Suspensions Flashcards
What are the three types of dispersed systems?
Molecular dispersion
Colloidal dispersion
Coarse dispersion
What is a dispersed system?
A system containing a dispersed phase (internal) and a continuous phase (dispersion medium)
What are the main differences between the dispersion systems?
Colloidal dispersion particles are 0.5μm. They are visible under….
What type of dispersion systems are pharmaceutical suspensions and emulsions?
Coarse dispersion systems
What is the difference between an emulsion and a suspension?
The difference between an emulsion and a suspension is based on the nature of the dispersed (internal) phase.
The dispersed phase of an emulsion is liquid
The dispersed phase of a suspension is solid
What is the difference between a colloidal dispersion and a coarse dispersion?
The difference between colloidal and coarse dispersions depends on the size of the dispersed phase.
A colloidal dispersion is between 1nm and 0.5μm
A coarse dispersion is >0.5μm
Why do we formulate pharmaceutical suspensions?
Drug insoluble in delivery vehicle
Mask the bitter taste of the drug by keeping it in solid form
Increase drug stability
Achieve controlled/sustained drug release
What are some pharmaceutical applications of suspensions?
Oral drug delivery,
Topical administration
Pareneteral use
What are the advantages of having a suspension in oral drug delivery?
- offers solution for patients with difficulty swallowing
- offer finely divided dispersed phase hence offering high surface area e.g. Mg stearate and Mg carbonate as antacids
- provide taste marking e.g. Paracetamol suspension more palatable than solution
Why are suspensions used in topical adminstration?
Can be used as liquid preparations e.g. Calamine lotion which contains ZnO and FeO
Is used as an astringent.
Can also be used as semi solid suspensions which often contain a high concentration of powder (20-50%) in an ointment base. Usually paraffin, Vaseline or lanolin
Why are suspensions used pareneterally?
We can control the rate of drug absorption and duration of action e.g. Eligard acetate (3month sustained release injectable suspensions for treatment of prostate cancer)
For SC and IM use only
Why are pharmaceutical suspensions not used for the IV route?
Dispersed phase may be too large and will clog up capillaries. If a suspension MUST be used for IV, the particles must be small enough to avoid emoblism
What factors will the suspension drug absorption be dependent on?
Drug absorption of a suspension depends on the solid drug particles dispersed in medium.
These need to be solubilised to be dissolved.
The rate limiting factor is therefore its dissolution
Compare a solution vs. Suspension in terms of onset and duration of action after IM injection
Solution has faster onset as drug is already in solubilised form and ready for absorption suspension:drugs will take longer to have effect as the solid particles need to be dissolved and then absorbed,
but a suspension has longer duration of action due to slower rate of dissolution.
What are the advantages of suspensions?
Allows us to formulate poorly water soluble drugs
Provides taste marking as unpleasant tastes are less obvious in suspensions than in solutions
Offers rapid absorption (compared to solid dosage forms)
Provides a sustained release option
Improves drug stability (compared to solutions)
Why is a well formulated suspension second only to a solution in terms of superior bioavailability ?
A solution is a uniform molecular dispersion, the active ingredient is already dissolved and will absorb into cells immediately.
A suspension contains the active drug in solid form in a liquid medium. It will still require some time to dissolve into solution and then be absorbed.
This means that in terms of bioavailbility, a suspension is better than a solid dosage form, but not as good as that of a solution
Why is the absorption of a suspension dissolution limited?
The solid particles of the suspension require time to dissolve into the medium.
If this does not occur, the suspension formulation will not be absorbed
What type of suspension will have a faster onset of action?
Aqueous suspensions as they are dissolved first. Oily suspensions have poor aqueous solubility, so their dissolution is still their rate limiting step
What type of suspension will have a longer duration of action?
Oily suspensions as they will dissolve slower. The active ingredient will be absorbed over a longer period of time, resulting in a prolonged duration of action
What can be added to suspensions to improve dispersion and absorption of fine particle size suspensions
Surfactants
What are the properties of the dispersed phase? (Particles)
- Finely dispersed particles have a tendency to aggregate, addition of surfactants tend to decrease this aggregation
- Chemical form of suspended drug (its solubility) can be increased if the particle size decreases (due to NW equation where the the rate of dissolution is proportional to surface area.)
But you need a balance between the surface area and particle size to prevent aggregation
What are the desirable qualities of an ideal suspension?
