Suspensions PDF

# Suspensions ## Introduction The internal phase (solid) is dispersed throughout the external phase (fluid) through mechanical agitation, with the use of certain excipients or suspending agents. An example of a suspension would be sand in water. The suspended particles are visible under a microscop...

# Suspensions ## Introduction The internal phase (solid) is dispersed throughout the external phase (fluid) through mechanical agitation, with the use of certain excipients or suspending agents. An example of a suspension would be sand in water. The suspended particles are visible under a microscope and will settle over time if left undisturbed. This distinguishes a suspension from a colloid, in which the suspended particles are smaller and do not settle. ## Definition A coarse dispersion of finely divided insoluble solid particles (the disperse phase) in a fluid (dispersion medium), which is mostly aqueous, and sometimes organic or oily. - Particle size above the colloidal size, (up to 1µm diameter called colloidal). - Particle size of suspension from 1µm to 100µm. - Suspensions supply the insoluble and distasteful substance in a pleasant taste, and providing a suitable form for application on skin, mucous membrane, and for parenteral administration. - The particles may be visible to the naked eye, usually must be larger than one micrometer. ## Classification Suspensions are classified into three groups: 1. Oral suspension (antibiotics suspension contains 125-500mg/5ml, and antacids) 2. External suspension (lotion) 3. Injectable suspension ## Physical Properties The concentration of dispersed phase may exceed 20%. Parenteral suspension contain 0.5-30% of solid particles, viscosity and particle size are significant factors which affect the ease of injection and the availability of drug in depot therapy. - The suspension must remain homogenous in the period between shaking and removing the dose. - The sediment on storage must be easily res-suspended with shaking. - It requires to be thick to reduce the rate of settling. - The suspended particle should be small and uniform in size to give smooth and elegant product. ## Pharmaceutical Applications - Used in case of patients have difficulty in swallowing solid dosage forms. - When drug is insoluble in suitable solvent it is formulated as suspension. - Some eye drops as hydrocortisone and neomycin are available as suspensions due to their insolubility. - The drugs which degrade in water, then aqueous solution should be avoided, and can be formulated in the form of suspensions. Oxytetracycline Hcl, it hydrolyzes rapidly in water, then it can suspend as calcium salt. - The prolonged contact between particles and dispersion medium can be reduced by using the drug as powder and re-suspended before use immediately. - A drug which degrades in the presence of water may be alternatively suspended in non-aqueous vehicle as phenoxymethylpenicillin is dispersed in coconut oil. - Some materials are required in finely divided solids in GIT to give large surface area, such as kaolin, magnesium carbonate, and magnesium trisilicate which are used as antacids and in diarrhea. - The adsorptive process properties of fine powders are used in some inhalations. The volatile components as menthol oil would be lost during use, but prolonged release is obtained if the active ingredient is adsorbed on magnesium carbonate prior preparation. - The taste of most drug is more noticeable if in solution than in insoluble form, for example paracetamol in suspension is more palatable for children than in elixir form. - Suspension of drugs can also be formulated in topical application as calamine lotion which is designed to leave a layer of active agent on skin after evaporation of dispersion medium. Some suspension was found in semisolid as pastes. - Suspension can also be formulated for parenteral administration to control rate of absorption. - Vaccines are often formulated as suspensions, which consist of dispersion of killed micro-organisms. - Some X-ray contrast media are also formulated as suspension as barium sulfate used oral or rectal for examination of alimentary tract. ## Interfacial Properties of Suspended Particles - Knowledge of the thermodynamic requirements is needed for successful stabilization of suspended particles. - Work must be done to reduce a solid to small particles and disperse them in continuous medium. - The large surface area of particles that result from comminution is associated with a surface free energy that makes the system thermodynamically unstable. - The particles are highly energetic and tend to regrouped to decrease surface area and surface free energy. - The particles in a liquid suspension tend to flocculate, i.e to form light, fluffy agglomerates that are held together by van der Waals forces. - Under certain conditions a compact cake is formed due to adhere particles by stronger forces to form aggregates. - Caking often occurs by growth and fusing together of crystals in the precipitates to produce a solid aggregate. - The formation of any type of agglomerate, either floccules or aggregates, is a measure of the system tendency to reach a thermodynamically stable state. - By dividing the solid into smaller particles, leading to increase