The document discusses different types of nanoparticles used in drug delivery, including liposomes, solid nanoparticles, polymeric nanoparticles, nanocapsules, nanospheres, dendrimers, nanotubes, nanowires, and nanocrystals. It also describes several methods for preparing nanoparticles, such as solvent evaporation, emulsions-diffusion, nanoprecipitation, salting out, and dialysis. Evaluation methods for prepared nanoparticles are discussed, including measuring yield, drug content, particle size, zeta potential, surface morphology, polydispersity index, in-vitro release studies, and kinetic studies.

1. Nano Particles
Introduction | Preparation | Evaluation
Department of Pharmaceutics, Karpagam College of
Pharmacy, Coimbatore
Navaneethakrishnan P
8/14/2019

2. Nano Particles
The prefix ―nano‖ comes from the ancient Greek vavoc through the Latin nanus meaning very
small. Nanotechnology defined as design characterization, production and applications of
structures, devices and systems by controlling shape and size at nanometer scale.
According to International System of Units (SI) nanotechnology is typically measured in
nanometers scale of 1 billionth of a meter (1nm corresponding to 10-9 m) referred as the „tiny
science‟. At this small size molecules and atoms work differently, behave as a whole unit in
terms of its properties and transport, provide a variety of advantages.
Nanoparticles (NPs) are defined as particulate dispersions or solid particles drug carrier that may
or may not be biodegradable. The drug is dissolved, entrapped, encapsulated or attached to a
nanoparticle matrix. The term nanoparticle is a combined name for both nanosphares and
nanocapsules.
Drug is confined to a cavity surrounded by a unique polymer membrane called nanocapsules,
while nanospheres are matrix systems in which the drug is physically and uniformly dispersed.
Where conventional techniques reaches their limits, nanotechnology provides opportunities for
the medical applications.
Types of Nanoparticle
1. Liposomes
2. Solid Nanoparticle
3. Polymeric nanoparticles
4. Nanocapsules
5. Nanospheres
6. Dendrimers
7. Nanotube
8. Nanowire
9. Nanocrystals

3. Figure 1: Schematic diagram representing the various types of nanoparticle use to develop MTIs.
(1A) Liposome; (1B) Polymeric nanoparticle; (1C) Dendrimer; (1D) Magnetic nanoparticle; (1E)
Micelle; (1F) Nanogel.
Liposomes
 Liposomes are concentric bilayered vesicles in which an aqueous volume is entirely enclosed
by a membranous lipid bilayer mainly composed of natural or synthetic phospholipids.
 Liposomes are characterized in terms of size, surface charge and number of bilayers.
 It exhibits number of advantages in terms of amphiphilic character, biocompatibility, and
ease of surface modification rendering it a suitable candidate delivery system for biotech
drugs.
 Liposomes have been used successfully in the field of biology, biochemistry and medicine
since its origin. These alter the pharmacokinetic profile of loaded drug to a great extent
especially in case of proteins and peptides and can be easily modified by surface attachment
of polyethylene glycol-units (PEG) making it as stealth liposomes and thus increase its
circulation half-life.

4. Solid Nanoparticle
 Solid lipid nanoparticles (SLN) were developed at the beginning of the 1990s as an
alternative carrier system to emulsions, liposomes and polymeric nanoparticles as a colloidal
carrier system for controlled drug delivery.
 Main reason for their development is the combination of advantages from different carriers
systems like liposomes and polymeric nanoparticles.
 SLN have been developed and investigated for parenteral , pulmonal and dermal application
routes. Solid Lipid Nanoparticles consist of a solid lipid matrix, where the drug is normally
incorporated, with an average diameter below 1 μm.
 To avoid aggregation and to stabilize the dispersion, different surfactants are used that have
an accepted GRAS (Generally Recognized as Safe) status.
 SLN have been considered as new transfection agents using cationic lipids for the matrix
lipid composition.
 Cationic solid lipid nanoparticles (SLN) for gene transfer can be formulated using the same
cationic lipids as for liposomal transfection agents.
Polymeric nanoparticles
 In comparison to SLN or nanosuspensions polymeric nanoparticles (PNPs) consists of a
biodegradable polymer.
 The advantages of using PNPs in drug delivery are many, being the most important that they
generally increase the stability of any volatile pharmaceutical agents and that they are easily
and cheaply fabricated in large quantities by a multitude of methods. Also, polymeric

