SUSPENSIONS1.ppt [Compatibility Mode]

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-Surfactants decrease the interfacial tension between drug particles and liquid and ... Polysorbate 80 is most widely used surfactant both for parenteral and oral  ...


Suspension: ¡ ¡



Definition A Pharmaceutical suspension is a coarse dispersion in which internal phase is dispersed uniformly throughout the external phase. The internal phase consisting of insoluble solid particles which is maintained uniformly through out the suspending vehicle with aid of single or combination of suspending agents. The external phase (suspending medium) is generally aqueous in some instance, may be an organic or oily liquid for non oral use.


(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 suspension 2- 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 Disadvantages Advantages:

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 aqueous solution: l Reduce the contact time between solid drug particles and dispersion media ⇒ increase the stability of drug like Ampicillin by making it as reconstituted powder. A drug that degraded in the presence of water ⇒ suspended in non-aqueous vehicles. Examples are phenoxymethypencillin/ coconut oil and tetracycline HCL/ oil l

Advantages And Disadvantages 3- Drug in suspension exhibits higher rate of bioavailability than several dosage forms. bioavailability is in following order, Solution > Suspension > Capsule > Compressed Tablet > Coated tablet 4- Suspension can mask the unpleasant/ bitter taste of drug. E.g. Chloramphenicol 5- Some materials are needed to be present as finely divided forms to increase the surface area. For example, Mg carbonate and Mg trisilcate are used to adsorb some toxins

Advantages And Disadvantages 6-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 propyliodone




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

Advantages And Disadvantages Disadvantages 1-Physical stability, sedimentation compaction can causes problems.


2-It is bulky, sufficient care must be taken during handling and transport. 3-It is difficult to formulate 4-Uniform and accurate dose can not be achieved unless suspension are packed in unit dosage form

Features Desired In Pharmaceutical Suspensions 1-The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking. 2-It should be easy to pour yet not watery and no grittiness. 3-It should have pleasing odour, colour and palatability. 4-Good syringeability. 5-It should be physically,chemically and microbiologically stable. 6-Parenteral/Ophthalmic sterilizable.




FACTORS TO BE CONSIDERED I. Particle size control: - Particle size of any suspension is critical and must be reduced within the range as determined during the preformulation study. -Too large or too small particles should be avoided. Larger particles will: A- settle faster at the bottom of the container B- particles > 5 um impart a gritty texture to the product which may cause irritation if injected or instilled to the eye C- particles > 25 um may block the needle -Too fine particles will easily form hard cake at the bottom of 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 the surface. Thus, 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.


However hydrophobic materials are easily wetted by non-polar liquids.


FACTORS TO BE CONSIDERED I-wetting agents include: 1-Surfactants -Surfactants decrease the interfacial tension between drug particles and liquid and thus liquid is penetrated in the pores of drug particle displacing air from them and thus ensures wetting. - 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 with preservatives such as methyl paraben and reduce antimicrobial 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 in one or more than one layer. This will provide hydrophillicity to drug particles and facilitate wetting.


Disadvantage:They cause deflocculation of suspension because force of attraction is declined.


e.g. acacia, tragacanth, alginates, gelatin, wool fat, egg yolk, bentonite, Veegum, Methylcellulose etc.

FACTORS TO BE CONSIDERED 3-Solvents ¡ The most commonly used solvents used are alcohol, glycerin, polyethylene glycol and polypropylene glycol. ¡

The mechanism by which they provide wetting is that solvent flows into the voids between particles to displace air and it coats and separates the material so that water can penetrate and wet the particles.

FACTORS TO BE CONSIDERED III. Sedimentation: Sedimentation means settling of particle or floccules occur under gravitational force in liquid dosage form. - Velocity of sedimentation expressed by Stoke’s equation:

FACTORS TO BE CONSIDERED Where, 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 be reduced by: 1- decreasing the particle size ¡

2- by minimizing the difference between the densities of the particles and the vehicle. The density of the vehicle of a suspension can be increased by adding the following substances either alone or in combination: polyethylene glycol, polyvinyl pyrolidone, glycerin, sorbitol, and sugar. 3-The velocity of sedimentation decreases as the viscosity of the vehicle increases. The viscosity and density of any vehicle are related to each other.


