as carboxylic acid or amine groups, can be involved. The charge is then dependent on the extent of ionization and is a function of the pH of the dispersion medium. Furthermore, surface charges can be developed due to the adsorption or desorption of protons. A variety of colloidal systems (e.g., polymers, metal oxides) fall into this group. For example, the surface hydroxyl groups of aluminum hydroxide gel can adsorb protons and become positively charged or may donate protons to become negatively charged.

 An important property is the point of zero charge (PZC),

which represents the pH at which the net surface charge is zero. More general, surface charges of dispersed particles may be caused by preferential adsorption of specific ions onto the surface. Surface charges can also be introduced by ionic surfactants. For example, oil globules in an O/W emulsion exhibit a surface charge if anionic or cationic surface active agents are used. The surfactant molecules are oriented at the oil/water interface so that the charged hydrophilic groups are directed towards the water phase. Ion deficiencies in the crystal lattice or interior of the particles may also cause surface charges.

 When a charged particle is dispersed within a dispersion

medium containing dissolved cations and anions, the surface charges of the particle interact with the dissolved ions in solution. The electric distribution at the interface is equivalent to a double layer of charge: a first layer being tightly bound(stern layer), and a second layer that is more diffusive. The zeta () potential is defined as the potential at the shear plane (interface separating layers that move with the particle from layers that do not move with the particle) and can be regarded as the "apparent" or "active" charge of the particle. Derjaguin, Landau, Verwey, and Overbeek developed a theory giving insight into the energy of interaction between suspended particles . This theory often referred to as the DLVO theory.

C- Colloidal Stability and DVLO Theory

DLVO theory suggests that the stability of a particle in solution is

dependent upon its total potential energy function VT. This theory recognizes that VT is the balance of several competing contributions: VT = VA + VR + VS VS is the potential energy due to the solvent, it usually only makes a marginal contribution to the total potential energy over the last few nanometers of separation. Much more important is the balance between VA and VR, these are the attractive and repulsive contributions. DVLO theory suggests that the stability of a colloidal system is determined by the sum of these van der Waals attractive (VA) and electrical double layer repulsive (VR) forces that exist between particles as they approach each other due to the Brownian motion they are undergoing.

This theory proposes that an energy barrier resulting from the repulsive force prevents two particles approaching one another and adhering together (figure 2 (a)). But if the particles collide with sufficient energy to overcome that barrier, the attractive force will pull them into contact where they adhere strongly and irreversibly together. Therefore if the particles have a sufficiently high repulsion, the dispersion will resist flocculation and the colloidal system will be stable. However if a repulsion mechanism does not exist then flocculation or coagulation will eventually take place. If the zeta potential is reduced (e.g. In high salt concentrations), there is a possibility of a secondary minimum being created, where a much weaker and potentially reversible adhesion between particles exists (figure 2 (b)).

These weak flocs are sufficiently stable not to be broken up by Brownian motion, but may disperse under an externally applied force such as vigorous agitation. Therefore to maintain the stability of the colloidal system, the repulsive forces must be dominant. How can colloidal stability be achieved? There are two fundamental mechanisms that affect dispersion stability (figure 3): Steric repulsion - this involves polymers added to the system adsorbing onto the particle surface and preventing the particle surfaces coming into close contact. If enough polymer adsorbs, the thickness of the coating is sufficient to keep particles separated by steric repulsions between the polymer layers, and at those separations the van der Waals forces are too weak to cause the particles to adhere. Electrostatic or charge stabilization - this is the effect on particle interaction due to the distribution of charged species in the system.

D. Rheological Properties
Rheology is the study of low and deformation of materials under the

influence of external forces. It involves the viscosity characteristics of powders, liquids, and semisolids. Rheological studies are also important in the industrial manufacture and applications of plastic materials, lubricating materials, coatings, inks, adhesives, and food products. Flow properties of pharmaceutical disperse systems can be of particular importance, especially for topical products such systems often exhibit rather complex rheological properties.

FORMULATION ADDITIVES
A. Surfactants Surfactants are defined as compounds "which possess in the same molecule distinct regions of hydrophilic and lipophilic character.'' Being amphiphilic in nature, surfactants have the ability to modify the interface between various phases Surfactants are useful in formulating a wide variety of disperse systems. They are required not only during manufacture but also for maintaining an acceptable physical stability of these thermodynamically unstable systems. Finely divided solid particles that are wetted to some degree by both oil and water can also act as emulsifying agents. This results from the fact that they can form a particulate film around dispersed droplets, preventing coalescence. Powders that are wetted preferentially by water form O/W emulsions, whereas those more easily wetted by oil form W/O emulsions.

