hand out to students suspension1

8/18/2019 Hand Out to Students Suspension1

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Pharmaceutical Dosage Form andCalculations

Suspension Chapter

Howard C. Ansel

Nicholas G. Popovich

Loyd V. Allen, Jr.

Lecturer: Dr. Majed R. Feddah


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Pharmaceutical Suspension

Chapter Objectives:At the end student should be able to:

Describe what pharmaceutical suspensions are and what roles they play in thepharmaceutical science.

Discuss the factors that affect the stability of suspensions, and explain flocculation. Describe settling and sedimentation theory, and calculate sedimentation rates. Define and calculate the two useful sedimentation parameters, sedimentation

volume and degree of flocculation.

Describe the approaches commonly used in the preparation of physically stablesuspensions.

Introduction: Pharmaceutical suspension is a coarse dispersion in which insoluble solids particles are

dispersed in a liquid medium. The particle diameter of the particles is greater than 0.1 µm. Some of the small particles exhibit Brownian movement in low viscosity vehicles. Most pharmaceutical suspension as Oral antibiotics, Anti-Acids, contains high concentration

of solid materials 20 to 30%.

Parenterals suspension intended to be taken as injections contains from 0.5 to 30% of solidparticles with small particles.

Classification:

1. Oral suspension.

Antibiotics, oral drops, anti-acids

2. Topical suspension

Calamine Lotion USP3. Parenterals suspension


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Pharmaceutical Applications: Suspension may be used pharmaceutically for a number of reasons: Drug that have very low solubility. Drug that have unpleasant taste.

Insoluble for of drugs may prolong the action of a drug by preventing rapiddegradation of the drug in the presence of water.

Criteria for good suspension: The dispersed particles should not settle rapidly. The settling particles should not form hard cake, but should be readily re-dispersed,

when the container is shaken. Not too viscous to poor freely from the orifice of the container, or to flow through a

syringe needles. The product must be fluid enough to spread easily over the affected area. Must not be so mobile that it runs off the surface to which is applied. Should have an acceptable odor and color. The dispersed phase must be chosen with care so as to produce a suspension having

optimum physical, chemical and pharmacologic properties.

Factors affecting the formulation of suspension: Particle size and particle size distribution. Specific surface area. Inhibition of crystal growth. Changes in polymorphic form.

These properties should do not change during storage.

Physical Stability of Suspension: Physical stability of suspension: The condition in which the particles do not aggregate and remain uniformly

distributed throughout the dispersion. This is an ideal situation and in reality not happened, so:

“Shake well before use” should be writte n on the bottle and the should easily re-suspended by a moderate amount of agitation.


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Interfacial Properties of Suspended Particles: The combinations of the of the particles results in the increase of the surface area of

the particles, hence increase of the free surface energy which makes the systemthermodynamically unstable..

In this case the particles is high energetic and tends to group to reduce the surfacearea.

The particles in the liquid suspension therefore tend to flocculate, and form tightfluffy conglomerates that held together by weak van der-waals forces.

In some cases these particles may adhere by stronger forces to form what aretermed aggregates (cake).

The formation of any types of agglomerate, either floccules or aggregates, is takenas a measure of the system tendency to reach more thermodynamically stabilitystable state.

To reach the stable state the system tends to reduce the surface free energy. Equilibrium is reached when ΔG = 0, this can be achieved by reduction of theinterfacial tension, by decreasing the interfacial area

The interfacial tension between particles can be reduced by the addition ofSurfactant.

But not reduced to the zero

The forces at the surface of the particles affect the degree of flocculation andagglomeration in a suspension.

Electrical barrier on surface:


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Charged particles repel or attract each other


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When the repulsion energy is high, the potential barrier is also high, & collision is

stopped. The system remains de-flocculated, and when sedimentation occurs, the particlesform a close packed arrangement with the smaller particles filling the voids betweenthe larger ones. Those particles are gradually pressed together by the weight of theones above.

In order to re-suspend and re-disperse these particles, it is again necessary toovercome the high energy barrier, this is not easy to achieve by agitation.

The particles tend to remain strongly attracted to each other and form a hard cake.

Summary:1. Flocculated particles : Are weakly bonded, settle rapidly, do not form cake,

and are easily re-suspended.

2. Deflocculated suspension : Particles settle slowly, and eventually formsediment in which aggregation occurs with resultant formation of a hard cakethat is difficult to re-suspend.


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Settling in Suspension: One aspect of physical stability in pharmaceutical suspension is concerned

with keeping the particles uniformly distributed through the dispersion.

It is not possible to prevent settling completely over the prolonged period oftime.

So it is necessary to consider the factors that influence the velocity of thesedimentation.

Factors influence the velocity of the sedimentation: Particle size, Density of the particles, Density of the medium, Gravity,

viscosity of the medium.

Problems encountered when formulating insoluble solids intosuspensions:Factors need to be considered when formulating insoluble solids into a suspension.

