Konwar Ranjit et al. Int. Res. J. Pharm.

2013, 4
(4)
INTERNATIONAL RESEARCH JOURNAL OF PHARMACY

ISSN 2230 – 8407

Review Article

NANOPARTICLE: AN OVERVIEW OF PREPARATION, CHARACTERIZATION AND APPLICATION

Konwar Ranjit*, Ahmed Abdul Baquee
Department of Pharmaceutics, Girijananda Chowdhury Institute of Pharmaceutical Science (GIPS), Hatkhowapara,
Azara, Guwahati, India
Email: ranjit.konwar09@gmail.com

Article Received on: 11/02/13 Revised on: 02/03/13 Approved for publication: 01/04/13

DOI: 10.7897/2230-8407.04408
IRJP is an official publication of Moksha Publishing House. Website: www.mokshaph.com
© All rights reserved.

ABSTRACT
In the last 30 years, particle size reduction technologies turned from an exploratory approach into a mature commercial drug delivery platform. Nanonization
technologies have gained a special importance due to a steadily increasing number of development compounds showing poor aqueous solubility. Many drug
delivery companies and academic research groups have contributed to the currently existing large variety of different technologies to produce drug
nanoparticles. These particles consist of pure active pharmaceutical ingredient (API) and are often stabilized with surfactants and/or polymeric stabilizers
adsorbed onto their surface. The mean particle size ranges normally from 1 nm up to 1000 nm.
Here we review formulation aspects, characteristics and application of nanoparticle as drug delivery system.
KEYWORDS: Nanoparticles, polymeric nanoparticles, targeting, drug delivery, drug release.

INTRODUCTION This systemic review focuses on Classification, method of

The prefix “nano” has found in last decade an ever- preparation, Characterization, and applications of
increasing application to different fields of the knowledge. nanoparticles.
Nanoscience, nanotechnology, nanomaterials or
nanochemistry are only a few of the new nano-containing Need for developing nanoparticles
terms that occur frequently in scientific reports, in popular The major goals in designing nanoparticles as a delivery
books as well as in newspapers and that have become system are to control particle size, surface properties and
familiar to a wide public, even of non- experts. The prefix release of pharmacologically active agents so as to achieve
comes from the ancient Greek να̃νος through the Latin nanus the site specific action of the drug at the rationale rate and
meaning literally dwarf and by extension, very small. Within dose.2 Polymeric nanoparticles offer some specific
the convention of International System of Units (SI) it is advantages over liposomes. For instance, they help to
used to indicate a reduction factor of 109 times. So, the increase the stability of drugs/proteins and possess useful
nanosized world is typically measured in nanometers (1nm controlled release properties.3
corresponding to 10-9 m) and it encompasses systems whose
size is above molecular dimensions and below macroscopic Advantages
ones (generally > 1 nm and < 100 nm). Some of the advantages of using nanoparticles as a drug
Nanotechnology is the science of the small; the very small. It delivery system are as follows;
is the use and manipulation of matter at a tiny scale. At this 1. Ease of manipulation of the particle size and surface
size, atoms and molecules work differently, and provide a characteristics of nanoparticles so as to achieve both passive
variety of surprising and interesting uses. Nanotechnology and active drug targeting after parenteral administration.
and Nanoscience studies have emerged rapidly during the 2. The nanoparticle surface can be modified to alter
past years in a broad range of product domains. It provides biodistribution of drugs with subsequent clearance of the
opportunities for the development of materials, including drug so as to achieve maximum therapeutic efficacy with
those for medical applications, where conventional minimal side effects of the drug.4
techniques may reach their limits. Nanotechnology should 3. Controlled release and particle degradation characteristics
not be viewed as a single technique that only affects specific can be readily modulated by the choice of matrix
areas. Although often referred to as the ‘tiny science’, constituents.
nanotechnology does not simply mean very small structures 4. Drug loading is relatively high and drugs can be
and products. Nanoscale features are often incorporated into incorporated into the systems without any chemical reaction;
bulk materials and large surfaces. Nanotechnology this is an important factor for preserving the drug activity.
represents the design, production and application of 5. Site-specific targeting can be achieved by attaching
materials at atomic, molecular and macromolecular scales, in targeting ligands to surface of particles or use of magnetic
order to produce new nanosized materials.1 Pharmaceutical guidance.
nanoparticles are defined as solid, submicron-sized (less 6. Liposomes and polymer based nanoparticulates are
than 100 nm in diameter) drug carrier that may or may not generally biodegradable, do not accumulate in the body and
be biodegradable. The term nanoparticle is a combined name so are possibly risk free.
for both nanospheres and nanocapsules. Nanospheres are 7. Small sized nanoparticles can penetrate through smaller
matrix system in which drug is uniformly dispersed, while capillaries, which could allow efficient drug accumulation at
nanocapsules are the system in which the drug is surrounded the target sites.
by a unique polymeric membrane. 8. Various routes of administration are available including
oral, nasal, parenteral, intra-ocular etc.5

