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A suspension in which all the particles remain discrete would, in terms of the DLVO theory, be considered to be stable. Flocculation should be carefully controlled, and the viscosity should not be too high to make redispersion difficult.
Controlled flocculation can be achieved by a combination of control of particle size and the use of flocculating agents. The most common categories of flocculating agents are electrolytes, surfactants, and polymers.
Electrolytes act by reducing the zeta potential, which brings the particles together to form loosely arranged structures. The flocculating power increases with the valency of the ions. Calcium ions having two valency electrons are more powerful than sodium or potassium ions with one valency electron. Trivalent ions are less commonly used because of their toxicity. The zeta potential decreases slowly when electrolytes are added to a positively charged deflocculated suspension.
At a certain stage, upon persistent addition, it becomes zero. Beyond that limit, zeta potential becomes negative. As zeta potential decreases, the sedimentation volume increases sharply up to a point. The sedimentation volume reaches its maximum value and remains relatively constant within a certain range of zeta potential, where it changes from low positive potential to low negative potential. When the potential becomes too negative, the sedimentation volume decreases again.
Both ionic and nonionic surfactants according to can be used as flocculating agents. Ionic surfactants cause flocculation by neutralizing the charge on particles. Because of long structure, nonionic surfactants are adsorbed onto more than one particle, thereby, forming a loose flocculated structure.
Linear and branched-chain polymer form a gel-like network that adsorbs onto the surface of dispersed particles, holding them in a flocculated state. Moreover, hydrophilic polymers can also function as protective colloids. In this capacity, flocs are sterically prevented from adhering to one another resulting in the formation of loose sediments.
At low polymer concentrations, when the drug particles are not completely covered by the polymers, the latter can form bridges between multiple particles leading to the formation of flocculation. The particles suspended in a pharmaceutical suspension are fully covered by the polymers, which creates steric stabilization at sufficiently high polymer concentration.
Some polymers, known as polyelectrolytes, can ionize in aqueous medium and the extent of ionization depends on the pH and the ionic strength of the dispersion medium. These polymers are able to act both electrostatically and sterically.
Linear polymers (e.g., sodium carboxymethylcellulose) serve better as flocculating agents; however, coiled polymers (e.g., polyvinylpyrrolidone) are not conducive to flocculation, due to their shape and so they produce steric stability.
The particle size of any suspension is critical and must be reduced within the range as determined during preformulation study. It is first necessary to ensure that the drug to be suspended is of a fine particle size prior to formulation as this will ensure a slow rate of sedimentation of the suspended particles.
Large particles, if greater than about 5µm diameter, will also impart a gritty texture to the product, and may cause irritation if injected or instilled into the eyes.
Crystal growth also known as Ostwald ripening is a process of aggregation of small-sized particles to produce large-sized particles. It is a phenomenon that may affect pharmaceutical suspensions by influencing the average particle size. Crystal growth sometimes is very important for suspension sedimentation, physical stability, redispersibility, appearance, and bioavailability.
Particles in dispersion may not maintain a constant size throughout its shelf life. One of the reasons for that change would be crystal formation. There is however a range of particle size and not a single value.
The surface free energy on smaller particles is comparatively more than that on larger particles. Therefore, smaller particles are more soluble in the dispersion medium. If the temperature rises, more materials are dissolved from the smaller particles, decreasing their size even more. When the temperature goes down, the drug attempts to recrystallize on the surface of existing particles. The larger particles will increase gradually in size as the smaller particles decrease in size. Thus, a slight change in temperature may cause the particle size spectrum shift to higher values.
This situation is especially true for slightly soluble drugs and can be initially eliminated by using a narrow particle size range. Surface active agents or polymeric colloids can also prevent crystal growth by being adsorbed on the particle surface.
Crystal growth in pharmaceutical suspension may also happen for polymorphic drugs. Metastable (i.e., the least stable form of the drug) is the most soluble and as the metastable form changes to a more stable form, solubility decreases, and crystallization occurs. This problem can be avoided by excluding the metastable form from the dispersion and by using the most stable polymorph of the drug. Amorphous metronidazole was found to convert to the monohydrate form in an aqueous suspension, thus favoring crystal growth. A combination of suspending agents, microcrystalline cellulose and carboxymethylcellulose was found to prevent the conversion.
Structured vehicles are generally aqueous solutions of natural and synthetic polymers, such as methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, acacia, gelatin, etc. They are viscosity-imparting agents and basically reduce the rate of sedimentation in dispersed systems. These vehicles are plastic or pseudoplastic in nature. Additionally, some degree of thixotropy is desirable.
For a deflocculated suspension, the shear-thinning property of the structured vehicle will allow easy redistribution of the particles from the small sediment. However, the ultimate sediment in a deflocculated system in a structured vehicle, as in other vehicles, may form a compact cake, which will not be resuspendable by the shear-thinning liquid. Therefore, a structured network, flocculated suspension, in a structured vehicle is preferred. When the shaking is discontinued, the vehicle goes back to its original higher consistency, and that keeps the particles suspended.
A flocculated suspension with no structured vehicle may not look elegant if the sedimentation volume is not close to 1. The concentration of polymer in a structured vehicle depends on the required consistency of the preparation and, therefore, on the particle size and density.
