It represents the microemulsion as a drug delivery system.

1. MICROEMULSION
Guided By:
Dr. Tejal Mehta,
Head of Department,
Pharmaceutical Technology & Biopharmaceutics
Prepared By:
Ishani Pandit,
M.Pharm, Sem -1,
Pharmaceutical Technology & Biopharmaceutics
14MPH109.

2. Content:
11/21/2014
2
 Introduction
 History
 Basic aspects of Microemulsion
 Theories of Microemulsion
 Phase behaviour of Microemulsion
 Components of Microemulsion
 Types of Microemulsiom
 Preparation of Microemulsion
 Characterization of Microemulsion
 Advantages, disadvantages & Applications
 Evaluation of Microemulsion
 Marketed Preparations
 conclusion

3. Introduction
 Microemulsions are thermodynamically stable, optically
transparent isotropic mixtures of a biphasic o/w system stabilized
with surfactants.
 The diameter of droplets in microemulsion may be in the range of
100Å to1000Å.
 Microemulsions can have characteristic properties such as ultralow
interfacial tension, large interfacial area and capacity to solubilize
both aqueous and oil-soluble compounds.
11/21/2014
3

4. Continue…
“Microemulsions are dispersions of nanometer-sized droplets of
an immiscible liquid within another liquid. Droplet formation is
facilitated by the addition of surfactants and often also co
surfactants.”
And they can be known as Modern colloidal drug delivery system.
11/21/2014
4

5. 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.
11/21/2014
5

6. Basic aspects of Microemulsion
 Microemulsion are fluid, transparent, thermodynamically stable oil
and water system and stabilized by a surfactant usually in
conjunction with co-surfactant.
 This includes normal micelles, revers micelles, cores and droplets of
water or oil and for some system like bi-continuous structure
neither oil nor water surrounds each other.
11/21/2014
6

7.  If a co-surfactant is used, it may sometimes be represented at a
fixed ratio to surfactant as a single component, and treated as a
single “pseudo-component”.
11/21/2014
7

8. Comparison between Emulsion &
microemulsion
EMULSION
 Thermodynamically unstable.
 In due time phases it is separate out.
 It is cloudy.
 Require large input of energy during its
preparation. higher cost.
 Droplet size > 500 nm
 Interfacial tension: high
 High viscosity
 Stable microstructure
MICROEMULSION
 Thermodynamically stable.
 In due time phases it is not separate out.
 It is transparent.
 Require low input of energy during its
preparation. relatively low cost.
 Droplet size 20-200 nm
 Interfacial tension: ultra low
 Low viscosity with Newtonian behavior.
 Dynamic (constantly fluctuating
interface)
11/21/2014
8

9. 11/21/2014
9

10. 11/21/2014
10

11. 11/21/2014
11

12. Theory of Microemulsion
 The understanding of basis for thermodynamic stability of
of microemulsion several thermodynamic theories are
proposed.
 In 1975, Ruckenstein and Chi considered the free energy formation
of microemulsion to be consisted of three contributions :
 Interfacial energy,
 Energy of interaction b/w droplets,
 Entropy of dispersion.
11/21/2014
12

13. Continue…
 The free energy of microemulsion formation can be considered to
depend on the extent to which surfactant lowers the surface
tension of oil-water interface and the change in entropy of the
system such that :
ΔGf = γ ΔA – T ΔS
 ΔGf = Free energy formation.
 γ = Surface tension of oil-water interface.
 ΔA = Change in interfacial area on microemulsion.
 ΔS = Change in entropy of system.
 T = Temperature.
11/21/2014
13

14. Phase Behaviour of Microemulsion
 The phase behaviour of simple microemulsion system composing
oil, water and surfactant can be studied with the aid of ternary
phase diagram.
11/21/2014
14

15. Continue…
11/21/2014
15

16. Continue…
 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 lameller liquid crystalline phase.
 μE:- Microemulsion.
11/21/2014
16

17. Continue…
 The co-surfactant is also amphiphilic with an affinity for both the oil
and aqueous phase.
 Eg. Alkyl amine, alkanoic acid, alkanoids, non ionic surfactant,
alcohol.
 A large no. of drug molecules are also acts as surface active agent
by themselves, which influence the phase behaviour.
 In this diagram a corner will represent the binary mixture of two
components such as surfactant/co-sufactant, water/drug or
oil/drug.
 At low concentration of surfactant there are certain phases exists in
equilibrium. These phases are refered to as WINSOR PHASES.
11/21/2014
17

18. Continue…
A. WINSOR-1 :- With two phases, the lower (o/w) microemulsion
phase in equilibrium with excess oil.
B. WINSOR-2 :- With two phases, upper (w/o) microemulsion phase
in equilibrium with excess water.
C. 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.
D. WINSOR-4 :- In single phase, with oil, water, and surfactant
homogenously mixed.
11/21/2014
18

