This document discusses self-microemulsifying drug delivery systems (SMEDDS). It begins with an introduction to SMEDDS and explains they are isotropic mixtures that can form microemulsions upon mild agitation and dilution in the GI tract. It then covers the definition of SMEDDS, the difference between SMEDDS and self-emulsifying drug delivery systems (SEDDS), the composition of SMEDDS including oils, surfactants, co-solvents and polymers. The document discusses the mechanism of emulsification for SMEDDS and factors affecting SMEDDS. It provides details on characterizing and solidifying SMEDDS before concluding with advantages and recent advances.

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SELF MICROEMULSIFYING
DRUG DELIVERY SYSTEMS
By:Rajesh L. Dumpala
(B.Pharm, M. Pharm.) PhD. ( Pursuing)
Research Scientist,
Alembic Research Centre. Vadodara
E.Mail:-rdumpala64@gmail.com

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CONTENTS
INTRODUCTION
 DEFINITION
DIFFERENCE BETWEEN SEDDS AND
SMEDDS
NEED
COMPOSITION
MECHANISM OF EMULSIFICATION
FACTORS AFFECTING SMEDDS
CHARCTERISATION
SOLIDIFICATION TECHNIQUE
ADVANTAGES OF SMEDDS
DRAWBACKS
RECENT ADVANCES
CONCLUSION
REFERENCES

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INTRODUCTION
The oral route is the preferred route for many chronic drug therapy
Currently various formulation strategies are in practice
Recently much attention has been paid to lipid base formulation
Approximately 35‐40% of new drug candidates have poor
water solubility

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Bio pharmaceutical classification system

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According to bio pharmaceutical classification
system(BCS) the classII drugs have poor solubility and
high permeability , thus the rate limiting process of
absorption is the drug dissolution step. Formulation plays
the major role in improving the rate and extent of
absorption of such drugs from GI tract.

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DEFINITION
Isotropic mixtures of natural or synthetic oils, solid or
liquid surfactants or alternatively one or more hydrophilic
cosurfactant and cosolvents .
Upon mild agitation followed by dilution in aqueous
media such as the GI fluids these systems can form
microemulsions.

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DIFFERENCE BETWEEN SEDDS AND SMEDDS
SEDDS SMEDDS
Produce opaque emulsions Produce transparent
microemulsion
Droplet size between 100-
300nm
Droplet size less than
50nm
Concentration of oil <20% Concentration of oil 40-
80%
Surfactants with HLB value
<12
Surfactants with HLB value
>12

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 A potential problem is that the drug may precipitate out of solution when
the formulation disperses in the GI tract, particularly if a hydrophilic
solvent is used (e.g.polyethylene glycol).
NEED OF SMEDDS:
If the drug can be dissolved in a lipid vehicle there is less potential
for precipitation on dilution in the GI tract, as partitioning kinetics will
favor the drug remaining in the lipid droplets

9. COMPOSITION
9
 Oils
 Surfactants
 Co solvents/Co surfactants
 Consistency builder
 Polymers
 Drug

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OILS
 It can facilitate self emulsification
 Both Long and medium chain triglyceride have been
used
 eg,olive oil,corn oil,Palm oil,Animal fats

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SURFACTANTS
Surfactant molecules can be classified based on the nature of
hydrophilic group within the molecule. The four main group
of surfactants are defined as follows,
1.Anionic surfactants,eg Pottasium laurate,SLS
2.Cationic surfactants,eg Quarternary ammonium halide.
3.Ampholytic surfactants,eg Sulfobetaines.
4. Nonionic surfactants,eg Polysorbate, Sorbitan
polyoxyethylene
The usual surfactant strength ranges between 30-60% w/w of
the formulation in order to form a stable SMEDDS

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 Help to dissolve hydrophilic surfactant and hydrophobic lipid base
 Play role of co surfactant in microemulsion systems
Examples: Glyceryl triacetate, propylene glycol etc.
Cosolvent:
Co-surfactant:
 Generally co-surfactant of HLB value 10-14 is used.
 Hydrophilic cosurfactants are preferably alcohols of intermediate chain
length
 which are known to reduce the oil/ water interface and allow the
spontaneous formulation of microemulsion
Eg. hexanol, pentanol and octanol

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Polymers
Should not ionizable at physiological pH and being capable
of forming matrix
Example: Hydroxy propyl methyl cellulose, Ethyl
cellulose, etc
Consistency builder
Example: tragacanth, cetyl alcohol, stearic acids
and /or beeswax

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BIOAVAILABILITY OF DRUGS FROM SMEDDS

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MECHANISM OF SELF EMULSIFICATION
Self-emulsification occur when the entropy change that
favors dispersion than the energy require to increase the
surface area of the dispersion.
∆G = ∑ Ni ╥ ri ²ɕ
∆ G=free energy associated with the process
N=no.of droplets,r=radius of droplet, ɕ=interfacial energy

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FACTORS AFFECTING SMEDDS
1.CONCENTRATION OF THE DRUG:
Drugs which are administered at high dose are not suitable for SMEDDS unless
they exhibit extremely good solubility in atleast one of the components of SMEDDS
preferably lipophilic base.
2.SOLUBILITY OF THE DRUG:
SMEDDS maintain the drug in solubilised form.If the surfactant & co surfactant
contribute to a great extent for solubilisation then there is risk for precipitation.
3.POLARITY OF THE LIPID PHASE:
The polarity of lipid phase is one of the factors that govern the release of the
drug from the microemulsion.

