NANOPARTICLES

(PHARMACEUTICS)

Mahwish Siddiqui
Nanoparticles
• Word ‘Nano' derived from the Greek word which
means dwarf or extremely small .

• Nanoparticles are solid colloidal particles ranging from

10 to 100 nm. (1nm corresponding to 10-9 m).
Drug is physically and Drug is confined to a cavity
uniformly dispersed in a surrounded by a polymer
matrix system. membrane.
Advantages
1. Increase in therapeutic efficacy of drugs and
decrease in side effects.

2. Controlled release of drug.

3. Drug loading is relatively high and drugs can be

incorporated into the systems without any chemical
reaction.

4. Site-specific targeting can be achieved. (Enhanced

permeability and retention EPR effect).

5. Decreased fed/fasted variability.

Preparation of Nanoparticles
• Preparation of Nanosized drug particles or
Nanocrystals

• Preparation of Polymeric Nanoparticles.

• Preparation of Solid-Lipid Nanoparticles.

• Preparation of Protein Nanoparticles.

• Top down approach
Comminution of larger particles down to
nanoparticles.
Examples:
• Wet Milling (efficient and successful).
• High pressure homogenization (time consunming).

• Top up approach
Precipitation starting from molecular solutions. e.g:
• Solvent/antisolvent method.
• Evaporative Precipitation into Aqueous Solution
(EPAS).
Preparation of Nanosized drug
particles or drug Nanocrystals
 Nanosized drug particles or drug Nanocrystals
• Nanocrystals are prepared from 100% drug with no
carriers.
• Stabilizers (ionic or nonionic surfactants) are added
during size reduction process to prevent particle
aggregation.
• Nonosized drug particles/crystals offer:
 Increased solubility of the drug.
 Increased dissolution and bioavailability.
 Increased adhesiveness to surface/cell membranes.
 Bioavailability independent of fasted/fed state.
• Within nanoparticle system the drug can either be
crystalline or amorphous.

Preparation of Nanocrystals by Wet Milling

1. Wet milling is a means that the drug particles are

dispersed in a surfactant/stabilizer solution and the
obtained macrosuspension is then subjected to
milling energy.
2. The classical milling process is the pearl mill (bead
mill).
3. The pearls or balls used as milling media consist of
ceramics, stainless steel, glass or highly
crosslinked polystyrene resin-coated beads.
4. Milling media, dispersion media (generally water),
stabilizer and drug are filled into the milling
chamber.

5. Shear force of impact, generated by the movement

of milling media, leads to the particle size
reduction.
FDA-approved Products devoloped with drug
nanoparticles

Product Drug Attributes

Emend Aprepitant Oral formulation of a poorly
Merck soluble drug.
Megace ES Megesterol Nanosized version offers
Par Pharma. acetate reduced dose volume.
TriCor Fenofibrate Drug absorption not effected
Abbott by fed/fasted state
Preparation of Polymeric
Nanoparticles
Polymeric Nanoparticles
Drug is incorporated within the polymer matrix
or drug is attached to the polymer surface.

Examples of polymers used:

• Poly (lactic acid) (PLA)

• Poly (lactide-co-glycolic acid) (PLGA)
• Poly (cyanoacrylates) (PCA).
• Polysaccharides (particularly chitosan)
Methods of preparation of polymeric
nanoparticles:

1. Emulsification-Solvent evaporation method.

2. Emulsification-Solvent diffusion method.

3. Salting out method.

4. Nanoprecipitation.
1. Solvent evaporation method:
I. Organic solvents such as dichloromethane,
chloroform or ethyl acetate are used to dissolve the
polymer which is also used as the solvent for
dissolving the hydrophobic drug.
II. The drug dissolved or dispersed in polymer solution
is then emulsified (by the help of high-speed
homogenizer or ultrasonication) in an aqueous
solution containing a surfactant or emulsifying agent
to form oil in water emulsion.
III. Once stable emulsion is formed, the organic solvent
is evaporated either by reducing the pressure or by
continuous stirring.
Solvent evaporation method
2. Emulsification-Solvent diffusion method:
I. A partially water-miscible solvent containing the polymer
and the drug is emulsified with an aqueous solution,
containing a surfactant.

II. For the success of this method, the polymer solvent and
water are mutually saturated at room temperature to
ensure the initial thermodynamic equilibrium of both
liquids.

III. The emulsion is diluted with an extensive amount of

water which induces solvent diffusion from the
dispersed droplets into the external phase, resulting in
the formation of colloidal particles.
IV. Finally, depending on its boiling point, the solvent
can be eliminated by evaporation or filtration. Such
diffusion process is milder than the direct
evaporation of the organic solvent from the
nanodroplets.
• Generally, nanospheres are produced by this method
but nanocapsules can be obtained just by adding a
small amount of oil, for example miglyol, in the
organic phase.
Emulsification-Solvent diffusion method
3. Salting out method
I. Organic phase
Polymer and drug are firstly dissolved in a water
miscible solvent such as acetone, tetrahydrofuran,
and ethanol.

