1. Alfred Martin Lecturer: Dr. Majid R. Feddah
Emulsions
Alfred Martin
Lecturer: Dr. Majid R. Feddah

2. Introduction
Emulsion consists of two immiscible liquids one of which is uniformly dispersed throughout the other as droplets of diameter greater than 0.1µm.
To prepare a stable emulsion a third phase, an emulsifying agent, is required.
Emulsions is a useful way to present oils and fats in a palatable form.
Emulsions for external use are known as a lotion.

3. Emulsions can vary considerably in viscosity and can present as liquids or semisolids.
Liquid emulsions can be used for oral, topical and parenteral medicaments while semisolid emulsions are usually only used topically.

4. Oil in Water or Water in Oil

5. Emulsion Types Simple Emulsion
Oil in Water, (O/W) the oil phase distributed as globules in the aqueous phase (continuous phase).
Water in oil, (W/O) the water is distributed through out the oil phase (continuous phase).
Multiple Emulsion:
W/O/W
O/W/O

6. Determining the type of emulsion
Water soluble dye to be dusted on the surface of the emulsion:
O/W the dye will be dissolve the color & diffuse through the system.
W/O, the dye will stay on as clumps on the tope of the emulsion.

7. Dilution Method
Dilution of the emulsion with water, if the emulsion mixed freely with water, thus it is O/W, if not so its W/O.

8. Types of emulsion continue…
Electrical current test:
Electrodes connected to the external electric source and immersed in the emulsion, if the external phase is water a current will pass through the emulsion.
A conductivity Meter
Basic Method

9. Staining tests
Filter paper soaked in cobalt chloride solution and allowed to dry
The filter paper will turns from blue to pink on exposure to stable O/W emulsion.
Fluorescence test upon exposure to UV light
o/w: shows spotty fluorescence under the microscope
w/o: shows continuous fluorescence under the microscope
Cobalt chloride strip
Cobalt chloride color turns to pink when wetted

10. Fluorescence Test (o/w)
Fluorescence of doxorubicin o/w emulsion (AJP (2) )

11. Pharmaceutical Applications
Convenient of orally water insoluble liquids, when the dispersed phase has unpleasant taste.
Increase the absorption (some ingredients such as vitamins are absorbed completely when emulsified with emulsifying agent).
For patients how can’t getting medicine and nutrition's orally. (I.V Emulsion)
In many cosmetics preparations (dermatological products, lotions and creams) because the ability for spreading is high over the skin.

12. In diagnostic agents in x-ray examination.
In aerosols preparation for producing foams.
To prepare stable and homogeneous mixtures of two immiscible liquids.
It permits the administration of a liquid drug in a form of globules.
Reduce the droplet size of the oil, make it more readily absorbed.
If the active ingredients irritating the skin, are less irritant when used as internal phase.

13. Methods of Emulsion Preparation
Emulsion may be prepared in different methods depends on:
The nature of emulsion component.
Available emulsion equipments.
In small scale a mortar and pestle, a mechanical blender, a homogenizer.
In large scale, large tanks, and high speed mixer homogenizer may be used to prepare an emulsion

14. Coalescence

15. In small scale Continental or dry gum method.
English or wet gum method.
Bottle method.

16. Continental Dry Gum Method
The method is also referred to as the 4-2-1
(Oil-Water-Gum).
In this method:
The acacia or O/W emulsifier is triturated with the oil in a dry wedgewood or porcelain mortar, until mixed.
A rough surface should be used, for good grinding to reduce the globules size.
Then the two parts of water are added all at once.
The mixture triturated immediately, rapidly and continuously until the primary emulsion is formed.
creamy white and produces a crackling sound.

17. Continental method continued.
Other liquid ingredients that are soluble in the external phase may then be added.
Solid substances such as preservatives, stabilizers colorants, and any flavoring material usually dissolved in a water then added to an emulsion.
Any substances that may interfere with the stability of emulsion may added at the end.

