Pharmaceutical Suspensions:A Review

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Dr. Mukesh Gohel, Dr. Rajesh Parikh, Amirali Popat, Ashutosh Mohapatra, Bhavesh Barot, Chetan Patel, Hardik Joshi, Krishnakant Sarvaiya, Lalji Baldaniya, Pritesh Mistry, Punit Parejiya, Ramesh Parmar, Stavan Nagori, Tushar Patel.

L. M. College of Pharmacy, Ahmedabad-India.

Dr. Mukesh Gohel

Dr. Mukesh Gohel

Dr. Rajesh Parikh

Dr. Rajesh Parikh

image

Top Row (Left to right): Bhavesh Barot, Hardik Joshi, Punit Parejiya, Pritesh Mistry, Amirali Popat.

Bottom Row (Left to right): Lalji Baldaniya, Tushar Patel, Ramesh Parmar, Chetan Patel, Ashutosh Mohapatra.

image

Krishnakant Sarvaiya and Stavan Nagori

1) Desired Characteristics And Applications Of Pharmaceutical Suspensions

1.1 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 through
out the 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.

1.2 Classification

1.2.1 Based On General Classes

Oral suspension

Externally applied suspension

Parenteral suspension

1.2.2 Based On Proportion Of Solid Particles

Dilute suspension (2 to10%w/v solid)

Concentrated suspension (50%w/v solid)

1.2.3 Based On Electrokinetic Nature Of Solid Particles

Flocculated suspension

Deflocculated suspension

1.2.4 Based On Size Of Solid Particles

Colloidal suspension (< 1 micron)

Coarse suspension (>1 micron)

Nano suspension (10 ng)

1.3 Advantages And Disadvantages

1.3.1 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

    1.3.2 Disadvantages
  • Physical stability,sedimentation and compaction can causes problems.
  • It is bulky sufficient care must be taken during handling and transport.
  • It is difficult to formulate

  • Uniform and accurate dose can not be achieved unless suspension are packed in
    unit dosage form
  • 1.4 Features Desired In Pharmaceutical Suspensions

  • 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.
  • 1.5 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
  • 2) Theory Of Pharmaceutical Suspensions

    2.1 Sedimentation Behaviour

    2.1.1 Introduction

    Sedimentation means settling of particle or floccules
    occur under gravitational force in liquid dosage form.

    2.1.2 Theory Of Sedimentation 1

    Velocity of sedimentation expressed by Stoke’s equation

    image

    Where, vsed.
    = sedimentation velocity in cm / sec

    d = Diameterof particle

    r = radius of particle

    ρ s= density of disperse phase

    ρ o= density of disperse media

    g = acceleration due to gravity

    η o = viscosity of disperse medium in poise

    Stoke’s Equation Written In Other Form

    V ' = V sed. εn

    V '= the rate of fall at the interface in cm/sec.

    Vsed.= 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

    2.1.3 Limitation Of Stoke’s Equation 1, 6

    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.

    2.1.4 Factors Affecting Sedimentation 5
    2.1.4.1 Particle size diameter (d)

    V α d 2

    Sedimentation velocity (v) is directly proportional to
    the square of diameter of particle.

    2.1.4.2 Density difference between dispersed phase and dispersion media (ρ
    s - ρo)

    V α (ρ s - ρo)

    Generally, particle density is greater than
    dispersion medium but, in certain cases particle density is less than dispersed
    phase, so suspended particle floats & is difficult to distribute uniformly
    in the vehicle. If density of the dispersed phase and dispersion medium are
    equal, the rate of settling becomes zero.

    2.1.4.3 Viscosity of dispersion medium (η )

    V α 1/ ηo

    Sedimentation velocity is inversely proportional to
    viscosity of dispersion medium. So increase in viscosity of medium, decreases
    settling, so the particles achieve good dispersion system but greater increase
    in viscosity gives rise to problems like pouring, syringibility and redispersibility
    of suspenoid.