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Limitations nanoparticulate toxicity reactions are observed due to
In spite of these advantages nanoparticles do have inhalation of particulate matter leading to lung and
limitations like, cardiovascular diseases.
1. Altered physical properties which lead to particle –
particle aggregation, making physical handling of Types of Nanoparticles
nanoparticles difficult in liquid and dry forms due to smaller Polymeric nanoparticles are colloidal structures composed of
size and larger surface area. synthetic or semi synthetic polymers. The drug is dissolved,
2. Smaller the particles size greater the surface area and this entrapped, encapsulated or attached to a nanoparticle matrix.
property makes nanoparticles very reactive in the cellular Depending upon the method of preparation, nanoparticles,
environment. nanospheres or nanocapsule can be obtained. Nanocapsules
3. Small particles size results in limited drug loading and are systems in which the drug is confined to a cavity
burst release. These practical problems have to be sorted out surrounded by a unique polymer membrane, while
before nanoparticles can be used clinically or made nanospheres are matrix systems in which the drug is
commercially available.6 physically and uniformly dispersed. The general synthesis
and encapsulation of polymer are represented in Fig.1.
Toxicity Polymers such as polysaccharide Chitosan-Polylactic acid,
These tiny particles can easily get the entry inside the body Polylactic acid coglycolic acid, Poly-caprolactone, Chitosan
through the skin, lungs or intestinal tract, depositing in nanoparticles have been used.
several organs and may cause severe adverse biological Solid lipid nanoparticles (SLN) have been proposed as a new
reactions by altering the physiochemical properties of tissue. type of colloidal drug carrier system suitable for intravenous
Non-biodegradable particles when used for drug delivery administration. The system consists of spherical solid lipid
may show accumulation on the site of the drug delivery, particles in the nanometres range, which is dispersed in
leading to chronic inflammatory reactions. Most of the water or in surfactant solution.7

Figure 1: Types of polymeric nanoparticles: According to the structural organization biodegradable nanoparticles are classified as Nanocapsules and
nanospheres. The drug molecules are either entrapped inside or adsorbed on the surface.

