PHM 3110 - Lecture 9 (Coarse Dispersions - Suspensions) Lecture Notes PDF

Suspensions Ms. Colette Gouveia Lecture 9  Introduction to Disperse Systems Dispersed systems consist of particulate matter, known as the dispersed phase, distributed throughout a continuous or dispersion medium. The dispersed material may range in size from particles of atomic...

Suspensions Ms. Colette Gouveia Lecture 9  Introduction to Disperse Systems Dispersed systems consist of particulate matter, known as the dispersed phase, distributed throughout a continuous or dispersion medium. The dispersed material may range in size from particles of atomic and molecular dimensions to particles whose size is measured in millimeters. The term "Disperse System" refers to a system in which one substance (Dispersed Phase) is distributed, in discrete units, throughout a second substance (Dispersed Medium).  Definition A Pharmaceutical suspension is a coarse dispersion (a heterogeneous system) in which the internal phase (therapeutically active ingredient) is dispersed uniformly throughout the external phase.  Suspensions The internal phase consisting of insoluble solid particles having a range of size(0.5 to 5 microns) which is dispersed uniformly through out the continuous phase with aid of single or combination of suspending agent. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non-oral use. Based on their density, finer particles may be self-suspending if the energy of Brownian motion exceeds the gravitational force on the particle such that the dispersion has a low viscosity. In addition to the use of suspensions as drug products,  Types of Suspensions Suspensions can be classified : Based particle size of dispersed phase - Colloidal Dispersion(Particle size is less than 1 nm) Visible in electron microscope. Diffuse very slowly.Colloidal silver solutions, cheese, butter, jelly, milk, shaving cream etc. - Coarse Dispersion(Particle size between 0.1-0.2 µm). (Particle size is greater than 0.2 µm). Visible under microscope. Do not diffuse.Grains of sand, most pharmaceutical emulsions and suspensions, red blood cells. - Nano suspensions (10 ng) Suspensions are the biphasic colloidal dispersions of nanosized drug particles stabilized by surfactants. The diameter of nanosuspension drug particles is typically between 10 and 50 nanometers (nm).  Classification of Suspensions Based on general classes (administration) Oral suspensions 1. Oral e.g. Paracetamol Suspension, Antacid Externally applied suspension 1. Topical e.g. Calamine lotion 2. Ophthalmic e.g Prednisolone acetate suspension 3. Otic e.g. Hydrocortisone-neomycin-polymyxin suspension 4. Rectal e.g. Barium Sulfate for Suspension, USP 5. Aerosols e.g. Tolnaftate spray Parenteral suspension 1. Vaccines e.g cholera vaccine and tetanus vaccine 2. Parenteral e.g. Insulin zinc suspension  Classification of Suspensions Based on physical state: - Suspensions - Aerosols - Gels - Foams Based on proportion of solid particles - Dilute Suspension (2 to 10% w/v solid) e.g. cortisone acetate, prednisolone acetate - Concentrated Suspension (50% w/v solid) e.g. Zinc oxide suspension Based on electrokinetic nature of solid particles - Flocculated suspension (Dispersed phase maybe a network of particles) - Deflocculated suspension. (Dispersed phase may consist of discrete particles)  Advantages and Disadvantages Advantages: 1. Suspensions can improve chemical stability of certain drug. E.g Procaine penicillin G. 2. Drugs in suspension exhibits higher rate of bioavailability than other dosage forms. - Solution > Suspension > Capsule > Compressed Tablet > Coated tablet 3. Duration and onset of action can be controlled. E.g Protamine Zinc-Insulin suspension. 4. Suspensions can mask the unpleasant/bitter taste of drug. E.g Chloramphenicol  Advantages and Disadvantages Disadvantages: 1. Physical stability, sedimentation and compaction can cause problems. 2. It is bulky. Sufficient care must be taken during handling and transport. 3. It is difficult to formulate. 4. Uniform and accurate dose can not be achieved unless suspension are packed in unit dosage form..  Qualities of a Good Suspension Uniformity of content Lack of microbial growth Settling volume Physical integrity Absence of particle size Physical stability change and API crystal Particle adhesion to the growth package. Palatability Polymorphic integrity Re- suspendability Chemical stability Absence of caking Drug release Deliverability Flow  Desired Features in a Pharmaceutical Suspension Ideal properties of suspension 1. Particles should settle slowly and should be readily re- dispersed upon shaking of the container. 2. The particle should not form a cake on settling 3. The viscosity should be such that the preparation can be easily poured. A highly viscous suspension would make pouring difficult. 4. It should be chemically and physically stable 5. It should be palatable (orally) 6. It should be free from gritting particles (external use) 7. The particle size of the suspension should remain fairly constant throughout long periods of undisturbed standing. Reasons for Formulating a Pharmaceutical Suspension 1. When the drug is insoluble in the delivery vehicle. E.g. Prednisolone suspension. 2. To mask the bitter taste of the drug. E.g. Chloramphenicol palmitate suspension. 3. To increase drug stability.. E.g. Oxy tetracycline suspension. 4. To achieve controlled/sustained drug release. E.g. penicillin procaine.  Dry Powders for Oral Suspension Several commercial preparations consist of dry powder mixtures or granules that are intended to be suspended in distilled water or some other vehicle prior to oral administration. Most drugs prepared as a dry mix for oral suspension are antibiotics. The dry products are prepared commercially to contain the antibiotic drug, colorants (FD&C dyes), flavorings, sweeteners (e.g., sucrose or sodium saccharin), stabilizing agents (e.g., citric acid, sodium citrate), suspending agents (e.g., guar gum, xanthan gum, methylcellulose), and preserving agents (e.g., methylparaben, sodium benzoate) that may be needed to enhance the stability of the dry powder or granule mixture or the liquid suspension. Attributes - physical stability - long shelf life Packaging - Unit-dose sachet Flocculated and Deflocculated Systems  Flocculated Suspensions Suspension in which particles are weakly bonded, settle rapidly, do not form a cake and are easily resuspended with a minimum of agitation. To avoid formation of a cake, intentional formation of a less rigid or loose aggregation of the particles held together by comparatively weak particle-to-particle bonds are formed. Such an aggregation of particles is termed a floc , Flocculated particles form a type of agglomeration that resists complete settling (although flocs settle more rapidly than fine, individual particles) but are less prone to compaction than unflocculated particles.  