1. EMULSION

2. EMULSION
An emulsion is liquid preparation containing two immiscible liquids, one of which is dispersed as globules (dispersed phase = internal phase) in the other liquid (continuous phase = external phase) that is stabilized by an emulsifying agent.

3. Examples of Pharmaceutical Emulsions:
Lotions
Liniments
Creams
Ointments
Vitamin drops

4. Types of emulsion:
Simple emulsions / Macroemulsion: containing one internal phase.
oil-in-water emulsion (o/w)
water-in-oil emulsion (w/o)
2. Multiple-emulsion: it contains two internal phases.
oil in water in oil (o/w/o)
water in oil in water (w/o/w)
Multiple emulsions can be used to delay release or to increase the stability of the active compounds

5. Different types of emulsions (O/W, W/O and multiple emulsions O/W/O and W/O/W

6. Differences between o/w emulsion and w/o emulsions
Water is the dispersion medium and oil is the dispersed phase
Oil is the dispersion medium and water is the dispersed phase
2. non greasy and easily removable from the skin
greasy and not water washable
3. used externally to provide cooling effect e.g. vanishing cream
used externally to prevent
evaporation of moisture from the surface of skin e.g. Cold cream
4. preferred for internal use as bitter taste of oils can be masked.
preferred for external use like creams.

7. Pharmaceutical applications of emulsions:
To mask the bitter taste and odor of drugs e.g castor oil, cod-liver oil
O/W is convenient means of orally administration of water-insoluble liquids
O/W emulsion facilitates the absorption of water-insoluble compounds comparing to their oily solution preparations (e.g. vitamins)
Oil-soluble drugs can be given parenterally in form of oil-in water emulsion. (e.g Paclitaxel which is an anti-cancer drug)

8. Pharmaceutical applications of emulsions:
Emulsion can be used for external application in cosmetic and therapeutic uses.
They can be used to prolong the release of the drug and thereby providing sustained release action.
Essential nutrients like carbohydrates, fats and vitamins can all be emulsified and can be administered to bed ridden patients as sterile intravenous emulsions.

9. Factors that affect emulsification
Interfacial Tension :
In case of two immiscible liquids
An explanation of this phenomenon is because of cohesive force between the molecules of each separate liquid exceeds adhesive force between two liquids. This is manifested as interfacial energy or tension at boundary between the liquids.

11. Therefore to prevent separation and coalescence emulsifying agents are used which reduce the interfacial tension. Thereby reducing the amount of energy needed to produce an emulsion.

12. 2.Surface free energy
The internal phase (oil or water) must be reduced to small droplets. This can be done only if necessary energy in the form of work is applied to create small droplets.
The energy or work can also be interpreted as surface free energy which makes an emulsion unstable.
Surface free energy, however small, promotes coalescence and emulsion instability.
Thus emulsifying agents provide a mechanical barrier to coalescence that counterbalances the surface free energy.

13. Three mechanisms are thought to provide this barrier –
Emulsifying agents may function by forming a strong pliable film around the dispersed droplets.
Charge repulsion – Charge repulsion can cause the droplets to repel each other and prevent coalescence. For example, the oil droplets in an aqueous phase usually possess an electric charge due to the nature of the emulsifying agent or resulting from absorption of ions from the solution.

14. Steric repulsion – Steric repulsion occurs when the long hydrocarbon chains of the surfactant or emulsifying agent prevent water droplets in an oily phase from contacting each other. Thus, a more hydrophilic emulsifying agent tends to produce an o/w emulsion whereas a more hydrophobic agent forms a w/o emulsion.

15. Emulsifying agents
Emulsifying Agents are the substances added to an emulsion to prevent the coalescence of the globules of the dispersed phase.
They are also known as emulgents or emulsifiers.
They act by reducing the interfacial tension between the two phases and forming a stable interfacial film.
The choice of selection of emulsifying agent plays a very important role in the formulation of a stable emulsion.

16. No single emulsifying agent possesses all the properties required for the formulation of a stable emulsion therefore sometimes blends of emulsifying agents have to be taken.