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Classification of Nanoparticles as DNA and can also be fabricated to metallic nanostructure
There are various approaches for classification of and nanotubes or to possess an encapsulation capacity.13
nanomaterials. Nanoparticles are classified based on one, Dendrimers have different reactive surface groupings
two and three dimensions. 8 (nanostructure) and compatible with organic structure such
as DNA so their prolific use is particularly in the medical
One dimension nanoparticles and biomedical fields. The pharmaceutical applications of
One dimensional system, such as thin film or manufactured dendrimers include nonsteroidal anti-inflammatory
surfaces, has been used for decades in electronics, chemistry formulations, antimicrobial and antiviral drugs, anticancer
and engineering. Production of thin films (sizes1-100 nm) or agents, pro-drugs, and screening agents for high-throughput
monolayer is now common place in the field of solar cells or drug discovery.14 Dendrimers may be toxic because of their
catalysis. These thin films are using in different ability to disrupt cell membranes as a result of a positive
technological applications, including information storage charge on their surface.15
systems, chemical and biological sensors, fibre-optic
systems, magneto-optic and optical device. Quantum Dots (QDs): Quantum dots are small devices that
contain a tiny droplet of free electrons. QDs are colloidal
Two dimension nanoparticles semiconductor nanocrystals ranging from 2 to 10 nm in
Carbon nanotubes (CNTs): Carbon nanotubes are diameter. QDs can be synthesized from various types of
hexagonal network of carbon atoms, 1 nm in diameter and semiconductor materials via colloidal synthesis or
100 nm in length, as a layer of graphite rolled up into electrochemistry. The most commonly used QDs are
cylinder. CNTs are of two types, single walled carbon cadmium selenide (CdSe), cadmium telluride (CdTe),
nanotubes (SWCNTs) and multi-walled carbon nanotubes indium phosphide (InP), and indium arsenide (InAs).
(MWCNTs) .The small dimensions of carbon nanotubes, Quantum dots can have anything from a single electron to a
combined with their remarkable physical, mechanical and collection of several thousands. The size, shape and number
electrical properties make them unique materials. They of electrons can be precisely controlled. They have been
display metallic or semi conductive properties, depending on developed in a form of semiconductors, insulators, metals,
how the carbon leaf is wound on itself. The current density magnetic materials or metallic oxides. It can be used for
that nanotubes can carry is extremely high and can reach one optical and optoelectronic devices, quantum computing, and
billion amperes per square meter making it a information storage. Colour coded quantum dots are used for
superconductor. The mechanical strength of carbon fast DNA Testing. Quantum dots (QDs) refer to the quantum
nanotubes is sixty times greater than the best steels. Carbon confinement of electrons and hole carriers at dimensions
nanotubes have a great capacity for molecular absorption smaller than the Bohr radiuos. QD nanocrystals are generally
and offering a three dimensional configuration. Moreover composed of atoms from groups II and VI (that is CdSe,
they are chemically and chemically very stable.9 CdS, and CdTe) or II and V (such as In P) at their core. A
shell (that is ZnS and CdS) can be further introduce to
Three dimension nanoparticles
prevent the surface quenching of excitons in the emissive
Fullerenes (Carbon 60): Fullerenes are spherical cages core and hence increase the photostability and quantum yield
containing from 28 to more than 100 carbon atoms, contain of emission.16 QDs also provide enough surface area to
C60. This is a hollow ball composed of interconnected carbon attach therapeutic agents for simultaneous drug delivery and
pentagons and hexagons, resembling a soccer ball. in vivo imaging, as well as for tissue engineering.17
Fullerenes are class of materials displaying unique physical
properties. They can be subjected to extreme pressure and Preparation of Polymeric Nanoparticles
regain their original shape when the pressure is released. Nanoparticles can be prepared from a natural material such
These molecules do not combine with each other, thus as proteins, polysaccharides and synthetic polymers. The
giving them major potential for application as lubricants. selection of inert matrix material is depends on many factors
They have interesting electrical properties and it has been like:18 (a) final size of nanoparticles required; (b) drug
suggested to use them in the electronic field, ranging from properties like aqueous solubility and stability; (c) surface
data storage to production of solar cells. Fullerenes are charge and permeability; (d) degree of biodegradability,
offering potential application in the rich area of biocompatibility and toxicity; (e) desired drug release
nanoelectronics. Since fullerenes are empty structures with profile; and (f) Antigenicity of the final product.
dimensions similar to several biological active molecules, The preparation method of nanoparticles can be classified in
they can be filled with different substances and find potential different ways:
medical application. 10 In the first, it can be classified as:
 Bottom-up technique
Dendrimers: Dendrimers represents a new class of
 Chemical reaction technique
controlled-structure polymers with nanometric dimensions.
 Top-down technique
Dendrimers used in drug delivery and imaging are usually
10 to 100 nm in diameter with multiple functional groups on  Combination technique
their surface, rendering them ideal carriers for targeted drug Nanoparticles can be obtained by using bottom-up processes,
delivery.11 The structure and function of dendrimers has i.e. precipitation starting from molecular solutions.
been well studied. Contemporary dendrimers can be highly Furthermore, comminution of larger particles down to
specialized; encapsulating functional molecules (i.e., nanoparticles (top-down) can be performed. Another way is
therapeutic or diagnostic agents) inside their core. 12 They are the combination of both principles (combination techniques).
considered to be basic elements for large-scale synthesis of The last way leads via a chemical reaction step directly to
organic and inorganic nanostructures with dimensions of 1 nanoparticles (chemical reaction approach).
to 100 nm 11. They are compatible with organic structure
such
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Figure 2: Overview of various principles to produce nanoparticles