Deflocculated Suspensions Suspension in which particles settle slowly, and eventually form a sediment in which aggregation occurs with the resultant formation of a hard cake which is difficult to resuspend by agitation. This phenomenon also called ‘cracking’ or ‘claying’. In deflocculated suspension larger particles settle fast and smaller remain in supernatant liquid so supernatant appears cloudy Deflocculated Suspension Flocculated Suspension THEORITICAL CONSIDERATIONS FOR SUSPENSIONS  SETTLING IN SUSPENSIONS One aspect of physical stability in pharmaceutical suspensions is concerned with keeping the particles uniformly distributed throughout the dispersion. It possible to prevent settling completely over a prolonged period of time by considering the factors that influence the velocity of sedimentation. i.e a. Theory of Sedimentation - Particle size - Effect of Brownian Movement b. Interfacial Properties of Suspended Particles c. Electro kinetic Properties d. Sedimentation of Flocculated Particles e. Sedimentation Parameters  Theory of Sedimentation Sedimentation Behaviour Sedimentation means settling of particle or floccules under gravitational force in liquid dosage form. Brownian motion The sedimentation velocity of particles in suspension is related to Size of the particles Density of the particles Viscosity of the dispersion medium Velocity of sedimentation is expressed by Stokes Equation THEORY OF SEDIMENTATION  Stokes Law is not applicable in the following conditions 1. The particle should be spherical, but in suspensions particle are largely irregular. 2. The particles do not interfere with one another during sedimentation, and free settling occurs. 3. Most pharmaceutical suspensions contain dispersed particles in concentrations of 5%, 10%, or higher percentages, hence the particles exhibit hindered settling. 4. The particles interfere with one another as they fall, and Stokes's law no longer applies.  Particle Size Particle size determines the packing arrangement and influence the settling behavior. They also affect the re- suspendability and stability. Particle size of any suspension is critical and must be reduced within the range as determined during the preformulation study. The velocity of fall of a suspended particle is greater for larger particles than it is for smaller particles - Symmetrical particle (barrel shaped particles of calcium carbonate) produces stable suspension without cracking. - Asymmetrical particle (needle shaped) forms hard cake, which cannot be re-dispersed.  Particle size diameter (d) According to the Stoke's equation, the velocity of sedimentation of particles in a suspension can be reduced by decreasing the particle size and also by minimizing the difference between the densities of the particles and the vehicle. V α d 2 where, Sedimentation velocity (v) is directly proportional to the square of diameter of particle.  Density of the Vehicle The density of the vehicle of a suspension can be increased by adding the following substances either alone or in combination: polyethylene glycol, polyvinyl pyrrolidone, glycerin, sorbitol, and sugar Density difference between dispersed phase and dispersion media (ρs - ρo) V α (ρs - ρo) Generally, particle density is greater than dispersion medium but, in certain cases particle density is less than dispersed phase, so suspended particle floats and is difficult to distribute uniformly in the vehicle. If density of the dispersed phase and dispersion medium are equal, the rate of settling becomes zero.  Viscosity of dispersion medium (ηo ) V α 1/ ηo Sedimentation velocity is inversely proportional to viscosity of dispersion medium. Hence, an increase in viscosity of medium, decreases settling, hence the particles achieve good dispersion system but a greater increase in viscosity gives rise to problems like pouring, syringibility and re-dispersibility of suspension.  Viscosity of Suspensions 1. Viscosity of suspensions is of great importance for stability and pourability of suspensions, since suspensions have least physical stability amongst all dosage forms due to sedimentation and cake formation. 2. As, the viscosity of the dispersion medium increases, the terminal settling velocity decreases thus the dispersed phase settle at a slower rate and they remain dispersed for longer time yielding higher stability to the suspension. 3. The viscosity and density of any vehicle are related to each other, so any attempt to change one of these parameters will also change the other one  Advantages and Disadvantages due to Viscosity of Medium Advantages High viscosity inhibits the crystal growth. High viscosity prevents the transformation of metastable crystal to stable crystal. High viscosity enhances the physical stability. Disadvantages High viscosity hinders the re-dispersibility of the sediments High viscosity retards the absorption of the drug. High viscosity creates problems in handling of the material during manufacturing.  Interfacial Properties of Suspended Particles The large surface area of the particles that results from the grinding is associated with a surface free energy that makes the system thermodynamically unstable, by which we mean that the particles are highly energetic and tend to regroup in such a way as to decrease the total area and reduce the surface free energy. The particles in a liquid suspension therefore tend to flocculate, that is, to form light, fluffy conglomerates that are held together by weak van der Waals forces. The flocs settle to form a higher sediment volume than unflocculated particles, the loose structure of which permits the aggregates to break up easily and distribute readily with a small amount of agitation. Under certain conditions—in a compacted cake, for example—the particles may adhere by stronger forces to form what are termed aggregates. Caking often occurs by the growth and fusing together of crystals in the precipitates to produce a solid aggregate.  