in total surface area AA, and consequently increase in surface free energy ΔF. ΔF = γ . ΔA Where y inter is the interfacial tension between the liquid medium and the solid particles. ## Surface Potential - The stability of lyophobic colloidal systems can generally be explained on the basis of the presence or absence of surface potential. This theory can also be extended to suspension systems. Surface potential exists when dispersed solid particles in a suspension possess charge in relation to their surrounding liquid medium. - Solid particles may become charged through different ways. If the suspension contains electrolytes, selective adsorption of a particular ionic species by the solid particles is a possibility. This will lead to the formation of charged particles. - Occasionally, the surface-active agents, which are already adsorbed at the solid-liquid interface, may ionize to give the particles positive or negative charge. Sodium dodecyl sulfate (SDS), for example, is anionic in aqueous medium. Solid particles can also be charged by ionization of functional group of the particles. - In this case, the total charge is a function of the pH of the surrounding vehicle. Peptide and protein molecules contain ionizable groups, such as -COOH and –NH2. Dispersed particles of these types of molecules will ionize. The sign and magnitude of the ionization mostly depend on the pH of the surrounding vehicle. ## Electric Double Layer - When dispersed particles are in contact with an aqueous solution of an electrolyte, the particles may selectively adsorb one charge species. If the adsorbed species is an anion, the particles will be overall negatively charged. The ions that give the particle its charge, anions in this case, are called potential-determining ions or co-ions. - Remaining ionic species in the solution are the rest of the anions and the total number of cations added. This means, there will be excess cations than anions in the dispersion medium. These cations having a charge opposite to that of the potential-determining ions are known as counter-ions. They are attracted to the negatively charged surface by electric forces. - counter-ions also repel the approach of any further anions to particle surface, once the initial adsorption is complete. These electric forces and thermal motion keep an equal distribution of all the ions in solution. It results in an equilibrium condition where some of the excess cations approach the surface and the rest of the cations will be distributed in decreasing the amounts as one move away from the charged surface. - This situation is explained in Fig. 1. The part of the solvent immediately surrounding the particles will almost entirely comprise of the counter-ions. This part of the solvent, along with these counter-ions is tightly bound to the particle surface and is known as the Stern layer. - Surrounding the Stern layer is the diffuse layer that contains more counter-ions than co-ions. The ions in this layer are relatively mobile and, because of thermal energy, they are in a constant state of motion into and from the main body of the continuous phase. ## Zeta Potentials - The electric double layer is formed in order to neutralize the charged particles in a suspension. The electrical potential at any point in a suspension system depends on its exact location. The potential in the diffuse layer gradually changes as one moves away from a solid particle. - The difference in electric potential between the actual or true surface of the particle and the electroneutral region is referred as Nernst potential (E). - The potential difference between the shear plane and the electroneutral region is known as the electrokinetic or zeta (z) potential. - The zeta potential is a key indicator of the stability of dispersions. The magnitude of the zeta potential indicates the degree of electrostatic repulsion between adjacent, similarly charged particles in a dispersion. For molecules and particles that are small enough, a high zeta potential will confer stability, i.e., the dispersion will resist aggregation. When the potential is small, attractive forces may exceed this repulsion and the dispersion may break and flocculate. So, suspension with high zeta potential (negative or positive) are electrically stabilized while those with low zeta potentials tend to coagulate or flocculate. ## Formulation of Suspensions ### 1. Particle Size Control - The rate of sedimentation of a suspended particle can be retarded by reduction in its size. - Large particles greater than 5µm diameter led to gritty texture to the product and may cause irritation if injected or instilled into the eyes. - The parenteral suspension depends on the particle size and shape and it is possible to block the hypodermic needle with particles over 25µm diameter. - A particular particle size chosen in order to control the release rate of the drug and its bioavailability. ### 2. The Use of Wetting Agents - Some insoluble solids may be easily wetted with water and will disperse easily through the aqueous phase with minimum agitation. - Most insoluble solids exhibit various degrees of hydrophobicity and not be easily wetted. - Some particles will form large porous clumps within the liquid while other remain attached to upper