Suspension A pharmaceutical suspension may be defined as a coarse

Suspension A pharmaceutical suspension may be defined as a coarse dispersion containing finely divided insoluble material suspended in a liquid medium or available in dry form to be distributed in the liquid when desired. Sterile suspensions are intended for injection or for ophthalmic use.

Drugs that are unstable if maintained for extended periods in the presence of an aqueous vehicle (e.g., many antibiotic drugs) are most frequently supplied as dry powder mixtures for reconstitution at the time of dispensing. This type of preparation is designated in the USP by a title of the form “for Oral Suspension.”

Most pharmaceutical suspensions consist of an aqueous dispersion medium, although in some instances it may be an organic or oily liquid. A disperse phase with a mean particle diameter of up to 1µm is usually termed a colloidal dispersion, and includes such examples a aluminium hydroxide and magnesium hydroxide suspensions. A solid in liquid dispersion, in which the particles are above colloidal size, is termed a coarse suspension.

The particles of the dispersed phase vary widely in size, from large, visible particles to colloidal dimensions, which fall between 1.0 nm and 0.5 μm in size. Course dispersions contain particles 10–50 μm in size and include suspensions and emulsions. Fine dispersions contain particles of smaller size, 0.5–10 μm. Magmas and gels represent such fine dispersions. Particles in a coarse dispersion have a greater tendency to separate from the dispersion medium than do the particles of a fine dispersion. Most solids in a dispersion tend to settle to the bottom of the container, because their density is higher than the dispersion medium.

Suspensions intended for injection must contain particles of a size such that they can pass freely through the syringe needle. Needle shaped crystals are frequently desirable. Ophthalmic suspensions should be formulated such that the particles don’t exceed 10µ. Below this size the patient don’t feel any pain.

For topical suspension, the particle size should be such that the patient should not feel gritty when applied to the skin. Also, the smaller the particle size the greater the covering and protective power of the preparation.

Routes of administration Suspension dosage forms are given by the oral route, injected intramuscularly or subcutaneously, instilled intranasally, inhaled into the lungs, applied to the skin as topical preparations, or used for ophthalmic or otic purposes in the eye or ear, respectively.

Advantages of suspension 1. Suspensions offer an alternative oral dosage form for patients who cannot swallow a tablet or capsule such as pediatric and geriatric patients. Oral antibiotics, analgesic and antipyretic drugs are commonly administered as suspensions to these groups of patients. 2. Suspensions are often used to deliver poorly water-soluble drugs which cannot be formulated as aqueous solutions.

3. Drugs that have an unpleasant taste may preferably be formulated as a suspension to reduce interaction of drug with taste receptors in the mouth. 4. Because suspended drug must undergo a dissolution step prior to crossing biological membranes, suspensions offer a way to provide sustained release of drug by parenteral, topical, and oral routes of administration.

5. Certain drugs are chemically unstable in solution but stable when suspended. In this instance, the suspension ensures chemical stability while permitting liquid therapy. If a drug is unstable in an aqueous medium, a different form of the drug, such as an ester or insoluble salt that does not dissolve in water may be used in the preparation of a suspension.

6. Drugs, such as antibiotics, that are unstable in the presence of an aqueous vehicle for extended periods of time are most frequently supplied as dry powder mixtures for reconstitution at the time of dispensing. This type of preparation is designated in the USP by the title “for Oral Suspension.” 7. The dose of a liquid form may be adjusted easily to meet the patient’s requirements.

Types of suspension Based on route of administration suspensions can be classified into the following categories 1. Oral suspensions Examples of oral suspensions are the oral antibiotic syrups, which normally contain 125 to 500 mg per 5 mL of solid material. When formulated for use as pediatric drops, the concentration of suspended material is correspondingly greater.

Antacid and radiopaque suspensions generally contain high concentrations of dispersed solids. 2. Topical suspensions Externally applied suspensions for topical use are designed for dermatologic, cosmetic, and protective purposes. The concentration of dispersed phase may exceed 20%.