Wetting of the particles The use of wetting agent allows removing this air from the surface and to easy penetration of the vehicle into the pores. Alcohol, glycerin, and propylene glycol are frequently used to remove adsorbed air from the surface of particles when aqueous vehicle is used to disperse the solids. When the particles are dispersed in a non-aqueous vehicle, mineral oil is used as wetting agent. Irrespective of the method of preparation, the solid particles must be wetted using any of the suitable wetting agents before the dispersion in the vehicle. Solid particles that are not easily wetted by aqueous vehicle after the removable of the adsorbed air are referred to as hydrophobic particles. Use of surface-active agents is necessary to reduce the interfacial tension between the particles and the vehicle thereby improving  DLVO Theory The scientists Deryaguin, Landau, Vervey and Overbeek developed a theory in the 1940s which dealt with the stability of colloidal systems. DVLO theory suggests that the stability of a colloidal system is determined by: The sum of the Vander 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. The Vander waal forces depend on chemical nature and size of particle. The electrostatic repulsive forces depend on density, surface charge and thickness of double layer.  Electrical Properties of Interfaces Electric double layer Consider solid surface in contact with solution of electrolyte containing ions In the adjacent figure, the particle is negatively charged, and the cations present in the surrounding vehicle are attracted to the negatively charged particle by electric forces that also serve to repel the approach of any anions. The adsorbed ions that give charge to surface' (in this case anions (-) are known as potential determining ions. Cations are attracted to the negative charge by electrical force of attraction known as counter ions or gegenions. These two layers of ions at the interface constitute a double layer of electric charge.  Electro thermodynamic or Nernst Potential 1. The difference in electric potential between the actual surface of the particle and the electroneutral region is referred to as Nernst potential. 2. The Nernst potential is controlled by the electrical potential at the surface of the particle due to the potential determining ions. 3. The greater this ratio, the greater the tendency for the ion to diffuse in one direction, and therefore the greater the Nernst potential required to prevent additional net diffusion 4. Nernst potential has little effect in the formulation of stable suspension.  Electrokinetic or Zeta Potential Zeta potential is defined as the difference between the surface of the tightly bound layer (shear plane)and the electroneutral region of the solution. Zeta potential governs the degree of repulsion between adjacent, similarly charged solid dispersed particles.  Electrokinetic or Zeta Potential The potential drops off rapidly at first, followed more gradual decrease as the distance from the surface increases. This is because the counter ions close to the surface acts as a screen that reduce the electrostatic attraction between the charged surface and those counter ions further away from the surface.  Deflocculation and Flocculation Deflocculation of particles is obtained when the zeta potential is higher than the critical value and the repulsive forces supersede the attractive forces. The addition of a small amount of electrolyte reduces the zeta potential. If the zeta potential goes is reduced below the critical value, the attractive forces supersede the repulsive forces and flocculation occurs.  Potential Energy Curves The forces at the surface of a particle affect the degree of flocculation and agglomeration in a suspension. Forces of attraction are of the London–van der Waals type and the repulsive forces arise from the interaction of the electric double layers surrounding each particle. The potential energy of two particles is plotted in Figure as a function of the distance of separation. Shown are the curves depicting the energy of attraction, the energy of repulsion, and the net energy, which has a peak and two minima  Kinetic Stability of Dispersed Systems Brownian Movement (Drunken walk): Brownian movement of particle prevents sedimentation by keeping the dispersed material in random motion. Brownian movement depends on the density of dispersed phase and the density and viscosity of the disperse medium. The kinetic bombardment of the particles by the molecules of the suspending medium will keep the particles suspending, providing particle size is below critical radius (r) for Brownian movement. Brownian movement can be observed, - If particle size is about 2 to 5µm, - When the density of particle and viscosity of medium are favorable.  EFFECT OF BROWNIAN MOVEMENT 1.For particles having a diameter of about 2 to 5 μm (depending on the density of the particles and the density and viscosity of the suspending medium), Brownian movement counteracts sedimentation to a measurable extent at room temperature by keeping the dispersed material in random motion. 2.It can be seen in the microscope that Brownian movement of the smallest particles in a field of particles of a pharmaceutical suspension is usually eliminated when the sample is dispersed in a 50% glycerin solution, having a viscosity of about 5 centipoise. 3. Hence, it is unlikely that the particles in an ordinary pharmaceutical suspension containing suspending agents are in a state of vigorous Brownian motion Methods for stabilizing suspension Physical stability can be achieved by maintaining the particle in Brownian motion i.e a) Provide electric charge on surface of dispersed particle: The like charge on the particles will prevent these coming closer together and thus maintaining a Brownian motion. b) Maintain solvent sheath around the particle: The solvent layer prevent the particle coming closer and maintains Brownian motion.  