MODULE 1. GENERAL CONCEPTS OF DRUG TECHNOLOGY. POWDERS. LIQUID DOSAGE FORMS.

CONTENT MODULE 2.  LIQUID MEDICAL FORMS.

LESSON 10. SUSPENSIONS.

 

Suspensions

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.

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

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

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.

 

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

 

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.

 

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.

 

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.

 

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:

 

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.

 

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.

 

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.

 

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.

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 Pharmaceutica	Minocycline 200 mg initially followed by 100 mg daily.	Anti-infective

 

List of medicinal suspensions available in USP

1.      Acetaminophen Oral Suspension

2.      Acetaminophen and Codeine Phosphate Oral Suspension

3.      Acyclovir Oral Suspension

4.      Albendazole Oral Suspension

5.      Alumina and Magnesia Oral Suspension

6.      Alumina, Magnesia, and Calcium Carbonate Oral Suspension

7.      Alumina, Magnesia, and Simethicone Oral Suspension

8.      Alumina and Magnesium Carbonate Oral Suspension

9.      Alumina and Magnesium Trisilicate Oral Suspension

10.  Diazoxide Oral Suspension

11.  Dicloxacillin Sodium for Oral Suspension

12.  Dihydroxyaluminum Aminoacetate Magma

13.  Doxycycline for Oral Suspension

14.  Doxycycline Calcium Oral Suspension

15.  Erythromycin Estolate Oral Suspension

16.  Erythromycin Estolate for Oral Suspension

17.  Erythromycin Estolate and Sulfisoxazole Acetyl Oral Suspension

18.  Erythromycin Ethylsuccinate Oral Suspension

19.  Erythromycin Ethylsuccinate for Oral Suspension

20.  Erythromycin Ethylsuccinate and Sulfisoxazole Acetyl for Oral Suspension

21.  Estradiol Injectable Suspension

22.  Estrone Injectable Suspension

23.  Ferumoxsil Oral Suspension

24.  Fluorometholone Ophthalmic Suspension

25.  Furazolidone Oral Suspension

26.  Gentamicin and Prednisolone Acetate Ophthalmic Suspension

27.  Griseofulvin Oral Suspension

28.  Hydrocortisone Injectable Suspension

29.  Hydrocortisone Acetate Injectable Suspension

30.  Hydrocortisone Acetate Ophthalmic Suspension

31.  Hydroxyzine Pamoate Oral Suspension

32.  Ibuprofen Oral Suspension

33.  Imipenem and Cilastatin for Injectable Suspension

34.  Indomethacin Oral Suspension

35.  Isoflupredone Acetate Injectable Suspension

36.  Ketoconazole Oral Suspension

37.  Loracarbef for Oral Suspension

38.  Magaldrate Oral Suspension

39.  Magaldrate and Simethicone Oral Suspension

40.  Milk of Magnesia

41.  Magnesium Carbonate and Sodium Bicarbonate for Oral Suspension

42.  Mebendazole Oral Suspension

43.  Medroxyprogesterone Acetate Injectable Suspension

44.  Megestrol Acetate Oral Suspension

45.  Meprobamate Oral Suspension

46.  Methacycline Hydrochloride Oral Suspension

47.  Amoxicillin for Injectable Suspension

48.  Methenamine Mandelate Oral Suspension

49.  Amoxicillin for Oral Suspension

50.  Amoxicillin Oral Suspension

51.  Methyldopa Oral Suspension

52.  Amoxicillin and Clavulanate Potassium for Oral Suspension

53.  Methylprednisolone Acetate Injectable Suspension

54.  Minocycline Hydrochloride Oral Suspension

55.  Nalidixic Acid Oral Suspension

56.  Naproxen Oral Suspension

57.  Natamycin Ophthalmic Suspension

58.  Ampicillin for Injectable Suspension

59.  Ampicillin for Oral Suspension

60.  Neomycin Sulfate and Hydrocortisone Otic Suspension

61.  Neomycin Sulfate and Hydrocortisone Acetate Ophthalmic Suspension

62.  Ampicillin and Probenecid for Oral Suspension

63.  Neomycin and Polymyxin B Sulfates and Dexamethasone Ophthalmic Suspension

64.  Neomycin and Polymyxin B Sulfates and Hydrocortisone Ophthalmic Suspension

65.  Neomycin and Polymyxin B Sulfates and Hydrocortisone Otic Suspension

66.  Neomycin and Polymyxin B Sulfates and Hydrocortisone

67.  Acetate Ophthalmic Suspension

68.  Neomycin and Polymyxin B Sulfates and Prednisolone

69.  Acetate Ophthalmic Suspension

70.  Neomycin Sulfate and Prednisolone Acetate Ophthalmic

71.  Nitrofurantoin Oral Suspension

72.  Nystatin Oral Suspension

73.  Nystatin for Oral Suspension

74.  Oxfendazole Oral Suspension

75.  Oxytetracycline and Nystatin for Oral Suspension

76.  Oxytetracycline Calcium Oral Suspension

77.  Oxytetracycline Hydrochloride and Hydrocortisone Acetate

78.  Penicillin G Benzathine Injectable Suspension

79.  Penicillin G Benzathine Oral Suspension

80.  Penicillin G Benzathine and Penicillin G Procaine Injectable

81.  Penicillin G Procaine Injectable Suspension

82.  Penicillin G Procaine for Injectable Suspension

83.  Penicillin G Procaine and Dihydrostreptomycin Sulfate Injectable Suspension

84.  Penicillin G Procaine, Dihydrostreptomycin Sulfate

85.  Chlorpheniramine Maleate, and Dexamethasone Injectable Suspension

86.  Penicillin G Procaine, Dihydrostreptomycin Sulfate

87.  Prednisolone Injectable Suspension

88.  Penicillin G Procaine, Neomycin and Polymyxin B Sulfates

89.  Hydrocortisone Acetate Topical Suspension

90.  Penicillin V for Oral Suspension

91.  Penicillin V Benzathine Oral Suspension

92.  Phenytoin Oral Suspension

93.  Chromic Phosphate P 32 Suspension

94.  Prednisolone Acetate Injectable Suspension

95.  Prednisolone Acetate Ophthalmic Suspension

96.  Prednisolone Tebutate Injectable Suspension

97.  Primidone Oral Suspension

98.  Progesterone Injectable Suspension

99.  Propoxyphene Napsylate Oral Suspension

100.        Propyliodone Injectable Oil Suspension

101.        Psyllium Hydrophilic Mucilloid for Oral Suspension

102.        Pyrantel Pamoate Oral Suspension

103.        Pyrvinium Pamoate Oral Suspension

104.        Rifampin Oral Suspension

105.        Rimexolone Ophthalmic Suspension

106.        Atovaquone Oral Suspension

107.        Simethicone Oral Suspension

108.        Sodium Polystyrene Sulfonate Suspension

109.        Spectinomycin for Injectable Suspension

110.        Aurothioglucose Injectable Suspension

111.        Sulfacetamide Sodium Topical Suspension

112.        Sulfacetamide Sodium and Prednisolone Acetate Ophthalmic Suspension

113.        Sulfadimethoxine Oral Suspension

114.        Sulfamethizole Oral Suspension

115.        Sulfamethoxazole Oral Suspension

116.        Sulfamethoxazole and Trimethoprim Oral Suspension

117.        Sulfisoxazole Acetyl Oral Suspension

118.        Testosterone Injectable Suspension

119.        Tetracycline Oral Suspension

120.        Bacampicillin Hydrochloride for Oral Suspension

121.        Tetracycline Hydrochloride Ophthalmic Suspension

122.        Tetracycline Hydrochloride Oral Suspension

123.        Thiabendazole Oral Suspension

124.        Thioridazine Oral Suspension

125.        Tobramycin and Dexamethasone Ophthalmic Suspension

126.        Tobramycin and Fluorometholone Acetate Ophthalmic

127.        Triamcinolone Acetonide Injectable Suspension

128.        Triamcinolone Diacetate Injectable Suspension

129.        Triamcinolone Hexacetonide Injectable Suspension

130.        Triflupromazine Oral Suspension

131.        Trisulfapyrimidines Oral Suspension

132.        Barium Sulfate for Suspension

133.        Barium Sulfate Suspension

134.        Betamethasone Sodium Phosphate and Betamethasone

135.        Brinzolamide Ophthalmic Suspension

136.        Calcium Carbonate Oral Suspension

137.        Calcium and Magnesium Carbonates Oral Suspension

