Lesson VII

EQUIPMENT FOR EMULSION PREPARATION

1. SMALL SCALE
2. LARGE SCALE
 Equipment for Small Scale Preparation

◦ 1. Mortar and pestle

◦ Advantages:
 low cast
 Simplest operation

Disadvantage:
 final particle size is larger than other equipment used.

2. Agitator (shaking)
This method is frequently applied in the emulsification of easily dispersed low viscosity oils. Under certain conditions,
intermittent shaking is considerably more effective than ordinary continuous shaking. Continuous shaking break not only the
phase to be dispersed but also the dispersion medium thus impair the emulsification.

3. Mechanical Mixers
Small electric mixers may be used to prepare emulsion at the prescription counters. They save time and energy and produce
satisfactory emulsions, when emulsifying agent is acacia or agar.
 Equipment for Large Scale Emulsion Preparations

◦ 1. Colloid Mills
◦ This is the passage of the mixed phases of the emulsion formula between a stator and a high speed rotor
revolving at speed of 2000 to 18000 rpm. The emulsion mixture is subjected to tremendous shearing
action which gives a fine dispersion of uniform size. The shearing action usually rise the temperature of
emulsion so a coolant is used to absorb the excess heat produced.
Advantages:
 very high shearing force is generated
 very fine particles are prepared
 useful for relatively viscous emulsion.
◦ 2. Homogenizer
◦ This equipment frequently produces a satisfactory emulsion where ingredients in the emulsion are mixed and passed
through this machine to produce the final product. Or, a course emulsion is passed through this machine for the purpose
of decreasing the particle size and obtain a greater degree of uniformity and stability. The circulation and turbulence
produced during the process is responsible for the homogenization of the preparation.

◦ 3. Ultrasonic Devices (ultrasonic vibrations)

◦ An oscillator of high frequency 100-500 kHz is connected to two electrodes between which is placed a piezoelectric
quartz plate. The quartz plate and electrodes are immersed in an oil bath and when the oscillator is operating, high
frequency waves flow through the fluid.

◦ 4. Microfluidizer
◦ The process subjects the emulsion to an extremely high velocity through microchannels into an interaction chamber as a
result particles are subjected to shear, turbulence, impact and cavitation.
◦ Advantages: no contamination of the final product and ease of production scale up.
 DETERMINATION OF HLB

◦ In the late 1940s, William Griffin introduced the Hydrophilic-Lipophilic Balance system as a way of
figuring out which emulsifier would work best with the oil phase of an emulsified product.
◦ All emulsifiers have a hydrophilic head (water loving) that is generally composed of a water soluble
functional group and a lipophilic tail (oil loving) generally composed of a fatty acid or fatty alcohol. The
proportion between the weight percentages of these 2 groups in a surfactant molecule is an indication of
the behavior that maybe expected from the product.
◦ An emulsifier that is lipophilic in character is assigned a low HLB number and an emulsifier that is
hydrophilic in character is assigned a high number. The midpoint is approximately ten and the assigned
values have ranged from one to forty.
 THEORY BEHIND HLB

◦ Emulsifier having low HLB tend to be oil soluble and materials having high values tend to be water
soluble. But, however, this doesn’t always be right.
◦ E.g. two emulsifiers may have the same HLB and exhibit different solubility characteristics. Further, one
should take a point into consideration that chemical type alone does not establish hydrophilic-lipophilic
balance. Thus soaps may range from strongly hydrophilic for sodium laurate to strongly lipophilic for
aluminum oleate.
 DETERMINATION OF HLB BY CALCULATION

◦ Each of the active agent may be assigned on HLB value, usually varying from 1 to 20. the higher the numeral value,
the more polar or hydrophilic will be the nature of the agent. It has been found out that W/O emulsions are formed when
HLB is 8 -18.
◦ This is very important in product quality and yield points of view, HLB values can be calculated theoretically or
experimentally.
Example:
1. A 1:1 mixture of Sorbitan Monostearate and Polyethylene 20 Sorbitan Monostearate can be used to provide an
average HLB value of 9.8
Because: Sorbitan monostearate HLB value = 4.7 and
Polyethylene sorbitan monostearate = 14.9
4.7 + 14.9 = 19.6 / 2 = 9.8 Ave. HLB
If a 2:1 mixture of Sorbitan tristearate HLB value of 2.1 and Polyethylene 40 stearate HLB value of 16.9 are combined,
what is the averge HLB value? Answer is 7.03
sorbitan tristearate HLB = 2.1 x 2 = 4.2
polyethylene 40 stearate HLB = 16.9 x 1 = 16.9

