Suspensions and emulsions Flashcards
What are suspensions
Dispersions of fine insoluble solid particles in a liquid medium
* 0.10 to 10microns
They have lyophobic colloidal dispersion and coarse dispersion properties
Inherently unstable
Conventions vs aqueous suspensions
Conventions - appear white and mostly in the coarse dispersion size range
Aqueous suspensions - nanoparticles <1 micron, translucent appearance
Rationale for suspensions
A liquid product of required drug strength for drugs of poor aqueous solubility = practically insoluble drugs can be administered
To optimise drug activity - antacid suspension compared with solid dosage forms
* Suspended as fine particles already compared to tablets = better activity as they have higher SA
To enhance drug stability in liquid form
* For drugs not stable in liquid form
* If drugs not in molecular form = no taste
To improve drug palpability in liquid
To improve drug BA
* Reduce particle size to nanoparticles = increase inherent solubility
Ideal medicinal suspensions
Particles of mono-dispersed size
Homogenous dispersion of particles throughout liquid vehicle
Particles remain dispersible over shelf life
Suspended particles settle slowly and are readily re-dispersible upon gentle shaking
Particle size is relatively unchanged over shelf life
Pour readily and evenly from their containers
Show chemical stability over shelf life
Show stability in physical attributes and continued preservation
Explain the forces governing suspension stability
Most suspended particles are negatively charged
* Adsorbed OH ions
o From ionisation of water = particles will be negatively charged
Presence of electric double layer and zeta potential
Magnitude of zeta potential influences particle repulsion and dispersibility
* Enables particles to separate and discrete
How is zeta affected by ionic strenght
How is zeta affected by surfactant concentration
Explain the DLVO theory
Primary minimum
* Deep well of attraction between particles at close range
* Particles aggregate irreversibly (coagulation)
Primary maximum
* Particles repel and remain deflocculated
* If conditions allow particle kinetic energy to overcome primary maximum = coagulation
Secondary minimum
* Weak attraction between particles causes formation of loose aggregates of particles (floccules)
* Particles do not approach close enough to coagulation
What state do you want suspensions to be in
Formulations aim for very strong primary maximum (deflocculated) or deep secondary minimum (flocculated)
Diffusion vs sedimentation
Brownian movement if particles <1-2 microns
o Hindered by flocculation and increased viscosity of medium
* Particles too large and particles cannot shift
Sedimentation under gravity for particles >0.5 microns
* Particles settle eventually to bottom of container
* Decrease inter-particle distance = primary maximum
* Promotes coagulation
Desired sedimentation pattern
Deflocculated - slow sedimentation but promotes irreversible coagulation
Flocculated - fast sedimentation but reversible
* Controlled slow sedimentation over shelf life
o Increase viscosity with water-soluble polymers
* To decrease sedimentation
* Allow patients to measure out uniform dose
Explain how immersional wetting affect suspensions
Stable suspensions require particles to be wetted and immersed in vehicle
Powder wettability is dependent on contact angle
Dissolution/ solubility issues of suspensions
Fast dissolution of particles in vivo is desirable for good BA
Drug has to remain suspended in vehicle and maintain dispersion state throughout shelf-life
What is ostwald ripening
Cyclical changes in temperature in storage
* Can cause small particles in suspension to disappear and larger particles to appear
Prevalent in suspensions that contain a range of particle sizes
* Not desirable - affects flocculation profile, sedimentation behaviour, dissolution, and BA
What are methods to minimise solubility issues and ostwal ripening
Methods
Careful control of particle size
* Balance BA, stability, solubility profile
Product formulated for poor solubility in vehicle
Methods to minimise ostwald ripening
Formulate suspension to contain particles of narrow size distribution
Flat solubility profile of drug over temperature range encountered
What are excipients required for suspensions
Similar to solutions
* Vehicle
* Preservatives
* Agents for enhancing chemical stability
* Taste modifiers
* Colouring agents
* Tonicity adjusting agents
For suspension stability
* Wetting agents
* Viscosity modifiers
* Flocculating agents
* Anti-solvents
Examples of wetting agents
Co-solvents - alcohol, glycerol
Surfactants must be low CMC - polysorbates, sorbitan esters
Hydrophilic polymers - acacia, tragacanth, xanthum gum
Examples of viscosity modifiers
Cellulose - MC, HPMC, CMC Na
Gums - tragacanth mucilage, xantham gum
Hydrate silicates - bentonite
Carbomers
Colloidal silica
What are flocculation modifiers
Intentional formation of a loose aggregation of particles held together by a weak particle-particle bond
* Reversible = must dissolve in vivo
Controlled flocculation
* Addition of electrolyte to produce satisfactory secondary minimum
o CaCl
o NaCl
* Bridge formation through polyvalent ions, surfactants or polymers
How can suspensions be manufactured
Quality standards and compendial requirements of suspensions
As per solutions
Additional notes
Uniformity of dosage units
* Content uniformity
Drug dissolution profile
Particle size and size distribution
Rheological properties - viscosity
Sedimentation parameters
Ease of redispersion
Thermal cycling - ostwald ripening
What are emulsions
2 phase systems comprising dispersion of a liquid as fine droplets in another immiscible liquid vehicle
Rationale for emulsions
Permits peroral administration of unpalatable oils
Allows IV injection of nutritional lipids
Oil phase serves as carriers to
* Enhance peroral BA of poorly water-soluble drugs
* Allow injection of higher drug concentration without associated toxicity and pain
Permits sustained drug delivery
* w/o and w/o/w emulsions for IM and SC