Sedimentation:

The factors affecting sedimentation rate of particles are described in Stokes’s equation.

= 2r2

( - )g

9

= Velocity of spherical particle of radius r and density , in a liquid of density , and

viscosity

Theory of Sedimentation: In diluted suspensions 2% or less the particles will not interfere one another

during sedimentation.

In most pharmaceutical preparation this is in not the case and theconcentration is much higher 20 or 30%.

In this case some estimation may be obtained by diluting the suspension andthis may affect the degree of flocculation and the de-flocculation of thesuspension.


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Effect of Brownian movement

For particles having diameter between 2 to 5 µm, (depending on the densityof the particles and the density and viscosity of the suspending medium),

Brownian movement counteracts (prevent) sedimentation to measurableextent at room temperature by keeping the dispersed material in randommotion.

In pharmaceutical suspension, no Brownian movement are observed, asmost of them are viscous preparation with suspending agents.

Sedimentation of Flocculated Particles:Whether the supernatant liquid is clear or turbid during the initial stages of settling is agood indication of whether the system is flocculated or deflocculated.

Sedimentation parameter:1. Sedimentation volume ( V), or the height H.

2. Degree of flocculation.

Flocculated:In flocculated suspensions, Flocs tend to fall together, producing distinct boundarybetween the sediment and the supernatant liquid.

Hence the liquid above the sediment is clear because even the small particles present inthe system are associated with the flocs.

Deflocculated:It is not the case in the deflocculated suspension having a range of particle size, andaccordance with Stokes law the larger particles settle more rapidly than the smallerones, hence no clear boundary is formed, and supernatant remain not clear for longertime.

Whether or not the supernatant liquid is clear or turbid during the initial stages ofsettling is a good indication of whether the system is flocculated or deflocculated


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Sedimentation VolumeSedimentation volume (F) = the ratio of the final or ultimate volume of the sediment, Vuto the original volume of the suspension Vo, before settling:

Degree of FlocculationIt is more useful parameter is than the sedimentation volume:

If we consider a suspension that is completely de-flocculated, the ultimate volume ofthe sediment will be small.

Writing this volume as V , based on equation (F = Vu/Vo), we have

F = V /Vo is the sedimentation volume of deflocculated.

The degree of flocculation (β) = the ratio of F to V or

Crystal Growth.Crystal growth is attributed to one of the followings mechanisms:

1. The growth of large particles at the expense of small ones, owing to a differencein solubility rates of different size particles.

F

F


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2. Temperature fluctuations on storage temperature cycling of a difference of 20°Cor more.

3. Change from one polymorphic form to another more stable crystalline form.

4. The crystal growth may also arise when the more energetic amorphous or glassyforms of a drug exhibit significantly greater initial solubility in water than theircorresponding crystalline forms.

5. The size reduction by crushing and grinding can produce particles whosedifferent surfaces exhibit high or low solubility rates, and this effect can becorrelated to differences in the free surface energy introduced duringcomminuting.

Crystal Growth Control:

Crystal growth and changes in particle size distribution can be controlled by:

1. Selection of particle with narrower range of particle sizes.

2. Selection of more stable crystalline form of the drug, which usually exhibitsdecreased solubility in water (which have the highest melting point.

3. Avoidance of the use of high energy milling during particle size reduction.

4. Use of wetting agent (water-dispersible surfactant) in formulating to scatter freesurface energy of particles by reducing the interfacial tension between the solid

and suspending vehicle.

5. Use protective colloid, such as gelatin, gums, or cellulosic derivatives, to form afilm barrier around the particle, thus inhibiting dissolution and subsequentcrystal growth.

6. Increase the vescosity of the vehicle to retard particle dissolution andsubsequent crystal growth.

7. Avoidance of temperature extremes during product storage, such as the

exposure to freeze-thaw conditioning.

Most drugs vary in particle size and in particle shape. This influence the physicalstability, appearance, bioavailability and potency of pharmaceutical suspension

The Use of Wetting Agent:The initial dispersion of an insoluble powder in a vehicle is an important step in manufacturingprocess.


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Some insoluble drug particles are easy wetted by the water by minimal mixing, andmost of the drugs however, will exhibit varying degrees of hydrophobicity and will noteasy wetted.

Some particles form large porous clumps with the liquid, others remain on the surface

and become attached to the upper part of the container.

Hydrophilic solids can be suspended easily in water without the aid of a water –dispersible surfactant or wetting agent.

Hydrophobic solids can be suspended in oil and non polar vehicles with the use of lipid-soluble surfactants.

Hydrophobic and Hydrophilic:Powders that are not easily wetted by water and show large contact angle with waterare called Hydrophobic. (Sulfur, charcoal, Magnesium stearate)

Powders that are readily wetted by water are called Hydrophilic. (Zinc oxide, Talk,Magnesium carbonate)

To ensure adequate wetting, the interfacial tension between the solid and the liquidmust be reduced so that the adsorbed air is displaced from the solid surfaces by theliquid.