Sedimentation in Different Systems In flocculated systems: The flocs tend to fall together (fast sedimentation due to large size) A distinct boundary between the sediment and the supernatant. The liquid above the sediment is clear because even the small particles present in the system are associated with the flocs In deflocculated systems (with a range of particle sizes): in accordance with Stokes' law, the larger particles sediment more rapidly than the smaller particles. No clear boundary is formed (unless 1 particle size is Sedimentation in Different Systems When sedimentation is studied in flocculated systems, it is observed that the flocs tend to fall together, producing a distinct boundary between the sediment and the supernatant liquid. In deflocculated suspensions, having a range of particle sizes, which according to Stokes Law, the larger particles settle more rapidly than the smaller particles.  Sedimentation Parameters The sedimentation volume, F, is defined as the ratio of the final, or ultimate, volume of the sediment, Vu, to the original volume of the suspension, Vo, before settling F= V /V u o If the ultimate volume of sediment is smaller than the original volume of suspension, then, F = 0.5. If the volume of sediment in a flocculated suspension equals the original volume of suspension, then F = 1 It is possible for F to have values greater than 1, meaning that the final volume of sediment is greater than the original suspension volume. This comes about because the network of flocs formed in the suspension is so loose and fluffy that the volume they are able to encompass is greater than the original volume of suspension. The sedimentation behaviour of flocculated and deflocculated suspensions. Methods for Formulation of Suspensions  Methods For Formulation of Suspensions 1. Use of controlled flocculation 2. Use of structured vehicle 3. Combination of both of the methods  Use of Controlled Flocculation Controlled flocculation of particles is obtained by adding flocculating agents, which are: 1. Electrolytes 2. Surfactants 3. Polymers  Addition of electrolytes to control flocculation Electrolytes act as flocculating agents by reducing the electric barrier between the particles, as evidenced by a decrease in the zeta potential and the formation of a bridge between adjacent particles to link them together in a loosely arranged structure. Electrolytes reduces the zeta potential surrounding the solid particles. This leads to decrease in repulsion potential and makes the particle come together to form loosely arrange structure (floccules). The flocculating power increases with the valency of the ions.  Addition of Surfactant to control flocculation Both ionic and non-ionic surfactants could be used to control flocculation Surfactant adsorbed on the surface of solid particle leading to neutralization or reversing the surface charge Since most of surfactants act as wetting agents and flocculating agents, the amount of surfactant to be added should be calculated based on this fact. The particles of bismuth subnitrate are positively charged originally. By addition of electrolyte (phosphate, -ve) the zeta potential fell near zero. At this neutralization value noted absence of caking. Continuing adding of negatively charged electrolyte resulted in changing the overall zeta potential of particles to negative and formation of cake. Addition of Polymers to control flocculation Polymers are long-chained, high molecular-weight compounds containing active groups spaced along their length. These agents promote flocculation through adsorption of part of the chain on the surface of particle and the remaining part project out into the dispersion medium. Formation of bridge between the projected parts leads to formation of floccules  Use of structured vehicle Structured vehicles called also thickening or suspending agents. They are aqueous solutions of natural and synthetic gums. These are used to increase the viscosity of the suspension. These structured vehicles entrapped the particle and reduces the sedimentation of particles but do not completely eliminate the particle settling. Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage. Too high viscosity is not desirable as: - It causes difficulty in pouring and administration. - It may affect drug absorption since they adsorb on the surface of particle and suppress the dissolution rate. - Structured vehicle is not useful for parenteral suspension because they may create problem in syringeability due to high viscosity. Formulation of Suspensions  Formulation of Suspension General Procedure First the particle size is reduced to a desired size with the help of mill or other equipment. The insoluble materials are levigated or grinded to a smooth paste with a vehicle containing the wetting agent. All soluble ingredients are dissolved in same portion of the vehicle and added to the smooth paste to get slurry. If preparing on small scale, the slurry is then transferred to a graduated cylinder and mortar is rinsed with successive portion of vehicle. If preparing on industrial scale, then slurry is transferred to a colloid mill or a disperser or any other equipment to completely wet the particles. Then a deflocculated suspension is obtained.  Formulation of Suspension In some instances, the dispersed phase has an affinity for the vehicle and is readily wetted by it. Other drugs are not penetrated easily by the vehicle and tend to clump together or to float on the vehicle. In the latter case, the powder must first be wetted to make it more penetrable by the dispersion medium Once the powder is wetted, the dispersion medium (to which have been added all of the formulation’s soluble components, such as colorants, flavorants, and preservatives) is added in portions to the powder, and the mixture is thoroughly blended before subsequent additions of vehicle. The suspension is then homogenized.  