WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
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`Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences al.ll World Journal of Pharmacy and Pharmaceutical Sciences
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` SJIF Impact Factor 6.041
` Volume 5, Issue 12, 1471-1537. Review Article ISSN 2278 – 4357
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`PHARMACEUTICAL SUSPENSIONS: PATIENT COMPLIANCE ORAL
`DOSAGE FORMS
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`*R. Santosh Kumar and T. Naga Satya Yagnesh
`
`GITAM Institute of Pharmacy, GITAM University, Rushikonda, Visakhapatnam,
`A.P-530045.
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`
`Article Received on
`19 October. 2016,
`Revised on 09 Nov. 2016,
`Accepted on 29 Nov. 2016
`DOI: 10.20959/wjpps201612-8159
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`*Corresponding Author
`R. Santosh Kumar
`GITAM Institute of
`Pharmacy, GITAM
`University, Rushikonda,
`Visakhapatnam, A.P-
`530045.
`
`ABSTRACT
`A pharmaceutical suspension is a coarse dispersion of insoluble solid
`particles in a liquid medium. The particle diameter in a suspension is
`usually greater than 0.5 μm. However, it is difficult and also
`impractical to impose a sharp boundary between the suspensions and
`the dispersions having finer particles. Suspensions are an important
`class of pharmaceutical dosage forms. The advantages of suspension
`dosage forms include effective dispensing of hydrophobic drugs;
`avoidance of the use of cosolvents; masking of unpleasant taste of
`certain ingredients; offering resistance to degradation of drugs due to
`hydrolysis, oxidation or microbial activity; easy swallowing for young
`or elderly patients; and efficient intramuscular depot therapy. In
`addition, when compared to solution dosage forms, relatively higher concentration of drugs
`can be incorporated into suspension products. The present review provides an overview of
`various aspects of suspensions such as classification of suspensions, theories of suspensions,
`various suspending agents, formulations aspects of suspensions, packaging of suspensions,
`evaluation of suspensions, stability of suspensions and recent research work that is being
`carried on suspensions.
`
`KEYWORDS: Suspensions, Suspending agents, Evaluation, Stability.
`
`INTRODUCTION
`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 having a specific range of size which is maintained uniformly throughout the
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`suspending vehicle with aid of single or combination of suspending agent. The external phase
`(suspending medium) is generally aqueous in some instance, may be an organic or oily liquid
`for non oral use.
`
`Classification
`1. Based on General Classes
`(cid:190) Oral suspension
`(cid:190) Externally applied suspension
`(cid:190) Parenteral suspension
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`2. Based on Proportion of Solid Particles
`(cid:190) Dilute suspension (2 to10%w/v solid)
`(cid:190) Concentrated suspension (50%w/v solid)
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`3. Based on Electro Kinetic Nature of Solid
`(cid:190) Particles
`(cid:190) Flocculated suspension
`(cid:190) Deflocculated suspension
`
`4. Based on Size of Solid Particles
`(cid:190) Colloidal suspension (< 1 micron)
`(cid:190) Coarse suspension (>1 micron)
`(cid:190) Nano suspension (10 ng)
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`Advantages
`(cid:153) Pharmaceutical Suspension can improve chemical stability of certain drug. E.g.Procaine
`penicillin G.
`(cid:153) Drug in suspension exhibits higher rate of bioavailability than other dosage forms.
`bioavailability is in following order,
`Solution > Suspension > Capsule > Compressed Tablet > Coated tablet
`(cid:153) Duration and onset of action can be controlled. E.g.Protamine Zinc-Insulin suspension.
`(cid:153) Suspension can mask the unpleasant bitter taste of drug. E.g. Chloramphenicol.
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`Disadvantages
`(cid:153) Physical stability, sedimentation and compaction can causes problems.
`(cid:153) It is bulky sufficient care must be taken during handling and transport.
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`(cid:153) It is difficult to formulate.
`(cid:153) Uniform and accurate dose cannot be achieved unless suspension are packed in unit
`dosage form.
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`Features Desired in Pharmaceutical
`(cid:153) The suspended particles should not settle rapidly and sediment produced, must be easily
`re-suspended by the use of moderate amount of shaking.
`(cid:153) It should be easy to pour yet not watery and no grittiness.
`(cid:153) It should have pleasing odour, colour and palatability.
