Microsporidia

Classification

Order of Microspora

General Information

Microsporidia are widespread small unicellular, obligate intracellular parasites which are transmitted via resistant double-walled (chitin containing) spores normally ingested by their hosts (Fig. 1, Amblyospora/Fig. 1, Encephalitozoon/Fig. 1, Table 1). When these spores hatch under suitable stimuli, a hollow polar tube (polar filament) is everted, enabling the tip to penetrate a host cell. The sporoplasm passes through the tube and enters the host cell cytoplasm, inside which asexual reproduction (schizogony = merogony, sporogony) is initiated (Fig. 1). Microsporidia lack mitochondria, but are typically eukaryotic. Nuclear division occurs in the absence of centrioles with spindles being anchored to dense plaques along the inner nuclear membrane. The systematic position of the Microsporidia is under discussion, since several authors consider them as fungi. Just recently a large number of Microsporidia turned out to be opportunistic agents and they are found in many AIDS patients.

System

Phylum: Microspora

Order: Microsporida

Suborder: Pansporoblastina

Genus: Pleistophora

Genus: Thelohania

Genus: Glugea

Suborder: Apansporoblastina

Genus: Nosema

Genus: Ichthyosporidium

Genus: Enterocytozoon

Genus: Septata

Genus Mrazekia

Important Species

Table 1. Some common microsporidian species

Reproduction

Fig. 1. Development of some microsporidian genera. Sporoplasms are shown without stippling, merogonic stages are shown with a simple surface membrane and light stippling, and sporogonic stages are shown with a dense surface coat. In Encephalitozoon species all stages are included in a host cell vacuole. In other genera the merogonic stages are free in the host cell cytoplasm or are found there within sporophorous vacuoles (SPV), the borders of which derive from the surface of the sporogonial plasmodia.

Host Cell Invasion

Although rather poorly known, the mechanism of cell invasion by Microsporidia has very peculiar characteristics. Microsporidia self-inject into their host cell by devaginating a membranous organelle (polar tube) which forces its way through the host cell plasmalemma and through which the parasite cytoplasm moves into the recipient cell (Host Cell Invasion/Fig. 1). Invasion is thus intrusive: this is the only case known among intracellular parasitic protozoa. Parasite development may occur either in the cytoplasm of the cell or within a parasitophorous vacuole; but whether this vacuole forms at invasion or later is not known. No recognition mechanisms have been described so far in this group. However, the signalling for polar tube extrusion is likely to be driven by recognition of a suitable target in the vicinity of the spore, and the detailed study of this phenomenon will certainly lead to identifying receptor-ligand interaction in this process.

Disease

Microsporidiosis.

Drug Absorption

Passage of Drugs Across Cellular Membranes:

Regardless of the route of administration, a drug usually must cross a number of membranes before it reaches its site of action. Membrane barriers may be composed of several layers of cells (eg, skin, vagina, cornea, placenta) or a single layer of cells (eg, enterocytes, renal tubular epithelial cells), or they may consist only of a boundary <1> Drugs and other molecules can cross cellular membranes by several processes. Passive transfer or simple diffusion is the most important for xenobiotics, although specialized transport systems are used for a limited number of therapeutic agents. In simple diffusion, movement of the drug is due to and directly related to its concentration gradient across the membrane. In the case of lipid diffusion, lipid-soluble substances dissolve in the lipid phase of the membrane and diffuse down their concentration gradients into the aqueous phase on the other side of the barrier. Thus, the ability of a compound to cross a membrane by simple lipid diffusion is a function of its degree of lipid solubility (lipid-to-water partition coefficient). The molecular mass of the drug, the thickness of the membrane(s), and the surface area available also influence the rate of diffusion. Many agents of pharmacologic interest are weak organic electrolytes. At physiologic pH, these weak acids or bases may be present partly in the ionized (dissociated) and partly in the nonionized (undissociated) form. The ratio between the respective forms depends on the drug’s dissociation constant (pKa) and the pH of the solution in which it is dissolved. The nonionized fraction may penetrate biologic membranes by lipid diffusion and become distributed across the membrane according to the degree of ionization on each side of the membrane and the extent to which the drug is bound to proteins or other macromolecules in the solutions bathing either side of the membrane. Membranes are more permeable to the undissociated molecule than to the ionized form, simply because the nonionized form is much more lipid soluble. Although a compound may be nonionized, it also may be so poorly soluble in lipids that it penetrates biologic membranes only to a limited extent. A degree of aqueous solubility is also necessary for a drug to be in solution in the body fluids on either side of a cellular membrane. It is supposed that aqueous pores exist in lipoproteinaceous biologic membranes. Lipid-insoluble compounds can easily diffuse through these pores, as well as directly through the membrane, at rates that depend on their molecular masses and concentration gradients. However, with ions or other polar compounds, the speed of transfer is determined by both the charge and molecular dimensions of the drug. When a hydrostatic or osmotic pressure difference exists across a membrane, water flows through the aqueous pores; this bulk fluid movement carries or “drags” solute molecules through the pores in the moving stream, provided that the solute molecules are smaller than the aqueous channels. Several specialized transfer processes account for the passage of certain organic ions and other large lipid-insoluble substances across biologic membranes. Active transport, facilitated diffusion, and exchange diffusion are 3 distinct types of carrier-mediated systems used for moving specific substances across cellular membranes. The highly selective carrier-mediated systems are principally used for transporting nutrients and natural substrates across biologic membranes. Pinocytosis is an important transport process in mammalian cells, particularly intestinal epithelial cells and renal tubular cells. Drugs that exist in solution as molecular aggregates, have large molecular masses themselves, or are bound to macromolecules may be transferred across membranes by pinocytosis.

Drug Absorption from the GI Tract:

Although the basic principles governing the absorption of drugs from the GI tract are understood, many confounding factors may play a role in modifying the process, and erratic responses may result. Some of the more important factors to be considered include the following: 1) molecular size and shape of the drug and its concentration, 2) degree of ionization at specific pH values (depends on pKa of the drug), 3) lipid solubility of the neutral or nonionized form of the drug, 4) chemical or physical interactions with coadministered drug preparations or even food constituents, 5) the pharmaceutical preparation and characteristics of the dosage form (especially the disintegration and dissolution rates of solid dosage forms), 6) morphologic and functional differences of the GI tract among the various animal species, 7) gastric motility, secretion, and the rate of gastric emptying, 8) intestinal motility and secretions as well as the intestinal transit time, 9) fluid volume within the GI tract, 10) osmolality of intestinal content, 11) intestinal blood and lymph flow, 12) disruption of the structural and functional integrity of the gastric and intestinal epithelium, and 13) drug biotransformation within the intestinal lumen by microflora, or within the mucosa by host enzyme systems.

Bioavailability:

This term is used to define the rate and extent to which a drug administered in a particular dosage form enters the systemic circulation intact. All of the considerations outlined above, as well as the particular product used, can influence bioavailability. Biotransformation by intestinal epithelial cells, and particularly by liver cells, can substantially reduce the amount of unchanged drug that enters the systemic circulation after administration PO. This is known as the “first-pass” effect and is significant for a number of drugs.

Drug Absorption from Topical Administration:

Drugs may be absorbed through the skin after topical application; however, the stratum corneum presents an effective barrier to movement of most drugs. The intact skin allows the passage of small lipophilic substances but efficiently retards the diffusion of water-soluble molecules in most cases. Lipid-insoluble drugs generally penetrate the skin slowly in comparison with their rates of absorption through other body membranes. Absorption of drugs through the skin may be enhanced by inunction or more rarely by iontophoresis if the compound is ionized. Certain solvents (eg, dimethyl sulfoxide [DMSO]) may facilitate the penetration of drugs through the skin. Damaged, inflamed, or hyperemic skin allows many drugs to penetrate the dermal barrier much more readily. The same principles that govern the absorption of drugs through the skin also apply to the application of topical preparations on epithelial surfaces.

Drug Absorption from Tracheobronchial Surfaces and Alveoli:

Because volatile and gaseous anesthetics have relatively high lipid-to-water partition coefficients and generally are rather small molecules, they diffuse practically instantaneously into the blood in the alveolar capillaries. Particles contained in aerosols can be deposited, depending on the size of the droplets, on the mucosal surface of the bronchi or bronchioles, or even in the alveoli. Most drugs are usually absorbed quite rapidly from these sites according to the principles discussed above.