Chemical Reactions based on wet ball milling (WBM). In order to produce

Chemical reactions, like polymerizations, are one way to nanocrystalline dispersions, a milling chamber is charged
produce nanoparticles; however they are normally not used with milling media (e.g. zirconium dioxide beads, silicium
for the production of drug nanoparticles consisting of pure nitride beads, polystyrene beads), aqueous stabilizer/
API. surfactant solution and micronized API. The moving milling
These techniques are commercially very important e.g. for media causes high shear forces and thus attrition of the drug
the production of pharmaceutical coating materials in the particles. For large scale production, the mill can be run in
form of latex dispersions. Chemical reactions can also be circulation mode, which means that the suspension is
used to manufacture polymeric nanoparticles consisting of a continuously pumped through the milling chamber until the
matrix forming polymer in which the API is embedded. The desired particle size of the drug nanocrystals is obtained.
drug load of such particles is normally significantly lower The drug particles are separated from the milling media by a
than 100% therefore they have to be distinguished from drug separating gap or a filter cartridge. The WBM technology is
nanoparticles produced via standard particle size reduction by far the most important particle size reduction method at
techniques. the moment. Currently there are 5 products on the market
using this technology; many others are still in development.
Bottom-up Approaches
High pressure homogenization (HPH) is another very
Bottom-up approaches start with drug molecules in solution.
important top-down technology. One can distinguish several
By changing the conditions of the system in solution, the process types. The first technology that was developed based
drug molecules start to precipitate in larger formations. In on HPH with a piston-gap homogenizer is a process
the classical precipitation process, the poorly soluble API is performed in aqueous media at room temperature. During
dissolved in a water miscible organic solvent. The the homogenization step, a coarse suspension is forced
precipitation is induced by mixing the drug solution with an through a very tiny homogenization gap. The particle size
aqueous phase. This is often referred to as the “solvent/ reduction is mainly caused by cavitation forces, shear forces,
antisolvent” approach. One approach was already developed and particle collision. Later, this principle was further
in the 1980’s by Sucker and colleagues. The principle of development as a process, which can be also performed in
classical precipitation has been then further developed by water-reduced and non-aqueous media. Drug nanoparticles
several academic and industrial research groups. Later also can be also generated by a high shear process using jet stream
more and more advanced precipitation technologies have homogenizers. In this case the collision of two fluid streams
been introduced. These technologies are also referred to as under high pressures up to 1700 bar leads to particle
particle engineering technologies. One interesting approach collision, shear forces and also cavitation forces. To preserve
is known as Evaporative Precipitation into Aqueous Solution the particle size, stabilization with phospholipids or other
(EPAS). For this process, the API is dissolved in an organic surfactants and stabilizers is required. A major disadvantage
solvent which is not miscible with water. The drug of this process is the required production time. In many
solution is sprayed into heated water resulting in an
cases, time consuming 50 to 100 passes are necessary for a
immediate evaporation of the organic solvent, thus drug
sufficient particle size reduction. This technology is now
nanoparticles are formed instantaneously. Spray-freezing
also used for one product on the market.
into liquid (SFL) and ultrarapid freezing (URF) are The last production principle is a relatively new one. The
alternative particle engineering processes developed by the combinative approach describes a process where at least two
same research group. different particle size reduction principles are combined. The
most common combination is a bottom-up process which is
Top-down Approaches combined with a top-down step.19
In contrast to the bottom-up technologies, one can also start In an another way the preparation of nanoparticles can be
with large API particles and break them down to small drug classified as: 20
nanoparticles. Therefore, this process type is regarded as A) Dispersion of preformed polymers
top- down technology. Currently particle size reduction 1. Solvent evaporation method
technologies of this type are by far commercially the most 2. Spontaneous emulsification or solvent diffusion method
important and successful. A very important technology is B) Polymerization of monomers

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C) Ionic gelation or coacervation of hydrophilic polymers D) Supercritical fluid technology: Conventional methods
D) Supercritical fluid technology such as solvent extraction-evaporation, solvent diffusion and
However, other methods such as particle replication in non- organic phase separation methods require the use of
wetting templates (PRINT) have also been described in the enormous amounts of organic solvents which are hazardous
21

