Dr. Satyajit Panda, M.Pharm, Ph.D (Asst.

professor)
Institute of Pharmacy & Technology, Salipur

NANOPARTICLES

By: SATYAJIT PANDA (ASST PROF)

INSTITUTE OF PHARMACY & TECHNOLOGY, SALIPUR

From the past few years nanotechnology is widely used for delivery of various drugs to the body
for increasing the bioavailability, reducing toxicity and controlled release. Under the
nanotechnology various formulations like nanoemulsions, nanosuspension, nanogels,
nanocapsules and nanospheres come. Speiser and coworkers first reported pharmaceutical
application of nanoparticles in the mid 1970s. Nanoparticles have been actively explored as
delivery systems for small drug molecules as well as macromolecules such as nucleic acids,
peptides, proteins, and hormones. By the use of this technology, nanoparticles can be prepared
which can be divided into two main families-

 Nanospheres: Which have a homogenous structure in the whole Particle

 Nanocapsule: Which exhibit a typical core shell structure

Goal of designing nanoparticles as a target delivery system are:

 Control the particle size

 Release of active drug constituent to the target site at the therapeutically rate

Advantages of Nanoparticles over the other dosage forms:

 Controlled release.
 Site specific targeting by attaching the ligands to the surface of the spheres.
 Easily pass through the smallest capillary vessels due to their tiny volume.
 Easily administered by various routes including oral, nasal, parentral etc.
 More uniform blood concentration.
 Improved patient compliance.
 Reduce dosing frequency thus increase bioavailability of drug.
 These can be freeze-dried so also obtained in a dry powder form.
Dr. Satyajit Panda, M.Pharm, Ph.D (Asst. professor)
Institute of Pharmacy & Technology, Salipur
 Non-toxic and biodegradable.
 Drug loading is relatively high than other dosages forms.

Preparation techniques for development of nanoparticles:

For preparation of nanoparticles, a large no of materials to be used like proteins, polysaccharides.

The preparation of nanoparticles should satisfy certain criteria. They are as follows

 Ability to incorporate large concentration of drug.

 Stability of the preparation after synthesis with a clinically acceptable shelf life.
 Controllable particle size and dispersability in aqueous vehicles for injection.
 Release of active agent with good control over wide time scale.
 Biocompatibility with a controllable biodegradability.
 Susceptibility to chemical modification.

Various methods have been searched by the researchers to make the particles in the nano range.
Nanoparticles can be obtained by polymerization of monomers entrapping the drug molecules, as
well as from the performed polymers. The basic methodologies of commonly used are described
as follows:

1. Solvent evaporation method:

In this method, there is conventional formation of o/w emulsion between a partially water
miscible solvent containing the polymer and the drug, and an aqueous phase containing the
stabilizer. In this polymer is dissolved in an organic solvent such as dichloromethane, chloroform
or ethyl acetate. Oil in water (o/w) emulsion is prepared by emusification of drug and polymer
mixture in aqueous solution which contain emulsifying agent, which result in formation of stable
emulsion. After that by using pressure reduction method or continuous stirring, organic solvent is
evaporated.The homogenizer speed, nature and stabilizer concentration along with the property
of polymer effect the size of nanoparticle. Usually high speed homogenizer or ultrsonication had
been used to reduce the size of nanoparticle to an optimum size. This method can only be applied
to liposoluble drugs, and limitations are imposed by the scale-up of the high energy requirements
in homogenization.

2. Double Emulsification Method:

A modification of the single-emulsion method is made by the preparation of a water-in-oil-in-

water (w/o/w) type multiple emulsion, which allows for the better incorporation of hydrophilic
drugs; this process is termed as the double- or multiple-emulsion method. The process consists of
adding the aqueous solution of the drug to the polymer solution in an organic solvent with
vigorous stirring to form the first w/o emulsion. This emulsion system is then added gently with
stirring to a large quantity of water containing PVA, resulting in a w/o/w double emulsion. The
solvent is then evaporated or extracted from the emulsion as previously described. The extraction
of the polymer solvent (e.g., acetone or acetonitrile) from the polymer droplets predominantly
Dr. Satyajit Panda, M.Pharm, Ph.D (Asst. professor)
Institute of Pharmacy & Technology, Salipur
takes place when the external phase (e.g., water) is miscible with the polymer solvent. On the
other hand, the evaporation process assumes the predominant step if the polymer solvent (e.g.,
dichloromethane) is not miscible with the external phase (e.g., water).

