Finding Dosage Strength of Reconstituted Solution

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.

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PHARMACEUTICAL SUSPENSIONS: PATIENT COMPLIANCE ORAL

DOSAGE FORMS

*R. Santosh Kumar and T. Naga Satya Yagnesh

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

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.041

Volume 5, Issue 12, 1471-1537. Re view Article ISSN 2278 – 4357

*Corresponding Author

R. Santosh Kumar

GITAM Institute of

Pharmacy, GITAM

University, Rushikonda,

Visakhapatnam, A.P-

530045.

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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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

 Oral suspension

 Externally applied suspension

 Parenteral suspension

2. Based on Proportion of Solid Particles

 Dilute suspension (2 to10%w/v solid)

 Concentrated suspension (50%w/v solid)

3. Based on Electro Kinetic Nature of Solid

 Particles

 Flocculated suspension

 Deflocculated suspension

4. Based on Size of Solid Particles

 Colloidal suspension (< 1 micron)

 Coarse suspension (>1 micron)

 Nano suspension (10 ng)

Advantages

 Pharmaceutical Suspension can improve chemical stability of certain drug. E.g.Procaine

penicillin G.

 Drug in suspension exhibits higher rate of bioavailability than other dosage forms.

bioavailability is in following order,

Solution > Suspension > Capsule > Compressed Tablet > Coated tablet

 Duration and onset of action can be controlled. E.g.Protamine Zinc-Insulin suspension.

 Suspension can mask the unpleasant bitter taste of drug. E.g. Chloramphenicol.

Disadvantages

 Physical stability, sedimentation and compaction can causes problems.

 It is bulky sufficient care must be taken during handling and transport.

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 It is difficult to formulate.

 Uniform and accurate dose cannot be achieved unless suspension are packed in unit

dosage form.

Features Desired in Pharmaceutical

 The suspended particles should not settle rapidly and sediment produced, must be easily

re-suspended by the use of moderate amount of shaking.

 It should be easy to pour yet not watery and no grittiness.

 It should have pleasing odour, colour and palatability.

 Good syringeability.

 It should be physically, chemically and microbiologically stable.

 Parenteral/Ophthalmic suspension should be sterilizable.

Applications

 Suspension is usually applicable for drug which is insoluble or poorly soluble.

E.g. Prednisolone suspension.

 To prevent degradation of drug or to improve stability of drug.

E.g. Oxytetracycline suspension.

 To mask the taste of bitter of unpleasant drug.

E.g. Chloramphenicol palmitate suspension.

 Suspension of drug can be formulated for topical application e.g. Calamine lotion.

 Suspension can be formulated for parentral application in order to control rate of drug

absorption.

 Vaccines as a immunizing agent are often formulated as suspension.

E.g. Cholera vaccine.

 X-ray contrast agent are also formulated as suspension.

E.g. Barium sulphate for examination of alimentary tract.

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 (ρ s -ρ o )g / 18η o

= 2r2 (ρ s -ρo )g / 9η o

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.

Limitation of Stoke's Equation

Stoke's equation applies only to:

 Spherical particles in a very dilute suspension (0.5 to 2 gm per 100 ml).

 Particles which freely settle without interference with one another (without collision).

 Particles with no physical or chemical attraction or affinity with the dispersion medium.

 But most of pharmaceutical suspension formulation has conc. 5%, 10%, or higher

percentage, so there occurs hindrance in particle settling.

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

Where,F¥ =sedimentation volume of deflocculated suspension

V¥ = sediment volume of completely deflocculated suspension.

(Sediment volume ultimate relatively small)

Vo =Original volume of suspension

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.

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.

Fig 1.2: Sedimentation Behaviour of Flocculated and Deflocculated Suspensions

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.

Brownian Movement (Drunken walk)

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

random motion.

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

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.

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

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:

 Neutral electrolytes such as KCl, NaCl.

 Calcium salts

 Alum

 Sulfate, citrates, phosphates salts

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 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.

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

 The wetting of particles

 Controlled flocculation

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.

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.

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

 Particles in the suspension are in form of loose agglomerates.

 Flocs are collection of particles, so rate of sedimentation is high.

 The sediment is formed rapidly.

 The sediment is loosely packed. Particles are not bounded tightly to each other. Hard cake

is not formed.

 The sediment is easily redispersed by small amount of agitation.

 The flocculated suspensions exhibit plastic or pseudo plastic behavior.

 The suspension is somewhat unsightly, due to rapid sedimentation and presence of an

obvious clear supernatant region.

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 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.

 In this type of suspension, the viscosity is nearly same at different depth level.

 The purpose of uniform dose distribution is fulfilled by flocculated suspension.

Important Characteristics of Deflocculated Suspensions

 In this suspension particles exhibit as separate entities.

 Particle size is less as compared to flocculated particles. Particles settle separately and

hence, rate of settling is very low.

 The sediment after some period of time becomes very closely packed, due to weight of

upper layers of sedimenting materials.

 After sediment becomes closely packed, the repulsive forces between particles are

overcomed resulting in a non-dispersible cake.

 More concentrated deflocculated systems may exhibit dilatant behavior.

 This type of suspension has a pleasing appearance, since the particles are suspended

relatively longer period of time.

 The supernatant liquid is cloudy even though majority of particles have been settled.

 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.

 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.

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.

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 (ρ s –ρ 1 ) 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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2. Co-solvents

Some solvents which themselves have high viscosity are used as co-solvents to enhance the

viscosity of dispersion medium.

Effects of Viscosity on Properties of Suspensions

As viscosity increases the sedimentation rate decreases, thus physical stability increases.

Clinical effectiveness of Nitro furantoin suspension increases as the viscosity of the

suspension increases. Viscosity strongly affects the retention time of polymeric suspensions

in the pre-corneal area of human eye.[3] Clearance rate of colloidal solutions from the nasal

cavity can be decreased by increasing their viscosity.[4] Per-cutaneous absorption of

Benzocaine increases as the viscosity of suspension increases.

Suspension Syringeability

Parenteral suspensions are generally deflocculated suspensions and many times supplied as

dry suspensions, i.e. in one bottle freeze dried powder is supplied and in another bottle the

vehicle is supplied and the suspension is to be reconstituted at the time of injection. If the

parenteral suspensions are flocculated one, their syringeability will be less i.e. difficult to

inject for the doctor or nurse and painful to patient due to larger floccule size. Parenteral

suspensions are generally given by intra muscular route. Now a days intravenous suspension

are also available with particle size less than 1 micron, termed as nano-suspension. Viscosity

of suspensions should be within table range for easy syringeability and less painful to patient.

Colloidal Properties

Colloids in suspension form chemical compounds such as ions in the solution, So the

suspension characteristics of colloids are generally ignored. Generally, colloids are held in

suspension form through a very slight Electro-negative charge on the surface of each of the

particle. This charge is called Zeta Potential. These minute charge called Zeta-potential is the

main function that determines ability of a liquid to carry material in suspension. As this

charge (Electro-negative charge) increases, more material can be carried in suspension by

liquid. As the charge decreases, the particles move closer to each other and that causes liquid

to decrease its ability to carry out material in suspension. There is a point where the ability to

carry material in suspension is exceeded and particles begin to clump together with the

heavier particles materials dropping out of the liquid and coagulating. Colloids in suspension

determine the ability of all iquids particularly water-based liquids to carry material. This also

applies to semisolids and solids.

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Formulation of Pharmaceutical Suspensions

Structured Vehicle

For the need of a stable suspension, the term 'Structured vehicle' is most important for

formulation view and stability criteria. The main disadvantage of suspension dosage form

that limits its use in the routine practice is its stability during storage for a long time. To

overcome this problem or to reduce it to some extent, the term 'Structured vehicle has got

importance. The structured vehicle is the vehicle in which viscosity of the preparation under

the static condition of very low shear on storage approaches infinity. The vehicle behaves like

a 'false body', which is able to maintain the particles suspended which is more or less stable.

The 'Structured vehicle' concept is applicable only to deflocculated suspensions, where hard

solid cake forms due to settling of solid particles and they must be redispersed easily and

uniformly at the time of administration. The Structured Vehicle concept is not applicable to

flocculated suspension because settled floccules get easily redispersed on shaking. Generally,

concept of Structured vehicle is not useful for Parenteral suspension because they may create

problem in syringeability due to high viscosity.

In addition, Structured vehicle should posses some degree of Thixotropic behaviour viz., the

property of GEL-SOL-GEL transformation. Because during storage it should be remained in

the form of GEL to overcome the shear stress and to prevent or reduce the formation of hard

cake at the bottom which to some extent is beneficial for pourability and uniform dose at the

time of administration.

Preparation of Structured Vehicle

Structured vehicles are prepared with the help of Hydrocolloids. In a particular medium, they

first hydrolyzed and swell to great degree and increase viscosity at the lower concentration.

In addition, it can act as a 'Protective colloid' and stabilize charge.

Density of structured vehicle also can be increased by:

 Polyvinylpyrrolidone

 Polyethylene glycols

 Glycerin

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Other Formulation Aspects

A perfect suspension is one, which provides content uniformity. The formulator must

encounter important problems regarding particle size distribution, specific surface area,

inhibition of crystal growth and changes in the polymorphic form. The formulator must

ensure that these and other properties should not change after long term storage and do not

adversely affect the performance of suspension. Choice of pH, particle size, viscosity,

flocculation, taste, color and odour are some of the most important factors that must be

controlled at the time of formulation.

Table 1.1: Various Components used Insuspension Formulation

They are added to disperse solids in

continous liquid phase.

They are added to floc the drug particles

They are added to increase the viscocity of

suspension.

Buffers and PH adjusting agents

They are added to stabilize the suspension to

a desired PH range.

They are added to aadjust osmotic pressure

comparable to biological fluid.

They are added to impart desired color to

suspension and improve elegance.

They are added to prevent microbial growth.

They are added to construct structure of the

final suspension.

List of Suspending Agents used for Manufacturing Suspensions

 Alginates

 Methylcellulose

 Hydroxyethylcellulose

 Carboxymethylcellulose

 Sodium Carboxymethylcellulose

 Microcrystalline cellulose

 Acacia

 Tragacanth

 Xanthan gum

 Bentonite

 Carbomer

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 Carageenan

 Powdered cellulose

 Gelatin

Most suspending agents perform two functions i.e. besides acting as a suspending agent they

also imparts viscosity to the solution. Suspending agents form film around particle and

decrease interparticle attraction.

A good suspension should have well developed thixotropy. At rest the solution is sufficient

viscous to prevent sedimentation and thus aggregation or caking of the particles. When

agitation is applied the viscosity is reduced and provide good flow characteristic from the

mouth of bottle.

Preferred suspending agents are those that give thixotropy to the media such as Xanthan gum,

Carageenan, Na CMC/MCC mixers, Avicel RC 591 Avicel RC 581 and Avicel CL 611.[3]

Avicel is the trademark of FMC Corporation and RC 591, RC 581 and CL 611 indicates

mixture of MCC and Na CMC. The viscosity of thixotropic formulation is 6000 to 8000 cps

before shaking and it is reduced to 300 to 800 cps after being shaken for 5 seconds.[3]

For aqueous pharmaceutical compositions containing titanium dioxide as an opacifying

agent, only Avicel RTM RC-591 microcrystalline cellulose is found to provide thixotropy to

the solution, whereas other suspending agents failed to provide such characteristics to the

product. Most of the suspending agents do not satisfactorily suspend titanium dioxide until

excessive viscosities are reached. Also they do not providethixotropic gel formulation that is

readily converted to a pourable liquid with moderate force for about five seconds.[13]

The suspending agents/density modifying agents used in parenteral suspensions are PVP

(polyvinylpyrrolidone), PEG (Polyethylene glycol) 3350 and PEG 4000.[4]

The polyethylene glycols, having molecular weight ranging from 300 to 6000 are suitable as

suspending agents for parenteral suspension. However, PEG 3350 and PEG 4000 are most

preferably used.[4]

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PVPs, having molecular weight ranging from 7000 to 54000 are suitable as suspending

agents for parenteral suspension. Examples of these PVPs are PVP K 17, PVP K 12, PVP K

25, PVP K 30. Amongst these K 12 and K17 are most preferred.[4]

The selection of amount of suspending agent is dependent on the presence of other

suspending agent, presence or absence of other ingredients which have an ability to act as a

suspending agent or which contributes viscosity to the medium. Stability of the suspensions

depends on the types of suspending agents rather than the physical properties of the drugs.

This evidence is supported through the study by Bufgalassi S et. al. They formulated aqueous

suspension of three drugs (Griseofulvin, Ibuprofen, Indomethacin). The suspending agents

used were Na CMC, MCC/CMC mixer and jota carageenan (CJ). Evaluation of suspension

was based on the physical and physico-chemical characteristics of the drugs, the rheological

properties of the suspending medium, corresponding drug suspension and the physical and

chemical stability of the suspension. They noted that the physical stability of suspension was

mainly dependent on the type of suspending agent rather than the physical characteristics of

the drug. The suspending agents which gave highest stability were jota carageenan (having

low-te mperature gelation characteristics) and MC/CMC (having thixotropic flux).

