SUSPENSIONS

Mr.R.R.PatilDr.Shivajirao Kadam College of

Pharmacy, Kasabe digraj

Definition

Suspension may be defined as preparation containing finely divided drug particles distributed somewhat uniformly throughout a vehicle in which the drug exhibits a minimum degree of solubility.

or

Suspensions are the biphasic liquid

dosage form of medicaments in which the

finely divided solid particles. The range of solid particles in suspension

from 0.5 to 5.0 micron. Suspensions are used in orally, parentally

and also externally. They are chemically stable than solution.

• According to the particle size of the dispersed phase, suspensions are divided into:Coarse suspension: which is a dispersion of particles with a

mean diameter greater than1 µm.

Colloidal suspension: Which is a dispersion of particles with a

mean diameter less than 1 µm

Reasons for Suspension If patient has a difficulty of swallowing solid

dosage forms (a need for oral liquid dosage form).

Faster rate of dissolution and oral absorption than solid dosage forms, yet slower than solutions.

Drugs that have very low solubility are usefully formulated as suspensions.

Drugs that have an unpleasant taste in their soluble forms (e.g., chloramphenicol (soluble) vs. chloramphenicol palmitate (insoluble )).

Properties of good Suspension Suspension should settle slowly & should

be readily redispersed upon shaking of the container.

The suspension is pourable.

Particles in suspension are small and relatively uniform in size. so that the product is free from a gritty texture.

Classification Based on General class→ Oral Suspension e.g. Paracetamol Suspension→ Externally Applied suspension e.g. Calamine lotion→ Parenteral Suspension e.g. Insulin zinc suspension

Based on proportion of Solid Particles

Dilute Suspension (2 to 10% w/v solid)

e.g. cortisone acetate, predinsolone acetate

Concentrated Suspension (50% w/v solid)

e.g. Zinc oxide suspension

Based on electrokinetic nature of Solid particle

Flocculated Suspension

Deflocculated Suspension

Based on Size of Particle Coarse Suspension

Suspensions having particle sizes of greater than about 1micron in diameter are called as coarse suspensions.

Colloidal Suspension

Suspensions having particle sizes of suspended solid less than about 1micron in size are called as colloidal suspensions.

FLOCCULATED SYSTEM In flocculated system the individual particle

are contact with each other to form loose aggregate & create network like structure.

Rate of sedimentation is high. Sediment is loosely packed. When shaking

it can be redisperse easily & reform the original suspension.

Flocculated suspensions not be elegant because they are difficult to remove from bottles or vials & on transferring from the bottle the floccules remaining sticking to the side of the bottle.

DE-FLOCCULATED or NON-FLOCCULATED SYSTEM

In deflocculated system the individual particle are exist as separate entities.

Rate of sedimentation is low. Sediment is tightly packed. When shaking

it can not be redisperse easily & form the cake.

Deflocculated suspensions be elegant. They have pleasing appearance bec. the substance remain suspended for sufficient long time.

CAKING IN SUSPENSION It is defined as the formation of a

nonredispersible sediment within a suspension system.

CAUSES: Crystal bridging & closed aggregate in formulation.

In crystal bridging, particle surface crystal growth occurs on two or more particles simultaneously in the steady formation.

Causes of cake formation Small changes in temperature that occurs

during shelf storage lead to unexpectedly rapid caking via crystal bridging.

A sedimented, highly coagulate suspension tends to form large coagules as the surface films present on coagulated particle causes the filmed particles to cling to each other.

Theory of Sedimentation

SEDIMENTATION:

Sedimentation means settling of particle (or) floccules occur under gravitational force in liquid dosage form.

Stokes equation:

d = Diameter of particle

r = radius of particle

V sed.= sedimentation velocity in cm / sec

ρs= density of disperse phase

ρo= density of disperse media

g = acceleration due to gravity

ηo= viscosity of disperse medium in poise

Limitation Of Stoke’s Equation.

