Pharmaceutical Suspension: Introduction & Classification (PDF)

# Introduction - Pharmaceutical suspension is a coarse dispersion where insoluble solid particles are dispersed in a liquid medium. - When the suspended solids are less than 1 µm, the system is referred to as a colloidal suspension. - When the suspended solids are greater than 1 µm in diameter, th...

# Introduction - Pharmaceutical suspension is a coarse dispersion where insoluble solid particles are dispersed in a liquid medium. - When the suspended solids are less than 1 µm, the system is referred to as a colloidal suspension. - When the suspended solids are greater than 1 µm in diameter, the system is a coarse suspension. - The upper limit of particle size for individual suspendable solids in a coarse suspension is approximately 50 to 75 µm. - Some small particles show Brownian movement when in low viscosity vehicles. # Pharmaceutical Suspensions - classification 1. Oral suspension - Antibiotics, oral drops, anti-acids 2. Topical suspension - Calamine Lotion USP 3. Parenteral suspension 4. Eye drops, Ear drops, etc. # Bioavailability of Drug The bioavailability of a drug is generally assumed to increase in the following sequence: 1. Solutions 2. Suspensions 3. Capsules 4. Tablets 5. Coated Tablets 6. Controlled Release Tablets # Particle Size Considerations - The mean particle size and the size distribution of suspended insoluble drugs are important considerations in formulating physically stable suspensions. - Drug particle size influences product appearance, settling rates, drug solubility, in vivo absorption, re-suspendability, and overall stability of pharmaceutical suspensions. # Criteria for good suspension - The dispersed particles should not settle rapidly. - Settling particles should not form a hard cake but should be readily re-dispersed after shaking the container. - The product should be fluid enough to flow freely from the orifice of the container, or into a syringe. It should also be fluid enough to spread easily over the affected area. - The suspension should not be mobile enough to run off of the surface to which it is applied. - The suspension should have an acceptable odor and color. - The dispersed phase must be chosen carefully to provide the optimum physical, chemical and pharmacologic properties. # Factors affecting formulation - Particle size and particle size distribution - Specific surface area - Inhibition of crystal growth - Changes in polymorphic form These properties should not change during storage. # Suspending Agents This table shows Suspending Agents, pH range for maximum stability, and common incompatibilities. | Suspending Agent | pH range for maximum stability | Common incompatibilities | | :--------------------------- |:---------------------------------:|:-----------------------------------------------------------------------------------------------| | Cellulosic | 3-10 | Tannins, cationic surfactants, and concentrated salt solution | | Carboxymethyl methyl-cellulose, Na microcrystalline cellulose | | | | Carboxymethylcellulose, sodium hydroxyethylcellulose | | | | Na-hydroxyethylcellulose | 2-10 | Insoluble in alcohol over 10% | | Hydroxypropylcellulose | 2-10 | Insoluble in alcohol over 10% | | Hydroxypropylmethylcellulose | 2-10 | Insoluble in alcohol over 10% | | Clays | 3-10 | Calcium ions and polyvalent cations-increase viscosity | | Bentonite (Colloidal aluminum silicate) | 3-10 | | | Colloidal magnesium aluminum silicate(hectorite) | 3-10 | Calcium ions- Increase viscosity. | | colloidal magnesium aluminum silicate (Attapulgite) | 3-10 | Calcium ions- Increase viscosity. | | Magnesium silicate (Sepiolite) | 3-10 | Calcium ions- Increase viscosity. | | Miscellaneous | | | | Carbomers. | 6-10 | Acids | | Gelatin (Pharmagels A & B). | 5-8 | Acids, Bases, and Aldehydes | | Polyethylene glycols (3350, 8000). | 3-10 | Phenols | | Povidone (K30) | 3-10 | Oils and Lecithin | | Lecithin | 5-8 | Insoluble in water | # Physical Stability of Suspension - Physical stability of suspension: - The condition where particles do not aggregate, and remain uniformly distributed throughout the dispersion. - Shake well before use: - This is an ideal situation, but in reality, this is not the case. This statement should be written on the bottle, and the product should be easily re-suspended by shaking it gently. # Interfacial Properties of Suspended Particles - The comminution, or size reduction, of particles increases the surface area of the particles. This also increases the free surface energy which makes the system thermodynamically unstable. - The particles are energetically excited and tend to group together to reduce the surface area. - The particles in a liquid