138.        Carbamazepine Oral Suspension

139.        Cefaclor for Oral Suspension

140.        Cefadroxil for Oral Suspension

141.        Cefixime for Oral Suspension

142.        Cefpodoxime Proxetil for Oral Suspension

143.        Cefprozil for Oral Suspension

144.        Cellulose Sodium Phosphate for Oral Suspension

145.        Cephalexin for Oral Suspension

146.        Cephradine for Oral Suspension

147.        Chloramphenicol and Hydrocortisone Acetate for Ophthalmic

148.        Chloramphenicol Palmitate Oral Suspension

149.        Chlorothiazide Oral Suspension

150.        Cholestyramine for Oral Suspension

151.        Ciclopirox Olamine Topical Suspension

152.        Clarithromycin for Oral Suspension

153.        Clindamycin Phosphate Topical Suspension

154.        Colestipol Hydrochloride for Oral Suspension

155.        Colistin Sulfate for Oral Suspension

156.        Colistin and Neomycin Sulfates and Hydrocortisone Acetate

157.        Corticotropin Zinc Hydroxide Injectable Suspension

158.        Cortisone Acetate Injectable Suspension

159.        Demeclocycline Oral Suspension

160.        Desoxycorticosterone Pivalate Injectable Suspension

161.        Dexamethasone Ophthalmic Suspension

162.        Dexamethasone Acetate Injectable Suspension

163.        Megestrol Acetate Oral Suspension

164.        Amoxicillin and Clavulanate Potassium for Oral Suspension

165.        Atovaquone Oral Suspension

166.        Brinzolamide Ophthalmic Suspension

167.        Cefpodoxime Proxetil for Oral Suspension

168.        Ferumoxsil Oral Suspension

169.        Megestrol Acetate Oral Suspension

170.        Sulfadimethoxine Oral Suspension

171.        Methylprednisolone Acetate for Rectal Suspension

172.        Ketoconazole Oral Suspension

173.        Cellulose Sodium Phosphate for Oral Suspension

174.        Hydrocortisone Rectal Suspension

175.        Tetracycline Hydrochloride Oral Suspension

176.        Sulfacetamide Sodium Topical Suspension

177.        Methylprednisolone Acetate for Rectal

 

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)	Strassenbu	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
7	Clavotrol 31.25mg Amoxycillin and 125mg Clauvulanic acid per 5 ml	Astra-Zeneca	Amoxycillin and Clauvulanic acid Two teaspoonful	Upper/lower respiratory tract infections

 

 

Definition of Suspension Pharmaceutical Liquid Dosage Form
A Pharmaceutical suspension is a coarse dispersion in which internal phase is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles having a specific range of size which is maintained uniformly through out the suspending vehicle with aid of single or combination of suspending agent. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.

Suspension is a preparation containing the solid ingredients in the form of subtle and not soluble, dispersed in a liquid carrier. Substances dispersed should be fine, should not be quick to settle, and when shake slowly, the precipitate should be dispersed again. Additives may be added to ensure the stability of the suspension but the suspension viscosity must ensure the preparation easy to shake and pour.

Some suspensions are prepared and ready for use, while others are prepared as solid mixtures intended for constitution just before use with an appropriate vehicle.

In the manufacture of suspension must be considered some factors, among other :

• the nature of the dispersed particles (degree of wetting of particles)

• wetting agent

• dispersing medium

• other components such as dyes, flavoring and preservatives used.

The suspension must be packed in appropriate containers above the liquid so it can easily shaken and poured. On the label must be printed “Shake and stored in closed and cool place”.

 

Classification of Suspension 

Based On General Classes

• Oral suspension

• Externally applied suspension : Topical suspensions, Otic Suspension, Ophtalmic suspensions

• Parenteral suspension

 

Based on Proportion of Solid Particles
• Dilute suspension (2 to10%w/v solid)

• Concentrated suspension (50%w/v solid)

Based on Electrokinetic Nature of Solid Particles

• Flocculated suspension

• Deflocculated suspension

Based on Size of Solid Particles

• Colloidal suspension (< 1 micron)

• Coarse suspension (>1 micron)

• Nano suspension (10 ng)

Advantages and Disadvantages of Suspension as Pharmaceutical Dosage Form

Advantages of Suspension

• Suspension can improve chemical stability of certain drug. E.g.Procaine penicillin G

• Drug in suspension exhibits higher rate of bioavailability than other dosage forms. bioavailability is in following order,

• Solution > Suspension > Capsule > Compressed Tablet > Coated tablet

• Duration and onset of action can be controlled. E.g.Protamine Zinc-Insulin suspension

• Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol

Disadvantages of Suspension

• Physical stability, sedimentation and compaction can causes problems.

• Susceptible to degradation and the possibility of chemical reaction between the ingredients in the solution where there is water as a catalyst.

• It is bulky sufficient care must be taken during handling and transport.

• It is difficult to formulate

• Uniform and accurate dose cannot be achieved unless suspension are packed in unit dosage form

Good and Desired Properties of Pharmaceutical Suspensions

• The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking.

• It should be easy to pour yet not watery and no grittiness.

• It should have pleasing odour, colour and palatability.

• Good syringeability.

• It should be physically, chemically and microbiologically stable.

• Parenteral/Ophthalmic suspension should be sterilizable.

Why Choose Suspensions as Pharmaceutical Dosage Form?

The Applications of suspensions:

• Suspension is usually applicable for drug which is insoluble or poorly soluble (Prednisolone suspension)

• To prevent degradation of drug or to improve stability of drug. (Oxytetracycline suspension)

• To mask the taste of bitter of unpleasant drug. (Chloramphenicol palmitate suspension)

• Suspension of drug can be formulated for topical application (Calamine lotion)

• Suspension can be formulated for parentral application in order to control rate of drug absorption.

• Vaccines as a immunizing agent are often formulated as suspension (Cholera vaccine)

• X-ray contrast agent are also formulated as suspension. (Barium sulphate for examination of alimentary trac)

 

·        Dispersion system consist of (1)- particulate matter (dispersed phase) (2)- continuous medium (dispersion medium)

·        Classification of dispersed systems (based on particle size)

 

1	Molecular dispersion	< 1 nm	Oxygen molecules, glucose solution
2	Colloidal dispersion	1nm- 0.5 mm	Natural polymers
3	Coarse dispersion	> 0.5 mm	Suspension and emulsion

·        Definition of suspension: Pharmaceutical suspensions are uniform dispersions of solid drug particles in a vehicle in which the drug has minimum solubility. Particle size of the drugs may vary from one formulation to the other depending on the physicochemical characteristics of the drug and the rheological properties of the formulation.

·        A suspension containing particles between 1 nm to 0.5 µm in size is called colloidal suspension. When the particle size is between 1 to 100 µm, the suspension is called coarse suspension. Most of the pharmaceutical suspensions are coarse suspension.

·        Majority of the marketed suspensions are available as dry powders that must be reconstituted before administration but occasionally some products in the market are ready-to-use. The first products are not very stable once reconstituted; must be used within 7 to 10 days.