    Advantages and Disadvantages due to viscosity of medium

    Advantages

  • High viscosity inhibits the crystal growth.
  • High viscosity prevents the transformation of metastable crystal to stable crystal.
  • High viscosity enhances the physical stability.
  • Disadvantages

  • High viscosity hinders the re-dispersibility of the sediments.
  • High viscosity retards the absorption of the drug.
  • High viscosity creates problems in handling of the material during manufacturing.
  • 2.1.5 Sedimentation Parameters


    Three important parameters are considered:

    2.1.5.1 Sedimentation volume (F) or height
    (H) for flocculated suspensions

    F = V u / 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 (VO)
    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= H u/ HO

    Where,Hu= final or ultimate height of sediment

    H O = 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.

    The sedimentation volume gives only a qualitative account of flocculation.

    Suspensions quantified by sedimentation volume

    Fig 2.1: Suspensions quantified by sedimentation volume (f)

    2.1.5.2 Degree of flocculation (β)

    It is a very useful parameter for flocculation

    Degree of flocculation

    2.1.5.3 Sedimentation velocity 3

    The velocity dx / dt of a particle in a unit centrifugal force can be expressed in terms
    of the Swedberg co-efficient ‘S’

    Sedimentation velocity

    Under centrifugal force, particle passes from position x 1at time t1
    to position x2at time t2 .

    2.1.6 The Sedimentation Behaviour Of Flocculated And Deflocculated Suspensions: 2


    Flocculated Suspensions

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

    Here, the sedimentation depends not only on the size of the flocs but also on the porosity of flocs. In flocculated suspension the loose structure of the rapidly sedimenting flocs tends to preserve in the sediment, which contains an appreciable amount of entrapped liquid. The volume of final sediment is thus relatively large and is easily redispersed by agitation.

    Sedimentation behaviour of flocculated and deflocculated suspensions

    Fig 2.2: 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.

    2.1.7 Brownian Movement (Drunken walk)1,4, 5

    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,
    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:

    Image

    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.

    2.2 Electrokinetic Properties

    2.2.1 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 2.3, 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.

    Zeta potential


    Fig 2.3: 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.

    2.2.2 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
  • 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.

    2.2.3 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 flocs 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.

    2.2.4 Method Of Floccules Formation

    The different methods used to form floccules are mentioned below:

    2.2.4.1 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.

    Caking diagram, showing the flocculation of a bismuth subnitrate suspension

    Fig 2.3: Caking diagram, showing the flocculation of a bismuth subnitrate suspension by means of the flocculating agent.

    (Reference: From A.Martin and J.Swarbrick, in sprowls, American Pharmacy, 6 th Edition, Lippincott, Philadelphia, 1966,p.205.)

    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.

    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.

    2.2.4.2 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.

    2.2.4.3 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.

    2.2.4.4 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.

    2.2.5 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.
  • The pressure distribution in this type of 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.
  • 2.2.6 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. In an experiment by Ramubhau D et al., sulfathiazole suspensions of both flocculated and deflocculated type were administered to
    healthy human volunteers. Determination of bioavailability was done by urinary free drug excretion. From flocculated suspensions, bioavailability was
    significantly lowered than deflocculated suspension. This study indicates the necessity of studying bioavailability for all flocculated drug suspensions.

    2.3 Rheological Behaviour

    2.3.1 Introduction

    Rheology is defined as the study of
    flow and deformation of matter. The deformation of any pharmaceutical system can be arbitrarily divided into two types:

    1) The spontaneous reversible deformation, called
    elasticity ;and

    2) Irreversible deformation, called flow.

    The second one is of great importance in any liquid
    dosage forms like suspensions, solutions, emulsions etc.

    Generally viscosity is measured as a
    part of rheological 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.

    η = S/D

    Where, S = Shear stress & D = Shear rate

    Viscosity has units dynes-sec/cm 2
    or g/cm-sec or poise in CGS system.

    SI unit of Viscosity is N-sec/m2

    1 N-sec/m2 = 10 poise

    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 2
    area each and separated by 1 cm distance.

    Figure showing the difference in velocity of layers

    Fig 2.4: 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 viscosity of that medium.

    In simple words the viscosity is the opposing force to flow, it is characteristic of the medium.