18. English or Wet Gum method
The same proportion of water, gum and oil is used.
Triturating of acacia with water in a mortar.
The oil then is added slowly in portions.
The mixture is triturated to emulsify the oil.
The mixture is thoroughly mixed for several minutes to insure uniformity of the emulsion.
Other substances may be added.

19. Bottle Method
It is used for volatile oils or oleaginous substances of low viscosity.
The powder acacia is placed in a dry bottle.
Two parts of oil then added.
The bottle is then shaken in a caped container.
A water is then added in portions.
When a primary emulsion is formed the other ingredients is added.
It is not suitable for viscous oils.

20. In situ Soap method
The emulsifying agent is formed during the mixing of
the oil and the water.
The two types of soaps are developed by this method:
Calcium soap.
Soft soap
Calcium Soap: It is W/O emulsion contain vegetable oils (Oleic acid in combination with lime water
(calcium hydroxide solution, USP).
Prepared by mixing equal volumes of oil & lime water.
The emulsifying agent is the calcium salt of the free fatty acid which is formed from the combination of the two entities.

21. Auxiliary Methods
To increase the quality of emulsion prepared by any of the pervious methods:
The emulsion is passed through a hand homogenizer.
The emulsion is forced to pass through a very small orifice which reduces the globules of the internal phase to a bout 5 µm.

22. Ideal Emulsifying agent
Colorless
Odorless.
Tasteless.
Non-toxic.
Non irritant.
Able to produce stable emulsions at low concentration.

23. Theories of Emulsification1
No universal theory of emulsification.
Because emulsion can be prepared using several different types of emulsifying agent, each of which depends for its action on a different principles to achieve a stable products.
Any theory to be acceptable should explain the followings:
The stability of the product.
The type of emulsion formed. 23 23

24. What happened when two immiscible liquids are agitated together?
Failure the two liquids to remain mixed, because :
The cohesive force between the molecules of each separate liquid is greater than the adhesive force between the two liquids.
The increase in the surface energy makes the system thermodynamically unstable,
Hence the droplets have a tendency to coalesce. 2

25. Types of emulsifying agents3
To prevent coalescence:
Introduce third material (Emulsifying agent), which form a film around the dispersed globules and prevent them from come to each other and form big one (globules).
Types of emulsifying agents 25 25

26. Surface Tension Theory
Surface tension is the force at the liquid surface which keeps the liquid together. This is why liquids tend to form spherical drops when they are sprayed in air.
If two drops of the same material or miscible liquid come in contact they will coalesce.
If two immiscible drops come together they will resist coalescence and tend to maintain their spherical shapes.
The forces at the drop surface responsible for keeping the liquids apart (immiscible) is called “ interfacial tension”.
Surface Active Agents (Surfactant) or wetting agents can be used to reduce the interfacial tension between the two liquids acting as emulsifiers or emulsifying agents.
Basically surfactants decrease the tendency of the “like/same” drops to coalesce.

27. Two Immiscible Liquids
Surface Tension
Interfacial Tension
La Place Pressure
Interfacial Tension

28. Interfacial Tension
Coalescence
Interfacial Tension

29. Types of Emulsifying Agents4
Surface active agents:
Adsorbed at oil/water interfaces to form monomolecular films - reduce interfacial tension.
Hydrophilic Colloids:
Form multi-molecular film around the dispersed droplets of oil in water (O/W) emulsion.
Finely divided solid particles:
Adsorbed at the interface between two immiscible liquid phases and form a film of particles around the dispersed globules. 29 29

30. Summary
All of them form a film around the globules, either mono, or multi layer, or particulate.
Table 18-1 page 488.

