A suspension is a disperse system in which solid, vehicle-insoluble particles (internal phase) are uniformly suspended by mechanical agitation and formulation design throughout the liquid vehicle (external phase). This dosage form is used for providing a liquid dosage form for insoluble drugs.
The stability of pharmaceutical suspension can be theoretically estimated prior to the beginning of the formulating process. Knowledge of interfacial properties, wetting, electric double layer, Nernst and Zeta potential, electrokinetic phenomenon, DLVO theory, flocculation, and deflocculation should ultimately help the formulator select the ingredients that are most appropriate for the suspension as well as formulate suspensions that are physically stable and suitable for administration to patients.
Theoretical considerations for pharmaceutical suspensions include:
1. Interfacial properties
The interfacial properties of the suspended material are an important consideration during the formulation of a suspension as it plays a vital role in modifying the physical characteristics of dispersion. In pharmaceutical suspensions, the solid phase remains as finely divided particles in the dispersion medium. Therefore, a large amount of interface is involved in the formation, which, in turn, affects the stability of suspension preparations.
The two most important interfacial properties include surface free energy and surface potential.
a. Surface free energy
A large surface area offered by finely divided solid materials is typically associated with large amount of free energy on the surface. The relation between the surface free energy and the surface area can be mathematically expressed as:
∆G = γ∆A
Where ∆G is the increase in surface free energy, ∆A is the increase in surface area, and γ is the interfacial tension between the solid particles and the dispersion medium.
The smaller the ∆G is, the more thermodynamically stable is the suspension. Therefore, a system with very fine particles is thermodynamically unstable because of high total surface area. Thus, the system tends to agglomerate in order to reduce the surface area and thereby the excess free energy.
Surface free energy may also be reduced to avoid the agglomeration of particles, which can be accomplished by reducing interfacial energy. When a wetting agent is added to the suspension formulation, it is adsorbed at the interface. This will result in a reduction of the interfacial tension, making the system more stable.
b. Surface potential
Surface potential exists when dispersed solid particles in a suspension possess charge in relation to their surrounding liquid medium. 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.
Dispersed solid particles in a suspension may have charge in relation to their surrounding vehicle through one of two situations.
- Selective adsorption of a particular ionic species by the solid particles if the suspension contains electrolytes. This will lead to the formation of charged particles as seen in the case of a dispersion of rubber particles in water.
- Ionization of functional group of the particles. In this case, the total charge depends on the pH of the surrounding vehicle.
Wetting in its simplest definition is the ability of a liquid to maintain contact with a solid surface, resulting from intermolecular interactions when the two (liquid and solid) are brought together. Insoluble drug particles are usually hydrophobic and therefore may not be easily wetted, i.e. the vehicle will not readily form a layer around the suspended drug particle.
It is also difficult to disperse solid particles in a liquid vehicle due to the layer of adsorbed air on the surface. Thus, the particles, even high density, float on the surface of the liquid until the layer of air is displaced completely.
To wet fully with an aqueous vehicle the contact angle (θ), i.e. the angle at which the liquid/vapor interface meets the surface of the solid, must be low. The contact angle (θ) may be defined in the Young equation stated below:
γl/v cos θ = γs/v – γs/l
Where γl/v , γs/v, γs/l are the interfacial tensions between the solid (drug)/vapor, liquid (vehicle)/vapor and solid (drug)/liquid (vehicle) respectively.
The use of wetting agent ensures adequate wetting by allowing the removal of air from the surface so that the adsorbed air is displaced from the solid surfaces by the liquid. It is important to ensure insoluble drug substances are sufficiently wetted, as this will ensure that the particles are homogeneously distributed in the formulation and thereby enable the correct dosage of drug to be removed when required by the patient.
Drug particles, if poorly wetted, will tend to aggregate spontaneously in an attempt to stabilize the system.
Sodium lauryl sulfate, alcohol, tragacanth mucilage, bentonite, polysorbates, 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. Excessive amounts of wetting agents can cause foaming or undesirable taste or odor.
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.