5. nanoparticles may have engineered specificity, allowing them to deliver a higher
concentration of pharmaceutical agent to a desired location.
 Polymeric nanoparticles are a broad class comprised of both vesicular systems
(nanocapsules) and matrix systems (nanospheres).
Nanocapsules
 Nanocapsules are systems in which the drug is confined to a cavity surrounded by unique
polymeric membrane whereas nanospheres are systems in which the drug is dispersed
throughout the polymer matrix.
 The various natural polymers like gelatin, albumin and alginate are used to prepare the
nanoparticles; however they have some inherent disadvantages like poor batchto- batch
reproducibility, prone to degradation and potential antigenicity.
 Synthetic polymers used for nanoparticles preparation may be in the form of preformed
polymer e.g. polyesters like polycaprolactone (PCL), poly lactic acid (PLA) or monomers
that can be polymerized in situ e.g. poly alkyl cyanoacrylate.
 The candidate drug is dissolved, entrapped, attached or encapsulated throughout or within the
polymeric shell/matrix. Depending on the method of preparation, the release characteristic of
the incorporated drug can be controlled.
 Polymeric nanoparticulate systems are attractive modules for intracellular and site specific
delivery. Nanoparticles can be made to reach a target site by virtue of their size and surface
modification with a specific recognition ligand. Their surface can be easily modified and
functionalized.

6. Nanospheres
 From its definition nanospheres are considered as a matrix system in which the matrix in
uniformly dispersed. These are spheric vesicular systems.
Dendrimers
 Dendrimers, a unique class of polymers, are highly branched macromolecules whose size and
shape can be precisely controlled.
 Dendrimers are fabricated from monomers using either convergent or divergent step growth
polymerization. The well-defined structure, mono dispersity of size, surface functionalization
capability, and stability are properties of dendrimers that make them attractive drug carrier
candidates.
 Drug molecules can be incorporated into dendrimers via either complexation or
encapsulation. Dendrimers are being investigated for both drug and gene delivery, as carriers
for penicillin, and for use in anticancer therapy.

7. Nanotube
 Carbon nanotubes (CNTs; also known as buckytubes) are allotropes of carbon with a
cylindrical nanostructure.
 Nanotubes have been constructed with length-to diameter ratio of up to 132,000,000:1, which
is significantly larger than any other material.
 These cylindrical carbon molecules have novel properties which make them potentially
useful in many applications in nanotechnology, electronics, optics, and other fields of
materials science, as well as potential uses in architectural fields.
 They may also have applications in the construction of body armor. They exhibit
extraordinary strength and unique electrical properties, and are efficient thermal conductors.
 Nanotubes are members of the fullerene structural family, which also includes the spherical
bucky balls. The ends of a nanotube may be capped with a hemisphere of the bucky ball
structure. Their name is derived from their size, since the diameter of a nanotube is on the
order of a few nanometers (approximately 1/50,000th of the width of a human hair), while
they can be up to 18 centimeters in length (as of 2010).
 Nanotubes are categorized as single-walled nanotubes (SWNTs) and multi-walled nanotubes
(MWNTs).Chemical bonding in nanotubes is described by applied quantum chemistry,
specifically, orbital hybridization.
 The chemical bonding of nanotubes is composed entirely of sp 2 bonds, similar to those of
graphite. These bonds, which are stronger than the sp3 bonds found in diamonds, provide
nanotubules with their unique strength. Moreover, nanotubes naturally align themselves into
"ropes" held together by Van der Waals forces.
Nanowire
 A nanowire is a nanostructure, with the diameter of the order of a nanometer (10−9 meters).
Alternatively, nanowires can be defined as structures that have a thickness or diameter
constrained to tens of nanometers or less and an unconstrained length. At these scales,
quantum mechanical effects are important — which coined the term "quantum wires".
 Many different types of nanowires exist, including metallic (e.g., Ni, Pt, Au), semiconducting
(e.g., Si, InP, GaN, etc.), and insulating (e.g., SiO2, TiO2).

