variables

on solid lipid
nanoparticles
Presented by
Ms. Amruta Sunil Ner

Guided by
Dr. Mrs. A. R. Madgulkar

AISSMS COLLEGE OF PHARMACY, PUNE-01

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Contents:
Introduction to SLNs
Methods of preparation
Formulation variables which affect SLNs
Properties affected by formulation variables
Stability
Applications

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 Introduction:
Definition:
Nanoparticles: nanoparticles are solid colloidal
particles which ranging in size from 10 to 1000nm (1
μm). They consist of macromolecular materials such as
adjuvant in vaccines or drug carriers in which the
active principle (the drug or biologically active
material) is dissolved, entrapped or encapsulated or to
which active principle is adsorbed or attached.

Solid lipid nanoparticles: solid lipid nanoparticles

are colloidal carriers which consist of spherical solid
lipid particles in nanometer range. They are made up of
lipid(s), emulsifier(s) and water.

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Advantages of SLN:
Controlled drug release
Targeting of drug
Increased drug stability
High drug loading capacity
Less toxic
Avoidance of organic solvents
Protection of drug
Large scale production
Wide spectrum of application.

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Disadvantages:
Particle growth.

Unpredictable gelation tendency.

Unexpected dynamics of polymorphic transitions.

Inherent low incorporation rate due to the

crystalline structure of the solid lipid.

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Components of solid lipid
nanoparticles:
 Lipids: Selection of lipid is based on solubility of drug in various
Lipids. There are various lipid are used like Stearic acid, Glyceryl
monostearate, Compritol ATO888(Glyceryl behenate),Precirol
ATO5(Glyceryl palmitostearate),Gelucire, Emulcire.
 Surfactants: Various lipophilic and hydrophilic surfactants are used.
lipophilic surfactants are used to enhance drug solubility in lipid.
Hydrophilic surfactants used to stabilize the formulation.
Lipophilic surfactants: Span 60,Sodium cholate, Soya lecithin.
Hydrophilic surfactants: Tween 80,Poloxamer 188.

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 Types of solid lipid
nanoparticles:
The type of SLNs depends:
The chemical nature of the active ingredient and
lipid,
The solubility of actives in the melted lipid,
Nature and concentration of surfactants,
Type of production (hot vs. cold HPH), and the
production temperature.
Fig. structural models for drug loading profiles in
SLNs

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Drug release:
Types:
• Control release

• Burst release

• Enzyme dependent release

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 Controlled release:

• This type of release showed with a uniform drug

profile throughout the lipid shell or an enriched
‘core’.

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Burst release:

Affected by 2 factors:
• Processing temperature
• Concentration of surfactant

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Enzyme release:

• Enzymatic release of drug from SLN takes

place by lipase/ colipase complex.
• Components accelerating degradation-
 Cholic acid sodium salt
 Tween 80
• Components preventing degradation-
 Waxes (cetyl palmitate)
 Poloxamer 407

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Methods of SLN
preparation:
A. Mechanical methods:
High shear homogenization
High pressure homogenization
Ultrasonication

B. Chemical methods:
Solvent evaporation
Microemulsions

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A. High pressure
homogenization:
Principle: It is based on principles of fluid
mechanics to produce extremely high fluid
pressures, and, thus energy dissipation rates in
the form of high shear stresses and cavitation
forces that act to reduce the size of dispersed
phase in emulsions.

• Two types:
1.Hot pressure homogenization
2.Cold pressure homogenization

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14
B. Probe sonication
method:

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C) Micro-emulsion dilution method:
Preparation of micro-emulsion
Dilution of micro-emulsion into near freezing
temperature at ratios of 1:25-1:50 to cold water
to form lipid nanoparticles.

D) Solvent evaporation method:

Lipid with drug mixed with water immiscible
solvent and then emulsified with water.
Emulsion is then subject to reduced pressure to
evaporate solvent and precipitate lipid particles
as aqueous dispersion.