    2.3.2 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=d2s l ) g/18η

    Where, v= Terminal settling velocity

    d= Diameter of the settling particle

    ρ s =Density of the settling solid (dispersed phase)

    ρl= Density of the liquid (dispersion medium)

    g=Gravitational acceleration

    η = Viscosity of the dispersion medium

    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.

    Kinematic Viscosity:

    It is defined as the ratio of viscosity (η) and the density (ρ) of the liquid.

    Kinematic viscosity = η/ ρ

    Unit of Kinematic viscosity is stokes and centistokes.

    CGS unit of Kinematic viscosity is cm2
    / sec.

    Kinematic viscosity is used by most official books like IP, BP, USP, and National formularies.

    Relative Viscosity:

    The relative viscosity denoted by ηr . It is defined as the ratio of viscosity of the
    dispersion (η) to that of the vehicle, η
    .

    Mathematically expressed as,

    ηr = η/η.

    2.3.3 Types Of Flow

    Flow pattern of liquid s can be divided
    mainly in two types

    2.3.3.1 Newtonian Flow

    Newton was the first scientist to observe the flow
    properties of liquids in quantitative terms.

    Liquids that obey Newton ’s law of flow are called Newtonian liquids, E.g.simple liquids.

    Newton’s equation for the flow of a liquid is

    S=ηD

    Where, S = Shear stress

    D =Shear rate

    Here, the shear stress and shear rate are directly proportional, and the proportionality constant is the Co-efficient of viscosity.

    If we plot graph of shear stress verses shear rate,
    the slope gives the viscosity. The curve always passes through the origin.

    Graph representing the Newtonian flow

    Fig 2.5: Graph representing the Newtonian flow

    2.3.3.2 Non-Newtonian Flow

    Emulsions, suspensions and semisolids have complex rheological behavior and thus do not obey Newton ’s law of flow and thus they are called non Newtonian liquids.

    They are further classified as under

    A)Plastic flow

    B)Pseudo-plastic flow

    C)Dilatant flow

    A)Plastic flow

    The substance initially behaves like an elastic body and fails to flow when less amount of stress is applied. Further increase in the stress leads to a nonlinear increase in the shear rate which then turns to linearity.

    Graph representing the Plastic flow

    Fig 2.6: Graph representing the Plastic flow

    Extrapolations of the linear plot gives ‘x’ intersect which is called yield value. This curve does not pass through the origin. As the curve above yield value tends to be straight, the plastic flow is similar to the Newtonian flow above yield value.

    Mechanism of plastic flow

    Fig 2.7: Mechanism of plastic flow

    Normally flocculated suspensions are associated with the plastic flow, where yield value represents the stress required to break the inter-particular contacts so that particles behave individually. Thus yield value is indicative of the forces of flocculation.

    B)Pseudo-plastic Flow

    Here the relationship between shear stress and the shear rate is not linear and the curve starts from origin. Thus the viscosity of these liquids can not be
    expressed by a single value.

    Graph representing the pseudo-plastic flow


    Fig 2.8: Graph representing the pseudo-plastic flow

    Normally, pseudo plastic flow is exhibited by polymer dispersions like:

    ® Tragacanth water

    ® Sodium alginate in water

    ® Methyl cellulose in water

    ® Sodium carboxy methyl cellulose in water

    C)Dilatant Flow

    In this type of liquids resistance to flow (viscosity) increases with increase in shear rate. When shear stress is applied their volume increases and hence they are called Dilatant. This property is also known as shear thickening.

    Graph representing the dilatant flow

    Fig 2.9: Graph representing the dilatant flow

    Dilatant flow is observed in suspensions containing
    more than 50% v/v of solids.

    2.3.4 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).

    Thixotropy

    Fig 2.10: Thixotropy

    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.

    2.3.5 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:

    2.3.5.1 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.

    2.3.5.2 Co-solvents

    Some solvents which themselves have high
    viscosity are used as co-solvents to enhance the viscosity of dispersion medium.

    2.3.5.3 Structured vehicles

    This part will be dealt in detail latter.