Table 1.2: Stability pH Range and Concentrations of Most Commonly used Suspending

Agents.

Concentrations used as

Suspending Agent

Hydroxypropylmethyl cellulose

Microcrystalline Cellulose

Colloidal silicone Dioxide

as thickening agents. They increase in viscosity of the solution, which is necessary to prevent

sedimentation of the suspended particles as per Stoke's's law. The suspension having a

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viscosity within the range of 200 -1500 milipoise are readily pourable.[3] Use of combination

of suspending agents may give beneficial action as compared to single suspending agent.

Hashem F et al. carried out experiment to observe effect of suspending agents on the

characteristics of some anti-inflammatory suspensions.[23] For Glafenine, the combination of

2% veegum and 2% sorbitol was best as compared to otherformulation of Glafenine. The

physical stability of Mefenamic acid and Flufenamic acid was improved by combining 2%

veegum, 2% sorbitol and 1% Avicel. Excellent suspension for Ibuprofen and Azapropazone

was observed by combining 1% veegum, 1% sorbitol and 1% alginate.

Some important characteristics of most commonly used suspension are mentioned below:

1. Alginates

Alginate salts have about same suspending action to that of Tragacanth. Alginate solution

looses its viscosity when heated above 600C. Due to depolymerization. Fresh solution has

highest viscosity, after which viscosity gradually decreases and acquires constant value after

24 hrs. Maximum viscosity is observed at a pH range of 5-9. It is also used as bulk laxative

and in food industry. Due to significant thickening effect, alginate is used at lower

concentration to avoid problem of viscosity. High viscosity suspensions are not readily

pourable. 1% solution of low viscosity grade of alginate has viscosity of 4-10 mPas at 200 C.

Chemically alginates are polymers composed of mannuronic acid and glucuronic acid

monomers. The ratio of mannuronic acid to glucuronic acid determines the raft-forming

properties. High ratio (e.g. 70% glucuronic acid) forms the strongest raft. Protanal LFR 5/60

is the alginate having high levels of glucuronic acid used in the cimetidine suspension

formulation. The concentration of alginate is optimized by raft-forming ability of the

suspension in order to avoid pourability problem by too much increase in viscosity of

suspension. In practice, alginate is used at concentration less than 10% w/w, particularly at

5% w/w.

2. Methyl Cellulose

Methyl Cellulose is available in several viscosity grades. The difference in viscosity is due to

difference in methylation and polymer chain length. Methylcellulose is more soluble in cold

water than hot water. Adding Methyl Cellulose in hot water and cooling it with constant

stirring gives clear or opalescent viscous solution. Methyl Cellulose is stable at pH range of

3- 11. As methyl Cellulose is non-ionic, it is compatible with many ionic adjuvants. On

heating to 50oC, solution of Methyl Cellulose is converted to gel form and on cooling, it is

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again converted to solution form. Methyl Cellulose is not susceptible to microbial growth. It

is not absorbed from G.I tract and it is non-toxic.

3. Hydroxyethyl Cellulose

Hydroxyethyl Cellulose (HEC) is another good suspending agent having somewhat similar

characteristics to Methylcellulose. In HEC hydroxyethyl group is attached to cellulose chain.

Unlike methylcellulose, HEC is soluble in both hot and cold water and do not form gel on

heating.

4. Carboxymethyl Cellulose (CMC)

Carboxymethyl Cellulose is available at different viscosity grades. Low, medium and high

viscosity grades are commercially available. The choice of proper grade of CMC is

dependent on the viscosity and stability of the suspension. In case of HVCMC, the viscosity

significantly decreases when temperature rises to 400C from 250C. This may become a

product stability concern. Therefore to improve viscosity and stability of suspension MV-

CMC is widely accepted. This evidence was supported through an experiment by change HC

et al. They developed topical suspension containing three active ingredient by using 1% MV-

CMC and 1% NaCl. The viscosity stability was improved by replacing HV-CMC by 1% MV-

CMC and 1% NaCl.

5. Sodium Carboxymethylcellulose (NaCMC)[3,6]

It is available in various viscosity grades. The difference in viscosity is dependent on extent

on polymerization. It is soluble in both hot and cold water. It is stable over a pH range of 5-

10. As it is anionic, it is incompatible with polyvalent cations. Sterilization of either powder

of mucilage form decreases viscosity. It is used at concentration up to 1%.

6. Microcrystalline Cellulose (MCC; Trade name- Avicel)[3,6,8]

It is not soluble in water, but it readily disperses in water to give thixotropic gels. It is used in

combination with Na-CMC, MC or HPMC, because they facilitate dispersion of MCC.

Colloidal MCC (attrited MCC) is used as a food additive, fat replacer in many food products,

where it is used alone or combination with other additives such as CMC.

It is found that MCC: alginate complex compositions are excellent suspending agents for

water insoluble or slightly soluble API. The advantages of MCC: alginate complex

compositions are that they provide excellent stability. Further suspensions prepared with

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them are redispersible with small amount of agitation and maintain viscosity even under high

shear environment.

7. Acacia[6]

It is most widely used in extemporaneous suspension formulation. Acacia is not a good

thickening agent. For dense powder acacia alone is not capable of providing suspending

action, therefore it is mixed with Tragacanth, starch and sucrose which is commonly known

as Compound Tragacanth Powder BP.

8. Tragacanth[6,2]

The solution of Tragacanth is viscous in nature. It provides thixotrophy to the solution. It is a

better thickening agent than acacia. It can also be used in extemporaneous suspension

formulation, but its use in such type of formulation is less than that of Acacia. The maximum

viscosity of the solution of Tragacanth is achieved after several days, because several days to

hydrate completely.

9. Xanthan Gum[3]

Xanthan gum may be incorporated at a concentration of 0.05 to 0.5% w/w depending on the

particular API. In case of antacid suspension, The Xanthan concentration is between 0.08 to

0.12% w/w. For ibuprofen and acetaminophen suspension, Xanthan concentration is between

0.1 to 0.3% w/w.

Wetting Agents[6,7]

Hydrophilic materials are easily wetted by water while hydrophobic materials are not.

However hydrophobic materials are easily wetted by non-polar liquids. The extent of wetting

by water is dependent on the hydrophillicity of the materials. If the material is more

hydrophilic it finds less difficulty in wetting by water. Inability of wetting reflects the higher

interfacial tension between material and liquid. The interfacial tension must be reduced so

that air is displaced from the solid surface by liquid.

Non-ionic surfactants are most commonly used as wetting agents in pharmaceutical

suspension. Non-ionic surfactants having HLB value between 7-10 are best as wetting agents.

High HLB surfactants act as foaming agents. The concentration used is less than 0.5%. A

high amount of surfactant causes solubilization of drug particles and causes stability probem.

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Ionic surfactants are not generally used because they are not compatible with many adjuvant

and causes change in pH.

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 in optimum concentration facilitate dispersion of particles. Generally we use non-

ionic surfactants but ionic surfactants can also be used depending upon certain conditions.

Disadvantages of surfactants are that they have foaming tendencies. Further they are bitter in

taste. Some surfactants such as polysorbate 80 interact with preservatives such as methyl

paraben and reduce antimicrobial activity.

All surfactants are bitter except Pluronics and Poloxamers. Polysorbate 80 is most widely

used surfactant both for parenteral and oral suspension formulation. Polysorbate 80 is

adsorbed on plastic container decreasing its preservative action. Polysorbate 80 is also

adsorbed on drug particle and decreases its zeta potential. This effect of polysorbate80

stabilizes the suspension. In an experiment by R. Duro et al., polysorbate 80 stabilized the

suspension containing 4% w/v of Pyrantel pamoate. Polysorbate 80 stabilized suspensions

through steric mechanism. At low concentration of polysorbate 80, only partial stabilization

of suspension was observed. In absence of polysorbate 80, difficulty was observed in re-

dispersion of sedimented particles.

Polysorbate 80 is most widely used due to its following advantages

 It is non-ionic so no change in pH of medium

 No toxicity. Safe for internal use.

 Less foaming tendencies however it should be used at concentration less than 0.5%.

 Compatible with most of the adjuvant.

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. They cause deflocculation of

suspension because force of attraction is declined. e.g. acacia, tragacanth, alginates, guar

gum, pectin, gelatin, wool fat, egg yolk, bentonite, Veegum, Methylcellulose etc.

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Solvents

The most commonly used solvents used are alcohol, glycerin, polyethylene glycol and

polypropylene glycol. The mechanism by which they provide wetting is that they are miscible

with water and reduce liquid air interfacial tension. Liquid penetrates in individual particle

and facilitates wetting.

Buffers[6,3,4]

To encounter stability problems all liquid formulation should be formulated to an optimum

pH. Rheology, viscosity and other property are dependent on the pH of the system. Most

liquid systems are stable at pH range of 4-10. This is the most important in case where API

consists of ionizable acidic or basic groups. This is not a problem when API consists of

neutral molecule having no surface charge.e.g. Steroids, phenacetin, but control of pH is

strictly required as quality control tool.

Buffers are the materials which when dissolved in a solvent will resist any change in pH

when an acid or base is added. Buffers used should be compatible with other additives and

simultaneously they should have less toxicity. Generally pH of suspension should be kept

between 7-9.5, preferably between 7.4-8.4. Most commonly used buffers are salts of week

acids such as carbonates, citrates, gluconates, phosphate and tartrates.

Amongst these citric acid and its pharmaceutically acceptable salts, phosphoric acid and its

pharmaceutically acceptable salts are commonly used in suspension formulation. However,

Na phosphate is most widely used buffer in pharmaceutical suspension system. Citric acid is

most preferable used to stabilize pH of the suspension between 3.5 to 5.0.

L-methionine is most widely used as buffering agent in parenteral suspension. Usual

concentration of phosphoric acid salts required for buffering action is between 0.8 to 2.0%

w/w or w/v. But due to newly found super-additive effect of L-methionine, the concentration

of phosphoric acid salts is reduced to 0.4% w/w or w/v or less.

Buffers have four main applications in suspension systems that are mentioned below:

 Prevent decomposition of API by change in pH.

 Control of tonicity

 Physiological stability is maintained

 Maintain physical stability

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For aqueous suspensions containing biologically active compound, the pH can be controlled

by adding a pH controlling effective concentration of L-methionine.

L-methionine has synergistic effects with other conventional buffering agents when they are

used in low concentration. Preferred amount of buffers should be between 0 to 1 grams per

100 mL of the suspension.

Osmotic Agents[6,3]

They are added to produce osmotic pressure comparable to biological fluids when suspension

is to be intended for ophthalmic or injectable preparation. Most commonly used osmotic

agents for ophthalmic suspensions are dextrose, mannitol and sorbitol.

The tonicity-adjusting agents used in parenteral suspension are sodium chloride, sodium

sulfate, dextrose, mannitol and glycerol.

Preservatives[3,4,5,6,7]

The naturally occurring suspending agents such as tragacanth, acacia, xanthan gum are

susceptible to microbial contamination. If suspension is not preserved properly then the

increase in microbial activity may cause stability problem such as loss in suspending activity

of suspending agents, loss of color, flavor and odor, change in elegance etc. Antimicrobial

activity is potentiated at lower pH.

The preservatives used should not be

 Adsorbed on to the container

 It should be compatible with other formulation additives.

 Its efficacy should not be decreased by pH.

This occurs most is commonly in antacid suspensions because the pH of antacid suspension is

6-7 at which parabens, benzoates and sorbates are less active. Parabens are unstable at high

pH value so parabens are used effectively when pH is below 8.2. Most commonly observed

incompatibility of PABA (Para amino benzoic acid) esters is with non-ionic surfactant, such

as polysorbate 80, where PABA is adsorbed into the micelles of surfactant. Preservative

efficacy is expected to be maintained in glass container if the closure is airtight, but now a

days plastic container are widely used where great care is taken in selection of preservative.

The common problem associated with plastic container is permeation of preservatives

through container or adsorption of preservatives to the internal plastic surface. The use of

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cationic antimicrobial agents is limited because as they contain positive charge they alter

surface charge of drug particles.

Secondly they are incompatible with many adjuvants.

Most common incidents, which cause loss inpreservative action, are,

 Solubility in oil

 Interaction with emulsifying agents, suspending agents

 Interaction with container

 Volatility

Active form of preservative may be ionized or unionized form.

For example active form of benzoic acid is undissociated form. The pKa of benzoic acid is

4.2. Benzoic acid is active below pH 4.2 where it remains in unionized form.

Fraction of undissociated preservative=1/1+antilog (pH-pKa)

The combination of two or more preservative has many advantages in pharmaceutical system

such as

 Wide spectrum of activity

 Less toxicity

 Less incidence of resistance

 Preservatives can be used in low concentration.

For example, older formulation of eye drops, contain combination of methyl and propyl

paraben, which provide antifungal and antibacterial property. Now a days, combination of

phenylethyl alcohol, phenoxetol and benzalkonium chloride are used in eye drops. EDTA

(ethylenediaminetetra-acetate) is also used in combination with other preservative. Propylene

glycol is added to emulsions containg parabens to reduce loss to micelles.