Sedimentation Parameters

1- 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.


F has values ranging from less than one to greater than one. normally F < 1



F < 1

Vu < Vo


F =1

Vu = Vo


The 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 CONSIDERED 2-Degree of flocculation (β) ¡

Degree of flocculation: 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) flocculated ß = -------------------(Vu/Vo) deflocculated


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 case when the sedimentation volume of the flocculated suspension is equal to the sedimentation volume of deflocculated suspension. - ß is more fundamental parameter than F since it relates the volume of flocculated sediment to that in a deflocculated system




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

Brownian Movement

Brownian movement depends on the density of dispersed phase and the density and viscosity of the disperse medium. The kinetic bombardment of the particles by the molecules of the suspending medium will keep the particles suspending.

2-5 µm

FACTORS TO BE CONSIDERED V. Electrokinetic Properties Zeta Potential ¡ 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.




The ions that gave the particle its charge, are called potential-determining ions. Immediately adjacent to the surface of the particle is a layer of tightly bound solvent molecules, together with some ions oppositely charged to the potentialdetermining ions. These two layers of ions at the interface constitute a double layer of electric charge (shear plane).




Zeta 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. This phenomenon is known as flocculation. Particles carry charge may acquire it from adjuvants as well as during process like crystallization, grinding processing, ionization of functional group of the particle, adsorption of ions from solution e.g. ionic surfactants.

FACTORS TO BE CONSIDERED VI. Deflocculation and flocculation Flocculated Suspensions ¡



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


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




In flocculated suspension the loose structure of the rapidly sedimenting flocs tends to preserve in the sediment, which contains an appreciable amount of entrapped liquid. The volume of final sediment is thus relatively large and is easily redispersed by agitation.

¡ Even the smallest particles are involved in

flocs, 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 and smaller remain in supernatant liquid so supernatant appears cloudy ¡


A comparison of properties of flocculated and defloccuated suspension particles

Sedimentation behaviour of flocculated and deflocculated suspensions

FACTORS TO BE CONSIDERED Flocculating 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 makes the particle come together to from loosely arrange structure (floccules). -

The flocculating power increases with the valency of the ions. As for example, calcium ions are more powerful than sodium ions because the velency of calcium is two whereas sodium has valency of one.







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 ↓




Both ionic and non-ionic surfactants can be used to bring about flocculation of suspended particles. Ionic surfactants: cause neutralization of the charge on each particle. The particles are then attracted towards to each other by van der waals forces and forms loose agglomerates. Non-ionic surfactant: they are adsorbed on to more than one particle thus forming a loose flocculated structure.

FACTORS TO BE CONSIDERED 3. 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 the particles and remaining part projecting out into the dispersed medium. Bridging between these later portions, also leads to the formation of flocs. P ro jec tion out into d isp ersion m ed ium

S o lid p artic le

A dsorption o n th e surfa ce of pa rticles

S olid p ar ticle

F orm a tion of b ridge be tw e en partic les

FACTORS TO BE CONSIDERED VI. Viscosity Of Suspensions ¡ Viscosity of suspensions is of great importance for stability and pourability of suspensions. ¡ As we know suspensions have least physical stability amongst all dosage forms due to sedimentation and cake formation. ¡ 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, the terminal settling velocity decreases yielding higher stability to the suspension.



On the other hand as the viscosity of the suspension increases, it’s pourability decreases and inconvenience to the patients for dosing increases. Thus, the viscosity of suspension should be maintained within optimum range to yield stable and easily pourable suspensions.


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 of dispersion medium. 3- Structured vehicles This 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 synthetic gums.


These are used suspension.


It is applicable only to deflocculated suspensions.







E.g. Methyl cellulose, sodium carboxymethyl cellulose, acacia, gelatin and tragacanth. These are non-toxic, pharmacologically inert, and compatible with a wide range of active and inactive ingredients. ¡

Method of preparation: ¡


These structured vehicles entrapped the particle and reduces the sedimentation of particles. Thus, the use of deflocculated particles in a structure vehicle 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 suspension because they may create problem in syringeability due to high 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 volume B- degree of flocculation. ¡



The determination of sedimentation volume provides a qualitative means of evaluation. A quantitative knowledge is obtained by determining the degree of flocculation.