Surfactant and polyphasic system

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Surfactant & polyphasic system
Department of Pharmacy (Pharmaceutics) | Sagar savale
Mr. Sagar Kishor Savale
[Department of Pharmacy (Pharmaceutics)]
2015-016
avengersagar16@gmail.com

Contents
1. Surfactant
1.1 Function
1.2 Classification
1.3 Physicochemical Background
1.4 HLB System
3. Oil
4. Phase Behavior
4.1 Ternary phase diagram
4.2 Pseudo Ternary Phase Diagram
5. Micelle
5.1 Micelle Formation
5.2 Kraft Point And Cloud Point
5.3 Types of Micelles
5.4 Effect of Micellization on Physical Properties
5.5 Factors Affecting CMC and Micellar Size
5.6 Stability of Micelle
5.7 Micellar Solubilization and Factors of Micelle Solubilization
5.8 Pharmaceutical Application of Micellar Solubilization
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6. Self-emulsifying drug delivery systems (SEDDS)
7. Self Micro-emulsifying Drug Delivery System (SMEDDS)
8. Multiple emulsion
9. Zeta potential
10. References
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Contents

Surfactant & polyphasic system
1. Surfactant
The molecules and ion are adsorbed at Interface kwon as Surfactant.
1.1 Function – To reduced interfacial tension , and surface tension.
Surfactant is a surface active agent which are used to prevent surface
tension and interfacial tension. It is important prevent interfacial fluidity,
it is amphiphilic molecule having Hydrophilic head and Lipophilic tail. It is
important for poorly water soluble drug and it is important to influencing
water solubility of poorly water soluble drug. It is important to prevent
the inter and intra subject variability.
It act as solubilizing agent, suspending and emulsifying agent, stabilizing
agent, wetting agent, detergent, Foaming agent.
It is important for preparation of Nanoemulsion, Nanosuspension,
Microemulsion.
It is important to show antibacterial as well as antimicrobial activity.
It is important for Novel drug delivery system, oral drug delivery system,
Targeted drug delivery system.
It is important to influencing oral bioavailability of poorly water soluble
drug.
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1.2 Classification
Surfactant molecules may be classified based on the nature of the hydrophilic group within the molecule. The four main
groups of surfactants are
defined as follows,
1. Anionic surfactants
2. Cationic surfactants
3. Ampholytic surfactants
4. Non ionic surfactants
1. Anionic Surfactants, where the hydrophilic group carries a negative charge such as carboxyl (RCOO-),sulphonate (RSO3-)
or sulphate (ROSO3-).
Examples: Potassium laurate, sodium lauryl sulphate.
2: Cationic surfactants, where the hydrophilic group carries a positive charge.
Example: quaternary ammonium halide.
3: Ampholytic surfactants (also called zwitterionic surfactants) contain both a negative and a positive charge.
Example: sulfobetaines.
4. Non ionic surfactants, where the hydrophilic group carries no charge but derives its water solubility from highly polar
groups such as hydroxyl or polyoxyethylene (OCH2CH2O).
Examples: Sorbitan esters (Spans), polysorbates (Tweens).
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1.3 Physicochemical Background
cohesive forces between molecules down into liquid
the intermolecular attractive forces is called surface tension cohesive forces between molecules down into liquid
the intermolecular attractive forces is called surface tension
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1.4 HLB System
1.HLB value – If high > more polar > more hydrophilic.
E.g. polyoxyethylene derivatives
2.HLB value- If low > less polar > more lipophilic.
E.g. sorbitan esters
Types of emulsion formation whether o/w or w/o depends on
the emulsifying agents used.
 O/W- HLB 9-12 – surfactant Soluble in water
 W/O – HLB 3-6 – surfactant Insoluble in water
The hydrophilic-lipophilic balance of a surfactant is a
measure of the degree to which it is hydrophilic or lipophilic,
determined by calculating values for the different regions of
the molecule, as described by Griffin in 1949[and
1954.[Other methods have been suggested, notably in 1957
by Davies.
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1. Griffin’s method
Griffin’s method for non-ionic surfactants as
described in
1954 works as follows:
HLB = 20 Mh/M
where Mh is the molecular mass of the
hydrophilic portion
of the molecule, and M is the molecular mass of
the whole molecule, giving a result on a scale of 0
to An HLB value of 0 corresponds to a completely
lipophilic/hydrophobic molecule, and a value of
20 corresponds to a completely
hydrophilic/lipophobic molecule.
The HLB value can be used to predict the
surfactant properties of a molecule:
< 10 : Lipid-soluble (water-insoluble)
> 10 : Water-soluble (lipid-insoluble)
1.5 to 3: anti-foaming agent.
3 to 6: W/O (water in oil) emulsifier.
7 to 9: wetting and spreading agent.
13 to 15: detergent.
12 to 16: O/W (oil in water) emulsifier.
15 to 18: solubilizers or hydrotropic.
2. Davies’ method
In 1957, Davies suggested a method based on calculating
a value based on the chemical groups of the molecule.
The advantage of this method is that it takes into account
the effect of stronger and weaker hydrophilic groups. The
method works as follows:
HLB = 7 +Σm
i=1 Hi n 0:475
where:
m - Number of hydrophilic groups in the molecule
Hi - Value of the i the hydrophilic groups (see tables)
n - Number of lipophilic groups in the molecule
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Aim of HLB Griffinˊs Scale
 Although the HLB approach is empirical, it does allow comparison between different chemical types of
surfactants.
 Besides that, it provides a systematic method of selecting mixtures of emulsifying agents to produce physically
stable emulsions.
 The higher surfactant HLB value, the more hydrophilic it is.
 The lower surfactant HLB value, the more lipophilic it is .
Determination of the Required HLB values and Blending of Surfactants
 Oils used in the formulation of emulsions require a certain HLB value to be formulated as w/o emulsion or o/w emulsion.
 For the same oil, the required HLB value for O/W emulsion is higher than the required HLB value for W/O emulsion.
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Calculation of the required HLB for a mixture of oils, fats or waxes
1. Multiply the required HLB of each ingredient by its fraction from the total oily phase.
2.Add the obtained values to get the total required HLB for the whole oily phase.
Example
Liquid paraffin 35%
Wool fat 1 %
Cetyl alcohol 1%
Emulsifier system 7%
Water to 100%
Solution
The total percentage of the oily phase is 37 and the proportion of each is:
Liquid paraffin 35/37 x 100 = 94.6%
Wool fat 1/37 x 100 = 2.7%
Cetyl alcohol 1/37 x 100 = 2.7%
The total required HLB number is obtained as follows:
Liquid paraffin (HLB 10.5) 94.6/100 X 10.5 = 9.93
Wool fat (HLB 10) 2.7/100 x 10 = 0.3
Cetyl alcohol (HLB 15) 2.7/100 X 15 = 0.4
Total required HLB = 10.6318-12-2015 11