Drug Absorption from Parenteral Delivery Sites:

After a drug has penetrated the skin, GI epithelium, or other absorbing surface, or has been deposited by injection into a body tissue, it comes into the immediate vicinity of capillaries. Solutes traverse the capillary wall by a combination of 2 processes: diffusion and filtration. Diffusion is the predominant mode of transfer for lipid-soluble molecules, small lipid-insoluble molecules, and ions. All drugs, whether lipid-soluble or not, cross the capillary wall at rates that are extremely rapid compared with their rates across other body membranes. In fact, the movement of most drug molecules in various tissues is limited only by the rate of blood flow rather than by the capillary wall. However, some endothelial cells, such as the blood-brain barrier, have much tighter intercellular junctions than others and, therefore, restrict drug movement more significantly. Aqueous solutions of drugs are usually absorbed from an IM injection site within 10-30 min, provided blood flow is unimpaired. Faster or slower absorption is possible, depending on the concentration and lipid solubility of the drug, vascularity of the site (there are differences between various muscle groups), the volume of injection, the osmolality of the solution, and other pharmaceutical factors. Substances with molecular weights >20,000 daltons are principally taken up into the lymphatics. Absorption of drugs from subcutaneous tissues is influenced by the same factors that determine the rate of absorption from IM sites. Some drugs are absorbed as rapidly from subcutaneous tissues as from muscle, although absorption from injection sites in subcutaneous fat is always significantly delayed. Increasing blood supply to the injection site by heating, massage, or exercise hastens the rate of dissemination and absorption. Spreading and absorption of a large fluid volume that has been injected SC may be facilitated by including hyaluronidase in the solution. The rate of absorption of an injected drug may be prolonged in a number of ways, including immobilization of the site, local cooling, a tourniquet, incorporation of a vasoconstrictor, an oil base, and implant pellets and other insoluble “depot” preparations. Among these depot preparations are drugs that are converted to less soluble salts (eg, procaine and benzathine penicillin) or less soluble complexes (eg, protamine zinc insulin), or that are administered as insoluble microcrystalline suspensions (eg, methylprednisolone acetate)

Oral Dosage Forms and Delivery Systems

Oral dosage forms comprise liquids (solutions, suspensions, and emulsions), semi-solids (pastes), and solids (tablets, capsules, powders, granules, premixes, and medicated blocks).

A solution is a mixture of 2 or more components that form a single phase that is homogeneous down to the molecular level. Solutions offer several advantages over other dosage forms. Compared with solid dosage forms, solutions are absorbed faster and generally cause less irritation of the GI mucosa. Moreover, phase separation on storage is not a concern with solutions, as it may be for suspensions and emulsions. The disadvantages of solutions include susceptibility to microbial contamination and the hydrolysis in aqueous solution of susceptible active ingredients. In addition, the taste of some drugs is more unpleasant when in solution. A range of additives is used in the formulation of oral solutions, including buffers, flavors, antioxidants, and preservatives. Oral solutions provide a convenient means of drug administration to neonates and young animals.

A suspension is a coarse dispersion of insoluble drug particles, generally with a diameter exceeding 1 µm, in a liquid (usually aqueous) medium. Suspensions are useful for administering insoluble or poorly soluble drugs or in situations when the presence of a finely divided form of the material in the GI tract is required. An example of the latter is the treatment of “frothy bloat” with dimethyl polysiloxanes, which relies on a dispersion of finely divided silica in the forestomach of ruminants. The taste of most drugs is less noticeable in suspension than in solution, due to the drug being less soluble in suspension. Particle size is an important determinant of the dissolution rate and bioavailability of drugs in suspension. In addition to the excipients described above for solutions, suspensions include surfactants and thickening agents. Surfactants wet the solid particles, thereby ensuring the particles disperse readily throughout the liquid. Thickening agents reduce the rate at which particles settle to the bottom of the container. Some settling is acceptable, provided the sediment can be readily dispersed when the container is shaken. Because hard masses of sediment do not satisfy this criterion, caking of suspensions is not acceptable.

An emulsion is a system consisting of 2 immiscible liquid phases, one of which is dispersed throughout the other in the form of fine droplets; droplet diameter generally ranges from 0.1-100 µm. The 2 phases of an emulsion are known as the dispersed phase and the continuous phase. Emulsions are inherently unstable and are stabilized through the use of an emulsifying agent, which prevents coalescence of the dispersed droplets. Creaming, as occurs with milk, also occurs with pharmaceutical emulsions. However, it is not a serious problem because a uniform dispersion returns upon shaking. Creaming is, nonetheless, undesirable because it is associated with an increased likelihood of the droplets coalescing and the emulsion breaking. Other additives include buffers, antioxidants, and preservatives. Emulsions for oral administration are usually oil (the active ingredient) in water, and facilitate the administration of oily substances such as castor oil or liquid paraffin in a more palatable form.

A paste is a 2-component semi-solid in which drug is dispersed as a powder in an aqueous or fatty base. The particle size of the active ingredient in pastes can be as large as 100 µm. The vehicle containing the drug may be water; a polyhydroxy liquid such as glycerin, propylene glycol, or polyethylene glycol; a vegetable oil; or a mineral oil. Other formulation excipients include thickening agents, cosolvents, adsorbents, humectants, and preservatives. The thickening agent may be a naturally occurring material such as acacia or tragacanth, or a synthetic or chemically modified derivative such as xanthum gum or hydroxypropylmethyl cellulose. The degree of cohesiveness, plasticity, and syringeability of pastes is attributed to the thickening agent. It may be necessary to include a cosolvent to increase the solubility of the drug. Syneresis of pastes is a form of instability in which the solid and liquid components of the formulation separate over time; it is prevented by including an adsorbent such as microcrystalline cellulose. A humectant (eg, glycerin or propylene glycol) is used to prevent the paste that collects at the nozzle of the dispenser from forming a hard crust. Microbial growth in the formulation is inhibited using a preservative. It is critical that pastes have a pleasant taste or are tasteless. Pastes are a popular dosage form for treating cats and horses, and can be easily and safely administered by owners.

A tablet consists of one or more active ingredients and numerous excipients and may be a conventional tablet that is swallowed whole, a chewable tablet, or a modified-release tablet (more commonly referred to as a modified-release bolus due to its large unit size). Conventional and chewable tablets are used to administer drugs to dogs and cats, whereas modified-release boluses are administered to cattle, sheep, and goats. The physical and chemical stability of tablets is generally better than that of liquid dosage forms. The main disadvantages of tablets are the bioavailability of poorly water-soluble drugs or poorly absorbed drugs, and the local irritation of the GI mucosa that some drugs may cause.

A capsule is an oral dosage form usually made from gelatin and filled with an active ingredient and excipients. Two common capsule types are available: hard gelatin capsules for solid-fill formulations, and soft gelatin capsules for liquid-fill or semi-solid-fill formulations. Soft gelatin capsules are suitable for formulating poorly water-soluble drugs because they afford good drug release and absorption by the GI tract. Gelatin capsules are frequently more expensive than tablets but have some advantages. For example, particle size is rarely altered during capsule manufacture, and capsules mask the taste and odor of the active ingredient and protect photolabile ingredients.

A powder is a formulation in which a drug powder is mixed with other powdered excipients to produce a final product for oral administration. Powders have better chemical stability than liquids and dissolve faster than tablets or capsules because disintegration is not an issue. This translates into faster absorption for those drugs characterized by dissolution rate-limited absorption. Unpleasant tastes can be more pronounced with powders than with other dosage forms and can be a particular concern with in-feed powders, in which it contributes to variable ingestion of the dose. Moreover, sick animals often eat less and are therefore not amenable to treatment with in-feed powder formulations. Drug powders are principally used prophylactically in feed, or formulated as a soluble powder for addition to drinking water or milk replacer. Powders have also been formulated with emulsifying agents to facilitate their administration as liquid drenches.

A granule is a dosage form consisting of powder particles that have been aggregated to form a larger mass, usually 2-4 mm in diameter. Granulation overcomes segregation of the different particle sizes during storage and/or dose administration, the latter being a potential source of inaccurate dosing. Granules and powders generally behave similarly; however, granules must deaggregate prior to dissolution and absorption.