31. Classification of Dispersed Systems
Range of particle size
Characteristics of the system
Examples
Molecular Dispersion
Less than 1.0nm (mµ)
Invisible in SEM, pass through ultra filters
Oxygen molecules, ordinary ions, Glucose
Colloidal Dispersion
1.0nm to 0.5µm
Could be detected under SEM
Colloidal silver solution
Coarse Dispersion
Greater than 0.5µm (µ)
Visible under microscope, not pass through normal filter 31
Ref. Martin chapter 15, colloids 31

32. Monomolecular Adsorption: 5
Surfactant:
Monomolecular Adsorption:
Surface active agents, reduce the interfacial tension because of their absorption at the oil water interface to form monomolecular layer films.
. The film should be:
Flexible, to reform rapidly in case of broken or disturbed.
The presence of surface charge, cause repulsion and enhance stability of the emulsion.
Combination of more then one emulsifier are used in the preparation of emulsion. 32 32

33. Recommendations Atlas of surfactants, recommends that:7
Atlas of surfactants, recommends that:
The hydrophilic Tween be combined with a lipophilic Span, varying the proportion so as to produce the desired O/W or W/O emulsion.
Tween 40 (polyoxyethylene sorbitan monopalmitate) and Span 80 for stabilization of emulsion.
Mix of different emulsifying agents produce stable emulsion such as , (sodium stearate, cholesterol, sodium lauryl sulfate, glyceryl monostearate, tragacanth and span).

34. The type of emulsion produced, depends on the properties of emulsifying agent used.
This characteristics is called Hydrophile-Lipophyl balance and referred to as (HLB).
It is the polar, and non-polar nature of the emulsifier.
Example: Sodium stearate C17H35COONa
─ The non-polar hydrophobic C17H35 is the lipophilic go to oil.
─Polar group hydrophilic ─ COONa go to water.
The balance between the lipophilic and the hydrophilic will determine the type of emulsion formed 34 34

35. HLB

36. HLB Whether a surfactant is an Emulsifier. Wetting agent. Detergent.9
Whether a surfactant is an
Emulsifier.
Wetting agent.
Detergent.
Solubilizing agent.
It will be predicted from a knowledge of (HLB).
Each emulsifying agent is assigned an HLB value. 36 36

37. HLB continued The usual range of HLB is between 1 to 20.10
The usual range of HLB is between 1 to 20.
Material that are highly polar or hydrophilic have higher number of HLB than materials less polar lipophilic low number of HLB.
Materials having an:
HLB value (3-6) are lipophilic & produce W/O.
HLB value (9-12) are hydrophilic and produce O/W. 37 37

38. Rule of Bancroft 11
The type of emulsion is a function of the relative solubility of the surfactant, the phase in which it is more soluble being the continuous phase.
Emulsifying agent with a high HLB is soluble in water and results in the formation of an (O/W) emulsion.
The reverse situation is true with surfactant of low HLB, which tend to form (water in oil) emulsions.

39. HLB Values of emulsifying agents12
HLB Values of emulsifying agents
Emulsifying agent
HLB value
Acacia
8.0
Sorbitan monolaurate
8.6
Sorbitan monostearate
4.7
Polysorbate 20
16.7
Polysorbate 60
14.9
Polysorbate 80
15.0
Sodium lauryl sulphate
40.0
Sodium oleate
18.0
Tragacanth
13.2
Triethanolamine oleate 12 39 39

40. II. Multi-molecular Adsorption & film formation13
Its hydrated Hydrophilic colloids, they considered as surface active agents because they appear at the oil water interface.
They differed from the surfactants in:
They do not cause an sufficient lowering of the interfacial tension.
They form multi-layer rather a monolayer film at the interface. 40 40

41. 14
The action as emulsifying agents is due to the multilayer formation around the droplets, so, strong film which resist coalescence.
Another effect promoting stability is the significant increase in the viscosity of the dispersion medium.
These emulsifying agents are hydrophilic, and they tend to promote the formation of O/W emulsions. 41 41

42. III. Solid Particle Adsorption15
Those solids particles are wetted by both oil and water, so they can act as emulsifying agents.
They presents water and oil interface, where they produce a film around the dispersed droplets.
By this way it prevent coalescence.
Powders which are wetted mainly by:
Water form O/W emulsion.
Oil they form W/O emulsion. 42 42