Calculation of ratio of emulsifier to produce a particular required HLB value
 One of the most important aspects of the HLB system is that HLB values are additive if the amount of each in a blend is
taken into account. Thus, blends of high and low HLB surfactants can be used to obtain the required HLB of an oil.
 The HLB of the mixture of surfactants, consisting of fraction x of A and (1-x) of B is assumed to be the algebraic mean of
the two HLB numbers, i.e.:
HLB mixture = x HLBA + (1-x) HLBB
Rearrangement the above equation in percent (%) form will be
A = 100 (X-HLBB) / (HLBA – HLBB)
B = 100 – A
Where X is the required HLB of the surfactant (oil) mixture
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Worked example
A formulator is required to formulate an o/w emulsion of the basic formula:
Liquid paraffin 50 g
Emulsifying agents (required HLB 10.5) 5 g
Water to 100 g
Calculate the fraction of Tween 80 (HLB of 15) and Span 80 (HLB of 4.3) used to produce a physically stable liquid
paraffin emulsion.
Solution
Assume that Tween 80 is A and Span 80 is B. So,
A = 100 (x-HLBB) / (HLBA-HLBB)
= 100 (10.5-4.3) / (15-4.3)
= 57.9%
B = 100 – A
= 100- 57.9 = 42.1 %
A = 57.9 × 5100 = 2.89 g
B = 5 – 2.89 = 2.11 g
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For the production of an optimum SMEDDS, high concentration of surfactant is required in order to reduce interfacial tension
sufficiently, which can be harmful, so co-surfactants are used to reduce the concentration of surfactants. Co-surfactants
together with the surfactants provide the sufficient flexibility to interfacial film to take up different curvatures required to form
micro-emulsion over a wide range of composition. Selection of proper surfactant and co-surfactant is necessary for the
efficient design of SMEDDS and for the solubilization of drug in the SMEDDS.
generally co-surfactant of HLB value is used. such as hexanol, pentanol and octanol which are known to reduce the oil water
interface
3. Oil
The oil represents the most important excipient in the SMEDDS formulation. it can solubilize the amount of the poorly water
soluble drug. Both long-chain triglyceride (LCT) and medium chain triglyceride (MCT) oils with different degrees of saturation
have been used in the design of SMEDDS.
It can not only solubilize large amount of lipophilic drugs or facilitate self-emulsification but also enhance the fraction of
lipophilic drug transported via intestinal lymphatic system, there by increase its absorption from GIT.
E.g. - Corn oil, olive oil, soybean oil, hydrolysed corn oil.
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Examples
Oil Phase
• Isopropyl Myristate
• Oleic acid
• Olive oil
• Mineral oil
• Medium chain triglyceride
• Soyabean oil
• Captex 355
• Isopropyl Palmitate
• Sunflower oil
• Safflower oil
Surfactant
• Tween 80
• Tween 40
• Span 40
• Labrafil M1944CS
• Polyoxyethylene-35-ricinoleate
• Brij 58
• CremophorEL
• Lecithin
Co-surfactant
• Propylene glycol
• Ethylene glycol
• Ethanol
• 1-butanol
• Isopropyl alcohol
• PEG 600
• Glycerol
• PEG 400
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4. Phase Behavior
4.1 Ternary phase diagram
WINSOR PHASE :- WI , WII , WIII ,
WIV
O :- Oil W:- Water
 L1:- A single phase region of normal
micelles or oil in water micro
emulsion.
L2:- A reverse micelles or water in oil
micro emulsion.
D :- Anisotropic lamellar liquid
crystalline phase
μE:- Microemulsion.
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 In this diagram a corner will represent the binary mixture of two components such as surfactant/co-
surfactant, water/drug or oil/drug.
 At low concentration of surfactant there are certain phases exists in equilibrium. These phases are
referred to as WINSOR PHASES .
 WINSOR-1 :- With two phases, the lower (o/w) microemulsion phase in equilibrium with excess oil.
 WINSOR-2 :- With two phases, upper (w/o) microemulsion phase in equilibrium with excess water.
 WINSOR-3 :- With three phases, middle microemulsion phase (o/w plus w/o, called bio-continuous) in equilibrium
with upper excess oil and lower excess water.
 WINSOR-4 :- In single phase, with oil, water, and surfactant homogenously mixed.
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4.2 Pseudo Ternary Phase Diagram
These diagrams were constructed with
oil, surfactant/co-surfactant and water
using Phase Titration method. The
procedure consisted of preparing
solutions Containing oil and the
different ratio of surfactant to co-
surfactant by weight such as: 1:1, 2;1,
3:1 etc, these solutions then vortexed for
5 min and isotropic mixture was
obtained. observed for their appearance
(turbid or clear). Turbidity of the
samples would indicate formation of a
coarse emulsion, whereas a clear
isotropic solution would indicate the
formation of a microemulsion.
Percentage of oil, smix and water. the
values were used to prepare Pseudo
ternary phase diagram.
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5. Micelle
Definition
The aggregation of monomers i.e. SAA in given solvent at particular temp. is known as MICELLE. Each micelle may contains
around 50 or more monomers in its structure and size may be about 50 A°. This 50 A° size is falls into colloidal range and hence
micelle called alternatively as Association colloids.
Critical Micelle Concentration
The concentration of monomer at which the micelles are start to form in solvent at particular temperature. Micelles form only
when the concentration of surfactant is greater than the critical micelle concentration (CMC). The no. of monomers that
aggregate to form micelle is known as Aggregation No. of micelle.
The Lowest concentration of surfactant at which micelle is from is known as CMC.
5.1 Micelle Formation
1. The process of formation of micelle is known as micellization.
2. Below CMC, the conc. of SAA adsorbed at interface of air and liquid and the exist individually. As the conc of SAA is incresed
the monomers gets saturated at surface, further addition leads saturation of bulk of solution.
3. After saturation of surface and bulk of solution, the monomers start to aggregate at this level the conc of SAA is reached to
CMC.
4. Further addition enhance the process of micelle formation.
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Fig-Process of Formation of Micelles
Micelle are not stable aggregate but dissociate ,regroup and reassocaiate. For e.g.-half life of Ionic surfactants is only a small
fraction of second.
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5.2 Kraft Point And Cloud Point
Kraft Point
1. The solubility of SAA depends on the temp. of system and adequate conc. of SAA is required to form micelle, this
relationship is stated by Kraft Pt.