A premix is a solid dosage form in which an active ingredient, such as a coccidiostat, production enhancer, or nutritional supplement, is formulated with excipients. Premix products are mixed homogeneously with feed at rates (when expressed on an active ingredient basis) that range from a few milligrams to ~200 g/ton of feed. They are administered to poultry, pigs, and ruminants. The density, particle size, and geometry of the premix particles should match as closely as possible those of the feed in which the premix will be incorporated to facilitate uniform mixing. Issues such as instability, electrostatic charge, and hygroscopicity must also be addressed. The excipients present in premix formulations include carriers, liquid binders, diluents, anti-caking agents, and anti-dust agents. Carriers, such as wheat middlings, soybean mill run, and rice hulls, bind active ingredients to their surfaces and are important in attaining uniform mixing of the active ingredient. A liquid binding agent, such as a vegetable oil, should be included in the formulation whenever a carrier is used. Diluents increase the bulk of premix formulations, but unlike carriers, do not bind the active ingredients. Examples of diluents include ground limestone, dicalcium phosphate, dextrose, and kaolin. Caking in a premix formulation may be caused by hygroscopic ingredients and is addressed by adding small amounts of anti-caking agents such as calcium silicate, silicon dioxide, and hydrophobic starch. The dust associated with powdered premix formulations can have serious implications for both operator safety and economic losses, and is reduced by including a vegetable oil or light mineral oil in the formulation. An alternate approach to overcoming dust is to granulate the premix formulation.

A medicated block is a compressed feed material that contains an active ingredient, such as a drug, anthelmintic, surfactant (for bloat prevention), or a nutritional supplement, and is commonly packaged in a cardboard box. Ruminants typically have free access to the medicated block over several days, and variable consumption may be problematic. This concern is addressed by ensuring the active ingredient is nontoxic, stable, palatable, and preferably of low solubility. In addition, excipients in the formulation modulate consumption by altering the palatability and/or the hardness of the medicated block. For example, molasses increases palatability and sodium chloride decreases it. Additionally, the incorporation of a binder such as lignin sulfonate in blocks manufactured by compression or magnesium oxide in blocks manufactured by chemical reaction, increases hardness. The hygroscopic nature of molasses in a formulation may also impact the hardness of medicated blocks and is addressed by using appropriate packaging.

Suspension

Suspension

A pharmaceutical suspension may be defined as a coarse dispersion containing finely divided insoluble material suspended in a liquid medium.

The physical chemist defines the word “suspension” as two-phase system consisting of an undissloved or immiscible material dispersed in a vehicle (solid, liquid, or gas).

Generally pharmaceutical suspensions contain aqueous dispersion phase however in some cases they may be an oily or organic phase. The suspensions have dispersed particles above the colloidal size that is mean particle diameter above 1µm.

[edit]

Routes of administration of suspension

Suspensions are used to administer insoluble and distasteful substances in a form that is pleasant to taste by providing a suitable form, for the application of dermatological materials to the skin and mucous membrane and for parenteral usage. Thus suspensions can be administered by oral, topical, parenteral and ophthalmic application

[edit]

Oral suspensions

Patients who have problems in swallowing solid dosage forms require drugs to be dispersed in a liquid. Oral suspensions permit the formulation of poorly soluble drugs in the form of liquid dosage form. As these suspensions are to be taken by oral route therefore they must contain suitable flavoring and sweetening agents. Drugs, which possess unpleasant taste in solution dosage form like paracetamol, chloramphenicol palmitate etc. can be formulated as palatable suspension as they are suitable for administration to peadiatric patients. Finely divided solids like kaolin, magnesium carbonate etc., when administered in the form of suspensions will be available to a higher surface area for adsorptive and neutralizing actions in the gastrointestinal tract.

[edit]

Topical suspensions

These suspensions are meant for external application and therefore should be free from gritty particles. There consistency may range from fluid to paste. Example of fluid suspension includes calamine lotion, which leave a deposit of calamine on the skin after evaporation of the aqueous dispersion phase. Zinc cream has a consistency of semisolid. Zinc cream consists of high percentage of powders dispersed in an oily (paraffin) phase.

[edit]

Parenteral suspensions

These suspensions should be sterile and should possess property of syringability. Parenteral suspensions are also used to control the rate of absorption. As the absorption rate of the drug is dependent on the dissolution rate of the solid. Therefore by varying the size of the dispersed solid particles the duration and absorption can be controlled. Vaccines are also formulated as dispersions of killed microorganisms for example in Cholera vaccine or as toxoid adsorbed on to substrate like aluminium hydroxide or phosphate for prolonged antigenic stimulus. For example adsorbed Diphtheria and Tetanus toxoid.

[edit]

Ophthalmic suspensions

These should also be sterile and should possess very fine particles. Drugs, which are unstable in aqueous solution, are formulated as stable suspensions using non-aqueous solvents. For example fractioned coconut oil is used for dispersing tetracycline hydrochloride for ophthalmic use.

[edit]

Properties of Suspensions

• Desirable properties of suspensions
• Suspensions should possess good pourability leading to ease of removal of dose from container.
• They should have good organoleptic properties.
• The particle size distribution should be uniform.
• There should be ease of redispersion of settled solid particles.
• They should be physically and chemically stable.
• They should be resistant against microbial contamination.

[edit]

Theories involved in disperse phase

Interfacial phenomenon

Smaller solid particles are used to disperse in a continuous medium. Smaller particle size and large surface area is associated with a surface free energy making it thermodynamically unstable. Thus the particles possess high energy which leads to grouping together to reduce surface free energy thus leading to formation of floccules. These floccules are held together among themselves and within by weak van der waals forces. However in cases where particles are adhered by stronger forces to form aggregates forming hard cake. These phenomena occur in order to make system more thermodynamically stable. In order to achieve a state of stability the system tend to reduce the surface free energy, which may be accomplished by reduction of interfacial tension that is achieved by use of surfactants.

Electrical Double layer and Zeta potential

Most surfaces acquire a surface electric charge when they come in contact with aqueous surface. A solid charged surface when in contact with an aqueous medium possesses positive and negative ions. The counter ions are attracted towards the surface co-ions that ions of like charge are repelled away from the surface. This results in the formation of an electrical double layer, made up of the charged particles. The charges influence the distribution of ions resulting in the formation of an electrical double layer, made up of the charged surface and a neutralizing excess of counter-ions over co-ions distributed in a diffuse manner in the aqueous medium resulting into electric potentials. The zeta potential refers to the electrostatic charge on the particles, which causes them to move in electric field towards a pole of opposite charge. Its magnitude may be measured using microelectrophoresis or any other of the electrokinetic phenomena. The two parts of the double layer are separated by a plane, the stern plane. The stern plane, which occur at a hydrated ion radius from the particle surface. The ions or molecules to be strongly adsorbed at the surface-termed specific adsorption rather than by electrostatic attraction. The specifically adsorbed ion or molecule may be uncharged e.g., with non-ionic surfactant. Surfactants specifically adsorb by the hydrophobic effect and impart effect on the stern potential. Thus the zeta potential is reduced by additives to the aqueous system in either (or both) of two different ways.

Sedimentation Concept

In dispersions the dispersed particles encounters between themselves as a result of Brownian movement. Depending upon the forces of interactions-electrical forces of repulsion, forces of attraction and forces arising due to solvation, the particles aggregate to form collection of particles. The collisions result in permanent contact of particles known as coagulation leading to the formation of larger aggregates, which sediment out known to exhibit flocculation or if the particles rebound they remain freely suspended and form stable system. These particles sediment according to stokes’ law.

According to Stokes’ law

v = 2a2g (σ-ρ)/9η

Where v is velocity of sedimentation, a is the radius of particles, σ density of solid particles, g is acceleration due to gravity and ρ is the density and η is the viscosity of the dispersion phase.

The equation of stokes’ law reflects that larger particles exhibit greater velocity of sedimentation. The velocity of sedimentation is inversely proportional to the viscosity of dispersion medium.

