Lecture (4) Suspensions PDF

Suspensions Lecture (4) Dr. Ahmed Y. Kira Lecturer of Pharmaceutics and Pharmaceutical Technology  Suspension Suspensions are biphasic, heterogenous disperse systems in which insoluble solid particles are suspended in a vehicle. Disperse sy...

Suspensions Lecture (4) Dr. Ahmed Y. Kira Lecturer of Pharmaceutics and Pharmaceutical Technology  Suspension Suspensions are biphasic, heterogenous disperse systems in which insoluble solid particles are suspended in a vehicle. Disperse systems consist of particulate matter known as the dispersed phase (internal phase), distributed throughout a continuous or dispersion medium (external phase). Based on the size of the dispersed phase, they are classified into : 1) Colloidal dispersion: From 1 nm to 0.5 µm 2) Coarse dispersion: Greater than 0.5 µm (Suspension) Colloidal Suspension Advantages of suspensions Suitable for insoluble drugs that required to be given in liquid dosage form. Taste improvement: Suitable for bitter taste drugs, as the tastes of the most drugs are obvious in solution rather than if in an insoluble form. Enhanced stability: Suitable for unstable drugs in aqueous medium, as suspensions decrease the contact time between particles and the medium. Enhanced bioavailability: compared to solid dosage form Solution > Suspension > Capsules > Tablets Suitable for controlling the absorption rate of the drugs. Disadvantages of suspensions Storage and transportation challenges. Sedimentation: tendency for solid particles to settle at the bottom of the container over time. Suspensions require shaking before use, to ensure uniformity of dose. Storage Requirements: Improper storage conditions (Temperature) can affect the disperse system. Classification of suspensions Based on the Electrokinetic properties of particles 1. Flocculated suspensions: The individual particles are in contact with each other to form loose aggregates called floccules. They are easily redispersible by moderate shaking, but the rate of sedimentation is fast. 2. Deflocculated suspensions: The dispersed particles exist as separate entities. They have a slow rate of sedimentation. However, when settling occurs, the sediment forms a highly compacted cake, which is difficult to redisperse.  Flocculated Suspension Deflocculated Suspension Particles form loose aggregates Particles exist as separate entities Rate of sedimentation is high Rate of sedimentation is low Sediment is rapidly formed Sediment is slowly formed Sediment does not form a hard cake Sediment forms a hard cake Sediment is easy to redisperse Sediment is difficult to redisperse Supernatant becomes clear very quickly Supernatant remains cloudy for a long time Product will be unpleasant in appearance Product will be pleasant in appearance  Controlled Flocculation Both deflocculated and flocculated systems have advantages and disadvantages: In Flocculated systems, the formed floccules are dispersible, however the rate of sedimentation is high. In Deflocculated systems, low rate of sedimentation, but have the tendency to form non-dispersible hard cake. Therefore, the main concern is to achieve a correct degree of flocculation (controlled flocculation).  Controlled Flocculation To achieve a correct degree of flocculation, one should understand definite properties of the suspended particles, such as: 1. Sedimentation rate 2. Double electric layer and Zeta potential 3. Repulsive/Attractive forces balance (DLVO Theory) 1) The sedimentation rate The various factors involved in the sedimentation rate can be explained according to the Stokes law: dx/dt is the rate of settling d is the diameter of the particles ρi is the density of the particle ρe is the density of the medium g is the gravity η is the viscosity of the medium  Stokes’ law Based on Stokes’ law, it is clear which variables can be varied to decrease the sedimentation rate. The gravity cannot be reduced, nor the density of the particles. However, the particle size, the density and the viscosity of the dispersion medium may be adjusted. 1) A first method to reduce the sedimentation rate is particle size reduction. 2) A second method to reduce the sedimentation rate is to increase the density and the viscosity of the dispersion medium. Particle size control Particle size of any suspension is critical and must be reduced within the range. Too large or too small particles should be avoided. Too fine particles will easily form hard cake at the bottom of the container Larger particles will: settle faster Particles > 5 µm impart a gritty texture to the product and also cause irritation if instilled to the eye Particles > 25 µm may block the needle if used for parenteral administration Rheology (Viscosity of suspension) Increasing the dispersion medium viscosity will decrease the settling rate. The viscosity must not be so high, so that pouring can occur more readily. For external use: easily spread and not to be fluid to runs off the skin For Injection: easily pass via the needle then retain its viscosity after injection. Liquid suspensions should display thixotropic flow properties; greater viscosity during storage (low shear stress), lower viscosity upon shaking (high shear stress) Suspending agents Suspending agents (Structured vehicle) (thickening agents): These substances act mainly by increasing the viscosity of the suspending medium and thus reducing the sedimentation rate of the dispersed particles. They must have the following properties: (a) Stable (b) compatible with other suspension components (c) To be associated with thixotropic features. Suspending agents (a) Natural Polysaccharides (Acacia, Tragacanth, Alginates, Xanthan