2. Kt is defined as the temp at which the solubility of surfactants is equal to CMC.
3. At Kt, conc. of surfactants is sufficient to form micelle.
4. It is seen that micelles are more soluble in water than monomers.
Cloud Point
At a particular temp and pressure the solubilized micelles gets separated out as a distinct phase which leads to appearance of
cloudy solution, this is known as cloud pt.
Procedure for determination of Cloud Point and Kraft point
Prepare 100 ml of 1 to 10 % aqueous solution containing nonionic surfactant (Triton X-45).
 Take 10 ml above solution in a test tube and either heat or cool with a temperature range of 0.5 to 1 ◦C in every time. Stabilize
the solution for 2 minutes to achieve thermal equilibrium.
Continue the process of either heating or cooling till you observe cloudiness or turbidity.
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Cloud point (Cp) is determined visually by noting the temperature at which turbidity is observed or disappeared. The average
of the temperatures of appearance and disappearance of turbidity is taken as the cloud point.
While for an aqueous solution containing dispersible nonionic surfactant, such as dispersible Triton X-45 in water under room
temperature, only the temperature of cloudy disappearance is taken as Kraft point.
Applications/Significance/Importance of Cloud point (Cp):
 Knowing the cloud point helps us to determine the storage stability since storing formulations at temperatures
significantly higher than the cloud point may result in phase separation and instability.
 The cloud point of petroleum products and biodiesel fuels is an index of the lowest temperature of their utility for certain
applications. Wax crystals of sufficient quantity can plug filters used in some fuel systems.
 For low-foam applications, the cloud point of the product should be just below the use temperature.
 Cloud point extraction is used for determination of pyrene in natural water.
 For determining of the Nickel and Zinc through the cloud point preconcentration.
 For finding out the lead from the water samples by using cloud point extraction flow injection-atomic absorption.
Applications/Significance/Importance of Kraft point (Kt):
Below Kraft point, mere increase in the concentration of the surfactant, micelle formation does not occur. Below the Kraft point,
an increase in the concentration of the surfactant leads to precipitation rather than micelle formation in the form of
insoluble mass.
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The solubility of the surfactant goes on increasing with increase in temperature, however, above the Kraft point; there is
the sudden increase in the solubility of the surfactant. This gives break in the plot of the solubility of the surfactant Vs
temperature. The temperature corresponding to the break is the Kraft temperature or point. It may be mentioned here that the
Kraft point varies with the pH of the solution as well as the ionic strength of the solution.
5.3 TYPES OF MICELLES
1. Spherical Micelle- In this type the Hydrophobic Tails oriented towards inner core and Hydrophilic heads towards polar
solvents. Ex. - Micelle in water
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2. Reverse Micelle - In this case Hydrophobic tails oriented towards non-polar solvent phase and head portion towards the
inner core Ex. - micelle formation in oil and water.
3. Laminar Micelle - Spherical and laminar micelle are inter convertible. In this type of micelle arrangement of monomer is in
a laminar manner.
Laminar micelle form at higher conc., initially micelles are of spherical type, but as conc. increases towards higher side leads
to formation of Laminar micelle.
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Polymeric Micelle
 Chemicals which have an amphiphilic nature (hydrophilic and hydrophobic portions) inherently have the capacity to form
micelles in aqueous solution. Micelles are generated when the hydrophobic portions are driven to an interior structure
while hydrophilic portions are turned outward facing toward the water.
 Most PolyVivo block copolymer products are inherently amphiphilic as they contain both hydrophobic polyester blocks
(PL) and hydrophilic poly(ethylene glycol) blocks (PEG).
5.4 Effect of Micellization on Physical Properties
1. Surface Tension - Below CMC the S.T decreases by Surfactant, however above CMC the further addition of surfactants
doesn’t affect S.T reduction.
2. Interfacial Tension - Similarly interfacial tension markly reduce below CMC but no affecting the I.T above CMC.
3. Equivalent Conductivity - is slightly decreased unto CMC and above it rapidly reduced to 0 value.
4. Solubility enhancement of poorly Water soluble drugs-below CMC there is little increased in solubility, but above CMC
there is rapidly increased in solubility of poorly water soluble drugs.
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1. At very low concentrations of
surfactant only slight change in
surface tension is detected.
2. Additional
surfactant decreases
surface tension
3.Surface becomes fully
loaded, no further change in
surface tension.
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5.5 Factors Affecting CMC and Micellar Size
 Structure of hydrophobic group: Increase in hydrocarbon chain length causes decrease in CMC and increase in
micellar size.
 Nature of hydrophilic group: Increase in chain length increases hydrophilicity and CMC.
 Nature of counter ions: The counter ions associated with charged group of ionic surfactants has a significant effect on
micellar properties.
Cationic surfactants - counter ion like Cl-
, Br-
leads to increase in micellar size.
Anionic surfactants – Na+
, k+
leads to increase in micellar size.
 Addition of electrolyte: Addition of electrolytes to ionic surfactants decreases CMC and increases the micellar size. This
is due to reduction in repulsion between charged head group of micelle.
 Addition of non-electrolyte: Addition of compounds like water soluble raises the CMC and decreases micelle formation.
 Effect of temperature: Mainly micelles of nonionic surfactants are get affected. As an increase in temperature up to cloud
point, an increase in micellar size and a decrease in CMC.
5.6 Stability of Micelle
 When dilute solution to below the CMC, some ionic micelles shown to have half-life of a centisecond or less.
 Micelle stability is slightly increased by an increase in alkyl chain length and affected small extent by the nature of the
counter-ion. Traces of hydrocarbon dissolved in the micelle interior appear to reduce the rate of micelle breakdown.
 Micelle stability increases with increasing concentration of amphipath above the CMC but decreases with increasing
temperature.