II. Aqueous phase

Aqueous phase is constituted by water, the salting
out agent and a stabilizer. Salting agent can be
electrolyte: MgCl2 , CaCl2 or non-electrolyte: Sucrose.
III. Emulsification
Then organic phase is added to the aqueous phase. The
miscibility of acetone and water is reduced by saturating
the aqueous phase, which allows the formation of an
o/w emulsion from the otherwise miscible phases.

IV. Salting out

Following of this procedure, a sufficient volume of water
is added to the mixture to facilitate the acetone diffusion
into aqueous phase resulting in polymer salting out as
nanosphere/ particles. Both the solvent and salting agent
are removed via cross flow filtration.
Salting out method
4. Nanoprecipitation or Solvent Displacement
Method
I. The polymer is dissolved in a water-miscible solvent of
intermediate polarity.

II. This solution is added into a stirred aqueous solution in

one shot, stepwise, dropwise or by controlled addition
rate.

III. Due to the fast spontaneous diffusion of the polymer

solution into the aqueous phase, the nanoparticles
form instantaneously in an attempt to avoid the water
molecules.
Nanoprecipitation
Preparation of Solid Lipid
Nanoparticles (SLNs)
Solid Lipid Nanoparticles (SLN):
These are nanoparticles made from solid lipids (high
melting point) dispersed in aqueous phase by the help
of emulsifiers.

Examples of lipids used include:

• Solid triglycerides
• Saturated phospholipids
• Fatty acids (stearic acid, palmitic acid)
• Steroids (cholesterol)
• Waxes (cetyl palmitate)
• Also termed “solidified oil in water emulsions”.

• Emulsifirers used commonly : Poloxamer, egg

lecithin, soyabean lecithin.

• Drug is incorporated within the lipid matrix or drug is

attached to the lipid nanoparticles surface.

• Solid-lipid nanoparticle dispersions have been

developed for parenteral, oral, ocular, dermal and
cosmetic applications.
Advantages of solid lipid nanoparticles
1. Feasibility of carrying both lipophilic and hydrophilic
drugs.

2. Most lipids being biodegradable, SLNs have excellent

biocompatibility.

3. No use of organic solvents involved.

4. Easy to sterilize. Aseptic production, filtration, gamma

irradiation are commonly used to achieve sterilization.

5. Easier to validate and gain regulatory approval.

Methods of preparation of SLNs:
1. High Pressure Homogenization (HPH)
1.1 Hot Homogenization
1.2 Cold Homogenization

2. Micro-emulsion Technique

3. Double Emulsion Technique

4. Solvent Injection Technique

1.1: Hot Homogenization
I. Melt lipid and dissolve or solubilize drug in the
lipid.
II. Disperse melted lipid in hot aqueous surfactant
solution at identical temperature.
III. Preparation of a pre-emulsion by means of
ultrasonication.
IV. High-pressure homogenization above the melting
point of the lipid.
V. Upon cooling the resultant hot o/w nanoemulsion
recrystallizes down to room temperature to form
SLNs.
Hot Homogenization
1.2: Cold Homogenization
I. Melt lipid and dissolve or solubilize drug in the
lipid.
II. The drug lipid mixture is rapidly cooled either by
means of liquid nitrogen or dry ice to convert it to
solid state.
III. Milling of the drug lipid mixture by means of a ball
mill or a jet mill.
IV. Disperse lipid microparticles in chilled emulsifier
solution to yield a pre-suspension.
V. This pre-suspension is subjected to high pressure
homogenization at or below room temperature
results in the formation of SLNs.
Cold Homogenization
 2. Microemulsion Technique
I. Solid lipids are melted at a temperature above the
melting point of the lipids (65-70°C).
II. Separately, a mixture of surfactant, co-surfactant and
water is heated to same temperature as the lipid and
then added to melted lipid under mild stirring.
III. A transparent, thermodynamically stable
microemulsion system is formed which is then
dispersed drop wise using a specially developed
thermostated syringe in to cold water with gentle
stirring.
IV. The produced SLNs are washed three times with
distilled water and lyophilized.
Microemulsion Technique
 3. Double Emulsion Technique
SLNs production by double emulsion technique
consists of two step:

I. In the first step, drug (hydrophilic drug) is dissolved in

aqueous solvent (inner aqueous phase) and then is
dispersed in lipid containing emulsifier/stabilizer (e.g.
lecithin), known as oil phase, to produce primary
emulsion (w/o).

