L48 - Suspensions and Emulsions 1 (Liquid Dosage Forms)

• Describe some characteristics of suspensions.

  - Drug is dispersed in external phase, NOT solubilised.

  
  

  - Solubility of drug in vehicle is low.

  
  

  - Colloidal = when particle size <0.5micrometers.
• Are suspensions physically stable?

  NO!

  
  

  - Sedimentation.

  
  

  - Particle-particle interactions.

  
  

  - Caking (compaction) can all occur.
• What 2 factors do we need to understand physical stability via?

  - Electrical properties of dispersed particles.

  
  

  - Effect of distance between particles on their subsequent interaction.
• How might particles gain a charge after being dispersed in an aqueous medium?

  
  

  What phenomenon does this lead to?

  -Ionisationof functional groups on drug molecule.

  -Adsorptionof ions onto surface.

  Leads toElectrical Double Layer Phenomenon

  
• What is zeta potential? What does it measure?

  - Measures the degree of electric charge on particles, relative to bulk medium that they're suspended in.

  
  

  - The boundary of the 2nd layer (electrical double layer phenomenon) has zeta potential.

  
• How can we stabilise suspensions by compressing the electric double layer?

  - Increase electrolyte conc.

  
  

  (we add electrolytes to suspension bc of electrical double layer phenomenon)

  
• What are the 3 possible states of interaction between particles?

  -Nointeraction.

  -Coaggulation(agglomeration).

  - Loose aggregation (flocculation).

  
• Describe the state of a solution when there is

  no interactionbetween particles.- Particles sufficiently distant from each other.

  
  

  - Thermodynamically stable.

  
  

  - No sedimentation.

  
• Describe the state of a solution where

  coaggulation (agglomeration)occurs between particles.- Intimate particle contact.

  
  

  - Can't redisperse particles on shaking.

  
  

  Pharmaceutically unacceptable!

  
• Describe the state of a solution where loose

  aggregation (flocculation)occurs between particles.- Loose, reversible, particles can redisperse on shaking.

  
  

  AKA flocculation.

  
• What is DVLO theory?

  Particles dispersed in liquid experience (electrical) repulsive and attractive forces (van der waals).

  
• What's the DVLO eqn?

  Vt = Va + Vr

  
  

  where Va = energy of attraction.

  
  

  Vr = energy of repulsion.

  
  

  Vt = overall energy of interaction between particles.

  
• Describe a potential energy curve for particles in suspension

  - 2 minimum and 1 maximum peaks.

  
  

  Primary minimum, primary maximum, secondary minimum.

  
• What does the


  first peakon a potential energy curve for particles in suspension show?Primary minimum:

  
  

  - Attractive forces predominate at short distances between particles.

  
  

  - Particles agglomerate if very close.

  
• What does flocculation mean?

  Weak attraction. Particles can redisperse on shaking.

  
• As interparticle distance is increased, what does the

  second peakshow on a potential energy curve for particles in suspension?Primary Maximum:

  
  

  - Repulsion!

  
  

  - As interparticle distance increases, repulsive forces predominate and particles remain in suspension.

  
• What does the last peak on a potential energy curve for particles in suspension show?

  Secondary Minimum:

  
  

  - Flocculation = weak attraction.

  
  

  - If interparticle distance is increased further, repulsive force decreases and particles are weakly attracted.

  
  

  - Depth of secondary minimum is key to determining system stability.

  
  

  - Particles redisperse on shaking.

  
• Describe how sedimentation occurs.

  - Particles sediment and sit at bottom due to gravity.

  
  

  - Larger particles reach bottom first.

  
  

  - Smaller particles occupy space between larger particles.

  
  

  - Particles at bottom gradually compressed by weight of those above, so sufficient energy is available to overcome primary repulsive forces.

  
  

  - Particles then close enough to form irreversible interactions at primary minimum.
• What is caking?


  Compaction of aggregates that settle at the bottom -particles are close enough to form irreversible interactions at the primary minimum.
• What is velocity of sedimentation (sedimentation rate) directly proportional to?

  
  

  What eqn illustrated this?

  - Particle radius.

  -Densityof particles.

  The bigger the radius, the higher the velocity.

  The Stokes Eqn illustrates this.

  
• How can we decrease sedimentation rate?

  - Reduce average particle diameter.

  
  

  - Increase vehicle viscosity.
• What is velocity of sedimentation (aka sedimentation rate) inversely proportional to?

  Viscosity!

  
  

  - The more viscous the suspension medium, the slower the rate of sedimentation.

  
• How can we control flocculation in a suspension where particles have a

  high zeta potentialand ahigh primary maximum(repulsion)?- Adding electrolytes.

  
  

  (reduces zeta potential, so helps us reach lower energy level).

  
  

  - Adding charged surfactants that decrease zeta potential.

  
  

  - Gives an energy of repulsion that gives a secondary minimum where flocs can be formed.

  
• What characteristics make an acceptable suspension?

  -Low sedimentation rate.

  
  

  - Dispersed phase is easily redispersed with gentle shaking.

  
  

  - Flow properties: easily removed from container.

  
  

  - Aesthetically pleasing.
• List some advantages of oral suspensions.

  - Good delivery system for low solubility drugs.

  
  

  - Avoids large volumes of solvent.

  
  

  - Taste masking.

  
  

  - Easy to swallow for children/elderly/dysphagia.

  
  

  - Controlled drug delivery.
• List some disadvantages of oral suspensions.

  - Can pt administer correct dose?

  
  

  - Physically unstable: sedimentation, particle interactions, caking.

  
  

  - Bulky to carry.
• What parameters do we need to control when developing oral suspensions?

  - Electrical properties of dispersed particles (electrical double layer phenomenon).

  - Effect of distance of particle separation (eg no interaction, coagulation, flocculation).

  - Viscosity: gravity! To control sedimentation.
• What physical properties do we need to consider when producing oral suspensions?

  -Particle size:increase stability by modifying sedimentation rate.

  - Reduce particle size to reduce sedimentation rate.

  -Wetting propertiesof the drug.
• How can we minimise particle size?

  By milling (physical) or controlled precipitation (chemical) methods..
• How do wetting properties of the drug affect suspensions?

  - Insoluble drug particles: hydrophobic, not easily wetted.

  
  

  - Add surfactants to help wetting: decrease interfacial tension.

  
  

  - Poorly wetted particles may lead to aggregation.
• Crystal Growth


  Do smaller particles have higher/lower dissolution rates in aqueous vehicles?

  What does an increase in temp mean?- Small particles have higher solubility/dissolution rates when dispersed in aqueous vehicles.

  
  

  - An increase in temp may mean smaller particles start dissolving.
• Where might crystallisation of a dissolved drug occur?

  - On the surface of larger particles (increasing diameter of suspended drug particles).
• How to hydrophilic polymers decrease crystal growth?


  - Adsorb onto suspended drug particles to protect them.
• How can we control crystal growth?

  -Temperature cycling(freeze-thaw cycles).

  - Monitorparticle diameterandphysical stability.