SUSPENSIONS1_ppt [Compatibility Mode].pdf

SUSPENSIONS

Suspension:¡ Definition¡ A Pharmaceutical suspension is a coarse

dispersion in which internal phase is disperseduniformly throughout the external phase.

¡ The internal phase consisting of insoluble solidparticles which is maintained uniformly throughout the suspending vehicle with aid of single orcombination of suspending agents.

¡ The external phase (suspending medium) isgenerally aqueous in some instance, may be anorganic or oily liquid for non oral use.

Suspension:

(500 um)

Classification of suspensions:

1- Based On General Classes¡ Oral suspension e.g. antacid, antibiotic¡ Externally applied suspension e.g.lotion ¡ Parenteral suspension ¡ Ophthalmic suspension2- Based On Proportion Of Solid Particles¡ Dilute suspension (2 to10% w/v solid) ¡ Concentrated suspension (50% w/v solid) 3- Based On Electrokinetic Nature Of Solid

Particles¡ Flocculated suspension ¡ Deflocculated suspension

Advantages And DisadvantagesAdvantages:1- Used for 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 aqueoussolution:l Reduce the contact time between solid drug

particles and dispersion media ⇒ increase thestability of drug like Ampicillin by making it asreconstituted powder.

l A drug that degraded in the presence of water ⇒suspended in non-aqueous vehicles.

Examples are phenoxymethypencillin/ coconut oil andtetracycline HCL/ oil

Advantages And Disadvantages

3- Drug in suspension exhibits higher rate of bioavailabilitythan several dosage forms. bioavailability is infollowing order,

Solution > Suspension > Capsule > CompressedTablet > Coated tablet

4- Suspension can mask the unpleasant/ bitter taste ofdrug. E.g. Chloramphenicol

5- Some materials are needed to be present as finelydivided forms to increase the surface area.

For example, Mg carbonate and Mg trisilcate are used toadsorb some toxins

Advantages And Disadvantages6-Suspension can be used for topical applications:An example is calamine lotion Bp ⇒ after evaporation of

dispersing media; the active agent will be left as light deposit

7- Can be used for parentral administration ⇒intramuscular (i.m.) to control rate of absorption

8- In vaccines

9- X-ray contrast media:an example is oral and rectal administration of

propyliodone

10-In aerosol ⇒ suspension of active agents in mixture ofpropellants

Advantages And Disadvantages

Disadvantages1-Physical stability, sedimentation and

compaction can causes problems.

2-It is bulky, sufficient care must be taken duringhandling and transport.

3-It is difficult to formulate

4-Uniform and accurate dose can not be achievedunless suspension are packed in unit dosageform

Features Desired In Pharmaceutical Suspensions

1-The suspended particles should not settle rapidly andsediment produced, must be easily re-suspended bythe use of moderate amount of shaking.

2-It should be easy to pour yet not watery and nogrittiness.

3-It should have pleasing odour, colour and palatability.

4-Good syringeability.

5-It should be physically,chemically and microbiologicallystable.

6-Parenteral/Ophthalmic suspension should besterilizable.

FACTORS TO BE CONSIDEREDI. Particle size control:- Particle size of any suspension is critical and must be

reduced within the range as determined during thepreformulation study.

-Too large or too small particles should be avoided.Larger particles will:A- settle faster at the bottom of the containerB- particles > 5 um impart a gritty texture to the product

which may cause irritation if injected or instilled to theeye

C- particles > 25 um may block the needle

-Too fine particles will easily form hard cake at the bottomof the container.

FACTORS TO BE CONSIDERED

II. Wetting of the particles- Hydrophilic materials (talc, ZnO, Mg2CO3) are easily

wetted by water while hydrophobic materials (sulphur,charcoal) are not due to the layer of adsorbed air on thesurface. Thus, the particles, even high density, float onthe surface of the liquid until the layer of air is displacedcompletely.

- The use of wetting agent allows removing this air fromthe surface and to easy penetration of the vehicle intothe pores.

- However hydrophobic materials are easily wetted bynon-polar liquids.