literature for production of nanoparticles. to the environment as well as to human beings. Therefore,
the supercritical fluid technology has been investigated as an
A) Dispersion of preformed polymers: It is the most alternative to prepare biodegradable micro- and
common technique used to prepare biodegradable nanoparticles. Supercritical fluids are environmentally safe.30
nanoparticles from poly (lactic acid) (PLA); poly (D, L A supercritical fluid can be generally defined as a solvent at
glycolide), PLG; poly (D, L-lactide-co-glycolide) (PLGA) a temperature above its critical temperature, at which the
and poly (cyanoacrylates) (PCA). 22, 23 fluid remains a single phase regardless of pressure.
Supercritical CO2 (SC CO2) is the most widely used
1. Solvent evaporation method: Organic solvents such as supercritical fluid because of its mild critical conditions
dichloromethane, chloroform or ethyl acetate are used to (Tc = 31.1 °C, Pc =
dissolve the polymer which is also used as the solvent for 73.8 bars), nontoxicity, non-flammability and low price. The
dissolving the hydrophobic drug. The drug dissolved or most common processing techniques involving supercritical
dispersed in polymer solution is then emulsified in an fluids are supercritical anti-solvent (SAS) and rapid
aqueous solution containing a surfactant or emulsifying expansion of critical solution (RESS). The process of SAS
agent to form oil in water emulsion. Once stable emulsion is employs a liquid solvent, e.g. methanol, which is completely
formed, the organic solvent is evaporated either by reducing miscible with the supercritical fluid (SC CO ), to dissolve
2
the pressure or by continuous stirring. For preparation of the the solute to be micronized; at the process conditions,
small uniform sized particle size, High-speed homogenizer because the solute is insoluble in the supercritical fluid, the
or ultrasonication may be employed.24 extract of the liquid solvent by supercritical fluid leads to the
instantaneous precipitation of the solute, resulting the
2. Spontaneous emulsification or solvent diffusion
formation of nanoparticles. The solvent power of
method: This is a modification of solvent evaporation
supercritical fluids dramatically decreases and the solute
method. This technique involves the use of water miscible eventually precipitates. This technique is clean because the
solvent along with a small amount of the water immiscible
precipitate is basically solvent free. RESS and its modified
organic solvent as an oil phase. An interfacial turbulence is process have been used for the product of polymeric
generated between the two phases due to spontaneous
nanoparticles.31, 32 Supercritical fluid technology technique,
diffusion of immiscible solvents leading to the formation of although environmentally friendly and suitable for mass
small particles. By increasing the concentration of water
production, requires specially designed equipment and is
miscible solvent decrease in the particle size can be more expensive.
achieved. Both solvent evaporation and solvent diffusion
methods can be used for hydrophobic or hydrophilic drugs. Characterization of Nanoparticles
For hydrophilic drug, a multiple w/o/w emulsion needs to be Nanoparticles are generally characterized by their size,
formed with the drug dissolved in the internal aqueous morphology and surface charge, using such advanced
phase.25 microscopic techniques as scanning electron microscopy
(SEM), transmission electron microscopy (TEM) and atomic
B) Polymerization method: In this method, monomers are force microscopy (AFM). The average particle diameter, their
polymerized to form nanoparticles in an aqueous solution in size distribution and charge affect the physical stability and
which drug may be dissolved. Drug may also be the in vivo distribution of the nanoparticles. Electron
incorporated by adsorption onto the nanoparticles after microscopy techniques are very useful in ascertaining the
polymerization completed. The nanoparticle suspension is overall shape of polymeric nanoparticles, which may
then purified to remove various stabilizers and surfactants determine their toxicity. The surface charge of the
employed for polymerization by ultracentrifugation and nanoparticles affects the physical stability and
resuspending the particles in an isotonic surfactant-free redispersibility of the polymer dispersion as well as their in
medium. This technique has been reported for making vivo performance.
polybutylcyanoacrylate or poly (alkylcyanoacrylate)
nanoparticles. 26, 27 Particle size
Particle size distribution and morphology are the most
C) Coacervation or ionic gelation method: The method important parameters of characterization of nanoparticles.
involves a mixture of two aqueous phases, of which one is Morphology and size are measured by electron microscopy.
the polymer Chitosan, a di-block co-polymer ethylene oxide The major application of nanoparticles is in drug release and
or propylene oxide (PEO-PPO) and the other is a polyanion drug targeting. It has been found that particle size affects the
sodium tripolyphosphate. In this method, positively charged drug release. Smaller particles offer larger surface area. As a
amino group of Chitosan interacts with negative charged result, most of the drug loaded onto them will be exposed to
tripolyphosphate to form coacervates with a size in the range the particle surface leading to fast drug release. On the
of nanometre. Coacervates are formed as a result of contrary, drugs slowly diffuse inside larger particles. As a
electrostatic interaction between two aqueous phases, drawback, smaller particles tend to aggregate during storage
whereas, ionic gelation involves the material undergoing and transportation of nanoparticle dispersion. Hence, there is
transition from liquid to gel due to ionic interaction a compromise between a small size and maximum stability
conditions at room temperature. 28, 29 of nanoparticles.33
Polymer degradation can also be affected by the particle size.
For instance, the degradation rate of poly (lactic-co-glycolic