Table 1.3: Preservatives and their Optimal Concentration

Name of the preservatives

0.006-0.05% oral suspension

0.02-0.4% topical formulation

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Flavoring and Coloring Agents

They are added to increase patient acceptance. There are many flavoring and coloring agents

are available in market. The choice of color should be associated with flavor used to improve

the attractiveness by the patient. Only sweetening agent are not capable of complete taste

masking of unpleasant drugs therefore, a flavoring agents are incorporated. Color aids in

identification of the product. The color used should be acceptable by the particular country.

Most Widely used Flavouring Agents are as Follows:

Table 1.4: Flavouring agents

Pepperment(oil,spirit,water)

Cardamom(oil,tincture,spirit)

Coloring Agents

Colors are obtained from natural or synthetic sources. Natural colors are obtained from

mineral, plant and animal sources. Mineral colours (also called as pigments) are used to color

lotions, cosmetics and other external preparations. Plant colours are most widely used for oral

suspension. The synthetic dyes should be used within range of 0.0005% to 0.001% depending

upon the depth of colour required and thickness of column of the container to be viewed in it.

Most widely used colours are as follows.

 Titanium dioxide (white)

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 Brilliant blue (blue)

 Indigo carmine(blue)

 Amaranth (red)

 Tartarazine(yellow)

 Sunset yellow(yellow)

 Carmine (red)

 Caramel (brown)

 Chlorophyll(green)

 Annatto seeds(yellow to orange)

 Carrots (yellow)

 Madder plant(reddish yellow)

 Indigo (blue)

 Saffron (yellow)

Sweetening Agents

They are used for taste masking of bitter drug particles.

Examples of sweetening agents are:

 Sweeteners

 Bulk sweeteners

 Sugars such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose,

maltose

 Hydrogenated glucose syrup

 Sugar alcohols such as sorbitol, xylitol, mannitol and glycerin

 Partially hydrolysed starch

 Corn syrup solids

 Artificial sweetening agents

 Sodium cyclamate

 Na saccharin

 Aspartame

 Ammonium glycyrrhizinate

A bulk sweeter is used at concentration of 15-70% w/w of the total weight of the suspension.

This concentration is dependent on presence of other ingredient such as alginate, which have

thickening effect.

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For example, in presence of alginate, sorbitol is used at concentration of 35-55% particularly

at 45% w/w of the total suspension composition. Hydrogenated glucose syrup can be used at

concentration of 55-70% w/w, when alginate is absent. Combination of bulk sweeteners can

also be used. e.g. Combination of sorbitol and hydrogenated glucose syrup or sucrose and

sorbitol. Generally the taste-masking composition consists of at least one sweetening agent

and at least one flavouring agent. The type and amount of flavouring and colouring agent is

dependent on intended consumer of such suspension e.g. pediatric or adult.

Sugar sweetener concentration is dependent on the degree of sweetening effect required by

particular suspension. The preferred amount of sugar sweetener should be between 40 to 100

gm per 100 mL of the suspension. Water soluble artificial sweeteners can also be added in

place of sugar sweetener or in addition to them. The amount of artificial sweetening agents

should be between 0 to 5 gms per 100 mL of suspension. Optimum taste-masking of API in

the suspension can be obtained by limiting the amount of water in the suspension, but the

amount of water must not be too low to hydrate MCC, Na CMC or other suitable suspending

agent. The low amount of water should provide a sufficient aqueous base to impart desired

degree of viscosity. The preferred total amount of water contained in the suspension should

be between 30 to 55 grams per 100 mL of suspension.

Humectants

Humectants absorb moisture and prevent degradation of API by moisture. Examples of

humectants most commonly used in suspensions are propylene glycol and glycerol. Total

quantity of humectants should be between 0-10% w/w. Propylene glycol and glycerol can be

used at concentration of 4% w/w.

Antioxidants

Suitable antioxidants used are as follows.

 Ascorbic acid derivatives such as ascorbic acid, erythorbic acid, Na ascorbate.

 Thiol derivatives such as thioglycerol, cysteine, acetylcysteine, cystine, dithioerythreitol,

dithiothreitol, glutathione

 Tocopherols

 Butylated hydroxyanisole (BHA)

 Butylated hydroxytoluene (BHT)

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 Sulfurous acid salts such as sodium sulfate, sodium bisulfite, acetone sodium bisulfite,

sodium metabisulfite, sodium sulfite, sodium formaldehyde sulfoxylate and sodium

thiosulfate.

 Nordihydroguaiaretic acid

4) Drug Release and Dissolution Study of Suspensions

Introduction

The drug release from suspensions is mainly through dissolution. Suspension share many

physico- chemical characteristic of tablet & capsules with respect to the process of

dissolution. As tablets and capsules disintegrate into powders and form suspension in the

biological fluids, it can be said that they share the dissolution process as a rate limiting step

for absorption and bioavailability.

Principles of Drug Release

Diffusion Controlled Dissolution:

The dissolution of suspension categorized in two ways:

 Dissolution profile for monodisperse system

 Dissolution profile for polydispersed system.

The basic diffusion controlled model for suspended particle was developed by Noyes

& Whitney and was later modified by Nernst.

DQ/dt = DA (Cs-Cb)/h

Where, dQ/dt = Dissolution rate

h = Diffusion layer thickness

Cs = solubility

Cb =bulk area of particle

This model represents the rapid equilibrium at the solid-liquid interface that produces a

saturated solution which diffuses into the bulk solution across a thin diffusion layer.

In this model the heterogeneous process of dissolution is limited to a homogeneous process of

liquid phase diffusion. For spherical particle with a changing surface area, cube-root

relationship which is derived by Hixson & Crowell.

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Formulation Factors Governing Drug Release

Wetting

Wetting of suspended particles by vehicle is must for proper dispersion.

Air entrapment on the particle promotes particles that rise to the top of the dispersion

medium, particle de-aggregation or other cause of instability. Poor wetting on drug particle

leads poor dissolution of particles and so retard release of drug.

Viscosity

The total viscosity of the dispersion is the summation of the intrinsic viscosity of the

dispersion medium and interaction of the particles of disperse phase.

As per Stokes-Einstein equation,

D= KT/6πηr

Intrinsic viscosity of medium affects the dissolution rate of particles because of the diffusion

effect. On enhancement of viscosity the diffusion coefficient decreases, which gives rise to a

proportionate decreases in rate of dissolution.

Effect of Suspending Agent

Different suspending agents act by different way to suspend the drug for example suspension

with the highest viscosity those made by xanthan gum and tragacanth powder shows

inhibitory effects on the dissolution rate. The suspension of salicylic acid in 1% w/v

dispersion of sodium carboxymethycellulose and xanthan gum indicating effect of viscosity

on hydrolysis of aspirin in GIT is not significant from a bioavailability point of view.

Bioavailability of Suspensions From Different Sites

1. Oral Suspensions

The bio-availability of an oral suspension is determined by the extent of absorption of drug

through GIT tract. Oral suspensions vary in composition. The vehicle varies in viscosity, pH

and buffer capacity. In short, the bio-availability of the oral suspension can be optimized by

selecting the appropriate drug particle sizes, site of optimal absorption, particle densities and

vehicle viscosities.

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2. Rectal Suspensions

The administration of the drug suspension by the rectum was accomplished by enema system.

Enemas are in large volume (50-100 ml) & limited patient compatibility. The bioavailability

of rectal suspension depends on absorption from rectal tissues and rectal blood flow.

3. Ophthalmic Suspensions

The viscosity of the vehicle and the particle size of the suspended drug particles affect the

bioavailability of ophthalmic suspension. Polymers (polyvinyl alcohol, polyvinyl

pyrrolidone, cellulose derivatives) used to impart the adequate viscosity and so the particle

settling is retarded. The particle size must be below 10 micron to retard the absorption from

cornea. The particle size is related with dissolution rate as well as retention within the

conjuctival sac. Particles either dissolves or are expelled out of the eye at the lid margin or at

the inner canthus. The time required for the dissolution and corneal absorption must be less

than the residence time of the drug in the conjuctival sac just for retention of particles. The

saturated solution of a suspension absorbed by cornea produce initial response, where as the

retained particles maintain the response as the particles dissolves and drug is absorbed. In

case of suspension having high particulate content, a greater mass of drug remains in the cul-

de-sac following drainage of the applied volume and remaining particles then dissolves in the

tear fluids and provide an additional drug in force, that transport the drug across the corneal

into the aqueous humor.

4. Parenteral Suspensions

Suitable vehicle in suspension for subcutaneous and intramuscular administration are water,

non-toxic oils (sesame, peanut, olive), organic solvent (propylene glycol, polyethylene

glycol, glycerin. When water is used as vehicle dissolved drugs rapidly diffuse into body

tissue leaving a depot of undissolved drug at the injection site. In case of parenteral

suspension the dissolution characteristic of drug at the site of injection controlled the rate at

which drug is absorbed in to the systemic circulation and its resulting bioavailability.

5. Dissolution Testing

Two methods are used for dissolution testing of suspensions.

1. Official Methods (Conventional Methods)

It is known as paddle method. Dissolution profile of the 500 mg sample suspension is

determined at 37degC in 900 ml of pH 7.2 phosphate buffer using the FDA paddle method at

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25 RPM. The apparatus consists of a cylindrical 1000- ml round bottom flask in a multiple -

spindle dissolution drive apparatus and immersed in a controlled temp bath maintained at

37degC. The paddle should position to extend to exactly 2.5 cm above the flask bottom. The

suspension is to be introduced carefully into the flask at the bottom using a 10- ml glass

syringe with an attachment 19-cm needle. Withdraw 2 ml of dissolution medium (and replace

with an equal volume of drug –free buffer) in a 5 ml glass syringe. Immediately filter through

a 0.2 um membrane and analyze.

2. Non-Official Methods (Non-Conventional Methods)

(Experimental Design Based Dissolution Apparatus for Suspensions)

Several types of apparatus were used for dissolution testing of suspensions but there is

drawback of retention of dissolving material within the confines of dissolution chamber &

sampling. Edmundson & Lees develop an electronic particle counting device for suspension

containing Hydrocrticosone acetate.

To explain the dissolution of commercially available Prednisolone suspension by a

magnetically driven rotating filter system.[33]

A methodology to determine the dissolution-rate profile of suspensions employing the FDA's

two bladed paddle method.[35]

Flow Through Apparatus for Dissolution of Suspensions

This method, which is based on the mass between solid and liquid phase in an exchange

column, is shown to avoid some disadvantage of the commonly used beaker method

employing fixed liquid volumes. Determination of dissolution rate profile of suspension using

the FDA's two bladed paddle method.[35]

Dialysis System

In the case of very poorly soluble drugs, where perfect sink condition would necessitate a

huge volume of solvents with conventional method, a different approach, utilizing dialysis

membrane, was tried as a selective barrier between the fresh solvent compartment and the

cell compartment containing the dosage form.

6. Dissolution Models' Studies

The following assumptions are employed for these models:

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The effective particle shape approximates a sphere. The diffusion co-efficient is

concentration independent. Sink condition exists. The interpretation of the apparent thickness

of the diffusion layer fundamentally differentiates each model.

da /dt =-2DCs /1

da /dt =-2DCs /K a

da /dts /αρ

Where,

a= particle diameter (cm)

t= time (sec)

D= diffusion co-efficient (cm /sec)

l= thickness of diffusion layer (cm)

r= density (g/cm)

In model I diffusion layer thickness is constant over the life time of the particle. For model II

& III the diffusion layer thickness is proportional to the one-half of first power of the particle

diameter.

In-Vivo In-Vitro Co-Relationship (IVIVC)[3]

 In Vivo Data In Vitro Data

 Peak plasma/serum concentraions Percent drug dissolution profiles

 AUC (plasma/serum) concentration Dissolution rate profiles

 Profile (To-T )

 Estimated AUC (plasma/serum) Intrinsic dissolution rates

 Plasma Concentration profile (To-∞)

 Pharmacokinetic modeling Dissolution-rate constants and Absorption-rate constant (Ka)

 Dissolution half-lives

 Absorption half-life

 Elimination half-life

 Drug excreted in the urine (T) Time for a certain percentage of Drug to dissolve

 (e.g. T30% ,T50%,T90% ,etc).

 Cumulative amount of drug excreted as a Parameters resulting from function of time

determination of dissolution Kinetics

 Percent drug absorbed-time profiles

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 First order percent remaining to be dissolved-time profiles

 Amount of drug absorbed per milliliter of Logarithmic probability plots the volume of

distribution percent drug dissolved-time profiles

 Statistical moment analysis Statistical moment analysis

 Mean residence time (MRT) Mean residence time (MRT)

 Mean absorption time (MAT) Mean dissolution time (MDT)

5) Quality Assurance and In-Process Quality Control (Ipqc) of Suspensions[1,2,3]

5.1 Introduction

Quality Assurance (QA) is a broad concept which takes into consideration all factors that

individually or combinely affect the quality of a product. It is a system which keeps a Critical

look on what has happened yesterday, what is happening today and what is going to happen

tomorrow so that it can ensure right quality of final product.

