SUSPENSION
Particle size range = 10 – 1000 μm.
Protomine zinc insulin → Suspension (form) → have prolonged action.
Dilute suspensions = May have 2-10% w/v solids.
Concentrated suspensions = may have up to 50% w/v solids e.g. ZNO suspension.
In the potential energy curve, deflocculated system represents the 10 minimum, while flocculated system represents 20 minimum → particles are separated by about 1000-2000 A0 & are loosely structured.
In size reduction of particles,
W = ∆ G = γSL . ∆A
W = increase in surface free energy; γSL = interfacial tension between liquid medium & solid particles; ∆A =
increase in surface area of the interface due to size reduction.
Flocculating agents: Electrolytes, Polymers, Surfactants.
Brownian Movement: It can be exhibited if size of particles is 2 -5 μm.
Increase in density of the medium decrease the rate of sedimentation. It can be increased by PVP, Sugars (sorbitol or dextrose), PEG, glycerine.
Physical stability of Suspension
The extent of sedimentation in suspension, is quantitatively expresse by two parameters, which give gross picture of physical stability. They are applicable to flocculated suspensions only. They are:
(i) Sedimentation Volume (F) or Vs:
Though it is denoted by volume, it is dimensionless number.
Or F
HU/ H = when a measuring cylinder is used & H = height of sediment.
Now if F =1 i.e. VU = V0 = No sedimentation = highest stability.
Now if F = 0 i.e. Vu = 0 ; complete sedimentation.
F is generally between 0-1.
Higher the value of sedimentation volume i.e. F higher the physical stability of suspension.
Degree of flocculation (β)
If β = 1 = theoretical minimum i.e. F = Fα
If β is near 1, it indicates deflocculated system.
In general, higher the value of β, greater the physical stability.
It is destructive method because deflocculated system is converted to flocculated system by addition of flocculating agents like electrolytes. Sedimentation volume (F) deflocculated is less than flocculated system.
To measure the efficiency of wetting agents Drave’s test is used i.e. lower the time the weighed skin of cotton yarn take to sink through a wetting solution in 500 ml graduated cylinder, higher the wetting efficiency of wetting agent.
Structured vehicles (Deflocculated suspension): These are the vehicles which exhibit pseudoplastic or plastic
rheologic behavior. They also possess some degree of thixotropy i.e. sol-gel-sol transformation during storage so help in stability of suspension.
Structured vehicles are usually prepared using hydrocolloids (swell in H2O & so increases viscosity & also act as
protective colloids & stablize charges.) examples of hydrocolloids
(i) Non-ionic type: Methyl cellulose, HPMC
(ii) Anionic type: Sodium CMC, Polyacrylic acid (carbopol)
(iii) Clays: Bentonite
These also acts as suspending agents.
Suspensions for oral use, contain high amount solids & need high amounts of suspending agents. Suspensions for parenteral use contain about 0.5% suspending agents.
When clays are used as suspending agent, preservative like methyl paraben are used to avoid from mould growth.
Water miscible co-solvents like alcohol, glycerine & propylene glycol are commonly used to disperse hydrocolloids.
A minimum amount of surfactant is used in dispersion of solids because they produce foam & create problems
during mixing at later stages.
Controled flocculation: Flocculated suspension:
Flocculating agent has to be added in control to avoid caking in deflocculated suspension. By two approaches:
(i) Most dispersed particles possess a surface charge. The intensity of this charge can be reduced by the addition of agents with an opposite charge (electrolytes). As a result, the zeta potential decreases & particles establish attractive forces between adjacent particles. E.g. for bismuth subnitrate (have + charge), monobasic potassium phosphate (KH2PO4) electrolyte is added. On addition of electrolyte, -vely charged phosphate ions get absorbed on +vely charged bismuth particles. So attractive forces begin to operate & floccules are formed & zeta potential decreases. Thus the absence of cake formation is well correlated with the maximum sedimentation volume. Since zeta potential is well correlated with cake formation & state of flocculation, it has become a quality control tool for the preparation of flocculated suspensions.
(i) Surfactants e.g. SLS, Sodi‐dioctyl sulfosuccinate (ionic types) & Tweens (non‐ionic) & polymers e.g. xanthan gum (anionic heteropolysaccharide) are long chain compounds. These substances act by absorbing a part of their chains on the particle surface & projecting out the remaining part into the medium. This type of bridging promotes the formation of floccules.
Typical relationship between caking, zeta potential & sedimentation volume. The suspension contains +vely charged Bismuth ions & flocculating agent is negatively charged (Phosphate ions)
Flocculation in structured vehicles:
For avoiding the supernatant becoming clear, rapidly in a flocculated suspension, structured vehicles are used. In pharmaceutical suspension, the yield value of a vehicle having the density of H2O must be about 0.3 dyne cm-2 to support solid particles having a diameter of 0.2 micron & a density of 1.5.
A low wet point coupled with a low flow point (& a small difference between the two) indicates good deaggregation or dispersion. The better the wetting agent, the lower the wet point value (expressed in ml per 100 gms & may, for example have values of 15 to 45 with a 10% additive concentration.)
Similarly, lower the flow point, better the wetting agent. The flow may have values at a 10% additive level in the range of 50-250.
Note that increasing the concentration of ions in the solution decreases the thickness of the diffuse double layer, by “swamping” & therefore aggregation is encouraged.
To determine whether a suspension is aggregated, a differential monometer can be used to compare the pressure of suspension near its bottom & top in a container. A deaggregated system exert more pressure near the bottom, but an aggregated system has same pressure at both points.
Caking is defined as the formation of a non-redisperrsible sediment with a suspension system. The major causes of
caking are crystal bridging & closed aggregate (coagulate) formation Crystal habit may be defined as the outward appearance of an agglomeration of crystals.
Suspension formulation:
(i) Precipitation method:
(a) Organic solvent precipitation
(b) By changing the pH of the medium: e.g. estradiol suspensions, insulin suspensions (PZI). It contain excessive amount of zinc to retard absorption.
(c) By double decomposition: E.g. zinc “polysulfide” by mixing zinc sulphate & sulfurated potash solution.
Dispersion method:
Protective colloids differ from surfactants as follows:
(i) They donot reduce interfacial tension
(ii) Used in higher conc. Than surfactants.
Protective colloids not only increase the zeta potential, but they also form a mechanical barrier or sheath around the particles.
Na CMC is used in a concentration upto 0.5% in injectable preparation.
„filnt‟ refers to clear, colourless, brilliant glass. It may be silicon coated to minimize the leaching of alkali from glass.
It is important to note that use of most viscometers & centrifuges in stability studies is not ideal for aggregated system because their use destroys the structure formed.
The freeze thaw cycling technique is particularly applicable to stressing suspensions for stability testing purposes. It is of prime importance to be alert for changes in absolute particle size, particle size distribution & crystal habit.
Antacids constitute a single class of drug, available in both suspension & tablet forms.
An important factors affecting drug absorption from an i.m. parenteral suspension is the degree of body movement (stirring) at the injection site. Colloid mill & ultrasonic equipment are useful for large scale production of suspensions.
Handerson pipette is used for measuring sedimentation volume.
