Emulsions Flashcards
What are the different types of emulsions?
Coarse emulsions (includes o/w, w/o, multiple emulsions)
Microemulsions (o/w, w/o, microemulsions)
Two immiscible liquids (oil and water) as well as a surfactant/emulsifier
What is an emulsion?
2 phased system in which
Internal or dispersed phase is fine droplets of liquid and is dispersed in the external or continuos phase
What is a common example of o/w emulsion?
Milk
What is an common example of w/o emulsion?
Butter
What are surfactants?
Surface active agents with 2 distinct regions (polar head group and hydrophobic tail)
They orient themselves preferentially at surfaces or interfaces
What effect do surfactants have on surface tension?
Surface tension of a surfactant solution decreases with increasing amounts of surfactant present at the surface
What happens if the surface layer of a solution becomes saturated with surfactants?
Micelles form to hide the hydrophobic tables of surfactants from the aqueous medium
What is the name of the concentration at which micelles first form?
Critical micellular concentration
What is the preferable dispersion medium for micelles and reverse micelles?
Micelles prefer to be in aqueous medium as their polar heads are I pointing outwards and they hide their hydrophobic tails
Reverse micelles prefer to be in hydrophobic medium for the opposite reason
What are examples of ionic surfactants ?
Sodium lauryl sulfate
Cetrimide (aka alkyltrimethylammonium bromide)
What are examples of non ionic surfactants?
Tween 20 (polyoxyethylene 20 sorbitan monolaurate) which has a higher CMC Tween 80 (polyoxyethylene 80 sorbitan monoleate) which has a lower CMC
What factors affect CMC and micelle size?
Structure of hydrophobic tail group Nature of hydrophilic head group Nature of counterion Effect of temperature Addition of electrolytes
How does the structure of hydrophobic tail group affect CMC and micelle size?
Increased length of carbon chain means a lower HLB value (higher lipophilicity)
This causes a decrease in CMC as a smaller concentration of surfactants is required for saturation
This also results in an increase in micelle size as the hydrocarbon portion is bigger
How does the nature of the hydrophilic head group affect CMC and micelle size?
Non ionic surfactants have lower CMC than ionic surfactants as there is no repulsion between the head groups
For Non ionic surfactants the longer oxyethylene chain results in increased CMC
How does the nature of the counterion affect CMC and micelle size?
For cationic surfactants Cl-<Cs+
The more weakly hydrated the counterion the larger the micelle as the counterions can be absorbed more readily onto the micelle surface and so decreases charge repulsion between polar head groups
How does temperature affect CMC and micelle size?
For non ionic surfactants, an increased temperature increases mi cellular size and decreases CMC until cloud point which is where separation into two phases occurs.
For ionic surfactants, temperature has a much smaller effect on the micellular properties
How does the addition of electrolytes affect CMC and micelle size?
Addition of electrolytes to ionic surfactants decreases CMC and increases micelle size
This results in reduction in magnitude of forces of repulsion between charged head groups in micelle and a consequent decrease in the electrical work required for micelle formation
How many counter ions are attracted close to the micelle?
70-80%
What forms the stern layer of an ionic micelle?
Head groups plus bound counter ions
What is the outer surface of higher stern layer in an ionic micelle?
The shear surface of the micelle
What is the kinetic micelle comprised of?
The core, and the stern layer
What is the gouy chapman electrical double layer?
Aka diffuse layer
This contains the remaining counter ions which neutralise charge,
The thickness of this double layer depends on the ionic strength of the solution.
More electrolytes = more thickness
What is the hydrophobic core surrounded by in a non ionic micelle?
The palisade layer which is essentially a shell of POE chains
What is trapped inside the palisade layer in a non ionic micelle?
Water molecules.
These are trapped mechanically and via hydrogen bonding with POE.
Hence non ionic micelles tend to be highly hydrated, and are often less symmetrical and larger than ionic micelles
Describe the different parts of the surface tension vs. Micelle concentration graph
Initial parallel line:
Surfactant solubility so no change in surface tension
Constant decreasing slope: migration of micelles too the surface resulting in a decrease in surface tension.
Final parallel line: surface is saturated, and micelles form.
How would you rank the vapours groups of surfactants (anionic, neutral, ionic) in terms of their irritancy potential to the biological membrane ? Why?
Non ionic surfactant have the least irritancy potential. These surfactants have no charge so they do not interact with the biological membrane and are less toxic
Cationic are the most toxic because they are positively charged. The phospholipids in our biological membrane and most other membrane bound proteins are negatively charged and will interact with the surfactant, disrupting the membrane.