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5.7 Micellar Solubilization and Factors of Micelle Solubilization
 Micelles can be used to increase the solubility of materials that are insoluble or poorly soluble in the dispersion medium used.
 This phenomenon is known as Solubilization.
 The solubilized substance is referred to the solubilizate.
1. Nature of Surfactant: If solubilizate is located within the core or deep within micelle − solubilization capacity increases
with increase in alkyl chain length. E.g. Barbiturates: Polysorbate 20 (C12) to Polysorbate 80 (C18)
2. Nature of Solubilizate: Non polar solubilizate are dissolved in micellar core and polar solubilizate orient themselves
towards the surface of micelles. Hydrophobic drugs solubilized in micelle core, as an increase in Lipophilic chain length
of surfactant and as the length increases, there is increase in micellar size and increases entry of drug into micelle.
3. Effect of temperature: In general, the amount of solubilized increase with a rise in temperature. E.g. Increase in
solubilization of Griseofulvin by surfactant like sodium cholate, sodium deoxycholate.
4. Effect of pH: Main effect of pH on solubilizing power of nonionic surfactants is to alter the equilibrium between ionized
and un-ionized drugs. E.g. for simple molecule, the unionized form is more solubilized.
5.8 Pharmaceutical Application of Micellar Solubilization
 Phenolic compounds, such as chloroxylenol, cresol are solubilized with soap to form clear solutions for use as
disinfectants.
 Solubility of steroids is increased using the polysorbates for ophthalmic formulations.
 Aqueous injections of water-insoluble vitamins like A, D, E and K are prepared using nonionic surfactants like
polysorbates.
 Nonionic surfactants are also efficient solubilizers of iodine.
 Polymeric micelle is used to target the cancerous tumor site.