Wetting agent is used to decrease the interfacial tension between the drug particles andthe liquid and in lesser extent, between liquid and air.

Polysorbates (Tweens) and sorbitan esters sulphate, sodium dioctylsulphosuccinate.

The role of surfactant in the preparation of suspension:By reducing the interfacial tension between solid particles and liquid so:

1. The contact area is lowered.

2. The air is escape from the surface of the particles.

3. Wetting and dispersion are promoted .


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Glycerin and similar hygroscopic substances are also valuable in levigatingthe insoluble materials.

Glycerin flows into the voids between the particles, to displace the air andduring mixing operation.

Control Flocculation:Once the powder is properly wetted and dispersed, attention should be given to keepthese powders flocculated and to prevent them from forming compact sediment that isdifficult to re-disperse.

Controlled flocculation is usually achieved by a combination of particle size control, theuse of Electrolytes to control the Zeta potential, and the addition of Polymers to enablecross linking to occur between particles and Surfactants

ElectrolytesElectrolytes acts as flocculating agent by reducing the electric barrier between theparticles by a decrease the zeta potential and the formation of bridge between adjacentparticles so as the link them together in a loosely arranged structured.

Example: Bismuth subnitrate in water.


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Surfactants:Ionic and nonionic surfactants have been used as flocculating agent of suspendedparticles.

The concentration of surfactant is critical since these compounds may also act as

wetting and deflocculating agents to achieve dispersion.

Examples:

Anionic /Docusate sodium, sodium lauryl sulfate.

Nonionic/ Polysorbate 65, Polysorbate 80, octoxynol-9,


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Polymers:Polymers are long chain, high molecular weight compounds containing active groupsspaced along their length.

These agents act as flocculating agents because part of the chain is adsorbed on theparticle surface, the other parts projecting toward the dispersion medium and hydrated.

Bridging between these particles lead to the formation of flocs.

Examples:

Xanthan gum (anionic heteropholysaccharide).

Addition of xanthan gum result in the increase of the sedimentation volume.

Hydrophilic polymers (Negatively charged) is used as protective colloids, particlescoated in this manner are less prone to cake than are uncoated particles.

The hydrophilic polymers posses a pseudo plastic flow in suspension so it will enhancethe physical stability of the suspension.

Gelatin (polyelectrolytic polymer, exhibit its flocculation that depends on the pH andionic strength of the dispersion medium.

Formulation of Suspension1. The use of structured vehicle.

2. Flocculation principle. To produce flocs that, although they settle rapidly,however, easily re-suspended with a minimum of agitation.

3. Flocculation in structured vehicle.


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Formulation of suspension summary

Structured VehiclesStructured vehicles are pseudo plastic and plastic in nature.


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Thixotropy associated with these two types of flow.

It acts by entrapping the particles so that, ideally, no settling occurs.

The shear thinning property of these vehicles does, however, facilitate the reformation

of a uniform dispersion when shear is applied.

Disadvantages:

Formation of hard cake when eventually settled .

Optimum physical stability and appearance will be obtained when the suspension isformulated with flocculated particles in a structured vehicle of the hydrophilic colloidaltype.

1. Flow readily from the container.

2. Possess a uniform distribution of particles in each dose.

Flocculation in Structured Vehicles:Although the controlled flocculation approach is good in regards of physical andchemical stability of the system.

A suspending agent is added to the system to retard sedimentation of the flocs.

Examples:

Carboxymethycellulose (CMC), Carbopol 934, Veegum, Tragacanth, or bentonite.

Alone or in combination

1. Reologic Considaration:

The principles of rheology may be applied to a study of the following factors:

2. The viscosity of a suspension, which affect the settling of particles.

3. The change in flow properties of the suspension when the container is shaken.

4. The spreading qualities of the lotion when it is applied to an affected area.


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Structured Vehicle preparation:

Ideal suspending Agent:High viscosity at negligible shear (during the shelf life of the product)

Low viscosity at high shearing rates (during pouring from the bottle or spreading in caseof lotion.

Pseudo plastic substances such as Tragacanth, sodium alginate, and sodiumCarboxymethylcellulose show these desirable qualities.

Newtonian liquid:

Glycerin, is suitable for suspending particles but is too high to pour easily and to spreadon the skin.

Glycerin shows the undesirable property of stickiness and it too hygroscopic to use inundiluted form.


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Suspending Agent:A suspending agent that is Thixotropic as well as pseudoplastic should prove to be usefulsince it forms a gel on standing and becomes fluid when disturbed.

Example:

Bentonit e and CMC 50:50 form thixotroy and pseudoplastic properties.

They produce excellent suspension.

Stability of Suspension: Rising the temperature: Leads to flocculation of sterically stabilized suspension.

Freezing: During freezing process, cause the particles to aggregate, and it remainaggregated even when the ice is melted.

In temperature fluctuation: Particle growth were observed (change the particlesize and particle size distribution and the polymorphic form of the particles.

hand out to students suspension1

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