21.1/3 = 7.03 Ave. HLB value

 APPLICATIONS OF SURFACTANTS DEPENDING ON HLB

◦ the HLB system is very useful to distinguish the surfactants according to their applications. generally the
applications for non-ionic surfactants within the following HLB ranges are as follows:

HLB Numbers Applications

4.6 W/O emulsifier
7-15 Wetting agent
8-18 O/W emulsifier
10-15 Detergent

10-18 Solubilizer
 CREAMING AND SEDIMENTATION
◦ CREAMING
◦ This the upward movement of the droplets relative to the continuous phase. It occurs when the dispersed phase is less
dense than the continuous phase as in O/W type emulsion.

◦ SEDIMENTATION
◦ This is the downward movement of the droplets relative to the continuous phase. If internal phase is heavier than the
external phase, globules will tend to settle down causing sedimentation as in the case of W/O type emulsion.
◦ This is often the undesirable result due to following reasons; if sufficient shaking is employed before each dose,
improper dosage of the internal phase may result, which is not acceptable to consumers.
◦ How to overcome:
◦ By using Stokes’ equation,
◦ V = d squared x g (Pp – Ps)/ 18n
◦ There are three factors that govern the rate of settling droplets.
◦ a. diameter of suspended droplets II
◦ b. viscosity of suspending medium III
◦ c. difference of densities between dispersed phase and the dispersion medium.
Manufacturing #5 Cod-liver Oil Emulsion
60mL
Laboratory Exercises #6 Castor Oil Emulsion 200mL
Submission and checking of the
exercise results next meeting.
# Aloe vera lotion 250mL
◦ The 2 factors to be use to reduce the rate of creaming or sedimentation.
◦ a. reduction of the particle size as rate of movement is a square root function of the particle diameter.
Particle diameter can be reduced up to 0.1um – 2.
◦ b. most frequent approach is to raise viscosity of the continuous phase for this and use viscosity
improver or thickening agent like methylcellulose, tragacanth or sodium alginate.
◦ But the increase thickness is only up to the acceptable limit so that emulsion can be poured easily.
◦ C. theoretically, if internal and external phase densities are the same, there would be no creaming or
sedimentation that would take place but it’s not possible practically as temperature change density.
 COALESCENCE AND BREAKING COALESCENCE
This is a complete fusion of droplets to decrease number of droplets that can lead to breaking of emulsion. Aggregation precedes
coalescence in emulsion; however, coalescence does not necessarily follow from aggregation. Coalescence is irreversible as in
coalescence protective sheath of emulsifier around the dispersed droplets no longer exist.
BREAKING:
This is the separation of internal phase and separation of that phase into a layer called breaking and the emulsion is termed as
cracked or broken.
To overcome the coalescence:
By using combination of surfactants that provide certain advantages
like: water interface of elastic film that will not rupture upon collision of emulsion droplets. Additional beneficial effect of mixed
emulsifier films could result from an increase in viscosity of the interfacial emulsifier film. A viscous interfacial film could
enhance emulsion stability because thinning of the film at the point of droplet contact would inhibited.
INVERSION:
An emulsion is said to be inverted when it changes from O/W type to W/O type or vice versa. The following factors can cause
inversion of emulsion:
• For example, an O/W emulsion having sodium stearate as the emulsifier can be inverted by addition of calcium chloride because
calcium stearate formed is a lipophilic emulsifier and favors the formation of a W/O product. Two phases is being cooled. This
takes place presumably because of the temperature dependent changes in the solubility of the emulsifying agents.
To avoid Inversion, exceed 50% of the total volume of the emulsion.
 EVALUATION OF EMULSION STABILITY