3. Parenteral suspensions Parenteral suspensions contain from 0.5% to 30% of solid particles. Viscosity and particle size are significant factors because they affect the ease of injection and the availability of the drug in depot therapy (injection of a drug with a substance that slows the release and prolongs the action of the drug)

Based on electro-kinetic properties 1. Deflocculated suspensions In a deflocculated system the dispersed particles remain as discrete units. Because the rate of sedimentation depends on the size of each unit, settling will be slow. The supernatant of a deflocculated system will continue to remain cloudy 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.

The repulsive forces between individual particles allow them to slip past each other as they sediment. The slow rate of settling prevents the entrapment of liquid within the sediment, which thus becomes compacted and can be very difficult to redisperse.

This phenomenon is also called caking or claying, and is the most serious of all the physical stability problems encountered in suspension formulation

2. Flocculated Suspension: A flocculated suspension is a suspension in which particles have undergone flocculation. The aggregation of particles in a flocculated system will lead to a much more rapid rate of sedimentation or subsidence because each unit is composed of many individual particles and is therefore larger.

The rate of settling will also depend on the porosity of the aggregate, because if it is porous the dispersion medium can flow through, as well as around, each aggregate or floccule as it sediments. 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. Such suspensions easily redispersed by moderate agitation. In a flocculated system the supernatant quickly becomes clear, as the large floes that settle rapidly are composed of particles of all sizes

In summary, deflocculated systems have the advantage of a slow sedimentation rate, thereby enabling a uniform dose to be taken from the container, but when settling does occur the sediment is compacted and difficult to redisperse.

Flocculated systems form loose sediments which are easily redispersible, but the sedimentation rate is fast and there is a danger of an inaccurate dose being administered; also, the product will look inelegant.

Physical Characteristics of Suspensions Suspensions should possess several basic chemical and physical properties. The dispersed phase should settle slowly, if at all, and be re-dispersed readily upon shaking. The solid particles should have a narrow particle size distribution, which does not cake on settling, and the viscosity should be such that the preparation pours easily.

In addition, the product should have an elegant appearance, be resistant to microbial growth and maintain its chemical stability.

Physical Features of the Dispersed Phase of a Suspension The reduction in the particle size is beneficial to the stability of the suspension in that the rate of sedimentation is reduced as the particles are decreased in size. The reduction in particle size produces slow, more uniform rates of settling.

However, reduction of the particle size to too fineness should be avoided, since fine particles have a tendency to form a compact cake upon settling. The result may be that the cake resists breakup upon shaking, and forms rigid aggregates of particles.

Dispersion Medium Highly flocculated particles usually settle too rapidly, that might hinders measurement of accurate dosage and, from an aesthetic point of view, produces too unsightly a supernatant layer. In many commercial suspensions, suspending agents are added to the dispersion medium to lend it structure.

Suspending agents Viscosity-increasing agent used to reduce sedimentation rate of particles in a vehicle in which they are not soluble. Agar Bentonite Carbomer (e.g., Carbopol) (Poly(acrylic acid) Carboxymethylcellulose sodium Hydroxyethyl cellulose Hydroxypropyl cellulose Hydroxypropyl methylcellulose Kaolin

Methylcellulose Tragacanth Veegum

When polymeric substances and hydrophilic colloids are used as suspending agents, it must be assured that the agent does not interfere with availability of the drug. These materials can bind certain medicinal agents, rendering them unavailable or only slowly available for therapeutic function. Also, the amount of the suspending agent must not be such to render the suspension too viscous to agitate or to pour.

Settling in suspensions One aspect of physical stability in pharmaceutical suspensions is concerned with keeping the particles uniformly distributed throughout the dispersion. Although it is seldom possible to prevent settling completely over a prolonged period of time, it is necessary to consider the factors that influence the velocity of sedimentation.

Several factors influence the sedimentation rate of particles in a suspension. Stokes’ law relates the diameter of the particles, the density of the particles and the medium, and the viscosity of the medium to the sedimentation rate: υ 2 r2 (ρ - ρo)g /9 η

Where υ is the sedimentation rate r is the radius of the particles ρ is the density of the particles ρo is the density of the medium g is the gravitational constant and η is the viscosity of the medium.