Examples of Pharmaceutical Suspensions:

A.     Antacid oral suspensions Antibacterial oral suspension

B.      Dry powders for oral suspension (antibiotic)

C.      Analgesic oral suspension

D.     Anthelmentic oral suspension

E.      Anticonvulsant oral suspension

F.       Antifungal oral suspension

 

Pharmaceutical applications of suspensions:

 

1)    Insoluble drug or poorly soluble drugs which required to be given orally in liquid dosage forms ( in case of children, elderly, and patients have difficulty in swallowing solids dosage forms)

2)    To over come the instability of certain drug in aqueous solution:

a.     Insoluble derivative formulated as suspension

An example is oxytetracycline HCL Þ calcium salt

                          (instable)                                            (stable)

b.     Reduce the contact time between solid drug particles and dispersion media Þ increase the stability of drug like Ampicillin by making it as reconstituted powder.

c.      A drug that degraded in the presence of water Þ suspended ion-aqueous vehicles. Examples are phenoxymethypencillin/ coconut oil   and tetracycline HCL/ oil

3)     To mask the taste: 

Examples are paracetamol suspension (more palatable) and chloramphenicol palmitate.

4)    Some materials are needed to be present as finely divided forms to increase the surface area. Fore example, Mg carbonate and Mg trisilcate are used to adsorb some toxins

5)    Suspension can be used topical applications:

An example is calamine lotion Bp Þ after evaporation of dispersing media; the active agent will be left as light deposit

6)    Can be used for parentral administration Þ intramuscular (i.m.) to control arte of absorption 

7)    In vaccines

 

 

 

 

 

 

 

e.g. Diphtheria and Tetanus vaccines

 

 

8)    X-ray contrast media: an example is oral and rectal administration of propyliodone

9)    In aerosol  Þ suspension of active agents in mixture  of propellants

Qualities of ideal suspension:  A well-formulated suspension should have the following properties:

1)    The dispersed particles should not settle readily and the settle should redispersed immediately on shacking. Ideally, the particles in a suspension should not sediment at any time during the storage period. Unfortunately, the present technology does not allow us to prepare such a suspension. Since one cannot completely avoid the sedimentation of particles, it is desirable that the particles should settle slowly. The easy redispersion of sedimented particles in a suspension is important for the uniformity of dose.

2)    The particle should not form a cake on settling

3)    The viscosity should be such that the preparation can be easily poured. A highly viscous suspension would make pouring difficult.

4)    It should be chemically and physically stable

5)    It should be palatable (orally)

6)    It should be free from gritting particles (external use)

 

 

 

 

FACTORS TO BE CONSIDERED

A-  Wetting of the particles:

 

 

 

·        It is difficult to disperse solid particles in a liquid vehicle due to the layer of adsorbed air on the surface. Thus, the particles, even high density, float on the surface of the liquid until the layer of air is displaced completely. The use of wetting agent allows removing this air from the surface and to easy penetration of the vehicle into the pores. Alcohol, glycerin, and propylene glycol are frequently used to remove adsorbed air from the surface of particles when aqueous vehicle is used to disperse the solids. When the particles are dispersed in a non-aqueous vehicle, mineral oil is used as wetting agent. Irrespective of the method of preparation, the solid particles must be wetted using any of the suitable wetting agents before the dispersion in the vehicle.

·        Solid particles that are not easily wetted by aqueous vehicle after the removable of the adsorbed air are referred to as hydrophobic particles. It is necessary to reduce the interfacial tension between the particles and the vehicle by using surface-active agents to improve the wettibility. Sodium lauryl sulfate is one of the most commonly used surface-active agents. Hydrophilic particles are easy to disperse in the aqueous vehicle once the adsorbed air is removed. Hydrophilic particles do not require the use of surface-active agents.

·        The main function of wetting agents: (1)- to reduce the contact angle between surface of solid particles and wetting liquid via displace the air in the voids (2)- surfactant

·        Examples of wetting agents are tragcanth mucilage, glycerin, glycols, bentonite and polysorbates.

·        Excessive amounts of wetting agents can cause foaming or undesirable taste or odor.

·        Contact angle can be used to measure wettibility, if the angle approximately equal or more than 90 ⁰, particles are floating well out of fluid.

B-Particle size:

·        Particle size of any suspension is critical and must be reduced within the range as determined during the preformulation study.

·         Too large or too small particles should be avoided. Larger particles will settle faster at the bottom of the container and too fine particles will easily form hard cake at the bottom of the container.

·        The particle size can be reduced by using mortar and pastel but in large-scale preparation different milling and pulverization equipments are used.

·        Limitation in particle size reduction (after reaching a certain particle size):

1.     Expensive and time consuming

2.     Movement of small particles due to brownian motion cause particles to aggregate, settle, form hard cake that it is difficult to redispersed 

C-Sedimentation:

·       

Sedimentation of particles in a suspension is governed by several factors: particle size, density of the particles, density of the vehicle, and viscosity of the vehicle. The velocity of sedimentation of particles in a suspension can be determined by using the Stoke’s law:

 

 

          Where:

          v = velocity of sedimentation

          d = diameter of the particle

          g = acceleration of gravity

_­1 = density of the particle

_­ = density of the vehicle

 = viscosity of the vehicle

·        According to the Stoke’s equation, the velocity of sedimentation of particles in a suspension can be reduced by decreasing the particle size and also by minimizing the difference between the densities of the particles and the vehicle. Since the density of the particles is constant for a particular substance and cannot be changed, the changing of the density of the vehicle close to the density of the particle would minimize the difference between the densities of the particles and the vehicle. The density of the vehicle of a suspension can be increased by adding the following substances either alone or in combination: polyethylene glycol, polyvinyl pyrolidone, glycerin, sorbitol, and sugar.

·        The viscosity of the vehicle also affects the velocity of sedimentation. It decreases as the viscosity of the vehicle increases. The viscosity and density of any vehicle are related to each other, so any attempt to change one of these parameters will also change the other one.

D-Electrokinetic Properties

·        Dispersed solid particles in a suspension may have charge in relation to their surrounding vehicle. These solid particles may become charged through one of two situations.

1.     Selective adsorption of a particular ionic species present in the vehicle. This may be due to the addition of some ionic species in a polar solvent. Consider a solid particle in contact with an electrolyte solution. The particle may become positively or negatively charged by selective adsorption of either cations or anions from the solution.

2.     Ionization of functional group of the particle. In this situation, the total charge is a function of the pH of the surrounding vehicle.

 

 

 

 

 

 

 

 

 

 

 

 

 

·        In the above figure, the particle is positively charged and the anions present in the surrounding vehicle are attracted to the positively charged particle by electric forces that also serve to repel the approach of any cations. The ions that gave the particle its charge, cations in this example, are called potential-determining ions. Immediately adjacent to the surface of the particle is a layer of tightly bound solvent molecules, together with some ions oppositely charged to the potential-determining ions, anions in this example. These ions, oppositely charged to the potential-determining ions, are called counterions or gegenions. These two layers of ions at the interface constitute a double layer of electric charge. The intensity of the electric force decreases with distance from the surface of the particle. Thus, the distribution of ions is uniform at this region and a zone of electrolneutrality is achieved.

E-Nernst and zeta potential-

·        The difference in electric potential between the actual surface of the particle and the electroneutral region is referred to as Nernst potential. Thus, Nernst potential is controlled by the electrical potential at the surface of the particle due to the potential determining ions. Nernst potential has little effect in the formulation of stable suspension.

·        The potential difference between the ions in the tightly bound layer and the electroneutral region, referred to as zeta potential (see the figure), has significant effect in the formulation of stable suspension. Zeta potential governs the degree of repulsion between adjacent, similar charged, solid dispersed particles.