Anion surfactants are not as bad
How can we identify the different emulsion types?
Via
Conductivity
Staining
Dilution/miscibility tests
How can emulsions be identified using the phase ratio rule?
This test compares the relative percentages of the 2 phases.
If water is in a higher proportion than oil, the emulsion will be o/w
If oil is in a high proportion than water, the emulsion will be w/o
What is the HLB value?
The hydrophilic lipophilic balance.
Where HLB = 20x(1-(MW lipo/MWtotal))
What are the limitations of HLB?
It is only for non ionic surfactants and does not accurately account for the hydrophilic part
What is the required HLB used for?
To calculate the required amounts of each surfactant
rHLB= HLB1x+HLB2y
with y=1-x
What is the Bancroft rule of thumb?
The phase in which an emulsifier (e,g, surfactant) is more soluble = the continuous phase of the surfactant
Low HLB surfactant is more hydrophobic so the external phase is oil.
High HLB surfactant is more hydrophilic so the external phase is water
What is the required HLB?
The property of an oil.
This is the relative polarity of a surfactant moisture needed to incorporate the oil into a o/w or w/o emulsion.
What is the RHLB for w/o emulsion?
Low?
How are conductivity tests used to determine emulsion type?
If the external phase is water, the emulsion will conduct electricity.
This can be measured using a voltmeter
How are staining tests used to determine emulsion type?
methylene blue is a water soluble dye
Sudan III is an oil soluble dye,
The dye that spreads quickly and evenly mixes with the external phase.
So If you have a Oil in water emulsion, the methylene blue will mix with water and will spread through emulsion very quickly. It will be even and blue colour.
If you try to mix it with oil, it will spread slowly. (Will spread a little but will take a long time.)
If it is a coarse emulsion it will look very patchy.
How are dilution and miscibility tests used to determine emulsion type?
If you put drop of methylene group (water soluble dye) on one side, the two drops will spread really quickly and will mix with emulsion
Water droplets next to the emulsion mixes with the external phase.
Oil droplet next to it will not mix.
The opposite is true with Sudan III
Why are emulsifiers needed?
An emulsion consists of 2 immiscible liquids. Without an emulsifier phase separation will occur as a result of stronger cohesive forces between molecules of the same type.
Although these liquids will mix a little upon vigorous shaking, eventually, they will separate again upon standing
Why are emulsions thermodynamically unstable?
Consider a 1ml oil dispersed as droplets in 1ml of water. This has a surface area of 600cm^2
This results in an increase in interfacial tension. Droplets will flow together and result in phase separation to become thermodynamically stable again
how can you overcome the interfacial energy, increase thermodynamic stability and maintain oil droplets finely/uniformly dispersed?
Can add a material that can adsorb at the interface and form a protective film which reduces interfacial energy
These are called emulsifiers (in the context of an emulsion)
What is an example of a mono molecular adsorption emulsifier?
Surfactants, these adsorb at the interface and reduce interfacial tension to prevent coalescence
What is an example of a multi molecular adsorption emulsifier?
Hydrophilic colloids.
E.g. Acacia, tragacanth, alignates, cellulose derivatives
These form a film around each oil globule and slow down coalescence by the presence of mechanical hydrophilic barriers between oil and water.
They also increase the viscosity of the dispersion medium, and exhibit electrostatic repulsion if they have ionisable groups
What is another class of emulsifiers used?
Solid particle adsorption,
Solid particles can be wetted by oil and water and arrange themselves at the interface
However solid particles cannot be dissolved
What are some examples of solid particles used as emulsifiers?
Aluminium and magnesium hydroxide and clays like bentonite are more hydrophilic so are used in o/w emulsions.
Carbon black and talc powder are more hydrophobic and are used in w/o emulsions
E.g. Facial mask
What is the stability of emulsions characterised by?
Absence of coalescence of internal phase,
Absence of creaming,
Maintenance of elegance (including appearance, odour, colour and physical properties)
What are the 4 classes of instabilities of emulsions?
Flocculation and creaming
Coalescence and breaking/cracking
Miscellaneous physical and chemical changes
Phase inversion
What is flocculation? (Emulsions)
Where droplets of the dispersed phase aggregate into loose clusters due to interaction of attractive and repulsive forces at the secondary minimum (think of DVLO graph)
What is creaming?
An instability of an emulsion due to density differences:
I.e. Two regions with a higher concentration of dispersed phase in one region (a lack of uniformity of drug distribution)
Which classes of instabilities of emulsions are reversible?