EMULSION PROPERTIES TO BE MONITORED DURING STABILITY TESTING

PROPERTY TEST METHOD
pH pH meter
Viscosity Rotational viscometer
Flow behavior Oscillatory shear viscosity with a complete thermometer
Tack/ texture Extensional and compressional deformation
Color Visual or colorimeter
Odor Organoleptic
Specific gravity Pycnometer
Separation Creaming value-visual or instrumental
Conductivity Conductivity meter
Droplet size distribution Microscopic examination (image analysis) and instrumental
Preservation Microbial challenge and/or assay
Vibration Shipping test or shaker table.
Active ingredient(s) Chemical or bio-assay
 To speed up stability evaluation of emulsion formulator commonly places the emulsion under
some sort of stress. Such as:

◦ 1. Aging and temperature

 varying period of time at temperatures that are higher than normally encountered.
 cycling between 4-45 C. this type of cycling approaches realistic shelf conditions but places emulsion
under enough stress to alter various emulsion parameters.
Temperature changes cause varied effects on following parameters of emulsion.
An acceptable emulsion should survive 2 or 3 freeze thaw cycles between 20-25 C with storage at each
temperature for not less than 48 hours.

◦ 2. Centrifugation
◦ 3. Agitation
 ADVANCED PHARMACEUTICAL EMULSIONS
◦ 1. MICRO EMULSIONS
◦ Other names: Transparent emulsion, Swollen micelle, micellar solution, Solubilized oil

◦ Hoar and Schulman introduced this concept who experimented a clear single-phase solution by titrating a
milky emulsion by hexanol.

◦ Micro emulsion is a homogenous, transparent, thermodynamically stable dispersions of water and oil,
stabilized by a surfactant (materials that form interfacial film), and a co-surfactant ( materials that ensures
flexibility of interfacial layer and reduces the interfacial tension).
◦ Composition:
• Oil
• Surfactant
• Co-surfactant
• Water
◦ Advantages:
Increase the rate of absorption
Increase bio-availability
Helpful in the taste masking
Eliminates variability in absorption
Helps in solubilizing lipophilic drugs
Disadvantages:
Use large concentration of surfactant and co-surfactant necessary for stabilizing micro droplets.
Limited solubilizing capacity for high melting substances
Stability is influenced by environmental factors such as, temperature and pH,. These factors change upon micro
emulsion delivery to the patient.
 TYPES OF MICRO-EMULSIONS

1. O/W micro-emulsion (oil droplets are dispersed in the continuous aqueous phase)

2. W/O micro-emulsion (water droplets are dispersed in the continuous oil phase)

3. Bio-continuous micro-emulsion (micro domains of oil and water are inter dispersed
within the system).

Note:
The interfaces of these three micro-emulsions are stabilized with the use of an appropriate combination of
surfactants and/or co-surfactants.
 PREPARATION METHODS OF MICRO-EMULSION

◦ 1. Phase Titration Method

◦ a. Dilution of an oil-surfactant mixture with water (W/O)
◦ b. Dilution of a water surfactant mixture with oil (O/W).
◦ c. mixing of all components at once. In some systems, the order of the ingredients
addition may determine whether a micro-emulsion forms or not.
2. phase-inversion Method
temperature range in which an O/W micro-emulsions inverts to a W/O type. Polyethylene are very unstable
with temperature. With increasing the temperature, the polyethylene group becomes dehydrated, altering
critical packing parameter which results in the phase inversion. For ionic surfactants: increasing
temperature, increase the electrostatic repulsion between the surfactant head groups thus causing reversal
of film curvature. Hence, the effect of temperature is opposite to the effect seen with non-ionic surfactants.
Applications:
1. Oral delivery system
2. Parenteral delivery system
3. Ophthalmic delivery system
4. Micro-emulsion in detergency
5. Micro-emulsions in cosmetics
6. Micro-emulsions in food
 MACRO-EMULSION