part of container. **Mechanism** - Wetting agent is used to reduce interfacial tension between solid and liquid by displacing the adsorbed air on the surface of solid by liquid. - The particles will then disperse readily throughout the liquid using intense shearing during mixing. - The concentration of wetting agent should be the lowest one which produce adequate wetting. **The wetting agents used are:** - **Surface active agents:** Surfactants possess an HLB value between 7 and 9 would be suitable for use as wetting agents. The wetting of solid occur due to a fall in interfacial tension between the solid and liquid. - **Hydrophilic colloids:** These include acacia, bentonite, tragacanth, alginates and cellulose derivatives. They act by coating the solid hydrophobic particles with a multimolecular layar, which increase the hydrophilicity to solid and thus promote wetting. These materials are also used as suspending agent. - **Solvents:** Alcohol, glycerol and glycols which are water miscible will reduce the liquid/ air interfacial tension. **Mechanism** - The solvent penetrate the loose agglomerates of powder displacing air from pores of the individual particles thus enabling wetting to occur by dispersion medium. ### Controlled Flocculation Is usually achieved by a combination of: 1. Particle size control, 2. The use of electrolytes to control zeta potential 3. And the addition of polymers to enhance cross linking to occur between particles. ### Flocculating Agents - In many cases, after incorporation of nonionic surfactant, a suspension will be deflocculated due to reduction in solid liquid interfacial tension, or due to formation of mechanical hydrophilic layer around each particle lead to aggregation. - The use of ionic surfactant may lead to two cases of suspension, - If the charge of particles neutralized then flocculation occurs. - Or if high density of charge accumulated on suspended particles then deflocculation will obtained. - To convert deflocculated suspension to flocculated one it is necessary to add electrolytes, surfactants and/or hydrophilic polymers **1- Electrolytes** - The addition of an inorganic electrolyte to the aqueous suspension will lower zeta potential of dispersed particles, then flocculation occurs. **Role of electrolyte** - Act as flocculating agents by reducing the electric barrier between the particles, and reduce zeta potential, and formation of bridge between particles to form a loosely arranged structure. **Example:** - If bismuth subnitrate dispersed in water, large positive charge and high zeta potential occur. Positive charge lead to repulsion between particles, the system should be deflocculated. - The addition of monobasic potassium phosphate to this system lead to adsorption of negative charge on particles and this lead to decrease the zeta potential. - Continue addition of potassium phosphate lead to gradual decrease of zeta potential to zero and then increase in negative direction. - When zeta potential become sufficiently negative deflocculation will occur - When zeta potential become sufficiently negative the sedimentation volume start to fall. - The absence of caking in the suspension correlates with the maximum sedimentation volume, which reflect the amount of flocculation. **2. Surfactants, both ionic and nonionic** - Ionic surfactant may cause flocculation by neutralization of the charge on the particles. - Nonionic surfactant has little effect on charge density of particles and adsorb on to more than one particle due to its linear structure thus forming loose flocculated structure. **3. Polymeric flocculated agents** - Starch, alginates, cellulose derivatives, tragacanth and silicates are examples of polymers which can be used to control the degree of flocculation. - These polymers form gel like network adsorbed on the surface of the dispersed particles due to its linear structure thus holding them in a flocculated state, although some settling can occur, and the sedimentation volume is large. - The same effect occur if high concentration of polymer is used which lead to coat the surface of each particle. During manufacture blending should not excessive because this may inhibit the cross linking between particles and result in adsorption of each molecule of polymer on to one particle only. - If this occur deflocculated system will occur due to the formation of hydrophilic barrier around each particle will inhibit aggregation. - These polymeric materials will also modify the viscosity of suspensions. ## Settling in Suspensions - Stability in pharmaceutical suspension is the keeping particles uniformly distributed throughout the dispersion. - Because it is impossible to prevent the settling over a prolonged period of time, it is necessary to consider the factors that influence the velocity of sedimentation. **Theory of sedimentation** The velocity of sedimentation is expressed by stokes law: v = d² (ps - po) g/18η. Where: - v = velocity of particles in cm/sec - d = the diameter of particle in cm - ps = the density of dispersed phase - po = the density of dispersion medium - g = the acceleration gravity - no = the viscosity of the dispersion medium - Dilute pharmaceutical suspension contains less than 2 g of solids/100ml of liquid. - In dilute suspension