43. Physical Stability of Emulsions16
Finished product and stability:
Absence of coalescence of the internal phase.
Absence of the creaming.
Maintenance of elegance with respect to appearance, Odor, Color, and other physical properties.
Agglomeration of the internal phase and separation from the product. 43 43

44. Physical stability continued17
Physical stability continued
Creaming, resulting from flocculation and concentration of the globules of the internal phase.
Is not considered as a mark of instability.
Creaming results from flocculation, which, represent potential steps toward complete coalescence of the internal phase.
In pharmaceutical dosage forms creaming is results in lack of uniformity of drug distribution. 44 44

45. Phase Inversion 18
It is the change of emulsion type from W/O to O/W or vice versa.
It is considered as emulsion irreversible instability.
Example:
An oil in water emulsion stabilized with sodium stearate can be inverted to the water in oil by adding calcium chloride to form calcium stearate.
Inversion occur by alteration in phase volume ratio.
Phase inversion can happen if:
Insufficient surfactant or emulsifying agent is used
Inappropriate emulsifying agent is used; e.g., high HLB surfactant for a w/o emulsion
Changing temperature or pH
Adding salts 45 45

46. Classification of the emulsion instability
Flocculation and creaming.
Coalescence and breaking.
Miscellaneous physical and chemical changes.
Phase inversion.

47. Instability of Emulsion19 47 47

48. Creaming and Stokes Law20
If the dispersed phase is less dense than the continuous phase (the case in O/W) emulsion, the velocity of sedimentation become negative, that results in upward creaming.
If the dispersed phase is heavier than the contiguous phase (the case in W/O) emulsion, the globules will settle in the bottom of the container (creaming in the downward direction). 48 48

49. Factors reducing creaming in emulsion21
Viscosity:
Increasing the viscosity of the external phase, by adding thickening agents such as Methylcellulose, Tragacanth, or Sodium alginate.
Globules size:
Reduction in the globules size by homogenization to reach below 2 to 5 µm. 49 49

50. Coalescence and Breaking22
Creaming is a reversible process.
It can re-dispersed by mixing and homogenization, as the oil globules are still surrounded by the protective film of the emulsifying agent.
Breaking is irreversible.
In this case the film surrounded the globules are destroyed and the oil tend to coalesces 50 50

51. Coalescence and Breaking23
Reduction in the globules size does not necessarily lead to increased the stability of the emulsion.
Optimum degree of dispersion for each particular system exists for maximum stability.
Viscosity alone does not produce stable emulsion, however viscous emulsion are more stable than mobile ones.
The phase volume ratio, the volume of oil and the volume of water in the emulsion, the best is 50 parts of water:50 parts of oil.
King showed that Reduction in the particle size does not necessarily lead to increased stability, rather he conclude that an optimum degree of dispersion for each particular system exists for maximum stability. As in the case of solid particles, if the dispersion is none uniform, the small particles wedge between larger ones, permitting stronger cohesion so that the internal phase may coalesce easily. Accordingly, a moderately coarse dispersion of uniform sized particles should have the best stability.
Viscosity alone does not produce stable emulsions; however, viscous emulsion may be more stable than mobile ones by virtue of the retardation of flocculation and coalescence.
Viscous or “tacky” emulsifiers seem to facilitate shearing of the globules as the emulsion is being prepared in the mortar, but this bears little or no relationship to stability. Knoechel and Wurster have shown that viscosity plays only a minor role in the gross stability of O/W emulsion. Probably an optimum rather than a high viscosity is needed to promote stability. 51 51

52. Coalescence Coalescence rate in emulsions can be a function of:
Droplet size
Oil viscosity
Oil volume fraction
shear rate and
chemical additives like surfactant and salts.