19. Components of Microemulsion
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
11/21/2014
19

20. Oil Component
 As compare to long chain alkanes, short chain oil penetrate the tail
group region to a greater extent and resulting in increased negative
curvature (and reduced effective HLB).
 Following are the different oil are mainly used for the formulation
of microemulsion:
1. Saturated fatty acid-lauric acid, myristic acid,capric acid
2. Unsaturated fatty acid-oleic acid, linoleic acid,linolenic acid
3. Fatty acid ester-ethyl or methyl esters of lauric, myristic and oleic
acid. 11/21/2014
20

21. Continue…
 The main criterion for the selection of oil is that the drug should
have high solubility in it.
 This will minimize the volume of the formulation to deliver the
therapeutic dose of the drug in an encapsulated form.
11/21/2014
21

22. Surfactants
 It is to lower the interfacial tension which will ultimately facilitates
dispersion process and provide a flexible around the droplets.
 Generally, low HLB (3-6) surfactants are suitable for w/o
microemulsion, whereas high HLB (8-18) are suitable for o/w
microemulsion.
11/21/2014
22

23. Co-surfactants
 They allow the interfacial film sufficient flexible to take up different
curvatures required to form microemulsion over a wide range of
composition.
1. Short to medium chain length alcohols (C3-C8) reduce the
interfacial tension and increase the fluidity of the interface.
2. Surfactant having HLB greater than 20 often require the presence
of co-surfactant to reduce their effective HLB to a value within the
range required for microemulsion formulation.
11/21/2014
23

24. Continue…
a) By reducing the interfacial tension
b) By increasing the flexibility and fluidity of the interface by
positioning itself between the surfactant tails which alters the solvent
properties of both the dispersed and continuous microemulsion
phases;
c) By lowering overall viscosity.
d) By being often soluble in both organic and aqueous phases, co-surfactants
help solubilise poorlysoluble compounds (e.g., peptides,
vitames)
11/21/2014
24

25. Types of Microemulsiom
 O/W Microemulsion
 W/O Microemulsion
 Bi continuous Microemulsion
11/21/2014
25

26. Preparation of Microemulsion
 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.
 Ultrasonicator can finally used to achieve the desired range for the
dispersed phase.
 It is then allow to equilibrate.
11/21/2014
26

27. Continue…
 Gel may be prepared by the addition of the gelling agent to above
microemulsion.
Eg. :- Carbomers – Cross linked polyacrylic acid
polymers.
Xanthan gum
Carbomers are widely used as gelling agents.
11/21/2014
27

28.  Figure shows the pseudo-ternary phase diagram with the area inside the frame
assigned on the phase diagram showing the micro-emulsion region. The area
outside the frame indicates a turbid region with multiphase systems. It could be
noted that the area of micro-emulsion region was considerably large since 1-
butanol acted as a co-surfactant and interacted with the surfactant monolayer to
increase the flexibility of the interfacial film.
11/21/2014
28

29. 11/21/2014
29
Phase
Behaviour
Studies
Characterization
Scattering
Technique
Nuclear
Magnetic
Resonance
Studies
Electron
Microscopic
studies
Viscosity
Measurement
Interfacial
Tension,
Electric
Conductivity

30. 1. Phase Behaviour Studies
 This study is very much essential for the determination of
surfactant by using phase diagram which provide information on
the boundaries of the different phases as the function of
composition variables and temperature and more important
structural organization can also be inferred.
 Phase behaviour studies also allow comparison of the efficiency of
the different surfactant for given application.
 In this study, the temperature and pressure remain fixed.
11/21/2014
30

31. 2. Scattering Technique
 In this technique Small Angle X-ray Scattering(SAXS), Small Angle Neutron
Scattering(SANS) and static as well as dynamic light scattering are widely
applied technique in the study of microemulsion.
 In this technique, the intensity of scattered radiation I(q) is maesured as
a function of scattering vector q,
q = (4π/λ) sin θ/2
θ = Scattering Angle.
λ = Wavelength of Radiation.
 Small Angle X-ray Scattering technique and Static Light Scattering
techniques both are used to determine the microemulsion droplet size
and shape.
 Dynamic Light Scattering is used to analyse the fluctuation in the
intensity of scattering by droplets due to Brownian motion.
11/21/2014
31

32. 3. Nuclear Magnetic Resonance Studies
 The structure and dynamics of micro emulsion can be studied by
using nuclear magnetic resonance techniques.
 Self diffusion measurements using different tracer technique
generally radio labeling. Supply information on the mobility of the
components.
11/21/2014
32

33. 4. Electron Microscopic Studies
 Microemulsion has been characterised by some electro
microscopic techniques although the high lability of the sample and
the possibilities of artifacts electron microscopy used to be
considered a misleading techniques in microemulsion studies.
11/21/2014
33