3. Electric double layer
When dispersed particles are in contact with an aqueous solution of an electrolyte, the particles may selectively adsorb one charge species and if the adsorbed species is an anion, the particles will be overall negatively charged. The above simply defines electric double layer as a structure that appears on the surface of an object when it is exposed to a fluid.
The ions that give the particle its charge, anions, in this case, are called potential-determining ions or co-ions. The 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 or gegenions. They are attracted to the negatively charged surface by electric forces. Gegenions also repel the approach of any further anions to particle surface, once the initial adsorption is complete. These electric forces and thermal motion keeps 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 moves away from the charged surface.
The Stern layer, the first layer (the part of the solvent immediately surrounding the particles) is tightly bound to the solid surface and contains mostly the counter-ions. Surrounding the Stern layer is the diffuse layer (second 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. These two layers are commonly known as the electric double layer.
Beyond the diffuse layer, the concentrations of co- and counter-ions are equal, that is, conditions of electric neutrality prevail throughout the remaining part of the dispersion medium. Thus, the electric distribution at the solid-liquid interface can be visualized as a double layer of charge.
The thickness of the double layer depends upon the type and concentration of ions in solution. It is important to note that the suspension, as a whole is electrically neutral despite the presence of unequal distribution of charges in the double layer.
Two other situations may arise. Should the concentration of counter-ions in the tightly bound layer be equal to that of the co-ions on the solid surface, then electric neutrality will occur at the shear plane and there will be only one layer of medium and ions, instead of double layer. However, if the total charge of the counter-ions in the stern layer exceeds the charge due to the co-ions, the net charge at the shear plane will be positive rather than negative. It means electric neutrality will be achieved where the electric double layer ends and the diffuse layer, will contain more co-ions than counter-ions. The charge density at any distance from the surface is determined by taking the difference in concentration between positive and negative ions at that point.
4. Nernst and Zeta potential
Nernst potential, (E) also known as surface or electrothermodynamic potential is the difference in electric potential between the actual surface of the particle and the electroneutral region. It is controlled by the electrical potential at the surface of the particle due to the potential determining ions. The potential difference between the shear plane and the electroneutral region is known as the electrokinetic or zeta (z) potential.
Zeta potential unlike Nernst potential (which has little effect in the formulation of stable suspension) has significant effect on the stability of a pharmaceutical suspension. Zeta potential governs the degree of repulsion between adjacent, similarly charged solid dispersed particles.
If the zeta potential is reduced below a certain value, which depends on the specific system under investigation, the attractive forces between particles due to van der Waals’ force, overcome the forces of repulsion and the particles come together to form floccules. This phenomenon is known as flocculation.
The magnitude of surface and zeta potentials is related to the surface charge and the thickness of the double layer. Zeta potential can be measured by microelectrophoresis, in which migration of the particles in a voltage field is observed through a microscope.
5. Electrokinetic phenomena
Electrokinetic phenomena (EKP) can be loosely defined as all those phenomena involving tangential fluid motion adjacent to a charged surface. They are manifestations of the electrical properties of interfaces under steady-state and isothermal conditions.
The presence of interfacial potentials may lead to the existence of four electrokinetic phenomena, which include electrophoresis, electroosmosis, sedimentation potential, and streaming potential. All of these properties are essentially the direct results of the movement of a charged surface with respect to an adjacent liquid phase.
Electrophoresis measures the movement of charged particles through a liquid under the influence of an applied potential difference. Electroosmosis may be considered the opposite of electrophoresis. In the latter, charged solid particles move relative to the dispersion medium under an applied potential, whereas in electroosmosis, the solid is rendered immobile but the liquid moves relative to the charged surface when a potential is applied.
Sedimentation potential is the potential generated when particles undergo sedimentation. Therefore, basically it is the reverse process of electrophoresis.
The streaming potential, which is essentially the reverse process of electroosmosis, is created by forcing a liquid to flow through a stationary solid phase (e.g., plug or bed of particles). Like electrophoresis, the other electrokinetic parameters can be used to determine surface or zeta potential and therefore, the stability of pharmaceutical dispersions.