`(cid:153) Good syringeability.
`(cid:153) It should be physically, chemically and microbiologically stable.
`(cid:153) Parenteral/Ophthalmic suspension should be sterilizable.
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`Applications
`(cid:153) Suspension is usually applicable for drug which is insoluble or poorly soluble.
`E.g. Prednisolone suspension.
`(cid:153) To prevent degradation of drug or to improve stability of drug.
`E.g. Oxytetracycline suspension.
`(cid:153) To mask the taste of bitter of unpleasant drug.
`E.g. Chloramphenicol palmitate suspension.
`(cid:153) Suspension of drug can be formulated for topical application e.g. Calamine lotion.
`(cid:153) Suspension can be formulated for parentral application in order to control rate of drug
`absorption.
`(cid:153) Vaccines as a immunizing agent are often formulated as suspension.
`E.g. Cholera vaccine.
`(cid:153) X-ray contrast agent are also formulated as suspension.
`E.g. Barium sulphate for examination of alimentary tract.
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`Theory of Pharmaceutical Suspensions
`1. Sedimentation Behaviour
`Introduction
`Sedimentation means settling of particle or floccules occur under gravitational force in liquid
`dosage form.
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`2. Theory of Sedimentation
`Velocity of sedimentation expressed by Stoke's equation:
` VSed= d2(ρs-ρo)g / 18ηo
` = 2r2 (ρs-ρo)g / 9ηo
`
`Where,
`v = sedimentation velocity in cm / sec
`d = Diameter of 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
`Stoke's Equation Written In Other Form
` V ' = Vsed. ε n
`V '= the rate of fall at the interface in cm/sec.
`V = velocity of sedimentation according to Stoke's low
`ε = represent the initial porosity of the system that is the initial volume fraction of the
`uniformly mixed suspension which varied to unity.
`n = measure of the "hindering" of the system & constant for each system.
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`Limitation of Stoke's Equation
`Stoke's equation applies only to:
`(cid:153) Spherical particles in a very dilute suspension (0.5 to 2 gm per 100 ml).
`(cid:153) Particles which freely settle without interference with one another (without collision).
`(cid:153) Particles with no physical or chemical attraction or affinity with the dispersion medium.
`(cid:153) But most of pharmaceutical suspension formulation has conc. 5%, 10%, or higher
`percentage, so there occurs hindrance in particle settling.
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`Factors Affecting Sedimentation
`1. Particle size diameter (d)
`2. Density difference between dispersed phase and dispersion media(ρ s- ρ o)
`3. Viscosity of dispersion medium(η)
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`3. Sedimentation Parameters
`Three important parameters are considered:
`1. Sedimentation volume (F) or height (H) for flocculated suspensions:
` F = Vu / Vo -------------- (A)
`
`Where, Vu = final or ultimate volume of sediment
`Vo = original volume of suspension before settling.
`Sedimentation volume is a ratio of the final or ultimate volume of sediment (Vu) to the
`original volume of sediment (V) before settling. Some time 'F' is represented as 'Vs' and as
`expressed as percentage. Similarly when a measuring cylinder is used to measure the volume
` F= Hu / Ho
`
`
`Where, Hu = final or ultimate height of sediment
`Ho = original height of suspension before settling Sedimentation volume can have values
`ranging from less than 1 to greater than1; F is normally less than 1. F=1, such product is said
`to be in flocculation equilibrium. And show no clear Supernatant on standing Sedimentation
`volume (F) for deflocculated suspension
`F¥ = V¥ / Vo
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`Where,F¥ =sedimentation volume of deflocculated suspension
`V¥ = sediment volume of completely deflocculated suspension.
`(Sediment volume ultimate relatively small)
`Vo=Original volume of suspension
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`3. Sedimentation Velocity3
`The velocity dx / dt of a particle in a unit centrifugal force can be expressed in terms of the
`Svedberg co-efficient 'S' Under centrifugal force, particle passes from position x at time t to
`position x at time t.
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`The Sedimentation Behaviour of Flocculated and Deflocculated Suspensions
`Flocculated Suspensions
`In flocculated suspension, formed flocks (loose aggregates) will cause increase in
`sedimentation rate due to increase in size of sedimenting particles. Hence, floculated
`suspensions sediment more rapidly.