FACTORS TO BE CONSIDERED

FACTORS TO BE CONSIDEREDI-wetting agents include:

1-Surfactants

-Surfactants decrease the interfacial tension between drugparticles and liquid and thus liquid is penetrated in the poresof drug particle displacing air from them and thus ensureswetting.

- Surfactants of HLB value 7 – 9 are used as wetting agents.

-Disadvantages of surfactants are:A- that they have foaming tendencies.B- they are bitter in taste.C-Some surfactants such as polysorbate 80 interact withpreservatives such as methyl paraben and reduceantimicrobial activity.

FACTORS TO BE CONSIDERED- Polysorbate 80 is most widely used surfactant both for

parenteral and oral suspension formulation.- Sodium laurylsulphate is used for external application.

2-Hydrophilic Colloids

- Hydrophilic colloids coat hydrophobic drug particles inone or more than one layer. This will providehydrophillicity to drug particles and facilitate wetting.

- Disadvantage:They cause deflocculation of suspensionbecause force of attraction is declined.

- e.g. acacia, tragacanth, alginates, gelatin, wool fat, eggyolk, bentonite, Veegum, Methylcellulose etc.

FACTORS TO BE CONSIDERED3-Solvents¡ The most commonly used solvents

used are alcohol, glycerin, polyethyleneglycol and polypropylene glycol.

¡ The mechanism by which they providewetting is that solvent flows into thevoids between particles to displace airand it coats and separates the materialso that water can penetrate and wet theparticles.

FACTORS TO BE CONSIDEREDIII. Sedimentation:Sedimentation means settling of particle or

floccules occur under gravitational force inliquid dosage form.

- Velocity of sedimentation expressed by Stoke’sequation:

FACTORS TO BE CONSIDEREDWhere, vsed.

= sedimentation velocity in cm / sec d = Diameterof particle r = radius of particle ρ s= density of disperse phase ρ o= density of disperse media g = acceleration due to gravity η o = viscosity of disperse medium in

poise

FACTORS TO BE CONSIDERED¡ According to the Stoke's equation, the velocity of

sedimentation of particles in a suspension can bereduced by:

1- decreasing the particle size

2- by minimizing the difference between the densities ofthe particles and the vehicle.

The density of the vehicle of a suspension can beincreased by adding the following substances eitheralone or in combination: polyethylene glycol, polyvinylpyrolidone, glycerin, sorbitol, and sugar.

3-The velocity of sedimentation decreases as the viscosityof the vehicle increases.

The viscosity and density of any vehicle are related toeach other.

FACTORS TO BE CONSIDERED¡ Sedimentation Parameters1- Sedimentation volume (F) or height (H) for

flocculated suspensions:

Definition: Sedimentation volume is a ratio of the final or ultimate volume of sediment (Vu) to the original volume of sediment (VO)before settling.

F = V u / VO Where, Vu = final or ultimate volume of sediment VO = original volume of suspension before settling.

FACTORS TO BE CONSIDERED¡ F has values ranging from less than one to greater than one.¡ normally F < 1

¡ When F < 1 Vu < Vo

When F =1 Vu = VoThe system is in flocculated equilibrium and show no clear supernatant

on standing.When F > 1 Vu > Vo

Sediment volume is greater than the original volume due to the network of flocs formed in the suspension and so loose and fluffy sediment

Sediment Volume

FACTORS TO BE CONSIDERED2-Degree of flocculation (β)

¡ Degree of flocculation: is the ratio of thesedimentation volume of the flocculated suspension,F, to the sedimentation volume of the deflocculatedsuspension, F∞

ß = F / F∞

(Vu/Vo) flocculated ß = --------------------

(Vu/Vo) deflocculated

FACTORS TO BE CONSIDERED¡ When the total volume of both the flocculated

and the deflocculated suspensions are same;

ß = (Vu)floc / (Vu)defloc

-The minimum value of ß is 1; this is the casewhen the sedimentation volume of theflocculated suspension is equal to thesedimentation volume of deflocculatedsuspension.