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6. Self-emulsifying drug delivery systems (SEDDS)
 Self-emulsifying drug delivery systems (SEDDS) are defined as isotropic mixtures of oils and surfactant.
 SEDDS are solid dosage form with a unique properties that is they are able to self emulsifying rapidly into fine of o/w
emulsion result in small droplet of oil dispersed in GI fluid that provide a large interfacial area enhancing the activity and
minimizing the irritation .
6.1 Advantage
 Enhanced oral bioavailability
 Selective targeting of drug(s) toward specific absorption in GIT.
 Protection of drug(s) from the hostile environment .
 Reduced variability including food effects.
 Protective of sensitive drug substances.

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6.2 Drawback SEDDS
 Lack of good predicative in vitro models for assessment of the formulations.
 The large quantity of surfactant use in self-emulsifying formulations (30-60%) irritates
 Volatile co-solvents can migrate on capsule shell.
6.3 Components of SEDDSs
1. Drug (API)
2. Surfactant
3. Oil [Reference of data slide no. 4 to 15]
6.4 Mechanism of self emulsification
 The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between
the oil and water phases
 In emulsification process the free energy (∆G) associated is given by the equation:

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6.5 General formulation Approach
 Preliminary solubility profiling studies are performed for selection of oil.
 Drug excipient compatibility studies.
 Preparation of a series of SEDDS system containing drug in various oil and surfactant with different combinations.
 Optimization of formulation on the basis of in vitro self-emulsification properties, droplet size analysis, stability studies,
robustness to dilution upon addition to water under mild agitation conditions.
6.7 Evaluation of SEDDS
 Dispersibility test
 Turbidimetric Evaluation
 Viscosity Determination
 Droplet Size Analysis and Particle
 size measurement
 Electro Conductivity Study
 Drug Content