Quality Control (QC) is a small part of QA and it is concerned with sampling, testing and

documentation during manufacturing and also after completion of manufacturing. Quality

control is the monitoring process through which manufacturer measures actual quality

performance, compares it with standards and acts on the causes of deviation from standard to

ensure quality product not once but every time.

Quality control system can be divided into two parts on basis of its function:

In Process Quality Control, and Final Quality control.

5.2 In Process Quality Control (Ipqc) of Suspensions

In process quality control is a process of monitoring critical variables of manufacturing

process to ensure a quality of the final product and to give necessary instruction if any

discrepancy is found. In process manufacturing controls are established and documented by

quality control and production personnel to ensure that a predictable amount of each output

cycle falls within the acceptable standard range.

For proper function of In process Quality control the following must be defined.[2]

Which process is to be monitored and at what phase?

Number of samples to be taken for analysis and frequency of sampling?

Quantitative amounts of each sample, Allowable variability, etc.

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Objectives of IPQC Tests[2]

 To minimize inter-batch and intra-batch variability.

 To ensure quality of final product.

 To ensure continuous monitoring of process variables which are going to affect the

quality of product.

 To ensure implementation of GMP in manufacturing.

 To give indication of existence of a functional Quality assurance system.

IPQC Tests of Suspensions

The tests are carried out during the manufacturing of suspension to ensure a stable, safe and

quality product. These include:

Appearance of Phases

This test is done for the dispersed phase and dispersion medium. For preparation of

dispersion phase for suspension usually purified water and syrup are used. The particle size

distribution, clarity of syrup, the viscosity of gum dispersion, quality control of water is

monitored to keep an eye on the product quality.

Viscosity of Phases

Stability of a suspension is solely dependent on the sedimentation rate of dispersed phase,

which is dependent on the viscosity of the dispersion medium. So this test is carried out to

ensure optimum viscosity of the medium so a stable, redispersible suspension can be formed.

The viscosity of the dispersion medium is measured before mixing with dispersed phase and

also viscosity after mixing is determined using Brooke field viscometer. The calculated

values are compared with the standard values and if any difference is found necessary

corrective action are taken to get optimized viscosity.

Particle Size of Dispersed Phase

Optimum size of drug particle in the dispersed phase plays a vital role in stability of final

suspension. So this test is carried out to microscopically analyze and find out particle size

range of drug then it is compared with optimum particle size required. If any difference is

found, stricter monitoring of micronisation step is ensured.

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pH Test

pH of the phases of suspension also contribute to stability and characteristics of formulations.

So pH of the different vehicles, phases of suspension, before mixing and after mixing are

monitored and recorded time to time to ensure optimum pH environment being maintained.

Pourability

This test is carried out on the phases of suspension after mixing to ensure that the final

preparation is pourable and will not cause any problem during filling and during handling by

patient.

Final Product Assay

For proper dosing of the dosage form it is necessary that the active ingredient is uniformly

distributed throughout the dosage form. So samples are withdrawn from the dispersed phase

after micronisation and after mixing with dispersion medium, assayed to find out degree of

homogeneity. if any discrepancy is found out it is suitably corrected by monitoring the

mixing step to ensure a reliable dosage formulation.

Zeta Potential Measurement

Value of Zeta potential reflects the future stability of suspensions so it monitored time to time

to ensure optimum zeta potential. Zeta potential is measured by either Zeta meter or micro-

electrophoresis.

Centrifugation Test

This test tells us about the physical stability of suspension. The product is checked for

uniform distribution of color, absence of air globules before packing.

Final Quality Control of Suspensions

The following tests are carried out in the final quality control of suspension:

 Appearance

 Color, odor and taste

 Physical characteristics such as particle size determination and microscopic photography

for crystal growth

 Sedimentation rate and Zeta Potential measurement

 Sedimentation volume

 Redispersibility and Centrifugation tests

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 Rheological measurement

 Stress test

 pH

 Freeze-Thaw temperature cycling

 Compatibility with container and cap liner

 Torque test

Stability of Suspensions

1. Introduction

Pharmaceutical suspensions are thermodynamically unstable system, so they always tend

towards the ultimate loss of stability. What one examines at a time is only the apparent

stability of the product.

Stability of suspension can be considered in two ways:

 Physical

 Chemical

2. Physical Stability

The definition of physical stability in context of suspensions is that the particles do not

sediment for a specific time period and if they sediment, do not form a hard cake. To achieve

this desired target, one must consider the three main factors affecting the physical stability.

A. Particle-Particle Interaction and its Behaviour

Derjaguin, Landau, Verwey & Overbeek explained a theory of attractive & repulsive forces

in context of lyophobic colloids viz., DLVO theory. This theory allows us to develop insight

into the factors responsible for controlling the rate at which the particles in the suspension

will come together to produce aggregate to form duplets or triplets. The process of

aggregation will accelerate the sedimentation and affect the redispersibility.

For this, the potential energy curves may be used to explain the sedimentation behaviour

which generally is indicative of the interaction of the two charged surfaces which gives rise

to two types pf suspension systems i.e. deflocculated and flocculated.

In deflocculated suspension systems, the particle dispersed carry a finite charge on their

surface. When the particles approach one another, they experience repulsive forces. These

forces create a high potential barrier, which prevent the aggregation of the particles. But

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when the sedimentation is complete, the particles form a closed pack arrangement with the

smaller particles filling the voids between the larger ones. And further the lower portion of

the sediment gets pressed by the weight of the sediment above. And this force is sufficient to

overcome the high energy barrier. Once this energy barrier is crossed, the particles come in

close contact with each other and establish strong attractive forces. This leads to the

formation of hard cake in a deflocculated system. The re-dispersion of this type of system is

difficult as enough work is to be done in order to separate the particle and create a high

energy barrier between them.

The another type viz., the flocculated system in which the particles remain in the secondary

minimum, which means that the particles are not able to overcome the high potential barrier,

so they remain loosely attached with each other. So, the particles here still experience a high

energy barrier, but are easily re-dispersible.

Fig 1.9. Potential Energy Curves for Particle Interaction in Suspension Systems.

To conclude, the deflocculated system provides the apparent stability, while the flocculated

system is necessary to achieve the long-term stability. And so far for the flocculation to

occur, repulsive forces must be diminished until the same attractive forces prevail.

Electrolytes serve to reduce the effective range of the repulsion forces operating on the

suspended particles, as evidenced by the decrease in Zeta Potential and the formation of the

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bridge between the adjacent particles so as to link them together in a loosely arranged

structure.

B. Interfacial Properties of Solids

A good pharmaceutical suspension should not exhibit the settling of suspended particles. This

can be achieved by reducing the particle size to a level of 5m to exhibit the Brownian motion.

As for the size reduction, work (W) is to be done which is represented as

W = ∆G =ɣ SL.∆A.

Where, ∆ G= increase in surface free energy

ɣ SL = interfacial tension between liquid medium & solid particles.

∆A = increase in surface area of interface due to size-reduction.

`The Size reduction tends to increase the surface-free energy of the particles, a state in which

the system is thermodynamically unstable.

In order to approach the stable state, the system tends to reduce the surface free energy and

equilibrium is reached when ∆G = 0, which is not desirable.

Thus, the following two approaches are used to retain the stability.

1) By reducing the ∆A. Provided that they are loosely attached (flocculated system) and are

easily redispersible.

2) By reducing the interfacial tension, the system can be stabilized, but cannot be made equal

to zero, as dispersion particles have certain positive interfacial tension. Thus, the manufacture

must add certain surface-active agents to reduce g to a minimum value, so that the system can

be stabilized.

Poly-Dispersibility: (Variation in Particle Size)

Range of particle size might have an influence on the tendency towards caking. When the

drug material is in the dispersed state, the dispersed material will have an equilibrium

solubility that varies relative to its particle size. Small particles will have higher equilibrium

solubility than the larger particles. So, these small particles will have a finite tendency to

solubilize subsequently precipitate on the surface of the larger particles (considering the

fluctuations in temperature).

Thus, the larger particle grows at the expense of the smaller particles. This phenomenon is

known as "Ostwald Ripening".

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This phenomenon could result in the pharmaceutically unstable suspensions (caking) & alter

the bio-availability of the product, through an alteration in the dissolution rate.

This problem can be surmounted by the addition of polymer (Hydrophilic Colloid) such as

cellulose derivatives, which provides the complete surface coverage of the particles, so that

their solubilization is minimized to some extent.

Another way is to have uniformity in particle size of the dispersed material, which is to be

considered prior to the manufacturing of suspensions.

C. Chemical Stability of the Suspensions

Most of the drug materials although insoluble, when suspended in a liquid medium has some

intrinsic solubility, which triggers the chemical reactions such as hydrolysis, to occur leading

to degradation. So, the particles that are completely insoluble in a liquid vehicle are unlikely

to undergo chemical degradation. The Chemical stability of the suspensions is governed by

the following facts:

It is assumed that the decomposition of the suspension is solely due to the amount of the drug

dissolved in aqueous phase. This solution will be responsible for drug decomposition and

more drug will be released from insoluble suspended particles within the range of solubility.

It behaves like a reservoir depot. So, the amount of the drug in the solution remains constant

inspite of the decomposition with time, Thus, primarily suspensions behave as a zero order.

But once all the suspended particles have been converted into the drug in the solution, the

entire system changes from zero order to first order, as now the degradation depends upon the

concentration in the solution. Thus, it can be said that suspension follows apparent zeroorder

kinetics.

CONCLUSION

The suspension is stable till the system follows zero order, but once it enters the first order

kinetics, the degradation is rapid. But, if the suspension is concentrated, the system will

require more time to convert from zero order to first order. And this is the reason that a

concentrated suspension is often stable enough to market, but a dilute is not. But a

concentrated suspension affects the physical stability of the suspension. So, the

manufacturing pharmacist should optimize both physical & chemical parameters of the

dispersed particles to achieve the desired stability of the suspensions.

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Packaging of Suspensions

Due to the world wide emergence of the drug regulations and increasing sophistication in

variety of dosage forms and development of new packaging materials, today pharmacist must

aware of wide range of packaging material that relates directly to the stability and

acceptability of dosage forms. For example, to optimize shelf life industrial pharmacist must

understand inter-relationship of material properties, while the retail pharmacist must not

compromise with the storage of the dosage forms. So because of that labeling and storage

requirements are important for both patient as well as pharmacist.

Pharmaceutical suspensions for oral use are generally packed in wide mouth container having

adequate space above the liquid to ensure proper mixing. Parenteral suspensions are packed

in either glass ampoules or vials.

Ideal Requirements of Packaging Material

 It should be inert.

 It should effectively preserve the product from light, air, and other contamination through

shelf life.

 It should be cheap. It should effectively deliver the product without any difficulty.

Materials Used for Packaging

Generally glass and various grades of plastics are used in packaging of suspension.

1. Glass

Generally soda lime and borosilicate glass are used in preparation of non sterile suspensions.

Some times it is advisable to use amber colored glass where light is the cause of degradation

of the product. Amber glass doesn't allow U.V light to pass through. Amber characteristics

can be developed in the glass by addition of various types of additives.

Table 1.5: Type of Glasses and Additives Giving Amber Colour

Additive Giving Amber Colour

FeO+ sulfur(in presence of reducing agent)

FeO+TiO2

Disadvantages of Glass Materials

 They are fragile. difficult.

 They are very heavy as compared to plastic so handling and transport is difficult.

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 Most important disadvantage of glass is that glass constituents get extracted in to the

product.

 So for sterile dosage forms powder glass test as well as water attack test has to be carried

out to ensure the amount of alkali material leached out in the product. Also typical test for

extractable material is some time carried out.

Table 1.6: Typical Characteristics of Borosilicate Glass For Example

Assay of Borosilicate Glass

Plastic

Due to the negative aspects of glass, coupled with the many positive attributes of the plastic

material significantly inroads for the use of plastic as packaging material for sterile as well as

non-sterile pharmaceutical suspensions.

Advantages Of Plastic Material:

 Non breakability.

 Light weight.

 Flexibility.

Materials used: - Polyethylene, PVC, polystyrene, polycarbonate etc.

Drug Plastic Consideration

There are mainly five factors which is to be considered during selection of plastic as a

packaging material for suspension.

 Permeation

 Leaching

 Sorption

 Chemical reaction

 Alteration of the physical properties of plastic.

E.g. Deformation of polyethylene containers is often caused by permeation of gas and

vapours from the environment. Also sometimes solvent effect is also found to be the factor

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for altering the physical properties of plastic viz., oils has softening effect on polyethylene

and PVC.

Closure and Liners

With an exception of ampoules all containers required elastomeric closure.

Factors affecting in selecting closure:

 Compatibility with product.

 Effect of processing should not affect the integrity of the closure.

 Seal integrity.

 It should be stable throughout the shelf life.

 Lot to lot variability has to be considered.

Factors Affecting in Selecting Liner

 Chemical resistance.