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 Methods of Preparation
Hot Pressure homogenization
Strengths weaknesses
• Scalable • Extremely energy intensive
• Mature technology process
• Continuous operation • Polydisperse distributions
• Commercially demonstrated • Biomolecule damage
• Not used for thermolabile drug

Cold pressure homogenization • Mature technology • Extremely energy intensive

• Continuous operation
• Commercially demonstrated •
• Mainly used for the
thermolabile and hydrophilic
drugs
Ultrasonication • Reduced shear stress
process
Polydisperse distributions
• Biomolecule damage
• Metal contamination potential
• Energy intensive process
• Polydisperse distributions

Microemulsion dilution • Low mechanical energy input • Extremely sensitive to change

• Theoretical stability • Labor intensive formulation
work
• Low nanoparticles
concentrations

Solvent evaporation • No dilution solidification • Residual organic solvent

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Formulation variables which
affect SLN:
Lipids
Surfactants
Processing parameters (stirring time, stirring rate,
rate of cooling, temperature)
Drug
Spray drying
Lyophilization
sterilization

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Factors which are
affected by
formulation variables:
Particle size

Polydispersity index (P.I.)

Zeta potential

% entrapment efficiency

 drug release

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Lipids:
Properties of lipids which affect SLNs:

Melting point of lipid

Concentration of lipid

Composition of lipids

Combination of lipids

Lipid crystallinity

Chemistry of lipids

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Effect of lipid melting point (M.P.) on
processing parameter
(In homogenization method)

lipid Stirring time Stirring rate Optimum cooling

condition

Witepsol W 35 8 minute 20,000 rpm 10 minute

(M.P. 450c) (in room
temperature)

Dynasan 116 10 minute 25,000 rpm 5 minute

(M.P. 640c) (in cool water)

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Lipid crystalline state:
Crystallization is a balance between attractive
intermolecular forces and entropic factors.
SLNs exhibits in various crystalline structure:
1. α-form.
2. β′-form.
3. β -form.
4. Super cooled melt

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 Lipid crystallization depends on:
• Rate of cooling
• type of hydrophobic group in surfactant.

Lipid crystallization mainly affects:

• Drug incorporation
• Drug release characteristics.

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 Effect of lipid matrix on drug release:

Different lipids give different release kinetics.

Example:

Release rate decreases in following order-

Triglyceryl stearate > triglyceryl palmitate >

myristin.
• Effect of waxes on drug release:

• Example – cetyl palmitate

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Effect of surfactants:
Effects are due to:

• Temperature
• Surfactant mixture/ cosurfactants,
surfactant to cosurfactant molar ratio
• HLB number
• Surfactant number (CPP)
• Amount of emulsifier, surfactant to lipid molar ratio
• Molecular weight and speed of redistribution
• Varying rates of adsorption onto interface

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Effect of temperature:
 Ionic surfactants: becomes more hydrophilic.
 Non ionic surfactants: becomes more hydrophobic.

Effect of surfactant mixture on particle size:

surfactant Particle size before Particle size

freezing after freezing
Tween 80(100%) 487.7 1459.7

Egg PC(100%) 397.1 440.3

Tween 80: Egg PC 227.2 329.5
(46:56)

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Effect of cosurfactant selection on lipid
nanoparticle characteristics:

cosurfactant Particle size (nm)Polydispersity

index

Sodium 99 0.30
taurocholate

Sodium 110 0.01

glycocholate

cholesterol 620 0.01

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 Effect of concentration of surfactant on:
Particle size

% entrapment efficiency

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Steric stabilizers:
Ex. Poloxamer 407
PEG
poloxamine 908
Effect due ethylene oxide/ propylene oxide
copolymers
Example No. of Molecular Adsorbed layer
ethylene oxide weight thickness
chains
Poloxamer 407 98 11500 12nm

Tween 80 20 1840 2nm

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• Effect of type of surfactants on drug release:

• Effect on enzymatic release:

• Enzymatic release of SLN takes place by lipase/ colipase
complex

• Components accelerating degradation-

 Cholic acid sodium salt(bile salt)
 Tween 80(ethylene oxide propylene oxide copolymer)