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6.8 Application
Self‐emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous
solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially
improve oral bioavailability. With future development of this technology, SEDDSs will continue to enable novel applications in
drug delivery and solve problems associated with the delivery of poorly soluble drugs.
7. Self Micro-emulsifying Drug Delivery System (SMEDDS)
 SMEDDS is an isotropic mixture of oil, surfactant, Cosurfactant and drug.
 Upon mild agitation followed by dilution in aqueous media, such as gastrointestinal (GI) fluids, the systems can form
fine oil in water (O/W) Microemulsions which usually have a droplet size less than 100 nm.
 Self-microemulsifying drug delivery systems (SMEDDS) have been successfully used to improve the solubility,
chemical stability, and oral bioavailability of many poorly water soluble drugs.
 They have characteristic properties such as a low interfacial tension, large interfacial area and capacity to solubilize
both aqueous and oil-soluble compounds.

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7.1 History
The Microemulsion concept was introduced as early as 1940s by Hoar and Schulman who generated a clear single-phase
solution by titrating a milky emulsion with hexanol. Schulman and co-worker (1959) subsequently coined the term
microemulsion The Microemulsion definition provided by Danielson and Lindman in 1981 will be used as the point of
reference.
7.2 Difference between SEDDS And SMEDDS
Sr.no. SEDDS SMEDDS
1 It is a mixture of Oil, Surfactant and
Drug
It is a mixture of Oil, Surfactant, Co-
surfactant and Drug
2 Droplet size is 100 – 300 nm Droplet size is less than 100 nm
3 It is a Turbid in nature It is Transparent in nature
4 It is Thermodynamically not Stable It is Thermodynamically Stable
5 Ternary Phase Diagrams are used to
optimized
Pseudo Ternary Phase Diagrams are used
to optimized

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7.3 Advantages
 Enhanced oral bioavailability and stability of drugs which show low bioavailability.
 Reduction of inter-subject and intra subject variation.
 Ease of manufacturing and scale up.
 Less amount of energy requirement.
 Ability to deliver peptides that are prone to Enzymatic hydrolysis in GIT.
 SMEDDS are used for both liquid and solid dosage forms.
 Useful in topical application.
7.4 Disadvantages
 One of the obstacles for the development of SMEDDS is the lack of good predicative in vitro models for assessment of the
formulations and Traditional dissolution methods do not work.
 The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in formulations.
7.5 Components of SMEDDS
1. Drug (API)
2. Surfactant
3. Oil
4. Co-surfactant
5. Co-solvent [Reference of data slide no. 4 to 15]

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7.6 Preparation of SMEDDS
 Drug has to dissolve in to oil phase (lipophilic part) of microemulsion.
 Water phase is combined with the surfactant and then Cosurfactant is added slowly with constant stirring until the
system is become transparent.
 The amount of surfactant and co-surfactant to be added and the parent oil phase that can be incorporated is
determined with the help of pseudo ternary phase diagram.
7.8 Mechanism of SMEDDS
 Self-Microemulsification occurs when the entropy change that favours dispersion is greater than the energy required
to increase the surface area of the dispersion. So, The free energy of the conventional emulsion is a direct function of
the energy required to create a new surface between the oil and water phases.
 In emulsification process the free energy (∆G) associated is given by the equation:
where,
∆G = free energy associated with the process
N = number of droplets
r = Radius of droplets
б = interfacial energy
The two phases of emulsion tend to separate with time to reduce the interfacial area, and subsequently, the emulsion is
stabilized by emulsifying agents.

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7.9 Evaluations of SMEDDS
 Scattering Technique
 Fourier transform-infrared spectroscopy (FT-IR)
 Transmittance (U.V.)
 Viscosity Determination
 Electro Conductivity Study
 Macroscopic evaluation
 Differential scanning Colariometry (DSC)
 Droplet Size Analysis and Particle Size Measurements
 Stability Testing Evaluation
7.10 Applications of SMEDDS
 Oral bioavailability enhancement poorly water soluble drugs
 Protection against Biodegradation
 Solid SMEDDS
 Supersaturable (S-SMEDDS)
 Ocular Drug delivery System
 Parenteral Drug Delivery System
 Topical Drug Delivery

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8. Multiple emulsion
8.1 Introduction
Emulsion - it is a biphasic liquid dosage from of medicament in which two immiscible phases of liquid one can dispersed in
finite globules in another liquid phase is known as Emulsion.
Multiple Emulsion – it is biphasic liquid dosage from of medicament in which two or more and more than two immiscible
phases of liquid one can dispersed in finite globules in another liquid phase is known as Multi emulsion. It is a Emulsion of
emulsion, double or triple emulsion” Dispersed phase contain smaller droplets that have the same composition as the external
phase. Liquid film which separate the liquid phases acts as a thin semi permeable film through which solute must diffuse in
order to travel from one phase to another Liquid Membrane System.
8.2 Types
There are divided in two types
1. Oil-in-water-in-oil (O/W/O) emulsion system.
2. Water-in-oil-in-water (W/O/W) emulsion system.