17. Criteria For The Selection of Emulsifying Agents :
An ideal emulsifying agent should posses the following characteristics:
It should be able to reduce the interfacial tension between the two immiscible liquids.
It should be physically and chemically stable, inert and compatible with the other ingredients of the formulation.
It should be non irritant and non toxic in the conc., used.
It should be organoleptically inert i.e. should not impart any color, odour or taste to the preparation.

18. It should be able to produce and maintain the required viscosity of the preparation.
It should be able to form a coherent film around the globules of the dispersed phase and should prevent the coalescence of the droplet of the dispersed phase.

19. Types of emulsifying agents:
Natural emulsifying agents from vegetable sources –
These consist of agents which are carbohydrates and include gums and mucilaginous substances. Since these substances are of variable chemical composition, these exhibit considerable variation in emulsifying properties. They are anionic in nature and produce o/w emulsions. They act as primary emulsifying agents as well as secondary emulsifying agents (emulsion stabilizers).
Since carbohydrates acts a good medium for the growth of microorganism, therefore emulsions prepared using these emulsifying agents have to be suitable preserved in order to prevent microbial contamination.
E.g. tragacanth, acacia, agar, pectin and starch.

20. 2. Natural emulsifying agents from animal sources -
The examples include gelatin, egg yolk and wool fat (anhydrous lanolin). Type A gelatin (Cationic) is generally used for preparing o/w emulsion while type B gelatin is used for o/w emulsions of pH 8 and above.

21. Lecithin and cholesterol present in egg yolk also act as emulsifying agent. They show surface activity and are used for formulating o/w emulsions.
However they are used only for extemporaneous preparation and not for commercial preparation as it darken and degrade rapidly in unpreserved systems.
Wool fat is mainly used in w/o emulsions meant for external use. They absorb large quantities of water and form stable w/o emulsions with other oils and fats.

22. 3.Semi-synthetic polysaccharides
Includes mainly cellulose derivatives like sodium carboxy methyl cellulose, hydroxyl propyl cellulose and methyl cellulose. They are used for formulating o/w type of emulsions. They primarily act by increasing the viscosity of the system. e.g. methyl cellulose, hydroxypropyl cellulose and sodium carboxy methyl cellulose.

23. 4.Surface active agent / Surfactants :
adsorbed at oil/water interface to form monomolecular film to reduce the interfacial tension.
This group contains surface active agents which act by getting adsorbed at the oil water interface in such a way that the hydrophilic polar groups are oriented towards water and lipophillic non polar groups are oriented towards oil, thus forming a stable film. This film acts as a mechanical barrier and prevents coalescence of the globules of the dispersed phase.

24. Surface active agent / Surfactants :
This group contains surface active agents which act by getting adsorbed at the oil water interface in such a way that the hydrophilic polar groups are oriented towards water and lipophillic non polar groups are oriented towards oil, thus forming a stable film. This film acts as a mechanical barrier and prevents coalescence of the globules of the dispersed phase.

25. Monomolecular adsorption by Surface-active agent :
In emulsion, the surface area is high to maintain the dispersion of the droplets. Thus, based on the above equation surface free energy becomes high consequently. The only way to keep it low is to reduce the interfacial tension.

26. Surface active agent (SAA) is molecule which have two parts, one is hydrophilic and the other is hydrophobic. Upon the addition of SAA, they tend to form monolayer film at the oil/water interface.

27. The functions of surface active agents to provide stability to dispersed droplets are as following:
Reduction of the interfacial tension
Form coherent monolayer to prevent the coalescence of two droplet when they approach each other
Provide surface charge which cause repulsion between adjacent particles

28. CLASSIFICATION OF SURFACTANT
They are classified according to the ionic charge possessed by the molecules of the surfactant e.g.,
anionic,
cationic,
non-ionic and
amphoteric

29. Determination of emulsion type
Water or oil miscibility test
Conductivity test
Dye solubility or staining test
Fluorescence test
Filter paper test

30. Water or oil miscibility test
A small amount of emulsion is examined upon unlimited dilution with water.
This may cause two facts-
If the emulsion remains stable, it is o/w emulsion.
If the emulsion doesn’t remain stable, it is w/o emulsion

31. Electrical Conductivity test
If the electricity is passed through the emulsion, it is o/w type emulsion as water is good conductor of electricity whereas oil is non-conductor and the result is observed by lighting.
Therefore, continuous phase of water runs electricity more than continuous phase of oil.
= Bulb glows with O/W
= Bulb doesn’t glow with W/O

32. Staining Test
A small amount of emulsion is mixed with scarlet red or methylene blue with volatile oil and examined under microscope.
if dispersed globules appear red, it is o/w type emulsion as scarlet red is soluble in oil but not in water.
If dispersed globules appear blue, it is w/o type emulsion as methylene blue is soluble in in water but not in oil.

