PHARMACEUTICAL SUSPENSIONS

(Dr.) Mirza Salman BaigAssistant Professor (Pharmaceutics)

AIKTC, School of Pharmacy,New PanvelAffiliated to University of Mumbai (INDIA)

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ØDefinition.

ØClassification.

ØBenefits & Limitations

ØApplications

Theoretic consideration of suspensions

Ø Formulation of suspensions

•Sedimentation•Brownian movement•Electrokinetic properties

CONTENTS

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WHY WE ARE USING SUSPENSIONS?

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The reasons for the formulation of a pharmaceutical suspension:

when the drug is insoluble in the delivery vehicle

To mask the bitter taste of the drug

To increase drug stability

To achieve controlled/sustained drug release

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

ØDrug in suspension exhibits higher rate of bioavailability than other dosage forms.

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

BENIFITS

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Physical stability , sedimentation and compaction can causes problems.

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

Ø It is difficult to formulate.

Ø Uniform and accurate dose can not be achieved unless suspension are packed in unit dosage form.

LIMITATIONS

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

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

Ø It should have pleasing odour , colour and palatability.

Ø Good syringeability.

Ø It should be physically,chemically and microbiologically stable.

Ø Parenteral /Ophthalmic suspension should be sterilizable.

Features Desired In Pharmaceutical Suspensions

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WHAT ARE SUSPENSIONS?

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• The term "Disperse System" refers to a system in which one substance (The Dispersed Phase) is distributed, in discrete units, throughout a second substance (the continuous Phase ).

• Suspensions are heterogenous

system consisting of 2 phases.

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DISPERSE SYSTEM

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A solid in liquid dispersion, in which the particle size is more than colloidal size.

DISPERSE SYSTEM

DISPERSION MEDIUM DISPERSED PHASE

oAqueous / oily liquid oInsoluble solid

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Definition

Ø A Pharmaceutical suspension is a coarse dispersion in which internal phase (therapeutically active ingredient)is dispersed uniformly throughout the external phase.

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Ø The internal phase consisting of insoluble solid particles having a range of size(0.5 to 5 microns) which is maintained uniformly through out the suspending vehicle with aid of single or combination of suspending agent.

Ø The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.

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Classification •Based On rout of administration Oral suspension Externally applied suspension Parenteral suspension

• Based On Electrokinetic Nature Of Solid Particles Flocculated suspension Deflocculated suspension

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In flocculated suspension, formed flocs (loose aggregates) will cause increase in sedimentation rate due to increase in size of sedimenting particles.

Ø Hence, flocculated suspensions sediment more rapidly.

ØHere, the sedimentation depends not only on the size of the flocs but also on the porosity of flocs.

Deflocculation and flocculation (Flocculated Suspensions)

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Deflocculated suspensions

Ø In deflocculated suspension, individual particles are settling.

Ø Rate of sedimentation is slow , which prevents entrapping of liquid medium which makes it difficult to re-disperse by agitation.

Ø This phenomenon called ‘caking’ or ‘claying’.

Ø In deflocculated suspension larger particles settle fast and smaller remain in supernatant liquid so supernatant appears cloudy.

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Theory of Suspensions • Sedimentation Behaviour• Sedimentation means settling of particle or

floccules under gravitational force in liquid dosage form.

• Velocity of sedimentation expressed by Stokes Equation

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• Where, vsed. = sedimentation velocity in cm / sec • d = diameter of particle • ρ s= density of disperse phase • ρ o= density of disperse media • g = acceleration due to gravity • η = viscosity of disperse medium in poise

Stokes Equation

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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)

Ø Particles which freely settle without collision .

Ø Particles with no physical or chemical attraction.

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Sedimentation Parameters

Sedimentation volume (F) or height (H) for flocculated suspensions:Definition:

Sedimentation volume is a ratio of the ultimate volume of sediment (Vu) to the original volume of sediment (Vo)before settling.