DLVO Theory

According to DLVO (Derjaguin Landau Verwey and overbeek) theory, in a dispersed system the interactions involved between particles are electrical repulsion and van der Walls attraction. The total potential energy of interaction is addition of these parameters. Fig.1. the curve between total energy of interactions versus distance between particles. In the curve the attraction predominates at small distances hence a very deep primary minimum. The attraction at large interparticle distance that produces the secondary minimum as the fall-off in repulsive energy with distance is more rapid than that of attractive energy. At intermediate distances double-layer repulsion is larger giving a primary maximum in the curve. If this maximum is large as compared to thermal energy of the particles the system would be stable. Otherwise the interacting particles will reach the energy depth of the primary minimum and irreversible aggregation. If the secondary minimum is smaller than thermal energy the particles will not aggregate but will always repel one another leading a de-flocculated system, but if it is significantly larger than thermal energy. A loose aggregate will form with the ease of redispersibility by shaking i.e., flocculation occurs. The depth of secondary minimum depends on particle size and particles should be of radius greater than 1 m. The particles possessing particle size less than 1 m exhibit great attractive forces for flocculation to occur. The height of the primary maximum energy barrier to coagulation depends on the zeta potential. The addition of electrolyte compresses the double layer and reduces the zeta potential, this has the effect of lowering the primary maximum and deepening the secondary minimum and is the principle of the controlled flocculation approach to pharmaceutical suspension. The primary maximum can also be lowered (and the secondary minimum deepened) by adding substances, such as ionic surfactants, which are adsorbed within the Stern Layer.

[edit]

Types of suspensions

Suspensions are classified as:

1. According to the route of administration

• Oral suspensions should be taken by oral route and therefore must contain suitable flavoring and sweetening agents.

• Topical suspensions meant for external application and therefore should be free from gritty particles.

• Parenteral suspensions should be sterile and should possess property of syringability.

• Ophthalmic suspensions should be sterile and should possess very fine particles

2. According to nature of dispersed phase and methods of preparation

The suspensions are classified as suspensions containing diffusible solids, indiffusible solids, poorly wettable solids, precipitate forming liquids and products of chemical reactions.

3. According to nature of sediment

Flocculated Suspensions, in this type the solid particles of dispersed phase aggregate leading to network like structure of solid particles in dispersion medium. The aggregates form no hard cake. These aggregates settle rapidly due to their size as rate of sedimentation is high and sediment formed is loose and easily redispersible. The suspension is not elegant, as dispersed phase tends to separate out from the dispersion medium. Therefore it is desired that flocculation should be carried out in a controlled manner so that a balance exists between the rate of sedimentation and nature of sediment formed and pourability of the suspension.

Non-flocculated Suspensions, in this type the solid particles exist as separate entities in dispersion medium. The sediments form hard cake. The solid drug particles settle slowly as rate of sedimentation is low. As sediments are formed eventually there is difficulty of redispersion. The suspension is more elegant as dispersed phase remain suspended for a long time giving uniform appearance.

[edit]

Various approaches for developing suspensions

Structured Vehicles

The approach employed in the preparation of physically stable suspensions involve the use of structured vehicle so that particles remain deflocculated and applying the principles of flocculation to produce floccules that settle rapidly with ease of dispersibility with a minimum agitation. Structured vehicles act by entrapping the deflocculated particles so that no settling occurs. Practically some degree of sedimentation usually takes place. The shear-thinning property of these vehicles facilitates the reformation of a uniform dispersion when shear is applied. Thus the product must flow readily from the container and possess a uniform distribution of particles in each dose. Controlled Flocculation From stability point of view a suspension in which all the particles remain discrete are regarded to be stable. However in pharmaceutical suspension solid particles are coarser and sedimentation is due to size of the particles. The electrical repulsive forces between the particles allow to form a closely packed sediment at the bottom, whereas the smaller particles fills within the voids of larger particles leaving a cloudy supernatant liquid due to colloidal particles. The particles, which form the lowest layer in the pack, are pressed by the weights of the particles above them thus overcoming the repulsive barrier. Whereas in the case of particles in the secondary minimum, which is a desirable state for a pharmaceutical suspension, the particles form a loose aggregates known as floccules. The sedimentation of floccules is rapid leading to loosely packed high volume sediment which are easily redispersible. The supernatant liquid is clear as colloidal particles get entrapped within the floccules and sediment with them. Particles with size greater than 1 m should posses high charge to show a deep secondary minimum for flocculation to occur as the attractive force depend on particle size, shape and concentration. It is essential with highly charged particles to control the depth of the secondary minimum to induce a desired flocculation state, which is achieved by the addition of electrolytes or ionic surfactants with reduction of zeta potential. This results in production of desired secondary minimum leading to floccules, which is termed as controlled flocculation (Fig.2).

Rheological Behaviour

Plastic or pseudoplastic flow is exhibited by flocculated suspension depending upon concentration. The apparent viscosity of flocculated suspensions is high when applied shearing stress is low but decreases as the applied stress increases and the attractive forces resulting in flocculation are overcome. The dialant flow is exhibited by the concentrated deflocculated suspensions. The apparent viscosity is low at low shearing stress however it increases as the applied stress increases. The rheological consideration are of interest to investigate the viscosity of a suspension as it affects the settling of dispersed particles, transformation of flow properties while a suspension is shaken and product is poured out of bottle and the spreading qualities of the lotion when it is applied to effected area.

[edit]

Formulation of Suspensions

Suspensions containing diffusible solids consist of solids insoluble in water but easily wettable. On shaking with water solid particles diffuse readily through out the liquid and remain suspended for a long time. The suspensions containing diffusible solids are prepared by triturating the solids in a mortar with sufficient quantity of vehicle to form a smooth cream. Any soluble nonvolatile substance is then added by separately dissolving them in a small quantity of vehicle. More vehicles are then added and any foreign particle is strained through a muslin cloth. Any volatile component is added at this stage and adding the required quantity of vehicle makes up the final volume.

Example: Magnesium Trisilicate Mixture

Magnesium Trisilicate 5.0 g

Light Magnesium Carbonate 5.0 g

Sodium bicarbonate 5.0 g

Concentrated Peppermint water 2.5 ml

Chloroform water 50.0 ml

Purified water qs to 100 ml

Suspensions containing indiffusible solids consist of substances, which do not remain distributed in the dispersion medium when shaken for long time to ensure uniformity of dose. They are prepared by adding a suitable thickening agent to the vehicle, which increases the viscosity of the vehicle and delays the separation or sedimentation of indiffusible particles.

Example: Calamine Lotion

Calamine 15.0 g

Zinc Oxide 5.0 g

Bentoite 3.0 g

Sodium Citrate 0.5 g

Liquified Phenol 0.5 ml

Glycerine 5 ml

Purified water qs to 100ml

Suspensions containing poorly wettable solids consist of substances, which are poorly soluble, and at the same time poorly wetted by the dispersion medium, and clump together with the difficulty to disperse. They are prepared by including suitable wetting agent in the formulation. These agents get adsorbed at the solid/liquid interface and promote wetting of the solid particles by the liquid of the dispersion medium.

Example: Sulphur Lotion

Precipitated Sulphur 4.0 g

Quillia Tincture 0.5 ml

Glycerin 2.0 ml

Alcohol (95%) 6 ml

Calcium hydroxide solution qs to 100ml

Suspensions of precipitate forming liquids consist of liquid tinctures which are alcoholic or hydroalcoholic extract of vegetable drugs which contain resinous material. When tinctures are added to water they precipitate. Precipitates are indiffusible and stick to the walls of the container. They are prepared by adding a suitable thickening agent prior to the addition of the precipitate forming liquid.

Example: Lobelia and Stramonium Mixture

Lobelia Ethereal Tincture 16 ml

Tragacanth mucilage 40 ml

Potassium Iodide 4 g

Chloroform water qs to 180 ml

Suspensions produced by chemical reactions are prepared by mixing two dilute solutions of reactants to form a fine precipitate. Generally precipitates so formed are diffusible and no suspending agent is required. If precipitate is indiffusible a suitable thickening or suspending agent may be added. They are prepared by dissolving the reactants separately in approximately half volumes of the vehicle and the two portions are then mixed together.