◦ They are kinetically stabilized mixtures of at least two immiscible liquids where one of the liquids has
droplets with a diameter greater than 0.1um. Macro-emulsions scatter light effectively and therefore
appear milky, because their droplets are greater than a wavelenght of light.
◦ This type of emulsion is thermodynamically unstable, but can be stabilized for a period of time with the
applications of kinetic energy.
◦ Surfactants(emulsifiers)
are used to reduce the interfacial between the two layers, and induce macro-emulsion
stability for a useful amount of time.
◦ Its stability are based on temperature, pH and the ionic strength of the solvent used.
◦ They are widely utilized today in automotive, beauty, cleaning and fabric care products as well as
biotechnology and in manufacturing.
 NANOEMULSION

◦ The term refers to a thermodynamically unstable dispersion of two immiscible liquids, such as oil and
water, stabilized by an interfacial film of surfactant molecules.

◦ The dispersed phase is typically of small particles or droplets, with a size range of 5 nm-200 nm, and has
very low oil/water interfacial tension.
◦ TYPES:
◦ 1. Nonionic (fatty alcohols, glycerol esters, fatty acid esters)
◦ 2. Anionic (contain carboxylate groups, soaps, sulfonates, divalent ions)
◦ 3. Cationic (Amines and quaternary ammonium compounds. Cetyl trimemethyl ammonium bromide.
◦ Advantages:
◦ 1. Increase the rate of absorption.
◦ 2. Eliminates variability in absorption.
◦ 3. Help solubilize lipophilic drug.
◦ 4. Provides aqueous dosage form for water insoluble drugs.
◦ 5. Increases bioavailability
◦ 6. Can be used in various routes like topical, oral and intravenous.
◦ 7. rapid and efficient penetration of the drug moiety provides protection from hydrolysis and oxidation as drug in oil phase
in O/W nanoemulsion is not exposed to attack by water and air.
◦ 8. liquid dosage form increases patient compliance.
◦ 9. less amount of energy required.
◦ 10. Can improve the efficacy of a drug, allowing the total dose to be reduced and minimizing side effects.
◦ Disadvantages:
◦ 1. The use of large concentration of surfactant and cosurfactant necessary for stabilizing the
nanodroplets. Limited solubilizing capacity for high melting substances.
◦ 2. Expensive
◦ 3. Nanoemulsion stability is influenced by environmental factors such as temperature and pH. These
factors change upon nanoemulsion delivery to patirnts.
◦ Factors to be considered in preparation of Nano-emulsions

◦ 1. surfactants must be carefully chosen so that an ultra low interfacial tension (<10-3mN/m) can be
attained at the oil/water interface which is a prime requirement to produce nano -emulsions.
◦ 2. concentration of surfactant must be high enough to provide the number of surfactant molecules needed
to stabilize the micro-droplets to be produced by an ultra low interfacial tension.
◦ 3. the interface must be flexible or fluid enough to promote the formation of nano-emulsions.
◦ METHODS OF PREPARATION
◦ 1. High pressure homogenization
◦ This method used a high very high pressure homogenizer/ piston homogenization to produce very small droplet
size up to 1 nm.

◦ 2. with the use of a microfluidizer, a device which uses a very high pressure positive displacement pump which
forces the product through interaction channel which contains “microchannels”.
◦ The product flows through a microchannel on to an impingement resulting in a very fine particle/ droplet size.
◦ The aqueous and oily phase are processed in an inline homogenizer to yield a coarse emulsion. The further it
proceed to microfluidizer to obtain a nanoemulsion.
◦ The coarse emulsion is passed through the interaction channel repeatedly to yield a desired size nanoemulsion.
◦ Applications:
◦ 1. Parenteral delivery (steroids, hormones, diuretics and antibiotics)
◦ 2. Topical delivery ( to avoid hepatic first pass metabolism of the drug and related toxicity effects). Use
for transdermal which aid the increase the permeability of the human stratum corneum, for cosmetics,
cancer therapy, vaccine therapy, prophylactic in bio-terrorism attack, I formulation of improved oral
delivery of poorly soluble drug, ocular and otic drug delivery,
◦ Intranasal drug delivery and pulmonary delivery.