3. Spontaneous emulsification or solvent diffusion method:

This is a modified version of solvent evaporation method. In this method, the water miscible
solvent along with a small amount of the water immiscible organic solvent is used as an oil
phase. Due to the spontaneous diffusion of solvents an interfacial turbulence is created between
the two phases leading to the formation of small particles. As the concentration of water miscible
solvent increases, a decrease in the size of particle can be achieved. Both solvent evaporation and
solvent diffusion methods can be used for hydrophobic or hydrophilic drugs. In the case of
hydrophilic drug, a multiple w/o/w emulsion needs to be formed with the drug dissolved in the
internal aqueous phase.

Schematic presentation of Emulsification solvent diffusion method

This technique presents several advantages, such as high encapsulation efficiencies, no need for
homogenization, high batch-to-batch reproducibility, ease of scale-up, simplicity, and narrow
size distribution. Disadvantages are the high volumes of water to be eliminated from the
suspension and the leakage of water-soluble drug into the saturated-aqueous external phase
during emulsification, reducing encapsulation efficiency.

4. Polymerization method:

Polmerization of monomers in an aqueous solution form the basis of this method. Two different
techniques are used for the preparation in aqueous solution.

a) Emulsion polymerization: - this method involves emulsification of monomer in non-solvent

phase.
Dr. Satyajit Panda, M.Pharm, Ph.D (Asst. professor)
Institute of Pharmacy & Technology, Salipur
b) Dispersion polymerization: - this method involves dispersion of monomer in non-solvent
phase.
Incorporation of drug in nanoparticles can be achieved either by dissolving the drug in
polymerization medium or by adsorption onto nanoparticle. Suspension of nanoparticles is
formed, which contain surfactants and stabilizers that are used in polymerization which has to be
removed by method like ultracentrifugation or by suspending them in isotonic medium which is
free of surfactant. Polybutylcyanoacrylate or poly (alkylcyanoacrylate) nanoparticles are been
prepared by this method. The polmer particle size had been affected by concentration of
stabilizer and surfactant involved in preparation.

Schematic presentation of Polymerization technique

5. Supercritical fluid technology:

Various conventional approaches like solvent diffusion, solvent extraction evaporation and
organic phase separation require the use of organic solvent are hazardous to the environment as
well as the physiological systems. Supercritical fluid technology thus has been invested as an
alternative to prepare biodegradable Nanoparticles. In the supercritical fluid technology both the
drug and the polymer are dissolved in a suitable organic solvent and are atomized through a
nozzle into supercritical CO2. The dispersed organic solvent phase and the antisolvent CO2
phase diffuse into each other and since CO2 is miscible only with the solvent, the solvent gets
extracted causing the supercritical fluid–insoluble solid to precipitate as nanoparticles. The rates
of two-way mass transfer are much faster than those for conventional organic antisolvents. When
the density of CO2 decreases, the atomization of the spray is intensified, resulting in faster mass
transfer rates associated with high surface area of the associated droplets, thus rapid nucleation
and smaller particle sizes. The dry, micronized powder is then collected following the
depressurization of CO2.