- Remain sufficiently homogenous for a period to allow removal of dose.
- Suspended materials should not settle too rapidly
- Suspended materials must be easily resuspendable
- not too fluid and not too viscous.
- must be an acceptable colour and odor
- uniform particle size
Why is the viscosity of the suspension important?
Suspensions should not be too viscous as this would hinder transfer onto skin, pouring, and flow through a syringe needle.
However suspensions should not be too fluid that it runs off the skin surface without giving the medicament a chance to have an effect
Why is the size of suspended particles important?
The size should be small and uniform to give a smooth, elegant product which is free from gritty texture
What are the theoretical conditions that must be considered when formulation a suspension?
Interfacial properties e.g.v
- surface free energy
- surface potential
- electric double layer
What is the surface free energy?
This is the amount of increase in free energy when the surface area increases (due to reduction in particle size)
ΔG= γΔΑ Where ΔG = increase in surface free energy ΔA = increase in surface area γ= interfacial tension.
Thus the smaller the ΔG, the more stable the suspension. This requires larger particle sizes.
What is the surface potential?
The potential the exists when dispersed solid particles in a suspension possess charge in relation to their surrounding liquid medium
What is the electrical double layer?
An electric distribution at the solid liquid interface as a result of potential determining ions which give the particle it’s charge and counter ions which have the opposite charge.
The double layer consists of a stern layer and a diffuse layer
How is the electrical double layer formed?
Ions that give the particle it’s charge = determining ions/co ions
Ions that have opposite charge to determining ions = counter ions/gegenions
What is the Nernst potential?
E
Potential difference between the actual solid surface and the electroneutral bulk (which is the dispersion medium)
What is the Nernst potential also known as?
The thermodynamic potential
What is the zeta potential?
ζ
The potential difference between the tightly bound layer stern layer and the bulk
What does the zeta potential do?
Governs the electrostatic force of repulsion between solid particles
What is the zeta potential also known as ?
The electrokinetic potential
What is wetting?
Wetting is the ability of a liquid to maintain contact with a solid surface,
This is done by overcoming the interfacial tension between hydrophobic solid and dispersion medium.
What is the wetting process?
Air is adsorbed on the surface of the solid
The wettability of the powdered dispersed phase can be predicted by observing the contact angle and determined by using the Young’s equation
How can the contact angle predict the wettability of the solid particle?
A smaller contact angle means the liquid is more spread out on the solid, indicating that the solid is hydrophilic
A contact angle of 90° = partial wetting
A contact angle of more than 90° indicates the solid is hydrophobic as it is non wetting
What are the 4 different kinds of electrokinetic phenomena?
Electrophoresis
Electroosmosis
Sedimentation potential
Steaming potential
What is electrophoresis?
This is a measurement of the movement of charged particles through a liquid under the influence of an applied potential difference
What is Electroosmosis?
This is where the solid is immobile but the liquid moves relative to the charged surface when a potential is applied
What is sedimentation potential?
This is the potential generated when particles undergo sedimentation
What is streaming potential?
This is created by forcing a liquid to flow through a stationary solid phase e,g, plug, or a bed of particles
What is the DLVO theory?
Derjaguin, Landau, Verwey, Overbeek
Theory of electrostatic stabilisation which explains the tendency of particles to agglomerate or remain discrete.
This depends on the stern potential and the thickness of the electrical double layer
What does the DLVO theory suggest?
The stability of a colloidal system is determined by the sum of the attractive forces (Van der Waals) and repulsive forces (electric double layer) which exists between particles as they approach each other due to Brownian motion
What is the formula for the additive parameters in the DLVO theory?
Vt= Va+ Vr
Where Vr = repulsion forces, from the double layer, and is defined as a positive value
And Va= attractive forces, WDV, defined as a negative value
Adding the two forces together makes it possible to describe the overall force acting on a colloidal particle as it approaches another particle at a Charged surface
What happens if the stern layer potential is greater than the van der Waals forces?
The repulsive forces dominate, preventing particles from coming close enough to allow the VDW forces to take effect.
This means particles remain discrete and the dispersion is stable
What happens if the vanderwaal forces predominate?
The attractive forces are stronger than the repulsive forces causing particles to approach close enough for VDW forces to take effect. The dispersion will be unstable and aggregation will occur
What causes the primary minimum?
When attractive forces predominate at very small distances
What causes the secondary minimum?
Attraction of particles at large inter particle distances.