suspension tend to flocculate, and form tight, fluffy conglomerates that are held together by weak van der waals forces. - In some cases, these particles may adhere by stronger forces to form what are termed aggregates or a cake. # Interfacial Tension in suspension - The formation of any type of agglomerate, either floccules or aggregates, is a measure of the system's tendency to reach a more stable state thermodynamically. # Reducing Interfacial Tension - To reach a stable state, a system tends to reduce its surface free energy. - Equilibrium is reached when ΔG=0, which can be achieved by reducing the interfacial tension, and by decreasing the interfacial area. - Interfacial tension between particles can be reduced by the addition of a surfactant, but not to zero. - The forces at the surface of the particles affect the degree of flocculation and agglomeration in a suspension. # Attraction and Repulsive Forces - Forces of attraction include both London forces and Van der Waals forces. - Repulsive forces arise from the interaction between the electric double layers surrounding each particle. # Electrical Barrier on Surface - This is diagrammatic representation of the electrical barrier caused by the electric double layer on two charged particles. - Arrows indicate the direction of attraction or repulsion due to charged particles. - (+) indicates positive charges, and (-) indicates negative charges. - Orange circle illustrates the particles, and the purple circles illustrate the electric double layer. # Charged Particles - This is a diagrammatic representation of charged particles. - The blue circles illustrate particles, and the red circle illustrates the repulsive force. - Arrows indicate the motion of the particles due to attraction or repulsion. # The Double Layer Model - This illustrates the electric double layer model. - The red circle represents the highly negative colloid. - The blue concentric circles represent the stern layer and the diffuse layer. - The yellow circles represent the positive counter ions and the red circles represent the negative co-ions. # Potential Energy - This is a potential energy diagram. - The x-axis represents the distance between particles. - The y-axis represents the energy of interaction. - The green line illustrates the attraction between particles. - The orange line, the attraction curve. - The blue line illustrates the repulsive force between particles. # Flocculation vs. Deflocculation - When repulsion energy is high, the potential barrier prevents collisions due to the energy requirements. - Deflocculated suspensions are stable, but if sedimentation takes place, they can be difficult to re-suspend. - In order to re-suspend and re-disperse these particles, you have to overcome the high-energy barrier. This is difficult to achieve by shaking the container. - The particles tend to remain strongly attracted to each other and form a hard cake. # Summary This text describes different properties of a dispersed system: 1. Flocculated Particles: - Are weakly bonded, settle rapidly, do not form a cake, and are easily re-suspended. 2. Deflocculated Suspensions: - Particles settle slowly, and eventually form a sediment. Aggregation occurs, and a hard cake forms. It is difficult to re-suspend. # Settling in Suspension - One aspect of physical stability in pharmaceutical suspension is concerned with ensuring the particles are uniformly distributed through the suspension. - It's impossible to prevent the sedimentation of particles entirely and for an extended period. - To prevent the formation of a hard cake, consider the following factors that influence the velocity of sedimentation: - Particle size - Density of the particles - Density of the medium - Gravity - Viscosity of the medium. # Problems formulating insoluble solids into suspensions - This section focuses on the importance of sedimentation when considering insoluble solids and creating a suspension. - The factors that affect the sedimentation rate of particles are described by Stokes's Equation: $v = \frac{2r^2(\sigma - \rho)g}{9\eta}$ - v = Velocity of a spherical particle of radius r and density σ, in a liquid of density ρ, and viscosity η. # Theory of Sedimentation - In diluted suspensions (2% or less), particles will not interfere with one another during sedimentation. - In most pharmaceutical preparations, this is not the case. The concentration is much higher-- typically 20% or 30%. - In this case, some estimation can be achieved by diluting the suspension. This may affect the degree of flocculation and de-flocculation of the suspension. # Effect of Brownian Movement - Particles having a diameter between 2 and 5 µm, (depending on the density of the particles and the suspending