• Components preventing degradation-

 Poloxamer 407(ethylene oxide propylene oxide copolymer)

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Drug:
Effect of drug nature:
• Lipophilic drug

• Hydrophilic drug

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Processing
parameters:
• Homogenization cycles

• Stirring time

• Stirring rate

• Rate of cooling

• Processing temperature

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 Effect of processing temperature on:
• Particle size
• Degradation
• Drug distribution
• Increase of processing temperature causes
burst release to take place.
1. burst release:
Fig. drug enriched shell model

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Lyophilization:
Following points considered:
• Effect of drug
• Effect of lipid content
• Selection of cryoprotector
• Concentration of cryoprotector
• Time of addition of cryoprotector

Effect of rate of cooling:

• Rapid cooling- gives small crystals
• Slow cooling- gives larger crystals

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Spray drying:
• During spray drying particle aggregation is
the main problem.
• Points to be considered to avoid particle
aggregation:
 Selection of lipids

 Concentration of lipids

 Addition of carbohydrates

 Use of ethanol-water mixture

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Sterilization:
Autoclaving:
Effect of surfactant-
 Poloxamer 188
 Lecithin

Sterile filtration: use it if particle size is less than

200nm.

Gamma irradiation

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Stability:
Properties considered:
• Particle size distribution (increase particle
size, gelation)
• Lipid crystallization state

Stability studies performed for effect of:

• Light
• Temperature
• Packaging material

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• Example: poloxamer 188 stabilized compritol
SLN:
• Stability achieved by:
 Temperature- 8oC
 Light- dark
 Container-siliconized vials.

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Effect of lipids and surfactants on SLNs stability:
Speed of lipid crystallinity and surfactant properties
affect speed of degradation of SLNs.
Example:
Lipid Surfactant
1. Dynasan 1. Poloxamer 407
116(Tripalmitin)
M.P.(640c)
2. Dynasan 114(Trimyristin)2. Sodium cholate
degradation
M.P.(56velocity
0
c) can be modulated by changing
surfactant ratio:
Degradation velocity:
Cholic acid > Lipoid E 80 > Tween 80 > Poloxamer
407.

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Applications:
SLN can be given by various routs as follows:
• Oral route

• Intravenous route

• Transdermal route

• Occular route.

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References:
1. Muller RH, Mäder K. Gohla S. Solid lipid nanoparticles
(SLN) for controlled drug delivery - A review of the state of
art. Eur. J. Pharm. Biopharm 2000;50: 161-177.
2. Khar RK, Vyas SP. Targeted and Controlled Drug Delivery.
CBS Publishers & Distributors.1st Edi,Vol.II,2002, 331-383.
3. Manjunath K, Reddy JS, Venkateswarlu V. Solid lipid
nanoparticles as drug delivery systems. Methods Find.
Exp. Clin. Pharmacol. 2005; 27:127-144. 
4. Mehnert W, Mäder K. Solid lipid nanoparticles -
Production, characterization and applications. Adv. Drug
Deliv. Rev 2001; 47:165-196.

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References:
5) Gupta R.B., Kompella U.B., Nanoparticle technology for drug
delivery, Taylor and Francis group,Vol.159,pg no.1-45.
6) Tassu D., Deelers M., Pathak Y., Nanoparticulates drug delivery
systems., Taylor and Francis group,Vol.166,pg no.89-98.
7) ) Freitas C, Muller RH, “Effect of light and temperature on zeta
potential and physical stability in solid lipid nanoparticle
dispersions”, Int. J. Pharm., 168, 1998, 221-228.
8) Olbrich C, Muller RH, “Enzymatic degradation of SLN- effect of
surfactant and surfactant mixtures”, Int. J. Pharm., 180, 1999, 31-
39.
9) Attama AA, Christel C, Muller- Goymann, “Effect of beeswax
modification on the lipid matrix and solid lipid nanoparticle
crystallinity”, Colloids and Surfaces A: Physicochem. Eng. Aspects,
315, 2008, 189- 195.

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Thank you…