Ingredients of Suspensions I - Insoluble drug. II- Vehicle (suspending medium). III- Wetting agents. IV- Compounds allowing control of stability and sedimentation (Flocculating, Suspending agent) V - Additives used to regulate the flow behavior. VI- pH regulators VII- Other additives ( flavour, colour, sweeteners, preservatives  Formulation Components Drug - A water-insoluble drug is usually the dispersed phase in an aqueous suspension. Drugs should be of uniform particle size in the range of 1–50μm Ease of wetting. Surface electric charge of the particles in suspension. Chemical stability of the drug, and possible interactions and incompatibilities with other suspension constituents. Vehicle (suspending medium). The most used vehicle used are : Distilled water or deionized water. Alcohol Solution of glycerol. Nonaqueous vehicles (Topical use). Structured vehicles are pseudoplastic and plastic in nature, it is desirable that thixotropy is associated. The mechanism is that liquid penetrates into individual particle and facilitates wetting. Formulation Components - Wetting Agents - Flocculating Agents - Suspending Agents  Wetting Agents - Hydrophilic materials are easily wetted by water while hydrophobic materials are easily wetted by non-polar liquids. - The extent of wetting by water is dependent on the hydrophilicity of the materials. - The concentration used is less than 0.5 %. Most materials will exhibit varying degrees of hydrophobicity and will not be easily wetted. Some particles will form large porous clumps within the liquid, whereas others remain on the surface and become attached to the upper part of the container. To ensure adequate wetting, the interfacial tension between the solid and the liquid must be reduced so that the adsorbed air is displaced from the solid surfaces by the liquid. Surfactants are wetting agents that reduce the surface tension of an aqueous medium and facilitate the wetting of hydrophobic particles. Wetting agents adsorb onto the particle surface and can partially coat the surface or form a complete monolayer. Examples of typical wetting agents are sodium lauryl sulfate and polysorbate 80.  Wetting Agents 1. Surface-active agents 2.Hydrophilic colloids 3. Solvents  Wetting Agents Surfactants Surfactants decrease the interfacial tension between drug particles and liquid for penetration into the pores of drug particle displacing air from them and facilitating wetting. Surfactants possessing an HLB value between about 7 and 9 would be suitable for use as wetting agents. The hydrocarbon chains would be adsorbed by the hydrophobic particle surfaces, whereas the polar groups project into the aqueous medium and become hydrated. Wetting of the solid occurs because of a decrease in interfacial tension between the solid and the liquid. Generally, we use non-ionic surfactants, but ionic surfactants can also be used depending upon certain conditions. Polysorbate 80 is most widely used due to its following advantages: - It is non-ionic so no change in pH of medium. - No toxicity. Safe for internal use  Surfactants Most surfactants are used at concentrations of up to about 0.1% as wetting agents and include: For oral use, the polysorbates (Tweens) and sorbitan esters (Spans). For external application, sodium lauryl sulphate, sodium dioctylsulphosuccinate and quillaia extract can also be used. For parenteral use: polysorbates, some of the poloxamers (polyoxymethylene/polyoxypropyle ne copolymers) and lecithin. Disadvantages in the use of this type of wetting agent include excessive foaming and the possible formation of a deflocculated system, which may not be required.  Hydrophilic Colloids These materials include acacia, bentonite, tragacanth, alginates, xanthan gum and cellulose derivatives, and will behave as protective colloids by coating the solid hydrophobic particles with a multimolecular layer. Impart a hydrophilic character to the solid and so promote wetting. Increase the viscosity of water by binding water molecules Support the growth of microorganisms Mostly anionic, except methylcellulose (neutral) and chitosan (cationic) Incompatible with quaternary antibacterial agents These materials are also used as suspending agents and may, like surfactants, produce a deflocculated system, particularly if used at high concentrations.  Solvents Materials such as alcohol, glycerol and glycols, which are water miscible, will reduce the liquid/air interfacial tension. The solvent will penetrate the loose agglomerates of powder displacing the air from the pores of the individual particles, so enabling wetting to occur by the dispersion medium. Alcohol, glycerin, propylene glycol, and other hygroscopic liquids are employed as wetting agents when an aqueous vehicle is to be used as the dispersion phase.  Flocculating Agents The next stage of the formulation process, after the addition of the wetting agent, is to ensure that the product exhibits the correct degree of flocculation. Controlled flocculation is usually achieved by a combination of particle size control, the use of electrolytes to control zeta potential, and the addition of polymers to enable crosslinking to occur between particles. Some polymers have the advantage of becoming ionized in an aqueous solution and can therefore act both electrostatically and sterically. These materials are also termed polyelectrolytes.  Flocculating Agents Suspended particles that have high charge density usually display deflocculation and caking upon sedimentation. Neutralization of charge of such particles results in flocculation. Flocculating agents enable suspended particles to link together in loose aggregates or flocs through weak bonds. These flocs settle rapidly but form large fluffy sediment which is easily redispersed.  Zeta potential is therefore a function of the surface charge of the particle. Because it reflects the effective charge on the particles and is therefore related to the electrostatic repulsion between them, the zeta potential has confirmed to be extremely related to the colloidal stability and maintains colloidal dispersion.  Flocculating Agents 1. Electrolytes 2. Surfactants 3. Polymers 4. Alteration in the pH of the preparation (generally to the region of minimum drug solubility).  1. Electrolytes The addition of an inorganic electrolyte to an aqueous suspension will alter the zeta potential of the dispersed particles and, if this value is lowered sufficiently, flocculation may occur. The ability of an electrolyte to flocculate hydrophobic particles depends on the valency of its counter-ions. Although they are more efficient, trivalent ions are less widely used than mono- or divalent electrolytes because: 1. They are generally more toxic. 