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`Here, the sedimentation depends not only on the size of the flocks 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.
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`Fig 1.2: Sedimentation Behaviour of Flocculated and Deflocculated Suspensions
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`Deflocculated suspensions In deflocculated suspension, individual particles are settling, so
`rate of sedimentation is slow which prevents entrapping of liquid medium which makes it
`difficult to re-disperse by agitation. This phenomenon also called 'cracking' or 'claying'. In
`deflocculated suspension larger particles settle fast and smaller remain in supernatant liquid
`so supernatant appears cloudy whereby in flocculated suspension, even the smallest particles
`are involved in flocs, so the supernatant does not appear cloudy.
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`Brownian Movement (Drunken walk)
`Brownian movement of particle prevents sedimentation by keeping the dispersed material in
`random motion.
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`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, provided that their size is below
`critical radius (r). Brownian movement can be observed, if particle size is about 2 to 5 mm,
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`when the density of particle & viscosity of medium are favorable. If the particles (up to about
`2 micron in diameter) are observed under a microscope or the light scattered by colloidal
`particle is viewed using an ultra microscope, the erratic motion seen is referred to as
`Brownian motion. This typical motion viz., Brownian motion of the smallest particles in
`pharmaceutical suspension is usually eliminated by dispersing the sample in 50% glycerin
`solution having viscosity of about 5 cps.
`
`The displacement or distance moved (Di) due to Brownian motion is given by
`equation:
` Di2=RTt
` N3πηr
`
`Where, R = gas constant
`T = temp. in degree Kelvin
`N = Avogadro's number
`η = viscosity of medium
`t = time
`r = radius of the particle
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`The radius of suspended particle which is increased Brownian motions become less &
`sedimentation becomes more important In this context, NSD i.e. 'No Sedimentation Diameter'
`can be defined. It refers to the diameter of the particle, where no sedimentation occurs in the
`suspensions systems. The values of NSD depend on the density and viscosity values of any
`given system.
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` Electrokinetic Properties
`1. 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. As shown in figure 1.3,
`the potential drops off rapidly at first, followed by more gradual decrease as the distance from
`the surface increases. This is because the counter ions close to the surface acts as a screen that
`reduce the electrostatic attraction between the charged surface and those counter ions further
`away from the surface.
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`Fig 1.3: Zeta potential
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`
`
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`Zeta potential has practical application in stability of systems containing dispersed particles
`since this potential, rather than the Nernst potential, governs the degree of repulsion between
`the adjacent, similarly charged, dispersed particles. If the zeta potential is reduced below a
`certain value (which depends on the particular system being used), the attractive forces
`exceed the repulsive forces and the particles come together. This phenomenon is known as
`flocculation.
`
`The flocculated suspension is one in which zeta potential of particle is -20 to +20 mV. Thus
`the phenomenon of flocculation and deflocculation depends on zeta potential carried by
`particles. Particles carry charge may acquire it from adjuvants as well as during process like
`crystallization, grinding processing, adsorption of ions from solution e.g. ionic surfactants. A
`zeta meter is used to detect zeta potential of a system.
`
`2. Flocculating Agents
`Flocculating agents decreases zeta potential of the suspended charged particle and thus cause
`aggregation (floc formation) of the particles.
`Examples of flocculating agents are:
`(cid:120) Neutral electrolytes such as KCl, NaCl.
`(cid:120) Calcium salts
`(cid:120) Alum
`(cid:120) Sulfate, citrates, phosphates salts
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`(cid:120) Neutral electrolytes e.g. NaCl, KCl besides acting as flocculating agents, also decreases
`interfacial tension of the surfactant solution. If the particles are having less surface charge
`then monovalent ions are sufficient to cause flocculation e.g. steroidal drugs. For highly
`charged particles e.g. insoluble polymers and poly-electrolytes species, di or trivalent
`flocculating agents are used.
`
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`3. Flocculated Systems
`In this system, the disperse phase is in the form of large fluffy agglomerates, where
`individual particles are weakly bonded with each other. As the size of the sedimenting unit is
`increased, flocculation results in rapid rate of sedimentation. The rate of sedimentation is
`dependent on the size of the flocs and porosity. Floc formation of particles decreases the
`surface free energy between the particles and liquid medium thus acquiring thermodynamic
`stability.