Flocculation and creaming. These can be reversed by shaking
What is coalescence?
Also known as cracking. This is where the dispersed phase droplets flow together to gain energy causing the surfactant layer to break down.
This is irreversible.
How is creaming related to stokes law?
We can use the stokes law to avoid creaming by:
Reducing the droplet size of internal phase up to a certain limit.
Increasing viscosity of external phase (e.g. By using hydrophilic colloids, or changing the storage temperatures)
Reducing density differences between the 2 phases
What is a limitation of reducing the density differences?
This is very hard to achieve
How can flocculation in emulsions be prevented?
By adding electrolytes on the dispersed droplets
How is flocculation related to creaming?
Flocculation = formation of clusters.
This will increase the rate of creaming
What is the difference between primary and secondary minimum flocculation?
Secondary minimum flocculation is unavoidable but is easy to redispersed.
Primary minimum flocculation precedes coalescence
How is coalescence prevented?
Reducing interfacial tension by addition of surfactant
Including the presence of a mechanical barrier by addition of hydrogel load
Making droplets have high charge density so that they repel each other
What are the 5 approaches to stabilise an emulsion?
Reducing interfacial tension with surfactant
Adding mechanical barrier (hydrophilic colloids)
Adding electrolytes for repulsion
Increasing viscosity (hydrophilic colloids)
Reducing globule size
What is a limitation to reducing globule size to stabilise an emulsion?
It will increase the surface free energy
How is the stability of an emulsion assessed?
Macroscopic examination- observing the degree of creaming or coalescence over time
Globule size analysis- microscope or coulter counter
Viscosity changes
Accelerated stability test which assesses storage at adverse temperatures and uses centrifugation, and viscosity to test for stokes law and high shear rates
What determines choice of the type of emulsion?
Route of administration
e.g. If oral, aqueous emulsions are used to mask the taste of fats and oils,
If IV, must be o/w as oil does not mix with our biological fluids
If IM, can be formulated as w/o if the water soluble drug is required as depot.
If for external use, emulsions can be o/w or w/o
What determines the choice of oil phase?
This might be your active ingredient (TPN) in which case the concentration is predeterned.
Examples may be castor oil, cdo liver oil, arachis oil, cotton seed oil, soya been oil, sunflower oil.
Externally applied oils include turpentine for lice treatment and chest rubs, benzyl benzoate for anti parasitic insecticide against life and mites responsible for scabies.
Most external emulsions contain oils that function as carriers for the active ingredient while also having a major effect on viscosity and drug transport
What should the emulsion consistency be for external application?
If w/o, emulsion should have greasier texture, high apparent viscosity, be occlusive and have enhanced absoprtion.
If o/w, emulsion should be less greasy, easily washed off
What should ideal emulsions exhibit?
Pseudoplasticity - be easy to pour
And Thixotropy- regain viscosity upon standing to prevent creaming and coalescence
Give examples of emulsions with high and low viscosities
Low visocsity: lotions and liniments
High viscosity: creams
What factors affect the emulsion viscosity?
Volume fraction (concentration) of dispersed phase
Droplet size and distribution
Viscosity of continuos phase
Nature and concentration of emulsifier
How does the volume fraction affect emulsion viscosity?
Increased volume fraction of internal phase results in increased overall viscosity as the viscosity of the product is higher than the viscosity of the external phSe alone.
This is due to the Einstein equation where
η=ηo(1+2.5φ)
η=viscosity of dispersion (can be emulsion or suspension)
ηο= viscosity of the dispersion medium (external phase)
φ=volume fraction (this is the concentration in v/v of the dispersed internal phase)
What can be done to dispersed phase to increase viscosity ?
Reducing globule diameter via homogenisation.
This is because smaller, more uniform droplets result in increased flocculation and parts of the continuous phase trapped inside aggregates of these droplets.
This will result in the apparent increase of the internal phase volume fraction
What type of emulsion is generally more viscous?
W/o is generally more viscous than o/w
How can viscosity of water be increased?
Addition of glycerol or syrup (sweeteners)
Addition of hydrocolloids
What is a limitation of adding glycerol or syrup to increase the viscosity of water? How can this be overcome?
Adding glycerol or syrup also increases the density difference between the two phases. This will accelerate creaming.
We can add hydro colloids instead which increase the viscosity of continuous phase without altering the density
How does viscosity of the continuous phase affect viscosity of the emulsion?
If oil is the continuous phase, the emulsion is more viscous that if water was the continuous phase.