53. 24
Cracking:
Is the coalescence of dispersed globules (internal phase) and separation of the disperse phase as a separate layer.
(It is irreversible process and re-dispersion cannot be achieved by shaking). 53 53

54. Effect of Electrolytes25
Effect of Electrolytes
Emulsion can be stabilized by electrostatic repulsion between the droplets, by increasing their zeta potential.
Lecithin is used to stabilize emulsion.
Lecithin produces very stable emulsion of triglyceride acids in water for intravenous administration.
The stability of these emulsion some times is poor because in clinical practice they are mixed with electrolytes, amino acids, and other compounds for parenteral nutrition.

55. The addition of positively charged species such as sodium and calcium ions or cationic amino acids, reduces the zeta potential and may cause flocculation.
Heparin, an anticoagulant, is a negatively charged polyelectrolyte that causes rapid flocculation in emulsions containing calcium and lecithin.

56. Evaluation of Stability27
Size frequency analysis form time to time as the product ages.
Microscopic observation of separated internal phase.
The particle diameters are measured, and a size frequency distribution of particles ranging from 0-0.9, etc.
Accelerating the separation process, which normally takes place under stress conditions.
These methods employ freezing, thaw-freezing cycles, and centrifugation.
Electrical conductivity changes, during short heating cooling heating cycles.
The stability index indicates the relative change in conductivity between two cycles.
The smaller the conductivity, the greater is the stability of the emulsion.
Size frequency analysis form time to time as the product ages.
Microscopic observation of separated internal phase.
The particle diameters are measured, and a size frequency distribution of particles ranging from 0.0 to 0.9, 1.0 to 1.9, 2.0 to 2.9, etc., cle The part size or diameter of the globules in micrometers is plotted on the horizontal axis range on the vertical axis.
Accelerating the separation process, which normally takes place under storage conditions.
These methods employ freezing, thaw-freezing cycles, and centrifugation.
Based on electrical conductivity changes, during nondestructive short heating cooling heating cycles.
Conductivity curves are plotted during the temperature cycle.
The stability index indicates the relative change in conductivity between two cycles.
The smaller the conductivity, the greater is the stability of the emulsion.

57. Source of contamination in emulsions
Contamination may be introduced from a variety of sources including:
Natural emulsifying agents, for example, starch, acacia gum etc, .
Water, if not properly stored.
Carelessly cleaned equipment.
Poor closures on containers.
Environment where the emulsion prepared.
Container and closures systems. 57 57

58. Preservation of Emulsion30
Is it necessary to achieve sterile condition in an emulsion?
What about emulsion for parenteral use?
Different components of emulsion:
Water, Oil, emulsifying agents, color, odor, and microbial contaminations.
Bacteria degrade nonionic & anionic emulsifying agents, (glycerin, and vegetable gums) which, presents as thickeners in the formula, resulting consequence deterioration of the emulsion 58 58

59. Preservation of Emulsion - 231
Preservation of Emulsion - 2
The main problem is to get adequate concentration of preservative in the system.
Factors should be considered to achieve this:
Emulsion is an heterogeneous system, hence partitioning of the preservative is occurs between water and oil phase.
Bacteria grow at the aqueous phase, and the preservative partitioned to the oil phase, hence the concentration of the preservative in aqueous phase in not enough to prevent bacterial growth. 59 59

60. Preservation of Emulsion - 332
The phase volume ratio is significant in this regards.
The preservative must be in an un-ionized state to penetrate the bacteria membrane.
The preservative must not be bound to other ingredients in the emulsion since the complex form (preservative-X) are ineffective as preservatives. 60 60

61. Preservatives used in Emulsions-4
Benzoic acid: (0.1% ) at pH below 5.
Esters of parahydroxybenzoic acid
such as methyl paraben (0.01 – 0.3%).
Chloroform Water (0.25% V/V).
Chlorocresol ( %).
Phenoxyethanol ( %).
Quaternary ammonium compounds (cetramide).
Organic mercurial compounds such as phenylmercuric nitrate and acetate ( %). 33 61 61