`
`The structure of flocs is maintained in sediment so they contain small amount of liquid
`entrapped within the flocs. The entrapment of liquid within the flocks increases the
`sedimentation volume and the sediment is easily redispersed by small amount of agitation.
`
`Formulation of Flocculated Suspension System
`There are two important steps to formulate flocculated suspension
`(cid:120) The wetting of particles
`(cid:120) Controlled flocculation
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`The primary step in formulation is that adequate wetting of particles is ensured. Suitable
`amount of wetting agents solve this problem which is described under wetting agents.
`
`Careful control of flocculation is required to ensure that the product is easy to administer.
`Such control is usually is achieved by using optimum concentration of electrolytes, surface-
`active agents or polymers. Change in these concentrations may change suspension from
`flocculated to deflocculated state.
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`Method of Floccules Formation
`The different methods used to form floccules are mentioned below:
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`1. Electrolytes
`Electrolytes decrease electrical barrier between the particles and bring them together to form
`floccules. They reduce zeta potential near to zero value that results in formation of bridge
`between adjacent particles, which lines them together in a loosely arranged structure.
`
`Electrolytes act as flocculating agents by reducing the electric barrier between the particles,
`as evidenced by a decrease in zeta potential and the formation of a bridge between adjacent
`particles so as to link them together in a loosely arranged structure. If we disperse particles of
`bismuth subnitrate in water we find that based on electrophoretic mobility potential because
`of the strong force of repulsion between adjacent particles, the system is peptized or
`deflocculated. By preparing series of bismuth subnitrate suspensions containing increasing
`concentration of monobasic potassium phosphate co-relation between apparent zeta potential
`and sedimentation volume, caking and flocculation can be demonstrated.
`
`
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`Fig 1.4: Caking Diagram, Showing the Flocculation of a Bismuth Subnitrate Suspension
`by Means of the Flocculating Agent.
`
`The addition of monobasic potassium phosphate to the suspended bismuth subnitrate particles
`causes the positive zeta potential to decrease owing to the adsorption of negatively charged
`phosphate anion. With continued addition of the electrolyte, the zeta potential eventually falls
`to zero and then increases in negative directions.
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`Only when zeta potential becomes sufficiently negative to affect potential does the
`sedimentation volume start to fall. Finally, the absence of caking in the suspensions correlates
`with the maximum sedimentation volume, which, as stated previously, reflects the amount of
`flocculation.
`
`2. Surfactants
`Both ionic and non-ionic surfactants can be used to bring about flocculation of suspended
`particles. Optimum concentration is necessary because these compounds also act as wetting
`agents to achieve dispersion. Optimum concentrations of surfactants bring down the surface
`free energy by reducing the surface tension between liquid medium and solid particles. This
`tends to form closely packed agglomerates. The particles possessing less surface free energy
`are attracted towards to each other by van der waals forces and forms loose agglomerates.
`
`3. Polymers
`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.
`
`4. Liquids
`Here like granulation of powders, when adequate liquids are present to form the link,
`compact agglomerate is formed. The interfacial tension in the region of the link, provide the
`force acting to hold the particles together. Hydrophobic solids may be flocculated by adding
`hydrophobic liquids.
`
`Important Characteristics of Flocculated Suspensions
`(cid:120) Particles in the suspension are in form of loose agglomerates.
`(cid:120) Flocs are collection of particles, so rate of sedimentation is high.
`(cid:120) The sediment is formed rapidly.
`(cid:120) The sediment is loosely packed. Particles are not bounded tightly to each other. Hard cake
`is not formed.
`(cid:120) The sediment is easily redispersed by small amount of agitation.
`(cid:120) The flocculated suspensions exhibit plastic or pseudo plastic behavior.
`(cid:120) The suspension is somewhat unsightly, due to rapid sedimentation and presence of an
`obvious clear supernatant region.
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`(cid:120) The pressure distribution in this type o suspension is uniform at all places, i.e. the
`pressure at the top and bottom of the suspension is same.
`(cid:120)
`In this type of suspension, the viscosity is nearly same at different depth level.
`(cid:120) The purpose of uniform dose distribution is fulfilled by flocculated suspension.
`
`Important Characteristics of Deflocculated Suspensions
`(cid:120)
`In this suspension particles exhibit as separate entities.