Example: Zinc Sulphide Lotion

Zinc Sulphate 4 g

Sulphurated Potash 4 g

Purified water qs to 100 ml

[edit]

Stability of Suspensions

The physical stability of a pharmaceutical suspension is the condition in which the particles do not aggregate and in which they remain uniformly distributed throughout the dispersions. In order to achieve this ideal situation the suspension should have additive, which are added to achieve ease in resuspension by a moderate amount of agitation. Taking a case example: In case of dispersion of positively charged particles that is flocculated by addition of an aninonic electrolyte like monobasic potassium phosphate. The physical stability of the system is enhanced by addition of carboxymethylcellulose, Carbopol 934, veegum, tragacanth or bentonite either alone or in combination. No physical incompatibility is recorded as majority of hydrophilic colloids are negatively charged and are compatible with anionic flocculating agents. When a flocculated suspension of negatively charged particles with a cationic electrolyte is prepared (aluminum chloride) the addition of hydrocolloid may result in an incompatible product resulting in stingy mass, which has no suspending action, and settle rapidly. In such a condition protective agent is added to change the sign on the particles from the negative to positive is employed which can also be achieved by the adsorption onto the particle surface by fatty acid amine or gelatin. Thus an anionic electrolyte is used to produce floccules that are compatible with negatively charged suspending agent.

[edit]

Quality control tests for suspensions

Sedimentation volume

Redispersibility is the major consideration in assessing the acceptability of a suspension. The measurement of the sedimentation volume and its ease of redispersion form two of the most common basic evaluative procedures. The sedimentation volume is the simple ratio of the height of sediment to initial height of the initial suspension. The larger the value better is the suspendability.

Particle size and size distribution

The freeze-thaw cycling technique used to assess suspension for stress testing for stability testing result in increase of particle growth and may indicate future state after long storage. It is of importance to study the changes for absolute particle size and particle size distribution. It is performed by optical microscopy, sedimentation by using Andreasen apparatus and Coulter counter apparatus. None of these methods are direct methods. However microscopic method allows the observer to view the actual particles. The sedimentation method yields a particle size relative to the rate at which particles settle through a suspending medium.

Rheological studies

Rheologic methods can help in determining the settling behaviour of the suspension. Brookefield viscometer with variable shear stress control can be used for evaluating viscosity of suspensions. It consist of T-bar spindle which is lowered into the suspension and the dial reading is noted which is a measure of resistance the spindle meets at various levels in the suspension. This technique also indicates in which level of the suspension the structure is greater due to particles aggregates. Data obtained on aged and stored suspension reveals whether changes have taken place.

Stability testing

It is not possible to conduct accelerated temperature studies as it can be done in solutions. The formulation exhibiting thixotropic properties a rise in temperature would change the properties. In this physical form, the preparation would exhibit parameters that could not be extrapolated to those that would exist in the normal system. The valid temperature data could be obtained that will be useful in the estimation of the physical stability of a product at normal storage conditions. The extended aging tests must be employed under various conditions to obtain the desired information.

[edit]

Sustained release suspensions

A suspension usually gives a longer duration of action as compared to an aqueous solution when given intramuscularly or subcutaneously. The drug is continuously dissolved to replenish what is being lost. The constraints are imposed by stability, syringeability, pain upon injection and minimum effective concentration. The sustained release by suspensions is achieved by decreasing surface area, diffusion coefficient and solubility. An example of sustained release suspension is that of insulin. Insulin is normally administered subcutaneously and it precipitates as an insoluble complex in the presence of zinc chloride and depending on the pH either an amorphous or crystalline form results. The crystalline form is less soluble than the amorphous form and result in longer duration of action. Extended insulin zinc suspension USP consist of crystalline zinc complex. Another example includes Penicillin G procaine a sparingly soluble form of penicillin G. Others include medroxyprogestrone acetate (Depo-provera), triamcinolone hexacetonide (Aristopan ) etc.

[edit]

Formulation Additives

In addition to vehicle, stabilizer, sweetening and flavouring agents, which are common in liquid dosage forms, the following additives are required to prepare suspensions which include:

[edit]

1. Suspending and Thickening agents

They are added with the objective to increase apparent viscosity of the continuous, phase thus preventing rapid sedimentation of the dispersed particles. The selection of the type and concentration of a suspending agent depends on sedimentation rate of dispersed particles, pourability and spreadibility. The ideal suspending agent should have a high viscosity at negligible shear i.e., during shelf storage and it should have a low viscosity at high shearing rates i.e., it should be free flowing during agitation, pouring and spreadibility. A suspending agent that is thixotropic as well as pseudoplastic should prove to be useful as it forms a gel on standing and becomes fluid when shaken. They include natural polysaccharides (Gum Acacia, Gum Tragacanth, Guar Gum, Sodiun Alginate, Xanthan Gum and Carrageenan), Semi-synthetic polysaccharides (Sodium Carboxymethylcellulose, Methyl Cellulose, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, Hydroxypropyl Methyl Cellulose and Microcrystalline Cellulose), Clays (Aluminium Magnesium Silicate, Bentonite and Hectorite) and synthetic agents (Carbomer, Colloidal silicon dioxide). Pseudoplastic substances like tragacanth, sodium alginate and sodium carboxymethyl cellulose show these desirable qualities. In cases of combination use of suspending agents like bentonite and CMC dispersions are both pseudoplastic and thixotropic.

A. Natural Polysaccharides

Gum Acacia :It is the dry exudates obtained from stems and branches of various species of Acacia. It has low thickening properties but it is a good protective colloid. It is used in combination with tragacanth and starch for internal preparations but is too sticky to be being a natural product, acacia may be frequently contaminated with microorganism such as Escherichia coli and Salmonella species and may need to be sterilized before use. Preservative such as chloroform water, benzoic acid or hydroxybenzoates should be included in formulations containing Gum Acacia.

Gum Tragacanth: Gum Tragacanth is dried exudates obtained from Astragalus gummifer or other species of Astragalus. It is widely used as suspending agent in form of tragacanth mucilage or compound tragacanth powder which consists of a mixture of acacia (20%), tragacanth (15%), starch (20%) and sucrose (45%). Tragacanth forms viscous solution or gels with water, depending on the concentration usually the powdered tragacanth is first dispersed in a wetting agent, such as alcohol, to prevent agglomeration on the addition of water. Tragacanth gels are non thixotropic and most stable at pH values between 4 and 7.5. Tragacanth is non-toxic and almost tasteless and is widely used in suspensions for internal use. Being less sticky, it may also be used for external applications.

Guar Gum: It consists of gum obtained from the ground endosperms of the seeds of Cyamopsis tetragonolobus belonging to family Leguminosae. Guar Gum disperses in hot and cold water to form a colloidal solution. A 1% aqueous dispersion has same viscosity to acacia mucilage, while 3% dispersion has similar viscosity to tragacanth mucilage. Guar Gum is a poor suspending agent for insoluble powders. It is employed as a thickener in lotions in concentrations up to 2.5%. Maximum stability is achieved at pH values between 3 and 9. Dispersions can be preserved with benzoic acid 0.2%.

Sodium Alginate: Sodium Alginate consists of purified carbohydrate product extracted from brown seaweeds by use of dilute alkali. It chiefly consists of sodium salt of alginic acid. Various grades are usually available commercially for different applications and yield solutions of various viscosities. Sodium Alginate is slowly soluble in water. It is normally used in concentrations of between 1% and 5%. A 1% solution has suspending properties similar to those of tragacanth mucilage. Maximum stability is achieved at pH values between 4 and 10. It is generally dispersed in a wetting agent, such as alcohol, glycerol or propylene glycol before addition to water to prevent lump formation.

Xanthan Gum: Xanthan Gum consists of the purified polysaccharide gum obtained by fermentation of a carbohydrate by bacteria of genus Xanthomonas chiefly Xanthomonas campestris. It is soluble in hot and cold water and produces a viscous product that is stable over a wide range of temperature and pH. A 1% solution has a viscosity of about 1000 centipoise. Xanthan Gum has been used as an alternative to tragacanth in the preparation of suspensions. In comparison to tragacanth, it is easier to use and is capable of preparing suspensions of better quality and improved consistency.