6. Salting Out:
Dr. Satyajit Panda, M.Pharm, Ph.D (Asst. professor)
Institute of Pharmacy & Technology, Salipur
The preparation method consists of adding an electrolyte-saturated (usually magnesium chloride
hexahydrate) or a non–electrolyte-saturated aqueous solution containing PVA as a viscosity
increasing agent as well as a stabilizer to an oil phase composed of the polymer and the drug
dissolved in acetone under continuous mechanical stirring at room temperature. The saturated
aqueous solution prevents complete miscibility of both the phases by virtue of the high salt
content. After the preparation of the initial water in- oil emulsion (w/o), water is immediately
added in sufficient quantity to cause a phase inversion from water-in-oil (w/o) to oil-in-water
(o/w) type emulsion; this induces complete diffusion of acetone from the internal nonaqueous
phase into the continuous external aqueous phase, thus leading to the formation of nanoparticles.
The final emulsion is then stirred overnight at room temperature to allow for the complete
removal of acetone. Centrifugation may also be used to remove the organic solvent, free PVA,
and electrolytes from the raw nanoparticle suspension, after which the nanoparticles can be
purified by cross-flow microfiltration and subsequently freeze-dried.

7. Spray Drying:
In this method, a solution or dispersion (w/o) of a drug in an organic solvent containing the
polymer is sprayed from the sonicating nozzle of a spray dryer and subsequently dried to yield
nanoparticles. The process parameters that can be varied include the inlet and outlet air
temperatures, spray flow, and compressed spray air flow (represented as the volume of the air
input). In a novel, low-temperature, freeze–spray-drying method, the solution or dispersion of the
drug in an organic solvent containing the dissolved polymer is sprayed or atomized through an
ultrasonic nozzle into a vessel containing liquid nitrogen overlaying frozen ethanol and frozen at
-800C and lyophilized. The liquid nitrogen is evaporated, whereupon the melting liquefied
ethanol extracts the organic solvent from the frozen droplets causing the particles to harden. The
nanoparticles are filtered and dried under vacuum. Higher encapsulation efficiency for
hydrophilic drugs can be achieved with the spraydrying method using aqueous solutions. With an
aim to avoid significant product loss due to nanoparticulate adhesion on to the interior wall of the
spray dryer, as well as to prevent the aggregation of the nanoparticles, a double nozzle spray-
drying method has been developed together with the use of mannitol as an antiadherent. In this
technique, drug solution or suspension in the polymer solution is sprayed from one nozzle, with
the aqueous mannitol solution being simultaneously sprayed from another nozzle. In this process,
the surface of the spray-dried nanoparticles gets coated with mannitol and the degree of
agglomeration is reduced.
Dr. Satyajit Panda, M.Pharm, Ph.D (Asst. professor)
Institute of Pharmacy & Technology, Salipur

Schematic presentation of Freeze spray drying technique

Applications of Nanoparticles:
1. Nanoparticles for oral delivery of Proteins and peptides: It is very difficult to use the
bioactive molecules (peptides and proteins) with suitable carriers. These suitable carriers remain
a challenge due to the fact that bioavailability of these molecules is limited and they get degraded
by enzymatic action. So the polymeric nanoparticles allow encapsulation of bioactive molecules
and have been employed as preoral drug carriers with the following objectives:
 Improvement of the bioavailability of drug with poor absorption characteristics.
 Controlled or sustained release of drug.
 Reduction of Gastrointestinal mucosa irritation cause by drugs.
 Assurance of the stability of drugs in the gastrointestinal tract.

2. Nanoparticles for drug delivery in the brain: In central nervous system the most important
factor is BBB (blood brain barrier) for the development of new drugs and it is characterized by
impermeable endothelial cells with tight junction, enzyme activity and active transport systems.
Basically the BBB only permits selective transport of molecules. A number of literatures are
accounted for the enhanced delivery of drugs to the brain using nanoparticles.
 Higher concentration gradient at the blood brain barrier that may enhance the transport
across endothelial cell layer and hence increased retention in the brain.
 Solubilization of endothelial cell membrane lipids by surfactant action of nanoparticles
leading to membrane fluidization and enhance drug permeability to blood brain barrier.
 Loosening of tight junction between endothelial cells and increase permeability of drug
or drug nanoparticles conjugates through these channels.
 Endocytosis of nanoparticles by the endothelial cells followed by the release of the drugs
intracellularly.
Dr. Satyajit Panda, M.Pharm, Ph.D (Asst. professor)
Institute of Pharmacy & Technology, Salipur
 Trancytosis of the drug bound nanoparticles through the endothelial cell layer.
 E.g. Polysorbate 80/LDL is capable for delivery. So the drugs which cannot easily cross
the BBB, can easily pass with the help of nanospheres.