34. 5. . INTERFACIAL TENSION, ELECTRICAL
CONDUCTIVITY AND VISCOSITY MEASUREMENTS
 Formation and properties of micro emulsion can be studied by the
measuring of Interfacial Tension. Ultra low values of Interfacial
Tension are correleated with phase behaviour, particularly the
existance of surfactant phase or middle phase micro emulsion in
equilibrium with aqueous and oil phase.
 To determine the nature of the continuous phase and to detect
phase inversion phenomena the electrical conductivity
measurement are highly useful.
 Viscosity measurements can indicates the presence of rod like or
warm like reverse micelles. It is used to determine the
hydrodynamic radius of droplets, as well as interaction b/w droplets
and deviations from spherical shape by fitting the results to
appropriate models. 11/21/2014
34

35. Advantages, Disadvantages &
Applications of Microemulsion
11/21/2014
35

36. Advantages:
11/21/2014
36
 Increase the rate of absorption
 Eliminates variability in absorption
 Helps solubilize lipophilic drug
 Provides a aqueous dosage form for water insoluble drugs
 Increases bioavailability
 Various routes like tropical, oral and intravenous can be used to deliver the
product.
 Rapid and efficient penetration of the drug moiety
 Helpful in taste masking
 Provides protection from hydrolysis and oxidation as drug in oil phase in o/w
micro-emulsion is not exposed to attack by water and air.
 Liquid dosage form increases patient compliance.
 Less amount of energy requirement.

37. Disadvantages:
Use of a large concentration of surfactant and co-surfactant
is necessary for stabilizing the droplets of
micro-emulsion.
Limited solubilizing capacity for high-melting substances
used in the system.
The surfactant should be nontoxic for use in
pharmaceutical applications.
Micro-emulsion stability is influenced by environmental
parameters such as temperature and pH. These
parameters change as micro-emulsion delivered to
patients.
11/21/2014
37

38. 11/21/2014
38
Parenteral
Administrati
on.
Applications
Oral drug
delivery.
Topical drug
delivery.
Ocular and
pulmonary
delivery.
Micro-emulsions
in
biotechnolo
gy

39. Parenteral Administration:
 In order to attain prolonged release and to administer parenterally
lipophilic substances that are not soluble in water, o/w
microemulsions may be used as carriers.
 It is administered by intravenous, intramuscular, or subcutaneous
route.
11/21/2014
39

40. Oral Drug Delivery system:
 They have short life, conformational stability and biodegradability.
So it is very difficult to produce their formulation for oral
administration.
 Microemulsions extensively studied for protection of biodegradable
drugs.
 Eg. Proteins and Peptides from biological environment of per-oral
route.
 In recent time pharmaceutical and biotechnology permit to
produced high amount of peptides and proteins.
11/21/2014
40

41. Topical drug Delivery System:
 The percutaneous route of administration has been extensively
studied where the drug transport from microemulsions were
recorded usually better than that from other ointments, gels and
creams.
 Eg. Release of Tetracycline HCl is higher as microemulsion than as
gel and cream.
11/21/2014
41

42. Occular & Pulmonary Delivery:
 For the treatment of eye diseases, drugs are essentially delivered
topically. O/W type of microemulsions have been investigated for
ocular administration to dissolve poorly soluble drugs, to increase
absorption and to attain prolong release profile.
 Lecithin-Tween 80 based microemulsions was developed and
characterized, which dissolved some poorly soluble drugs such as
Atropine, Chloramphenicol and Indomethacin.
11/21/2014
42

43. Microemulsion in Biotechnology:
 Many enzymatic and bio-catalytic reactions are conducted in pure
organic or aqua organic media. Biphasic media also used for these
type of reaction. The use of water poor media is relatively
advantageous.
 Enzymes in low water content and have,
-Increased solubility in nonpolar reactants.
-Possibilities of shifting thermodynamic equilibrium in
favour of condensation.
-Improve thermal conductivity of the enzymes, enabling
reactions to be carried out at higher temperature.
11/21/2014
43

44. Other Applications:
Micro-emulsions can improve skin penetration of lycopene.
Micro-emulsion as a vehicle for transdermal permeation of nimesulide
Micro-emulsion in enhanced oil recovery, detergency, cosmetics, agrochemicals,
food. Microemulsions in environmental remediation and detoxification.
Micro-emulsions as fuels, as lubricants, cutting oils and corrosion inhibitors,
coatings and textile finishing.
Micro-emulsions in microporous media synthesis (micro-emulsion gel technique)
Micro-emulsions in analytical applications.
Micro-emulsions as liquid/membranes Novel crystalline colloidal arrays as
chemical sensor materials 11/21/2014
44

