The formulation of suspensions possessing optimal physical stability depends on whether the particles in suspension are to be flocculated or to remain deflocculated. One approach involves the use of a structured vehicle to keep deflocculated particles in suspension. A second approach depends on controlled flocculation as a means of preventing cake formation. A third, a combination of the two previous methods, results in a product with optimum stability.

Wetting of Particles in Formulation of Suspensions

The initial dispersion of an insoluble powder in a vehicle is an important step in the formulation of suspensions and requires further consideration. Powders sometimes are added to the vehicle, particularly in large-scale operations, by dusting on the surface of the liquid. It is frequently difficult to disperse the powder owing to an adsorbed layer of air, minute quantities of grease, and other contaminants. The powder is not readily wetted, and although it may have a high density, it floats on the surface of the liquid. Finely powdered substances are particularly susceptible to this effect because of entrained air. They fail to become wetted even when forced below the surface of the suspending medium.

Powder Wettability

The wettability of a powder can be ascertained easily by observing the contact angle that powder makes with the surface of the liquid. The angle is approximately 90◦ when the particles are floating well out of the liquid. A powder that floats low in the liquid has a lesser angle, and one that sinks obviously shows no contact angle. Powders that are not easily wetted by water and accordingly show a large contact angle, such as sulfur, charcoal, and magnesium stearate, are said to be hydrophobic. Powders that are readily wetted by water when free of adsorbed contaminants are called hydrophilic. Zinc oxide, talc, and magnesium carbonate belong to the latter class.

Wetting Agents

Surfactants are quite useful in the preparation of a suspension in reducing the interfacial tension between solid particles and a vehicle. As a result of the lowered interfacial tension, the advancing contact angle is reduced. This displacement of air from the surface of particles promotes wetting and deflocculation. The deflocculating effect of octoxynol, a nonionic surfactant, in enhancing the dissolution rate of prednisolone from tablets. The tablets break up into fine granules that are deflocculated in suspension. The deflocculating effect is proportional to the surfactant concentration. However, at very high surfactant concentration, 15 times the critical micelle concentration, the surfactant produces extensive flocculation.

Glycerin and similar hygroscopic substances are also valuable in levigating the insoluble material. Apparently, glycerin flows into the voids between the particles to displace the air. During the mixing operation, it coats and separates the material so that water can penetrate and wet the individual particles. The dispersion of particles of colloidal gums by alcohol, glycerin, and propylene glycol, allowing water to subsequently penetrate the interstices, is a well-known practice in pharmacy.

To select suitable wetting agents with a well-developed ability to penetrate the powder mass, imagine a narrow trough, several inches long. This trough is made of a hydrophobic material like Teflon or coated with paraffin wax. At one end of this trough, the powder is placed, while at the other end, a solution of the wetting agent is added. The rate at which the wetting agent solution penetrates into the powder can be directly observed. This observation occurs as the solution moves from one end of the trough to the other.

Controlled Flocculation in Formulation of Suspensions

Assuming that the powder is properly wetted and dispersed, we can now consider the various means of producing controlled flocculation. This approach helps prevent the formation of compact sediment that is difficult to redisperse. The materials used to produce flocculation in suspensions, namely electrolytes, surfactants, and polymers.

Electrolytes

Electrolytes act as flocculating agents by reducing the electric barrier between the particles, as evidenced by a decrease in the zeta potential. They also form a bridge between adjacent particles, linking them together in a loosely arranged structure.

Potassium Phosphate As an Electrolyte

If we disperse particles of bismuth subnitrate in water, we find that, based on electrophoretic mobility studies, they possess a large positive charge, or zeta potential. Because of the strong forces of repulsion between adjacent particles, the system is peptized or deflocculated. By preparing a series of bismuth subnitrate suspensions containing increasing concentrations of monobasic potassium phosphate.

The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles causes the positive zeta potential to decrease. This occurs due to the adsorption of the negatively charged phosphate anion. With the continued addition of the electrolyte, the zeta potential eventually falls to zero and then increases in the negative direction.

Microscopic examination of the various suspensions shows that maximum flocculation occurs at a certain positive zeta potential. This flocculation will persist until the zeta potential becomes sufficiently negative for deflocculation to occur once again. The onset of flocculation coincides with the maximum sedimentation volume determined. F remains reasonably constant while flocculation persists, and only when the zeta potential becomes sufficiently negative to effect repeptization does the sedimentation volume start to fall. Finally, the absence of caking in the suspensions correlates with the maximum sedimentation volume, which reflects the amount of flocculation. At less than maximum values of F, caking becomes apparent.