the particles not interfere with one another during sedimentation and free settling occur. - In suspension contain 5-10% of solids or higher exhibit hindered settling. The particles interfere with each other and stokes law not applied. - Physical stability of suspension obtained when concentration of solids from 0.5-2% of solids, when the original suspension is concentrated, addition of diluent affect on flocculation and deflocculation of the system and change the particle size distribution. - In order to account the non- uniformity in particle shape and size in real system, stokes equation written in general form: v = Kd² (ps - po) g/18ηo Which K is constant determined by experiment **Limitations of Stokes' Law** - Stokes' law is valid for diluted pharmaceutical suspensions that are composed of no more than 2% solids. In a diluted suspension, the solid particles settle without interference from one another in what is termed free settling. In a concentrated suspension, this interference may occur, and may hinder the settling results. - Particle shape and size are also important in Stokes' equation. This equation assumes spherical and monodisperse particles, which may not be encountered in real systems. - Stokes' equation is invalid if the density difference in the equation is negative(i.e., the particles are lighter than the dispersion medium). In this case, floatation will occur. - Stokes' equation may not show the real sedimentation rate when the solid content is high. The equation contains only the viscosity of the medium. However, the high solid content imparts additional viscosity to the system, which must be taken into consideration if the correct rate of settling is to be determined. - Although Stokes' equation does not consider many important parameters, it, nevertheless, provides a very good estimate, based on what further investigation can be carried out to determine the exact rate of sedimentation. ## Effect of Brownian Movement - Brownian movement control the sedimentation of particles having a diameter of about 2-5µm depending the density of particles and the density and the viscosity of suspending medium at room temperature keeping the dispersed material in random motion. - It may be seen by microscope that Brownian movement of the smallest particles eliminated when the sample is dispersed in 50% glycerin solution having a viscosity of about 5 cps. - Brownian movement is another factor that can influence the accuracy of the results obtained in Stokes' equation. If the particle in a dispersion is too small, the molecular bombardment can cause a random motion, known as Brownian movement, which is not uniform throughout the dispersion. - Brownian movement counteracts sedimentation to a measurable extent. Therefore, the actual rate of sedimentation may greatly deviate from the one calculated using Stokes' equation. As the particle size is reduced, Brownian movement becomes significant. Below a critical radius, the movement will be sufficient to keep the particles from sedimentation. ## Sedimentation Parameters ### 1. Sedimentation Volume F - Is defined as the ratio of final or ultimate volume of the sediment, Vu to the original volume of suspension, Vo, before settling - F = Vu/Vo - F range from 0.5:1. - F is normally less than 1, and in this case the ultimate volume of sediment is smaller than the original volume of suspension in which F= 0.5 - In flocculated suspension the volume of sediment equal the original volume of suspension then F = 1, in this case no clear supernatant on standing. - It is possible F greater than 1, this means that final volume of sediment greater than original volume of suspension. This is due to flocs formed in suspension are so loose and fluffy which the volume become greater than the original volume of suspension. In this case F = 1.5, and sufficient extra vehicle is added. - The sedimentation volume gives a qualitative account of flocculation. ### 2. Degree of Flocculation β - If we consider a suspension that completely deflocculated, the ultimate volume of sediment will be relatively small. - F = V/ Vo - In which F is the sedimentation volume of the deflocculated suspension. - The degree of flocculation ẞ, is defined as the ratio of F to For - β = F/F - Substituting equations 2 and 3 in equation 4 we obtain: - β = ---------- - The degree of flocculation is more fundamental parameter than F since it relates the volume of flocculated sediment to the deflocculated system. ## Difference between Flocculation and Deflocculation - In deflocculated suspension the dispersed particles remain as separate units. - The rate of sedimentation depends on the size of each unit, settling will be slow. - The repulsive forces between individual particles allow them to slip past each other during sedimentation. - The slow rate of settling prevent the entrapment of liquid within the sediment, thus it become compacted and difficult to re-disperse. - This phenomenon is also called caking or claying and is the most serious physical stability problem. - The supernatant of deflocculated system will remain cloudy due to very slow rate of settling of the smallest particles. - In flocculated system aggregation of particles occur and lead to much more rapid rate of sedimentation because