    2.3.6 Measurement Of Viscosity

    Different equipments called viscometers are used to measure viscosity of different fluids and semisolids. Few of them are

    2.3.6.1 Ostwald Viscometer

    It is a type of capillary viscometer. There is ‘U’ shape tube with two bulbs and two marks as shown in the following figure,

    Ostwald Viscometer

    Fig 2.11: Ostwald Viscometer

    It is used to determine the viscosity of Newtonian
    liquids.


    Principle:

    When a liquid flows by gravity, the time required for the liquid to pass between two marks, upper mark and lower mark, through a vertical capillary tube is determined. The time of flow of the liquid under test is compared with the time required for a liquid of known viscosity (usually water).

    The viscosity of unknown liquid η1
    can be determined using the equation,

    Image

    Where, ρ1=Density of unknown liquid
    ρ2= Density of known liquid

    t 1= Time of the unknown liquid

    t 2= Time of the known liquid

    η 2= Viscosity of known liquid

    2.3.6.2 Falling sphere viscometer

    Falling sphere viscometer consists of cylindrical transparent tube having graduated section near the middle of its length and generally a steel ball that is allowed to fall through the tube.

    Falling Sphere Viscometer

    Fig 2.12: Falling Sphere Viscometer

    The tube is filled with the liquid whose viscosity is to be determined and the ball is allowed to fall. The velocity of the falling ball is measured and viscosity is calculated using stoke’s law.

    Image

    Where, d= Diameter of the falling ball
    ρ s =Density of the sphere

    ρ l=Density of liquid

    g= Gravitational acceleration
    v = Terminal settling velocity

    Asd2g/18 is constant can be
    replaced by another constant ‘K'

    Therefore, the equation will be,

    Image

    2.3.6.3 Cup and Bob Viscometer

    It is a type of rotational viscometer.

    Cup and Bob Viscometer


    Fig 2.13: Cup and Bob Viscometer

    2.3.6.4 Cone and Plate Viscometer

    Cone and plate viscometer


    Fig 2.14: Cone and plate viscometer

    It is more suitable for viscous fluids and
    semisolids.

    2.3.7 Effects of Viscosity on Properties of
    Suspensions

    As viscosity increases the sedimentation rate decreases, thus physical stability increases. Clinical effectiveness of Nitrofurantoin suspension increases as the
    viscosity of the suspension increases.2 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 iscosity. 4 Per-cutaneous absorption of Benzocaine increases as the viscosity of suspension increases. 5

    2.3.8 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.

    2.4 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 semi-solids and solids.

    3) Formulation Of Pharmaceutical Suspensions

    3.1 Structured Vehicle

    3.1.1 Introduction

    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.

    What do you mean by Structured Vehicle?

    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.

    Let it be clear that ‘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
  • Sugars
  • Polyethylene glycols
  • Glycerin
  • 3.2 Other Formulation Aspects

    3.2.1 Introduciton1

    Suspension formulation requires many points to be
    discussed. 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 odor are some of the most important factors that must be controlled at the time of formulation.

    3.2.2 Formulation Components

    The various components, which are used in suspension formulation, are as follows.


    Components


    Function

    API

    Active
    drug substances

    Wetting
    agents

    They
    are added to disperse solids in continuous liquid phase.

    Flocculating
    agents

    They
    are added to floc the drug particles

    Thickeners

    They
    are added to increase the viscosity of suspension.

    Buffers
    and pH adjusting agents

    They
    are added to stabilize the suspension to a desired pH range.

    Osmotic
    agents

    They
    are added to adjust osmotic pressure comparable to biological fluid.

    Coloring
    agents

    They are added to impart desired color to suspension and improve elegance.

    Preservatives

    They
    are added to prevent microbial growth.

    External
    liquid vehicle

    They are added to construct structure of the final suspension.


    Table3.1 Various components used in suspension formulation

    Combination of all or few of the above mentioned
    components are required for different suspension formulation.

    3.2.3 Flow Chart For Manufacturing Of Suspensions
    2
    3.2.4 Suspending Agents


    List Of Suspending Agents

  • Alginates
  • Methylcellulose
  • Hydroxyethylcellulose
  • Carboxymethylcellulose
  • Sodium Carboxymethylcellulose
  • Microcrystalline cellulose
  • Acacia
  • Tragacanth
  • Xanthan gum
  • Bentonite
  • Carbomer
  • 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

    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.