 The compounds most frequently used in pharmacy are colloidal clays,

such as bentonite (aluminum silicate) and veegum (magnesium aluminum silicate). These compounds tend to be adsorbed at the interface and also increase the viscosity of the aqueous phase. They are frequently used in conjunction with a surfactant for external purposes, such as lotions or creams. The common concentration of a surfactant used in a formulation varies from 0.05 to 0.5% and depends on the surfactant type and the solids content of the dispersion. In practice, very often combinations of surfactants rather than single agents are used to prepare and stabilize disperse systems. The combination of a more hydrophilic surfactant with a more hydrophobic surfactant leads to the formation of a complex film at the interface. A good example for such a surfactant pair is the Tween-Span system.

 B. Protective Colloids and Viscosity-Imparting Agents

Protective colloids of natural origin, such as gelatin, acacia, and

tragacanth. Dispersing a natural gum within water yields a thick, viscous liquid called a mucilage. Mucilages are used primarily to aid in suspending insoluble substances within liquids because their colloidal character and viscosity can help to prevent sedimentation. synthetic, water-soluble substances sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, and methyl cellulose. Many of these substances are used as protective colloids at low concentrations (<0.1%) and as viscosity builders at relatively high concentrations (>0.1%). Since these agents do not reduce the surface and interfacial tension significantly, it is often advantageous to use them in combination with surfactants.

 C. pH-Controlling Agents
A properly formulated disperse system should exhibit an acceptable

physical stability over a wide range of pH values. If a specific pH is required, the system can be maintained at the desired pH value using an adequate buffer. This is especially important for drugs that possess ionizable acidic or basic groups in which the pH of the vehicle often influences the stability and/or solubility. These buffering salts or electrolytes must be used with extreme caution since small changes in electrolyte concentration can alter the surface charge of the dispersed phase and, thus, affect the overall stability of the system. Most disperse systems are stable over a pH range of 4-10 but may flocculate under extreme pH conditions. Therefore, each dispersion should be examined for pH stability over an adequate storage period.

 D. Preservatives Preservation against microbial growth is an important aspect of

disperse systems, not only with respect to the primary microbiological contamination, but also in terms of the physical and chemical integrity of the system Aqueous liquid products are prone to microbial contamination because water in combination with excipients derived from natural sources (e.g., polypeptides, carbohydrates) serves as an excellent medium for the growth of microorganisms. Besides the pathogenic hazards, microbial contamination can result in discoloration or cracking (separation into two bulk phases) of the products. The evolution of carbon dioxide gas may result in the explosion of containers. Pseudomonas aeruginosa, Salmonella species, Staphylococcus aureus, and Escherichia coli. Chlorocresol, chlorobutanol, benzoates, phenylmercuric nitrate, parabens, and others

 E. Antioxidants Many pharmaceutical products undergo oxidative deterioration upon

storage because the therapeutic ingredients or adjuvants oxidize in the presence of atmospheric oxygen. Vitamins, essential oils, and almost all fats and oils can be oxidized readily. The decomposition can be particularly significant in disperse systems, such as emulsions, because of the large area of interfacial contact and because the manufacturing process may introduce air into the product. Antioxidants that give protection primarily in the aqueous phase include sodium metabisulfite, ascorbic acid, thioglycerol, and cysteine hydrochloride. Oil-soluble antioxidants include lecithin, propyl gallate, ascorbyl palmitate, and butylated hydroxytoluene.

Sedimentation and Stokes' Law

The control of sedimentation is required to ensure a sufficient and

uniform dosage. Sedimentation behavior of a disperse system depends largely on the motion of the particles which may be thermally or gravitationally induced. If a suspended particle is sufficiently small in size, the thermal forces will dominate the gravitational forces and the particle will follow a random motion owing to molecular bombardment, called "Brownian motion. The distance moved or displacement, Di, is given by:

where R is the universal gas constant, T is the absolute temperature, t is

the time, N is the Avogadro's number, is the viscosity, and r is the particle radius. Note that the displacement, Di, decreases with increasing radius of the particle, r.