However the viscosity of o/a emulsions can be increased by adding syrups,glycerol or hydrophilic colloids
How does the nature and concentration of the emulsifier affect the viscosity of the emuslion?
Hydrophilic colloids will form multi molecular layers around oil droplets. This increases the volume fraction of the internal phase and increases the viscosity of the continuous phase in o/w emulsions.
Ionic surfactants cause flocculation of particles with greater apparent viscosity
Nature of fatty acid forming anionic surfactants..
What are the 5 points to consider when deciding the choice of emulsifier?
Compatibility with active ingredients and other formulation additives
Stability during preparation
Non toxic for intended application route and concentration used.
Little or no taste/colour.
Should be able to for stable emulsion by preventing coalescence and cracking
Why must toxicity be considered when choosing an emulsifier?
If emulsion is for the oral route or goes inside the body, we have to be vigilant about toxicity. Non ionic surfactants are preferred but these are expensive
Which surfactants are widely used?
Polsaccharides,
glycerol esters,
cellulose Ethers
Polysorbates
What surfactant is used for external preparations.?
Cetrimide. This is cationic
Which surfactants are used pareneterally?
Lethicin, polysorbat 80 (tween80) MC, gelatin, serum albumin
What is saponification?
The reaction between a fatty acid and metal salt at 65 degrees. This forms a soap
What is the difference between Monovalent and divalent metal salts in the formation of surfactants?
Monovalent salts = one chain of fatty acid per cation hence more hydrophilic so used for o/w emulsions e.g. White liniment
Divalent salts = two chains of fatty acid per cation hence more lipophilic and so is used for w/o emulsions e.g. Zinc cream BP
What is one way that anionic surfactants can be formed?
By reaction with a metal counter ion via saponification.
This requires a metal salt at 65 degrees
What is one way that cationic surfactants are formed?
Surfactant + counter ion (can be Cl- or Br-)
These form mostly quaternary compounds known as preservatives
What are the advantages and disadvantages of non ionic surfactants?
+ low toxicity
Greater degree of compatibility with other additives
Less sensitivity to pH changes and electrolytes
- more sensitive to temperature
Expensive
What is an amphoteric surfactant?
A surfactant with both positive and negative charge e.g. Lethicin
What are the other formulation additives?
Buffers Density modifiers Humectants Antioxidants Flavours, colours, perfumes, sweetness
What is the purpose of buffers in suspensions?
Maintains chemical stability,
Controls tonicity
Ensures physiological compatibility (addition of electrolytes)
What is the role of density modifiers in emulsions?
Stokes law. If density difference between the two phases are minimal then reduced craeaming occurs.c
What is the role of humectants in emulsions.?
These prevent th product from drying out after application ion to the skin e.g. Glycerol, PEG, PG
What is the role of antioxidants in emulsions?
To prevent oxidation of the oil
What are the three different methods of emulsions formation?
Dry gum method (continental method)
Wet gum method (English method)
Bottle method (Forbes method)
What is the dry gum method?
Aka continental method.
This is where you Triturate the emulsifier with oil.
Add water all at once and stir rapidly until cracking nose occurs for o/w
What is the wet gum method for emulsions formation?
Triturate emulsifier with external phase. Add internal phase in small portions.
This is for both o/w and w/o emulsions
What is the bottle Method for formulating emulsions?
Aka forbes method.
E.g.
Oil and acacia is mixed in a dry bottle and shaken vigorously between addition steps
Why are anionic surfactants in impatience with polyvalent cations?
They often cause phase reversal.
Deionised water is necessary to formulate emulsions with anionic surfactants and polyvalent cations as the addition of an electrolyte reduces charge density between the globules, making them more easy to coalesce. This can result in salting out of the emulsifier
How else may emulsifiers precipitate out?
Following the addition of material they are not soluble in. E.g. Hydrophilic colloids may precipitate upon addition of alcohol
How does temperature affect coalescence in emulsions?
Increased temperature causes increased motions of globules.
This increases the chance of collisions so coalescence is much higher.
What the most physically stable emulsions?
Those with a mean globule diameter of 0.5-0.25μm.
Nb: IV emulsions must have globule size of <4μm to avoid emboli
What can multiple emulsions be used for?
Multiple emulsions like w/o/w can be used for sustained release similar to how w/o emulsions are used for IM injection of water soluble vaccines.
Multiple emulsions exhibit a much lower viscosity than w/o emulsions, hence are easier to inject
What are microemulsions?
These are not actually emulsions, nor are they in the micro size.