2. If hydrophilic polymers, which are usually negatively charged, are included in the formulation they may be precipitated by the presence of trivalent ions. The most widely used electrolytes include the sodium salts of acetates, phosphates and citrates, and the concentration chosen will be that which produces the desired degree of flocculation. Care must be taken not to add excessive electrolyte or charge reversal may occur on each particle, so forming, once again, a deflocculated system.  2. Surfactants Ionic surface-active agents may also cause flocculation by neutralizing the charge on each particle, thus resulting in a flocculated system. Non-ionic surfactants will, of course, have a negligible effect on the charge density of a particle but may, because of their linear configurations, adsorb on to more than one particle, thereby forming a loose flocculated structure.  3. Polymeric flocculating agents Polymeric flocculating agents Starch, alginates, cellulose derivatives, tragacanth, carbomers and silicates are examples of polymers that can be used to control flocculation. Their linear branched-chain molecules form a gel- like network within the system and become adsorbed on to the surfaces of the dispersed particles, thus holding them in a flocculated state. Although some settling can occur, the sedimentation volume is large, and usually remains so for a considerable period. Viscosity Modifiers (suspending agents) Viscosity Modifiers (suspending agents) These are usually hydrophilic polymers that are added to a suspension to increase viscosity, inhibit agglomeration and retard sedimentation. Most suspending agents have hydrophilic and hydrophobic regions, which interact with a suspension particle surface. These exert their effect by entrapping the solid dispersed particles within their gel-like network, so decreasing interparticle attraction and preventing sedimentation. At low concentrations many suspending agents can be used to control flocculation, and it must be realized that if large quantities are to be used to enhance viscosity the degree of flocculation may also be altered.  Suspending Agents 1.Polysaccharides Acacia Tragacanth Alginates Starch Xanthan gum (Keltrol) 2. Water-soluble celluloses Methylcellulose (Celacol, Methocel) Hydroxyethylcellulose (Natrosol) Carmellose sodium (sodium carboxymethylcellulose) Microcrystalline cellulose 3. Hydrated silicates bentonite, magnesium aluminum silicate and hectorite 4. Carbomers (carboxymethylcellulose ) 5. Colloidal silicon dioxide (Aerosil) Other Additives Buffers Preservatives Buffers are the materials Preservatives are often added in which when dissolved in a aqueous suspensions because solvent will resist any change suspending agents and sweeteners in pH when an acid or base is are good media for microorganisms. added. Naturally occurring suspending agents such as tragacanth, acacia, To encounter stability xanthan gum are susceptible to problems all liquid formulation microbial contamination. should be formulated to an This leads to loss in suspending optimum pH. activity of suspending agents, loss of Generally, pH of suspension color, flavor and odor, change in elegance etc. preferably at 7.4-8.4. Examples are: Propylene glycol, Most used buffers are salts of Disodium EDTA (0.1%), weak acids such as Benzalkonium chloride (0.01-0.02%) carbonates, citrates, Benzoic acid (0.1%) gluconates, phosphate  Sweeteners, Flavors, and Colourants Sweeteners are often added to suspensions to reduce any unpleasant taste of the partially dissolved drug and to improve palatability in general. Examples : sorbitol, corn syrup, sucrose, saccharin, and aspartate. Flavoring Agents are added to increase patient acceptance of the product. Since sweeteners are not capable of complete taste masking of unpleasant drugs , a flavoring agent is incorporated. - Examples :Ginger, Sarsaparilla syrup, Anise oil, Glucose, Spearmint oil. Colourants are added to provide a more aesthetic appearance to the final product. Choice of colourant is usually tied to the choice of flavor, and their choices are also linked to the patient population, such as age group and geographic region, and the therapeutic need. Colours are obtained from natural or synthetic sources. The synthetic dyes should be used within range of( 0.0005 % to 0.001%) Most widely used colors are as follows. - Titanium dioxide (white), Brilliant blue (blue), Indigo carmine(blue), Amaranth (red), Tartarazine (yellow), Annatto seeds(yellow to orange). Humectants Antioxidants Humectants absorb Ascorbic acid derivatives moisture and prevent such as ascorbic acid, degradation of API by erythorbic acid and thiol moisture. derivatives such as thio- Examples of humectants glycerol, cytosineand most commonly used in acetyl cysteine suspensions are propylene Tocopherols glycol ,glycerol. Total quantity of humectants should be between 0-10 % w/w. Preparation of Suspensions - Precipitation method - Dispersion Method  Precipitation Method Three precipitation methods are used: Organic solvent precipitation: - Water insoluble drugs can be precipitated by dissolving them in water- miscible organic solvent and then adding organic phase to distilled water under standard conditions. E.g Prednisolone is precipitated from a methanolic solution to produce a suspension in water. - Organic solvents used are ethanol, methanol, propylene glycol and polyethylene glycol. Precipitation by pH: - The method of changing the pH of medium is more readily accomplished and does not present the same difficulties associated with organic solvent precipitation. - This method is applicable only to those drugs in which solubility is dependent on pH value. Examples include Estradiol Suspension and Insulin Suspension. Double Decomposition: - Double decomposition method In this method two water soluble reagent forms a water insoluble product. Example: White Lotion NF is prepared by slowly adding zinc sulfate solution in a solution of sulphurated potash to form a precipitate of zinc polysulphide.This method involves simple chemistry. Example includes White Lotion  Dispersion Method In this method, the vehicle must be formulated so that solid phase is easily wetted and dispersed. - The use of surfactant is desirable to ensure uniform wetting of hydrophobic solid. - The use of suspending agent such as synthetic polymer, natural gums and others maybe indicated depending upon specific application. - The actual dispersing of solids may or may not cause particle size reduction. If particle size reduction occurs, the particles obtained may have different solubilities and this may lead to super saturation of the system. Evaluation of Suspensions  Evaluation of Suspensions Suspensions can be evaluated for stability by using the following methods; 1. Sedimentation method 2. Rheological method 3. Electro kinetic method 4. Micromeritic method  Sedimentation Method Two parameters are studied for determination of sedimentation. 