 For any given system, one can defined as "no sedimentation diameter''

(NSD), below which value the Brownian motion will be sufficient to keep particles from sedimentation. The value of NSD obviously depends on the density and viscosity of the respective system. Increasing the radius of the suspended particles, Brownian motion becomes less important and sedimentation becomes more dominant. These larger particles therefore settle gradually under gravitational forces. The basic equation describing the sedimentation of spherical, monodisperse particles in a suspension is Stokes' law. It states that the velocity of sedimentation, v, can be calculated as follows:

where r is the particle radius, d is the particle diameter, p1 and p2 are

the densities of the particle and dispersion medium, respectively, g is the acceleration caused by gravity, and is the viscosity of the medium.

 The settling velocity is proportional to the second power of the particle

radius or particle diameter. It is apparent that agglomerates and flocculates settle more rapidly than individual particles. Since both gravity and buoyancy are operating simultaneously on the particle, either upward movement or downward movement results. Stokes' law is rigorously applicable only for the ideal situation in which uniform and perfectly spherical particles in a very dilute suspension settle without turbulence, inter-particle collisions, and without chemical/physical attraction or affinity for the dispersion medium Since the sedimentation rate increases with increasing particle size, it is apparent that particle size reduction is beneficial to the stability of suspensions The rate of sedimentation may also be appreciably reduced by increasing the viscosity of the continuous phase. But this can only be achieved within a practical limit. From Stokes' law, it can also be seen that if the density difference of both phases is eliminated, sedimentation can be entirely prevented.

Flocculation and Deflocculation Phenomena

The zeta potential is a measurable indication of the apparent particle charge in the dispersion medium. When its value is relatively high, the repulsive forces usually exceed the

attractive forces. Accordingly, the particles are individually dispersed and are said to be "deflocculated. Thus, each particle settles separately, and the rate of sedimentation is relatively small. The settling particles have plenty of time to pack tightly by falling over one another to form an impacted bed. The sedimentation volume of such a system is low, and the sediment is difficult to redisperse. The supernatant remains cloudy even when settling is apparent. Controlled flocculation is the intentional formation of loose agglomerates of particles held together by comparatively weak bonding forces. This can be achieved by the addition of a preferentially adsorbed ion whose charge is opposite in sign to that of the zeta potential-determining ions. Thus, the apparent active charge of the particles is progressively lowered.

 At certain concentration of the added ion, the forces of repulsion are sufficiently small that the forces of attraction start to predominate. Under these conditions the particles may approach each other closely and form loose

agglomerates, termed "flocs," "flocculates," or "floccules" ("flocculated" system). The loose structure permits the flocculates to break up easily and distribute uniformly with only a small amount of agitation. Controlled flocculated systems usually develop a clear supernatant solution above the loose sediment. Flocculating agents can be simple electrolytes that are capable of reducing the zeta potential of suspended charged particles monovalent ions (e.g., sodium chloride, potassium chloride) and di- or trivalent ions (e.g., calcium salts, alums, sulfates, citrates or phosphates). When formulating a delocculated system, a number of materials may be used as dispersion aids. Deflocculating agents include polymerized organic salts of sulfonic acid that can alter the surface charge of the particles by physical adsorption.

Crystal Growth and Polymorphism

The crystal growth in disperse systems may be attributed to one or more of the following mechanisms: Ostwald ripening, temperature changes, and

polymorphic transformation. Ostwald ripening is the growth of large particles at the expense of smaller ones as a result of a difference in the solubility of the particles of varying sizes. The surface free energy of small particles is greater than that of large particles. Therefore, small particles can be appreciably more soluble than larger ones. A concentration gradient results, with higher drug concentrations in the area of small particles and lower drug concentrations in the area of large particles. Thus, according to Fick's law of diffusion, the dissolved particle molecules diffuse from the environment of the smaller particles to the environment of the larger particles. An increase in the concentration in the area of the large particles leads to crystallization and particle growth. Thus, small particles become smaller, whereas large particles become larger upon storage.