Aluminum Chloride As an Electrolyte

When aluminum chloride is added to a suspension of sulfamerazine in water, the initially negative zeta potential of the sulfamerazine particles is progressively reduced. This reduction occurs due to the adsorption of the trivalent aluminum cation. As more electrolyte is added, the zeta potential reaches zero and then becomes positive. Colloidal and coarse dispersed particles can possess surface charges that vary with the pH of the system. A key property of pH-dependent dispersions is the zero point of charge—the pH at which the net surface charge is zero. The desired surface charge can be achieved by adjusting the pH through the addition of HCl or NaOH, resulting in a positive, zero, or negative surface charge. For instance, the negative zeta potential of nitrofurantoin decreases significantly when the pH of the suspension changes from basic to acidic.

Surfactants

Surfactants, both ionic and nonionic, have been used to bring about flocculation of suspended particles. The concentration necessary to achieve this effect would appear to be critical because these compounds can also act as wetting and deflocculating agents to achieve dispersion.

The influence of xanthan gum, an anionic heteropolysaccharide, on the flocculation characteristics of sulfaguanidine was studied. This effect was also observed with bismuth subcarbonate and other drugs in suspension. The addition of xanthan gum increased the sedimentation volume, likely due to a polymer-bridging phenomenon.

Polymers

Hydrophilic polymers also act as protective colloids, reducing the tendency of particles to cake compared to uncoated particles. These polymers exhibit pseudoplastic flow in solution, which helps promote the physical stability of the suspension. Gelatin, a polyelectrolytic polymer, exhibits flocculation dependent on the pH and ionic strength of the dispersion medium. Sodium sulfathiazole, when precipitated from an acid solution in the presence of gelatin, remains free-flowing in the dry state and does not cake when suspended. Normally, sulfathiazole carries a negative charge in aqueous vehicles. The coated material, precipitated from acid solution in the presence of gelatin, however, was found to carry a positive charge. This is due to gelatin being positively charged at the pH at which precipitation was carried out.

The improved properties result from the positively charged gelatin-coated particles being partially flocculated in suspension, likely because the high negative charge has been replaced by a smaller positive charge. Positively charged liposomes have been used as flocculating agents to prevent the caking of negatively charged particles. Liposomes, which are non-toxic vesicles made of phospholipids, can be prepared in various particle sizes and are adsorbed onto the negatively charged particles.

Flocculation in Structured Vehicles

The ideal formulation of suspensions would seem to be when flocculated particles are supported in a structured vehicle. The process involves dispersion of the particles and their subsequent flocculation. Finally, a lyophilic polymer is added to form the structured vehicle. In developing the formulation, care must be taken to ensure the absence of any incompatibility between the flocculating agent and the polymer used for the structured vehicle.

A limitation is that virtually all the structured vehicles in common use are hydrophilic colloids and carry a negative charge. This means that an incompatibility arises if the charge on the particles is originally negative. Flocculation in this instance requires the addition of a positively charged flocculating agent or ion. In the presence of such a material, the negatively charged suspending agent may coagulate and lose its suspendability. This situation does not arise with particles that bear a positive charge, as the negative flocculating agent that the formulator must employ is compatible with the similarly charged suspending agent.

A method to circumvent incompatibilities between an anionic suspending agent and a cationic flocculating agent is to reverse the charge on the particle. This can be achieved through the use of a positively charged surface active material such as gelatin. Adsorption of gelatin to the surface of a negatively charged particle can reverse the particle charge when the continuous phase is adjusted to a relatively low pH. This may permit flocculation to be achieved with an anionic flocculating agent such as citrate ion or phosphate ion. Addition of these flocculating agents would be compatible with polymeric suspending agents that largely consist of molecules of anionic charge. This effect can also be achieved using surface active amines, provided their toxicity does not prevent their use.

preparation of suspensions

The small-scale preparation and formulation of suspensions may be undertaken readily by the practicing pharmacist with the minimum of equipment. The initial dispersion of the particles is best carried out by trituration in a mortar, the wetting agent being added in small increments to the powder. Once the particles have been wetted adequately, the slurry may be transferred to the final container. The next step depends on whether the deflocculated particles are to be suspended in a structured vehicle, flocculated, or flocculated and then suspended. Pre-formulated vehicles are commercially available to pharmacists to facilitate the extemporaneous preparation of suspensions. These products are essentially aqueous structured vehicles that contain cellulosic suspending agents, surfactants, buffering agents, and electrolytes. Some products may contain sweetening agents. Pre-formulated suspending vehicles are available at acidic or basic pH to match physical and chemical stability requirements of different drugs.

Reference of (Formulation of Suspensions):

1. Sinko, P. (2011). Martin’s Physical Pharmacy and Pharmaceutical Sciences. Baltimore, : Lippincott Williams & Wilkins, a Wolters Kluwer business.
2. Felton. L. (2013). Remington Essentials of Pharmaceutics. London. UK: Pharmaceutical Press.