45. Evaluation of Microemulsion
Parameters Technique used
Phase Behaviour Phase contrast microscopy
&freeze fracture TEM
Size and Shape Transmission Electron
Microscopy(TEM), SEM
Rheology Brookfield viscometer
Conductivity Conductivity meter
Zeta potential Zetasizer
pH pH meter
Drug release studies Franz Diffusion Cells
Physical stability study Ultracentrifuge 11/21/2014
45

46. Different catagories of drugs solubilized in
Microemulsion:
Category Drugs
Anti-neoplastics Doxorubicin
Peptide Drug Cyclosporin
Sympatholytic Timolol
Local Anaesthetics Lidocaine, Benzocaine, Tetracaine
Steroids Hydrocortisone, Testosterone
Anxiolytics Diazepam
Vitamins Tocopherol, Ascorbic acid
Anti inflammatory Indomethacin 11/21/2014
46

47. Marketed lipid based and surfactant based
formulations
Drug Product Component
Amprenavir Agenerase TPGS, PEG 400, Propylene glycol
Ritonavir Norvir Ethanol, oleic acid, cremophor EL, BHT
Ritonavir/ lopinavir Kaletra Oleic acid, cremophor EL, propylene glycol
Saquinavir Fortovase Medium chain mono-digllycerides, povidone, α-
tocopherol
Tipranavir Aptivus Ethanol, Polyoxyl 35 castor oil, propylene glycol, mono-diglycerides
of caprylic acid/capric acid
Cyclosporin Neoral Corn oil mono-diglycerides, cremophor RH40, ethanol,
propylene glycol, α-tocopherol
Cyclosporin Gengraf Ethanol, PEG, Cremophor EL, polysorbate 80, sorbitan
monooleate
Sirolimus Rapimmune Phosal 50 PG, Polysorbate 80
Doxecalciferol Hectoral Medium chain triglycerides, ethanol, BHA
Progesterone Prometrium Peanut oil, lecithin, glycerin 11/21/2014
47

48. Marketed Products
Proprietary
name
Oil Phase (w/v) Emulsifier (w/v) Active
Ingredients
(w/v)
Other
Ingredients
Abbolipid
(10%,20%)
Soya oil+safflower
oil (5%/10% each)
3-sn-PC from Egg
(0.74% / 1.2%)
--- Glycerol (2.5%)
NaOH
Deltalipid (10%,
20%)
Soya oil (10%/20%) Egg Phospholipids
(1.2%/1.2%)
--- Glycerol (2.5%)
NaOH
Oleic Acid (0.3%)
Intralipid (10/20) Soya oil (10%/20%) 3-sn-PC from Egg
yolk
(0.6% / 1.2%)
--- Glycerol (2.5%)
NaOH
Intralipid 30 Soya oil 30% 3-sn-PC from Egg
yolk (30%)
--- Glycerol (1.67%)
NaOH
Lipofundin MCT
(10%/20%)
Soya oil + Middle
chain Triglycerides
(5%/10% each)
Egg Phospholipids
(min 68% 3-sn-PC)
(0.8 % / 1.2%)
--- Glycerol (2.5%)
NaOH
Sod. Olate
11/21/2014
α Tocopherol
48

49. Proprietary Name Oil Phase (w/v) Emulsifier (w/v) Active
Ingredients
(w/v)
Other Ingredients
Diazepam Lipuro (1%
/ 2%)
Soya Oil + Middle
Chain Triglycerides
Egg Lecithin Diazepam
(1% / 2%)
Glycerol
Sod. Oleate
NaOH
Disoprivan
(1% / 2%)
Soya Oil 3-sn-PC Propofol
(1% / 2%)
Glycerol
NaOH
Etomidat Lipuro Soya Oil + Middle
Chain Triglycerides
Egg Lecithin Etomidate Glycerol
Sod. Oleate
NaOH
Lipotalon Soya Oil (10%) Egg Phospholipids
(1.2%)
Dexamethason
e-21-palmitate
(0.4%)
Glycerol
Propofol Abbot 1% Soya Oil Egg Lecithin Propofol (1%) Glycerol
NaOH
Stesolid Soya Oil Phospholipids
from egg yolk
Diazepam (3%) Glycerol, Acetylated
Monoglycerides, NaOH
11/21/2014
49

50. Conclusion
 Microemulsions are optically isotropic and thermodynamically
stable liquid solutions of oil, water and amphiphile.
 Microemulsions are readily distinguished from normal emulsions by
their transparency, low viscosity and more fundamentally their
thermodynamic stability.
 Drug delivery through microemulsions is a promising area for
continued research with the aim of achieving controlled release
with enhanced bioavailability and for drug targeting to various sites
in the body.
11/21/2014
50

51. Thank You
11/21/2014
51