each unit composed of many individual particles and therefore larger. - The rate of settling is rapid and depend on the porosity of aggregates, since the dispersion medium can flow through and around floccule as it sediment. - The aggregates will produce loose and fluffy floccules of higher porosity, the volume of the final sediment large and will easily be re-dispersed by moderate agitation. - In flocculated system the supernatant become clear due to rapid rate of settling of floccules. - In flocculated system inaccurate dose obtained due to rapid rate of sedimentation and the product look inelegant. - The deflocculated system has an advantage that accurate dose obtained due to slow rate of sedimentation. - A deflocculated system with sufficiently high viscosity lead to low sedimentation rate and this would be an ideal situation, but it cannot be guaranteed that the system would remain homogenous during shelf life. When the suspension is partially flocculated and viscosity is controlled so that the sedimentation rate is at a minimum. ## Rheology of Suspensions - An ideal suspension showed high apparent viscosity at low rate of shear. On storage the suspended particles either settle very slowly or remain suspended. - At high rate of shear, or by moderate shaking the viscosity fall sufficiently to be poured easily from the container. - If the product used externally it should be spread easily, but should not be so fluid to run off the skin surface. - If the suspension used for injection, it should pass easily through a hypodermic needle with only moderate pressure applied to the syringe plunger. - A flocculated system fulfills these criteria. In such a system pseudo plastic or plastic behavior is exhibited and breakdown under shear, and this is time dependent reversibility of this loss of structure which is termed thixotropy. - A deflocculated system, would exhibit Newtonian behavior. - If high concentration of solids it exhibits dilatancy. - Although flocculated system may exhibit thixotropy and plasticity, unless a high concentration of solid present, it may be not sufficient to prevent rapid settling particularly if a surfactant or electrolyte used as flocculating agent. In this case suspending agent is used to enhance viscosity of the system. - Hydrophilic polymers are used to increase viscosity by forming gel to prevent sedimentation. ## Viscosity Modifiers #### 1. Polysaccharides - **A- Acacia gum:** - This natural is often used as thickening agent in suspension. It is not good thickening agent but used due to its action as protective colloid. - It became acidic during storage due to enzymatic activity, it also contain an oxidase enzyme which may cause deterioration of active agent. - Because of stickiness of acacia it is rarely used in external preparations. - **a) Tragacanth:** - It is better thickening agent than acacia due to its thixotropic and pesudoplastic properties and it can be used for internal and external products. - It is stable in pH range from 4-7.5. - **Disadvantage:** It takes several days for hydration and to achieve maximum viscosity. - **Alginates and alginic acid:** - It has suspending properties similar to those of tragacanth. - Aliginates must not heated above 60C which lead to loss of viscosity due to depolmerization. - Its viscosity fall after 24 hrs. - It shows maximum stability at pH range of 5-9 and at low pH the acid ppt. - Sodium alginate is the most widely used, but it is anionic and will be incompatible with cationic materials and heavy metals. - **a) Starch:** - It is rarely used. - It is constituent of compound tragacanth. - It is used with Sodium CMC. ## Formulation Additives #### 1. Buffers - **Role:** - It maintain chemical stability due to presence of flocculating agent. - control isotonicity. #### 2. Density Modifiers - **Role:** - increase the viscosity and decrease sedimentation. - From stokes law if the density of dispersed medium and dispersion medium is equal no sedimentation occurs. #### 3. Flavors, Colors and Perfumes - **Role:** - Added to give color and flavor for suspension which adsorbed on disperse phase. - The inclusion of these materials may alter the physical properties of suspension. #### 4. Humectants - **Role:** - Prevent drying of the product after application. - Glycerol and propylene glycol are examples of humectants. - It is used in conc. 5% for external application. #### 5. Preservatives - **Role:** - prevent the growth of bacteria during use. - Example: sodium benzoate, benzoic acid, and parabens #### 6. Sweeting Agents - **Role:** - To give suitable taste. - Examples: sucrose, sorbitol, glycerol. - It has adversely effect on rheological properties. - Synthetic sweeteners affect on degree of flocculation. ## Preparation of Suspension #### On small scale 1. Grinding and levigating the insoluble powder in mortar with a vehicle to form a paste using stabilizer. 2. Add the reminder of liquid phase gradually in which any soluble material will be dissolved. 3. Then the slurry is transferred to graduated cylinder. 4. The mortar is rinsed with many portions of the vehicles and added to slurry in graduated cylinder and complete the volume. #### On large scale Colloidal mill used in preparation of suspension which depend on the high velocity.