 Small fluctuations in temperature can accelerate this effect. Small particles dissolve to a greater extent when the temperature increases and

then re-crystallize on the surface of existing larger particles as the temperature drops. The suspension becomes coarser, and the mean particle size spectrum shifts to higher values. Crystal growth due to temperature fluctuations during storage is of importance especially when the suspensions are subjected to temperature cycling of 20C or more. These effects depend on the magnitude of temperature change, the time interval, and the effect of temperature on the drug's solubility and subsequent recrystallization process. As crystal growth generally increases with an increase in particle solubility, the excipients that tend to increase the particle solubility should be kept to a minimum. Many pharmaceutical gums can absorb onto the surfaces of drug crystals and, thus, can be used to inhibit the crystal growth. In a dilute suspension, crystal growth increases with the degree of agitation because the mass transfer in the bulk fluid is increased (conventional transport).

 Polymorphism refers to the different internal crystal structures of a chemically identical compound.
Drugs may undergo a change from one metastable polymorphic form to a more stable polymorphic form. Also, the crystal habit might change due to the degree of solvation or

hydration. The formation of distinct new crystalline entities during storage is possible. Various drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). The rate of conversion from a metastable into the stable form is an important criteria to be considered with respect to the shelf life of a pharmaceutical product. Polymorphic changes have also been observed during the manufacture of steroid suspensions. When steroid powders are subjected to dry heat sterilization, subsequent rehydration of anhydrous steroid in the presence of an aqueous vehicle results in the formation of large, needle-like crystals.

Methods of Evaluating Suspensions

Suspensions are generally evaluated with respect to their particle size, electrokinetic properties (zeta potential), and rheological characteristics. The sedimentation volume of a pharmaceutical suspension can be evaluated

using simple, inexpensive, graduated, cylindrical graduates (100-1000 mL). It is defined as the ratio of the equilibrium volume of sediment, Vu, to the total volume of the suspension, Vo. F = Vu / Vo The value of F ranges between 0 and l and increases as the volume of suspension that appears occupied by the sediment increases. It is normally found that the greater the value of F, the more stable the product. When F = 1, no sediment is apparent and caking is absent, and the suspension is considered esthetically pleasing. This method of evaluation is quite useful in determining the physical stability of suspensions. It can be used to determine the settling rates of flocculated and deflocculated suspensions by making periodic measurement of sedimentation height.

 The degree of flocculation, , is defined as the ratio of the sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the suspension when deflocculated, F . It is expressed as:

=F/F
The degree of flocculation, therefore, is an expression of the increased

sediment volume resulting from flocculation. For example, if has a value of 5.0, this means that the volume of sediment in the flocculated system is five times that in the deflocculated state. As the value of approaches unity, the degree of flocculation decreases. Great care must be exercised when using graduated cylinders because decreases in the diameter of small containers can produce a "wall effect," which often affects the settling rate or ultimate sedimentation volume of flocculated suspensions. Small containers have a tendency to hold up the suspensions due to adhesive forces acting between the container's inner surface and the suspended particles.

Emulsion
An emulsion is a two-phase system consisting of at least two

immiscible liquids (or two liquids that are saturated with each other), one of which is dispersed as globules (internal or dispersed phase) within the other liquid phase (external or continuous phase), generally stabilized by an emulsifying agent.

Types of Emulsions
Macroemulsions Based on the nature of the dispersed phase and the dispersion medium, two types of macroemulsions can be distinguished. If the continuous phase is an aqueous solution and the dispersed phase an oil, the system is called an oil-in-water emulsion. Such an O/W emulsion is generally formed if the aqueous phase constitutes more than 45% of the total weight and a hydrophilic emulsifier is used.

 Conversely, when the aqueous phase is dispersed within the oil, the

system is called a water-in-oil emulsion. W/O emulsions are generally formed when the aqueous phase constitutes less than 45% of the total weight and a lipophilic emulsifier is used. Generally, O/W emulsions are more popular than W/O emulsions in the pharmaceutical field, especially when they are designed for oral administration. In the cosmetic industries, lotions or creams are of either the O/W or the W/O type, depending on their applications. O/W emulsions are most useful as water-washable drug bases and for general cosmetic purposes, while W/O emulsions are employed more widely for the treatment of dry skin and emollient applications. Determination of emulsion type Phase dilution test Dye solubility test Conductivity test

Multiple Emulsions
Multiple emulsions are more complex systems. If a simple emulsion is

further dispersed within another continuous phase, these systems are called multiple emulsions. Water-in-oil-in-water (W/O/W) and oil-in-water-in-oil systems (O/W/O) are the two basic types of multiple emulsions Recently multiple emulsions have been developed with the purpose of prolonging the release of incorporated drugs. This technology has gained particular interest for the microencapsulation of peptides/proteins and hydrophilic drugs. To increase the encapsulation efficiency of hydrophilic compounds W/O/W, O/W/O, W/O/O, and W/O/O/O emulsions have been used. Cosmetics; application of multiple emulsions as super moisturizing product bases, combining the benefits of O/W and W/O emulsions.