Carrageenan: Carrageenan consists of hydrocolloidal material extracted from certain red seaweeds of class Rhodophyceae. It is soluble in 30 parts of water at 80o forming a viscous clear or slightly opalescent solution. Dispersions of Carrageenan are stable at pH values between 4 and 10. Carrageenan is used in pharmacy and the food industry as a suspending and gelling agent.

B. Semi-Synthetic Polysaccharides:

The Semi-Synthetic polysaccharides used as suspending and thickening agents mainly consists of derivatives of the natural polysaccharide, cellulose.

Sodium Carboxymethyl cellulose: It is also known as Carmellose Sodium, it consists of the sodium salt of Carboxymethyl ether derivative of cellulose. Different viscosity grades are available which yield 1% aqueous solutions with viscosities in the range of 6 to 4000 centipoise. It is used in the concentrations ranging from 0.25% to 1% in suspensions meant for oral, topical and parenteral use. It is soluble in hot as well as cold water forming stable mucilage within the range of 5 and 10. Being anionic, it is incompatible with the cationic compounds. Aqueous preparations that is unlikely to be stored for long periods should contain an antimicrobial preservative.

Methyl cellulose: It consists of the ethyl ether derivative of cellulose. It dispersed slowly in cold water to form colloidal solution but is insoluble in hot water. It is mainly employed as a suspending and viscosity increasing agent for both internal and external preparations. Various grades are available and are classified according to the viscosity of a 2% solution at 20o. The use of the lower viscosity grades is preferred at concentrations up to 5% while higher viscosity grades are used at concentration of 0.5% to 2%. An aqueous dispersion may be prepared by adding the methyl cellulose to about one third the required amount of boiling water and when the powder is thoroughly hydrated, adding the remainder of the water preferably in form of ice and stirring until homogeneous. Methyl cellulose is nonionic and is stable over a wide range of pH values. Heating an aqueous dispersion first causes a decrease in viscosity followed by dehydration and gelling at 50o C. On cooling, however viscosity returns to normal.

Hydroxyethyl cellulose: It consists of the hydroxyethyl ether derivative of cellulose and is mainly used as viscosity increasing agent. It is soluble in cold as well as hot water and produces a clear solution that is stable even at higher temperatures. Various grades are available that differs in their aqueous viscosities. Solution display maximum stability in pH range 2 to 10.

Hydroxypropyl cellulose: It consists of hydroxypropyl ether derivative of cellulose and is mainly used as a viscosity enhancing agent for oral and topical use. It is soluble in water below 40o C and insoluble above this temperature. A wide range of grades are available that differs in their aqueous solution viscosities. Maximum stability is demonstrated at pH range 2 to 10.

Hydroxypropyl methyl cellulose: It is also known as Hypermellose, it consists of the hydroxypropyl derivative of methyl cellulose. It has properties similar to those of methyl cellulose but produces aqueous solutions with higher gelling points. Various grades are available that differs in their aqueous solution viscosities.

Microcrystalline cellulose: Microcrystalline cellulose is widely used as suspending agent, either alone or in conjunction with other cellulose derivatives such as Carboxymethyl cellulose sodium or hypermellose or with clays such as bentonite.

C. Clays:

Clays are inorganic materials, mainly hydrated silicates derived from natural sources. They form highly thixotropic gels. The gels must be preserved with suitable antimicrobial agents as clays are liable to heavy contamination with microbial spores.

Aluminium Magnesium Silicate: Also known as Veegum, Aluminium Magnesium Silicate is mainly used at a concentration range of 0.5% to 2% as a suspending agent for both internal and external preparations. A number of different grades are available; which are distinguished by the degree of alkalinity and the viscosity of an aqueous dispersion. Dispersions in water are thixotropic, and at concentration of 10% a firm gel is obtained. The viscosity of dispersions is increased by heating, by addition of electrolytes and at higher concentration by ageing.

Bentonite: Bentonite is a natural colloidal hydrated aluminium silicate found in the midwest of USA and Canada. Although it is insoluble in water, it absorbs large quantities of it and may swells up to 12 times its original volume. Bentonite in contact with water forms either sols or gels depending on its concentration. It is generally used at a concentration in between 0.5% to 2% for suspending powders in aqueous preparations such as calamine lotion. Dispersion shows maximum stability at pH values between 3 and 10.

Hectorite: Hectorite is a natural colloidal magnesium silicate having properties similar to bentonite. It swells up to 36 times its original volume and forms highly thixotropic gels at concentration of 1 to 2%. It may contain traces of lithium and fluorine and is mainly used in suspensions for external use.

D. Synthetic Agents:

The quality of synthetic agents tends to be less variable than that of suspending agents derived from natural sources.

Carbomer: Carbomer is a high molecular weight polymer of acrylic acid crosslinked with allyl sucrose. It dispersed in water to form an acidic colloidal solution of low viscosity, which produces a high viscous gel on neutralization with inorganic or organic bases like sodium hydroxide, triethanolamine, etc. several viscosity grades are available and the usual concentration used varies from 0.1% to 4% as suspending agent. Carbomer gels are most viscous between pH 6 and 11. The viscosity is reduced on lowering the pH to below 3 or rising above 12. Electrolytes also reduce the viscosity of carbopol dispersions. Carbomer is susceptible to oxidation especially on exposure to light and hence formulations should be stabilized by addition of appropriate antioxidants and chelating agents. Aqueous dispersion of Carbomer should also contain an antimicrobial preservative.

Colloidal Silicon dioxide: This is a form of Silicon dioxide having colloidal dimensions. It acts as a suspending agent by forming aggregates which associates to form three dimensional networks, thus preventing sedimentation. In a concentration between 1.5 to 4%, it acts as a suspending stabilizer while at higher concentrations, it forms a soft gel. Aqueous dispersions generally have a pH of 4 and neutralization does not affect the binding capacity.

[edit]

2. WETTING AGENTS:

Although some insoluble solids get easily wetted by water, most of them exhibits hydrophobicity and does not get easily wetted by it. Wetting agents are additives which are usually added to decrease this hydrophobicity. These agents generally get adsorbed at the solid-liquid interface and promote wetting of the solid particles by the liquid of the dispersion medium. A variety of substances including the following have been employed as wetting agents.

Surfactants: Generally, Surfactants possessing HLB values between 7 and 9 have been employed as wetting agents. These orient themselves at solid-liquid interface and decrease the interfacial tension between the particles of the dispersed phase and the dispersed medium. Most surfactants are used at concentration of 0.1 to 0.2%. The minimum concentration that is sufficient to cause wetting should generally be employed since an excess of these agents may cause foaming in the preparation. Examples of surfactants employed for oral preparation includes polysorbates, sorbitan, esters, etc. for external preparations, sodium lauryl sulfate, sodium dioctyl sulfosuccinate and quillia extracts can also be used.

Hydrophilic Polymers: Various hydrophilic colloids such as acacia, bentonite, colloidal silicon dioxide and cellulose derivatives have also been employed as wetting agents. These act by coating the surface of hydrophobic particles and imparting hydrophilic character to these.

Hydrophilic Liquids: Hydrophilic liquids such as alcohol, glycerol, propylene glycol, etc. are sometimes employed as wetting agents. These penetrate the loose aggregates of solid particles and displace the air from the pores thus facilitating wetting of the particles by the dispersion medium.

[edit]

3. DISPERSING AGENT

These additives are generally added as an aid to uniform distribution and dispersion of solid particles of the dispersed phase. Such agents are generally used during the preparation of deflocculated suspensions where they get adsorbed at the solid-liquid interface. Wetting agents such as surfactants are often employed as dispersing agents. Other agents used for this purpose include agents such as Darvans, Daxads, etc. which carry a good surface charge and get absorbed on the particles of the dispersed phase thus preventing their agglomeration.

[edit]

4. FLOCCULATING AGENTS:

These are substances added to cause controlled aggregation of the particles of the dispersed phase in a suspension. Examples of such agents include surfactants, electrolytes and hydrophilic polymers.

Surfactants: Ionic as well as non-ionic surfactants may be employed as flocculation agent. The ionic surfactants such as sodium lauryl sulphate and sodium dioctyl sulfosuccinate act by neutralizing the surface charge on the particles of the dispersed phase, thereby reducing inter-particulate repulsion and causing aggregation. Non-ionic ones such as Spans and Tweens are believed to function by formation of bridges between the adjacent particles.