    The 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. 15 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-temperature gelation characteristics) and MC/CMC (having thixotropic flux).


    Suspending agents


    Stability pH range


    Concentrations used as suspending
    agent

    Sodium
    alginate

    4-10

    1
    – 5 %

    Methylcellulose

    3-11

    1
    – 2 %

    Hydroxyethylcellulose

    2-12

    1-2
    %

    Hydroxypropylcellulose

    6-8

    1-2
    %

    Hydroxypropylmethylcellulose

    3-11

    1-2
    %

    CMC

    7-9

    1-2
    %

    Na-CMC

    5-10

    0.1-5
    %

    Microcrystalline
    cellulose

    1-11

    0.6
    – 1.5 %

    Tragacanth

    4-8

    1-5
    %

    Xanthangum

    3-12

    0.05-0.5
    %

    Bentonite

    PH
    > 6

    0.5
    – 5.0 %

    Carageenan

    6-10

    0.5
    – 1 %

    Guar
    gum

    4-10.5

    1-5
    %

    Colloidal
    silicon dioxide

    0-7.5

    2
    – 4 %

    Table 3.2 Stability pH range and coentrations of most commonly used suspending agents.5

    Suspending agents also act 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 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. 14 carried out experiment to observe effect of suspending agents on the characteristics of some anti-inflammatory suspensions. For Glafenine, thecombination 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:

    3.2.4.1 Alginates3,6

    Alginate salts have about same suspending action to
    that of Tragacanth. Alginate solution looses its viscosity when heated above 60 ºC. 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 20 ºC. 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 which is described in
    U.S. patent No: 4,996,222.

    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.

    3.2.4.2 Methylcellulose6

    Methylcellulose 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 Methylcellulose in hot water and cooling it with constant stirring gives clear or opalescent viscous solution. Methylcellulose is stable at pH range of 3-11. As methylcellulose is non-ionic, it is compatible with many ionic adjuvants. On heating to 50 ºC, solution of Methylcellulose is converted to gel form and on cooling, it is again converted to solution form. Methylcellulose is not susceptible to microbial growth. It is not absorbed from
    G.I tract and it is non-toxic.

    3.2.4.3 Hydroxyethylcellulose6

    Hydroxyethylcellulose (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.

    3.2.4.4 Carboxymethylcellulose (CMC)

    Carboxymethylcellulose 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 HV-CMC, the viscosity significantly decreases when temperature rises to 40 ºC from 25 ºC. 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 chang HC et al. 16 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.

    3.2.4.5 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 %.

    3.2.4.6 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.

    U.S. Patent No. 4,427,681 describes that, attrited MCC coprocessed with CMC together with titanium dioxide (opacifying agent) can be used for thixotropic pharmaceutical gels.

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

    Formulation of dry powder suspensions with MCC:
    alginate complexes produce an excellent dry readily hydratable and dispersible formulation for reconstitution. For dry powder suspension formulation MCC: alginate complex is incorporated at a concentration of 0.5-10 % w/w of the
    total dry formulation.

    Commonly, Na-CMC is used as the coprecipitate in MCC. Na CMC normally comprised in the range of 8 to 9 % w/w of the total mixture. These mixtures are available from FMC under trademark; Avicel RTM CL – 611, Avicel RTM RC – 581, Avicel RTM RC – 591. Avicel RC- 591 is most commonly used. It contains about 8.3 to 13.8 % w/w of Na CMC and other part is MCC.

    3.2.4.7 Acacia6

    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.

    3.2.4.8 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.

    3.2.4.9 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.

    3.2.5 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 problem.

    Ionic surfactants are not generally used because they are not compatible with many adjuvant and causes change in pH.

     FLOW CHART FOR MANUFACTURING OF SUSPENSIONS

    Fig. 3.1 Examples of wetting agents used in different suspension formulation.