This occurs because the fall off in repulsive energy with distance is more rapid than that of attractive energy
What does the depth of the secondary minimum depend on?
Particle size.
Particles may need to have a radius of >1μm before the attractive force is sufficiently great for flocculation to occur
How can particulate behaviour be controlled?
By manipulating radius and distance between particles in the Hamaker equation:
Vr=2πεαψ^2 x 10^[-kH] and Va=-Aa/12H
Where A= Hamaker's constant ε = permittivity of medium H= distance between particles ψ= surface potential k= Debye-Huckel reciprocal length parameter a= radius of particle
What is a deflocculated suspension?
Where the dispersed particles remain as individual discrete particles.
These systems sediment slowly
The rate of sedimentation is dependent on the size of the particles
They form a cloudy supernatant as the slow sedimentation can still be seen as ppt.
Particles will cake upon standing and be difficult to redisperse
What is a flocculated suspension?
Where the dispersed particles come together to form large clumps or flocs.
These sediment faster, resulting in a clear supernatant
Upon standing, the particle will not cake and will be easily redispersed
What is the primary minimum?
areaon the DLVO graph where the attractive force is highest.
Particles falling under this minimum tend to aggregate as the force of attraction is too high and dominates the overall interactive forces making it very hard to disperse these particles even by hard shaking as they are bonded by very strong attractive forces.
What is the energy barrier?
This is the maximum repulsive energy required to maintain the particles in dispersed unit.
If you want particles to get attracted they need to at least overcome that barrier.
Why is the energy barrier not the ideal energy area for a suspension?
- At the energy maximum, the repulsive forces between the particles are too high so particles do not aggregate.
- initially this may seem to be an ideal situation to form a suspension, but particles will only remain discrete if the kinetic energy of the is below the total interaction energy then.
- so if there is a change in any other external factor and there is an increase in kinetic energy, the particles will try to overcome that energy barriercausing them to come close together.
- If this kinetic energy is high enough they will try to aggregate again.
- Particles will then fall down into the primary minimum area.
- The energy barrier region is therefore quite risky as any slight changes in conditions like temperature may cause particles to aggregate again.
Why is the secondary minimum ideal for suspensions?
Ideally you want the particles to be in the secondary minimumregion as attractive forces are quite minimum.
Particles will try to form loose aggregates which are easier to redisperse
What are the different stability concerns with suspensions?
A stable system may undergo flocculation -> coagulation -> sedimentation ultimately ending in phase separation
Or it may undergo sedimentation first -> flocculation -> coagulation resulting in much denser caking and phase separation
What are the cases of physical instability of suspensions?
Forces at the surface of dispersed particles,
What is the theory of sedimentation?
The velocity or rate of sedimentation is expressed by STOKES law
ν= d^2(ρs-ρo)g/18ηo Where ν= sedimentation velocity in cm/sec d= particle diameter in cm (for spherical particles) g= acceleration due to gravity ρs= particle density ρo= density of dispersion medium ηo= viscosity of dispersion medium in poise
When can stokes law be applied?
In dilute pharmaceutical suspensions (0.5μm)
For discrete spherical particles falling under the influence of gravity
For suspensions where the liquid flow around particles is laminar or streamlined
When does stokes law not apply?
pharmaceutical suspensions that contain dispersed phase in concentrations of 5-10% or higher percentages which results in hindered settling
Particle sizes <0.5μm as the effect of Brownian motion counteract the sedimentation due to gravity .
For sedimentation to occur in these systems, a force greater than gravity must be used. (We use centrifuge)
When the solid content in a suspension is high
What is the equation used to accommodate particles with different shapes?
v’=vε^n
Where v’ = corrected rate of settling
ε= porosity of system
n= constant
What is the sedimentation volume ratio?
F
This is the volume of sediment / original volume of suspension
What does the sedimentation to volume ratio mean?
If F 1 this means that the suspension has not sedimented. E.g. If F is 1.5
If F = 1 this means that the suspension is in ideal flocculation equilibrium
How is the sedimentation rate determined?
By plotting a graph of F vs. Time and finding the gradient
What is the degree of flocculation?
β
This is the ultimate sediment volume of flocculated suspension / the ultimate sediment volume of a deflocculated suspension
What is crystal growth or Ostwald ripening?
Changes in the size of suspended particles which can cause caking, changes in sedimentation and altered bioavailability of the suspension.