Microemulsions
Microemulsion'; transparent-solutions of a model four-component

system . Basically, microemulsions consist of water, an oily component, surfactant, and co-surfactant. In contrast to macroemulsions, microemulsions are optically transparent, and thermodynamically stable. Terms as transparent emulsions, micellar solutions, solubilized systems, and swollen micelles have all been applied to the same or similar systems. Nonetheless, emulsions and microemulsions may be differentiated on the basis of particle size: microemulsions contain particles in the nanometer size range (typically 10-100 nm), whereas conventional emulsions (or macroemulsions, coarse emulsions) contain particles in the micrometer range.

Formulation and Preparation Techniques for Emulsions

The preparation techniques for emulsions requires that energy be in-

troduced into the system, either by trituration, homogenization, agitation or heat. It has been suggested that the formulator first determine the physical and chemical characteristics of the drug, which include the structure formula, melting point, solubilities in different media, stability, dose, and specific chemical incompatibilities. Then the required emulsifying agent(s) and its (their) concentration(s) should be identified. Emulsifying Agents Emulsions are thermodynamically unstable systems. However, using appropriate emulsifying agents(emulsifiers) to decrease the interfacial tension, the stability of these systems can be significantly increased.

 A satisfactory emulsifier should have a reasonable balance between its

hydrophilic and hydrophobic groups, produce a stable emulsion (both initially and during storage), be stable itself, be chemically inert, be nontoxic and cause no irritation upon application, be odorless, tasteless, and colorless, and be inexpensive. Emulsifying agents can be classified into the following three groups: Surfactants that are adsorbed at oil/water interfaces to form monomolecular films and reduce interfacial tension. Natural macromolecular materials, which form multimolecular films around the disperse droplets of O/W emulsions. They are frequently called auxiliary emulsifying agents and have the desirable effect of increasing the viscosity of the dispersion medium. Very finely disperse solids, which are adsorbed at the liquid/liquid interfaces, forming films of particles around the disperse globules.

 Surfactants can be classified using the hydrophile-lipophile balance

(HLB) system . The HLB system provides a scale of surfactant hydrophilicity (HLB values range from 0 to 20, 20 corresponding to the highest possible hydrophilicity) that simplifies emulsifier selection and blending. Surfactants with a low HLB value (<6) tend to provide stable W/O emulsions; those with a high HLB value (>8) tend to stabilize O/W emulsions. Emulsification Techniques
The location of the emulsifier, the method of incorporation of the

phases, the rates of addition, the temperature of each phase, and the rate of cooling after mixing of the phases considerably affect the droplet size distribution, viscosity, and stability of the final emulsion. Roughly four emulsification methods can be distinguished:

 Addition of the internal phase to the external phase, while

subjecting the system to shear or fracture. Phase inversion technique: the external phase is added to the internal phase. For example, if an O/W emulsion is to be prepared, the aqueous phase is added to the oil phase. First a W/O emulsion is formed. At the inversion point, the addition of more water results in the inversion of the emulsion system and the formation of an O/W emulsion. The phase inversion technique allows the formation of small droplets with minimal mechanical action and heat. A classical example is the so-called dry gum technique, which is a phase inversion technique when hydrophilic colloids are part of the formulation. First the dry hydrocolloid (e.g., acacia, tragacanth, methyl cellulose) is dispersed within the oil phase. Then water is added until the phase inversion occurs to form a O/W emulsion.

 Mixing both phases after warming each. This method is

frequently used in the preparation of ointments and creams. Alternate addition of the two phases to the emulsifying agent. In this method, the water and oil are added alternatively, in small portions, to the emulsifier. This technique is especially suitable for the preparation of food emulsions. Emulsion Stability Coalescence Stress Tests Thermal Stress Gravitational Stress

Evaluation of Emulsion Stability

Phase Separation Rheological Property Determination

Electrical Property Measurements

Particle Size Measurement

CR 4TH M