Electrolytes: Electrolytes such as sodium salt of acetates, phosphates and citrates have been commonly employed as flocculating agents. These acts by neutralizing the surface charge on the particles of the dispersed phase thereby reducing the electrical barrier between them. The effectiveness of the electrolytes as flocculating agents depends on the valance of the ions of these electrolytes. Thus, divalent ions are ten times more effective then the monovalent ions while trivalent ones are thousand times more effective. The concentration of the electrolytes used should be minimum that is required to cause flocculation since an excess may cause reversal of this phenomenon.

Hydrophilic Polymers: Hydrophilic polymers such as alginates, cellulose derivatives, tragacanth, carbomers, silicates, etc. have also been know to cause flocculation of particles of the dispersed phase. These polymers have a linear branched chain structure and form a gel like network within the system. They get adsorbed on to the surface of the dispersed particles and hold them in a flocculated state.

[edit]

Some Suspension Products available in USA

Some Suspension Products available in USA.
S. No.	Product name	Manufacture	Active Ingredient s & dose	Indications
1.	Megac (40 mg/ml)	Bristol –Meyer	Megestrol acetate 20ml/day i.e., 800 mg/day	Anorexia
2.	Tegretal (100 mg/5ml.)	Novartis Pharmaceuticals Ltd.	Carbamazepine 400mg/day (one teaspoonful four times a day	Anticonvulsants
3.	Indocin oral suspension 25 mg/5 ml	Merck and Co.	Indomethacin oral suspension 5-50 mg two times a day	Rheumatoid arthritis Anti-inflammatory
4.	Visatryl oral suspension 25 mg/ml	Pfizer	Hydroxazine Pamoate 50-100 mg four times a day	Antianxiety
5.	Septra Suspension (40 mg Trimethoprin + 200 mg sulphamethoxazole /5 ml	Monarch	Trimethoprin + sulphamethoxazole Two to four spoonful every 12 hours for 10-14 days	Urinary Tract Infection Otitis media
6.	Naprosyn suspension (125mg /5 ml)	Roche Lab	Naproxen 250 mg two times a day	NSAIDs Arthritis
7.	Paxil suspension 10mg/5 ml	Glaxo-Smith Kline	Paroxetin hydrochloride 20 mg/day	Antidepressants
8.	Minocin suspension (50mg/5ml)	Lederle Pharmaceutical	Minocycline 200 mg initially followed by 100 mg daily.	Anti-infective

[edit]