 Appearance

 Gas and vapour transmission.

 Removal torque.

 Heat resistance.

 Shelf life.

 Economical factors.

3. FDA Regulations for Packaging

When FDA evaluates drug, the agency must be firmly convinced that package for a specific

drug will preserve the drug's efficacy as well as its purity, identity, strength and quality for

the entire shelf life.

The FDA does not approve the container as such, but only the material used in container. A

list of substance "Generally recognized as safe" (GRAS) have been published by FDA. Under

the opinion of qualified experts they are safe in normal conditions. The material does not fall

in this category (GRAS) must be evaluated by manufacturer and data has to be submitted to

FDA. The specific FDA regulation for the drug states that "container, closure and other

components of the packaging must not be reactive, additive or absorptive to the extent that

identity, strength, quality, or purity of the drug will be affected".

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4. Storage Requirements (Labelling)

 Shake well before use

 Do not freeze

 Protect from direct light (For light sensitive drugs).

5. Innovations in Suspensions

1. Taste Masked Pharmaceutical Suspensions

Un-palatability due to bad taste is a major concern in most of the dosage forms containing

bitter drugs. In case of suspensions also taste masking is being applied to mask bitterness of

drugs formulated. The taste masking approaches for suspensions can be summarized.

Polymer Coating of Drugs

The polymer coat allows the time for all of the particles to be swallowed before the threshold

concentration is reached in the mouth and the taste is perceived. The polymers used for

coating are

 Ethyl cellulose

 Eudragit RS 100

 Eudragit RL 100

 Eudragit RS 30 D

 Eudragit RL 30 D

Polymer coated drug powders are also used for preparation of reconstitutable powders that

means dry powder drug products that are reconstituted as suspension in a liquid vehicle such

as water before usage. These reconstitutable polymer coated powders are long shelf-life and

once reconstituted have adequate taste masking.

Encapsulation with a Basic Substance

Here a basic substance is mixed with a bitter tasting drug which is insoluble at high pH. The

mixer is then encapsulated with a polymer (cellulose derivative, vinyl derivative or an acid

soluble polymer for example copolymer of dimethyl ammonium methyl methacrylate). The

drug after encapsulation are suspended, dispersed or emulsified in suspending medium to

give the final dosage form.

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Polymer Coated Drug with a Basic Substance

This method has claimed to give stable taste masked suspensions on reconstitution (taste

masked for prolonged period).

Coating and pH Control

Those drugs which are soluble at high pH are preferably be maintained in a suspension at a

low pH where the drug exhibit maximum insolubility. Similarly drugs which are soluble at

low pH are preferably maintained in suspension at a high pH where the drug is insoluble.

Also applying polymeric coating to the drug substance avoids solubilization of drug when

administered providing taste masking.

Table 1.7: Some Examples of Taste Masked Suspensions:

Nano-Suspension:

pH control and polymer coating(with Eudragit

RS) The coated drug is suspended in water based

liquid constituted at an optimum pH.

Roxithromycin-I And

ROxithromycin-II

Polymer coating with Eudragit RS 100

Polymer coating with Eudragit RS 100

Polymer coating

(Eudragit 100:Cellulose acetate, 60:40 or 70:30)

Nano-suspension of potent insoluble active pharmaceutical ingredient will become improved

drug delivery formulations when delivered to at sizes less than 50 nm.

When delivered I.V. at sizes less than 50 nm, the suspension particles avoids the normal

reticulo-endothelial system filtration mechanisms and circulates for long periods. The

suspension particles may be insoluble API particles or nanoparticle polymeric carriers of

soluble or insoluble drugs and may be useful in delivering genetic therapeutic materials

targeted to the cells.

In transdermal delivery application, control of particulates in the 10-50 nm size range should

allow the formulation of API in formats that match requirements of delivery rates and for

penetration depth target. The drug particulates may involve insoluble active structures or

active either soluble or insoluble in degradable polymeric structures.

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For oral delivery, nanometer size particles may allow delivery of API through the intestinal

wall into the blood stream, at desired rates and with minimal degradation in the GI tract.

Insoluble particles at these sizes may be designed to be transportable across this barrier.

Another strategy involves encapsulation of active drugs in nano-particulate degradable

polymer structures.

Preparation of Nano-Particles

The technology used should produce nanoparticles of insoluble API or of encapsulated APIs.

A new reactor system has been developed known as Multiple Stream Mixer or Reactor

(MMR) produces nano-particles by several methods.

Principle:- The system (MMR) conducts two or more streams of reactants to an interaction

zone where the streams collid at high velocity under extreme pressure.

Designing of Nano-Particle Formulations

Using the MMR, nano-particles formulation can be designed using several approaches.

Direct Reactions

It is carried out if the API is a result of a synthesis which yields an insoluble material. The

reactant streams can be fed into the MMR to yield particles of nanometer size.

pH Shift Reaction

Many APIs are soluble as a basic form and insoluble as active acid form. The synthesized

material dissolve in a basic medium constitutes one feed stream, into the MMR, which an

acidifying element. The result of collision reaction is a nano-particle suspension of insoluble

active acid form.

Controlled Re-crystallization

This approach enables preparation of nanosuspension from API feed material made in a kilo

lab or other sources of synthesized solution to the problem of producing nanoparticles from

any insoluble API feed material. The API is dissolved in a solvent and the dissolved API

from one input stream and other stream is either water or water solution which recrystallizes

the insoluble active on contact because the recrystallization occurs in a ultra turbulent

collision zone, the resultant insoluble API forms as nano-particles. After necessary clean up

process the API can be dispersed into the aqueous final formulation (saline for injection) by

passage through dispersion or mixing system (micro-fluidized fluid processing system).

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Because the intrinsic API crystallizes where formed as nanoparticles, they can be re-

dispersed as nanosuspension.

Sustained Release Suspensions

Sustained release is a method to increase only the duration of action of drug being formulated

without affecting onset of action. In suspension sustained release affected by coating the drug

to be formulated as suspension by insoluble polymer coating. The polymer coating provides

sustained release and also masks the taste of the bitter drug. The polymer used for sustained

release in suspension is enlisted as follows as Ethyl cellulose, Eudragit, Cellulose acetate, etc.

The main advantage of sustained release suspension is to decrease in dosing frequency.

Recent Literature on Suspensions

Reason for

Formulating into

Suspensions

The ability of polyvinyl

pyrrolidine (PVP) and

bovine serum albumin

(BSA) in inhibition of

crystal growth in

suspensions containing

acetaminophen as a

model drug was

evaluated.

Bovine Serum Albumin

above a critical

concentration in

combination with Poly

Vinyl Pyrolidine induces its

inhibitory effect on crystal

growth.

Extraction of pectin

from waste of orange

fruit peel and further

characterization for

useful alternative

pharmaceutical

excepient.

Orange peel

pectin powder

The release rate of drug is

decreased with increase in

the orange peel pectin

powder percentage in the

formulation. Orange peel

pectin powder showed good

binding and suspending

properties at 10%w/w and

2%w/v respectively.

Extraction of mucilage

from banana peel and

further characterization

for useful as alternative

pharmaceutical

excepient.

Banana peel

mucilage

powder,

Sodium CMC

The release rate of drug is

decreased with increase in

the banana peel mucilage

powder percentage in the

formulation. Banana peel

mucilage powder showed

good binding and

suspending properties at

10%w/w and 2%w/v

respectively.

Sensory evaluation as well

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test of difference and

analysis could be an

useful methodology in

quality control of oral

liquid pharmaceutical

formulations.

as chemical,

physicochemical and

microbiological tests would

be necessary for quality-

control of drugs, mainly in

the liquid-oral

pharmaceutical

formulations.

To mark its bitter taste,

followed by the study

of its dissolution

behaviour at pH 6.8 of

the oral cavity and

pleasant taste

perception test.

The granules of carbopol

prepared by sodium

metabisulphite and methyl

paraben sodium and coated

by opadry® enteric had

maximally reduced the

bitterness of artemether.

To evaluate different

concentration of

suspending agents for

their suitability for the

formulation of

sustained release

suspension containing

ambroxol HCL

microcapsules.

The suspension prepared

with xanthan

gum(0.3%w/v) as a

suspending agent showed a

optimun drug release and

was found to be ideal for

sustained release

preparation.

Ambroxol

hydrochloric acid

To prepare taste

masked suspension of

Ambroxol

Hydrochloride by

obtaining the intensely

bitter taste of

Ambroxol

Hydrochloride.

Drug-resin complexes

effectively masked bitter

taste of Ambroxol HCL

Azithromycin

Ambroxol HCL

Too develop dry

suspensions for

reconstitution like

Azithromycinand

Ambroxol HCL using

powder blends

techniques.

Xanthan gum,

Sodium CMC,

Acacia

Formulation with xanthum

gum (5% and 2.5%) showed

excellent sedimentation

volume and degree of

flocculation.

Pediatric Azithromycin

suspension formulated

by employing various

suspending agents

exhibited good

suspendability and give

higher dissolution rate

than those formulated

with Azithromycin.

HPMC sodium,

CMC, Acacia,

Gum tragacanth

Among the formulated

suspensions (HPMC)

showed better in vitro drug

release profile as well as

better physical stability

compared to other

formulated suspensions.

To prepare an

acceptable suspension

The dry physically mixed

powder ( HPMC) was more

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either as dry physical

mixture powder or

granules to be

reconstituted, Through

studying the effect of

various type and

concentration of

suspending agent on

the release profile of

the drug.

Colloidal

Silicone

Dioxide

stable than the granular

suspension (Colloidal

Silicone Dioxide) since the

expiration date for dry and

granular suspension were

3.24 and 2.7 years

respectively.

To study the

rheological and

sedimentation

behaviour of BSS in

the presence of various

additives in order to

prepare a stable radio-

opaque colloid that can

be used for medical

investigations.

A new Barium sulphate

opaue suspension was

developed by sodium CMC,

tri sodium citrate, which

gave good contrast both in

acidic and alkaline region

for fluoroscopic survey of

gastro intestinal tracts.

To search for a cheap

and effective natural

excepient that can be

used as an effective

alternative for the

formulation of

pharmaceutical

suspensions.

Acacia,

Tribulus

terrestris

mucilage

Tribulus terrestris mucilage

could be used as a

suspending agent. They

have low rate of

sedimentation, high

viscocity, slightly basic

pHand are easily

redispersible.

To mask the taste of the

cefuroxime axetil and

to improve patient

compliance.

Indion 214,

Indion 204,

Indion 234

CA forms complex with

Indion-214 by two methods

like batch method and

kneading using. The

product which showed best

taste masking and drug

release was formulated into

suspension. Suspension was

again evaluated and in

invivo studies were carried

out to check the

bioavailabity of suspension.

To formulate for oral

cefuroxime axetil

suspensions.

Considering the ideal

characterstics of prepared

suspension formulations,

this product can be added to

drug market.

To mask the taste of the

Cefuroxime axetil by

dry suspension

formulation using

The granules were prepared

by using different ratios of

Cefuroxime axetil to

lubritabshow good taste

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

lipophilic vehicle such

as Hydrogenated

Cotton Seed oil

(Lubritab) as taste

masking agent.

masking property for

Cefuroxime axetil shows

good taste as compared to

market preparation.

To search for a natural

excepient which is cost

effective that can be

used as an alternative

for the formulation of

pharmaceutical

suspensions.

Acacia and

Eulophia

herbacea

mucilage

Eulophia herbacea mucilage

could be used as a

suspending agent. They

have low rate of

sedimentation, high

viscocity, Weak acidic pH

and are easily redispersable.

To improve the

chemical stability,

increase the

bioavailability and

controlled the duration

and

onset of action of the

drug

Improved chemical

stability, bioavailability

and controlled the duration

and onset of action of the

drug was achieved by

employing Piperine.

To formulate tasteless

complexes of

chlorpheniramine

maleate with indion

234 and attempt was

made to develop stable

and taste masked

suspension

formulation.

Veegum,

Sodium

Carboxy Methyl

cellulose

Chlorpheniramine maleate

was successfully taste

masked and formulated into

suspension formulation.

To investigate the

effect of structural

vehicles and other

formulating factors on

physical stability and

rhelogical behaviour of

ciprofloxacin

suspension.

Sodium CMC,

HPMC,

Veegum.

The formulation containing

NaCMC (0.25% w/v),

veegum (0.1%w/v) and

Nacl (0.05%w/v) was the

most stable formulation by

alternating the amount

ratios of formulation

factors, the best rhelogical

behaviour and the most

proper thixotropy may be

achieved.

To restrict greatly the

further development of

oral preparations and

clinical applications of

these drugs.

Eudragit L 100 shown

better release profile and

good taste masking property

at 1:3 drug and polymer

ratio ansd shown taste as

compared to marketed

preparation.

Dextromethorphan

hydrobromide

To mask the intensely

bitter taste of

Dextromethorphan

Drug-Resin complexes

effectively masked bitter

taste of Dextromethorphan

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

Hydrobromide using

ion exchange resin and

to formulate oral

suspension of the taste

masked drug.

To develop a stable

suspension formulation

of Diclofenac.