F = Vu / Vo

Where, Vu = final or ultimate volume of sedimentVo = original volume of suspension before settling

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F has values ranging from less than one to greater than one. When F < 1 Vu < Vo

When F =1 Vu = Vo

The system is in flocculated equilibrium and show no clear supernatant on standing.

When F > 1 Vu > VoSediment volume is greater than the original volume due to the network of flocs formed in the suspension and so loose and fluffy sediment

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The sedimentation volume gives only a qualitative account of flocculation.

Fig : Suspensions quantified by sedimentation volume (f)

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Degree of flocculation (β)It is the ratio of the sedimentation volume of the flocculated suspension ,F , to the sedimentation volume of the deflocculated suspension, F∞

ß = F / F∞

(Vu/Vo) flocculatedß = --------------------

(Vu/Vo) deflocculated

Ø The minimum value of ß is 1,when flocculated suspension sedimentation volume is equal to the sedimentation volume of deflocculated suspension.

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Brownian Movement

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

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

Ø The kinetic bombardment of the particles by the molecules of the suspending medium will keep the particles suspending, provided that their size is below critical radius (r).

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Electro kinetic Properties

The zeta potential is defined as the difference in potential between the surface of the tightly bound layer (shear plane) and electro-neutral region of the solution.

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

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

Ø This phenomenon is known as flocculation

Ø The flocculated suspension is one in which zeta potential of particle is -20 to +20 mV

Ø Thus the phenomenon of flocculation and deflocculation depends on zeta potential carried by particles.

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Ø The formulation of a suspension depends on whether the suspension is flocculated or deflocculated.

Ø Three approaches are commonly involved

1. Use of structured vehicle 2. Use of controlled flocculation3. Combination of both of the methods

:FORMULATION OF SUSPENSIONS

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Ø Structured vehicles called also thickening or suspending agents.Ø They are aqueous solutions of natural and synthetic gums.Ø It is applicable only to deflocculated suspensions. E.g. methyl cellulose, sodium carboxy methyl cellulose, acacia, gelatin and tragacanth.Ø These structured vehicles entrapped the particle andreduces the sedimentation of particles.Ø Thus, the use of deflocculated particles in a structure vehicle may form solid hard cake upon long storage.

Ø Structured vehicle is not useful for Parenteral suspension because they may create problem in syringeability due to high viscosity.

Structured vehicle

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FORMULATION OF SUSPENSIONSINGREDIENTS FOR

VISCOSITY :-

Viscosity is a measure of a fluid's resistance to flow.

It describes the internal friction of a moving fluid.

A fluid with large viscosity resists motion because its molecular makeup gives it a lot of internal friction.

A fluid with low viscosity flows easily because its molecular makeup results in very little friction when it is in motion.

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Suspending agent are also known as hydrophilic colloids which form colloidal dispersion with Water and increase the viscosity of the continous phase.Ø Suspending agent form film around particle and decrease interparticle attraction.Ø Most suspending agents perform two functionsi.e. besides acting as a suspending agent they also imparts viscosity to the solution.

1) Suspending agents

Ø Preferred suspending agents are those that give thixotropy to the media such as Xanthan gum, CarageenanEg. Methylcellulose, Hydroxyethylcellulose, Carboxymethylcellulose, Microcrystalline cellulose, Acacia, Tragacanth, Carbomer, Gelatin

SURFACE TENSION"Surface tension is a contractive

tendency of the surface of a fluid that allows it to resist an external force."

FORMULA USED TO CALCULATE SURFACE TENSION :-

Where,Where,  γ = surface tension  θ = contact angle  ρ = density g = acceleration due to gravity r = radius of tube

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Hydrophilic materials are easily wetted by water while hydrophobic materials are not.

Ø However hydrophobic materials are not easily wetted by Water (polar liquids)

Ø The extent of wetting by water is dependent on the hydrophillicity of the materials.