This occurs more commonly for polymorphic drugs and is affected by temperature
What causes crystal growth/Ostwald ripening?
Small particles dissolve preferentially compared to a rage particles due to their high surface free energy.
The metastable form is the most soluble form. As the metastable form changes to a more stable form, the solubility decreases and the formation of crystals occur
What sort of flocculation system is used in the ideal suspension?
A partially flocculated system. This depends on the relative magnitude of repulsion and attraction between particles.
How is flocculation controlled?
By a combination of
Particle size control and use of flocculating agents
How is controlled flocculation achieved using flocculating agents?
Flocculating agents may include polymers. The addition of these promote cross linking between adjacent particles
Polymers can also coat the surface of particles and achieve steric repulsion
Electrolytes can also be added to utilise electrostatic repulsion
Why is particle size control utilised?
Particle size affects a variety of things in suspensions:
- Smaller particles have a slower sedimentation rate and therefore a better stability.
- Smaller particles have less mechanical irritation whereas particles >5μm may cause irritation after injection or instillation into eye due to grittiness.
- Smaller particles are easier to administration (e.g. Via needles)
- range of size controls the dissolution rate
How is particle size control utilised?
A narrow size range of air articles can prevent crystal growth due to temperature fluctuations during storage
Narrow size range also prevents compact packing
What are the differnet flocculating agents used?
Surfactants
Polymerics flocculating agents
Electrolytes
How do surfactants help control flocculation?
As well as acting as a wetting agent, the ionic surfactant can act as a flocculating agent by neutralising the surface charge of particles and reducing the repulsion forces
How do polymeric flocculating agents help control flocculation?
Starch, alignates, cellulose derivatives, tragacanth, carbomers and silicates are all examples of polymeric flocculating agents.
These enable cross linking between particles and hold them in a flocculating state.
What is a limitation of polymeric flocculating agents?
If each polymer molecule absorbed onto one particle only, steric repulsion occurs, resulting in deflocculation
How do electrolytes help control flocculation?
Electrolytes can change the ζ potential which is largely dependent on the blanch of higher counter ions.
Trivalent ions are more efficient but are less widely used than mono and divalent ions due to toxicity as they can cause the precipitation of negatively charged molecules.
What are the most widely used electrolytes to control flocculation ?
Sodium salts of
acetates,
Phosphates,
Citrates
What is the limitation of using electrolytes as flocculating agents?
Too much electrolytes can result in charge reversal
How does too much electrolytes result in charge reversal?
- If you have a suspension in which the particles are highly positively charged, this corresponds to a very high zeta potential
- This causes particles to repel each other. The suspension remains deflocculated.
- This means the particles settle down and form a hard cake which is difficult to redisperse.
- But if you start adding increasing amounts of electrolytes the zeta potential will drop
- This is due to the absorption of negatively charged ions on the surface of a particle which neutralises the positive charge and causes
- At a certain concentration of electrolytes, the line sedimentation to volume ratio on the graph will be straight.
- If this is constant, it means that the ratio is approximately close to 1 which indicates a completely flocculated state.
- In this region there is no caking .
- This will remain constant unless the zeta potential decreases to a significantly negative charge.
- upon continual addition of the electrolyte, the zeta potential will decrease beyond 0 and into the negative region.
- Once it starts to decrease in negative direction there is a fall in curve or sedimentation volume ratio.
- The resultant suspension is deflocculated and caking occurs again.
Why is a structured vehicle used?
If the suspension is flocculated but the floccules have a tendency to settle down quickly, you can always add some thickening or suspending agents to reduce the sedimentation rate.
This will also help to maintain all the floccules in a suspended state which makes the suspension more appealing.
We use viscosity imparting agents.
What are viscosity imparting agents also known as?
Thickening/suspending agents
What are the characteristics of a viscosity imparting agent?
Non toxic,
pharmacologically inert
Compatible with a wide range of active and inactive ingredients.
Applicable to deflocculated suspensions, flocculated suspensions, and in a structured system aqueous solutions of natural and synthetic polymers.
Easily dissolved or dispersed in water
Potentially providing ideal rheological properties
What are some examples of polymeric viscosity imparting agents?
Natural and synthetic polymers e.g. Methylcellulose, sodium carboxymethylcellulose, acacia, tragacanth
What is the composition of a typical suspension?