Stoke's equation applies only to:

› Spherical particles in a very dilute suspension (0.5 to 2 gm per 100 ml)

› Particles which freely settle without collision .

› Particles with no physical or chemical attraction.

Brownian Movement

Brownian movement of particle prevents sedimentation by keeping the dispersed material in random motion.

Brownian movement depends on the density of dispersed phase and the density and viscosity of the disperse medium.

Brownian movement can be observed,

If particle size is about 2 to 5µm,

When the density of particle & viscosity of medium are favorable.

Electro kinetic properties Zeta PotentialThe zeta potential defined as the difference

between the surface of the tightly bound layer (shear plane) & the electroneutral region of the solution.

SURFACE

Tightly bound layer

Electroneutral region

As the potential drops off rapidly at first, followed more gradual decrease as the distance from the surface increases.

This is because the counter ions close to the surface acts as a screen that reduce the electrostatic attraction between the charged surface and those counter ions further away from the surface.

Zeta potential has practical application in stability of systems containing dispersed particles .

Since this potential, rather than the Nernst potential, governs the degree of repulsion between the adjacent, similarly charged, dispersed particles.

If the zeta potential is reduced below a certain value , the attractive forces exceed the repulsive forces, and the particles come together.

Zeta Potential (mV) Stability behavior of Colloid

From 0 to ±5, Rapid Coagulation or flocculation

From ±10 to ±30 Incipient instability

From ±30 to ±40 Moderate stability

From ±40 to ±60 Good stability

More than ±61 Excellent stability

STRUCTURED VEHICLE Structured vehicle also called as thickening

agent or suspending agent. They increases the viscosity of the

continuous phase so that the particles remain suspended for a sufficient long time.

These structured vehicles entrapped the particle and reduces the sedimentation of particles.

Although, these structured vehicles reduces the sedimentation of particles.

Acacia, Tragacanth & sodium alginate not very commonly used.

The semi-synthetic structured vehicles are widely used.

E.g. methyl cellulose, CMC, hydroxypropyl methyl cellulose etc.

Clays such as hydrated aluminium silicate or magnesium silicate also used as thickening agent.

Wetting Agent

Wetting agent or substance which reduce the interfacial tension between the solid particle & liquid phase.

It is adsorbed at the solid/liquid interface, in such way that the affinity of the particles for the surrounding medium is increased & interparticular forces are decreased.

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.

e.g. alcohol in tragacanth mucilage, glycerin or glycol in sodium alginate etc.

Excessive amount wetting agent lead to foaming or undesirable taste or odour to suspension.

Flocculating agent or Surfactant

Flocculating agent or surfactant are reduces the interfacial tension.

They act like, surfactant with negative charge are adsorbed on the particles, minimise flocculation in the presence of positive ions because of natural repulsion of like charge.

e.g. of negative charge surfactant sodium lauryl sulphate, sodium dioctyl sulphocinate etc.

Non-ionic surfactant also have negative charge surfactant in solution.

Tweens, carbowaxses are frequently used.

Dispersing agent Some particles have not sufficient surface

energy, so that particles come together & forms large particle.

To overcome that difficulty the substance may be introduced in the suspension & those called dispersing agent.

These substance increase the zeta potential & do not allow the particles to come together to form large particles.

They also act as stabiliser in suspension.

e.g. glyceryl monostearate, polyoxethylene glycol, sorbitan etc.

Preservatives used in suspension

It should effective against wide range of micro-organisms.

It should be physically & chemically stable.

It should be non-toxic & compatible with other added substance.

e.g. benzoic acid, sodium benzoate, methyl & propyl paraben.

FORMULATION METHODS FOR SUSPENSION

Suspension Containing Diffusible Solids

Suspension Containing Indiffusible Solids

Suspension Containing Poorly Wettable Solids

Suspension Produced by Chemical Reaction

Suspension Containing Diffusible Solids

Some insoluble solids are light & easily wettable.