·         If the zeta potential is reduced below a critical value, the force of attraction between particles succeed the force of repulsion, and the particles come together. This phenomenon is referred to as flocculation and the loosely packed particles are called floccule.

F-Deflocculation and flocculation:

·        Deflocculation of particles is obtained when the zeta potential is higher than the critical value and the repulsive forces supersede the attractive forces.

 

·        The addition of a small amount of electrolyte reduces the zeta potential. When this zeta potential goes below the critical value, the attractive forces supersede the repulsive forces and flocculation occurs.

·        The following table illustrates the relative properties of flocculated and Non-flocculated suspension

 

 

 

 

Flocculated Non-flocculated Particles forms loose aggregates and form a network like structure Rate of sedimentation is high Sediment is rapidly formed Sediment is loosely packed and doesn’t form a hard cake Sediment is easy to redisperse Suspension is not pleasing in appearance The floccules stick to the sides of the bottle Particles exist as separate entities Rate of sedimentation is slow Sediment is slowly formed Sediment is very closely packed and a hard cake is formed Sediment is difficult to redisperse Suspension is pleasing in appearance They don’t stick to the sides of the bottle

 

 

 

 

 

 

 

 

 

 

·        It should be noted that the deflocculated suspensions should be avoided because of the formation of irreversible solid hard cake. Although flocculated suspensions sediment faster and form a clear supernatant, these are easy to redisperse.

·        The following figure shows the effect of period of standing on flocculated and deflocculated suspension:

 

G-Thixotropic suspension-A thixotropic suspension is the one that is viscous during storage but loses consistency and become fluid upon shaking. A well-formulated thixotropic suspension would remain fluid long enough for the easy dispense of a dose but would slowly regain its original viscosity within a short time.

 

Method of preparation

The preparation of suspension includes three methods: (1) use of controlled flocculation and (2) use of structured vehicle (3)- combination of both of the two pervious methods. The following is the general guidelines to suspension formulation:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A-Structured vehicle

·        Structured vehicles called also thickening or suspending agents. They are aqueous solutions of natural and synthetic gums. These are used to increase the viscosity of the suspension.

·        Methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, acacia, gelatin and tragacanth are the most commonly used structured vehicle in the pharmaceutical suspensions. These are non-toxic, pharmacologically inert, and compatible with a wide range of active and inactive ingredients.

·        These structured vehicles entrapped the particle and reduces the sedimentation of particles. Although, these structured vehicles reduces the sedimentation of particles, not necessarily completely eliminate the particle settling. Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage.

·        The risk of caking may be eliminated by forming flocculated particles in a structured vehicle.

·        Note that too high viscosity isn’t desirable and it causes difficulty in pouring and administration. Also, it may affect drug absorption since they adsorb on the surface of particle and suppress the dissolution rate.

·        Structured vehicles are pseudoplastic or plastic in their rheological behaviors

·        In the following table is summary of suspending agents

B-Controlled flocculation

·        Controlled flocculation of particles is obtained by adding flocculating agents, which are (1)-electrolytes (2)- surfactants (3)- polymers

              Typical Flocculation agents

 

 

1-Addition of electrolyte to control flocculation

 

 

·        Most frequently used flocculating agents are electrolytes, which reduce the zeta potential surrounding the solid particles. This leads to decrease in repulsion potential and makes the particle come together to from loosely arrange structure (floccules).

·         The flocculating power increases with the valency of the ions. As for example, calcium ions are more powerful than sodium ions because the velency of calcium is two whereas sodium has valency of one.

·        The following figure shows the flocculation of a bismuth subnitrate suspension by means of monobasic potassium phosphate (flocculating agents).

 

The particles of bismuth subnitrate are positively charged originally. By addition of electrolyte (phosphate, -ve) the zeta potential fell dowear zero. At this neutralization value noted absence of caking. Continuing adding of negatively charged electrolyte resulted in changing the overall zeta potential of particles to negative and formation of cake.

 

 

 

2-Addition of surfactant to control flocculation

 

 

·        Both ionic and non-ionic surfactants could be used to control flocculation

·        Surfactant adsorbed on the surface of solid particle leading to neutralization or reversing the surface charge

·        Since most of surfactants act as wetting agents and flocculating agents, the amount of surfactant to be added should be calculated based on this fact.

3- Addition of polymers to control flocculation

 

 

·        Polymers are long-chained, high molecular-weight compounds containing active groups spaced along their length.

·        These agents promote flocculation through adsorption of part of the chain on the surface of particle and the remaining part project out into the dispersion medium. Formation of bridge between the projected parts leads to formation of floccules (see the following figure)

 

 

 

 

 

 

 

 

 

 

·        Hydrophilic polymers also act as protective colloids resulting in coated particles have fewer tendencies to form cake.

·        Polymers exhibits pseudoplastic flow in solution that promotes the physical stability of suspension

·        Some polymers like gelatin stabilize the suspension based on the pH and ionic strength of dispersion medium (carry charge)

·        An example of polymer is xanthan gum

·        Positively charged Liposomes (vesicles of phospholipids) adsorbed oegatively charged particles to prevent caking formation.

 

B-   Flocculation in structured vehicles

·        Sometimes suspending agents can be added to flocculated suspension to retard sedimentation

·        Examples of these agents are Carboxymethylcellulose (CMC), Carbopol 934, Veegum, and bentonite

·       

It should be noted that physical incompatibility can limit the addition of suspending agent

 

 

 

 

 

 

 

 

 

 

 

 

·        Under this circumstance, the formulator can protect particle by changing sign of particle from negative to positive using protective colloids. This is illustrated by the following figure:

 

Ready to use suspension and extemporaneous preparation

 

·        Ready to use suspension is manufactured as you learn in this class

·        Extemporaneous suspension is unordinary preparation that pharmacist wants to prepare to a water-insoluble drug that exists in tablet or capsule for situations when liquid dosage from is needed. The following steps could be done to prepare extemporaneous suspension:

1.     Put the tablet or capsule content in mortar and crush it

2.     Add the suspending vehicle slowly with mixing

3.     You could add any flavoring agent or coloring agent available

4.      Example of ready available suspending agents are Roxanes diluent and Cologel 

Evaluation of suspensions

 

Suspensions are evaluated by determining their physical stability. Two useful parameters for the evaluation of suspensions are sedimentation volume and degree of flocculation. The determination of sedimentation volume provides a qualitative means of evaluation. A quantitative knowledge is obtained by determining the degree of flocculation.

1.     Sedimentation volume: (F), sedimentation volume of a suspension is expressed by the ratio of the equilibrium volume of the sediment, V_u, to the total volume, V_o of the suspension.

                                           F = V_u/V_o

The value of F normally lies between 0 to 1 for any pharmaceutical suspension. The value of F provides a qualitative knowledge about the physical stability of the suspension.