From the equation, it is apparent that the velocity of fall of a suspended particle is greater for larger particles than it is for smaller particles. Reducing the particle size of the dispersed phase produces a slower rate of sedimentation. Also, the greater the density of the particles, the greater the rate of sedimentation, provided the density of the vehicle is not altered

Because aqueous vehicles are used in pharmaceutical oral suspensions, the density of the particles is generally greater than that of the vehicle. If the particles were less dense than the vehicle, they would tend to float, and floating particles would be quite difficult to distribute uniformly in the vehicle.

The rate of sedimentation may be appreciably reduced by increasing the viscosity of the dispersion medium. However, a product with too high viscosity is not generally desirable because it pours with difficulty and it is equally difficult to redisperse the suspensoid.

Therefore, if the viscosity of a suspension is increased, it is done so only to a modest extent to avoid these difficulties. The viscosity characteristics of a suspension may be altered not only by the vehicle used but also by the solid content. As the proportion of solid particles in a suspension increases, so does the viscosity.

The most important consideration in formulation of suspensions is the size of the drug particles. In most pharmaceutical suspensions, the particle diameter is between 1 and 50 μm.

Effect of Brownian movement For particles having a diameter of about 2 to 5 µm (depending on the density of the particles and the density and viscosity of the suspending medium), Brownian movement counteracts sedimentation to a measurable extent at room temperature by keeping the dispersed material in random motion.

Brownian movement of the smallest particles of a pharmaceutical suspension is usually eliminated when the sample is dispersed in a 50% glycerin solution, having a viscosity of about 5 centipoise. Hence, it is unlikely that the particles in an ordinary pharmaceutical suspension containing suspending agents are in a state of vigorous Brownian motion.

Sedimentation of Flocculated Particles When sedimentation is studied in flocculated systems, it is observed that the flocs tend to fall together, producing a distinct boundary between the sediment and the supernatant liquid. The liquid above the sediment is clear because even the small particles present in the system are associated with the flocs.

Such is not the case in deflocculated suspensions having a range of particle sizes, in which, in accordance with Stokes's law, the larger particles settle more rapidly than the smaller particles.

No clear boundary is formed (unless only one size of particle is present), and the supernatant remains turbid for a considerably longer period of time. Whether the supernatant liquid is clear or turbid during the initial stages of settling is a good indication of whether the system is flocculated or deflocculated, respectively.

Sedimentation Parameters Two useful parameters that can be derived from sedimentation studies are sedimentation volume, V, or height, H, and degree of flocculation. Sedimentation volume The sedimentation volume, F, is defined as “the ratio of the final, or ultimate, volume of the sediment, Vu, to the original volume of the suspension, Vo, before settling”.

F Vu/V0 The sedimentation volume can have values ranging from less than 1 to greater than 1. F is normally less than 1, and in this case, the ultimate volume of sediment is smaller than the original volume of suspension, in which F 0.5.

If the volume of sediment in a flocculated suspension equals the original volume of suspension, then F 1. Such a product is said to be in ―flocculation equilibrium‖ and shows no clear supernatant on standing. It is therefore pharmaceutically acceptable.

It is possible for F to have values greater than 1, meaning that the final volume of sediment is greater than the original suspension volume. This comes about because the network of flocs formed in the suspension is so loose and fluffy that the volume they are able to encompass is

Degree of flocculation A more useful parameter for flocculation is β, the degree of flocculation. If we consider a suspension that is completely deflocculated, the ultimate volume of the sediment will be relatively small. Writing this volume as V , based on equation, we have F V /V0

Where F is the sedimentation volume of the deflocculated, or peptized, suspension. The degree of flocculation, β, is therefore defined as the ratio of F to F , or β F/F Substituting the value of F and F β