33. Fluorescence test
oils give fluorescence under UV light, while water doesn’t. Therefore, O/W emulsion shows spotty pattern while W/O emulsion fluoresces.

34. Filter paper test
A filter paper is treated with Calcium chloride and when dried, it turns blue.
Now one or two drops of sample is placed on the filter paper and observed-
If the color changes to pink, then it is o/w type
If there is no change in color, then it is w/o type

35. Preparation Techniques:
Techniques used on laboratory scale :
Addition of internal phase to the external phase, while subjecting the system to shear or fracture.
Phase inversion technique: The external phase is added to the internal phase. E.g. if o/w emulsion is to be prepared, the aqueous phase is added to the oily phase. First w/o emulsion is formed. At the inversion point the addition of more water results in the inversion of the emulsion system and formation of an o/w emulsion. This phase inversion technique allows the formation of small droplets with minimal mechanical action and heat. A classical example is the dry gum method.

36. Mixing both phases after warming each:
This method is used for creams and ointments.
Alternate addition of two phases to the emulsifying agent: In this method, the water and oil are added alternatively, in small portions to the emulsifier.

37. Self-study (later) Continental or dry gum method
Wet gum method or English method
Bottle or Forbes bottle method
Auxiliary method
In situ soap method

38. LARGE SCALE PRODUCTION OF EMULSIONS:
Commercially, emulsions are prepared in large volume mixing tanks and refined and stabilized by passage through a colloid mill or homogenizer. The internal phase can be reduced to small droplets by application of energy in the form of heat, mechanical agitation, ultrasonic vibration or electricity.
Application of energy :
Energy may be supplied in the form of heat, homogenization or agitation.

39. Emulsification by Vaporization (Condensation method) :
Vaporization is an effective way of breaking almost all bonds between molecules of a liquid. So emulsions may be prepared by passing vapor of a liquid into an external phase that contains suitable emulsifying agent. This process is called condensation method.

40. Disadvantages :
slow
can be used for preparing dilute emulsions of materials having a relatively low vapor pressure.

41. 2. Emulsification by Change in temperature (Phase inversion technique) :
Change in temperature can be used as an effective way of making emulsion by phase inversion technique. In this method first the emulsion is prepared at a higher temperature. On cooling phase inversion takes place and a stable inversion with finely divided internal phase is produced.

42. Change in temperature due to cooling brings about phase inversion
Change in temperature due to cooling brings about phase inversion. The temperature at which phase inversion takes place is called phase inversion temperature (PIT). PIT is generally considered to be the temperature at which the hydrophilic and the lipophilic properties of the emulsifier are in balance and is therefore also called the HLB temp. PIT depends upon emulsifier concentration.

43. An o/w emulsion stabilized by a nonionic surfactant (e. g
An o/w emulsion stabilized by a nonionic surfactant (e.g. polyoxyethlene – derived surfactant) contains micelles of the surfactant as well as emulsified oil. When temperature is raised, the water solubility of the surfactant decreases; as a result the micelle are broken and the size of emulsified oil droplets begins to increase. A continued rise in temperature causes separation into oil phase, a surfactant and water. It is near this temperature that now water insoluble surfactant begins to form a w/o emulsion containing both water –swollen micelle and emulsified water droplets in a continuous oil phase.

44. 3. Low energy emulsification :
The emulsification by change in temperature requires considerable expenditure of energy during both heating and cooling cycles of emulsion formation. In low energy emulsification, all of the internal phase, but only a portion of the external phase is heated. After emulsification of the heated portions, the remainder of the external phase is added to the emulsion concentrate, or the preformed concentrate is blended into the continuous phase.

45. In those emulsions in which a phase inversion temperature exists, the emulsion concentrate is preferably prepared above PIT which results in emulsion having extremely small droplets size. Good emulsions can be prepared by this method with careful control of variables like emulsification temperature, mixing time, mixing intensity, amount of external phase employed during emulsification and the method of blending.

