Formulation considerations

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Chapter: Pharmaceutical Drugs and Dosage: Dosage forms - Suspensions

Suspensions are formulated to meet key quality requirements as outlined earlier.

Formulation considerations

Suspensions are formulated to meet key quality requirements as outlined earlier. Additional formulation considerations for suspensions include managing the bitterness and grittiness of the API, and dose volume. For example, a highly bitter API is likely to impart an unpleasant taste to the suspension due to its solubility in the suspension vehicle, even though this solubility may be extremely low. A gritty particle shape of an API, such as needle-shaped crystals, is likely to have poor mouthfeel unless the particle size of the suspension is reduced significantly. In addition, reasonable dose volume for a patient is one teaspoon (5 mL) or one tablespoon (15 mL) or other nondecimal multiples of these measures. Total dose volume that may be administered per day is also limited by the maximum allowed daily dose of other ingredients, such as the artificial sweetener and the preservative.

Typically, the following ingredients are used in suspensions.

1. Drug: A water-insoluble drug is usually the dispersed phase in an aqueous suspension. Drugs should be of a narrow particle size distri-bution within the range of 1–50 μm.

2. Wetting agents: The surface of dispersed drug particles can be either hydrophilic or hydrophobic. Drugs with hydrophobic surfaces are usually difficult to disperse in an aqueous medium. Wetting agents are surfactants that reduce the surface tension of an aqueous medium and facilitate the wetting of hydrophobic particles. Wetting agents adsorb onto the hydrophobic particle surface to either partially coat the surface or form a complete monolayer. Examples of typical wet-ting agents are sodium lauryl sulfate and polysorbate 80.

3. Suspending agents: Suspending agents are hydrophilic colloids, such as cellulose derivatives, acacia, and xanthan gum that are added to a suspension to increase viscosity inhibit agglomeration, and decrease sedimentation. Suspending agents may also interact with the sus-pended particle’s surface to facilitate wetting and reduce the tendency to agglomerate upon interparticle collisions. Typical suspending agents are listed in Table 16.1. Although increasing the viscosity of a suspension improves its physical stability, on oral administra-tion highly viscous suspensions may prolong gastric emptying time, slow drug dissolution, and decrease the absorption rate. Thus, the dose volume of a suspension and in situ fluid viscosity on dilution of the suspension in the gastric fluid must be considered to understand potential impact on oral drug absorption.

Table 16.1 Commonly used suspending agents

4. Flocculating agents: Suspended particles that have high charge den-sity display deflocculation and caking upon sedimentation. Such sus-pensions have high particle–particle electrostatic repulsion and do not settle rapidly. Such suspensions are called deflocculated because they display uniform distribution of particles without any settling/ separation or flocculation for extended periods of time. However, once they settle, they form a strong cake that is difficult to redisperse. Addition of oppositely charged formulation ingredient(s) to such a suspension results in partial neutralization of effective charge (i.e., zeta potential) on the particles through the formation of the electri-cal double layer. This results in suspended particles being weakly linked together in loose aggregates or flocs. These flocs settle rap-idly but form large fluffy sediment, which is easily redispersed. Such suspensions are called flocculated suspensions—and the formulation ingredients that promote flocculation are called flocculating agents. Flocculated suspensions are preferred over deflocculated systems to enable rapid redispersibility upon shaking.

5. Preservatives: Preservatives are often added in aqueous suspensions because suspending agents and sweeteners are good media for micro-bial growth. Some preservatives are ionic, such as sodium benzoate, and may interact or form complexes with other suspending ingredients— thus reducing their preservative efficacy. 

Table 16.2 Commonly used antimicrobial preservatives

Thus, effective aqueous concen-tration of the preservative must be monitored and controlled. Solvents, such as alcohols, glycerin, and propylene glycol, may also have some preservative effect depending on their concentration. Typical microbial preservatives are listed in Table 16.2.

6. Sweeteners, flavors, and colorants: Sweeteners are often added to sus-pensions to reduce any unpleasant taste of the partially dissolved drug and to improve palatability in general. Examples include sorbitol, corn syrup, sucrose, saccharin, acesulfame, and aspartame. Flavors are added to enhance patient’s acceptance of the product. Colorants are added to provide a more esthetic appearance to the final product. Choice of col-orant is usually tied to the choice of flavor, and their choices are also linked to the patient population, such as age group and geographic region, and the therapeutic need. For example, red colorant is usually used with strawberry flavor for pediatric formulations.

Table 16.3 shows two examples of suspension formulations. One is benzoyl peroxide topical suspension, which is used for treating mild to moderate acne. The other is triamcinolone diacetate parenteral suspension, which is used for treating allergic disorders.