    Wetting is achieved by: 9,6

    3.2.5.1 Surfactants

    Surfactants decrease the interfacial tension between drug particles and liquid and thus liquid is penetrated in the pores of drug particle displacing air from them and thus ensures wetting. Surfactants 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., 17
    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.
  • 3.2.5.2
    Hydrophilic Colloids

    Hydrophilic colloids coat hydrophobic drug particles
    in one or more than one layer. This will provide hydrophillicity to drug particles and facilitate wetting. 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.

    3.2.5.3 Solvents

    The most commonly used solvents used are alcohol,
    glycerin, polyethylene glycol and polypropylene glycol. The mechanism by which they provide wetting is that they are miscible with water and reduce liquid air interfacial tension. Liquid penetrates in individual particle and facilitates wetting.

    3.2.6 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
  • 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.

    3.2.7 Osmotic Agents6,3

    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.

    3.2.8 Preservatives3,6,4,5,7

    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 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 in preservative 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.

    Image

    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.

    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.

    List Of Preservatives


    Name of preservatives


    Concentration range

    Propylene
    glycol

    5-10
    %

    Disodium
    edentate

    0.1
    %

    Benzalkonium
    chloride

    0.01-0.02
    %

    Benzoic
    acid

    0.1
    %

    Butyl
    paraben

    0.006-0.05
    % oral suspension

    0.02-0.4
    % topical formulation

    Cetrimide

    0.005
    %

    Chlorobutanol

    0.5
    %

    Phenyl
    mercuric acetate

    0.001-0.002
    %

    Potassium
    sorbate

    0.1-0.2
    %

    Sodium
    benzoate

    0.02-0.5
    %

    Sorbic
    acid

    0.05-0.2
    %

    Methyl
    paraben

    0.015-0.2
    %

    Table
    3.3 Preservatives and their optimal concentration.
    5

    3.2.9Flavoring And Coloring Agents2,3,6,11

    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.

    3.2.9.1 Most widely used Flavoring agents are as follows: 13

    Acacia

    Ginger

    Sarsaparilla syrup

    Anise oil

    Glucose

    Spearmint oil

    Benzaldehyde

    Glycerin

    Thyme oil

    Caraway oil

    Glycerrhiza

    Tolu balsam

    Cardamom (oil, tincture, spirit)

    Honey

    Vanilla

    Cherry syrup

    Lavender oil

    Vanilla tincture

    Cinnamon (oil, water)

    Lemon oil

    Tolu balsam syrup

    Citric acid syrup

    Mannitol

    Wild cherry syrup

    Citric acid

    Nutmeg oil

    Clove oil

    Methyl salicylate



    Cocoa

    Orange oil

    Cocoa syrup

    Orange flower water

    Coriander oil

    Peppermint (oil, spirit, water)

    Dextrose

    Raspberry

    Ethyl acetate

    Rose (oil, water)

    Ethyl vanillin

    Rosemary oil

    Fennel oil

    Saccharin sodium

    Table 3.4: Flavouring agents

    3.2.9.2 Coloring agents 2,13

    Colors are obtained from natural or synthetic
    sources. Natural colors are obtained from mineral, plant and animal sources.
    Mineral colors (also called as pigments) are used to color lotions, cosmetics,
    and other external preparations. Plant colors 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 color required and thickness of column of the
    container to be viewed in it.

    Most widely used colors are as follows.

    · Titanium dioxide (white)

    · 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)

    3.2.10 Sweetening Agents 3

    They are used for taste masking of bitter drug
    particles. Following is the list of sweetening agents.

    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
  • Mixture of thereof
  • 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.
    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 flavoring agent. The type and amount of flavoring and coloring 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.

    3.2.11 Humectants3

    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.

    3.2.12 Antioxidants3

    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)
  • 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

    4.1 Introduction1

    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 thatthey share the dissolution process as a rate limiting step for absorption and bio-availability.

    Image

    4.2 Principles Of Drug Release 2

    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.

    Image

    4.3 Formulation Factors Governing Drug Release

    2

    4.3.1 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.
  • 4.3.2 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/6лηr

  • 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
  • 4.3.3 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.
  • 4.4 Bioavailability Of Suspensions From Different Sites2

    4.4.1 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.
  • 4.4.2 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.
  • 4.4.3 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.

