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MPharm > Suspensions and emulsions > Flashcards

Suspensions and emulsions Flashcards

1
Q

What are suspensions

A

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

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2
Q

Conventions vs aqueous suspensions

A

Conventions - appear white and mostly in the coarse dispersion size range
Aqueous suspensions - nanoparticles <1 micron, translucent appearance

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3
Q

Rationale for suspensions

A

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

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4
Q

Ideal medicinal suspensions

A

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

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5
Q

Explain the forces governing suspension stability

A

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

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6
Q

How is zeta affected by ionic strenght

A
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7
Q

How is zeta affected by surfactant concentration

A
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8
Q

Explain the DLVO theory

A

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

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9
Q

What state do you want suspensions to be in

A

Formulations aim for very strong primary maximum (deflocculated) or deep secondary minimum (flocculated)

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10
Q

Diffusion vs sedimentation

A

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

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11
Q

Desired sedimentation pattern

A

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

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12
Q

Explain how immersional wetting affect suspensions

A

Stable suspensions require particles to be wetted and immersed in vehicle
Powder wettability is dependent on contact angle

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13
Q

Dissolution/ solubility issues of suspensions

A

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

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14
Q

What is ostwald ripening

A

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

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15
Q

What are methods to minimise solubility issues and ostwal ripening

A

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

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16
Q

What are excipients required for suspensions

A

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

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17
Q

Examples of wetting agents

A

Co-solvents - alcohol, glycerol
Surfactants must be low CMC - polysorbates, sorbitan esters
Hydrophilic polymers - acacia, tragacanth, xanthum gum

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18
Q

Examples of viscosity modifiers

A

Cellulose - MC, HPMC, CMC Na
Gums - tragacanth mucilage, xantham gum
Hydrate silicates - bentonite
Carbomers
Colloidal silica

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19
Q

What are flocculation modifiers

A

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

20
Q

How can suspensions be manufactured

A
21
Q

Quality standards and compendial requirements of suspensions

A

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

22
Q

What are emulsions

A

2 phase systems comprising dispersion of a liquid as fine droplets in another immiscible liquid vehicle

23
Q

Rationale for emulsions

A

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

24
Q

Explain the emulsion theory

A

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

25
Q

Explain schulman and cockbain theory

A

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

26
Q

What is Bancroft’s rule

A
  • Hydrophilic emulsifier will promote o/w emulsion
  • Lipophilic emulsifier will promote w/o emulsion
27
Q

What are molecular films and solid particulate films

A

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

28
Q

Explain the emulsion formulation

A

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

29
Q

What is an ideal emulsion

A
  • No coalescence
  • No creaming/ sedimentation/ flocculation
  • No phase inversion
  • No phase separation
  • Consistent particle size, appearance, odour, colour and other attributes on storage
30
Q

What are factors influencing stability

A

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

31
Q

What are coalescence

A

Occurs when emulsifier film is disrupted
* Occurs when globules drain into each other to form a large globule
Results in phase separation
Irreversible process

32
Q

What are causes of coalescence

A

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

33
Q

What are creaming, sedimentation and flocculation

A

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

34
Q

How can you minimise creaming, sedimentation and flocculation

A
  • Reducing oil droplet size
  • Increasing viscosity/ density of continuous phase
  • Control of concentration of disperse phase
35
Q

Explain Stokes equation

A

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

36
Q

What is phase inversion

A

o/w inverts to w/o emulsion

Some causes
* Disperse phase volume ration exceeds critical value (<50% or >74%)
* Change in emulsifier HLB

37
Q

Explain ostwald ripening

A

Can occur for emulsions with heterogenous size distribution
On storage small globules merges into one large globule
* Results in phase separation

38
Q

Summarise strategies for emulsion stabilisation

A
39
Q

What are some oil phases used for emulsions

A

Active agent
* Liquid paraffin
* Cod liver oil
* Arachis oil
* Soya bean oil
* Benzyl benzoate (preservative)

Carrier for oil-soluble drugs
* Vegetable oils
* Paraffins
* Triglycerides

40
Q

What are emulsifiers

A

Stabilise emulsions
* Promote emulsification; maintain droplet size
Control emulsion properties
* o/w or w/o; physical properties

41
Q

Give examples of ionic surfactants as emulsifiers

A

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

42
Q

Give examples of non ionic surfactants as emulsifiers

A
  • 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
43
Q

Give examples of fatty amphiphiles as emulsifiers

A
  • Fatty alcohols
    o Cetyl alcohol
    o Stearyl alcohol
    o Cetostearyl alcohol
  • Fatty acids
    o Stearic acid
    o Palmitic acid
  • Monoglycerides
    o Glyceryl monostearate
44
Q

Give examples of other emulsifiers

A

Poloxamers
Polysaccharides
Phospholipids
Sterols for w/o
Solid - colloidal silica

45
Q

What are HLB

A

They reflect polarity of emulsifiers

HLB of 3-6 = w/o
HLB of 8-16 = o/w

46
Q

Other excipients required for emulsions

A

Buffering agents
Antioxidants
Preservatives
Density modifiers
Humectants

47
Q

Quality standards and compendial requirements for emulsions

A

Uniformity of dosage unit
Assessment of stability
* Macroscopic examination
* Globule size analysis
* Viscosity measurement
* Creaming index

MPharm (20 decks)

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