1. Emulsion Definition Applications Classification
Theory of emulsification
Stability of emulsion
Preservation of emulsion
Emulsion preparation
Nascent method
Dry gum
Wet gum
Incorporation of drugs into emulsion
Microemulsion

2. Emulsion
An emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid phases, one of which is dispersed as globules in the other liquid phase, stabilized by the presence of an emulsifying agent.
Butter, margrine, salad dressings.
Why it is thermodynamically unstable: creating small droplets will create large surface area. Since the surface has the tendency to decrease due to surface tension, emulsions are unstable.
Internal vs. external; dispersed vs. continuous phase.
A’. Two immisicble liquids, not emulsified; B’. An emulsion of Phase B dispersed in Phase A; C’. The unstable emulsion progressively separates; D’. The (purple) surfactant positions itself on the interfaces between Phase A and Phase B, stabilizing the emulsion

3. Pharmaceutical application of emulsions
O/W emulsion is convenient for oral dosing
To cover unpleasant taste
To increase oral absorption
I.V. O/W, if oral o/w not possible (RES uptake)
External use (topical cream)
A broad-spectrum antifungal agent administered orally to treat a variety of fungal infections.

4. Emulsion types Types Oil-in-water (o/w) Water-in-oil (w/o)
Oil-in-water-in-oil (o/w/o)
Water-in-oil-in-water (w/o/w)
Determination of o/w or w/o
Water soluble dye (e.g., methylene blue)
Dilution of emulsions
Conduction of current
Oil dose not mean that it has to be the conventional oil. Any liquid that is not miscible with water will be just OK. Double emulsion is rarely used. It might be good to increase the stability of a certain chemical. However, the chemical has to diffuse through several layers to be released, making the drug not biologically available.

5. Theory of emulsification
Change from A to B will significantly increase of the surface area of phase.
e.g., if 1 cm3 of mineral oil is dispersed into globules having diameter of 0.01 mm in 1 cm3 of water, how much will be the surface area increased.
The surface area will become 600 m2 (greater than a basketball court); the surface free energy will increase by 8 calories. Therefore, emulsions are thermodynamically unstable, and the droplets have the tendency to coalesce.
Emulsifying agents are needed to decrease the surface tension and to stabilize the droplets.
Emulsifying agents can prevent coalescence or at least reduce its rate to negligible. It will form a film around the dispersed globules. The strength of an emulsifying agent lies in its ability to form a firm film.

6. Classification of emulsifying agents
Surface active agents (monomolecular film)
Hydrophilic colloids (multimolecular film)
Finely divided solid particles (Particulate film)

7. Monomolecular adsorption
This explains why a surfactant with a HLB value of 8-16 helps the formation of o/w emulsion, whereas one with an HLB value of 3-8 aids the formation of w/o emulsion.
Rule of Bancroft: The type of the emulsion is a function of the relative solubility of the surfactant, the phase in which it is more soluble being the continuous phase.

9. It is necessary to have a predominantly hydrophilic emulsifier in the aqueous phase and a hydrophobic agent in the oil phase to form a complex film at the interface. SCS – chol lead to a complex film, and thus excellent emulsion. Oleyl alcohol does not pack well. So the emulsion is unstable.

10. Multimolecular adsorption and film formation
1. Hydrated lyophilic colloids (hydrocolloids)
providing a protective sheath around the droplets
imparting a charge to the dispersed droplets (so that they repel each other)
swelling to increase the viscosity of the system (so that droplets are less likely to merge)
2. Classification of hydrocolloids
vegetable derivatives, e.g., acacia, tragacanth, agar, pectin, lecithin
animal derivatives, e.g., gelatin, lanolin, cholesterol
Semi-synthetic agents, e.g., methylcellulose, carboxymethylcellulose
Synthetic agents, e.g., carbomers (PEG and acrylic acid)
Acacia is a carbohydrate gum soluble in water and form O/W emulsions. Emulsion prepared with acacia is stable over a wide range of pH.
Gelatin is a protein. It has been used for many years as an emulsifying agent. Type A: derived from acid treated precursors, having a IE of 7-9. it acts best at pH 3.
Type B: IE = 5, best at pH 8. This affects the stability a lot.
Lecithin is natural, from eggs or plants. A mixture of lipids, mainly PC, PI, PE, PS, and phsophatidic acid.
Choleseterol is a major component of wool alcohols. It is cholesterol that gives wool fat its capacity to absorb water and form a w/o emulsion.

11. Solid particle adsorption
Description: Finely divided solid particles that are wetted to some degree by both oil and water can act as emulsifying agents. This results from their being concentrated at the interface, where they produce a particulate film around the dispersed droplets to prevent coalescence.
Example of agents: bentonite (Al2O3.4SiO2.H2O), veegum (Magnesium Aluminum Silicate), hectorite, magnesium hydroxide, aluminum hydroxide and magnesium trisilicate
Auxiliary Emulsifying Agents
A variety of fatty acids (e.g., stearic acid), fatty alcohols (e.g., stearyl or cetyl alcohol), and fatty esters (e.g., glyceryl monostearate) serve to stabilize emulsions through their ability to thicken the emulsion. Because these agents have only weak emulsifying properties, they are always use in combination with other emulsifiers.