 

F= 1	No sedimentation, no clear supernatant
F =0.5	50% of the total volume is occupied by sediment
F > 1	Sediment volume is greater than the original volume due to formation of floccules which are fluffy and loose

 

2.     Degree of flocculation: (ß), degree of flocculation is the ratio of the sedimentation volume of the flocculated suspension, F, to the sedimentation volume of the deflocculated suspension, F_¥

                                      ß = F / F_¥

                                           (V_u/V_o) _flocculated

                                      ß = ——————–

                                           (V_u/V_o) _{deflocculated}

When the total volume of both the flocculated and the deflocculated suspensions are same; the degree of flocculation, ß = (V_u)_floc/(V_u)_defloc .The minimum value of ß is 1; this is the case when the sedimentation volume of the flocculated suspension is equal to the sedimentation volume of deflocculated suspension. ß is more fundamental parameter than F since it relates the volume of flocculated sediment to that in a deflocculated system 

Rheological consideration: viscosity of suspension affects and controls the settling of dispersed particle. It, also, affects pouring the product from bottle and spreading qualities in case of lotion. Best viscosity for suspension is to be high during storage to prevent sedimentation and to be low at high shear to ease the administration.  Thus, pseudoplastic/ thixotrpic and plastic/ thixotropic suspending agents could be use for this purpose. Combination of two suspending agents can enhance the stability of suspension

Ingredients of suspension:

1.     Active ingredient 2.     Wetting agent 3.     Suspending agent 4.     Flocculated agent 5.     Protective colloid 6.     Sweetener

7.     Preservative 8.     Buffer system 9.     Color agent 10.                       Flavor agent 11.                       Antifoaming agent 12.                       Preservative

 

 

 

 

 

Agent

Class

Typical buffering agents, flavors, colorants, and preservative used in suspensions:

Buffer         Flavor           Colorant       Preservative

Ammonia solution Citric acid Fumaric acid Sodium citrate   Cherry Grape Methyl salicylatte Orange Peppermint   D &C Red No. 33 FD &C Red No. 3 D &C Yellow No. 33   Butylparaben Methylparaben Propylparaben Sodium benzoate

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Packaging and Storage of Suspensions:

1) Should be packaged in wide mouth containers having adequate air space above the liquid.

2) Should be stored in tight containers protected from: freezing, excessive heat & light

3) Label: “Shake Before Use” to ensure uniform distribution of solid particles and   thereby uniform and proper dosage.

4) Stored in room temperature if it is dry powder (25 ⁰C). It should be stored in the refrigerator after opening or reconstitute (freezing should be avoided to prevent aggregation)

 

Stability of suspension

 

1.     Appearance, color, odor and taste 2.     pH 3.     Specific gravity 4.     Sedimentation arte 5.     Sedimentation volume 6.     Zeta potential measurement 7.     Compatibility with container 8.     Compatibility with cap liner 9.     Microscopic examination 10.            Determination crystal size 11.            Determination uniform drug distribution

A-Physical stability:

 

 

 

 

 

 

 

 

 

 

B-Chemical stability:

1.     Degradation of active ingredient 2.     Viscosity change 3.     antimicrobial activity: a.     Incompatibility with preservative b.     Degradation of preservative c.      Adsorption of preservative onto drug particle

 

 

 

 

•  Suspensions are preparations containing finely divided, undissolved drug particles dispersed throughout a liquid vehicle.

•  depending on the concentration and size of the undissolved suspended particles, suspensions  assume a degree of opacity.

•  Suspensions are one type of disperse systems, common among pharmaceutical preparations.

•  The suspended particles are referred to as the ………………………, the ………………………, or ……………………….

•  The vehicle is termed the ……………………… or ……………………… phase.

•  The particles of the disperse phase may be colloidal (about 1 µm or less), fine (about 1 f.Lm), or coarse (lOO f.Lm).

•  Particles of greater density have a tendency to settle and form a sediment.

•  The addition of suspending agents, which add viscosity to the vehicle, is one method of maintaining the dispersed phase in suspension.

•  Before administration, it is essential to redistribute any ……………………… particles to assure uniform dosing.

•  Suspensions are formulated for administration by a number of routes, including:

1.                     oral;

2.                      otic;

3.                      ophthalmic;

4.                      epidermal;

5.                      parenteral (by injection).

•  Ophthalmic suspensions must be:

•  ……………………… and the suspension must be ……………………… or ………………………to eliminate any grittiness that might cause irritation

 

 

 

Antioxidants UsePharmaceutical Suspension

Antioxidants are included in pharmaceutical solutions or suspensions to enhance the stability of therapeutic agents that are susceptible to chemical degradation by oxidation. Typically antioxidants are molecules that are redox systems that exhibit higher oxidative potential than the therapeutic agent or, alternatively, are compounds that inhibit free radical-induced drug decomposition.

Typically in aqueous solution antioxidants are oxidised (and hence degraded) in preference to the therapeutic agent, thereby protecting the drug from decomposition. Both water-soluble and
water-insoluble antioxidants are commercially available, the choice of these being performed according to the nature of the formulation.

Suitable antioxidants used are as follows.

• Ascorbic acid derivatives such as ascorbic acid, erythorbic acid, Na ascorbate.

• Thiol derivatives such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol, dithiothreitol, glutathione

• Tocopherols

• Butylated hydroxyanisole (BHA)

• Butylated hydroxytoluene (BHT)

• Sulfurous acid salts such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite, sodium

• metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate, and sodium thiosulfate.

• Nordihydroguaiaretic acid

Antioxidants used for aqueous formulations include: sodium sulphite, sodium metabisulphite, sodium formaldehyde sulphoxylate and ascorbic acid.

Antioxidants used in oil-based solutions include: butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and propyl gallate.

Typically antioxidants are employed in low concentrations (0.2% w/w) and it is usual for the concentration of antioxidant in the finished product to be markedly less than the initial concentration, due to oxidative degradation during manufacture of the dosage form.

Antioxidants may also be employed in conjunction with chelating agents, e.g. ethylenediamine tetraacetic acid, citric acid, that act to form complexes with heavy-metal ions, ions that are normally involved in oxidative degradation of therapeutic agents.

 

Pre Formulation for Suspensions : Introduction and Requirement

Suspension is a preparation containing the solid ingredients in the form of subtle and not soluble, dispersed in a liquid carrier. The main aim in the preparation of suspension is to keep the suspended particles dispersed and for this number of components which belongs to the vehicle itself.

Structured Vehicle

For the need of a stable suspension, the term Structured vehicle is most important for formulation view and stability criteria. The main disadvantage of suspension dosage form that limits its use in the routine practice is its stability during storage for a long time. The structured vehicle is the vehicle in which viscosity of the preparation under the static condition of very low shear on storage approaches infinity. The vehicle behaves like a ‘false body’, which is able to maintain the particles suspended which is more or less stable.

Structured vehicle concept is applicable only to deflocculated suspensions, where hard solid cake forms due to settling of solid particles and they must be redispersed easily and uniformly at the time of administration. Flocculated suspension settled floccules get easily redispersed on shaking that is why structured vehicle concept is not applicable.

 

Particle size

The particle size play a key role in the formulation of suspension, particles must be of small size. This decreases rate of sedimentation. Particle size for the preparation for parenteral and ophthalmic use, is better less than 5microns. More than 25microns cause blockage of the needle. Spherical shape is best for suspension formulation. And there will be the crystal growth on standing for certain period of time. This is because as the temperature decreases, the solubility decreases and leads to formation of crystallization. Its better to take powder having less variation in their size. Because the small particles have more solubility and so their size decreases continuously, whereas the size of larger particles will keep on increasing.

Wetting agents

Wetting agents are surfactants. They function by reducing the contact angle and interfacial tension between the dispersed phase and dispersed medium. A liquid phase containing suitable wetting agent helps in passing of liquid through the powder when it is added and hence it displaces the air around the particles. Non-ionic surfactants functioning as wetting agents should posses HLB value between 7 to 10. Eg., Sodium lauryl sulphate – anionic surfactant; Sorbitan esters- Non-ionic surfactant.

 

Flocculating agents

Flocculating agents is Non-ionic wetting agents decreases the interference tension between the particles and liquid medium so that deflocculation is achieved. The ionic surfactant can produce both flocculated and deflocculated suspension. It is based on the charge on particle. Electrolytes generally reduce the zeta potential and increase in flocculation. Ionic and non-ionic surfactants can cause flocculation. Various polymers will form network and assist in flocculation.

In addition agents to increase viscosity and protective colloids which form a hydration layer on the surface of dispersed phase. They function as protective colloid in low concentration and at more than 0.1% concentration, they increase the viscosity of dispersion medium.