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acid) was found to increase with increasing particle size in sample based on forces between the tip and the sample
vitro. 34
surface. Samples are usually scanned in contact or noncontact
mode depending on their properties. In contact mode, the
There are several tools for determining nanoparticle size as topographical map is generated by tapping the probe on to
discussed below: the surface across the sample and probe hovers over the
conducting surface in non-contact mode. The prime
Dynamic light scattering (DLS) advantage of AFM is its ability to image non-conducting
Currently, the fastest and most popular method of samples without any specific treatment, thus allowing
determining particle size is photon-correlation spectroscopy imaging of delicate biological and polymeric nano and
(PCS) or dynamic light scattering (DLS). DLS is widely microstructures.39 AFM provides the most accurate
used to determine the size of Brownian nanoparticles in description of size and size distribution and requires no
colloidal suspensions in the nano and submicron ranges. mathematical treatment. Moreover, particle size obtained by
Shining monochromatic light (laser) onto a solution of AFM technique provides real picture which helps understand
spherical particles in Brownian motion causes a Doppler the effect of various biological conditions.40
shift when the light hits the moving particle, changing the
wavelength of the incoming light. This change is related to Surface Charge
the size of the particle. It is possible to extract the size The nature and intensity of the surface charge of
distribution and give a description of the particle’s motion in nanoparticles is very important as it determines their
the medium, measuring the diffusion coefficient of the interaction with the biological environment as well as their
particle and using the autocorrelation function. . The photon electrostatic interaction with bioactive compounds. The
correlation spectroscopy (PCS) represent the most colloidal stability is analyzed through zeta potential of
frequently used technique for accurate estimation of the nanoparticles. This potential is an indirect measure of the
particle size and size distribution based on DLS. 35 surface charge. It corresponds to potential difference
between the outer Helmholtz plane and the surface of shear.
Scanning Electron microscopy The measurement of the zeta potential allows for predictions
Scanning electron microscopy (SEM) is giving about the storage stability of colloidal dispersion. High zeta
morphological examination with direct visualization. The potential values, either positive or negative, should be
techniques based on electron microscopy offer several achieved in order to ensure stability and avoid aggregation
advantages in morphological and sizing analysis; however, of the particles. The extent of surface hydrophobicity can
they provide limited information about the size distribution then be predicted from the values of zeta potential. The zeta
and true population average. For SEM characterization, potential can also provide information regarding the nature
nanoparticles solution should be first converted into a dry of material encapsulated within the nanocapsules or coated
powder, which is then mounted on a sample holder followed onto the surface.41
by coating with a conductive metal, such as gold, using a
sputter coater. The sample is then scanned with a focused Surface hydrophobicity
fine beam of electrons.36 The surface characteristics of the Surface hydrophobicity can be determined by several
sample are obtained from the secondary electrons emitted techniques such as hydrophobic interaction chromatography,
from the sample surface. The nanoparticles must be able to biphasic partitioning, adsorption of probes, contact angle
withstand vacuum, and the electron beam can damage the measurements etc. Recently, several sophisticated analytical
polymer. The mean size obtained by SEM is comparable techniques are reported in literature for surface analysis of
with results obtained by dynamic light scattering. Moreover, nanoparticles. X – Ray photon correlation spectroscopy
these techniques are time consuming, costly and frequently permits the identification of specific chemical groups on the
need complementary information about sizing distribution. surface of nanoparticles.42
Transmission electron microscope Drug loading
TEM operates on different principle than SEM, yet it often Ideally, a successful nanoparticulate system should have a
brings same type of data. The sample preparation for TEM is high drug-loading capacity thereby reduce the quantity of
complex and time consuming because of its requirement to matrix materials for administration. Drug loading can be
be ultra thin for the electron transmittance. The nanoparticles done by two methods:
dispersion is deposited onto support grids or films. To make  Incorporating at the time of nanoparticles production
nanoparticles withstand the instrument vacuum and facilitate (incorporation method)
handling, they are fixed using either a negative staining
 Absorbing the drug after formation of nanoparticles by
material, such as phosphotungstic acid or derivatives, uranyl
incubating the carrier with a concentrated drug solution
acetate, etc, or by plastic embedding. Alternate method is to
(adsorption /absorption technique).
expose the sample to liquid nitrogen temperatures after
Drug loading and entrapment efficiency very much depend
embedding in vitreous ice. The surface characteristics of the
on the solid-state drug solubility in matrix material or
sample are obtained when a beam of electrons is transmitted
polymer (solid dissolution or dispersion), which is related to
through an ultra thin sample, interacting with the sample as
the polymer composition, the molecular weight, the drug
it passes through.37
polymer interaction and the presence of end functional
groups (ester or carboxyl).43
Atomic force microscopy
Atomic force microscopy (AFM) offers ultra-high resolution
Drug Release
in particle size measurement and is based on a physical
A central reason for pursuing nanotechnology is to deliver
scanning of samples at sub-micron level using a probe tip of
drugs, hence understanding the manner and extent to which
atomic scale.38 Instrument provides a topographical map of
the drug molecules are released is important. In order to