Helpful vehicle for drug delivery to and into skin
Explain the emulsion theory
Hypothesis
* If interfacial tension of o/w is lowered, emulsification is achievable with smaller free energy
o Surfactant lowers interfacial tension
Observations
* Sod lauryl sulfate effectively lowers interfacial tension but is an ineffective emulsifier
* Acacia is weakly surface active but produces stable emulsions
Schulam and Cockbain
* Stable emulsions have interfacial condensed films of sufficient flexibility that resisted rupture and produced lower interfacial tension
o Components must be cohesive to give tight film - if not tight film oil will join together
o Sufficient flexibility - to accommodate the changes in shape of droplets
Explain schulman and cockbain theory
Emulsification is best achieved by forming an interfacial coherent film
* Formed by blending an oil-soluble emulsifier with water soluble emulsifier with significant binding forces between the emulsifiers
What is Bancroft’s rule
- Hydrophilic emulsifier will promote o/w emulsion
- Lipophilic emulsifier will promote w/o emulsion
What are molecular films and solid particulate films
Molecular films
* Soluble surfactants form monomolecular film at oil-water interface
* Soluble polymers (hydrophilic colloids) form multi-molecular films at oil-water interface
Solid particulate films (pickering emulsions)
* Cohesive, fine particles (size < dispersed liquid droplets)
* Adsorbed at oil-water interface because they are wetted by both the aqueous and oil phases
Explain the emulsion formulation
Components
* Oil and water phases
* Stabiliser
* Other excipients
Emulsion type
* w/o or o/w
* Droplet size
Formulation
* Method of preparation - energy input
* Chemical nature of emulsifier
* Phase volume ratio (Vo and Vw)
o ~50% disperse phase up to 74%
* Less than 50% will be unstable
What is an ideal emulsion
- No coalescence
- No creaming/ sedimentation/ flocculation
- No phase inversion
- No phase separation
- Consistent particle size, appearance, odour, colour and other attributes on storage
What are factors influencing stability
Size and polydispersity of dispersed globules
Viscosity of continuous medium
Phase volume ratio
Characteristics of emulsifier film
* Use several emulsifier to achieve this
* Must be interfacial and condense film = globule interact and bind with one another, must not be prone to rupture
Degradation of emulsifiers
Microbial contamination
Temperature
Addition of incompatible ingredients
What are coalescence
Occurs when emulsifier film is disrupted
* Occurs when globules drain into each other to form a large globule
Results in phase separation
Irreversible process
What are causes of coalescence
Incompatible ingredient
o Adding cationic agents to emulsions with anionic emulsifier
o Adding ethanol/ electrolytes to emulsions with non-ionic surfactants
Bacterial contamination
Chemical degradation of emulsifier
Extreme temperature changes
o Binding forces will reduce = change film from condense to non-condense
o Ice can pierce emulsifier film
What are creaming, sedimentation and flocculation
Inhomogeneity where there are regions that are richer in dispersed phase than other regions
Emulsifier film is intact and dispersed droplets retain individual identity
Reversible processes but not desirable
* Increases likelihood of coalescence
* Affects dosing uniformity
* Results in an inelegant product
How can you minimise creaming, sedimentation and flocculation
- Reducing oil droplet size
- Increasing viscosity/ density of continuous phase
- Control of concentration of disperse phase
Explain Stokes equation
Globules < 1microns = nanomulsions
* Brownian movement maintains stability
Globules > 1micron
* Sedimentation if densityd > densityc
* Creaming if densityd < densityc
Reduce globule size to prevent creaming and sedimentation
* To reduce size, increase energy input
* Critical size must not be smaller than 1micron
* Add viscosity modifiers to maintain globule size
What is phase inversion
o/w inverts to w/o emulsion
Some causes
* Disperse phase volume ration exceeds critical value (<50% or >74%)
* Change in emulsifier HLB
Explain ostwald ripening
Can occur for emulsions with heterogenous size distribution
On storage small globules merges into one large globule
* Results in phase separation
Summarise strategies for emulsion stabilisation
What are some oil phases used for emulsions
Active agent
* Liquid paraffin
* Cod liver oil
* Arachis oil
* Soya bean oil
* Benzyl benzoate (preservative)
Carrier for oil-soluble drugs
* Vegetable oils
* Paraffins
* Triglycerides
What are emulsifiers
Stabilise emulsions
* Promote emulsification; maintain droplet size
Control emulsion properties
* o/w or w/o; physical properties
Give examples of ionic surfactants as emulsifiers
Anionic = o/w (monovalent soaps) OR w/o (divalent or trivalent soaps)
o Salts of long chain fatty acids
* Na stearate
* Ca oleate
o Alkyl sulfates
* Na lauryl sulfate
Cationic = o/w emulsions
o Quaternary ammonium compounds
* Cetrimide
Requires non-ionic agent to form condensed film
Give examples of non ionic surfactants as emulsifiers
- Polyoxyehtylene glycol ethers (cetomacrogols)
o Ceto group allows for hydrophobic nature - Sorbitan esters (spans)
o Oil soluble = w/o - Polyethylene sorbitan esters (tweens)
o Water soluble = o/w
Give examples of fatty amphiphiles as emulsifiers
- Fatty alcohols
o Cetyl alcohol
o Stearyl alcohol
o Cetostearyl alcohol - Fatty acids
o Stearic acid
o Palmitic acid - Monoglycerides
o Glyceryl monostearate
Give examples of other emulsifiers
Poloxamers
Polysaccharides
Phospholipids
Sterols for w/o
Solid - colloidal silica
What are HLB
They reflect polarity of emulsifiers
HLB of 3-6 = w/o
HLB of 8-16 = o/w
Other excipients required for emulsions
Buffering agents
Antioxidants
Preservatives
Density modifiers
Humectants
Quality standards and compendial requirements for emulsions
Uniformity of dosage unit
Assessment of stability
* Macroscopic examination
* Globule size analysis
* Viscosity measurement
* Creaming index