Ø If the material is hydrophobic then it is difficulty to wet by water.

2) Wetting Agents

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Surfactants decrease the interfacial tension between drug particles and liquid thus liquid is penetrated in the pores of drug particle displacing air from them and thus ensures wetting.Ø Generally, we use non-ionic surfactants

ØPolysorbate 80 is most widely used due to its following advantages

§ It is non-ionic so no change in pH of medium

§ No toxicity. Safe for internal use.

3) Surfactants

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The commonly used solvents used are glycerin, polyethylene glycol and polypropylene glycol.

Ø The mechanism by which they provide wetting is that they are miscible with water and reduce liquid air interfacial tension.

Ø Liquid penetrates in individual particle and facilitates wetting.

4) Solvents

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They are added to produce osmotic pressure comparable to biological fluids when suspension is to be intended for ophthalmic or injectable preparation.

Ø Most commonly used osmotic agents are

Ø dextrose,Ø mannitol Ø sorbitol.Ø sodium chloride,Ø sodium sulfateØ glycerol.

5) Osmotic Agents

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Ø Naturally occurring suspending agents such as tragacanth, acacia, xanthan gum are susceptible to microbial contamination.

Ø This leads to:

§ loss in suspending activity of suspending agents,

§ loss of color, flavor and odor, § change in elegance etc.

6) Preservatives

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Name of preservatives

Concentration range

Propylene glycol 5-10%Disodium EDTA 0.1%Benzalkonium chloride 0.01-0.02%Benzoic acid 0.1%Butyl paraben 0.006-0.05% oral

suspension0.02-0.4% topical formulation

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Ø They are added to increase patient acceptance.

Ø Only sweetening agent are not capable of complete taste masking of unpleasant drugs therefore, a flavoring agents are incorporated

Ø E.g.

7) Flavoring And Coloring Agents

Mint Ginger Sarsaparilla syrup

Anise oil Glucose Spearmint oilBenzaldehyde Glycerin Thyme oil

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Colors are obtained from natural or synthetic sources.

Ø Plant colors are most widely used for oral suspension.

Ø The synthetic dyes should be used within range of( 0.0005 % to 0.001%)Ø Color aids in identification of the product.

Ø Brilliant blue (blue) Ø Indigo carmine(blue)Ø Amaranth (red)Ø Tartarazine (yellow)

8) Coloring agents 

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They are used for taste masking of bitter drug particles.

Bulk sweeteners

Sugars such as Sucrose, xylose, ribose, glucose, mannose. Sugar alcohols such as sorbitol, xylitol, mannitolA bulk sweeteners is used at concentration of 15-70 %Artificial sweetening agents

Sodium cyclamate, Sodium saccharin, Aspartame

9) Sweetening Agents

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Humectants absorb moisture and prevent degradation of API by moisture.

Ø Examples of humectants most commonly used insuspensions are propylene glycol , glycerol

Ø Total quantity of humectants should be between 0-10 % w/w.

10) Humectants

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Ascorbic acid derivatives such as ascorbic acid, erythorbic acid,

Ø Thiol derivatives such as thio glycerol, cytosine, acetylcysteine, Ø Ø Tocopherols

Ø Butylated hydroxy anisole(BHA)

Ø Butylated hydroxytoluene (BHT)

Ø Sodium bi sulfite,

Ø Sodium sulfateacetone

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11) Antioxidant

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Wetting agents They are added to disperse solids in continuous liquid phase.

Flocculatingagents

They are added to floc the drug particles

Thickeners They are added to increase the viscosity of suspension.

Buffersand pH adjusting agents

They are added to stabilize the suspension to a desired pH range.

Osmoticagents

They are added to adjust osmotic pressure comparable to biological fluid.

Coloringagents

They are added to impart desired color to suspension and improve elegance.

Preservatives They are added to prevent microbial growth.

Externalliquid vehicle

They are added to construct structure of the final suspension.

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Label

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