Routes of Administration: Oral Suspensions Flashcards
Define a disperse system
- A two phase heterogenous system in which an insoluble or immiscible dispersed phase is distributed through a continuous phase
How are the disperse systems typically classified?
Based upon the size of the dispersed phase
1. Molecular dispersions < 1nm e.g. glucose solutions
2. Colloidal dispersions between 1 nm and 1 micrometer e.g. micro emulsions, nanoparticles, micelles
3. Corase dispersions > 1 micrometre e.g. suspensions, emulsions
Define a pharmaceutical suspension.
- A liquid disperse system consisting of particles distributed within a liquid vehicle
What are pharmaceutical suspensions classified as?
- As a coarse or colloidal dispersion
How do suspensions appear as?
- They are not optically clear and appear cloudy
What are the reasons for formulating an oral pharmaceutical suspension?
- To deliver poorly water-soluble drugs which cannot be formulated as
aqueous solutions - To mask the bitter taste of the drug
- To increase drug stability
- To achieve controlled/sustained drug release
Which forces can particles dispersed in liquid exhibit?
Van der Waals
Electrostatic repulsion forces
What determines the degree of flocculation and aggregation?
Forces at the surface of the particle
Describe a flocculated system.
- Suspended particles are formed into floccules (Van der Waals forces) rather than separate particles.
- Sediment will be large and the redispersion is easy
What is meant by controlled flocculation?
a mechanism to prevent particle caking in suspension formulations.
How can we induce flocculation, and how can this be achieved?
- Reducing the surface charge of particles
- Can be achieved through the addition of surfactants and ionic salts.
Describe a deflocculated system.
- A system in which particles are individually and uniformly dispersed throughout the liquid medium.
- It will remain deflocculated when repulsive energy
between the suspended particles is high.
Why is a deflocculated system not ideal as pharmaceutical suspensions?
Deflocculated particles may settle slowly over time results in the formation of a layer of particle sediment at the bottom of the suspension which will be difficult to re-suspend.
Compare particles in a deflocculated suspension and a flocculated.
Deflocculated = exist in separate entities
Flocculated = From loose aggregates (flocs)
Compare the sedimentation rate between a flocculated and deflocculated suspension.
Deflocculated = slow
Flocculated = Rapid
Compare the sedimentation structure between deflocculated and flocculated.
Deflocculated = compact
Flocculated = scaffold-like loose
Compare the redispersion of a flocculated and deflocculated suspensions.
Deflocculated = difficult
Flocculated = Easy
Compare the supernatant liquid between a deflocculated and flocculated suspension.
Deflocculated = cloudy
Flocculated = generally clear
What does an ideal suspension have?
- Solid materials mono dispersed as spheres and evenly suspended in 3D throughout the liquid vehicle for a prolonged period
Describe the stability of suspensions.
- Inherently thermodynamically unstable and will over time through random motion of particles aggregate unless sufficient repulsive forces are present.
What properties must a suspension have to ensure a uniform dose?
- Particles settle slowly.
- Particles are readily and uniformly re-dispersed upon shaking.
- Particle size remains consistent over time.
- Viscosity is high enough to ensure a uniform dose, but not so viscous that the
suspension cannot be easily poured from the bottle.
What can the movement of particles be caused by?
- Brownian motion
- Gravity
- External agitation e.g. shaking by patients
What does particle motion affect?
The inter-particulate distance and thus the flocculation status of the suspension
Describe how particles behave in a deflocculated system.
- Behave as individual small particles
Describe how particles behave in a flocculated system.
- Clump together and behave as individual large particles with porous structure
Which particles are subject to Brownian motion?
Small particles < 2 micrometers
Describe brownian diffusion.
- irregular movement within the medium
- diffusion from high to low conc
- provides more homogenous particle distribution
- smaller particles diffuse more rapidly
- for particles > 2micrometres diffusion will be negligible
- increasing medium viscosity will reduce diffusion
What is sedimentation?
- It is the downward particle movement due to gravity
- Particle movement is critical for successful suspension formulations
Describe the optimal sedimentation pattern for a deflocculated system.
- A slow sedimentation rate
Describe the relationship between particle size and sedimentation?
- Particle size has a direct effect on the ease of maintenance of a uniform
suspended phase - Submicron suspension: Brownian motion helps to keep the particles in a
dispersed state. - Larger particles: the effect of gravity becomes significant
if reversibility is required to ensure dosing in reproducible which system would be better?
Flocculated
What does stoke’s law state?
The velocity of a suspended particle falling under gravity
is directly proportional to the particle’s size
State the ways to reduce sedimentation rate.
- Particle size reduction – increases diffusion.
- Reduce particle density – but at the same time increases particle size thus may have adverse effects.
- Increase medium density – e.g. adding dextrose.
- Increase medium viscosity – e.g. adding polymers like hydroxypropyl
methylcellulose, reduces both diffusion and sedimentation. - Increase temperature – increases diffusion constant, but effect is limited within
normal range of temps.
What is zeta potential?
Provides a measure of the magnitude of the electrostatic or charge repulsion between particles at the slipping plane between the particle and its associated double layer and the the solvent.
How does an electrical double layer form?
- In an aqueous solution, the water molecules undergo self-ionisation reaction and produces
ions/charges:
– H2O ⇄ H+ (cations) + OH- (anions) - Solid/drug particle surface gives an apparent negative charge in liquid.
- The system needs to maintain an overall neutral charge
- Cations form a layer around the apparently ‘anionic’ solid particle form the “electrical
double layer”.
If the zeta potential is reduced below a certain value what happens?
The attractive forces between particles due to
van der Waals’ force, overcome the forces of repulsion and the particles come together to form
floccules.
If a suspension has a large negative or positive zeta potential what happens?
The particles within it tend to successfully repel each other.
Describe the effect of excipients on the electrical double layer.
- At low concentrations will only affect diffuse layer –
easier to neutralise the particle charge, thinning diffuse
layer. - At higher concentrations will also affect the fixed layer
– charge on the particle surface will decrease.
What is the critical micelle conc? (CMC)
the concentration of surfactants above
which micelles form
What happens above the CMC?
micelles form with a hydrophobic core in which hydrophobic
drug may dissolve.
What happens below the CMC?
surfactants will cover the particles surface
Why are surfactants used at a concentration below the CMC?
To reduce interfacial tension between particle and liquid medium (i.e. enhance suspension stability)
State the characteristics of an ideal suspension.
- Appropriate viscosity
- Cake formation - no hard caking, forming of sediment, particles on standing
- Sedimentation - particles settle down slowly
- Dispersion - particle readily re-disperse on shaking container
Which excipients are used to improve palatability?
Flavours, sweeteners and colourings
Why are preservatives used?
Prevent microbial growth
Why are buffers used?
To maintain the pH of the aqueous system
Describe the nature of buffers and what this affects?
Ionic in nature so will affect flocculation behaviour
What is a buffer?
A mixture of a weak acid/base and salts
Why are suspending agents used?
Reduce particle sedimentation.
Why are flocculating agents used?
Decreases zeta potential of the suspended charged particle - cause aggregation of the particles
- The final excipient added to the formulation
- For example ionic material NaCl, surfactants
What is a chemical stabiliser?
– Improve chemical stability of the drug, this includes:
– Antioxidants e.g. ascorbic acid at 0.2%w/v.
– Chelators e.g. disodium salt of EDTA
What is a wetting agent?
– Reduce interfacial tension between particle and liquid medium.
– Improve homogeneity of drug particle distribution.
– E.g. using surfactants below their critical micelle concentration.