II. A double emulsion (w/o/w) is formed after addition of

aqueous solution of hydrophilic emulsifier (e.g. poloxamer,
PVA) followed by stirring.
Double emulsion technique.
4. Solvent-injection method
I. In solvent injection (or solvent displacement)
method the lipid and the drug are dissolved in a
water-miscible organic solvent (ethanol, acetone,
isopropanol)

II. This solution is injected through a syringe needle in

water under stirring.

III. Lipid precipitates as nanoparticles while contacting

water, encapsulating the drug.
Preparation of Protein
Nanoparticles
Protein Nanoparticles
• Natural biomolecules such as proteins are an
attractive alternative to synthetic polymers which are
commonly used in drug formulations because of
their safety.

• In general, protein nanoparticles offer a number of

advantages including biocompatibility and
biodegradability.

• They can be prepared under mild conditions without

the use of toxic chemicals or organic solvents.
Protein Nanoparticles
Protein Biological Source Properties
Albumin Egg white, bovine serum water soluble protein, nontoxic,
albumin and human biodegradable, easy to prepare,
serum albumin (HSA) nonimmunogenic, easily attachable
to covalent linkage.

Gelatin Controlled hydrolysis of Easy to crosslink, easily sterilized,

fibrous, insoluble inexpensive in nature, no
protein and collagen contamination with pyrogens.
which is obtained from
the skin, bones and
connective tissues.

Gliadin Extracted from wheat Gliadin is suitable for the oral and
topical drug delivery system. Used
for the preparation of
mucoadhesive formulation because
it has capability to adhere on the
mucus membrane.
Protein Biological Source Properties
Elastin Connective tissue Elasticity and tensile strength.
Biocompatibility, biodegradability,
natural occurrence, nontoxic and
stability,
Zein Corn kernel Nontoxic, stable, and
biodegradable.
Milk Protein Obtained from milk There are two types of milk protein
used in drug delivery application
which are β-lacto globulin (BLG) and
casein.
BLG has good gelling ability which
was used as drug delivery
application.
Casein exist as micelles size of
ranges of 100–200 nm, it used to
transport the calcium and amino
acid. Casein can withstand with heat
and mechanical forces
Methods of preparation of Protein
nanoparticles
1. Emulsification Method.

2. Desolvation Method/Coacervation Method.

3. Electrospray Method.
 1. Emulsification Method
I. There are two main strategies concerning emulsification by
solvent evaporation method. The first method depends on
the preparation of single emulsion (w/o), and the second
depends on the preparation of double emulsions (w/o/w).

II. These methods utilize high-speed homogenization or

ultrasonication, followed by evaporation of the solvent
during the continuous magnetic stirring at room
temperature or under reduced pressure.

III. Solidified nanoparticles can be collected by

ultracentrifugation.
 2. Desolvation Method/ Coacervation method
I. This method is also called coacervation method. Under
this method, a desolvation agent such as natural salt or
alcohol is added into the aqueous solution of albumin.

II. By adding of desolvation agents, protein starts changing

its structure slowly. Now at certain level protein, clumps
will be made and finally nanoparticles will be formed
due to crosslinking.

III. To separate the particles, the turbidity of the system

should be increased.
• Acetone when used as an antisolvent produces smaller
albumin nanoparticles than those obtained by using
ethanol

• An increase in antisolvent/solvent ratio decreases the

particle size due to rapid extraction or diffusion of the
solvent into the antisolvent phase.

• Drugs can be loaded into particles by surface adsorption

or by entrapping the drugs in the particles during the
preparation process.
3. Electrospray Method
Electrospray is a relatively new technique.
I. Protein and drug are dispersed in a common
suitable solvent and placed within a capillary tube.

II. Then, protein solution is pulled out of the capillary

tube forming a thin jet which breaks up into
droplets under influence of electric field.

III. On the collection plate, the formation of

nanoparticles depends on the strength of the
electric field and the nature of the protein solution.
Electrospray Technique
• The evaporation of solvent takes place when the
electrosprayed jet travels from the capillary to the
collector, so the distance must be long enough in
order to completely evaporate the solvent,
otherwise, protein particles will fuse together.
 Supercritical fluid technology
• A SCF is a fluid that has been compressed and heated above
its critical temperature (Tc) and critical pressure (Pc).

• In such conditions, its physicochemical properties are

intermediate between a gas and a liquid. This is a new state
of matter, in which the fluid behaves like a gas and also has
the typical density of a liquid and thus its solvating
properties.

• Supercritical carbon dioxide (scCO2) is the most widely

used SCF because it has mild critical conditions, is abundant,
inexpensive and non-flammable
• In this method, the polymer and the drug are dissolved in
a supercritical fluid and the solution is allowed to expand
as it exits through a tiny nozzle.

• The solvent leaves its supercritical state and the solute

eventually precipitates.

• This method is suitable for low-molecular-weight

polymers only.