Smedds

1. Self Micro Emulsifying Drug Delivery Systems

2. Table of Contents
Introduction
Composition
Formulation design
Mechanism of self emulsification
Applications
Advantages and Limitations
Recent advances
Conclusion
References
2

3. INTRODUCTION
Self micro emulsifying drug delivery (SMEDDS) are defined
as isotropic mixtures of natural or synthetic oils, solid or
liquid surfactants, or alternatively, one or more hydrophilic
solvents and co-solvents/surfactants.
The concept was introduced by Haur and Schulman in 1940’s,
who generated a single phase solution by titrating a milky
emulsion with hexanol.
Schulman and co-workers in 1959 subsequently coined the
term microemulsion.
Micro emulsion have been successively used to improve the
solubility, chemical stability and oral bioavalability of poorly
soluble drugs ( class II and IV as per BCS classification)[1]
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4. Fig1: Pictorial representation of SMEDDS[2]
4

5. Components
Drug Lipids
Triglycerides
Fatty
acids/esters
Surfactants Cosurfactants
Composition
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6. 1) Drug:
 The ideal log p value of the drug should be (log p>2)
No extensive first pass metabolism.
 Drug should be soluble in lipids, solvents and co-solvents .
2) Oil :
Oils solubilizes lipophilic drugs
Facilitates intestinal lymphatic uptake
Modified/ hydrolyzed vegetable oils- good emulsification systems[3].
Oils
6

7. Medium chain triglycerides (MCT) having carbon atoms between 6 and 12
are directly transported by portal blood to the systemic circulation.
Long chain triglycerides (LCT) having carbon atoms greater than 12 are
transported via intestinal lymphatics
MCT are widely used due to:
 Higher solvent capacity
 No oxidation
Examples: LCT: soya bean oil, corn oil, peanut oil,
• MCT: miglycol 812,captex 355, labrafac
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8. Surfactants:
Surfactants assist instantaneous formation of o/w
droplets
Surfactants used to stabilize microemulsion system
Medium chain length alcohols (C3–C8) are commonly
employed as co-surfactants
Non ionic with high HLB value
High HLB and hydrophilicity leads to excellent
spreading properties
Example: Polysorbate 20 (tween 20), Polysorbate 80
(tween 80), Sorbitan monooleate (Span 80),Polyoxy-
35-castor oil( Cremophor RH40)[7].
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9. Co-surfactant:
Ensures flexibility of the interfacial
layer i.e, Co-surfactants it reduces the
interfacial tension to a negative
value.
are added to further lower the
interfacial tension between the oil
and water phase, to fluidize the
hydrocarbon region of interfacial
film, and to influence the film
curvature.
Examples: short chained alcohol (
ethanol, propanol, butanol)
Glycol (propylene glycols)[4].
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10. Mechanism of Self Emulsification
• The free energy formed in SMEDDS can be given by the following equation
Where,
∆G – free energy accompanying the process (apart from the free energy of mixing),
N – Total number of droplets
πr2 –area of the droplets
σ – Energy at the interface [1]
Lower the interfacial energy. lower the free energy
 Self-emulsification occurs when the energy involvement in the dispersion is greater than
the energy required for the formation of droplets
∆G=∑Nπr2σ
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11. Screening
Selection of suitable drug candidate and
excipients
Construction of Pseudoternary Phase
diagram
Preparation of SMEDDS
Characterization of SMEDDS
Formulation design
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12. SCREENING :
Solubility Studies: These are mainly useful for the selection of the most suitable
excipients that can be used in the preparation of SMEDDS and helps in the
prediction of drug precipitation in vivo.
Screening of Surfactants and Cosurfactants for their self emulsification ability.
The emulsification ability of surfactants can be known by mixing the equal
proportions of selected oil and surfactant which is followed by homogenization[5].
12

13. Construction of Pseudoternary Phase Diagram:
These are the diagrams which represent change in phase
behavior of the system according to the change in composition.
Ternary phase diagram is used to study the phase behavior of
three components. In SMEDDS, this represents the system with
three components like oil, water, and surfactant.
But in case of addition of fourth component, the ternary
diagram can be called pseudoternary phase diagram and corner
can be the mixture of two components like surfactant and
cosurfactant.
Ternary diagram contains three corners that correspond to the
100% of the particular component[7].
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14. Pseudoternary diagrams are constructed by keeping the ratio of any
two of the four components as constant and this ratio along with the
remaining two components generally forms three corners of the phase
diagram.
 This fixed (mixture) ratio is generally formed by the combination of
surfactant and cosurfactant and sometimes it may be the mixture of oil
and surfactant.
This is mixed with the required volume of the third phase like oil or
cosurfactant ,then the other component which is usually water is added
in incremental amounts and for every addition of fourth component,
the solution should be tested for the clarity, flowability, time for self-
emulsification, and dispersibility. The total percent concentration of all
components in each mixture should be 100%/