These are colloidal dispersion systems which are:
Thermodynamically stable,
Optically isotropic,
Transparent and a faint blue.
The droplets are in 10-200nm range and the volume fraction of the dispersed phase is 0.2-0.8
These systems have a low viscosity and are spontaneously forming so are easy to prepare
Why are microemulsions spontaneously forming?
Due to small droplet size they have a very high SA.
low surface tension is essential for formation and stability
Formation requires significant levels of surfactant. Usually a co surfactant is also added.
What are the advantages of having microemulsions?
These demonstrate the ability for sustained release and increases the bioavailability of drugs
What are the components of microemulsions?
Water
Oil (mineral, vegetable, di and triglycerides, fatty acid esters)
Surfactant (non ionic, amphoteric and less commonly: anionic and cationic)
Cosurfactant (usually short and medium chain alcohols)
What are the pharmaceutical applications of a microemulsion?
Ease of peparation Clarity Long term stability Ability to be filtered Vehicle for drugs of different lipophilcities Low viscosity
What are the disadvantages of microemulsions?
Biological incompatibility of surfactant and/or co surfactants used.
E.g. Cationic, anionic surfactants and short chain alcohols.
May cause toxicity?
What are the specific advantages of a w/o microemulsion?
Protection of water soluble drugs
Sustained release of water soluble drugs
Increased bioavailability
What are the specific advantages of o/w microemulsions?
Increased solubility of lipophilic drugs
Increased bioavailability
What are the specific advantages of bicontinuous microemulsions?
They are promising for topical (incl. epidermal and ocular) drug delivery due to their good spreading and wetting properties on the skin and ocular surface
How are microemulsions placed on the ternary phase diagram? What does this tell us?
In regions with high surfactant, you see microemulsions forming. This tells us that a lot of surfactant is required for the formation of this system
What do microemulsions look like in comparison to normal emulsions?
A “normal” emulsion tends to look milky because the globules are large enough to block light as it is a coarse emulsion
Microemulsion globules are too small so it looks clear.
How do microemulsions differ in appearance to liquid crystals?
Liquid crystal tend to have a high viscosity. So if you turn them upside they might stay there.
They are sort of like a gel.
LC also displays biefringence
Micro emulsions are more like water, and do not display birefrengence
What are nano emulsions?
Systems with globules 20-500nm - bigger than micro emulsions, names are misleading.
These are:
Transparent,
Less surfactant required to form,
Requires energy to form (in the process of homogenisation)
Not thermodynamically stable so over time, phase inversion and coalescence may occur,
What is bicontinuous unique to?
Microemulsions.
I.e. You can’t have a bicontinuous nano emulsion
Why are nano emulsions not thermodynamically stable?
The globules are much bigger than micro emulsions,
Although they have a high surface area, they also have high surface free energy so they may coalesce over time to reduce this
How can we tell the difference between micro and nano emulsions?
Visually examine them for phase separation (nano emulsions will phase separate eventually.)
Use polarised LM for phase contrast.
Use freeze-fracture transmission EM (micro and nano emulsions will have different structure. Nano will have larger holes?)
Electrical conductivity measurements (Microemulsions contain water so will conduct)
Viscosity measurements (microemulsions have lower viscosity)
Light scattering techniques for droplet size determination (micro emulsions have smaller droplet size)
What are Neoral and Sandimmune?
Cyclosporin formulations used in transplant patients amongs other uses
What is cyclosporine?
Hydrophobic lipophilic compound which requires solubilisation for clinical use
What were the issues that arose with using Sandimmune?
Problems with unpredictable pharmacokinetic parameters.
Large inter and intra patient variations
Unpredictable bioavailability when taken with food.
What is Sandimmune? (Physicochemically)
An oil based product
Forms crude o/w emulsion in the gut
Requires further emulsification by bile salts and digestion by pan creative enzymes prior to absorption
What is Neoral? (Physicochemically)
A preconcentrate which forms a homogenous microemulsion immediately on contact with gastrointestinal fluids
This microemulsion is less dependent on bile salts for absorption.
What are the implications of having a preconcentrate -> microemulsion like Neoral?
More consistent and predictable pharmacokinetic behaviour compared to Sandimmune.
Increased AUC, Cmax and Tmax
Decreased inter and intra patient variation
Smaller and more consistent decrease in bioavailability when administered with food
How are emulsions used to prepare micro and nano particles?
The drug and polymer are first dissolved in volatile organic phase.
The o/w emulsion is prepared.
The organic phase is then evaporated and centrifuged to collect drug loaded polymer particles