    4.4.4 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.

    4.5 Dissolution Testing

    Two methods are used for dissolution testing of suspensions.

    4.5.1 Official Methods (Conventional Methods):8

    It is known as paddle method.

  • Dissolution profile of the 500 mg sample suspension is determined at 37°C in 900 ml of pH 7.2
    phosphate buffer using the FDA paddle method at 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 37°C.
  • 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 µm membrane and analyze.
  • 4.5.2 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.5
  • Shah tried to explain the dissolution of commercially available Prednisolone suspension by a magnetically driven rotating filter system.6
  • Stram & co-workers gave a methodology to determine the dissolution–rate profile of suspensions employing the FDA’s two-bladed paddle method Flow–through
    apparatus developed by F. Langebucher which is mostly used for dissolution testing of suspensions.7
  • Potential energy curves for particle interactions in suspension systems

    Fig 4.1: Flow through apparatus


    Flow Through Appratus For Dissolution Of Suspensions:

  • This method, which is based on the mass transfer 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.
  • Strum & co- workers also had worked on determination of dissolution rate profile of suspension using the FDA’s two bladed paddle method. 8

  • 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.

    4.6 Dissolution Models’ Studies 3

    The following assumptions are employed for these models:

  • 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.


    MODEL


    EQUATION


    CHARACTERISTIC

    I

    da/dt = -2DCs/ l

    Static

    II

    da/dt=-2DCs / Ka

    a

    III

    da/dt = 4DCs/ αρ

    a

    Where,

    a=
    particle diameter (cm)

    t=
    time (sec)

    D= diffusion co-efficient (cm

    2

    /sec)

    l=
    thickness of diffusion layer (cm)

    ρ=
    density (g/cm

    3

    )

  • 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.
  • 4.7 In-Vivo In-Vitro Co-Relationship (Ivivc) 3

    In Vivo Data In Vitro Data

    Peak plasma/serum oncentraions Percent drug dissolution
    profiles

    AUC (plasma/serum) concentration Dissolution rate profiles

    Profile (To-t)

    Estimated AUC (plasma/serum) Intrinsic dissolution
    rates

    Concentration profile (T0 -∞
    )

    Pharmacokinetic
    modeling Dissolution-rate constants and

    ·
    Absorption-rate
    constant (K

    a

    )
    dissolution half-lives

    ·
    Absorption
    half-life

    ·
    Elimination
    half-life

    Drug
    excreted in the urine (T

    0-t

    ) Time for a certain
    percentage of

    Drug to dissolve (e.g. T

    30%

    ,

    T

    50%

    ,
    T

    90%

    , etc).

    Cumulative
    amount of drug excreted as a Parameters
    resulting from

    function
    of time
    determination of dissolution

    Kinetics

    Percent
    drug absorbed-time profiles
    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
    .1

    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.1

    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.
  • Objectives of IPQC tests are summarized
    below: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:

    5.2.1 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.

    5.2.2 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.

    5.2.3 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.

    5.2.4 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.

    5.2.5 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.

    5.2.6 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.

    5.2.7 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.

    5.2.8 Centrifugation Test

    This test tells us about the physical stability of
    suspension.

    5.2.9 The product is checked for uniform distribution of color, absence of air globules before packing.

    5.3 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
  • Rheological measurement
  • Stress test
  • pH
  • Freeze-Thaw temperature cycling
  • Compatibility with container and cap liner
  • Torque test
  • 6) Stability Of Suspensions

    6.1 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:

    1. Physical
    2. Chemical

    6.2 Physical Stability

    1, 3, 5

    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.

    6.2.1 Particle-Particle Interaction And Its Behaviour 1, 5

    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 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.

    Laboratory MMR System

    Fig 6.1.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 bridge between the adjacent
    particles so as to link them together in a loosely arranged structure.

    6.2.2 Interfacial Properties Of Solids

    1

    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 = γ

    SL
    . ∆A.

    Where, ∆G = increase in surface free energy

    γ

    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 re-dispersible.