6. DLVO Theory
Particle collision in a suspension preparation may occur due to Brownian motion or differential sedimentation rates. This results to either the formation of aggregates or redispersion of the particles. The outcome of collision depends on the attractive or repulsive forces between the particles and determines the quality of the preparation.
As mentioned previously, zeta potential plays a very important role in suspension stability. A minimum, known as the critical zeta potential, is required to prepare a stable suspension. A system with low critical zeta potential indicates that only a minute charge is required for stabilization and it will show marked stability against the added electrolytes.
The precipitation of suspension can be brought about by adding electrolytes. The precipitating power increases rapidly with the valence of the ions. This is known as the Schulze-Hardy rule.
Derjaguin and Landau and Verwey and Overbeek worked independently and used the knowledge from Schulze-Hardy rule to describe the stability of lyophobic colloids to develop this theory (the classic DLVO theory) which explains the result of particle interaction in lyophobic colloids.
The stability of colloidal systems is an important subject from both academic and industrial points of view. The colloid stability of such systems is governed by the balance of various interaction forces such as van der Waals attraction, double-layer repulsion, and steric interaction. These interaction forces have been described at a fundamental level such as in the well know theory due to Deryaguin and Landau (1941) and Verwey and Overbeek (1948); the DLVO theory.
The DLVO theory can also be applied to coarse suspension systems. According to this theory, the potential energy of interaction between particles, VT is the result of repulsion due to electrical double layer, VR and attraction due to van der Waals’ force, VA and can be shown by:
VT = VR + VA
VR depends on several factors including the zeta potential of the system, the particle radius, the interparticular distance, the dielectric constant of the medium, whereas the factors that affect VA includes the particle radius and the interparticular distance.
In addition to electric stabilization, steric stabilization can also be applied to prepare a stable dispersion. Substances such as nonionic surfactants, when adsorbed at the particle surface, can stabilize a dispersion, even when there is no significant zeta potential.
7. Flocculation and Deflocculation
As defined in the classification of suspension based on the electrokinetic nature of solid particles, a flocculated suspension is a suspension in which the supernatant quickly becomes clear, because of the formation of large flocs that settle rapidly. A deflocculated suspension on the other hand is a suspension in which the dispersed particles remain as discrete separated units. The supernatant remains cloudy for an appreciable time after shaking, due to the very slow settling rate of the smallest particles in the product.
Whether or not a suspension is flocculated or deflocculated depends on the relative magnitudes of the forces of repulsion and attraction between the particles. A deflocculated system has a zeta potential higher than the critical value when the repulsive forces supercede the attractive forces. The supernatant of a deflocculated system will continue to remain cloudy and the particles suspended for an appreciable time after shaking, due to the very slow settling rate of the smallest particles in the product, even after the larger ones have sedimented due to the force of gravitation.
During sedimentation, the smaller particles fill the void between the larger ones; and the particles lowest in the sediment are gradually pressed together by the weight of the particles above. Both situations increase the closeness of the particles; and, thus, they are attracted by a large amount of van der Waals’-London force. A close-packed, hard cake-like residue is formed, which is difficult, if not impossible, to redisperse. This phenomenon is also called caking or claying and is the most serious of all the physical stability problems encountered in suspension formulations.
Flocculation occurs at the secondary energy minimum when the particles are far apart from each other upon the addition of a small amount of electrolyte which reduces the zeta potential of the deflocculated system. Once it is below the critical value, the attractive forces supercede the repulsive forces, producing flocculation.
The nature of the sediment of a flocculated system is also quite different from that of a deflocculated one. The structure of each aggregate is retained after sedimentation, thus entrapping a large amount of the liquid phase. Flocculation can also be brought about by flocculating agents other than electrolytes (e.g., nonionic surfactants).
In a flocculated system, the supernatant quickly becomes clear, as the large floes that settle rapidly are composed of particles of all sizes. Aggregation in the primary minimum will produces compact floccules, whereas a secondary minimum effect will produce loose floccules of higher porosity. Whichever occurs, the volume of the final sediment will still be large and will easily be redispersed by moderate agitation.
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