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obtain such information most release methods require that nanoparticles can translocate to the blood stream and
the drug and its delivery vehicle be separated. The drug distribute all over the body. Targeting strategies to improve
loading of the nanoparticles is generally defined as the the interaction of nanoparticles with adsorptive sites
amount of drug bound per mass of polymer (usually moles (enterocytes and M-cells of Peyer’s patches) in the GI tract
of drug per mg polymer or mg drug per mg polymer); it utilizes specific binding to ligands or receptors and
could also be given as percentage relative to the polymer. nonspecific adsorptive mechanism. The surface of
The technique used for this analysis is classical analytical enterocytes and M cells shows cell-specific carbohydrates,
methods like UV spectroscopy or high performance liquid which can serve as binding sites to nanoparticle drug carriers
chromatography (HPLC) after ultracentrifugation, ultra with appropriate ligands. Certain glycoproteins and lectins
filtration, gel filtration, or centrifugal ultrafiltration. bind selectively to this type of surface structure by specific
Quantification is performed with the UV spectroscopy or receptor-mediated mechanism.
HPLC. Drug release assays are also similar to drug loading
assay which is assessed for a period of time to analyze the Brain: The brain is probably one of the least accessible
mechanism of drug release.44 organs for the delivery of drugs due to the presence of the
blood–brain barrier (BBB) that controls the transport of
Methods of evaluation for release of drugs endogenous and exogenous compounds, thus providing the
Various methods which can be used to study the in vitro neuroprotective function. Drugs normally unable to cross the
release of the drug from nanoparticles are: BBB could be delivered to the brain after binding to the
(i) Side-by-side diffusion cells with artificial or biological surface-modified poly (butyl cyanoacrylate) (PBCA)
membranes. nanoparticles.46
(ii) Dialysis bag diffusion technique.
(iii) Reverse dialysis bag technique. Tumor cell targeting: Anticancer drugs, which usually
(iv) Agitation followed by ultracentrifugation/ centrifugation. have large volume of distribution, are toxic to both normal
(v) Ultra-filtration or centrifugal ultra-filtration techniques. and cancer cells. Therefore, precise drug release into highly
specified target involves miniaturizing the delivery systems
Commonly release study is carried out by controlled to become much smaller than their targets. With the use of
agitation and centrifugation. As the method is time nanotechnology, targeting drug molecules to the site of
consuming and technical difficulties encountered in the action is becoming a reality resulting in a personalized
separation of nanoparticles from release media, the dialysis medicine, which reduces the effect of the drug on other sites
technique is generally preferred. while maximizing the therapeutic effect. This goal is mainly
There are five possible mechanisms for drug release: (a) achieved by the small size of these particles, which can
desorption of drug bound to the surface, (b) diffusion penetrate across different barriers through small capillaries
through the nanoparticle matrix, (c) diffusion through the into individual cells. In addition, nanoparticles can be
polymer wall of nanocapsule, (d) nanoparticles matrix prepared to entrap, encapsulate, or bind molecules
erosion, or (e) a combined erosion–diffusion process.45 The improving the solubility, stability and absorption of several
kinetic analysis of drug release from nanoparticles can be drugs, as well as avoiding the reticulo-endothelial system,
described by a biexponential function thus protecting the drug from premature inactivation during
its transport. In fact, it has been shown that nanoparticles
C = Ae-αt + Be-βt have the ability to carry various therapeutic agents including
DNA, proteins, peptides and low molecular weight
Where C is the concentration of drug remaining in the compounds. Among all of them, liposome and polymer-
nanoparticles at time t, A and B are system characteristic based nanoparticulates are the most widely used
constants (A is used for diffusion control system and B for nanoparticles as drug delivery systems, as these compounds
erosion control system) and α, β are rate constants that can are generally biodegradable, do not accumulate in the body
be obtained from semi logarithmic plots.45 In general drug and they are possibly risk-free. For instance, several
release rate depends upon solubility, diffusion and anticancer drugs, including paclitaxel, 5-fluorouracil,
biodegradation of the matrix materials. doxorubicin, have been successfully formulated using
polymers and liposomes as drug delivery systems.
Applications of Nanoparticulate Delivery Systems
a) Nanoparticle as drug delivery systems Respiratory tract: One of the most common entry passages
The use of pharmacological agents is frequently limited by for nanoparticles is respiratory tract. Nanoparticles could
drug resistance at the target level owing to physiological avoid normal phagocytic defences therein respiratory tract
barriers cellular mechanism is encountered. In addition, and gain access to systemic circulation and may reach to
many drugs have a poor solubility, low bioavailability and CNS. Aerosol therapy using nanoparticles as drug carrier is
they can be quickly cleared in the body by the gaining importance for delivering therapeutic compounds.
reticuloendothelial system. Furthermore, the efficacy of The lung is an attractive target for drug delivery due to non-
different drugs, such as chemotherapeutical agents, is often invasive administration via inhalation aerosols, avoidance of
limited by dose- dependent side effects. first-pass metabolism, direct delivery to the site of action for
the treatment of respiratory diseases and the availability of a
Gastrointestinal tract: Other portals for entry are GI and huge surface area for local drug action and systemic
Skin. It is known that the kinetics of particle uptake in GI absorption of drug. Colloidal carriers (i.e., nanocarrier
tract depends on diffusion and accessibility through mucus systems) in pulmonary drug delivery offer many advantages
initial contact with enterocytes, cellular trafficking and post- such as the potential to achieve relatively uniform
translocation events. The smaller the particle diameter is, the distribution of drug dose among the alveoli, achievement of
faster they could diffuse through GI secretion to reach the improved solubility of the drug from its own aqueous
colonic enterocytes Following uptake by GI tract
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 Konwar Ranjit et al. Int. Res. J. Pharm. 2013, 4
solubility, a sustained drug release which consequently coated with human molecules. The chip is designed to emit
reduces dosing frequency, improves patient compliance, an electrical impulse signal when the molecules detect signs
decreases incidence of side effects and the potential of drug of a disease. Special sensor nanobots can be inserted into the
internalization by cells.47 body under the skin where they check blood contents and
warn of any possible diseases. They can also be used to
b) For gene delivery monitor the sugar level in the blood. Advantages of using
The key ingredient of polynucleotide vaccines, DNA, can be such nanobots are that they are very cheap and easy to
produced cheaply and has much better storage and handling produce.53 Gold nanoparticles are being used for detection of
properties than the ingredients of the majority of protein- cancer. Gold nanoparticles have been used as ultrasensitive
based vaccines. However, there are several issues related to fluorescent probes to detect cancer biomarkers in human
the delivery of polynucleotides which limit their application. blood. The method is very sensitive and could also be
These issues include efficient delivery of the polynucleotide employed in direct detection of viral or bacterial DNA. Gold
to the target cell population and its localization to the nanoparticles are promising probes for biomedical
nucleus of these cells and ensuring that the integrity of the applications because they can be easily prepared and, unlike
polynucleotide is maintained during delivery to the target other fluorescent probes such as quantum dots or organic
site. Nanoparticles loaded with plasmid DNA could also dyes, don't burn out after long exposure to light.54
serve as an efficient sustained release gene delivery system
due to their rapid escape from the degradative endo- d) Tissue repair
lysosomal compartment to the cytoplasmic compartment. 48 Tissue repair using iron oxide nanoparticle is accomplished
Following the intracellular uptake and endolysosomal either through welding, apposing two tissue surfaces then
escape, nanoparticles could release DNA at a sustained rate heating the tissues sufficiently to join them, or through
resulting in sustained gene expression. This gene delivery soldering, where protein or synthetic polymer-coated
strategy could be applied to facilitate bone healing by using nanoparticles are placed between two tissue surfaces to
PLGA nanoparticles containing therapeutic genes such as enhance joining of the tissues. Temperatures greater than
bone morphogenic protein.46 50°C are known to induce tissue union induced by the
denaturation of proteins and the subsequent entanglement of
c) For Diagnosis and Bioimaging adjacent protein chains.55 This is believed to be nanoparticles
A number of molecular imaging techniques are available, that strongly absorb light corresponding to the output of a
such as optical imaging (OI), magnetic resonance imaging laser are also useful for tissue-repairing procedures.
(MRI), ultrasound imaging (USI), positron emission Specifically, gold- or silica-coated iron oxide nanoparticles
tomography (PET) and others have been reported for imaging have been designed to strongly absorb light.56 The
of in vitro and in vivo biological specimens.49, 50 The current nanoparticles are coated onto the surfaces of two pieces of
development of luminescent and magnetic nanoparticles tissue at the site where joining was desired. This technique
advances bio imaging technologies. 51 Two different types of affords methods to minimize tissue damage by using the
nanoparticles have been widely used for imaging: least harmful wavelengths of light and/or lower powered
luminescent nanoprobes for OI and magnetic nanoparticles light sources. Stem cells are the body’s master cells and have
for MRI. There are also dual-mode nanoparticles for a unique ability to renew them and give rise to other
simultaneous imaging by OI and MRI.52 Nanobiotech specialized cell types.
scientists have successfully produced microchips that are