gum) (b) Semisynthetic (cellulose derivatives) (Methyl cellulose, Sodium Carboxymethyl Cellulose, microcrystalline cellulose (Avicel), hydroxyethyl cellulose) (c) Hydrated silicates (Bentonite, Magnesium aluminum silicate(veegum), Hectorite) (d) Synthetic compounds (Carboxy polymethylene (Carbopol), Colloidal silicon dioxide (Aerosil)) Suspending agents Each suspending agent has its own mechanism of action. It is common to use more than one category of them to exert a synergistic effect on rheological behavior, as well as improve the stability of suspensions. For example, magnesium aluminum silicate and xanthan gum are used in nystatin oral suspension. The silicate exerts a synergistic effect with xanthan gum, enhancing the thixotropic characteristic of the suspension. Suspending agents The following are the most common suspending agents used in dispensing: (a) Tragacanth BP: Used in internal or external suspensions at a concentration of 0.2% (b) Compound tragacanth powder BP (containing 15% tragacanth, 20% acacia, 20% starch and 45% sucrose): Used in internal suspensions at a concentration of 2.0% (c) Bentonite BP: Used in external suspensions at concentrations of 2%–3% (e.g., calamine lotion) 2) Electric double layer and Zeta potential Electric Double Layer is the phenomenon playing a fundamental role in the electrostatic stabilization of colloids. When a colloidal particle moves in the dispersion medium, a layer of the surrounding liquid remains attached to the particle. The outer surface of this layer is called the slipping plane. The value of the electric potential at the slipping plane is called the zeta potential (ζ). It is a very important parameter as it is related to the strength of the electrostatic repulsion force between particles.  Stern layer Diffuse layer Slipping plane Bulk fluid Surface potential Electrical potential Stern potential Zeta potential Distance from particle surface 2) Electric double layer and Zeta potential Electric Double Layer is the layer surrounding a particle of the dispersed phase and including: 1. Stern layer: A fixed layer of charges which are fixed firmly onto the particle surface. 2. Diffuse layer: A diffused layer of counter ions containing opposite ions which are mobile. The electrical potential within the electrical double layer has the maximum value on the particle surface, or Stern layer. This potential drops with increasing distance from the Particle surface. 2) Electric double layer and Zeta potential The magnitude of the zeta potential gives an indication of the potential stability of the colloidal system. A dividing line between stable and unstable aqueous dispersions is generally taken at either +30 or -30 mV. If all the particles have a large negative or positive zeta potential > ± 30 mV, they will repel each other and there is dispersion stability. If the particles have low zeta potential values < ± 30 mV , then there is no force to prevent the particles coming together and there is dispersion instability. 3) Repulsive/Attractive forces balance (DLVO Theory) The formation of stable associations will depend on the balance between repulsive electrostatic forces and the attractive van der Waals forces between particles. The Derjaguin–Landau–Verwey–Overbeek (DLVO) theory is concerned with the energies of attraction (VA) and repulsion (VR) between similar particles and predicts the overall energy of interaction (VT). VT = VA + VR From this, conclusions can be made about the stability behavior of the suspension. VR VA The Primary Minimum Zone Particles in the primary minimum zone show a higher energy of attraction than repulsion (low ζ) and are therefore likely to move closer together. subsequently they will coagulate and form larger particles. Such behavior is undesirable for pharmaceutical suspensions as it will have serious negative effects on the reproducibility of dosing from the system. The Primary Maximum Zone Particles in the primary maximum zone show a higher energy of repulsion (high ζ) than attraction and are therefore likely to remain separate or ‘deflocculated’. At first sight this would appear to be a good formulation strategy for pharmaceutical suspensions, however, if the particles gained any kinetic energy > VT, the attractive force would dominate, and the particles enter the primary minimum zone. The Secondary Minimum Zone Particles in this zone show a higher energy of attraction but with a lower magnitude than the primary minimum zone and therefore show limited attraction to each other and behave as ‘floccules’, loose aggregates of individual particles. if the kinetic energy of particles was > VT, particles will repel each other and will not flocculate and exist as individual particles Such behavior is desirable for pharmaceutical suspensions as it will combine the advantages of flocculated and deflocculated systems.  Promotion of flocculation The correct degree of flocculation can be achieved by adding a flocculating agents. Flocculating agents such as, electrolytes, Surfactants, and Polymers. These agents act either by affecting the electrical double layer and hence, reducing the zeta potential (Charge neutralization) or by forming bridges between the particles, thus holding them in a loosely flocculated state. Electrolytes They act as flocculating agents by neutralizing the charges on the particles surface, thus reducing zeta potential. This results in decreasing the repulsion and making particles come together to form a loosely arranged structure. Examples are sodium salts of acetates, phosphates and citrates. The flocculating power increases with the valance of ions (Calcium ions are more powerful than sodium ions) Continued addition of electrolyte will decrease Zeta potential till equals zero, then further addition will change zeta potential into the negative direction.  