12. Auxiliary emulsifying agents
Auxiliary (secondary) emulsifying agents include those compounds that are normally incapable themselves of forming stable emulsion. Their main values lies in their ability to function as thickening agents and thereby help stabilize the emulsion.

13. Physical stability of emulsion
Creaming
Creaming is the upward movement of dispersed droplets of emulsion relative to the continuous phase (due to the density difference between two phases)
Stoke’s law: dx/dt = d2 (i-e)g/18h
dx/dt = rate of setting
D = diameter of particles
 = density of particles and medium
g = gravitational constant
h = viscosity of medium
Reversible. Need to be shaken well prior to use. It does not look good. Also, if not uniformally distributed, required amount of the active ingradient might not be achieved.

14. Physical stability of emulsion
Breaking, coalescence, aggregation
Breaking is the destroying of the film surrounding the particles.
Coalescence is the process by which emulsified particles merge with each to form large particles.
Aggregation: dispersed particles come together but do not fuse.
The major fact preventing coalescence is the mechanical strength of the interfacial film.

15. Physical stability of emulsion
Phase inversion
An emulsion is said to invert when it changes from an o/w to w/o or vice versa.
Addition of electrolyte
Addition of CaCl2 into o/w emulsion formed by sodium stearate can be inverted to w/o.
Changing the phase:volume ratio
Changing from a soft soap into a hard soap, a hydrophilic surfactant into lipophilic surfactant.

16. Preservation of emulsions
Growth of microorganisms in emulsions
Preservatives should be in aqueous phase.
Preservatives should be in unionized state to penetrate the bacteria
Preservatives must not bind to other components of the emulsion
Bacteria have been shown to degrade non-ionic and anionic surfactants, glycerin, and vegetable gums. This will damage the emulsion.

17. Methods of emulsion preparation
Continental or dry gum method
English of wet gum method
Bottle or Forbes bottle method
Auxiliary method
In situ soap method
Calcium soaps: w/o emulsions contain oils such as oleic acid, in combination with lime water (calcium hydroxide solution, USP). Prepared by mixing equal volumes of oil and lime water.
In situ soap method is also called nascent soap methods. Nascent means beginning to exist or to develop. The emulsifier is formed as the emulsions are made.

18. Nascent soap
Oil phase: olive oil/oleic acid; olive oil may be replaced by other oils, but oleic acid must be added
Lime water: Ca(OH)2 should be freshly prepared.
Equal volume of oil and lime water
The emulsion formed is w/o or o/w?
Method of preparation:
Bottle method:
Mortar method: when the formulation contains solid insoluble such as zinc oxide and calamine.

19. Dry gum method (4:2:1 method)
The continental method is used to prepare the initial or primary emulsion from oil, water, and a hydrocolloid or "gum" type emulsifier (usually acacia). The primary emulsion, or emulsion nucleus, is formed from 4 parts oil, 2 parts water, and 1 part emulsifier. The 4 parts oil and 1 part emulsifier represent their total amounts for the final emulsion.
In a mortar, the 1 part gum (e.g., acacia) is levigated with the 4 parts oil until the powder is thoroughly wetted; then the 2 parts water are added all at once, and the mixture is vigorously and continually triturated until the primary emulsion formed is creamy white.
Additional water or aqueous solutions may be incorporated after the primary emulsion is formed. Solid substances (e.g., active ingredients, preservatives, color, flavors) are generally dissolved and added as a solution to the primary emulsion. Oil soluble substance, in small amounts, may be incorporated directly into the primary emulsion. Any substance which might reduce the physical stability of the emulsion, such as alcohol (which may precipitate the gum) should be added as near to the end of the process as possible to avoid breaking the emulsion. When all agents have been incorporated, the emulsion should be transferred to a calibrated vessel, brought to final volume with water, then homogenized or blended to ensure uniform distribution of ingredients.