Table 16.3 Examples of suspension formulations


The large surface area of the suspended fine particles is associated with high surface-free energy that makes the system thermodynamically unsta-ble. Generation of fine particles by milling, which is commonly used for pharmaceutical suspensions, generates particles with higher energy per unit surface area than the parent, unmilled API crystals. This is attributed to the preferred orientation of functional groups of a molecule during crys-tallization. During crystallization, hydrophobic regions of an API, which interact less favorably with the solvent of crystallization, get embedded on the inside of the crystal structure, whereas hydrophilic regions are exposed to the surface. When such a material is milled, the inner hydrophobic sur-face gets exposed. This is a high-energy surface in an aqueous environ-ment because it resists interaction with water and has the propensity to self-aggregate to decrease the total surface area and surface-free energy.

Stabilization of high-energy fine particles can be accomplished through the use of suspending agents that increase solution viscosity, reduce surface tension, and/or coat the surface of the dispersed particles. In addition, the use of formulation ingredients, such as hydrophilic polymers, that facilitate the formation of lose associations of dispersed particles through the forma-tion of relatively weak bonds with each other, can contribute to a phenom-enon called flocculation.

Flocculation is the formation of loose, light, and fluffy flocs (associa-tions of particles) held together by weak van der Waals forces. In contrast, particles in deflocculated suspensions tend to exhibit strong interparticle attraction forces, leading to aggregation. 

Figure 16.1 Formation of flocs and cake in pharmaceutical suspensions. Suspensions often form loose networks of flocs that settle rapidly, do not form cakes, and are easy to suspend. However, settling and aggregation may result in the formation of cakes that is difficult to resuspend.

Aggregation occurs in a compact cake situation, that is, growth and fusing together of crystals in the pre-cipitates to form a solid cake. Figure 16.1 illustrates the difference between flocs and cake in pharmaceutical suspensions.

Forces at the surface of the dispersed particles affect the degree of floc-culation and agglomeration in a suspension. Generally, the forces of attrac-tion are of the van der Waals type, whereas the repulsive forces arise from the interaction of the electric double layers surrounding each particle (Figure 16.2). When the repulsion energy is high, collision of the particles is opposed. The system remains deflocculated. However, when sedimen-tation is complete, the particles form a close-packed and strongly bound structure. Those particles lowest in the sediment are gradually pressed together by the weight of the ones above. The repulsive energy barrier is thus overcome, allowing the particles to come into close contact with each other. The reduced bonding potential energy at a critical interparticulate distance allows the forces of attraction to dominate and caking to occur (Figure 16.3).

To resuspend and redisperse caked particles in a suspension, it is neces-sary to overcome the high-energy barrier. Since this is not easily achieved by agitation, the particles tend to remain strongly attracted to each other and form a hard cake. When the particles are flocculated, the particles equilibrate in the second energy minimum, which is at a distance of separa-tion of ~1000–2000 Å—sufficient to form the loosely structural flocs.

Figure 16.2 Illustration of particle surface charge and zeta potential on the surface of a particle. Interparticle interactions in a suspension are determined by the zeta poten-tial, the net charge at the end of an electrical double layer on the particle surface. This electrical double layer is formed by the selective adsorption of oppositely charged ionic species in solution to an electrostatically charged particle surface.

Figure 16.3 Bonding potential energy between particles as a function of distance, in the absence of surface charge. The forces of attraction between particles are dependent on the distance between the particles and are maximized at an optimum distance. Caking in a suspension is facilitated if interparticulate distance allows the forces of attraction to dominate and form strong bonds.

Caking is undesirable, since a caked dispersed phase is difficult to redisperse. Flocculating agents can prevent caking, whereas deflocculat-ing agents increase the tendency to cake. To convert a suspension from a deflocculated to a flocculated state, the following flocculating agents are often used:

1. Electrolytes: Electrolytes act as flocculating agents by reducing the electric barrier between the particles. The addition of an inorganic electrolyte to an aqueous suspension alters the zeta potential of the dispersed particles. Flocculation occurs when the zeta potential is lowered sufficiently. The most widely used electrolytes include sodium salts of acetate, phosphate, and citrate.

2. Surfactants: Ionic surfactants may also cause flocculation by neutral-ization of the charge on each particle. An example of ionic surfactant is sodium lauryl sulfate.

3. Hydrophilic polymers: Particles coated with hydrophilic polymers are less prone to caking than uncoated particles. Especially for particles that lack strong electrostatic surface charge, using nonionic hydro-philic polymers, which act as protective colloids, can contribute to flocculation. These polymers exhibit pseudoplastic (i.e., shear-thinning, viscosity reduces upon exposure to shear) flow in solution. This prop-erty serves to promote physical stability within the suspension by maintaining high viscosity when the suspension is stagnant, whereas allowing easy pourability by reduction of viscosity when the suspen-sion is mixed.