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Characterization
1. Droplet size analysis and particle size measurement
2. Turbidimetric Evaluation
3. Viscosity Determination
4. Refractive Index and Percent Transmittance
5. Dispersibility test
6. Electro conductivity Study:
7. In Vitro Diffusion Study
8. Drug content
9. Thermodynamic stability study

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Droplet size analysis and particle size measurement
 Determined by photon correlation spectroscopy using a
Zetasizer.
 Zetasizer able to measure sizes between 10 to 5000 nm.

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Turbidimetric Evaluation
Nepheloturbidimetric evaluation is done to monitor the growth of
emulsification.
 Fixed quantity of Selfemulsifying system is added to fixed
quantity of suitable medium (0.1N hydrochloric acid) under
continuous stirring (50 rpm) on magnetic plate at ambient
temperature.

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Viscosity Determination
 The rheological properties of the micro emulsion are
evaluated by Brookfield viscometer.
 This viscosity determination conform whether the system is
w/o or o/w.

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• Refractive index and percent tranmittance proved the transparency
of formulation.
• The refractive index of the system is measured by refractometer by
placing drop of solution on slide and it compare with water (1.333).
• The percent transmittance of the system is measured at particular
wavelength using UV-spectrophotometer keeping distilled water as
blank
Refractive Index and Percent Transmittance

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•The efficiency of self-emulsification of oral nano or micro emulsion is
assessed using a standard USP dissolution apparatus 2.
•One milliliter of each formulation was added to 500 mL of water at 37
± 0.5 0C.
•A standard stainless steel dissolution paddle rotating at 50 rpm
provided gentle agitation.
• In vitro performance of the formulations is visually assessed using
the following grading system:
Dispersibility test

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Grade A:
Rapidly forming (within 1 min) nanoemulsion, 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 2 min
Grade D:
Dull, grayish white emulsion having slightly oily appearance that is slow to emulsify (longer
than 2 min).
Grade E:
Formulation, exhibiting either poor or minimal emulsification with large oil globules present on
thesurface.
Grade A and Grade B formulation will remain as nanoemulsion when dispersed in GIT. While
formulation falling in Grade C could be recommend for SEDDS formulation.
Dispersibility test

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Electro conductivity Study:
The SMEDD system contains ionic or non-ionic surfactant,oil, and
water.
so, this test is used to measure the electroconductive nature of
system. The electroconductivity of resultant system is measured by
electroconductometer.
In Vitro Diffusion Study:
Performed to study the release behavior of formulation from liquid
crystalline phase around the droplet using dialysis technique.
Drug content:
Drug from pre-weighed SMEDDS is extracted by dissolving in suitable
solvent. Drug content in the solvent extract was analyzed by suitable
analytical method against the standard solvent solution of drug.

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Thermodynamic stability studies
Freeze thawing was employed to evaluate the stability of
formulations. The formulations were subjected to 3 to 4
freeze-thaw cycles, which included freezing at – 4°C for 24
hours followed by thawing at 40°C for 24 hours. Centrifugation
was performed at 3000 rpm for 5 minutes. The formulations
were then observed for phase separation. Only
formulations that were stable to phase separation were
selected for further studies.

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Various solidification techniques are
1. Capsule filling with liquid and semisolid self-emulsifying
formulations
2. Spray drying
3. Adsorption to solid carriers
4. Melt granulation
5. Melt extrusion/extrusion spheronization
SOLIDIFICATION TECHNIQUES FOR TRANSFORMING
LIQUID/SEMISOLID SMEDDS TO SOLID-SMEDDS

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For semisolid formulations, it is a four-step process:
(i) heating of the semisolid excipient to at least 20˚C above its melting
point
(ii) incorporation of the active substances (with stirring)
(iii) capsule filling with the molten mixture and
(iv) cooling to room temperature.
1. Capsule filling with liquid and semisolid self-emulsifying
formulations
For liquid formulations, it involves a two-step process: filling of the
formulation into the capsules followed by sealing of the body and cap of
the capsule, either by banding or by micro spray sealing.