medium) can be counteracted or prevented by Brownian movement at room temperature. Brownian movement helps maintain the dispersed material in a random motion. - In pharmaceutical suspensions, Brownian movement is not generally observed. This is because most of them are viscous preparations that contain suspending agents. # Sedimentation of Flocculated Particles - Whether the supernatant liquid is clear or turbid during the initial stages of settling is a good indication of whether the system is flocculated or deflocculated. - The following are considered sedimentation parameters: 1. Sedimentation volume V, or the height H 2. Degree of flocculation. # Flocculated Particles - When particles are flocculated, the energy barrier is too large to overcome. The particles remain together at a distance between 1000 and 2000 A. - This distance is sufficient to form loosely structural flocks. - Optimum physical stability and appearance can be gained by formulating a suspension with flocculated particles and a structured vehicle that is hydrophilic colloidal. - The suspension should: - Flow readily from the container. - Possess a uniform distribution of particles in each dose. - In flocculated suspensions, floccules tend to fall together, producing a distinct boundary between the sediment and the supernatant liquid. - Hence, the liquid above the sediment is clear because even the small particles present in the system are associated with the floccules. # Deflocculated - Deflocculated suspensions are different. The suspension may have a range of particle sizes, and in accordance with Stokes' law, the larger particles settle more rapidly than the smaller ones. That means that no clear boundary is formed. The supernatant remains unclear for a longer time. - Whether or not the supernatant liquid is clear or turbid during the initial stages of settling is a good indication of whether the system is flocculated or deflocculated. # Evaluation of Suspension - The following are common evaluation parameters for a suspension: 1. Sedimentation Volume 2. Degree of Flocculation # Sedimentation Volume - Sedimentation volume (F) is a ratio of the final (or ultimate) volume of sediment Vu to the original volume of suspension V₀, before settling. The formula is: $F = \frac{V_u}{V_o}$ - The system is said to be in flocculation equilibrium when F=1. This implies that there is no clear supernatant on standing. # Degree of Flocculation - The degree of flocculation is a more useful value than sedimentation volume. - The degree of flocculation, (β), is the ratio of F to V∞ where F∞ is the sedimentation volume of the deflocculated suspension, or: $β = \frac{F}{F∞}$ - If the suspension is completely deflocculated, the ultimate volume of sediment will be small. The value is V∞ and the formula can also be written as: $β = \frac{(V_u/V_o) flocculated}{(V∞/V_o) deflocculated}$ - $β = \frac{V_u}{V∞}$ - This figure illustrates that the degree of flocculation, β, is the ratio of the sediment volume of flocculated suspension to the sediment volume of deflocculated suspension. # Principle of Flocculation - Once the powder is wetted and dispersed, attention should be given to keeping the powder flocculated to prevent compact sediment. The sediment should be re-dispersed easily. Materials used to produce flocculation include: - Electrolytes - Surfactants - Polymers # Surfactants and Suspension - Surfactants are useful in the preparation of suspensions because they reduce the interfacial tension between solid particles and the liquid. - This lowering of interfacial tension: - Lowers the contact area - Allows the air to escape from the surface of the particles - Promotes wetting and dispersion. **Levigation** - Glycerin and similar hygroscopic substances are used in levigation to improve the dispersion of the particles. The glycerin flows into the voids between the particles, displacing the air. This helps even during the mixing process. # Surfactants - Ionic and nonionic surfactants act as flocculating agents in suspensions. - Anionic Examples include: - Docusate sodium - Sodium lauryl sulfate - Nonionic examples include: - Polysorbate 65 - Polysorbate 80 - Octoxynol-9 - It's important to note that surfactant concentration is critical. High concentrations can act as wetting and deflocculating agents, leading to effective dispersion. # Polymers - Polymers are long chain molecules with high molecular weight, composed of active groups spaced along their length. - Polymers act as flocculating agents because part of the chain is adsorbed on the particle surface. The remaining parts project out into the dispersion medium, acting as a bridge between particles. This leads to the formation of floccules. - This figure