62. Rheologic properties of Emulsion
The flow properties of emulsion is important according to the type of use:
In dermatological preparations:
Spreadability is essential.
In case parenteral preparations:
Flow of emulsion through needles is important.
The removal of emulsion from bottle and tubes 62 62

63. Most emulsion exhibit Non-Newtonian flow.
The behavior of an emulsion in the various operations employed in the large-scale preparations.
Most emulsion exhibit Non-Newtonian flow. 63 63

64. Antioxidant
Some oils are liable to degradation by oxidation and therefore antioxidant may be added to the formulation.
Antioxidants used in oral emulsions which are odorless and tasteless include ascorbic acid, citric acid, sodium metabisulphite and sodium sulphite.

65. Micro-emulsions
Clear, transparent solution, solubilized systems, micro-emulsions may not be thermodynamically stable.
Its between stable solubilized solutions and ordinary emulsions.
Micro-emulsion contain droplets of oil in a water phase or droplets of water in oil with diameters of about 10 to 100 nm.

66. A third phase is used for emulsification of the system such as surfactant and co-surfactant .
The micro-emulsion is studied as drug delivery system for the following reasons:
To increase bioavailability of the drug poorly soluble in water by incorporation of the drug into the internal phase.
Micro-emulsion have also been considered as topical drug delivery systems.

67. Micro-emulsion continued
Hydrophilic surfactants may be used to produce transparent o/w emulsion of many oils including flavor oils and vitamin oils such as A, D and E.
Surfactant in the HLB range of 15 to 18 have been used in preparation of such emulsions.
Surfactants commonly used in the preparation of such oral liquid formulations are:
Polysorbate 60
Polysorbate 80
Hydrophilic surfactants may be used to produce transparent O/W emulsion of many oils, including flavor oils and vitamin oils such as A, D and E.
Surfactant with HLP range of 15 to 18 are the most widely used in preparation of such emulsion.
These emulsions are dispersions of oil, not true solutions; however, because of the appearance of the product, the surfactant is commonly said to solubilize to oil.
Surfactant commonly sued in the prepration of such oral liquid formulations are polysorbate 60 and Plysorbate 80.

68. Advantages of microemulsion
Rapid and efficient oral absorption of drug compared to solid dosage form.
Enhance trans-dermal drug delivery through increased drug diffusion into the skin.
Potential application of micro-emulsion in the development of artificial red blood cells and in the targeting of cytotoxic drugs to cancer cells.

69. Micro-emulsions
Micro-emulsions are thermodynamically stable, thus they are self emulsifying and require almost no shear; i.e., they form instantaneously as the internal phase is dispersed in the continuous phase.
Micro-emulsions are prepared by carefully selecting the surfactants with or without co-surfactants.
Examples are vitamin emulsions such as A, D and E or flavor oils.
High HLB surfactants are used (15 to 18) such polysorbate 60 or 80.
These emulsions look like but are not solutions.
Some drugs are embedded in certain solid surfactants and then encapsulated.
These are called SMEDDS and form a micro-emulsion as they dissolve in GI fluids.
They are supposed to give better bioavailability than simple solid dosage forms.

70. Nano-emulsions These are almost similar in size to micro-emulsions
(1 nm -100 nm) but they are not thermodynamically stable.
They also look transparent.
The following factors are required to form Nano-emulsions:
The dispersed phase has to be quite insoluble in the continuous phase.
The surfactant(s) chosen should not form lyotropic liquid crystalline ‘micro-emulsion’ phases.
Have excess of surfactants to be able to cover the large surface area of the small droplets.
Introduce very high shear to break the droplets into the required very small size.

71. Examples of oral emulsions
1. Mineral oil emulsion:
Mineral oil ml
Acacia g
Syrup ml
Vanillin mg
Alcohol 60ml
Purified water (qs) ml
Prepared by dry gum method.
Simethicone Emulsion
Caster oil emulsion