The suspension were

prepared with HPMC were

stable and easily

redispersable.

To develop a niosomal

drug delivery system

for fluconazole, A

triazole antifungal drug

that acts by inhibition

of the ergosterol

component of the

fungal cell membrane,

Because neosomal

formulations have

better permeability due

to presence of

hydrophillic and

lipophillic moities.

Hence a delivery

system based on

cholesterol and non

ionic surfectant may

have an advantage in

the antifungal activity

of fluconazole.

Niosomes are comparitively

stable at lower

temperatures. Thus on the

basis of studies conducted

we can state that niosomes

possess great potential as

drug delivery carriers and

hence the formulated

fluconazole niosomal

suspension can be further

evaluated for its in vitro

performance.

To extract, Evaluate

and to findout the

potentials as a

suspending agent of

natural mucilage

obtained from the

nutlets of the plant

Lallemantia

royleana(balango).

Butea

monospermama

and Leucaena

leucocephala,

Xanthan gum

The mucilage of

Lallemantia royleana has

good properties to be used

as a suspending agent and

the performance is

comparable with that of

chitosan and xanthan gum

since it is of natural origin,

nontoxic, and of good

biocompatibility.

Formulation and

evaluation of

gatifloxacin suspension

by adding acacia

powder in different

ratio an all five

formulations.

Hydroxypropyl

methylcellulose

(HPMC) and

Acacia

On increasing the

concentration of acacia

powder in suspensions

improved the physical

stability.

To evaluate the effects

of polymers with

different ionic

Sodium CMC showed the

best diuretic effect in rats,

with increase of urine

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

characterstics on the

physicochemical

parameters of

developed

pharmaceutical

suspensions containing

HCTZ for pediatric

use.

volume and of electrolyte

excretion. HPMC showed

caking formation, that result

in a product lacking in dose

consistency because of

failure to obtain and

maintain a good degree of

dispersion.

Evaluation of grewia

plysaccharide gum as a

suspending agent by

comparing the

suspending ability to

xanthan gum, Sodium

CMC, Acacia gum.

Xanthan gum,

Sodium CMC,

Acacia

Grewia polysaccharide gum

(freeze-dried) may provide

a suitable alternative to

sodium CMC or Acacia as

suspending agent in

pharmaceutical oral

suspensions, Providing a

really avaiable and

affordable option in the

countries where it is found

growing abundantly, Wild

or cultivated.

To evolve a physically

chemically stable and

elegant and palatable

suspension using

suspending agents in

varying proportions.

Formulation with sodium

CMC has better stable,

bioavailabilty when

compared to veegum and

marketed preparation.

The physical and

chemical stability of a

phospholipid stabilzed

suspension of

itraconazole crystals

employed as a model

water-insoluble drug

dispersion.

Lipoid E80,

Sodium oleate

The phospholipid

hydrolysis kinetics and

mechanisms proposed at

liquid-liquid interfaces are

consistent with the results

obtained at the solid-liquid

junction.

To investigate the

combined effect of

viscocity enhances and

anti-floculant using full

factorial design.

Locust bean

gum, Sodium

aliginate

The eight formulations were

made by factorial design,

later optimized batch was

prepared after desirability

analysis and validated the

obtained value with

predicted showing good

reliability of the design,

highest r2 and lowest sum

of squares of residual was

observed for the responses.

The prepared suspension

showed high sedimentation

volume, High

redispersibility and

optimum viscocity

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

following Non-Newtanian

type behaviour.

To prepare palatable

liquid formulation by

masking the intensely

bitter taste of

metronidazole.

Drug-Resin complexes

effectively masked bitter

taste of metronidazole.

To study the

suspending property of

holy basil seed

mucilage by

formulating suspension

of metronidazole.

The mucilage powder with

the minimum concentration

of 0.8% w/v formed a stable

metronidazole suspension

and thus proved to be a

good natural suspending

agent.

To isolate the mucilage

using microwave

assisted extraction

technique and to

evaluate its excepient

properties.

The mucilage can be

isolated effeciently by using

microwave irradiation from

Vigna mungo(Black gram

seeds) and can be used as an

effective suspending agent

and tablet binder in oral

pharmaceutical

formulations.

Methanol(70%v/v)

extracts of capparis

aphylla aerial part

(MECA), Carica

papaya leaves

(MECP) and

Feronia limonia

fruit(MEFL)

To develop

combinational herbal

oral male contraceptive

suspensions containing

potential antifertility

agents from

ethnomedicinal plants.

The methanol extracts of

Capparis aphyla aerial part,

Carica papaya leaves and

Feronia limonia fruit could

be formulated as

combinational herbal oral

suspensions with

convincing quality control

parameters.

To isolate a natural

pharmaceutical

excepient fron tamarind

seed and to check its

utility as an effective

suspending agent in the

formulation of

pharmaceutical

suspensions.

Tamarind seed

polysaccharide

The isolated TSP powder

can be used as an effective

suspending agent in

suspensions and the

formulated suspension

shown drug release and

easily re-dispersable.

Isolation of natural

pharmaceutical

excepient from the

seeds of Plantago

Ovata as a natural

suspending agent.

The Isapgol mucilage

powder can be used as an

effective suspending agent

in suspensions and the

formulated suspension were

stable.

To formulate

norfloxacin suspension

using norfloxacin

The product had acceptable

physical properties and the

ingredients used in the

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

powder and to evaluate

the physical and

chemical stability of

the formulation.

formula did not affect

chemical stability of the

drug under the studied

conditions.

To investigate the

influence of type and

concentration of

cellulosic suspending

agents on the physical

and chemical stability

of nystatin in

suspensions.

SCMC 358 cp,

SCMC 1485 cp,

SCMC 1240 cp,

Avicell RC 591

The shelf-lives of the

bufferd suspensions were

more or less the same but

much higher than that of the

unbufferd suspensions.

Ondansetron

hydrochloric acid

To improve the patient

compliance of drug, an

attempt was made to

sustain the release and

to mask the taste of the

ODH using ion

exchange resin (Indion

244).

Micro

crystalline

cellulose,

Sodium CMC,

Guar gum

Formulated sustained

release suspension restricts

the release of ODH which

may reduce the dosing

frequency. Na CMC was

giving better suspending

property as compared to

Guar gum and MCC.

The possilbilty of

developing a level

correlation between

percent drug released

and percent drug

absorbed for

oxcarbazepine

suspension.

Targum and

sodium aliginate

IV/IVC developed by level

A correlation makes

oxcarbazepine dissolution

profile meaningful, as it

allows predicting inprocess

quality control of

Oxcarbazepine suspension.

To study the

comparative dissolution

behaviour of marketed

paracetamol

suspensions.

Sodium CMC

10000CPS

Avicel RC 591

The importance of

dissolution testing for

suspensions and proper

selection of the suspending

agents during their

formulations should be duly

emphasized to ensure batch-

to-batch reproducibility and

consistent

pharmacological/biological

activity.

To search for cheap

and effective natural

excepients that can be

used as an effective

alternative for the

formulation of

pharmaceutical

suspensions.

Ocimum

basilicum

mucilage,

tomato powder

and tragacanth

gum.

The mucilage from osimum

basilicum seeds may be

used as a pharmaceutical

adjuvant and as suspending

agent at 2%w/v, depending

on its suspending ability

and the stability of the

resulting suspension.

To formulate and

evaluate a new, cheap

and effective natural

Trigonella

foenum

graecum

The extracted mucilagenous

substance of Trigonella

foenum graecum is edible,

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

suspending agent that

can be used as an

effective alternative for

traditional suspending

agent.

has the potential as a

suspending agent even at

lower concentration (1-3%

w/v) and can be used as a

pharmaceutical adjuvant.

To investigate the

effect of Adansonia

digitata as a suspending

agent in pharmaceutical

formulations using

paracetamol as the

model drug.

Sodium carboxy

methyl

cellulose,

Adansonia

digitata gum

The profiles of paracetamol

pediatric suspensions

containing AD appeared to

be better than those of Na

CMC, suggesting its

potential as a suspending

agent in formulation of

pharmaceutical suspensions.

To search for a cheap

and effective natural

excepient that can be

used as an effective

alternative for the

formulation of

pharmaceutical

suspensions.

Tragacanth

gum, gum

acacia, tamarind

gum.

All concentrations

employed, compound

tragacanth gum had the

strongest suspending ability

relative to the other

materials due to the high

viscocity of compound

tragacanth gum, it can be a

stabilizer of choice when

high viscocity is desired &

also serve as good

thickening agent in both

pharmaceutical & food

industries.

The suspending

properties of Khaya

senegalensis gum were

evaluated

comparatively with

those of Acacia

sieberiana and Acacia

senegal gums at a

concentration range of

0.2 to 5.0%w/v in

2.4%w/v paracetamol

suspension.

Acacia

sieberiana and

Acacia senegal,

a standard

reference but

Khaya

senegalensis

gum.

Acacia sieberiana at

concentrations above

5%w/v may be used to

dissolve paracetamol

powder, Khaya gum has

potential to suspend

paracetamol and may

provide a substitute

excepient in the liquid

formulation of paracetamol

and perhaps curb the

problem of paediatric

mortalities assosciated with

organic chemicals used as

solubilzing agents in

paracetamol.

To develop cheap and

effective natural

excepient that can be

used as an effective

alternative for the

formulation of

pharmaceutical

Cactus mucilage

(Opuntia ficus

indica, Opuntia

stricta)

The mucilages of Opuntia

spp. ( Opuntia ficus- indica

and Opuntia stricta) can be

used as alternatives to Na

CMC as suspending agents

in suspension formulations.

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

To search for a cheap

and effective natural

excepient that can be

used as an effective

alternative for the

formulation of

pharmaceutical

suspensions.

Abelmoschus

esculentus

mucilage,

sodium CMC,

tragacanth gum.

The extracted mucilage of

Abelmoschus esculentus is

non toxic, has the potential

as a suspending agent even

at lower concentration

(4%w/v) and can be used as

a pharmaceutical adjuvant.

To investigate

indigenous plant

sources containing

polysaccharides, devise

a cost effective

extraction procedure

and evaluate its use as a

multi-functional

excepient.

Mucilage of

psyllium

polysaccharide

(pps), sodium

CMC

The psyllium

polysaccharide (PPS)

mucilage was found to have

a promising potential for its

use as a suspending agent

when compared to the other

suspending agents.

To search for a cheap

and effective natural

excepient and to

evaluate the mucilage

obtained from the

endosperm of Borassus

flabellifer as a

suspending agent that

can be used as an

effective alternative for

the formulation of

pharmaceutical

suspension.

Compound

tragacanth

powder,

Lepidium

sativum

mucilage.

The extracted mucilage of

Lepidium sativum has the

potential as a suspending

agent even at lower

concentrations and can be

used as a pharmaceutical

adjuvant.

To evaluate Lepidium

sativum mucilage as a

suspending agent,

compare this with

suspension prepared by

using tragacanth as a

suspending agent and

marketed paracetamopl

suspension.

Compound

tragacanth

powder,

Lepidium

sativum

mucilage.

The extracted mucilage of

Lepidium sativum has the

potential as a suspending

agent even at lower

concentrations and can be

used as a pharmaceutical

adjuvant.

To prepare a stable

suspension for

rifampicin through

preparation of different

formulas of rifampicin

aqueous suspension

either as ready to use or

as granular powder to

be reconstituted.

Methyl

cellulose,

Sodium CMC,

Xanthan gum.

The MC had better

dissolution rate compared

with the other suspension

and the rheogram showed

that the MC was less

viscous than the other

suspension, it was found

that the granular rifampicin

was more stable than the

ready to use suspension,

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

since the expiration date of

granular rifampicin was 2.6

years, while the expiration

date of ready to use

suspension was 1.8 years.

To overcome the

problem of bitter

taste,degradation &

sedimentation, the

various trails of

rifampicin oral

suspension were

developed by using

four different

suspending agents and

then it was evaluated

for their physic-

chemical parameters.

Tween-80

Sodium CMC

Carbomer-934,

Sodium starch

glycollate,

Xanthan gum.

The suspension (Xanthan

gum as a suspending agent)

was considered as stable,

uniform, pleasant tasting

and readily redispersible

Rifampicin oral suspension.

To assess physical

stability of that

prepared formulations

according to ICH guide

lines.

Sodium

aliginate,

Veegum(0.4%),

Xanthan gum.

The suspension containing

veegum, calcium chloride

was the best formulation

among all the suspension

prepared.

The manufacture of

suspension cassia

roxburghii seed gum

were evaluated by

comparing with Acacia

gum and compound

Tragacanth gum at

concentration 2.5 and

3%w/v in

sulphamethoxazole

suspension.

Acacia

compound,

Tragacanth,

Xanthan gum.

The Cassia roxburghii

filtered mucilage as a novel

suspending agent in the

preparation of

sulphamethoxazole

suspensions and could be

employed as stabilizer and

thickener of choice in

pharmaceutical suspension

preparation.

To determine the

rheological and

stability properties of

sulphamethoxazole

suspension using

cedrela gum as a

suspending agent.