46. EQUIPMENTS USED IN EMULSIFICATION
Various types of equipment are available to bring about droplet break up and emulsification either in laboratory or in production. Such equipment can be divided into four categories :
Mechanical stirrers (Propellent and Turrbine)
Homogenizers
Ultrasonifiers
Colloid mills

47. EMULSION STABILITY ( INSTABILITY)
Physical Instability of Emulsions
The instability of pharmaceutical emulsions may be classified as the following:
Flocculation
Creaming or sedimentation
Coalescence or Aggregation
Cracking or Breaking
Phase inversion

48. Types of physical INSTABILITY of emulsion

49. 1.Flocculation
Flocculation is defined as a weak reversible association between emulsion droplets which are separated by trapped continuous phase.
However these aggregates can easily be redispersed upon shaking. It is considered as a precursor to the irreversible coalescence.
It differs from coalescence mainly in that interfacial film and individual droplets remain intact.

50. 1.Flocculation
Flocculation is influenced by the charges on the surface of the emulsified globules. The reversibility of flocculation depends upon strength of interaction between particles as determined by
a. the chemical nature of emulsifier,
b. the phase volume ratio,
c. the concentration of dissolved substances, specially electrolytes and ionic emulsifiers.

51. 2.Creaming and sedimentation :
The upward or down ward movement of dispersed droplets is termed creaming or sedimentation respectively. Creaming or sedimentation occurs when the dispersed droplets or floccules separate under the influence of gravity to form a layer of more concentrated emulsion, the cream. In any emulsion, creaming or sedimentation takes place depending on the densities of disperse and continuous phases.

52. Generally a creamed emulsion can be restored to its original state by gentle agitation. Most oils are less dense than water so the oil droplets in an o/w emulsion rise to the surface to form an upper layer of cream. In w/o emulsions, the cream results from the sedimentation of water droplets and forms the lower layer.

53. Factors affecting rate of creaming :
Rate of creaming is governed by Stoke’s law.
As per Stoke’s law
υ = 2r 2(ρ1 - ρ2 ) g / 9η
where
υ = rate of creaming or sedimentation
r = radius of droplets of dispersed phase
ρ1 = density of dispersed phase
ρ2 = density of continuous phase
g = gravitational rate constant
η = viscosity of continuous phase.

54. Droplet size :
As per Stoke’s law, rate of creaming is directly proportional to the square of radius or diameter of the droplet size. Smaller is the diameter of the droplet, lesser will be the rate of creaming. So reduction in droplet size by using a homogenizer helps in reducing creaming or sedimentation.

55. Difference in densities of dispersed and continuous phase :
As per Stoke’s law no creaming is possible if densities of the two phases are equal. So Creaming can be avoided by adjusting the density of dispersed phase.

56. Viscosity of the continuous phase :
As per Stoke’s law, rate of creaming is inversely proportional to viscosity of the continuous phase. So increase in viscosity of the continuous phase by adding thickening agents can reduce the rate of creaming.

57. Factor affecting viscosity of emulsions:
Viscosity of continuous phase : Viscosity of emulsion is directly proportional to the viscosity of continuous phase. Clays and gums increase the viscosity of continuous phase. For w/o emulsions addition of polyvalent metal soaps or use of high melting waxes and resins in the oil phase can be used to increase the viscosity.
Volume of internal phase : Depends upon the volume of internal phase. More the volume of internal phase greater is the viscosity.
Particle size of dispersed phase : On the particle size of dispersed phase Smaller the globule size, more will be the viscosity. That is why emulsion stability can be improved by reduction in globule size.

58. 3.Coalescence:
It is the process in which the dispersed phase droplets join/merge to form larger particles and the emulsion generally cannot be recovered by simple agitation. When two droplets come into contact i.e. as a floccule, thin liquid films composed of continuous phase and adsorbed emulsifier are formed between them. Coalescence takes place in two distinct steps. It begins with the drainage of these films as the droplets approaches one another and ends with film rupture. Hence, the major factor which prevents coalescence is the mechanical strength of electrical barrier. That is why natural gums and proteins are so useful as auxiliary emulsifiers when used at low level , but can even be used as primary emulsifiers at high concentration.