30. 2. Adsorption to solid carriers
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 Free flowing powders may be obtained from liquid SE
formulations by adsorption to solid carriers.
 The adsorption process is simple and just involves addition of
the liquid formulation onto carriers by mixing in a blender.
 A significant benefit of the adsorption technique is good content
uniformity. SEDDS/SMEDDS can be adsorbed at high levels (up
to 70% (w/w)) onto suitable carriers.
.

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This technique involves the preparation of a formulation by mixing
lipids, surfactants, drug, solid carriers, and solubilization of the
mixture before spray drying.
The solubilized liquid formulation is then atomized into a spray of
droplets. The droplets are introduced into a drying chamber, where
the volatile phase (e.g. the water contained in an emulsion)
evaporates, forming dry particles under controlled temperature and
airflow conditions.
.
3.Spray drying

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4.Melt granulation
Melt granulation is a process in which powder agglomeration is obtained through
the addition of a binder that melts or softens at relatively low temperatures.
5.Melt extrusion/extrusion spheronization
Melt extrusion is a solvent-free process that allows high drug loading (60%), as
well as content uniformity. Extrusion is a procedure of converting a raw material
with plastic properties into a product of uniform shape and density, by forcing it
through a die under controlled temperature, product flow, and pressure
conditions.

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ADVANTAGES
 Protection of sensitive drug substances.
 Readily accessible for absorption.
 When a polymer is incorporated in terms of gives prolonged release
of medicament.
 Low viscosity.
 They are comprised of aqueous and oily components and therefore
can accommodate both hydrophilic as well as lipophilic drugs.

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 Liquid or solid dosage forms.
 Produce reproducible plasma profile
 Has potential to deliver peptides that are processed to enzymatic hydrolysis
in GIT.
 Enhanced oral bioavailability enabling reduction in dose.
 Increase the dissolution and permeability.
 .Thus SMEDDS protect drugs against hydrolysis by enzymes in the GI tract
& reduce the presystemic clearance in the GI mucosa & first pass
metabolism

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1.Alterations (reduction) in gastric transit.
2. Increase in effective luminal drug solubility
3. Stimulation of intestinal lymphatic transport
4. Changes in the biochemical barrier function of the GI tract
5. Changes in the physical barrier function of the GI tract
6. Effect of oils on the absorption
BIOPHARMACEUTICAL ASPECTS:

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ADVANTAGES OF SMEDDS OVER EMULSION
SMEDDS not only offer the same advantages of emulsions of facilitating the
solubility of hydrophobic drugs
But also overcomes the drawback of the layering of emulsions after sitting
for a long time.
SMEDDS can be easily stored since it belongs to a thermodynamics
stable system
The particle size is small
The bioavailability of the drug is therefore improved
SMEDDS offer numerous delivery options like filled hard gelatin capsules or
soft gelatin capsules or can be formulated in to tablets whereas emulsions can
only be given as an oral solutions.

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Drawbacks
1. Lack of good predictive in vitro models
2. Formulation potentially dependant on digestion
3. In-vitro ,in-vivo correlation needs to be
developed
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•Self-emulsifying sustained/controlled-release tablets
•Self-emulsifying suppositories
•Self-emulsifying nanoparticles
•Self-emulsifying sustained/controlled-release pellets
•Self-emulsifying capsule
Recent Advances

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.
Images of pure drug substance (left), solid SMEDDS (right magnification)

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EXAMPLES OF MARKETED SEDDS FORMULATIONS:
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EXAMPLES OF MARKETED FORMULATIONS:

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• Self‐emulsifying drug delivery systems are a promising approach for the
formulation of drug compounds with poor aqueous solubility.
•With future development of this technology, SEDDSs and SMEDDs will
continue to novel applications in drug delivery and solve problems
associated with the delivery of poorly soluble drugs.
• As improvements or alternatives of conventional liquid SEDDS,
S‐SEDDS are superior in reducing production cost, simplifying industrial
manufacture, and improving stability as well as patient compliance.
CONCLUSION:

42. Referance
1 .Pouton .C.W . Lipid formulations for oral administration of drugs non-emulsifying,
self-emulsifying and ‘ self-microemulsifying ’ drug delivery systems. Eur J Pharm
Sci . 2000 ; 11 : S93 - S98 .
2 . Constantinides.P.P . Lipid microemulsions for improve dissolution and oral
absorption physical and biopharmaceutical aspects Pharm Res . 1995 ; 12 : 1561
– 1572
3.. Patravale.B.Vandana , Date.A. Abhijit , Oral self micro emulsifying systems:
Potentialin DDS, Pharma Technology, Express Pharma Pulse special feature,
May 29, 2003, 44-48.
4. Charman.A. Susan … et al., Self emulsifying drug delivery systems: Formulation
and Biopharmaceutics Evaluation of an Investigational lipophillic Compound,
Pharmaceutical Research,9 (1), 1998, 87-93.
5. http://www.springer.link.com/content/m2614m3134562/20
6. http://www.ncbi.n/m.nih.gov/pubmed/20659556
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