15. • The three corners of the typical ternary
diagram represent three components, that is,
A, B, and C.
• The arrow towards BA indicates increase in
proportion of A from 0% concentration (at
point B) to 100% concentration (at point A),
the arrow towards AC indicates the increase
in proportion of C from 0% concentration (at
point A) to 100% concentration (at point C)
• Similarly the arrow towards CB indicates the
increase in proportion of B from 0%
concentration (at point C) to 100%
concentration (at point B).

16. • Composition at point “O” can be known by the
following.
(i) Draw a line that is parallel to CB from point O
towards AB. The point where this line intersects with
AB indicates the percent composition of A at point O
(X).
(ii) Then, percent composition of B at point O can be
known by drawing a line that is parallel to AC towards
BC. The point where this line intersects with BC
indicates the percent composition of B at point O (Y).
(iii) Similarly, the percent composition of C at point O
can be known by drawing a line that is parallel to AB
towards AC (Z)

17. • WINSOR PHASE BEHAVIOUR DIAGRAMS:
• 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

19. • Grade A: Rapidly forming microemulsion emulsion, having a
clear or bluish appearance.
• Grade B : Rapidly forming slightly less clear emulsion having
a bluish white appearance.
• Grade C: Fine milky emulsion that formed within
• Grade D: Dull, greyish white emulsion having slightly oily
appearance that is slow to emulsify

21. PREPARATION OF SMEDDS:
The preparation involves the addition of drug to the mixture of oil, surfactant,
and co-surfactant and then it should be subjected to vortexing. In some cases,
drug is dissolved in any one of the excipients and the remaining excipients are
added to the drug solution .
The solution should be properly mixed and tested for the signs of turbidity.
The solution should be heated for the formation of clear solution[8].
21