List of medicinal suspensions available in USP

Acetaminophen Oral Suspension

Acetaminophen and Codeine Phosphate Oral Suspension

Acyclovir Oral Suspension

Albendazole Oral Suspension

Alumina and Magnesia Oral Suspension

Alumina, Magnesia, and Calcium Carbonate Oral Suspension

Alumina, Magnesia, and Simethicone Oral Suspension

Alumina and Magnesium Carbonate Oral Suspension

Alumina and Magnesium Trisilicate Oral Suspension

Diazoxide Oral Suspension

Dicloxacillin Sodium for Oral Suspension

Dihydroxyaluminum Aminoacetate Magma

Doxycycline for Oral Suspension

Doxycycline Calcium Oral Suspension

Erythromycin Estolate Oral Suspension

Erythromycin Estolate for Oral Suspension

Erythromycin Estolate and Sulfisoxazole Acetyl Oral Suspension

Erythromycin Ethylsuccinate Oral Suspension

Erythromycin Ethylsuccinate for Oral Suspension

Erythromycin Ethylsuccinate and Sulfisoxazole Acetyl for Oral Suspension

Estradiol Injectable Suspension

Estrone Injectable Suspension

Ferumoxsil Oral Suspension

Fluorometholone Ophthalmic Suspension

Furazolidone Oral Suspension

Gentamicin and Prednisolone Acetate Ophthalmic Suspension

Griseofulvin Oral Suspension

Hydrocortisone Injectable Suspension

Hydrocortisone Acetate Injectable Suspension

Hydrocortisone Acetate Ophthalmic Suspension

Hydroxyzine Pamoate Oral Suspension

Ibuprofen Oral Suspension

Imipenem and Cilastatin for Injectable Suspension

Indomethacin Oral Suspension

Isoflupredone Acetate Injectable Suspension

Ketoconazole Oral Suspension

Loracarbef for Oral Suspension

Magaldrate Oral Suspension

Magaldrate and Simethicone Oral Suspension

Milk of Magnesia

Magnesium Carbonate and Sodium Bicarbonate for Oral Suspension

Mebendazole Oral Suspension

Medroxyprogesterone Acetate Injectable Suspension

Megestrol Acetate Oral Suspension

Meprobamate Oral Suspension

Methacycline Hydrochloride Oral Suspension

Amoxicillin for Injectable Suspension

Methenamine Mandelate Oral Suspension

Amoxicillin for Oral Suspension

Amoxicillin Oral Suspension

Methyldopa Oral Suspension

Amoxicillin and Clavulanate Potassium for Oral Suspension

Methylprednisolone Acetate Injectable Suspension

Minocycline Hydrochloride Oral Suspension

Nalidixic Acid Oral Suspension

Naproxen Oral Suspension

Natamycin Ophthalmic Suspension

Ampicillin for Injectable Suspension

Ampicillin for Oral Suspension

Neomycin Sulfate and Hydrocortisone Otic Suspension

Neomycin Sulfate and Hydrocortisone Acetate Ophthalmic Suspension

Ampicillin and Probenecid for Oral Suspension

Neomycin and Polymyxin B Sulfates and Dexamethasone Ophthalmic Suspension

Neomycin and Polymyxin B Sulfates and Hydrocortisone Ophthalmic Suspension

Neomycin and Polymyxin B Sulfates and Hydrocortisone Otic Suspension

Neomycin and Polymyxin B Sulfates and Hydrocortisone

Acetate Ophthalmic Suspension

Neomycin and Polymyxin B Sulfates and Prednisolone

Acetate Ophthalmic Suspension

Neomycin Sulfate and Prednisolone Acetate Ophthalmic

Nitrofurantoin Oral Suspension

Nystatin Oral Suspension

Nystatin for Oral Suspension

Oxfendazole Oral Suspension

Oxytetracycline and Nystatin for Oral Suspension

Oxytetracycline Calcium Oral Suspension

Oxytetracycline Hydrochloride and Hydrocortisone Acetate

Penicillin G Benzathine Injectable Suspension

Penicillin G Benzathine Oral Suspension

Penicillin G Benzathine and Penicillin G Procaine Injectable

Penicillin G Procaine Injectable Suspension

Penicillin G Procaine for Injectable Suspension

Penicillin G Procaine and Dihydrostreptomycin Sulfate Injectable Suspension

Penicillin G Procaine, Dihydrostreptomycin Sulfate

Chlorpheniramine Maleate, and Dexamethasone Injectable Suspension

Penicillin G Procaine, Dihydrostreptomycin Sulfate

Prednisolone Injectable Suspension

Penicillin G Procaine, Neomycin and Polymyxin B Sulfates

Hydrocortisone Acetate Topical Suspension

Penicillin V for Oral Suspension

Penicillin V Benzathine Oral Suspension

Phenytoin Oral Suspension

Chromic Phosphate P 32 Suspension

Prednisolone Acetate Injectable Suspension

Prednisolone Acetate Ophthalmic Suspension

Prednisolone Tebutate Injectable Suspension

Primidone Oral Suspension

Progesterone Injectable Suspension

Propoxyphene Napsylate Oral Suspension

Propyliodone Injectable Oil Suspension

Psyllium Hydrophilic Mucilloid for Oral Suspension

Pyrantel Pamoate Oral Suspension

Pyrvinium Pamoate Oral Suspension

Rifampin Oral Suspension

Rimexolone Ophthalmic Suspension

Atovaquone Oral Suspension

Simethicone Oral Suspension

Sodium Polystyrene Sulfonate Suspension

Spectinomycin for Injectable Suspension

Aurothioglucose Injectable Suspension

Sulfacetamide Sodium Topical Suspension

Sulfacetamide Sodium and Prednisolone Acetate Ophthalmic Suspension

Sulfadimethoxine Oral Suspension

Sulfamethizole Oral Suspension

Sulfamethoxazole Oral Suspension

Sulfamethoxazole and Trimethoprim Oral Suspension

Sulfisoxazole Acetyl Oral Suspension

Testosterone Injectable Suspension

Tetracycline Oral Suspension

Bacampicillin Hydrochloride for Oral Suspension

Tetracycline Hydrochloride Ophthalmic Suspension

Tetracycline Hydrochloride Oral Suspension

Thiabendazole Oral Suspension

Thioridazine Oral Suspension

Tobramycin and Dexamethasone Ophthalmic Suspension

Tobramycin and Fluorometholone Acetate Ophthalmic

Triamcinolone Acetonide Injectable Suspension

Triamcinolone Diacetate Injectable Suspension

Triamcinolone Hexacetonide Injectable Suspension

Triflupromazine Oral Suspension

Trisulfapyrimidines Oral Suspension

Barium Sulfate for Suspension

Barium Sulfate Suspension

Betamethasone Sodium Phosphate and Betamethasone

Brinzolamide Ophthalmic Suspension

Calcium Carbonate Oral Suspension

Calcium and Magnesium Carbonates Oral Suspension

Carbamazepine Oral Suspension

Cefaclor for Oral Suspension

Cefadroxil for Oral Suspension

Cefixime for Oral Suspension

Cefpodoxime Proxetil for Oral Suspension

Cefprozil for Oral Suspension

Cellulose Sodium Phosphate for Oral Suspension

Cephalexin for Oral Suspension

Cephradine for Oral Suspension

Chloramphenicol and Hydrocortisone Acetate for Ophthalmic

Chloramphenicol Palmitate Oral Suspension

Chlorothiazide Oral Suspension

Cholestyramine for Oral Suspension

Ciclopirox Olamine Topical Suspension

Clarithromycin for Oral Suspension

Clindamycin Phosphate Topical Suspension

Colestipol Hydrochloride for Oral Suspension

Colistin Sulfate for Oral Suspension

Colistin and Neomycin Sulfates and Hydrocortisone Acetate

Corticotropin Zinc Hydroxide Injectable Suspension

Cortisone Acetate Injectable Suspension

Demeclocycline Oral Suspension

Desoxycorticosterone Pivalate Injectable Suspension

Dexamethasone Ophthalmic Suspension

Dexamethasone Acetate Injectable Suspension

Megestrol Acetate Oral Suspension

Amoxicillin and Clavulanate Potassium for Oral Suspension

Atovaquone Oral Suspension

Brinzolamide Ophthalmic Suspension

Cefpodoxime Proxetil for Oral Suspension

Ferumoxsil Oral Suspension

Megestrol Acetate Oral Suspension

Sulfadimethoxine Oral Suspension

Methylprednisolone Acetate for Rectal Suspension

Ketoconazole Oral Suspension

Cellulose Sodium Phosphate for Oral Suspension

Hydrocortisone Rectal Suspension

Tetracycline Hydrochloride Oral Suspension

Sulfacetamide Sodium Topical Suspension

Methylprednisolone Acetate for Rectal

[edit]

Some Suspension Products available in India

Some Suspension Products available in India.
S. No.	Product name	Manufacture	Active Ingredients & dose	Indications
1.	Cerecetam (1g/5ml)	Intas Pharmaeuticals Ltd.	Piracetam 2 Teaspoonful	Mental Retardation, Learning problem in children
2.	Sucral (1g/10 ml)	Strassenburg	Sucralfate (1g four times a day)	Duodenal gastric ulcer
3.	Acicot (1g/10 ml)	Skymax	Sucralfate (1g four times a day)	Duodenal gastric ulcer
4.	Gelusil (625 mg Magnesium trisilicate and 312 mg Aluminium hydroxide gel per 5 ml)	Wammer Pharma	Magnesium trisilicate and Aluminium hydroxide gel (5-10 ml) Half an hour after meal	Antacid
5.	Diaba-M (100 mg Metronidazole and 100 mg ofloxacin)	Sun Pharma	Metronidazole and ofloxacin 5 ml two times a day	Diarrhoea
6.	Zenotin (50 mg/5 ml)	Mankind Pharma	Metronidazole and ofloxacin 50 mg-100 mg	Diarrhoea of mixed origin
6.	Clavotrol 31.25 mg Amoxycillin and 125 mg Clauvulanic acid per 5 ml	Astra-Zeneca	Amoxycillin and Clauvulanic acid Two teaspoonful	Upper/lower respiratory tract infections

Authors:

Dr. Javed Ali, Dr. Sanjula Baboota and Dr. Alka Ahuja

Granules for oral solutions or suspensions

Presentations of granules that are intended to be issued to the patient as granules to be swallowed
as such, to be chewed, or to be taken in or with water or another suitable liquid, are outside the
scope of this general monograph.
Definition
Granules for oral solutions or suspensions are multidose preparations consisting of solid, dry
aggregates of powder particles sufficiently resistant to withstand handling. They contain one or
more active ingredients with or without excipients and, if necessary, authorized colouring matter
and flavouring substances. They may contain antimicrobial preservatives and other excipients in
particular to facilitate dispersion or dissolution and to prevent caking.
After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral
solutions or Oral suspensions, as appropriate.
Visual inspection
Inspect the granules. Evidence of physical instability is demonstrated by noticeable changes in
physical appearance, including texture (for example, clumping of granules, presence of loose
powder). A change in colour may indicate chemical degradation or microbial contamination.

Powders for oral solutions, oral suspensions or oral drops

Presentations of powder (usually single-dose presentations, for example, a small sachet) that are
intended to be issued to the patient as a powder, to be taken in or with water or another suitable
liquid, are outside the scope of this general monograph. Such preparations are controlled by the
monograph for Oral powders.
Definition
Powders for oral solutions, suspensions or drops are multidose preparations consisting of solid,
loose, dry particles of varying degrees of fineness. They contain one or more active ingredients,
with or without excipients and, if necessary, authorized colouring matter and flavouring substances.
They may contain antimicrobial preservatives and other excipients in particular to facilitate
dispersion or dissolution and to prevent caking.

page 8
After dissolution or suspension in the prescribed liquid, they comply with the requirements for Oral
solutions, Oral suspensions or Oral drops, as appropriate.
Manufacture
In the manufacture of powders for oral solutions, suspensions or drops, the components of the
powder mixture are passed through a sieve to remove lumps and particle aggregates. The weighed
masses of the sieved components, preferably of a narrow particle size distribution, are then
transferred to a suitable mixer. The greatest risk of segregation of the powder mixture usually
occurs when emptying the mixer container and when the powder mixture is dosed into the
containers. Ensuring the suitability of the mixing equipment and the dosing devices is, therefore,
critical.
Visual inspection
Inspect the powder. Evidence of physical instability is demonstrated by noticeable changes in
physical appearance, including texture (for example, clumping). A change in colour may indicate
chemical degradation or microbial contamination.

Oral drops

Definition
Oral drops are Liquid preparations for oral use that are intended to be administered in small
volumes with the aid of a suitable measuring device. They may be solutions, suspensions or
emulsions.
Visual inspection
Inspect the drops. Drops that are solutions should be clear and free from any precipitate. Evidence
of physical instability of drops that are suspensions is demonstrated by the formation of flocculants
or sediments that do not readily disperse on gentle shaking. Evidence of physical instability of drops
that are emulsions is demonstrated by phase separation that is not readily reversed on gentle
shaking. A change in colour (or cloudiness of solutions) may indicate chemical degradation or
microbial contamination of the drops.
Dose and uniformity of dose of oral drops
Into a suitable, graduated cylinder, introduce by means of the dropping device the number of drops
usually prescribed for one dose or introduce by means of the measuring device the usually
prescribed quantity. The dropping speed does not exceed 2 drops per second. Weigh the liquid,
repeat the addition, weigh again and carry on repeating the addition and weighing until a total of 10
masses are obtained. No single mass deviates by more than 10% from the average mass. The total
of 10 masses does not differ by more than 15% from the nominal mass of 10 doses. If appropriate,
measure the total volume of 10 doses. The volume does not differ by more than 15% from the
nominal volume of 10 doses.
Containers
Oral drops are normally supplied in suitable multidose containers that allow successive drops of the