Suspensions

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Oral

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– Materials that required to bein finely divided form in gastrointestinal tract

– More palatable than solutionsfor children

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Topical administration

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– Calamine lotion, zinc cream

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Inhalation

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prolonged release of volatiles

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Solubility and stability

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poorly soluble drugs formulated assuspensionsKaolin or magnesium carbonate are used foradsorption of toxins or to neutralise excess acidity

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Pharmaceutical suspensions

Advantages

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– Useful for formulation oflow-solubility drugs

– Effective at masking taste

– Ideal for patients who havedifficulty swallowing solid-dosage forms

– Active may be required in afinely divided solid form

– In formulations to control drug delivery rate

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Pharmaceutical suspensions

Disadvantages

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– Fundamentally unstable

– Aesthetic suspension formulationdifficult to attain

– Bulky formulations

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Desired features of apharmaceutical suspensions

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• Dispersion should settle slowlyand be easily dispersed with gentle shaking

• Particle size of dispersedmedium should remain constant

• Suspension should pour readilyand evenly

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What parameters can we control?

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Dispersed phase

• Particle size• Surface properties of particles

Vehicle (continuous phase)

• Control viscosity• Use of electrolytes• Addition of surfactants

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According to DLVO theory

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disperse system will be stable if repulsiveforces prevent interaction between particles. However – pharm suspension is also physicallyunstable because will SEDIMENT with larger particles fist then smaller ones ingaps and the cakeDefloculated systems CANNOT be guaranteedto remain stable throughout lifetime of product

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Steric hindrance (polymer chains)

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repulsion between hydrated surfaces - stabilisingforces observed since the use of non-ionic polymers as stabilisers

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Positive enthalpy from approaching chainsdue to steric interactions

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Also entropic – volume restriction limitingmovements of polymer chains; osmotic effect due to solvent attempting to dilutethe overlapping polymer chains.

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repulsive interactions

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Look at effect of repulsive interaction and the electric double layersreach into solution from the particle surface. Repulsive interactions aresurface forces and therefore anything you add to the system that will adsorb toor affect charge distribution will impact on the repulsive interaction. Theattractive interaction is defined largely by the particle size, shape and chemistry.

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stability of hydrophobic sold

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is treated interms of the energy changes which take place as the particles approach

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There are different distance dependencies of attractive and repulsive forces – i.e. range into solution.

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If the distancethe diffuse layer reaches into solution is increased then no secondary minimumand basically no interaction between particles – stable but for sedimentationIf the diffuselayer is smaller them repulsive forces fade away very quickly from surface andattractive forces dominate – no primary maximum and coagulation occurs

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Repulsion betweenhydrated surfaces

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•The approach of particlescoated with hydrated polymer leads to repulsion:

–Steric repulsion: Positiveenthalpy change and negative entropy change

– Osmotic pressure

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Excipients

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• Similar to solutions but alsoneed to stabilise the suspension

• Problems to overcome to createa stable formulation

– Sedimentation

– Caking

– Flocculation

– Particle growth

– Adhesion to container wall

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You want to avoid aggregation

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Minimise caking by controlled flocculation.

Deflocculated system has advantage of slowsedimentation but sediment ‘cakes’ – uniform dosing.

Flocculated system – loose sediment that iseasily redispersed but sediments fast leading to inaccurate dosing and inelegance. So go for partial (controlled) flocculation.

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Common excipients for oral suspension formulation

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•Vehicle–Purified water (oral), Buffers (citric acid/sodiumcitrate), Co-solvents, Electrolytes

•Surfactants

•Hydrophilic polymers

•Preservatives

•Sweeteners/flavours

•Antioxidants

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Wetting agents

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•Must reduce interfacial tensionbetween particle and dispersion medium to improve wetting

•Surface-active agents

•Hydrophilic colloids

•Solvents

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Flocculated/deflocculated systems

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Upon adding wetting agent need to determine if formed flocculated ordeflocculated suspension – depends on relative magnitude of attractive andrepulsive forces. Even a dispersion defined as stable will eventually sedimentif particles are coarse

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Deflocculation

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leads to ‘cake’ or ‘clay’ formation

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Flocculation

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- secondary minima – particles sediment rapidlyentrapping continuous phase and remaining discrete

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Interaction energy-distance curve

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Look at effect ofrepulsive interaction and the electric double layers reach into solution fromthe particle surface. Repulsive interactions are surface forces and thereforeanything you add to the system that will adsorb to or affect charge distributionwill impact on the repulsive interaction. The attractive interaction is definedlargely by the particle size, shape and chemistry.So adding electrolyte will have an effect on thetotal interaction energy

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Interaction energy-distance curve -2

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For example …this slide with low electrolyte concentration and therefore a thick diffuselayer. In this case repulsive interactions dominate and there is noflocculation (this deflocculated case is ideal if particles are colloidal insize but not if they are larger due to sedimentation – leads to slowsedimentation and caking

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Interaction energy-distance curve -3

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If increaseelectrolyte concentration slightly you reduce the thickness of the electricdouble layer (so the reach into solution of the repulsive interactions enoughto bring in a secondary minimum (weak aggregation – flocculation). This is goodfor coarse suspension – the system will redisperse on shaking but the large‘flocs’ prevent caking

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Interaction energy-distance curve - 4

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If increaseelectrolyte concentration too much the repulsive interactions weaken and wewould eventually remove the barrier to coagulation leading to a coagulated andstable aggrgate – this is of course bad whatever the size of the particles.

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Controlled flocculation

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Ideal – deflocculated systemwith sufficiently high viscosity to prevent sedimentation

Real – prepare partially flocculatedsystem– Control particle size

– Control zeta potential

– Addition of polymers

Flocculating agents support the‘floc’ and increase sedimentation volume

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Flocculating agents

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Electrolytes– Ions of opposite charge willreduce thickness of double layer creating a secondary minimum (flocculation)electrolytes willreduce thickness and result in flocculated system but if add too much will leadto coagulation (removal of primary maximum); ions of opposite charge (Schultze– Hardy)

•Surface active agents– Affect electric (zeta)potential

•Hydrophilic polymers– Adsorb to particles leading toloosely flocculated structures

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Rheology

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study of flow – viscosity characteristics ofpowders, fluids and semisolids

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Newtonian flow

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constant viscosity regardless of shear rate

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Non-Newtonian flow

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change in viscosity with increasing shear rate

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Flocculated system

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newtonian or dilatant – increase viscocity undershear

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Polysaccharides

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– not that effective (when used on its own) fordense powder. 2. tragacanth – pseudoplastc properties good thickening agent forboth internal and external use – mainly in extemp preps. 3. alginates – similarproperties to tragacanth sodium alginate most widely used in this class. 4.xanthan gum – anionic polysaccharide – widely used for oral use (up to 2% and stableover wide pH range.

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Celluloses

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– must be water sol. Disperse in water toproduce viscous colloidal solutions e.g. methylcellulose andhydroxyethylcellulose.)

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Silicates

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– bentonite,magnesium aluminium silicate, hectorite – hydrate readility absorbing up to 12times their weight of water – gels are thixotropic (reversible time-dependentdecrease in viscosity)

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Stability of suspensions

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Inorder to quantify sedimentation, the ratio of sedimentation layer volume tototal suspension volume is used. R = h x/ ho