59. 4. Cracking or Breaking
An emulsion of two liquids without a stabilizer will quickly separate back to the original state of two separate liquid layers, a phenomenon known as breaking or cracking.
This state is approached via several distinct processes, some of which are reversible such as flocculation and creaming and or irreversible process such as coalescence.

60. Reasons for cracking : Globule size :
If globule size is big, (more than 1-3 µm), emulsion may first cream and then crack. A homogenizer can reduce the size of globules.
2. Storage Temperature :
Extremes of temperature can lead to cracking. When water freezes, it expands, so undue pressure is expected on dispersed globules and the emulsifying film., which may lead to cracking. On the other hand, increase in temperature decreases the viscosity of the continuous phase and disrupts the integrity of interfacial film. An increasing number of collisions between droplets will also occur, leading to increased creaming and cracking.

61. 3. Addition of a common solvent - e. g
3. Addition of a common solvent - e.g. addition of a solvent in which the two phases are soluble (alcohol)
4. Microbial contamination may destroy the emulsifying agent.
5. Addition of an incompatible emulsifying agent
e.g. monovalent soap + divalent soap
e.g. anionic + cationic emulsifying agent

62. 6. Incorporation of excess disperse phase
7. Chemical decomposition of emulsifying agent –
e.g. alkali soaps decomposed by acids
e.g. monovalent soaps salted out by electrolytes such as NaCl
e.g. nonionic emulsifying agents are incompatible with phenols
e.g. alcohol precipitates gums and gelatin

63. 5. Phase inversion
In phase inversion o/w type emulsion changes into w/o type and vice versa.It is a physical instability.It may be brought about -
By the addition of an electrolyte e.g. addition of CaCl2 into o/w emulsion formed by sodium stearate can be inverted to w/o.
by changing the phase volume ratio
by temperature changes.

64. Phase inversion can be minimized by:
1- using the proper emulsifying agent in adequate concentration
2- keeping the concentration of dispersed phase between 30 to 60 % storing the emulsion in a cool place.

65. Chemical instability of emulsions
This may be due to
Oxidation
Hydrolysis
Microbial growth.

66. Oxidation:
Many organic compounds are subject to autoxidation upon exposure to air. Emulsified lipids are particularly sensitive to attack. Many drugs commonly incorporated into emulsions are subject to autoxidation and resulting decomposition.
Upon autoxidation, unsatuarated oils, such as vegetable oils, give rise to rancidity with resultant unpleasant odor , appearance, and taste. On the other hand, mineral oil and related saturated hydrocarbons are subject to oxidative degradation only under rare circumstances.

67. Autoxidation is a free radical chain reaction. It can be inhibited
by the absence of oxygen,
by a free radical chain breaker,
by a reducing agent.

68. Examples of antioxidants :
Gallic acid, Propyl gallate
Ascorbic acid – Suitable for oral use products
Sulphites - Suitable for oral use products
L-tocopherol - pharmaceuticals and cosmetics - Suitable for oral preparations e.g. those containing vit A
Butylated hydroxyl toluene - pharmaceuticals and cosmetics - Pronounced odor, to be used at low conc.
Butylated hydroxy anisole - pharmaceuticals and cosmetics

69. Microbial growth
Emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides., all of which readily support the growth of a varity of microorganisms. Even in the absence of any of the above mentioned ingredients, the mere presence of a mixture of lipid and water in intimate contact frequently allows microorganisms growth. So preservative is a must for emulsions.

70. Antimicrobial agents
Quaternaries - Chlorhexidine and salts - Broad spectrum
Benzalkonium chloride
Cetyl trimethyl ammonium bromide

71. EVALUATION OF EMULSION STABILITY
The primary objective of studying stability emulsion is to predict its shelf life under normal storage conditions. The final evaluation of the product for its shelf life must be done in the container in which it is packed because :
the ingredients may interact with the container,
some material may leach out from the container,
loss of water and volatile ingredients may occur through the container or closures.

72. The problem of stability assessment under normal conditions is that they last long periods of time. To shorten the time many types of stress tests conditions are used to provide a basis for prediction of the stability of an emulsion. These can provide valuable information but one must be aware of the risk that changes occurring under stress conditions may not necessarily take place under normal storage conditions.