1. Sedimentation volume 2. Degree of flocculation (β)  Sedimentation Method Sedimentation volume The suspension formulation(50mL) is poured separately into100mL measuring cylinders and sedimentation volume is read after 1,2,3 and 7days,and there after at weekly intervals for 12 weeks. Triplicate results are obtained for each formulation. Sedimentation volume is defined as the ratio of the ultimate volume of sediment to the original volume of suspension before settling. It is calculated according to the equation: F = Vu/Vo Where, F =sedimentation volume , Vu = final or ultimate volume of sediment Vo= initial volume of suspension before settling.  Degree of flocculation(β) It is the ratio of the sedimentation volume of the flocculated suspension ,F , to the sedimentation volume of the deflocculated suspension, F∞ ß = F / F∞ ß = (Vu/Vo) flocculated (V ∞ /Vo) deflocculated ß = Vu V∞ The minimum value of ß is 1,when flocculated suspension sedimentation volume is equal to the sedimentation volume of deflocculated suspension.  Rheological Method It provides information about settling behaviours i.e., the arrangement of the vehicle and the particle structural features. Brookfield viscometer is used to study the viscosity of the suspension. It is mounted on a Heli path stand and using a T-bar spindle. T-bar spindle is made to descend slowly into the suspension and the dial reading on the viscometer is then a measure of the resistance the spindle meets at various level. This technique also indicates at which level of the suspension the structure is greater owing to particle agglomeration. The dial reading is plotted against the number of turns of the spindle. The better suspension show a lesser rate of increase of dial reading with spindle turns, i.e. the curve is horizontal for long periods.  Rheological Method The experimental methods involve the study of the system from lower to higher rates of shear. The resultant thixotropic curves are compared with those of the standard products. - Shear stress rpm - Flow curves for 5% suspending agents in water show thixotropy Rheological evaluation is used as a quality control parameter for comparing products. The consistency of suspensions are evaluated using Cup and Bob or Cone and Plate viscometers. These are not applicable for flocculated suspensions because the structure of the flocs are destroyed during the analysis. ELECTROKINETIC METHOD  Electrokinetic Method- Zeta Potential The zeta potential of the formulated suspensions was determined using a Zeta Plus.(Brook haven Instruments Corporation ,USA). Approximately 1mL of suspension was transferred into a plastic cuvette using a pipette and diluted with distilled water. The Brookhaven zeta potential software was used for the measurement. Parameters set to a temperature of 250C and refractive index(1.33). The zeta potential of the formulations was determined on day 0,7, 14,21and day 28 post formulation.  Zeta Potential Zeta potential has practical application in stability of systems containing dispersed particles. Since this potential, rather than the Nernst potential, governs the degree of repulsion between the adjacent, similarly charged, dispersed particles. If the zeta potential is reduced below a certain value , the attractive forces exceed the repulsive forces, and the particles come together  Micromeritic Method The stability of suspension depends on the particle size of the dispersed phase. Change in the particle size with reference to time will provide useful information regarding the stability of a suspension. A change in particle size distribution and crystal habit studied by - microscopy coulter - counter method Rheology of Suspensions  Rheological properties of Flocculated suspensions suspensions Tend to exhibit plastic or pseudoplastic flow depending on the concentration because the apparent viscosity of flocculated suspensions is relatively high when the applied shearing stress is low, but it decreases as the applied stress increases and the attractive forces producing the flocculation are overcome. Deflocculated suspensions Concentrated deflocculated dispersions tend to exhibit dilatant flow. because the apparent viscosity of a concentrated deflocculated suspension is low at low shearing stress but increases as the applied stress increases. This effect is due to the electrical repulsion that occurs when the charged particles are forced close together causing the particles to rebound and creating voids into which the liquid flows, leaving other parts of the dispersion dry. In addition to the rheological problems associated with particle charge, the sedimentation behaviour is also influenced by the rheological properties of the liquid continuous phase. Rheological Properties of Suspensions Thixotropic suspension are viscous during storage but loses consistency and become fluid upon shaking. A well-formulated thixotropic suspension would remain fluid long enough for the easy dispense of a dose but would slowly regain its original viscosity within a short time. The sol like behaviour also helps in uniform spreading of dermatological preparations. Therefore, to maintain these properties ,the flow properties of the dispersion medium should be studied, since it is largely responsible for determining the rheology of the suspensions. The preformulation studies include evaluation of vehicles used in the suspension. An optimum viscosity of this medium should be selected through experimentation.  