On that reason, they readily mix with water & on shaking, diffuse through the liquid for long enough to ensure even distribution in each dose.

Such substance are known as diffusible or dispersible solids.

List of diffusible solids commonly used in oral preparations

Calcium Carbonate..antacidLight Kaolin…treat diarrhea

Light Magnesium Carbonate..laxativeMagnesium Trisilicate…antacid

Rhubarb Powder…digestive problems

Method of Preparation Finely powder Take insoluble powder in a mortar. Add sufficient vehicle to produce smooth

paste. Add any non-volatile solid ingredients in

part of the vehicle, and mix well. Add any volatile solid ingredients,

previously dissolved in some of the vehicle & mix well.

Add any liquid ingredients.

Rinse the mortar & pestle with successive volume of vehicle until they are quiet clean, transferring the rinsing to the bottle.

Make up to the volume with vehicle & shake thoroughly.

CONTAINER & STORAGE: Dispensed medicines i.e. mixture, lotion

etc. Thick container with wide mouth. Store in cool place. Very low temp. May cause suspended

particles to aggregated

Suspension Containing Indiffusible Solids

Indiffusible particles will not distributed in a vehicle long enough.

So that the correcting this problem is to increases the viscosity of the vehicle by adding a thickening agent.

Used Internally Indiffusible solids

Aspirin..fever & pain Chalk..antacid

Phenobarbiton..sedative Sulphadimidine…chalmydia

Used Externally Indiffusible solids

Calamine..pain & itching Hydrocortisone..inflammation

Sulphur..antibacterial Zinc oxide..irritation

Tragacanth powder mainly used suspending agent for that type of preparation.

Tragacanth powder is used in the ratio of 2 gm per 100 ml of the suspension.

Tragacanth mucilage it is used in the ratio of ¼ th of the volume of the suspension.

Tragacanth mucilage is used only when the vehicle is chloroform water or water.

Bec. If it added to preparations containing a medicinally active vehicle, the mucilage replace medicinally active vehicle, there by decreasing their activity.

In such cases tragacanth powder must be used as suspending agent.

Method for Preparation Finely powder the Indiffusible solid

particles take in a mortar. Add any diffusible or soluble solids. Add tragacanth powder or mucilage &

mix thoroughly. If only Indiffusible substance is to be

incorporated, mix it with tragacanth powder in a mortar.

Add sufficient vehicle to produce smooth cream.

Then add more vehicle to make up the final volume.

Suspension Containing Poorly Wettable Solids

Some substance e.g. sulphur & hydrocortisone are both insoluble in water & poorly wetted by it.

Those are produce clumps & it is difficult to disperse in aqueous liquids.

Also produce foam on shaking because it is satbilised by the film of unwettable solid at the liquid /air interface.

On that reason added satisfactory wetting agent, those must be reduced the interfacial energy between the solid & liquid.

Those agent adsorbed at the solid/liquid interface in such a way that the affinity of the particles for the surrounding medium is increased, while the interparticular forces are decreased.

e.g. alcohol in tragacanth mucilage, glycerin

& glycol in sodium alginate, Quillaia extracts have been used in sulphur lotion etc.

Suspension Produced by Chemical Reaction

Chemical reaction method are used to produce insoluble active constituents in the lotion.

In that method highly diluted solutions of reacting substance are mixed together.

So as to form very finely divided precipitates that can be easily distributed throughout the liquid on shaking.

Precipitates so formed are generally diffusible in nature therefore no need any suspending agent.

Zinc sulphide lotion B.P.C produced by this method.

Packaging of Suspensions Pharmaceutical suspensions for oral use

are generally packed in wide mouth container having adequate space above the liquid to ensure proper mixing.

Parenteral suspensions are packed in either glass ampoules or vials.

Ideal Requirements of Packaging Material

It should be inert.

It should effectively preserve the product from light, air, and other contamination.