 

Rheological considerations of suspensions

 The viscosity of the medium is to be considered, because the settling of the particles depends on visocity. Next comes, when the suspension is changed from one container to another or during shaking, the variation in the flow properties should be considered. In case of suspensions intended for external use, the spreading capability should be considered. An agent that becomes a gel during storage conditions and when we shake, looses its viscosity is best.

 

Preservatives Used in Pharmaceutical Suspensions

The naturally occurring suspending agents such as tragacanth, acacia, xanthan gum are susceptible to microbial contamination. If suspension is not preserved properly then the increase in microbial activity may cause stability problem such as loss in suspending activity of suspending agents, loss of color, flavor and odor, change in elegance etc. Antimicrobial activity is potentiated at lower pH.

 

Preservatives are included in pharmaceutical dosage form to control the microbial bioburden of the formulation. Ideally, preservatives should exhibit the following properties:

• possess a broad spectrum of antimicrobial activity encompassing Gram-positive and Gram-negative bacteria and fungi

• be chemically and physically stable over the shelf-life of the product

• have low toxicity.

• should not be Adsorbed on to the container

• should be compatible with other formulation additives.

• Its efficacy should not be decreased by pH.

This occurs most is commonly in antacid suspensions because the pH of antacid suspension is 6-7 at which parabens, benzoates and sorbates are less active. Parabens are unstable at high pH value so parabens are used effectively when pH is below 8.2. Most commonly observed
incompatibility of PABA (Para amino benzoic acid) esters is with non-ionic surfactant, such as polysorbate 80, where PABA is adsorbed into the micelles of surfactant.

 

The combination of two or more preservative has many advantages in pharmaceutical system such as

• Wide spectrum of activity

• Less toxicity

• Less incidence of resistance

• Preservatives can be used in low concentration.

Propylene glycol is added to emulsions containing parabens to reduce loss to micelles. 

 

List of Preservatives and Their Optimal Concentration.

 

Name of preservatives	Concentration range
Propyleneglycol	5-10 %
Disodium edentate	0.1 %
Benzalkonium chloride	0.01-0.02 %
Benzoic acid	0.1 %
Butylparaben	0.006-0.05 % oral suspension 0.02-0.4 % topical formulation
Cetrimide	0.005 %
Chlorobutanol	0.5 %
Phenyl mercuric acetate	0.001-0.002 %
Potassium sorbate	0.1-0.2 %
Sodium benzoate	0.02-0.5 %
Sorbic acid	0.05-0.2 %
Methyl paraben	0.015-0.2 %

 

alkyl esters of parahydroxybenzoic acid (0.001–0.2%). Usually a combination of two members of this series is employed in pharmaceutical solutions, typically methyl and propyl parahydroxybenzoates (in a ratio of 9:1). The combination of these two preservatives enhances the antimicrobial spectrum. Now a days, combination of phenylethyl alcohol, phenoxetol and benzalkonium chloride are used in eye drops. EDTA (ethylenediaminetetra-acetate) is also used in combination with other preservative.

 

Factors affecting preservative efficacy in oral suspension

 

The activity of a preservative is dependent on the correct form of the preservative being available in the formulation at the required concentration to inhibit microbial growth (termed the minimum inhibitory concentration: MIC). Unfortunately, in many liquid formulations, the concentration of preservative within the formulation may be affected by the presence of other excipients and by formulation pH. Factors that directly affect the efficacy of preservatives in oral solutions include:

1.     the pH of the formulation

2.     the presence of micelles

3.     the presence of hydrophilic polymers.

The pH of the formulation. In some aqueous formulations the use of acidic preservatives, e.g. benzoic acid, sorbic acid, may be problematic. 

 

Active form of preservative may be ionized or unionized form. For example active form of benzoic acid is undissociated form. The pKa of benzoic acid is 4.2. Benzoic acid is active below pH 4.2 where it remains in unionized form. The activity of the unionised form of the acid in this respect is due to the ability of this form to diffuse across the outer membrane of the microorganism and eventually into the cytoplasm. The neutral conditions within the cytoplasm enable the preservative to dissociate, leading to acidification of the cytoplasm and inhibition of growth.

 

The presence of micelles

If the preservative exhibits lipophilic properties (e.g. the unionised form of acidic preservatives, phenolics, parabens), then partition of these species into the micelle may occur, thereby decreasing the available (effective) concentration of preservative in solution. 

 

The presence of hydrophilic polymers

It has been shown that the free concentration of preservative in oral solution formulations is reduced in the presence of hydrophilic polymers, e.g. polyvinylpyrrolidone, methylcellulose. This is due to the ability of the preservative to interact chemically with the dissolved polymer. As described above, this problem is addressed by increasing the concentration of preservative in the formulation. In certain circumstances the preservative may be incompatible with hydrophilic polymers in the formulation due to an electrostatic interaction. Therefore, cationic hydrophilic polymers should not be used in conjunction with acidic preservatives in oral solution formulations. 

 

Preservative efficacy is expected to be maintained in glass container if the closure is airtight, but now a days plastic container are widely used where great care is taken in selection of preservative. The common problem associated with plastic container is permeation of preservatives through container or adsorption of preservatives to the internal plastic surface. The use of cationic antimicrobial agents is limited because as they contain positive charge they alter surface charge of drug particles. Secondly they are incompatible with many adjuvants. 

 

Most common incidents, which cause loss in preservative action, are,

• Solubility in oil

• Interaction with emulsifying agents, suspending agents

• Interaction with container

• Volatility

 

Buffers in Pharmaceutical Suspensions

To encounter stability problems all liquid formulation should be formulated to an optimum pH. Rheology, viscosity and other property are dependent on the pH of the system. Most liquid systems are stable at pH range of 4-10.

This is the most important in case where API consists of ionizable acidic or basic groups. This is not a problem when API consists of neutral molecule having no surface charge.e.g. Steroids, phenacetin, but control of pH is strictly required as quality control tool.

Buffers are employed within pharmaceutical solutions to control the pH of the formulated product. When buffers dissolved in a solvent, it will resist any change in pH when an acid or base is added. Buffers used should be compatible with other additives and simultaneously they should have less toxicity. Generally pH of suspension should be kept between 7-9.5, preferably between 7.4-8.4. Most commonly used buffers are salts of week acids such as carbonates, citrates, gluconates, phosphate and tartrates.

Amongst these, citric acid and its pharmaceutically acceptable salts, phosphoric acid and its pharmaceutically acceptable salts are commonly used in suspension formulation. However, Na phosphate is most widely used buffer in pharmaceutical suspension system.

Citric acid is most preferable used to stabilize pH of the suspension between 3.5 to 5.0.

L-methionine is most widely used as buffering agent in parenteral suspension. Usual concentration of phosphoric acid salts required for buffering action is between 0.8 to 2.0 % w/w or w/v. But due to newly found super-additive effect of L-methionine, the concentration of phosphoric acid salts is reduced to 0.4 % w/w or w/v or less.

 

Examples of buffer salts used in pharmaceutical solutions include:

• acetates (acetic acid and sodium acetate): circa 1–2%

• citrates (citric acid and sodium citrate): circa 1–5%

• phosphates (sodium phosphate and disodium phosphate): circa 0.8–2%.

Typically pH control is performed:

• to maintain the solubility of the therapeutic agent in the formulated product. The solubility of the vast number of currently available drugs is pH-dependent and, therefore, the solubility of the therapeutic agent in the formulation may be compromised by small changes in pH

• to enhance the stability of products in which the chemical stability of the active agent is pH-dependent.

Buffers have four main applications in suspension systems that are mentioned below:

• Prevent decomposition of API by change in pH.