Packaging and Storage of Suspensions All suspensions should be packaged in widemouth containers having adequate airspace above the liquid to permit thorough mixing by shaking and ease of pouring. Most suspensions should be stored in tight containers protected from freezing, excessive heat, and light. It is important that suspensions be shaken before each use to ensure a uniform distribution of solid in the vehicle and thereby uniform and proper dosage. Other Suspensions  Suspensions for Topical Administration They can be fluid preparations, such as Calamine Lotion, which are designed to leave a light deposit of the active agent on the skin after quick evaporation of the dispersion medium. Some suspensions, such as pastes, are semisolid in consistency and contain high concentrations of powders dispersed - usually - in a paraffin base. It may also be possible to suspend a powdered drug in an emulsion base, as in Zinc Cream.  Suspensions for Parenteral Use Suspensions can also be formulated for parenteral administration to control the rate of absorption of the drug. By varying the size of the dispersed particles of active agent, the duration of activity can be controlled. The absorption rate of the drug into the bloodstream will then depend simply on its rate of dissolution. Innovations of Suspensions  Recent advances in Suspensions 1. Nano suspensions. 2. Taste masked pharmaceutical suspensions. 3. Sustained release suspensions  Nano Suspensions Nanosuspension is defined as very finely dispersed solid drug particles in an aqueous or organic vehicle for either oral and topical use or parenteral and pulmonary administration. The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600 nm. Nanosuspensions differ from nanoparticles. Nanoparticles are commonly polymeric colloidal carriers of drugs whereas solid lipid nanoparticles are lipidic carriers of drugs. In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size, leading to an increased dissolution rate and therefore improved bioavailability.  Nanosuspensions Advantages Disadvantages Can be applied for the poorly Physical stability, water-soluble drugs. Rapid dissolution and tissue sedimentation and targeting can be achieved by IV compaction can cause route of administration. problems. Oral administration of It is bulky sufficient care nanosuspensions provide rapid must be taken during and improved bioavailability. Long-term physical stability due handling and transport. to the presence of stabilizers. Uniform and accurate Nanosuspensions can be dose cannot be achieved incorporated in tablets, pellets, unless suspension. hydrogels.  Taste masked Suspensions Un-palatability due to bad taste is a major concern in most of the dosage forms containing bitter drugs. In case of suspensions also taste masking is being applied to mask bitterness of drugs formulated. Taste masking is defined as a perceived reduction of an undesirable taste that would otherwise exist The taste masking approaches for suspensions are: - Addition of sweeteners, flavours & Amino acids - Inclusion Complexation - Ion-Exchange Resins - Polymer coating of drugs - Miscellaneous Taste masking Approaches - Use of Effervescent Agent - Microencapsulation - Rheological Modifications - Salt Preparation - Solid Dispersion Systems - Wax Embedding of Drug etc.  Sustained release Suspensions 1.Sustained release is a method used to increase only the duration of action of drug being formulated without affecting onset of action. 2.In suspensions, sustained release is affected by coating the drug to be formulated as suspension by insoluble polymer coating. 3.The polymer coating provides sustained release and also masks the taste of the bitter drug. The polymer used for sustained release in suspension is as follows as: - Ethyl cellulose, - Eudragit - Cellulose acetate, etc. The main advantage of sustained release suspension is decrease in dosing frequency. Sustained-Release Suspensions utilize 1. coated beads, 2. drug-impregnated wax matrix, 3. microencapsulation, 4. ion exchange resins 5. The use of a combination of ion exchange resin complex and particle coating has resulted in product success via the Pennkinetic system.  The Pennkinetic system is formed by reacting a drug in its ionic state with a suitable polymer matrix. By this technique, ionic drugs are complexed with ion exchange resins, and the drug–resin complex particles coated with ethyl cellulose. In liquid formulations (suspensions) of the coated particles, the drug remains adsorbed onto the resin but is slowly released by the ion exchange process in the gastrointestinal tract.  Conclusion 1. Pharmaceutical suspensions are solid dispersion of insoluble or sparingly-soluble drugs, in aqueous or oily vehicles. They are intended for oral administration, topical application or parenteral administration of drugs. Aerosol suspension of finely divided, or micronized drugs, is also another class of pharmaceutical preparations intended for inhalation. 2.Suspension of drugs for oral administration is an easy way to administer insoluble, or sparingly soluble, drugs to infants and elderly who have difficulty in administering drugs in tablet or capsule forms. Also, for rapid absorption of some insoluble drugs, which are slowly absorbed from tablet dosage form, such as griseofulvin, prepared in suspensions form of the micronized drug. 3.The insoluble basic drug, or the insoluble salt or compound of a drug, is frequently used rather than using the soluble salt, to retard absorption of the drug. This is used for the preparation of prolonged released dosage forms to avoid frequent administration of the drug. Sometimes insoluble salts or compounds of the dugs are used to avoid the bitter taste of the soluble form; for example, the use of chloramphenicol palmitate in suspension, instead of using the very bitter soluble chloramphenicol. 4. Some eye drops or ear drops are also prepared in suspension form for drugs which are sparingly soluble, or intentionally using the insoluble form to prolong the time of action of the drug, such as corticosteroid preparations.