We can therefore say that β

Formulation of Suspensions The approaches commonly used in the preparation of physically stable suspensions fall into two categories 1. The use of a structured vehicle to maintain deflocculated particles in suspension 2. The application of the principles of flocculation to produce flocs that, although they settle rapidly, are easily resuspended with a minimum of agitation

Structured vehicles are pseudoplastic and plastic in nature. It is frequently desirable that thixotropy be associated with these two types of flow. Structured vehicles act by entrapping the particles (generally deflocculated) so that, ideally, no settling occurs. In reality, some degree of sedimentation will usually take place. The shear-thinning property of these vehicles does, however, facilitate the reformation of a uniform dispersion when shear is applied

Wetting of particles The initial dispersion of an insoluble powder in a vehicle is an important step in the manufacturing process and requires further consideration. 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, and they fail to become wetted even when forced below the surface of the suspending medium.

Powders that are not easily wetted by water (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.

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 lowered, air is displaced from the surface of particles, and wetting and deflocculation are promoted.

i.e Glycerin flows into the voids between the particles to displace the air and, during the mixing operation, 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.

Controlled Flocculation Assuming that the powder is properly wetted and dispersed, we can now consider the various means by which controlled flocculation can be produced so as to prevent formation of a compact sediment that is difficult to redisperse.

Electrolytes act as flocculating agents by reducing the electric barrier between the particles, as evidenced by a decrease in the zeta potential and the formation of a bridge between adjacent particles so as to link them together in a loosely arranged structure.

If we disperse particles of bismuth subnitrate in water, 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.

The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles causes the positive zeta potential to decrease owing 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, as shown in Figure.

Similar correlation when aluminum chloride was added to a suspension of sulfamerazine in water. In this system, the initial zeta potential of the sulfamerazine particles is negative and is progressively reduced by adsorption of the trivalent aluminum cation. When sufficient electrolyte is added, the zeta potential reaches zero and then increases in a positive direction.

Surfactants, both ionic and nonionic, have been used to bring about flocculation of suspended particles. The effect of Xanthan gum (an anionic heteropolysaccharide) was studied on the flocculation characteristics of sulfaguanidine, bismuth subcarbonate, and other drugs in suspension. Addition of xanthan gum resulted in increased sedimentation volume, presumably by a polymer-bridging phenomenon.

Flocculation in structured vehicles Although the controlled flocculation approach is capable of fulfilling the desired physical chemical requisites of a pharmaceutical suspension, the product can look unsightly if F, the sedimentation volume, is not close or equal to 1.

Consequently, in practice, a suspending agent is frequently added to retard sedimentation of the flocs. Such agents as carboxymethylcellulose, Carbopol 934, Veegum, tragacanth, and bentonite have been employed, either alone or in combination.

This can lead to incompatibilities, depending on the initial particle charge and the charge carried by the flocculating agent and the suspending agent. For example, suppose we prepare a dispersion of positively charged particles that is then flocculated by the addition of the correct concentration of an anionic electrolyte such as monobasic potassium phosphate.

We can improve the physical stability of this system by adding a minimal amount of one of the hydrocolloids just mentioned. No physical incompatibility will be observed because the majority of hydrophilic colloids are themselves negatively charged and are thus compatible with anionic flocculating agents.

If, however, we flocculate a suspension of negatively charged particles with a cationic electrolyte (aluminum chloride), the subsequent addition of a hydrocolloid may result in an incompatible product. Under these circumstances, it becomes necessary to use a protective colloid to change the sign on the particle from negative to positive.

This is achieved by the adsorption onto the particle surface, a fatty acid amine (which has been checked to ensure its nontoxicity) or a material such as gelatin, which is positively charged below its isoelectric point. We are then able to use an anionic electrolyte to produce flocs that are compatible with the negatively charged suspending agent.

This approach can be used regardless of the charge on the particle.