shows the effect of a polymer on flocculation. - The yellow circles represent suspended particles. - The black line represents the polymer. - The image illustrates flocculation. # Flocculation in Structured Vehicles - Controlled flocculation is very effective in providing physicochemical stability. - A suspending agent is added to the system to retard sedimentation of the flocs and to increase the sedimentation volume. Examples of suspending agents include: - Carboxymethycellulose (CMC) - Carbopol 934 - Veegum - Tragacanth - Bentonite - You can use these suspending agents alone or in combination. # Suspending Agents - Suspending agents fall into these categories: 1. Natural Polysaccharides - Tragacanth - Acacia gum - Starch - Agar - Guar gum - Carrageenan - Sodium alginate - Care should be taken in using natural materials because of: - Microbial contamination - Variability in quality - Variability in price 2. Semi-synthetic Polysaccharides - Methylcellulose (Celacol, Cologel) - Hydroxyethylcellulose (Natrasol 250) - Sodium Carboxymethylcellulose (carmellose sodium) - Microcrystalline cellulose (Avicel) 3. Clay - Bentonite - Aluminum magnesium silicates - Magnesium aluminum alginate 4. Synthetic Thickeners - Carbomer (Carboxyvinyl polymer, Carbopol) - Colloidal silicon dioxide (Aerosil, Cab-o-sil) - Polyvinyl alcohol 5. Miscellaneous Compounds - Gelatin and other viscosity-increasing agents. # Physical Stability of Suspension - The following factors can affect the physical stability of a suspension: - Rising temperature - Freezing - Temperature fluctuation - **Rising Temperature.** - An increase in temperature leads to an unstable suspension. - **Freezing.** - During freezing, the particles aggregate and remain aggregated when the ice melts. - **Temperature Fluctuation.** - Particle growth is commonly observed (which also changes the particle size and distribution) due to changes in the polymorphic form of the particles. # Dispersed Systems - Dispersed Systems are characterized by the particle size of the dispersed phase. - **Coarse Dispersion.** - The particle size ranges from 10-50 µm. - Examples include suspensions, and emulsions. - **Fine Dispersion.** - The particle size ranges from 0.5-10 µm. - Examples include magmas and gels. - **Colloidal Dispersion.** - The particle size ranges from 1.0nm-0.5 µm. # Suspensions - This section discusses the rate of sedimentation of particles in suspensions. - It also looks at Stokes' Law. - The various factors involved in the rate of settling of the particles are summarized in this formula from the equation of Stoke's Law: $dx / dt =d²(P₁-P)g/18 η$ - dx / dt = the rate of setting - d= diameter of particles - P₁ = density of the particles - Pe = density of the medium - g = gravitational constant - η = viscosity of the medium # Importance of Stokes' Law - Stokes' Law was derived for suspensions that have an ideal set of conditions, where: - The particles are uniform and perfectly spherical. - The suspension is significantly dilute. - Particles settle without producing turbulence or colliding with other particles. - Particles have no chemical or physical attraction or affinity for the medium. - The basic concept of the equation is to provide a valid indication of the factors that are important to prepare a suspension of particles. - It also can be used to provide a clue to possible adjustments that can be made to the formulation to decrease the rate of sedimentation. # Limitations of Stokes' Law - The formula is not precisely applicable where: - The suspension is not very dilute - Particles are irregularly shaped and of various particle diameters - The fall of particles results in turbulence and collision - Particles have some affinity for the medium. # Thermodynamic Stability of Dispersed Systems - The large surface area of the solid particles of dispersed phases results from comminution (size reduction). This association with surface free energy makes the system thermodynamically unstable. - Therefore, particles tend to regroup to reduce the total surface area and reduce the overall surface free energy. - Particles in suspension tend to flocculate by weak Van der Waal forces, forming agglomerates. - The surface free energy (ΔG) of a suspension is: $ΔG = Y_{SL} ΔΑ$ - Y_{SL} is the interfacial tension. - The following approaches can yield stable emulsions: - Reduce Y_{SL} by adding a surface active agent. - Reduce ΔΑ by controlled flocculation. # Kinetic Stability of Dispersed Systems - This section discusses the theory of sedimentation: - **Sedimentation Behaviour.** Sedimentation means settling of particles or floccules under gravitational force in a liquid dosage form. - **Brownian Motion.** - **Velocity of Sedimentation.