• Control of tonicity

• Physiological stability is maintained

• Maintain physical stability

For aqueous suspensions containing biologically active compound, the pH can be controlled by adding a pH controlling effective concentration of L-methionine. L-methionine has synergistic effects with other conventional buffering agents when they are used in low concentration.

Preferred amount of buffers should be between 0 to 1 grams per 100 mL of the suspension.

It must be remembered that the buffer system used in solution formulations should not adversely affect the solubility of the therapeutic agent, e.g. the solubility of drugs may be affected in the presence of phosphate salts.

Flavoring and Coloring Agents in Pharmaceutical Suspension

Flavoring and coloring agents are added to increase patient acceptance.

The choice of color should be associated with flavor used to improve the attractiveness by the patient. Only sweetening agent are not capable of complete taste masking of unpleasant drugs therefore, a flavoring agents are incorporated. Color aids in identification of the product. The color used should be acceptable by the particular country.

 

Flavoring Agent in Pharmaceutical Suspensions

The four basic taste sensations are salty, sweet, bitter and sour. It has been proposed that certain flavours should be used to mask these specific taste sensations. In particular:

Most widely used Flavoring agents are as follows:

Acacia	Fennel Oil	Peppermint
Anise Oil	Ginger	Raspberry
Caraway Oil	Glycerin	Rose Oil
Cardamon	Glycerrhiza	Rosemary Oil
Cherry syrup	Honey	Sarsaparilla syrup
Cinnamon	Lavender Oil	Spearmint Oil
Citric acid syrup	Lemon Oil	Thyme Oil
Clove Oil	Mannitol	Vanilla
Cocoa	Nutmeg Oil	Tolu balsam syrup
Coriander Oil	Orange Oil	Wild cherry syrup
Ethyl vanillin	Orange flower water

Usually a combination of flavours is used to achieve the optimal taste-masking property.

Coloring Agents in Pharmaceutical Suspensions

Colours are pharmaceutical ingredients that impart the preferred colour to the formulation. When used in combination with flavours, the selected colour should ‘match’ the flavour of the formulation, e.g. green with mint-flavoured, red for strawberry-flavoured formulations.

Colors are obtained from natural or synthetic sources. Natural colors are obtained from mineral, plant and animal sources. Mineral colors (also called as pigments) are used to color lotions, cosmetics, and other external preparations. Plant colors are most widely used for oral suspension. The synthetic dyes should be used within range of 0.0005 % to 0.001 % depending upon the depth of color required and thickness of column of the container to be viewed in it.

Most widely used colors are as follows.
1. White:

• Titanium dioxide

2. Blue

• Brilliant blue

• Indigo carmine

• Indigo

3. Red

• Amaranth

• Carmine

4. Yellow

• Tartarazine

• Sunset yellow

• Carrots

• Saffron

• Annatto seeds(yellow to orange)

• Madder plant(reddish yellow)

5. Green

• Chlorophyll

6. Brown

• Caramel (brown)

Wetting Agents for Suspensions

The degree of wettability depends on the affinity of drugs for water and whether the solids are hydrophilic of hydrophobic. Hydrophilic solids are easily wetted by water and can increase the viscosity of aqueous
suspensions. Hydrophobic solids repel water but can be wetted by non-polar liquids.

Hydrophilic solids usually can be incorporated into suspensions without the use of wetting agent. The majority of drugs in aqueous suspension are, however, hydrophobic. These are extremely difficult to suspend and frequently float on the surface of water and polar liquid due to entrapped air and poor wetting.

The extent of wetting by water is dependent on the hydrophillicity of the materials. If the material is more hydrophilic it finds less difficulty in wetting by water. Inability of wetting reflects the higher interfacial tension between material and liquid. The interfacial tension must be reduced so that air is displaced from the solid surface by liquid.

Wetting agents are surfactants that lower the interfacial tension and contact angle solid particles and liquid vehicle. Non-ionic surfactants are most commonly used as wetting agents in pharmaceutical suspension. Non-ionic surfactants having HLB value between 7-10 are best as wetting agents.

 

The usual concentration of surfactant varies from 0.05 to 0.5% and depends on the solids content intended for suspension. The use of surfactants as wetting agents will also retard crystal growth. On the other hand, employing surfactants at conc. less than 0.05% can result incomplete wetting and greater than 0.5% may solubilize ultra-fine particles and lead eventually to changes in particle size distribution and crystal growth, also causes stability problem. The high HLB surfactants are also foaming agents; however, foaming is an undesirable property during wetting of suspension for formulation. The concentration used is less than 0.5 %.

Polysorbate-80 is still the most widely used surfactant for suspension formulation because of its lack of toxicity and compatibility with most formulation ingredients. The rate of wetting is often determined by placing measured amount of powder on the undisturbed surface of water containing a given conc. of surfactant and measuring the time required to completely wet and sink the powder.

Ionic surfactants are not generally used because they are not compatible with many adjuvant and causes change in pH.

 

Surfactants 
Surfactants decrease the interfacial tension between drug particles and liquid and thus liquid is penetrated in the pores of drug particle displacing air from them and thus ensures wetting. Surfactants in optimum concentration facilitate dispersion of particles.

Disadvantages of surfactants are that they have foaming tendencies and bitter in taste. Some surfactants such as polysorbate 80 interact with preservatives such as methyl paraben and reduce antimicrobial activity.

All surfactants are bitter except Pluronics and Poloxamers. Polysorbate 80 is most widely used surfactant both for parenteral and oral suspension formulation. Polysorbate 80 is adsorbed on plastic container decreasing its preservative action. Polysorbate 80 is also adsorbed on drug particle and decreases its zeta potential. This effect of polysorbate 80 stabilizes the suspension.

Polysorbate 80 advantages are :

• non-ionic surfactant means no change in pH of medium

• No toxicity. Safe for internal use.

• Less foaming tendencies, should be used at concentration less than 0.5%.

• Compatible with most of the adjuvant.

Hydrophilic Colloids

Hydrophilic colloids coat hydrophobic drug particles in one or more than one layer. This will provide hydrophillicity to drug particles and facilitate wetting. They cause deflocculation of suspension because force of attraction is declined. e.g. acacia, tragacanth, alginates,
guar gum, pectin, gelatin, wool fat, egg yolk, bentonite, Veegum, Methylcellulose etc.

Solvents

The most commonly used solvents used are alcohol, glycerin, polyethylene glycol and polypropylene glycol. The mechanism by which they provide wetting is that they are miscible with water and reduce liquid air interfacial tension. Liquid penetrates in individual particle and facilitates wetting.

 

LIST AND CHARACTERISTIC OF SUSPENDING AGENTS USED FOR SUSPENSION

Most suspending agents perform two functions. Besides acting as a suspending agent they also imparts viscosity to the solution. Suspending agents form film around particle and decrease interparticle attraction. Suspending agents also act as thickening agents. They increase in viscosity of the solution, which is necessary to prevent sedimentation of the suspended particles as per Stoke’s’s law.
A good suspension should have well developed thixotropy. At rest the solution is sufficient viscous to prevent sedimentation and thus aggregation or caking of the particles. When agitation is applied the viscosity is reduced and provide good flow characteristic from the mouth of bottle.

List of Suspending Agents
• Alginates
• Methylcellulose
• Hydroxyethylcellulose
• Carboxymethylcellulose
• Sodium Carboxymethylcellulose
• Microcrystalline cellulose
• Acacia
• Tragacanth
• Xanthan gum
• Bentonite
• Carbomer
• Carageenan
• Powdered cellulose
• Gelatin

The selection of amount of suspending agent is dependent on the presence of other suspending agent, presence or absence of other ingredients which have an ability to act as a suspending agent or which contributes viscosity to the medium.

The stability of the suspensions depends on the types of suspending agents rather than the physical properties of the drugs. the physical stability of suspension was mainly dependent on the type of suspending agent rather than the physical characteristics of the drug.