Starch, alginates, cellulose polymers (sodium carboxymethylcellulose), gum (tragacanth), carbomers, and silicates are examples of polymeric flocculat-ing agents. Their linear branched chain molecules form a gel-like network within the system, thus increasing the viscosity of the aqueous vehicle, and become adsorbed on the surfaces of the dispersed particles, thus acting as protective colloids.

Whether a suspension is flocculated or deflocculated depends on the relative magnitudes of the electrostatic forces of repulsion and the forces of attraction between the particles. When zeta potential is relatively high, the repulsive forces usually exceed the attractive forces. Consequently, dis-persed particles remain as discrete units and settle slowly. The suspension is deflocculated. The slow rate of settling prevents the entrapment of liquid within the sediment, which thus becomes compacted and can be very dif-ficult to redisperse. This phenomenon is called caking.

Flocculated systems form lose sediments, which are easily redispersible. However, the sedimentation rate is faster than deflocculated suspensions. Association of particles with each other in a flocculated system leads to a rapid rate of sedimentation because each unit is composed of many indi-vidual particles and is, therefore, larger. Supernatant of a deflocculated system remains cloudy for an appreciable time after shaking due to the very slow settling rate of the smallest particles in the suspension. 

Table 16.4 Properties of flocculated and deflocculated suspensions

In con-trast, the supernatant of a flocculated system quickly becomes clear as the flocs, composed of lose agglomerates of particles of all sizes, settle rap-idly. If the sedimentation rate is too fast, the dispensed dose may not be accurate. Therefore, an optimum suspension formulation should only be partially flocculated. In addition, viscosity is controlled so that the sedi-mentation rate is minimized. Controlled flocculation is usually achieved by a combination of particle size control, the use of electrolytes to control zeta potential, and the addition of polymers to enable the formation of weak networks in solution that entangle and form weak bonds between the dispersed particles. Differences between flocculated and deflocculated suspensions are summarized in Table 16.4.

Quantitating the degree of flocculation

Sedimentation studies can quantitatively define the sedimentation volume and degree of flocculation/deflocculation of a system. As illustrated in Figure 16.4, the sedimentation volume, F, is defined as the ratio of the final volume of the sediment, Vu, to the original volume of the suspension, V0 before settling. Thus,

F = Vu/V0

The sedimentation volume can have values from less than 1 (particle set-tling) to greater than 1 (particle swelling). It is usually less than 1. That is, the final volume of sediment is smaller than the original volume of suspen-sion. Particle swelling can occur for a freshly prepared suspension that has not been allowed enough time to equilibrate to fully hydrate all solid com-ponents. If the volume of sediment in a flocculated suspension is equal to the original volume of suspension, then F = 1. Such a product is believed to be in flocculation equilibrium and shows no clear supernatant on standing.

Figure 16.4 A schematic illustrating the differences in the sediment quality and volume between a deflocculated and a flocculated suspension. On placing undisturbed in a measuring cylinder, an equal volume of a flocculated suspension forms a larger mass of a more porous sediment than a deflocculated suspension.

Physics of particle sedimentation: Stokes’ law

The control of sedimentation rate of dispersed particles is required to ensure uniform dosing of a pharmaceutical system. Sedimentation of a disperse system depends on the motion of the particles, which may be thermally or gravitationally induced. If a suspended particle is sufficiently small in size, random Brownian motion dominates over unidirectional gravitational pull. When the radius of the suspended particles is increased, Brownian motion becomes less important and sedimentation becomes dominant. These larger particles, therefore, settle gradually under gravitational forces. Stokes’ law describes the sedimentation of suspended particles in suspensions:


V is the velocity of sedimentation

r is the particle radius

d is the particle diameter

ρ1 and ρ2 are the densities of the particles and dispersion medium, respectively

g is the acceleration of gravity

η is the viscosity of the medium

As the diameter is squared in Stokes’ law, a reduction in particle size by ½ will reduce the sedimentation rate by (½)2 or a factor of 4. Thus, particle size control is an important element in the formulation of stable suspensions.

In addition, doubling the viscosity of a suspension will decrease the sedimentation rate by a factor of 2. Increasing the viscosity of a suspen-sion reduces the rate of settling of dispersed particles, changes the flow properties of a suspension, and affects the spreading qualities of a lotion. Viscosity can be increased by the addition of hydrophilic polymers or gums that act as suspending agents. An ideal suspending agent should have a high viscosity at negligible shear and should be free flowing during agitation, pouring, and spreading. A suspending agent that is thixotropic as well as pseudoplastic should prove to be useful since it forms a gel on standing and becomes fluid when distributed.

Stokes’ law further indicates that if the difference in density between the suspended particle and the suspension medium can be matched, the sedimentation rate would be reduced to zero. Density of a drug particle is an inherent property of the crystal structure and packing, and may not be altered readily. However, the density of the suspension medium can be increased by increasing the solids content of the liquid or solution. This, however, needs to be balanced with an increase in solution viscosity and reduction of pourability.

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