`(cid:120) Particle size is less as compared to flocculated particles. Particles settle separately and
`hence, rate of settling is very low.
`(cid:120) The sediment after some period of time becomes very closely packed, due to weight of
`upper layers of sedimenting materials.
`(cid:120) After sediment becomes closely packed, the repulsive forces between particles are
`overcomed resulting in a non-dispersible cake.
`(cid:120) More concentrated deflocculated systems may exhibit dilatant behavior.
`(cid:120) This type of suspension has a pleasing appearance, since the particles are suspended
`relatively longer period of time.
`(cid:120) The supernatant liquid is cloudy even though majority of particles have been settled.
`(cid:120) As the formation of compact cake in deflocculated suspension, Brookfield viscometer
`shows increase in viscosity when the spindle moves to the bottom of the suspension.
`(cid:120) There is no clear-cut boundary between sediment and supernatant. Flocculation is
`necessary for stability of suspension, but however flocculation affects bioavailability of
`the suspension.
`
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`Rheological Behaviour
`Generally viscosity is measured as a part ofrheological studies because it is easy to measure
`practically. Viscosity is the proportionality constant between the shear rate and shear stress, it
`is denoted by η = S/D
`Where, S = Shear stress & D = Shear rate
`Viscosity has units dynes-sec/cm or g/cmsec
`or poise in CGS system.
`SI unit of Viscosity is N-sec/m
`1 N-sec/m = 10 poise
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`1 poise is defined as the shearing stress required producing a velocity difference of 1 cm/sec
`between two parallel layers of liquids of 1cm area each and separated by 1 cm distance.
`
`
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`Fig 1.5: Figure Showing the Difference in Velocity of Layers
`
`
`As shown in the above figure, the velocity of the medium decreases as the medium comes
`closer to the boundary wall of the vessel through which it is flowing. There is one layer
`which is stationary, attached to the wall. The reason for this is the cohesive force between the
`wall and the flowing layers and inter-molecular cohesive forces. This inter-molecular force is
`known as Viscocity of that medium. In simple words the viscocity is the opposing force to
`flow, It is characteristic of the medium.
`
`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 –ρ1) g/18η
`Where, v= Terminal settling velocity
`d= Diameter of the settling particle
`r =Density of the settling solid (dispersed phase)
`r = Density of the liquid (dispersion medium)
`g=Gravitational acceleration
`η = Viscosity of the dispersion medium
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`So as the viscosity of the dispersion medium increases, the terminal settling velocity
`decreases thus the dispersed phase settle at a slower rate and they remain dispersed for longer
`time 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. Now a day's structured vehicles are used to
`solve both the problems.
`
`Thixotropy
`Thixotropy is defined as the isothermal slow reversible conversion of gel to sol. Thixotropic
`substances on applying shear stress convert to sol(fluid) and on standing they slowly turn to
`gel (semisolid).
`
`Thixotropic substances are now a day's more used in suspensions to give stable suspensions.
`As Thixotropic substances on storage turn to gel and thus that their viscosity increases
`infinitely which do not allow the dispersed particles to settle down giving a stable suspension.
`When shear stress is applied they turn to sol and thus are easy to pour and measure for
`dosing. So Thixotropic substances solve both the problems, stability and pourability.
`
`Negative Thixotropy and Rheopexy
`Negative Thixotropy is a time dependent increase in the viscosity at constant shear.
`Suspensions containing 1 to 10% of dispersed solids generally show negative Thixotropy.
`
`Rheopexy is the phenomenon where sol forms a gel more rapidly when gently shaken than
`when allowed to form the gel by keeping the material at rest. In negative Thixotropy, the
`equilibrium form is sol while in Rheopexy, the equilibrium state is gel.
`
`Different Approaches to Increase the Viscosity of Suspensions
`Various approaches have been suggested to enhance the viscosity of suspensions. Few of
`them are as follows:
`
`1. Viscosity Enhancers
`Some natural gums (acacia, tragacanth), polymers, cellulose derivatives (sodium CMC,
`methyl cellulose), clays(bentonite) and sugars (glucose, fructose) are used to enhance the
`viscosity of the dispersion medium. They are known as suspending agents.
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`www.wjpps.com Vol 5, Issue 12, 2016.
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` KINDERFARMS Ex. 1014
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