Dispersed phase (insoluble drugs) Continuous phase (usually water) Wetting agents Flocculating agents Suspending agents (viscosity inducing agents, density inducing agents)
Others (preservatives, sweeteners, colourants)
What must be considered to achieve a physically stable suspension?
a combination of
1) the use of the structured vehicle to maintain deflocculated particles in suspension
2) application of the principles of flocculation
What is the ultimate intention when considering the formulation of a suspension?
To achieve a product which flows readily from the container and possesses a uniform distribution of particles in each dose
What are the overall considerations that must be taken to formulate a suspension?
Choice of dispersed phase
Particle size control (stokes law)
Use of wetting agents (surfactants, hydrophilic colloids, cosolvents)
Use of flocculating agents (electrolytes, surfactant, polymers to encourage flocculation)
Use of viscosity modifiers
What dictates the choice of the dispersed phase?
Compatibility of the drug with other excipients
Particle size and distribution
Ionic character (particle surface charge)
Polymorphic nature of the dispersed drug
What is a wetting agent?
A compound which when dissolved in water lowers the interfacial tension between the solid and dispersion medium
It also aids in displacing air phase at the solid interface and replacing it with a liquid one
What are the three main types of wetting agents?
Surface active agents
Hydrophilic colloids
Solvents
What surface active agents are used?
0.1% concentration of Surfactants with HLB 7-9
Polysorbates like tween are used in oral suspensions
Sodium lauryl sulphate, sodium dioctyl sulphosuccinate are used for external suspensions
Polysorbates, poloxamers and lecithin are used for parenteral suspensions
How do surface active agents act as wetting agents?
The hydrocarbon chain is adsorbed by the hydrophobic particle surfaces while the polar groups project into the aqueous medium thus bringing the solid and liquid phases together.
What are the disadvantages of using surface active agents?
Excessive foaming
Possible formulation of deflocculated system
Due to electrostatic repulsion (?)
What hydrophilic colloids are used as wetting agents?
Acacia, bentonite, tragacanth, alginates, xanthan gum, cellulose derivatives
How do hydrophilic colloids act as wetting agents?
They behave as protective colloids by coating the solid hydrophobic particles with a multi molecular layer which imparts hydrophilic character to the solid
What is the disadvantage with using hydrophilic colloids?
They may produce deflocculated systems particularly if used at low concentrations (why?)
What solvents are commonly used as wetting agents?
Alcohol, glycerol, glycols (these are water miscible)
How do solvents act as wetting agents?
These liquids flow into the voids between hydrophobic particles and displaces the air on the surface and in the pores of individual particles.
Particles are separated to allow water to penetrate and wet the particles
What are the main types of viscosity modifiers?
Polysaccharides Water soluble cellulose a Hydrated silicates Carbomers Colloidal silicon dioxide
Which polysaccharides are commonly used as viscosity modifiers?
Acacia Tragacanth Alignates Starch Xanthan gum
What water soluble cellulose a are commonly used as viscosity modifiers?
Methylcellulose
Hydroxy methylcellulose
What hydrated silicates are commonly used as viscosity modifiers?
Bentonite
Magnesium aluminium silicate
Hectorite
How are suspensions prepared on a small scale?
Grinding/levitating insoluble material in mortar to form a smooth paste with solvent containing the dispersion stabiliser
The slurry is transferred to a graduate and the mortar is rinsed with successive portions of the dispersion stabiliser
The final volume is then made
How are suspensions made on a large scale?
Colloidal mills are used.
Suspensions are made based on the principle of shearing
This consists of a high velocity rotor and stator.
You feed the components as a slurry
Then, Size reduction takes place when the liquid comes in between the gap present between rotor and stator
What are the ideal rheological properties of a suspension?
Storage: (upon standing)
High apparent viscosity at low rates of shear.
This is so that the suspended particles settle very slowly or preferably remain permanently suspended
Upon shaking:
Apparent viscosity should fall sufficiently to allow the suspension to be easily poured
Upon leaving:
Original apparent viscosity should be regained after a relatively. Short time to maintain adequate physical stability.
What is the type of ideal rheological property given to suspensions?
Thixotropic pseudoplasticity
What is pseudoplasticity?
Shear thinning
What is Thixotropy?
Time dependent regain of structure that has been lost by shearing
How are suspensions assessed?
By their
Particle size and size distribution (crystal growth over storage)
Sedimentation parameters (including volumes, degrees and rates)
Ease of redispersibility (tendency to cake)
Viscosity measurements