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8.3 Methods of preparation
Either by the re-emulsification of a primary emulsion or they can be produced when an emulsion inverts from one type to another.
1. Two Step Emulsification (Double Emulsification)
2. Phase Inversion Technique (One Step Technique)
3. Membrane Emulsification Technique
Two Step Emulsification: - (Double Emulsification)

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Membrane Emulsification Technique

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8.4 characterization
 Average globule size & size distribution
 Area of interfaces
 Rheological evaluation
 Percent drug entrapment
8.5 Stability of Multiple Emulsion
 Depending upon equilibrium between water, oil and surfactant.
 Unfortunately multiple emulsion are thermodynamically unstable.
 Possible indication of instability include:
1. Leakage of the contents from the inner aqueous phases
2. Rupture of oil layer on the surface of the internal droplet i. e. expulsion of internal droplet in external phase.
3. Shrinkage and swelling of the internal drops due to osmotic gradient across the oil membrane
4. Phase separation

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8.6 Methods to stabilize multiple emulsion
A. Liquid crystal stabilized multiple emulsion
B. Stabilization in the presence of electrolytes
C. Stabilization by forming polymeric gel
A B C

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8.7 Application
 Controlled and Sustained Drug Delivery
 Drug Targeting
 Vaccine Adjuvant
 Cosmetics preparation
 Taste masking of the drug

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9. Zeta potential
 Zeta potential is a scientific term for electro kinetic potential in colloidal dispersions.
 It is usually denoted using the Greek letter zeta (ζ), hence ζ - potential.
 The electric potential at the boundary of the double layer is known as the Zeta potential of the this particles
and has values that typically range from +100 mV to -100 mV.
 Zeta potential: It is the potential observed at the shear plane.
 Zeta potential or electro-kinetic potential is defined as the difference in the potential between shear plane and
electro-neutral region of lotion the solution.
 Zeta potential is more important than Nernst potential because the electrical double layer also moves, when the
particle is under motion.

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Nernst potential: It is the potential of the solid surface itself owing to the presence of potential determining ions.
Nernst potential or electro thermodynamic potential is defined as the difference in potential between the actual
surface and the electro neutral region of the solution.

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9.1 Factors affecting zeta potential
 pH : In aqueous media, the pH of the sample is one of the most important factors that affects its zeta potential. zeta
potential versus pH curve will be positive at low pH and negative at high pH. There may be a point where the plot passes
through zero zeta potential. This point is called isoelectric point and is very important from a practical consideration.
 Thickness of double layer: The thickness of the double layer depends upon the concentration of ions in solution and can
be calculated from the ionic strength of the medium The higher the ionic strength, the more compressed the double layer
becomes. The valiancy of the ions will also influence double layer thickness.

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9.2 Zeta Potential Measurement
Zeta potential is not directly measurable, it can be calculated using theoretical models like electro kinetic
phenomena and electroacoustic phenomena.
1. Electro kinetic Phenomena:
a. Electrophoresis:
The movement of charged particle relative to the liquid it is suspended in under the influence of an electric field.
Zeta potential of dispersion is measured by applying an electric field across the dispersion. Particles within the
dispersion with a zeta potential will migrate towards the electrode of opposite charge with a velocity proportional to
the magnitude of the zeta potential.
The velocity of a particle in a unit electric field is referred to as its electrophoretic mobility. Zeta potential is related
to the electrophoretic mobility by the Henry equation

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9.3 Henry equation
UE = 2 ε z f(κa)/3η
Where:
UE = electrophoretic mobility,
z = zeta potential,
ε = dielectric constant,
η = viscosity
f(κa) = Henry’s function.

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2. Electroacoustic phenomena: The electroacoustic technique characterizes the dynamic mobility of particles in
colloidal systems.
 In this method, a high frequency electric field is applied to the samples, causing charged particles to oscillate
and to produce a sound wave of the same frequency.
 The oscillation (dynamic mobility) of the particles is described by its magnitude and phase angle. The sound
wave is detected and analyzed to determine the motion of the particles.
9.4 DLVO Theory
 The scientists Derjaguin, Landau, Verwey and Overbeek developed a theory in the 1940s which dealt with the
stability of colloidal systems.
 DVLO theory suggests that, the stability of a colloidal system is determined by the sum of the vander Waals
attractive (VA) and electrical double layer repulsive (VR) forces that exist between particles as they approach
each other due to the Brownian motion they are undergoing.
 The vander waal forces depend on chemical nature and size of particle. The electrostatic repulsive forces
depend on density, surface charge and thickness of double layer.