A suspension of ideal

characterstics of high

viscocity at negligible shear

and low viscocity upon

agitation was obtained with

cedrela gum and HPMC as

a suspending agents,

Cedrela gum could be

substituted for synthetic and

more expensive HPMC in

the formulation of

pharmaceutical suspensions.

To assess the

suspending ability of

the gum from Sesamum

indicum leaves for

Compound

tragacanth,

Acacia,

Sesamum gum

Sesamum indicum was

compared with acacia gum

and mainly tragacanth, a

commonly used suspending

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

utilization in

pharmaceutical

suspensions.

Suspensions were

prepared with sesamum

gum in comparision to

tragacanth(mainly) and

acacia.

agent on pharmaceutical

suspensions. It produced

acceptable suspensions

which would yield uniform

dose due to its ease of

redispersibility and no

formation of aggregates &

can be employed as a

thickener and suspending

agent for formulation of

pharmaceutical suspensions.

To search for a cheap

and effective natural

excepient that can be

used as an effective

alternative for the

formulation of

pharmaceutical

suspensions.

Albizia gum,

Compound,

tragacanth,

Acacia gum,

Gelatin

Zygia>Compound

Tragacanth gum> Acacia

gum> Gelatin> Albizia

zygia gum had the strongest

suspending ability relative

to the other gums.

To extemporaneously

formulae a liquid

dosage form from

commercially available

tablets and establish the

chemical stability of

the drug.

Sodium CMC,

Veegum,

Sodium acetate

The spiranolactone

solubility is low that an

accurate estimate of

thermodynamic parameters

cannot be ascertained using

the conditions in the study.

To provide a

microparticle

containing oral liquid

sustained release

dosage form for use in

pediatric and geriatric

patients.

The formulated suspension

can be used as a sustained-

release formulation for

theophylline in treatment of

obstructive pulmonary

disorders.

To determine the

pharmaceutical

acceptability and

chemical stability of

drug in two

extemporaneously

compounded

suspension

formulations prepared

from capsule.

Temozolomide oral

suspensions may allow oral

patients who are unable to

swallow capsules to receive

temozolomide treatment,&

if compounded in a suitable

environment, could reduce

the potential for drug

exposure to health workers

and family members from

opening capsules.

To mask the intensely

bitter taste of tinidazole

(TNZ) and to formulate

a palatable liquid

formulation of the

taste-masked drug, by

Drug-resin complexes

effectively masked bitter

taste of tinidazole.

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

novel Ion exchange

resin method to

overcome taste

problem with

traditional system.

To isolate a novel bio

material from the seeds

of Buchanania Lanzan

and to evaluate their

potential for sustained

drug delivery by

formulating various

nano suspension using

methylene chloride as

organmic solvent and

biomaterial.

The isolated bio polymer

has shown its potentiality

for formulating nano

suspension. The polymer

can serve as potential

polymer for formulating

various drug loaded nano

suspensions.

To select a new cheap,

effective alternative

natural suspending

agent for

pharmaceutical

suspensions.

Leucaena

Latisiliqua seed

gum,

Tragacanth,

Acacia

The suspending ability of

the suspending agents were

in the order of Leucaena

Latisiliqua gum>

Compound Tragacanth>

Acacia. Then the gum of

Leucaena Latisiliqua can be

employed as stabilizer and

thickener of choice when

high viscocity is desired.

To isolate and

investigate the

pharmaceutical

properties of the

isolated mucilage from

Spinacia oleracea L.

Leaves, to assess its

suitability as a new

innovative suspending

agent in a

pharmaceutical

formulation.

Mucilage of

Spinacia

oleracea L.

Leaves

The mucilage of S.oleracea

L. Leaves could be used as

a suspending agent, and the

performance was found to

be superior to both

tragacantrh and bentonite.

The gum of Moringa

oleifera has got

properties to be used as

a suspending agent and

the performance in

comparable with that of

gum tragacanth.

The suspensions are

pseudoplastic in their

behaviour and their

viscocity decreases with

increase in shear rate, which

is an essential property in

the formulation of Moringa

oleifera gum suspension.

The suspending properties

of Moringa oleifera gum is

comparable with that of

gum tragacanth.

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Santosh et al. World Journal of Pharmacy and Pharmaceutical Sciences

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... The conventional use of "Rafts" is as a support for swimmers due to its structural feasibility to float over the water for a longer period. 6,7 Hence, pharmaceutical scientists have designed such a carrier system that can float over the GI fluid/content. The key mechanism in rafts formation in pharmaceutical preparations involve the formation of a viscous gel-like content when the gel-forming agents come in contact with GI fluid and become swelled to make a few layers of rafts. ...

... The key mechanism in rafts formation in pharmaceutical preparations involve the formation of a viscous gel-like content when the gel-forming agents come in contact with GI fluid and become swelled to make a few layers of rafts. 7 The preparations usually contain alkaline substances that form CO 2 gas and make the rafts float due to having very low bulk density. Nevertheless, among various gel-forming agents, alginates are most popular due to its high thickening, gel-forming, and stabilizing properties. ...

... There are several advantages of raftforming technology in pharmaceutical formulations such as-rapid and long-term action of the drug, better patient compliance and no interaction with the digestive process. 7,8 Cinnarizine (1-(Diphenylmethyl)-4-(3-phenyl-2propenyl) piperazine) is usually prescribed in the management of vestibular and associated symptoms. However, cinnarizine hydrochloride belongs to the labyrinthine sedative and peripheral antivasoconstrictor class of drugs that acts directly in both peripheral and central origin of the central nervous system. ...

The main objective of this research was to develop a sustained-release suspension of cinnarizine hydrochloride using raft-forming technique. This innovative approach has been utilized to formulate a series of suspension formulations using hydroxypropyl cellulose (HPC) as a release-retardant polymeric agent. Cinnarizine sustained-release suspensions were prepared by physical mixing method with varying concentrations and combinations of HPC, sodium citrate, sodium saccharin, calcium carbonate, sodium alginate, methyl hydroxybenzoate and propyl hydroxybenzoate. The formulations were subjected for determination of floating time, floating lag time, weight of the raft, physical appearance and in-vitro dissolution. The dissolution was conducted through USP apparatus 2 (paddle type) in 0.1N hydrochloric acid medium having pH 1.2. The key findings of the study demonstrate that a stable sustained-release suspension of cinnarizine can be formulated using raft-forming approach for increased bioavailability and patient-convenience. Dhaka Univ. J. Pharm. Sci. 19(1): 15-24, 2020 (June)

... Liquid dosage forms are classified based on the number of phases present into two types: Monophasic (solutions) and biphasic (suspensions and emulsions) [23]. a. Oral solutions are monophasic clear liquids for oral use comprising of one or more active ingredients dissolved in a suitable solvent system [24]. b. ...

... Oral suspensions are biphasic liquid dosage forms for oral use comprising of one or more APIs suspended in a suitable solvent. They tend to sediment with time; nevertheless, they can be readily re-dispersed by shaking into a uniform suspension that remains appropriately stable to allow the accurate dose to be delivered [24]. d. ...

• Shivakalyani Adepu
• Seeram Ramakrishna

The drug delivery system enables the release of the active pharmaceutical ingredient to achieve a desired therapeutic response. Conventional drug delivery systems (tablets, capsules, syrups, ointments, etc.) suffer from poor bioavailability and fluctuations in plasma drug level and are unable to achieve sustained release. Without an efficient delivery mechanism, the whole therapeutic process can be rendered useless. Moreover, the drug has to be delivered at a specified controlled rate and at the target site as precisely as possible to achieve maximum efficacy and safety. Controlled drug delivery systems are developed to combat the problems associated with conventional drug delivery. There has been a tremendous evolution in controlled drug delivery systems from the past two decades ranging from macro scale and nano scale to intelligent targeted delivery. The initial part of this review provides a basic understanding of drug delivery systems with an emphasis on the pharmacokinetics of the drug. It also discusses the conventional drug delivery systems and their limitations. Further, controlled drug delivery systems are discussed in detail with the design considerations, classifications and drawings. In addition, nano-drug delivery, targeted and smart drug delivery using stimuli-responsive and intelligent biomaterials is discussed with recent key findings. The paper concludes with the challenges faced and future directions in controlled drug delivery.

... The pH of the formulated suspension remained fairly constant with no significant difference (p ≥ 0:05) throughout the 4-week study period (Table 5). This indicates the absence of any physico-chemical change and confirms the stability of the formulated suspension [20,23,24]. A key attribute of a good pharmaceutical suspension is its easy pourability, and to achieve this, the flow time should be relatively short with a corresponding apparent viscosity [16,20,23]. ...

... This indicates the absence of any physico-chemical change and confirms the stability of the formulated suspension [20,23,24]. A key attribute of a good pharmaceutical suspension is its easy pourability, and to achieve this, the flow time should be relatively short with a corresponding apparent viscosity [16,20,23]. This phenomenon was also observed in the formulated suspension (Table 5), an indication that the suspension can easily be poured from its primary package. ...

• Frederick William akuffo Owusu
• Christiana O. Asare
• Philomena Enstie
• Mordey Karen

Management of diarrhea has evolved over the years from relatively inadequate interventions in the early years to more successful physiological approaches. The use of herbal medicinal products and supplements has grown significantly over the past three decades, with more than half of the global population depending on it for some aspect of their primary health care needs. This study is aimed at formulating solid and liquid oral dosage forms of the ethanolic extract of Cola nitida seeds for the treatment of diarrhea. The flow property of the dried ethanolic extract was determined and subsequently formulated into granules for encapsulation. The ethanolic extract was also used in formulating an oral suspension. Pharmacopeia tests such as uniformity of weight, disintegration, drug content, and dissolution were carried out on the formulated capsules. The formulated suspension was also assessed using the following parameters; viscosity, flow rate, drug content, dissolution, sedimentation rate, and sedimentation volume. The dried ethanolic extract and formulated granules exhibited good flow properties. The formulated capsules exhibited optimal in vitro release of extract (>90% after 45 minutes) and passed the uniformity of weight, disintegration, and drug content tests. The formulated suspension also passed the drug content test and had a good sedimentation rate, sedimentation volume, and flow rate. The formulated suspension also exhibited pseudoplastic flow, optimal viscosity, and a good in vitro release profile (>90% after 45 minutes). Capsules and suspension of the ethanolic extract of Cola nitida seeds have been successfully formulated and can be used as standard dosage forms for the management of diarrhea.

... Common mechanisms of flocculation in liquid formulations might be due to reduced repulsion between charged particles by polyelectrolytes, by adsorption of nonionic polymers, and free energy changes which result when particles approach each other so closely. This makes the space between the particles too small for polymer molecules in solution [32]. The degree of flocculation of suspensions prepared at 0.5 and 1.5% w/v suspending agents concentration is depicted in Figure 6. ...

• Tsadkan Gebremeskel Haile
• Gereziher Gebremedhin Sibhat
• Ebisa Tadese
• Fantahun Molla Kassa

Various species of the genus Grewia have been investigated for different pharmaceutical applications as excipients, yet a study on the potential use of Grewia ferruginea mucilage (GFM) as a suspending agent is lacking. Thus, this study is aimed at evaluating the efficacy of Grewia ferruginea mucilage (GFM) as a suspending agent in metronidazole benzoate suspension. The suspensions were prepared using 0.5%, 1%, 1.5%, and 2% w/v of GFM and compared with suspensions prepared from xanthan gum (XGM) and sodium carboxyl methyl cellulose (SCMC) in similar concentrations. The prepared suspensions were evaluated for visual appearance, pH, rheology, sedimentation volume, redispersibility, degree of flocculation, and in vitro drug release profile. Stability study was done at different storage conditions for three months. The results indicated that all the prepared suspension formulations exhibited pseudoplastic flow characteristics with viscosity imparting ability of the suspending agents in the order of XGM > GFM > SCMC (p < 0:05). The flow rate and redispersibility of the formulations prepared with GFM were significantly lower than those with SCMC and higher than those prepared with XGM. At 0.5% w/v suspending agent concentrations, the sedimentation volume of the formulations was in the order of XGM > GFM > SCMC (p < 0:05). However, at all other concentrations, the sedimentation volume of the formulations prepared with GFM had similar results with XGM but exhibited significantly higher sedimentation volume than SCMC. The formulations with GFM showed a higher degree of flocculation at 0.5% w/v concentration but were comparable at 1.5% w/v with XGM containing formulations. The pH, assay, and in vitro release profile of all assessed formulations were within the pharmacopial limit. Thus, based on the finding of this study, it can be concluded that Grewia ferruginea bark mucilage has the potential to be utilized as a suspending agent in suspension formulations.

... Menambahkan flocculating agents, untuk menurunkan potensial zeta dari partikel suspensi yang bermuatan. Dalam hal ini, suspensi dibuat menjadi flocculated system agar partikel mudah terdispersi kembali [7]. ...