22. Characterization
Visual
Droplet size
analysis
Zeta potential
measurement
Time for
emulsification
Cloud point
determination
Thermodynam
ic study
Viscosity
measurement
Dilution
studies
Characterization of Smedds:
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23. CHARACTERIZATION OF SMEDDS:
Visual Evaluation: The assessment of self emulsification is possible by visual
evaluation. After dilution of SMEDDS with water, the opaque and milky white
appearance indicates the formation of macroemulsion whereas the clear,
isotropic, transparent solution indicates the formation of microemulsion .
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24. Droplet Size Analysis:
The droplet size is mainly dependent on the nature and
concentration of surfactant. Microemulsion formed upon dilution
with water produces droplets of very narrow size and size
distribution for effective drug release, in vivo absorption, and
also stability
Time for Emulsification:
The time needed for selfemulsification for different formulations
can be assessed generally using dissolution apparatus USP type
II in which the formulation is added dropwise to the basket
containing water and observing the formation of clear solution
under agitation provided by paddle at 50 rpm[9]
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25. Cloud Point Determination:
Cloud point is generally determined by gradually increasing
the temperature of water bath in which the formulation is
placed and measured spectrophotometrically.
Zeta Potential :
Zeta potential is generally measured by zeta potential
analyzer, Value of zeta potential indicates the stability of
emulsion. Higher zeta potential indicates the good stability
of formulation[9].
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26. Viscosity Measurements:Viscosity of diluted SMEDDS
formulation that is microemulsion is generally determined by
rheometers like Brookfield cone and plate rheometer fitted with
cone spindle or rotating spindle Brookfield viscometer .
Dilution Studies : It is done in various diluents like double
distilled water, simulated gastric fluid (SGF), and
simulated intestinal fluid (SIF)
Refractive index: The constant refractive index indicates the
thermodynamic stability of the formulation . Usually the
refractive index measurements are carried out using
refractometers[10] .
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27. APPLICATIONS
Improvement in solubility and
bioavailability
Protect drug from biodegradation
Enhance drug loading capacity
SMEDDS for herbal and traditional
medicines
Controlled release formulation
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28. APPLICATIONS
Paenteral
administration
Oral drug
delivery
Topical drug
delivery
Ocular and
pulmonarydrug
delivery
Microemulsions
in
biotechnology
Delivery of
peptides
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29. MARKETED PREPARATIONS
Brand Drug Dosage form Indications
Neoral® Cyclosporine Soft gelatin
capsule
immunosuppr
essant
Norvir® Ritonavir Soft gelatin
capsule
HIV antiviral
Lipire® Fenofibrate Hard gelatin
capsule
Lowering of TG
level
Convule® Valproic acid Soft gelatin
capsule
Antiepileptic
Table: 1 Applications of SMEDDS reported in literature[12]
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30. ADVANTAGES
Enhanced oral bioavailability
Selective drug targeting towards specific absorption window in GIT
Ease of manufacture and scale up
Potential to deliver peptides that are processed to enzymatic hydrolysis in
GIT
Useful for both solid or liquid dosage form[8]
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31. LIMITATIONS
Lack of predictive in vitro
models for assessment of
the formulation is the most
important problem in the
development of SMEDDS.
To mimic this, in-vitro
model stimulating the
digestive processes of the
duodenum has to be
developed.
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32. RECENT ADVANCES
• Supersaturable SMEDDS: Telmisartan (TMS)
• Self micro-emulsifying mouth dissolving film (SMMDF) :
SMMDF of vitamin D3 for infants
• Formulations of lecithin linker for SE delivery of nutraceuticals
• Sponges carrying SMEDDS : alginate based composite as
gastroretentive carrier for curcumin loaded SMEDDS
• Herbal SMEDDS: Ginkgo biloba extract loaded SMEDDS[11]
• Self-double emulsifying drug delivery system: pidotimod-
SDEDDS
• Positively charged SEDDS[2]
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33. CONCLUSION
• For poorly water soluble drugs, a self-emulsifying drug
delivery method in solid dosage form increases
solubility/dissolution, absorption, and bioavailability.
• This approach is best for lipophilic medicines because the
subsequent emulsification allows for quicker disintegration and
absorption.
• SMEDDS outperforms competing colloidal vehicles in terms of
cost savings, ease of industrial manufacturing, and improved
stability and patient compliance.
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34. REFERENCES
1) Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS)–
challenges and road ahead. Drug delivery. 2015 Aug 18;22(6):675-90.
2) https://www.researchgate.net/figure/Method-for-the-preparation-of-
SMEDDS_fig1_348407856
3) Deshmukh AS. Recent advances in self emulsifying drug delivery system.
International Journal of Pharmaceutical Sciences and Nanotechnology. 2015 Feb
28;8(1):1-5glycol.
4) Savale S, Chalikwar S. Self Micro Emulsifying Drug Delivery System
(SMEDDS): A Review. Asian Journal of Biomaterial Research. 2017;3(2):12-7.
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35. 5) Akula S, Gurram AK, Devireddy SR. Self-microemulsifying drug delivery
systems: an attractive strategy for enhanced therapeutic profile. International
scholarly research notices. 2014;2014.
6) Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and
computational approaches to estimate solubility and permeability in drug
discovery and development settings. Advanced drug delivery reviews. 1997 Jan
15;23(1-3):3-25.
7)https://www.jyoungpharm.org/sites/default/files/JYoungPharm_10_2_132_1.pdf
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36. 8) Sharma V, Singh J, Gill B, Harikumar SL. SMEDDS: A novel approach for
lipophilic drugs. International Journal of Pharmaceutical Sciences and Research.
2012 Aug 1;3(8):2441.
9) Sharma V, Singh J, Gill B, Harikumar SL. SMEDDS: A novel approach for
lipophilic drugs. International Journal of Pharmaceutical Sciences and Research.
2012 Aug 1;3(8):2441.
10) Jaiswal P, Aggarwal G. Bioavailability enhancdement of poorly soluble drugs by
smedds: a review. Journal of drug delivery and therapeutics. 2013 Jan 14;3(1).
11) Zhang L, Zhang L, Zhang M, Pang Y, Li Z, Zhao A, Feng J. Self-emulsifying
drug delivery system and the applications in herbal drugs. Drug delivery. 2015
May 19;22(4):475-86.
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37. 12)Jaiswal P, Aggarwal G. Bioavailability enhancdement of poorly soluble drugs
by smedds: a review. Journal of drug delivery and therapeutics. 2013 Jan 14;3(1).
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