low concentration Electrolytes Care must be taken to electrolyte concentration as: At low concentration: Their effect will be located only within the diffuse layer, as, and therefore will not affect the zeta potential. At optimum concentration: They aren't just result in a greater effect on the diffuse layer, but some of the charges Optimum concentration will migrate through it into the fixed layer and become adsorbed onto the surface of the particle itself. In this case the zeta potential will be decreased. At higher concentration: Charge reversal may be occurred, and it will alter the zeta potential of the dispersed particles, forming a deflocculated system again. For example: Addition of monobasic potassium phosphate (-ve flocculating agent) to a suspension of bismuth subnitrate (+ve charged particles) Sedimentation Volume Zeta Potential Surfactants They act as flocculating agents by neutralizing the charges or by forming bridges between particles. The effects will be dependent on the chemistry of the surfactant itself. whether it is ionic (cationic, anionic) or nonionic. 1) Ionic surfactants cause flocculation to occur by neutralization of the charge on each particle, depending on the charge already present on the particle. 2) Nonionic surfactants have no effect on charge density but may act by forming bridges between the particles Polymers Polymeric flocculating agents used to control the degree of flocculation by forming gel like network adsorbed on the surface of the dispersed particles. Examples: Starch, alginates, celluloses, and tragacanth. Excessive blending may inhibit cross linking, so each polymer particle attached to one particle only resulting in deflocculation High concentration of polymer will result in deflocculation.  Formulation Considerations There are many factors that need to be considered during the formulation of a pharmaceutical suspension. Particle size control (Discussed) Viscosity (Discussed) Flocculation (Discussed) Mixing and homogenization Wetting  Mixing and Homogenization Mixing Uniform dispersion of drug in vehicle requires efficient mixing. The mixers employed in manufacturing of pharmaceutical suspension must have the capacity to mix viscous material. Size Reduction and Homogenization As discussed earlier, particle size can affect the sedimentation rate and redispersion of the sedimented particles. For small scale, the particle size can be reduced by pestle and mortar. For large-scale manufacturing, homogenizers, such as colloid mill can be used.  Wetting Problems The main requirement to produce a pharmaceutical suspension is to achieve suitable wetting of solid particles by the liquid vehicle. One of the problems that should be considered during the formulation of suspension is that the powder may not be readily wetted. This may be due to the adsorbed air or using a lyophobic material, thus, the particles, even with high density, float on the surface of the liquid until the layer of air is displaced completely.  Wetting Problems Low wetting occur due to the adsorbed air and the high interfacial tension between the powder and the dispersion medium. Because of this tension, the contact angle between the liquid and the solid phases remains very high. Which figure represents good wetting properties ?? Liquid Particle surface  Wetting agents For good wetting properties the interfacial tension between solid and liquid must be reduced so the adsorbed air is displaced by the liquid. The use of wetting agent allows removing this air from the surface and to easy penetration of the liquid into the pores of the particles. Also, hydrophobic materials are easily wetted by nonpolar solvents. Wetting agents Surfactant Hydrophilic colloids Solvents Surfactants Surfactants decrease the interfacial tension between drug particles and liquid thus decreasing the contact angle and the liquid is penetrated into the surface pores of drug particle displacing air from them and thus ensures wetting. Generally, non-ionic surfactants as spans and tweens are used. As they are Nontoxic and safe for internal use. N.B. surfactant can cause excessive foaming. Hydrophilic colloids Act by coating the hydrophobic particles with multimolecular layer giving hydrophilic characters thus promoting wettability Solvents. For example: acacia, bentonite, tragacanth, and cellulose derivatives. Solvents The most commonly used solvents are alcohol, glycerin, and polypropylene glycol. They act by penetrating the voids between particles, displacing the entrapped air, and enabling wetting to occur by the dispersion medium Thes solvents are miscible with water and can reduce liquid air interfacial tension.  Properties of a good suspension a) The dispersed particles should settle slowly and should redisperse immediately on shaking. b) The product should remain sufficiently homogenous for at least the period between shaking the container and removing the required dose. c) The viscosity of the suspension should be easily removed from the container and transferred to the site of application without any difficulty. d) The sediment produced on standing should not form a hard cake. e) Any suspended particles should be small and uniformly sized in order to give a smooth, elegant product free from grittiness. f) The size of the suspended particles should remain constant during long periods of standing. g) It should produce thixotropic property.  Thank You Any questions ? Pharmaceutics Department Faculty of Pharmacy Delta University for Science and Technology