Stability pH range and concentrations of most commonly used suspending agents for suspension

Suspending agents	Stability pH range	Concentrations used as suspending agent
Sodium alginate	4-10	1-5 %
Methylcellulose	3-11	1-2 %
Hydroxyethylcellulose	2-12	1-2 %
Hydroxypropylcellulose	6-8	1-2 %
Hydroxypropylmethylcellulose	3-11	1-2 %
CMC	7-9	1-2 %
Na-CMC	5-10	0.1-5 %
Microcrystalline cellulose	1-11	0.6-1.5 %
Tragacanth	4-8	1-5 %
Xanthangum	3-12	0.05-0.5 %
Bentonite	>6	0.5-5.0 %
Carageenan	6-10	0.5-1 %
Guar gum	4-10.5	1-5 %
Colloidal silicon dioxide	0-7.5	2-4 %

Characteristics of Most Commonly Used Suspending agent for suspension 

Alginates 

• Alginate salts have about same suspending action to that of Tragacanth.

• Alginate solution looses its viscosity when heated above 60 ºC. due to depolymerization.

• Fresh solution has highest viscosity, after which viscosity gradually decreases and acquires constant value after 24 hrs.

• Maximum viscosity is observed at a pH range of 5-9.

• Due to significant thickening effect, alginate is used at lower concentration to avoid problem of viscosity. High viscosity suspensions are not readily pourable.

• 1 % solution of low viscosity grade of alginate has viscosity of 4-10 mPas at 20 ºC.

• Chemically alginates are polymers composed of mannuronic acid and glucuronic acid monomers. The ratio of mannuronic acid to glucuronic acid determines the raft-forming properties. High ratio (e.g. 70 % glucuronic acid) forms the strongest raft.

• The concentration of alginate is optimized by raft-forming ability of the suspension in order to avoid pourability problem by too much increase in viscosity of suspension. In practice, alginate is used at concentration less than 10 % w/w, particularly at 5 % w/w.

Methylcellulose

• Methylcellulose is available in several viscosity grades, difference in methylation and polymer chain length.

• Methylcellulose is more soluble in cold water than hot water. Adding Methylcellulose in hot water and cooling it with constant stirring gives clear or opalescent viscous solution.

• Methylcellulose is stable at pH range of 3-11.

• As methylcellulose is non-ionic, it is compatible with many ionic adjuvants.

• On heating to 50 ºC, solution of Methylcellulose is converted to gel form and on cooling, it is again converted to solution form

Hydroxyethylcellulose

• Hydroxyethylcellulose (HEC) having somewhat similar characteristics to Methylcellulose.

• In HEC hydroxyethyl group is attached to cellulose chain. Unlike methylcellulose, HEC is soluble in both hot and cold water and do not form gel on heating.

Carboxymethylcellulose (CMC)

• Carboxymethylcellulose is available at different viscosity grades : Low, medium and high

• The choice of proper grade of CMC is dependent on the viscosity and stability of the suspension.

• In case of HV-CMC, the viscosity significantly decreases when temperature rises to 40 ºC from 25 ºC. This may become a product stability concern. Therefore to improve viscosity and stability of suspension MV-CMC is widely accepted.

Sodium Carboxymethylcellulose (NaCMC)

• It is available in various viscosity grades, difference in viscosity dependent on extent on polymerization.

• It is soluble in both hot and cold water and stable over a pH range of 5-10.

• As it is anionic, it is incompatible with polyvalent cations.

• Sterilization of either powder of mucilage form decreases viscosity.

• It is used at concentration up to 1 %.  

Microcrystalline Cellulose (Avicel)

• It is not soluble in water, but it readily disperses in water to give thixotropic gels. It is used in combination with Na-CMC, MC or HPMC, because they facilitate dispersion of MCC.

• MCC coprocessed with CMC together with titanium dioxide (opacifying agent) can be used for thixotropic pharmaceutical gels.

• MCC: alginate complex compositions are excellent suspending agents for water insoluble or slightly soluble API. The advantages of MCC: alginate complex compositions are that they provide excellent stability. Further suspensions prepared with them are redispersible with small amount of agitation and maintain viscosity even under high shear environment.

• Commonly, Na-CMC is used as the coprecipitate in MCC. Na CMC normally comprised in the range of 8 to 9 % w/w of the total mixture. These mixtures are available from FMC under trademark; Avicel RTM CL – 611, Avicel RTM RC – 581, Avicel RTM RC – 591. Avicel RC- 591 is most commonly used. It contains about 8.3 to 13.8 % w/w of Na CMC and other part is MCC.

Acacia

• Acacia is not a good thickening agent, but widely used in extemporaneous suspension formulation.

• For dense powder acacia alone is not capable of providing suspending action, therefore it is mixed with Tragacanth, starch and sucrose which is commonly known as Compound Tragacanth Powder BP.

Tragacanth

• Tragacanth solution is viscous iature, it provides thixotrophy to the solution.

• It is a better thickening agent than acacia.

• The maximum viscosity of the solution of Tragacanth is achieved after several days, because several days to hydrate completely.

Xanthan Gum

• Xanthan gum may be incorporated at a concentration of 0.05 to 0.5 % w/w depending on the particular API :

1.     Antacid suspension : Xanthan concentration is 0.08 to 0.12 % w/w.

2.     ibuprofen and acetaminophen suspension : Xanthan concentration is 0.1 to 0.3 % w/w.

Formulation, Composition and Manufacturing of Pharmaceutical Suspensions

perfect suspension provides content uniformity. Some problems occurs in the formulating of suspensions and many parameters should be consider such as particle size distribution, specific surface area, inhibition of crystal growth and changes in the polymorphic form. These and other properties should not change after long term storage and do not adversely affect the performance of suspension. Choice of pH, particle size, viscosity, flocculation, taste, color and odor are some of the most important factors that must be controlled at the time of formulation.

Suspensions Formulation Components and Ingredients
The various components, which are used in suspension formulation, are as follows.

Components	Function
API	Active drug substances
Wetting agents	to disperse solids in continuous liquid phase
Flocculating agents	to floc the drug particles
Thickeners/Suspending Agent	to increase the viscosity of suspension
Buffers and pH adjusting agents	to stabilize the suspension to a desired pH range
Osmotic agents	to adjust osmotic pressure comparable to biological fluid
Coloring agents	to impart desired color to suspension and improve elegance
Preservatives	to prevent microbial growth
External liquid vehicle	to construct structure of the final suspension

Combination of all or few of the above mentioned components are required for different suspension formulation. In the manufacture of suspension, there are two kinds of systems, namely:

a. Deflocculation system

b. flocculation system

In the flocculation system, flocculate particles are weakly bound, settles quickly and easily re-suspended and did not form a cake. While in the deflocculation system, Deflocculated particles settle slowly and will eventually form sediment and aggregation occurs and then subsequent harsh cakes and difficult to suspended again.

Manufacturing of Suspension

Suspension can be made by using two methods, namely:
1. Dispersion methods

2. Precipitation method, this method is divided again into three kinds :

• precipitation with organic solvents

•  precipitation with a pH change of media

•  precipitation with double decomposition

1. Dispersion methods

Finely divided powder, dispersed in the carrier solvent. Generally, as the carrier solvent is water. In formulating suspension, the important thing is particles must be dispersed well in water, dispersing powder that is not soluble in water, sometimes difficult. This is caused due to the presence of air, fat and other contaminants on the surface of the powder.

2. Precipitation method

With organic solvents made with substances that are insoluble in water, was dissolved in an organic solvent which can be mixed with water, then add distilled water to certain conditions. Organic solvents used are ethanol, methanol, propylene glycol and glycerin. To note with this method is control of particle size, ie the occurrence of polymorph or hydrate form of crystals.