It should effectively deliver the product without any difficulty.

It should be cheap.

STORAGE REQUIREMENTS & LABELLING

LABEL: Shake well before use Do not freeze Protect from direct light(for light

sensitive drugs) In case of dry suspensions powder the

specified amount of vehicle to be mixed may indicated clearly on label.

STORAGE:

Suspensions should be stored in cool place but should not be kept in a refrigerator.

Freezing at very low temperatures should be avoided which may lead to aggregation of suspended particles.

Stored at controlled temperature from 20-25 0c

Manufacturing Equipment Used in Dispersion System

Dispersion system is defined as a heterogenous two phase system in which internal (dispersed, discontinous ) phase is distributed or dispersed within the continuous (external) phase or vehicle.

e.g. Suspensions & Emulsions

PROPELLER MIXERS

The most often used mixing implement is marine propeller mixer.

These machines use rounded, pitched, three blade design that produces mostly axial flow.

They provide good flow and blending capabilities in small batches of low to medium viscosities.

Propellers mixers can be installed on vertical centerline or through the side wall of process vessel.

They can be operated at around 300-400rpm.

These are used mostly for liquid-liquid blending applications in some easily producible suspensions.

PROPELLER MIXERS

Turbine mixers The most versatile of all mixers in

the entire span of mixing equipments are the axial and radial flow turbines.

Turbines mixers can be made to handle huge batches, even up to 5,00,00gal & suitable for emulsification process.

Radial Flow turbine

Axial flow turbine

High speed Dispersers It is also called as saw blade disperser.

This machine consists of a variable speed shaft connected to an impeller with a serrated edge.

The tip speed is set around 4000 ft/min. The diameter of impeller should be 1/3

of diameter of vessel.

The impeller should be located one impeller diameter off the bottom of vessel

It can deagglomerating particles when the viscosities between 10,000 to 20,000cps.

Application: It is used for pigment dispersion, dye

stuffs

Limitations: Air incorporation is another problem so

it is best used for suspensions and not for emulsions.

High speed disperser

Colloid mill It is used to disperse the solids into liquids

and to emulsify liquid-liquid systems.

These generally used as polishing machines for emulsions or suspensions because they produce fine particle or droplet size product to enhance a products stability.

They are operated at speed of 3600 rpm

Fine suspensions and size reduction equipment

Types:1. Triple roll mill

2. Ball mill

A three roll mill or triple roll mill is a machine that uses shear force created by three horizontally positioned rolls rotating in opposite directions and different speeds relative to each other, in order to mix, refine, disperse, or homogenize viscous materials fed into it.

TRIPLE ROLL MILL

BALL MILL It is used for size reduction fine solid

discrete particles or for deagglomeration of very tightly bound agglomerates.

The machine consists of cylindrical drum into which a charge of heavy spherical balls usually metal or ceramic is loaded along with the components of the dispersion.

EVALUATION OF SUSPENSIONS

SEDIMENTATION METHOD

The suspension formulation(50mL)was poured separately into 100mLmeasuring cylinders and sedimentation volume was read after 1,2,3 and 7days, and there after at weekly intervals for 12weeks.

Sedimentation volume was calculated according to the equation:

F =Vu/Vo

Where , F = sedimentation volumeVu = ultimate height of sedimentVo = initial height of total suspension

Micromeritic method

The stability of suspension depends on the particle size of the dispersed phase.

Change in the particle size with reference to time will provide useful information regarding the stability of a suspension.

A change in particle size distribution and crystal habit studied by

microscopy coulter counter method

PHOTOMICROSCOPIC TECHNIQUE

Rapid processing of photo micrographs is enhanced by attaching Polaroid camera to the piece of monomolecular microscope.

By using this photo micrographs we can determine the changes in physical properties and stability of suspensions.

pH MEASUREMENT

VISUAL INSPECTION With visual inspection, the ingredients

and the final products are carefully examined for purity and for appearance .