• Tazyinul Qoriah Alfauziah

Menurut Farmakope Indonesia edisi V, Suspensi adalah sediaan cair yang mengandung partikel padat tidak larut yang terdispersi dalam fase cair. Faktanya memang hampir 70% obat yang ada di pasaran tidak larut dalam air. Apoteker sebagai perancang formula sediaan memiliki banyak pertimbangan yang mendasarinya. Suspensi merupakan partikel padat yang terdispersi. Partikel-partikel tersebut memiliki kecenderungan untuk bersatu dan membentuk suatu gumpalan sehingga mengendap di dasar botol. Fenomena ini disebut dengan flokulasi. Flokulasi ini merupakan fenomena yang tidak dapat terhindarkan dari suatu sediaan suspensi. Namun demikian hal ini dapat ditanggulangi dengan mengocok terlebih dahulu sediaan sebelum digunakan, atau bahasa kerennya adalah redispersi. Sehingga sediaan suspensi yang baik adalah suspensi yang dapat dengan mudah terdispersi kembali setelah terjadi pengendapan.Untuk menjaga kestabilan, sediaan perlu disimpan dalam kondisi yang tepat. Umumnya sediaan suspensi sebaiknya disimpan pada tempat yang kering dan tidak terpapar cahaya matahari secara langsung. Adapun pada beberapa sediaan, ada yang perlu disimpan pada lemari es atau kondisi khusus lainnya.Kata kunci : Suspensi, kocok dahulu, obat

• Susanne Page
• Anikó Szepes

This chapter provides an overview of the importance and relevance of solid state properties in different phases of drug product development. The galenical tetrahedron outlines the general considerations of pharmaceutical development, which ensure that a drug product fulfills the requirements regarding quality, safety, and efficacy. Accordingly, the relationship is described between key solid state properties of the drug substance and drug product bioavailability, stability, and manufacturability. State-of-the-art knowledge is summarized about the influence of solid state characteristics on formulation properties of liquid dosage forms (solutions and suspensions), solubility enhanced formulations (lipid-based formulations, solid solutions, and amorphous dispersions), and solid dosage forms. Drug-excipient interactions are discussed and special attention is paid to process-induced transformations of the solid form during manufacturing operations. Some key aspects of solid form control strategy during manufacturing and drug product shelf life are addressed. In addition, a few regulatory requirements are also mentioned in relation to physico-chemical characteristics of the drug substance.

The rheological measurements indicate strength of network in the suspension dyes containing microparticles, where the entanglement of these particles subsequently stabilize the whole system for their the long‐term stability. This study aimed to determine the effect of the concentration (1, 5, or 8 wt%) of colloidal microcrystalline cellulose (MCCS) as suspending agent on the long‐term stability and rheology of the vegetable carbon (C) and calcium carbonate (CC) suspended in water–glycerine mixture. These suspensions as ready‐to‐use black and white liquid dyes containing 10 wt% C or CC were assessed for particle size, Turbiscan stability index (TSI), steady shear, thixotropy and dynamic viscoelasticity. After 370 days, the black dyes showed excellent stability (TSI ≪ 0.5) at 4 °C and 25 °C already at 1 wt% MCCS, while the white dyes showed reasonable stability (TSI 1–3) only at 5 and 8 wt% MCCS. Dye formulations exhibited a relatively liquid‐like viscoelastic behaviour, while they showed extremely shear‐thinning behaviour with a network structure dependent on the concentration of the MCCS as exhibited by the increase in thixotropy and the existence of the measurable yield stress.

To improve the absorption of poorly water-soluble 20(S)-protopanaxadiol (20(S)-PPD), novel 20(S)-PPD-loaded redispersible dry suspension and dry emulsion were developed in this study. 20(S)-PPD dry suspension (PPD-DS) was prepared by enabling drug fully dispersed with suspending agent Avicel CL611 and solubilizer Poloxamer 188. 20(S)-PPD dry emulsion (PPD-DE) was prepared by employing oleic acid as oil phase, Cremophor RH-40 as surfactant, and n-butyl alcohol as co-surfactant. Both PPD-DS and PPD-DE were evaluated for their physicochemical characterization after being dispersed in distilled water. The in vivo pharmacokinetics was evaluated by UPLC-MS/MS. The droplet size of PPD-DS and PPD-DE was in the scope of 1446–1653 nm and 652.8–784.5 nm. The sedimentation volume ratios of PPD-DS and PPD-DE were both at value of 1. The zeta potential of PPD-DS and PPD-DE were from − 53.7 to − 70.4 mV and − 27.5 to − 34.5 mV, respectively, which indicated stable systems. PPD-DS and PPD-DE both achieved dramatically enhanced aqueous solubility and higher perfusion of 20(S)-PPD in rats' intestine. Although statistically, no oral bioavailability enhancements of 20(S)-PPD were achieved in PPD-DE and PPD-DS, there were some improvements in the pharmacokinetic behaviors. Especially, PPD-DS could be a promising drug delivery carrier for 20(S)-PPD with the advantages of long-term stability, dosing flexibility, and the convenience of administering to infants and to those who have difficulty swallowing tablets or capsules.

• Pratibhash Chattopadhyay
• Ram B. Gupta

Drug delivery systems improve the therapeutic efficacy and safety of drugs by delivering them at a controlled rate depending on the body requirements and the site of action. These systems aid in reducing the amount of drug required, the number of doses, side effects, and bioinactivation. Currently, delivery systems for drug targeting and controlled release are being developed using drug nanoparticles. Several techniques, such as spray drying and milling, have been used in the past for the manufacture of drug nanoparticles, but these methods have several disadvan-tages. Supercritical fluid technologies such as RESS and SAS do provide novel methods for particle formation, but in most cases, they still cannot produce particles in the nanometer range (<300 nm) necessary for drug targeting and controlled release. In this work, we propose a technique that can produce drug particles in the nanometer range with a narrow size distribution. This new technique is a modification of the currently existing SAS technique and involves the use of a vibrating surface that atomizes the jet into microdroplets. The ultrasonic field generated by the vibrating surface also enhances mass transfer through increased mixing. The new technique is demonstrated for the production of tetracycline nanoparticles as small as 125 nm in size with a narrow size distribution. Particle sizes are easily controlled using this technique by changing the vibrational intensity of the vibrating surface.

• Wen Zhi He
• Quan-Ling Suo
• Zhao Hua Jiang
• Hai Long Hong

One of the key processes of SEDS precipitation is droplet formation due to jet break-up at the exit of an injection device. In this work, a prefilming atomizer was designed on the basis of the mechanisms of atomization and applied to the SEDS process to precipitate ephedrine from ethanol solution using supercritical CO2 as antisolvent with the aim of evaluating the efficiency of the atomizer and studying the influence of operating variables (concentration, pressure, temperature, solution flow rate, and CO2 flow rate) on sizes of the particles micronized. The solution to be atomized was driven through a coaxial annular passage with spiral slots in the atomizer as a thin film swirling with 45°. The atomizing CO2 was driven through another passage (the inner capillary) to form a jet stream to impinge on the film at 45°. Upon violent interaction with jet streams, the solution sheet was effectively disintegrated into fine drops and the mixing of supercritical fluid (SF) and solution was intensified for increased transfer rates. Long needle-like or short rod-like uncoagulated particles were obtained by the SEDS process in a wide range of experimental conditions. The mechanisms that control particle sizes were explained in terms of liquid atomizing mechanism, nucleation, and growth processes of particles. Particle size did not seem to depend on pressure and temperature in all the experiments performed.

• Mohammed Jafar
• A. Aejaz

Ampicillin trihydrate is used as an antibacterial agent, with an oral dose of 250-500 mg three to four times a day. Reconstitutable Ampicillin trihydrate dry syrup is currently available in the market, where reconstitution of the product has to be done by the consumer, which may lead to handling errors. In addition, the shelf life of reconstitutable dry syrup is only for about a week after reconstitution. Ampicillin trihydrate was attempted to formulate into ready mix oral suspension with improved stability and shelf life. In the first approach of preparation, water was used as suspending medium and pH of the formulations was chosen is in the range of 5 to 6-5. In the second approach, oils like fractionated coconut oil and refined sunflower oil were used as suspending media. The content uniformity of the prepared formulations was analyzed and found to be within the limits. Physical characteristics like sedimentation volume, ease of redispersability and viscosity were evaluated. Particle size determination revealed that majority of the particles was in the size range of 15- 75 μm. In vitro dissolution studies were carried out and all the formulations showed 100% dissolution at 50th minute. Stability studies were carried out at 25°C/60% RH and 30°C/60% RH for 90 days. The drug content was analyzed on 7th, 14th ...... 90th day on an interval of 7 days. Sedimentation volume, viscosity, ease of redispersability, particle size distribution and in vitro dissolution were analysed on 1st and 90th day. Formulation FI and FIV showed Considerable amount of drug degradation. All other formulations did not show appreciable changes when evaluated. Ampicillin trihydrate degradation during the accelerated stability studies was carried out for 30th day sample using TLC method. It was found that the Rf value of Ampicillin trihydrate in both standard solution as well as formulation was found to be same. This confirmed that there was no degradation of Ampicillin. Hence it was concluded that Ampicillin trihydrate could be formulated into ready mix oral suspension with improved stability and optimum dissolution characteristics.

• Allen, L.V., Jr
• N.G. Popovich
• H.C. Ansel

Long established as a core text for pharmaceutics courses, this book is the most comprehensive source on pharmaceutical dosage forms and drug delivery systems. Content coincides with the CAPE, APhA, and NAPLEX competencies. This edition includes updated drug information and has an increased focus on physical pharmacy. Coverage incorporates all new dosage forms on the market as well as those in the current US Pharmacopoeia-National Formulary. Updated photos are included. An "Applying the Principles and Concepts" section at the end of each chapter provides activities for the application of the material. A companion website includes the fully searchable text and a quiz bank with more than 200 questions written in NAPLEX format. © 2011, 2005 by Lippincott Williams & Wilkins. All rights reserved.

• A.K. Kulshreshtha
• O.N. Singh
• G.M. Wall

Written by experts from academia, industry and regulatory agencies, Discusses the development of stable pharmaceutical suspensions Suspension dosage form is a preferred and widely accepted dosage forms for insoluble or poorly soluble drugs for various therapeutic applications. The suspension dosage form has long been used for insoluble and poorly soluble drugs for making oral, topical and parenteral products. Pharmaceutical Suspensions, From Formulation Development to Manufacturing provides the reader with a broad overview of suspension drug product technology. Individual chapters in this book focus on suspension formulation principles, excipients, analysis, pharmaceutical development, preclinical, clinical and regulatory aspects, as well as the emerging technology of nanosuspensions as nanomedicine. Various chapters in the book are written by authors from academia, regulatory agencies and industries who are experts in their respective fields. The book includes over 600 bibliographic citations, numerous tables and illustrations. Pharmaceutical Suspensions is the only volume to date that systematically follows the suspension dosage development approach used widely in the pharmaceutical industries starting with pre-formulation/formulation development, pre-clinical evaluation and critical characterization method development, continuing to clinical trial essentials and ending with technology transfer essentials and regulatory filing guidance. Pharmaceutical Suspensions, From Formulation Development to Manufacturing provides a useful resource for pharmaceutical scientists, process scientists/engineers involved in the areas of research and development of pharmaceutical suspension dosage forms as well as for advanced pharmacy undergraduate and graduate students who want in-depth knowledge of suspension dosage form.

• K.P.R. Chowdary
• Lankalapalli Srinivas

Ibuprofen suspensions were formulated employing its solid dispersions in HPMC, PVP, PEG and dextrin and were evaluated for particle size, physical stability and dissolution rate. Ibuprofen suspensions formulated employing its solid dispersions exhibited good suspendability and gave higher dissolution rates of ibuprofen than those formulated with ibuprofen alone and commercial products. Suspension formulated with solid dispersion in dextrin gave highest improvement in dissolution rate and efficiency. Dissolution of ibuprofen from the suspensions obeyed Hixson-Crowell's cube root equation. Good linear relationships were observed between particle size and dissolution rate and efficiency. Smaller particles gave higher dissolution rate and efficiency values.

• J. Edwin
• S. Edwin
• S. Dosi

The present study was undertaken to evaluate the mucilage obtained from the leaves of Hibiscus rosasinensis Linn as a suspending agent. A suspension of CaCO3 was prepared using 2 % w/v of hibiscus mucilage as suspending agent and it is evaluated for its stability using the parameters like, sedimentation volume, viscosity, redispersibility and pH. The suspending effect of hibiscus mucilage was compared with CaCO3 suspensions prepared using 2 % w/v of suspending agents such as acacia and tragacanth. The results obtained indicated that the hibiscus mucilage could be used as a suspending agent. It has low rate of sedimentation, high viscosity, slightly basic pH and is easily redispersible. These effects were comparable with that of the standard suspending agents like acacia and tragacanth. The mucilage isolated from the leaves of Hibiscus rosasinensis can be used as a pharmaceutical adjuvant.

Finding Dosage Strength of Reconstituted Solution

Source: https://www.researchgate.net/publication/326293246_PHARMACEUTICAL_SUSPENSIONS_PATIENT_COMPLIANCE_ORAL_DOSAGE_FORMS

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