Rheologic considerations The principles of rheology can be applied to a study of the following factors: The viscosity of a suspension as it affects the settling of dispersed particles, The change in flow properties of the suspension when the container is shaken and when the product is poured from the bottle, and the spreading qualities of the lotion when it is applied to an affected area

The ideal suspending agent should have a high viscosity at negligible shear, that is, during shelf storage; and it should have a low viscosity at high shearing rates, that is, it should be free-flowing during agitation, pouring, and spreading. Pseudoplastic substances such as tragacanth, sodium alginate, and sodium carboxymethylcellulose show these desirable qualities.

Shear rate is the rate at which a fluid is sheared or “worked” during flow. In more technical terms, it is the rate at which fluid layers or laminae move past each other. . The shear stress, τ, is the force per area, dynes/cm2. The viscosity, η, is the relationship between the shear stress and the shear rate

The Newtonian liquid glycerin is included in the graph for comparison. Its viscosity is suitable for suspending particles but is too high to pour easily and to spread on the skin. Furthermore, glycerin shows the undesirable property of tackiness (stickiness) and is too hygroscopic to use in undiluted form. Newtonian fluid definition is - a fluid whose viscosity does not change with rate of flow.

A suspending agent that is thixotropic as well as pseudoplastic should prove to be useful because it forms a gel on standing and becomes fluid when disturbed.

Pharmaceutical applications of suspensions Suspensions can be used as oral dosage forms, applied topically to the skin or mucous membrane surfaces, or given parenterally by injection. Suspensions as oral drug delivery systems 1. Many people have difficulty in swallowing solid dosage forms and therefore require the drug to be dispersed in a liquid.

2. Some materials are required to be present in the gastrointestinal tract in a finely divided form, and their formulation as suspensions will provide the desired high surface area. Solids such as kaolin, magnesium carbonate and magnesium trisilicate, for example, are used for the adsorption of toxins, or to neutralize excess acidity.

3. The taste of most drugs is more noticeable if it is in solution rather than in an insoluble form. Paracetamol is available both in solution as Paediatric Paracetamol Oral Solution and also as a suspension. The latter is more palatable, and therefore particularly suitable for children. For the same reason chloramphenicol mixtures can be formulated as suspensions containing the insoluble chloramphenicol palmitate.

Suspensions for topical administration Suspensions of drugs can also be formulated for topical application. They can be fluid preparations, such as Calamine Lotion, which are designed to leave a light deposit of the active agent on the skin after quick evaporation of the dispersion medium. Some suspensions, such as pastes, are semisolid in consistency and contain high concentrations of dispersed powders. It may also be possible to suspend a powdered drug in an emulsion base, as in Zinc Cream.

Suspensions for parenteral use and inhalation therapy Suspensions can also be formulated for parenteral administration in order to control the rate of absorption of the drug. By varying the size of the dispersed particles of active agent, the duration of activity can be controlled. The absorption rate of the drug into the bloodstream will then depend simply on its rate of dissolution.

If the drug is suspended in a fixed oil such as arachis or sesame, the product will remain after injection in the form of an oil globule, thereby presenting to the tissue fluid a small surface area from which the partitioning of drug can occur. The release of drug suspended in an aqueous vehicle will be faster, as some diffusion of the product will occur along muscle fibres and become miscible with tissue fluid. This will present a larger surface area from which the drug can be released.

Vaccines for the induction of immunity are often formulated as dispersions of killed microorganisms, as in Cholera Vaccine, or of the constituent toxoids adsorbed on to a substrate of aluminium hydroxide or phosphate, as in Adsorbed Diphtheria and Tetanus Vaccine. Thus a prolonged antigenic stimulus is provided, resulting in a high antibody titre.

Some X-ray contrast media are also formulated in this way. Barium sulphate, for the examination of the alimentary tract, is available as a suspension for either oral or rectal administration, and propyliodone is dispersed in either water or arachis oil for examination of the bronchial tract.

The adsorptive properties of fine powders are also used in the formulation of some inhalations. The volatile components of menthol and eucalyptus oil would be lost from solution very rapidly during use, whereas a more prolonged release is obtained if the two active agents are adsorbed on to light magnesium carbonate prior to the preparation of a suspension.