** This velocity is expressed by Stokes' Equation. # Stokes Equation - The Stokes equation describes the rate of sedimentation of particles, as shown in this formula: $ v = \frac{d^2(\rho_s - \rho_o)g }{18\eta}$ - V_{sed} = sedimentation velocity in cm / sec - d = diameter of particle - $\rho_s$ = density of disperse phase - $\rho_o$ = density of disperse media - g = acceleration due to gravity - η = viscosity of disperse medium in poise. # Limitation of Stokes' Equation - Stokes' equation is limited to the following conditions: - Spherical particles in very dilute suspension (0.5 to 2 gm per 100 ml). - Particles that freely settle without collision. - Particles with no physical or chemical attraction. # Sedimentation Parameters - The Sedimentation volume (F) or height (H) are used for flocculated suspensions. - Definition: Sedimentation volume is the ratio of the ultimate volume of sediment (Vu) to the original volume of suspension (V₀) before settling. The formula is: $F = \frac{V_u}{V_o}$ - V_u = final (or ultimate) volume of the sediment - V₀ = original volume of suspension before settling. - The F values range from less than one to greater than one. - When F<1: V_u<V₀ - When F=1: V_u=V₀ - The system is said to be in flocculation equilibrium and there is no clear supernatant on standing. - When F>1: V_u> V₀ - The sediment volume is greater than the original volume. This is likely due to the network of flocs formed in the suspension. The sediment is loose and fluffy and may require extra vehicle (added) to contain the sediment. - The sedimentation volume gives a qualitative account of flocculation. This figure shows how the final sediment volume changes based on the F value (0.5, 1.0, and 1.5). # Degree of Flocculation (β) - The degree of flocculation (β) is the ratio of the sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the deflocculated suspension, F∞. - The formula is: $β = \frac{F}{F∞}$ - It can also be written as: $β = \frac{(V_u/V_o) flocculated}{(V∞/V_o) deflocculated}$ $β = \frac{V_u}{V∞}$ - The minimum value of β is 1. This occurs when the flocculated suspension sedimentation volume is equal to the sedimentation volume of the deflocculated suspension. # Brownian Movement and Kinetic Stability - Brownian movement of a particle prevents sedimentation by keeping the dispersed material in random motion. - Brownian movement depends on the density of the dispersed phase and the density and viscosity of the disperse medium. The kinetic bombardment of the particles by molecules in the suspending medium keeps the particles suspending. - Particle size must be below the critical radius (r) for Brownian movement. # Electric Double Layer for Dispersed Systems - An electric double layer occurs when a solid surface is in contact with a solution containing electrolytes. - Some cations adsorb on the solid surface and the adsorbing ions give the surface a charge (known as potential determining ions). There is a counter ion layer, or gegenions, which are anions attracted to the positive charge. The positive and negative charges form an electric double layer. - The shear plain illustrated here is bb' rather than aa' because of the tightly bound layer. - The first layer is aa' to bb', and the second layer is bb' to cc'. The second layer has a more negative charge. # Zeta Potential - The zeta potential is the difference in potential between the surface of the tightly bound layer (shear plane) and the electro-neutral region of the solution. - Zeta potential has practical application in stability of systems containing dispersed particles. - If the zeta potential is reduced below a certain value, attractive forces will exceed repulsive forces. This leads to flocculation, where the particles come together. - The zeta potential in flocculated suspension is typically between -20mV and +20mV. - The phenomena of flocculation and deflocculation depend on the zeta potential carried by the particles. # Deflocculation and Flocculation (Flocculated Suspensions) - In flocculated suspensions, formed flocs or loose aggregates will cause an increase in the sedimentation rate because of the greater size of the sedimenting particles. - Flocculated suspensions sediment more rapidly, and the sedimentation depends not only on the size of the flocs, but also on their porosity. - The figure shows a flock of dispersed particles. # Deflocculated Suspensions - In deflocculated suspensions, individual particles are settling. - The rate of sedimentation is slow which prevents the entrapment of the liquid medium. This makes it difficult to redisperse the suspension by shaking the container. - This is a common phenomenon called caking or claying. In deflocculated suspensions, larger particles