- ß is more fundamental parameter than F sinceit relates the volume of flocculated sediment tothat in a deflocculated system

FACTORS TO BE CONSIDEREDIV. Brownian Movement

¡ Brownian movement ofparticle preventssedimentation by keeping thedispersed material in randommotion.

¡ Brownian movement dependson the density of dispersedphase and the density andviscosity of the dispersemedium.

¡ The kinetic bombardment ofthe particles by themolecules of the suspendingmedium willkeep the particles

suspending.

2-5 µm

Brownian Movement

FACTORS TO BE CONSIDERED

V. Electrokinetic Properties

Zeta Potential¡ The zeta potential is

defined as thedifference in potentialbetween the surface ofthe tightly bound layer(shear plane) andelectro-neutral regionof the solution.

FACTORS TO BE CONSIDERED

¡ The ions that gave the particle its charge, arecalled potential-determining ions.

¡ Immediately adjacent to the surface of theparticle is a layer of tightly bound solventmolecules, together with some ionsoppositely charged to the potential-determining ions.

¡ These two layers of ions at the interfaceconstitute a double layer of electric charge(shear plane).

FACTORS TO BE CONSIDERED¡ Zeta potential governs the degree of repulsion

between the adjacent, similarly charged,dispersed particles.

¡ If the zeta potential is reduced below a certainvalue, the attractive forces exceed therepulsive forces, and the particles cometogether. This phenomenon is known asflocculation.

¡ Particles carry charge may acquire it fromadjuvants as well as during process likecrystallization, grinding processing, ionizationof functional group of the particle, adsorptionof ions from solution e.g. ionic surfactants.

FACTORS TO BE CONSIDEREDVI. Deflocculation and flocculationFlocculated Suspensions

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

¡ Hence, flocculated suspensionssediment more rapidly.

¡ Here, the sedimentation depends notonly on the size of the flocs but also onthe porosity of flocs.

flock

FACTORS TO BE CONSIDERED¡ In flocculated suspension the loose structure

of the rapidly sedimenting flocs tends topreserve in the sediment, which contains anappreciable amount of entrapped liquid.

¡ The volume of final sediment is thus relativelylarge and is easily redispersed by agitation.

¡ Even the smallest particles are involved inflocs, so the supernatant appears clear.

FACTORS TO BE CONSIDERED

Deflocculated suspensions¡ In deflocculated suspension, individual particles are

settling.¡ rate of sedimentation is slow.¡ which prevents entrapping of liquid medium which

makes it difficult to re-disperse by agitation.

¡ This phenomenon called ‘cacking’ or ‘claying’.

¡ In deflocculated suspension,larger particles settle fast andsmaller remain in supernatant liquidso supernatant appears cloudy

cake

A comparison of properties of flocculated and A comparison of properties of flocculated and defloccuated suspension particlesdefloccuated suspension particles

Sedimentation behaviour of flocculated and deflocculated suspensions

FACTORS TO BE CONSIDEREDFlocculating agents:1. Electrolytes (e.g. Nacl, sulfate, citrates, phosphates salts) - reduce the zeta potential surrounding the solid particles.

This leads to decrease in repulsion potential and makesthe particle come together to from loosely arrangestructure (floccules).

- The flocculating power increases with the valency of theions. As for example, calcium ions are more powerfulthan sodium ions because the velency of calcium is twowhereas sodium has valency of one.

¡ EX: bismuth subnitrate with KH2PO4

Caking Diagram

Caking Diagram¡ In 1st caking zone :

Addition of KH2PO4à↓in +ve zeta potential (owing to adsorption of negatively charged phosphate anion) which accompanied by ↑in Vu/Vo

¡ In Non caking zone:↑ KH2PO4à More reduction in Zeta zone

( ~ zero) while Vu/Vo remain unchanged (approached the plateau)

In 2nd caking zone:↑ KH2PO4à ↑ zeta potential in negative direction till becomes sufficient to re-induce deflocculated suspension while Vu/Vo ↓

FACTORS TO BE CONSIDERED2.Surfactants

¡ Both ionic and non-ionic surfactants can be used to bringabout flocculation of suspended particles.