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9.5 Methods for stabilizing colloids
1. Stability can be obtained by surrounding colloidal particle with:
2. An electrical double layer (electrostatic or charge stabilization).
3. Adsorbed or chemically attached polymeric molecules (steric stabilization).
9.6 Application
 Flocculate
 Suspension
 Emulsion
 Ceramics
 Waste water

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 C.V.S Subhramanyam, A textbook of Physical pharmaceutics, Vallabh Prakashan, Second Edition, 2000, page no-326 to 330.
 Remington, The Science And practice of pharmacy, 19th Edition, volume first,1995, page no-176,273.
 Alfred Martin,James swarbrick,Arthur Cammarata et.al,Varghese publishing House, 3rd edition,1992,page no-457,473.
 M.E. Aulton, Pharmaceutics science of dosage form design, 2nd Edition, p. 88-89
 Leon Lachman, The Theory and Practice of Industrial Pharmacy, 3rd edition, p. 106
 H.A. Liebereman, M.M. Rieger, G.S. Banker, Pharmaceutical Dosage Forms: Disperse Systems,2nd Edition, Vol.3, p. 216-220
 Sanjay K. Jain, Vandana Soni, Benley’s Text Book of Pharmaceutics, p.68-74
 Ram I. Mahato Pharmaceutical Dosage Forms and Drug Delivery,CRC press pharmacy education series, p.111-119
 Nita K. Pandit & Robert R. Soltis, Introduction to the Pharmacetical Sciences 2nd Edition, p.54-55
 Swarbrick James, Boylan James C. ”Encyclopedia of Pharmaceutical Technology”, 2nd ed. (2002), Marcel Dekker, U.S.A,
pp.2639-2644.
 Mahato Ram I. “Pharmaceutical Dosage Forms and Drug Delivery” (2007), CRC Press, Taylor and Francis Group, pp. 107-
119.
10. References

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 Patel PA, Chaulang GM, Akolkotkar A, Mutha SS, Handicap SR and Bhosale AV. “Self Emulsifying Drug Delivery System:
A Review” Research J. Pharm. And Tech. 2008; 1(4): 313-323.
 T. Gershanik and S. Benita, "Positively-charged self-emulsifying oil formulation for improving oral bioavailability of
progesterone," Pharm. Dev. Technol. 1, 147–157 (1996).
 Vyas S.P. and Khar R.K., Targeted and controlled Drug Delivery, Novel Carrier System, CBS Publishers and Distributers
PVT. Ltd., New Delhi,First Edition, 2002, P.P.280-303.
 Weiner M,B ernstin IL Advance Reaction to drug formulation Agents. New York; Marcel Dekker, Inc, 1989
 Kawakami, K. and Yoshikawa, T. Microemulsion formulation for enhanced absorption of poorly soluble drug I Prescription
design. Journal of Controlled Release; 2002; 81; 65-74.
 Lawrence, M. J. and Rees, G. D. Microemulsion-based media as novel drug delivery systems. Adv. Drug Delivery Rev.;
2000; 45; 89-121.
 Nishad Deshmukh, Vesicular and Particulate Drug Delivery Systems, CAREER Publications, First Edition March 2010,
P.P.105-140.
 Kumar, P. and Mital, K. L. Handbook of microemulsion:Science and Technology. Marcel Dekker, New York, Basel; 1999.
 Ozawa, K.; Olsson, U. and Cawes, A. Oil-induced structural change in nonionic microemulsions. Journal of Dispersion
Science and Technology; 1986; 22(1); 119-124.
 Kanchan Kohali, Sunny Chopra ,Deepika Dhar , Saurabh Arora ; Self-Emulsifying Drug Delivery Systems: An Approach To
Enhance Oral Bioavailability. J Drug Discovery Today : 2010; 15;960.
 L.chia li,Y.tian,(2012) Encyclopedia of Pharmacetical Technology. 2nd edition.Volume-3.Marcel Dekk Series,page.no.3020-
3031.
 Malvern (2010) User Manual of Zetasizer Nano. MANO317-5.0, United Kingdom,Page.No.15.1-15.12

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