settle fast and smaller particles remain in the supernatant liquid, causing the supernatant liquid to be cloudy. - The figure illustrates the caking process. # Controlled Flocculation - Electrolytes (ionic substances) act as flocculating agents by reducing the electrical barrier between particles. They do this by decreasing the zeta potential and forming bridges between adjacent particles. - Surfactants and polymers can also act as flocculating agents. # Effect of Electrolytes - At low electrolyte concentration: the repulsive force is dominant. - At high electrolyte concentration: The repulsive force is reduced and coagulation occurs. - The figure illustrates the electrostatic repulsion effect. - This section describes the specific effect of electrolytes on bismuth sub nitrate particles. - **Bismuth sub nitrate** particles possess a positive charge. - The addition of **monobasic potassium phosphate** (KH2PO4) leads to a decrease in positive zeta potential. - The decrease in zeta potential is a result of the adsorption of negative phosphate ions. The zeta potential increases in the negative direction. - At certain positive zeta potential, maximum flocculation occurs. - The onset of flocculation coincides with the maximum sedimentation volume. - When the zeta potential becomes sufficiently negative, repeptization or deflocculation takes place. Sedimentation volume (F) will fall again. # Effect of Surfactants - Surfactants improve dispersion because they reduce surface tension. - They also act as wetting and deflocculating agents. - Ionic surfactants, such as SLS, sometimes cause flocculation. # Effect of Polymers - Hydrophilic polymers act as protective colloids, and they also act as flocculating agents. - The polymer chains adsorb on multiple particles, forming a bridge between the particles, and leading to flocculation. - Xanthum gum is a common example of a flocculating polymer. # Physical Stability of Suspensions - An increase in temperature leads to flocculation of sterically stabilized particles. This is especially the case with suspensions that are stabilized by non-ionic surfactants because of the importance of the repulsion force. It is dependent on the amount of surfactant adsorbed on the particles. The energy of repulsion is reduced on heating due to the dehydration of the surfactant. This leads to an increase in attraction, which causes the particles to flocculate. - During the freezing process, the particles overcome the repulsive barrier due to ice formation. The particles come close enough to each other and experience attractive forces (as a result of the primary minimum of the DLVO theory). This can lead to the formation of aggregates. # Oswald Ripening - Temperature fluctuations can change the particle size distribution in a suspension. - Particle growth is common when the solubility of the particles is dependent on the temperature. - If the temperature is high, small particles dissolve and form a saturated solution. When the temperature decreases, solute is deposited on larger crystals. This results in larger crystals because of the crystal size increase in the large size crystals. - Oswald ripening can be reduced by the addition of a polymer or a surfactant. - Polymers such as PVP can adsorb on the drug, an example being acetaminophen. A hydration sheath forms around the polymer molecule. This inhibits the approach of drug molecules from the solution to the crystal surface during the deposition process. - High molecular weight polymers, such as PVA, are more effective in promoting this process. # Effect of Excipients on Suspension Stability - Flocculation by sorbitol is dependent on the cloud point of the suspension. The stability of a suspension generally decreases, due to the interaction with excipients. - Low cloud point surfactants (low solubility) require less sorbitol to induce flocculation. - The cloud point is the temperature above which an aqueous solution of a water-soluble surfactant becomes turbid. - The amount of preservative, such as Benzalkonium Cl, can change the zeta potential. # References - P.J. Sinko. *Martin's Physical Pharmacy and Pharmaceutical Sciences*, Fifth edition, Lippincott Williams and Wilkins, Indian Edition distributed by B.I. Publications Pvt. Ltd, 2006. - C.V.S Subrahmanyum. *Textbook of Physical Pharmaceutics*, Vallabh Prakashan. This document appears to be a set of slides for a university course on the principles of suspension formulation in pharmaceutics. It covers a range of topics including the different types of suspensions, how to create a stable suspension, and the factors that influence sedimentation. This is a very helpful resource for understanding the science behind creating stable suspensions.