20. Preparing emulsion by dry gum method
Cod liver oil mL
Acacia g
Syrup mL
Flavor oil mL
Purified water, qs ad mL
Accurately weigh or measure each ingredient
Place cod liver oil in dry mortar
Add acacia and give it a very quick mix
Add 25 mL of water and immediately triturate to form the thick, white, homogenous primary emulsion
Add the flavor and mix
Add syrup and mix
Add sufficient water to total 100 mL
Cod liver oil, as its name suggests, is an oil extracted from cod livers. It is a nutritional supplement, in the past commonly given to children. Cod liver oil is one of the most effective providers of omega-3 fatty acids and is widely taken to ease the pain and joint stiffness associated with arthritis but has also been clinically proven to have a positive effect on heart, bone and brain health, as well as helping to nourish skin, hair and nails. [citation needed]
As well as being an excellent source of vitamin A and vitamin D, it is also a good source of omega-3 fatty acids (EPA and DHA). Depending on the quality of the oil, the flavor and aroma range from a mild sardine-like flavor, to an intense and obnoxious odor of rotten fish and rancid oil. High quality cod liver oil is "a pale-yellow, thin, oily liquid, having a peculiar, slightly fishy, but not rancid odor, and a bland, slightly fishy taste." It has recently become popular to flavor cod liver oil with citrus or mint essence to make it more palatable. People who grew up in Asia often have terrible childhood memories of being force-fed Scott's Emulsion (a popular brand of cod liver oil supplement) until the orange-flavoured version was released.
Cod liver oil is made by cooking cod livers with steam and then pressing/decanting the cooked livers to extract the oil. By contrast, fish oils are extracted from the cooked whole body tissues of fatty fish during the manufacture of fish meal. Cod liver oil and fish oil are similar but have a somewhat different composition: fish oil has a much lower content of vitamins A and D compared to liver oils.
This may pose a problem in that one may need to exceed the Recommended Dietary Allowance (RDA) of vitamins A and D in order to obtain therapeutic amounts of EPA and DHA from cod liver oil. These vitamins are fat soluble, so it's possible for dietary excess (well above the RDA) to accumalate and become harmful.
Because the body naturally produces vitamin D when exposed to sunlight, a common way to benefit from both oils while avoiding a vitamin D overdose is to take cod liver oil during late fall through winter, and fish oil during spring through summer. The ideal dosage and timing of consumption depends on your seasonal sun exposure (and therefore natural vitamin D production). The only way to be certain of any possible vitamin D deficiencies or overdosing (from supplements) is to have your levels checked.
On the other hand, the RDA of vitamin D is considered by many to be strongly understated. Most adults don't even meet the RDA. In 2005 researchers at the University of California reported that Vitamin D can dramatically lower the risk of developing different types of cancers, cutting in half the chances of getting breast, ovarian, or colon cancer
Triturate (Tricherat): To rub, crush, grind, or pound into fine particles or a powder; pulverize.

21. Wet gum method
In this method, the proportions of oil, water, and emulsifier are the same (4:2:1), but the order and techniques of mixing are different. The 1 part gum is triturated with 2 parts water to form a mucilage; then the 4 parts oil is added slowly, in portions, while triturating. After all the oil is added, the mixture is triturated for several minutes to form the primary emulsion. Then other ingredients may be added as in the continental method. Generally speaking, the English method is more difficult to perform successfully, especially with more viscous oils, but may result in a more stable emulsion.
Mucilage: A sticky substance used as an adhesive.

22. Bottle method
This method may be used to prepare emulsions of volatile oils, or oleaginous substances of very low viscosities. This method is a variation of the dry gum method. One part powdered acacia (or other gum) is placed in a dry bottle and four parts oil are added. The bottle is capped and thoroughly shaken. To this, the required volume of water is added all at once, and the mixture is shaken thoroughly until the primary emulsion forms. It is important to minimize the initial amount of time the gum and oil are mixed. The gum will tend to imbibe the oil, and will become more waterproof.

23. Auxiliary method
An emulsion prepared by other methods can also usually be improved by passing it through a hand homogenizer, which forces the emulsion through a very small orifice, reducing the dispersed droplet size to about 5 microns or less.

24. Incorporation of medicinal agents
Addition of drug during emulsion formation
Addition of drugs to a preformed emulsion
1. Addition of oleaginous materials into a w/o emulsion
2. Addition of oleaginous materials to an o/w emulsion
3. Addition of water soluble materials to a w/o emulsion
4. Addition of water soluble materials to an o/w emulsion
Oleaginous materials in o/w emulsion: a, occasionally, a small amount of oily material is added if sufficient emulsifier was used in the original formation
B, a small amount of oil-soluble drug can be added if it is dissolved in a very small quantity of oil.
Potentional drug solvent interaction should be avoided.

25. Microemulsion
Microemulsions are thermodynamically stable, optically transparent, isotropic mixtures of a biophasic oil-water system stabilized with surfactants.
Microemulsion
Emulsion
Stability
Thermodynamically
Kinetically
Transparent
Yes No
Size nm
Mainly mm
Formation
Spontaneous
Type
o/w, w/o, cylinder
o/w, w/o, w/o/w, o/w/o
Unique emulsion or swelled micelles.
Thermodynamically stable--- formed spontaneously. Surfactants and co-surfactants make the surface tension to zero.
Transparent is due to its smaller size, which cannot reflex visible light.

27. Pharmaceutical applications of microemulsions
Increase bioavailability of drugs poorly soluble in water
Topical drug delivery systems
glyceryl oleate+polyoxyl 40 fatty acid derivatives (surfactants)/tetraglycol (co-surfactant)/isopropyl palmitate/water by constructing pseudo-ternary phase diagrams at fixed co-surfactant/surfactants (CoS/S) ratios

28. Preparation of nanoparticles from microemulsion precursors