    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 γ SL to a minimum value, so that the system can
    be stabilized.

    6.2.3 Poly-Dispersity: (Variation in
    particle size)

    18

    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
    ”.

    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.

    6.3 Chemical Stability
    Of The Suspensions

    39

    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 zero-order 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.

    {mospagebreak title=Packaging Of Suspensions }

    7) Packaging Of
    Suspensions

    7.1 Introduction

    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.

    7.2 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.
  • 7.3 Materials Used For
    Packaging


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

    7.3.1 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.

    Type of glass

    Additive giving amber color

    Soda lime

    FeO + sulfur (in presence of reducing agent)

    Borosilicate

    FeO+TiO 2


    Table
    7.1 Type of glasses and additives giving amber colour


    Disadvantages Of Glass Materials:

  • They are fragile.
  • They are very heavy
    as compared to plastic so handling and transport is difficult.
  • 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. For example:


    Assay of borosilicate glass


    Value


    Initial pH


    6


    Final pH


    8


    pH change


    ± 0.24


    SiO

    2

    ppm


    21.0


    Na ppm


    301


    K ppm


    0.74


    Al ppm


    1.3


    Ba ppm


    0.7

    Table 7.2: Typical characteristics of borosilicate glass

    7.3.2
    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 for altering the physical
    properties of plastic viz., oils has softening effect on polyethylene and PVC.

    7.3.3 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 vapor
    transmission.
  • Removal torque.
  • Heat resistance.
  • Shelf life.
  • Economical factors.
  • 7.4 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
    ”.

    7.5 Storage
    Requirements (Labelling)

  • Shake well before use
  • Do not freeze
  • Protect from direct light (For light sensitive drugs).
  • 8. Innovations In Suspensions

    8.1 Taste Masked Pharmaceutical Suspensions 41, 42

    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 as

    8.1.1 Polymer Coating Of Drugs 1

    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.

    8.1.2 Encapsulation With A Basic Substance 2

    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.

    8.1.3 Polymer Coated Drug With A Basic Substance
    2

    This method has claimed to give stable taste masked
    suspensions on reconstitution (taste masked for prolonged period)

    8.1.4 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.

    Sr.
    No

    Name
    of the drug

    Taste
    masking approach

    01

    RISPERIDONE

    pH
    control and polymer coating (with Eudragit RS)

    The
    coated drug is suspended in water based liquid constituted at an optimum pH.

    02

    ROXITHROMYCIN-I AND ROXITHROMYCIN-II

    Polymer
    coating with Eudragit RS 100

    03

    DICLOFENAC

    Polymer
    coating with Eudragit RS 100

    04

    LEVOFLOXACIN

    Polymer
    coating (Eudragit 100 : cellulose acetate, 60:40 or 70:30)

    Table 8.1: Some examples of taste masked suspensions

    8.2 Nano-Suspension

    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 nano-particle 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.
  • 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.
  • 8.2.1 Preparation Of Nano-Particles:

    The technology used should produce nano-particles 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 collide at high velocity under extreme pressure.

    8.2.2 Designing Of Nano-Particle Formulations:

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

    8.2.2.1 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.

    8.2.2.2 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.

    8.2.2.3 Controlled re-crystallization

    This approach enables preparation of nano-suspension from API feed material made in a kilo lab or other sources of synthesized solution to the problem of producing nano-particles 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). Because the intrinsic API crystallizes where formed as nano-particles, they can be re-dispersed as nano-suspension.

    Laboratory MMR System

    Fig 8.1: Laboratory MMR System

    8.3 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 decrease in dosing
    frequency.

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    Information Zone: 

    Comments

    skongara's picture

    Hi, I was wondering if you have any comments on reducing or eliminating entraped air in the suspension while mixing and homogenising. you can mail your comments to sandeepkongara@nexgenpharma.com
    somansmail's picture

    hi go through it its really great effort.. and useful for all
    -- -- Regards... Rahul Soman, M. Pharmacy, PhD - Research Scholar, National Institute of Technology, NIT Campus PO, Calicut, Kerala GPAT SPECIAL