¡ Ionic surfactants: cause neutralization of the charge oneach particle. The particles are then attracted towards toeach other by van der waals forces and forms looseagglomerates.

¡ Non-ionic surfactant: they are adsorbed on to more thanone particle thus forming a loose flocculated structure.

FACTORS TO BE CONSIDERED3. Polymers (e.g. alginate, starch, cellulose derivatives) ¡ Polymers possess long chain in their structures. The part

of the long chain is adsorbed on the surface of theparticles and remaining part projecting out into thedispersed medium. Bridging between these laterportions, also leads to the formation of flocs.

Form ation of b ridge betw een partic les

P rojec tion out into d ispersion m edium

A dsorption on the surface of particles

Solid p artic le Solid particle

Form ation of b ridge betw een partic les

P rojec tion out into d ispersion m edium

A dsorption on the surface of particles

Solid p artic le Solid particle

FACTORS TO BE CONSIDEREDVI. Viscosity Of Suspensions¡ Viscosity of suspensions is of great

importance for stability and pourability ofsuspensions.

¡ As we know suspensions have least physical stabilityamongst all dosage forms due to sedimentation and cakeformation.

¡ As the sedimentation is governed by Stoke’s law,

v=d2 (ρs -ρ l ) g/18η

So as the viscosity of the dispersion medium increases, theterminal settling velocity decreases yielding higherstability to the suspension.

FACTORS TO BE CONSIDERED¡ On the other hand as the viscosity of the

suspension increases, it’s pourabilitydecreases and inconvenience to the patientsfor dosing increases.

¡ Thus, the viscosity of suspension should bemaintained within optimum range to yieldstable and easily pourable suspensions.

FACTORS TO BE CONSIDERED¡ Different Approaches To Increase The Viscosity Of Suspensions:1-Viscosity Enhancers

- Some natural gums (acacia, tragacanth),- polymers, cellulose derivatives (sodium CMC, methyl cellulose)- clays(bentonite)- sugars (glucose, fructose)

2- Co-solvents- Some solvents which themselves have high viscosity

are used as co-solvents to enhance the viscosity ofdispersion medium.

3- Structured vehiclesThis part will be dealt in detail latter.

Method of preparation:

¡ The preparation of suspension includes three methods:

(1) use of controlled flocculation (2) use of structured vehicle (3) combination of both of the two pervious

methods. The following is the general guidelines to

suspension formulation:

Method of preparation

Method of preparation:A-Structured vehicle¡ Structured vehicles called also thickening or suspending

agents.

¡ They are aqueous solutions of natural and syntheticgums.

¡ These are used to increase the viscosity of thesuspension.

¡ It is applicable only to deflocculated suspensions.

¡ E.g. Methyl cellulose, sodium carboxymethyl cellulose,acacia, gelatin and tragacanth.

These are non-toxic, pharmacologically inert, andcompatible with a wide range of active and inactiveingredients.

Method of preparation:¡ These structured vehicles entrapped the particle and

reduces the sedimentation of particles.

¡ Thus, the use of deflocculated particles in a structurevehicle may form solid hard cake upon long storage.

¡ Note that too high viscosity isn’t desirable:a-it causes difficulty in pouring and administration.b-it may affect drug absorption since they adsorb on the

surface of particle and suppress the dissolution rate.

- Structured vehicle is not useful for Parenteral suspensionbecause they may create problem in syringeability due tohigh viscosity.

Method of preparation:B-Controlled flocculation¡ Controlled flocculation of particles is obtained by

adding flocculating agents, which are:(1)-electrolytes (2)- surfactants (3)- polymers

C-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

Evaluation of suspensions:¡ Suspensions are evaluated by determining their

physical stability.¡ Two useful parameters for the evaluation of

suspensions are;A- sedimentation volumeB- degree of flocculation.

- The determination of sedimentation volumeprovides a qualitative means of evaluation.

- A quantitative knowledge is obtained bydetermining the degree of flocculation.