73. Stress conditions normally employed for stability studies are
(a) Time stress
(b) thermal stress
(c) Centrifugation

74. Thermal stress:
The instability of emulsion at higher temperature may include phenomenon such as temperature dependent solubility, degradation reactions occurring only at higher temperature, temperature induced phase changes and altered rheological behavior, structural deformation and reformation.
It is considered reasonable to use the time for destabilization at 40o C multiplied by 4 to give an estimate of shelf life at room temperature.

75. Aging and temperature:
In this method the sample of emulsion is stored at various temperatures and parameters like viscosity, % of phase separation, particle size, zeta potential, rheolgical parameters, electrical conductivity are monitored . The normal effect of aging an emulsion at elevated temp. is acceleration of the rate of coalescence or creaming and this is usually coupled with changes in viscosity.

76. The two most common procedures for running aging test are:
To age one sample of the emulsion at different temperatures ; for instance 4oC, room temperature, 35o C , 43oC, for 2,4,and 6 weeks.
Freeze – thaw cycle test: To age the same sample and cycle the temperature many times between two extreme value:. Such a test is completed after 4-5 days.

77. Phase inversion temperature :
-It is the temperature at which the emulsion inverts. This method is useful for assessing stability of o/w emulsions.

78. Gravitational stress (Centrifugation) :
The shelf life can be predicted rapidly by observing the separation of dispersed phase due to creaming or coalescence when emulsion is exposed to centrifugation. Stoke’s law shows that creaming is a function of gravity, so increase in gravity accelerates separation. It has been found that centrifugation at 3750 rpm in a 10 cm radius centrifuge for a period of 5 hrs is equivalent to the effect of gravity for about one year. Gravitational stress such as centrifugation may allow phase separation to occur quickly.

79. Agitation
Simple mechanical agitation can contribute to the energy with which two droplets impinge upon each other. Agitation can bring about coalescing of globules and then breaking of emulsion. (Preparation of butter from milk). Conventional emulsions may deteriorate from gentle rocking on a reciprocating shaker. This is related to impingement of droplets and in part to reduction of viscosity of a normal thixotropic system.

80. PARAMETERS FOR ASSESSING THE EMULSION STABILITY
Physical parameters :
The most useful parameters commonly measured to assess the effect of stress conditions on emulsions include :
Phase separation
Viscosity
Electrophoretic properties
Particle size analysis

81. Phase Separation :
The rate and extent of phase separation after aging of an emulsion may be observed visually or by measuring the volume of separated phase. The separated phase may be due to coalescence or due to creaming.

82. Viscosity :
Changes in viscosity during aging can give an idea about shelf life of an emulsion. Viscometers of cone plate type or instruments having co-axial cylinders can be used to measure the viscosity.

83. Electrophoretic properties
Zeta potential : The zeta potential enables the formulator to evaluate the effect of the repulsive forces between globules.
Electrical conductivity: It can also be used to evaluate emulsion stability. The electrical conductivity of o/w or w/o emulsions is determined with the aid of Pt electrodes.
Dielectric constant measurements : An inverse relationship existed between log of rate of increase in dielectric constant and the absolute temperature . This can be used as a prediction test.

84. FORMULATION OF EMULSION USING HLB METHOD
Hydrophilic-Lipophilic Balance (HLB):
HLB: the ratio between the hydrophilic portion of the molecule to the lipophilic portion of the molecule.
The higher the HLB of an agent the more hydrophilic it is.
Spans are lipophilic and have low HLB.
Tweens are hydrophilic and have high HLB.

86. Calculation of HLB: Griffin equation: HLB = 20 (1 – S / A) where
S: saponification number of the ester
A: the acid number of the fatty acid
 Davis equation:
HLB = hydrophilic group number – lipophilic group number + 7
The HLB mixture of surfactants consisting of a fraction of x of A and (1-x) of B can be calculated as follows:
HLB mixture = x HLB A + (1-x) HLBB

87. Problems:

88. References Pharmaceutics- The SCIENCE OF DOSAGE FORM by Aulton
The theory and practice of Industrial Pharmacy by Lachman
Sprowl’s American Pharmacy