3. Long circulation of nanoparticles: Basically nanoparticles are able to target tumors which
are localized outside MPS (Mononuclear Phagocytic system). For long circulation of
nanoparticles a major break came in the field when hydrophilic polymer (PEG, Poloxamine and
Polysaccharides) is coated to the surface of nanoparticles by which opposite effect is produced to
the uptake by the MPS. The coating provides a cloud of hydrophilic and neutral chain at the
particle surface which repels plasma proteins. As a result coated nanoparticles become invisible
to MPS and remain for a longer duration during circulation.

4. Targeting on the tumor: Nanoparticles are able to deliver the concentrate dose of the drug to
the tumor targets through permeability enhancing and retention effect or active targeting by
ligands on the surface of nanoparticles. It can reduce the toxicity by reducing the drug exposure
of health tissue by limiting drug distribution to the target organ.

5. Polymeric nanoparticles in diabetes treatment: Polymer systems: Copolymers of N,N-

dimethyl aminoethyl methacrylate and polyacrylamide act as molecular gate systems. These
“Molecular gate” systems are composed of an insulin reservoir and a delivery rate–controlling
membrane. At normal body pH (pH = 7.4) polymer swells and closes the gate. At lower pH
polymer shrink, when the blood glucose level increases, thus opening the gates. Eg: Ceramic and
polymeric nanoparticles, gold nanoparticles.

6. Nanoparticles role in preventon of multi drug resistance: The p-glycoprotein is an efflux

pump which rejects the positively charged drugs. Over expression of this transport protein will
decrease the drug sensitivity in tumor cells. Nanoparticle loaded drugs have protection against
this protein due to lysosomal localization. Eg : Polyisohexylcyanoacrylate nanoparticle bound
doxorubicin.
Approach : To combine two different anticancer agents in one nanoscale construct, which can
prove lethal to such resistant cells.
Dr. Satyajit Panda, M.Pharm, Ph.D (Asst. professor)
Institute of Pharmacy & Technology, Salipur
7. Nanoparticles for oral delivery of peptides and proteins: Polymeric nanoparticles allow
encapsulation of bioactive molecules and protect them against enzymatic and hydrolytic
degradation. Colloidal carrier system, such as nanoparticles are capable of enhancing the
interaction mechanisms of the drug delivery system and the epithelial cells in the GI tract. Eg:

 Insulin-loaded nanoparticles.
 Peptides(eg:granulocyte colony stimulating factor, erythropoietin) and particles by
covalent coupling to vitamin B-12.
8. Solid-lipid nanoparticles: These are submicron colloidal carriers (50-100 nm) composed of
physiological lipid dispersed in water. Offer better protection to drug against chemical
degradation (no access of water to inner core of the lipid particle). It has combined advantage of
liposomes, polymeric nanoparticles and emulsions. USE:In chemotherapy of tuberculosis,
cancer.

9. Quantum dots: Quantum dots (QDs) are semiconducting materials consisting of a

semiconductor core (CdSe), coated by a shell (e.g., ZnS).(10–100 Å) in radius. They have bright
fluorescence, broad UV excitation and high photostability. So they are adopted for in vitro
bioimaging for tracking of intracellular process for longer time. Advantage: Biopsy can be
avoided.

10. Nanoshells in cancer therapy: Nanoshells are miniscule beads coated with gold. By
manipulating the thickness of the layers these are designed to absorb specific wavelengths of
light. Most useful nanoshells absorb near-infrared light, which can easily penetrate several
centimeters of human tissue. The absorption of light by the nanoshells creates an intense heat
that is lethal to cells.