Some of the selected Drugs as Nano Drug Delivery System

Name of the drug Purpose

Clonazepam To determine the drug loading capacity & drug release. 59
Morphine To study antinociceptive activity and blood brain delivery. 60
Adriamycin To enhance effective delivery of Adriamycin. 61
Dexamethasone To increase the amount of drug release with respect to pure drug. 62
Tamoxifen To increase the local concentration of tamoxifen in estrogen receptor positive breast cancer cells. 63
Cyclosporin A To form stable suspension of submicron particles of Cyclosporin A. 64
Praziquantel To study the effect of formulation variables on size distribution. 65
Aspirin Capable of releasing the drug in a slow sustained manner. 66
Docetaxel For effective delivery of drug to solid tumors. 67
Estradiol To increase oral bioavailability of Estradiol. 68
Cyproterone To improve skin penetration of the poorly absorbed drug Cyproterone. 69
Curcumin For coating curcumin onto a metal stent by electrophoretic deposition thereby avoiding problem with restenosis after
percutaneous coronary intervention.70
Ropivacaine To decrease the systemic toxicity of ropivacaine. 71
Didanosine For sustained release of Didanosine. 72
Lamivudine Increased bioavailability of lamivudine is observed when tested in AIDS patients. 73
Simvastatin To enhance effective delivery of poorly water soluble drug simvastatin. 74
Doxorubicin To improve oral bioavailability of Doxorubicin. 75
Amphotericin B To improve oral bioavailability and to show reduced nephrotoxicity compared to intravenous fungizone. 76
Rifampicin To formulate Rifampicin for aerosol delivery in a dry powder, which is suited for shelf stability, effective dispersibility
and
extended release with local lung and systemic drug delivery. 77
Curcumin To enhance the transport of curcumin to brain and to enhance the delivery system to cross the BBB. 78

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 Konwar Ranjit et al. Int. Res. J. Pharm. 2013, 4
Some Marketed Nanoformulations
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Brand Name API Company treatment. Current Drug Delivery. 2005; 2:369-381. http://dx.doi.org
Daunoxome Doxorubicin Gilead Sciences. /10.2174/156720105774370159 PMid:16305440
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Amphotec Amphotericin B Alza Pharmaceutical Research. 2006; 5:561-573.
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