8.  Molecular nanowires are composed of repeating molecular units either organic (e.g. DNA) or
inorganic (e.g. Mo6S9-xIx)
 The nanowires could be used, in the near future, to link tiny components into extremely small
circuits. Using nanotechnology, such components could be created out of chemical
compounds.
Nanocrystals
 Nanocrystal is any nanomaterial with at least one dimension ≤ 100nm and that is single
crystalline. More properly, any material with a dimension of less than 1 micrometer, i.e.,
1000 nanometers, should be referred to as a nanoparticle, not a nanocrystal. For example, any
particle which exhibits regions of crystallinity should be termed nanoparticle or nanocluster
based on dimensions. These materials are of huge technological interest since many of their
electrical and thermodynamic properties show strong size dependence and can therefore be
controlled through careful manufacturing processes.
 Crystalline nanoparticles are also of interest because they often provide single-domain
crystalline systems that can be studied to provide information that can help explain the
behavior of macroscopic samples of similar materials, without the complicating presence of
grain boundaries and other defects.
 Semiconductor nanocrystals in the sub-10nm size range are often referred to as quantum
dots. Crystalline nanoparticles made with zeolite are used as a filter to turn crude oil onto
diesel fuel at an ExxonMobil oil refinery in Louisiana, a method cheaper than the
conventional way.
 The term NanoCrystal is a registered trademark of Elan Pharma International Limited
(Ireland) used in relation to Elan’s proprietary milling process and nanoparticulate drug
formulations.
Preparation of Nanoparticle
Solvent Evaporation
 Solvent evaporation method first developed for preparation of nanoparticles.
 In this method firstly nanoemulsion formulation prepared.
 Polymer dissolved in organic solvent (dichloromethane, chloroform or ethyl acetate).

9.  Drug is dispersed in this solution. Then this mixuture emulsified in an aqueous phase
containing surfactant (polysorbates, poloxamers sodium dodecyl sulfates polyvinyl alcohol,
gelatin) make an oil in water emulsion by using mechanical stirring, sonication, or micro
fluidization (high-pressure homogenization through narrow channels).
 After formation of emulsion the organic solvent evaporate by increased the temperature and
reduced pressure with continuous stirring.
Emulsions - Diffusion Method
 This method patent by Leroux et al it is modified form of salting out method.
 Polymer dissolve in water-miscible solvent (propylene carbonate, benzyl alcohol), this
solution saturated with water.
 Polymer-water saturated solvent phase is emulsified in an aqueous solution containing
stabilizer.
 Then solvent removed by evaporation or filtration. Advantages of this method are high
encapsulation efficiencies (generally 70%), no need for homogenization, high batch-to-batch
reproducibility, ease of scale up, simplicity, and narrow size distribution.
 Some disadvantage of this method is reported 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.

10. Nanoprecipitation method
 This is another method which is widely used for nanoparticle preparation which is also called
solvent displacement method. This technique was first described by Fessi at al. 1989.
 In this method precipitation of polymer and drug obtained from organic solvent and the
organic solvent diffused in to the aqueous medium with or without presence of surfactant.
 Tamizhrasi at al prepared Lumivudine loaded nanoparticles. Firstly drug was dissolved in
water, and then cosolvent (acetone used for make inner phase more homogeneous) was added
into this solution. Then another solution of polymer (ethyl cellulose, eudragit) and propylene
glycol with chloroform prepared, and this solution was dispersed to the drug solution. This
dispersion was slowly added to 10 ml of 70% aqueous ethanol solution.
 After 5 minutes of mixing, the organic solvents were removed by evaporation at 35° under
normal pressure, nanoparticles were separated by using cooling centrifuge (10000 rpm for 20
min), supernatant were removed and nanoparticles washed with water and dried at room
temperature in a desicator.
Salting Out Method
 This technique was introduced and patented by Bindschaedler et al. and Ibrahim et al.
 Salting out method is very close to solvent-diffusion method. This technique based on the
separation of water-miscible solvent from aqueous solution by salting out effect (Catarina
PR et al., 2006).
 In this method toxic solvents are not used. Generally acetone is used because it is totally
miscible with water and easily removed.

11.  Polymer and drug dissolved in a solvent which emulsified into a aqueous solution
containing salting out agent (electrolytes, such as magnesium chloride and calcium
chloride, or non- electrolytes such as sucrose) but salting out can also be produced by
saturation of the aqueous phase using colloidal stabilizer/ emulsion stabilizer/ viscosity
increasing agent such as polyvinylpyrrolidone or hydroxyethylcellulose, PVA,
Poly(ethylene oxide), PLGA and poly(trimethylene carbonate).
 After preparation of o/w emulsion diluted with addition of sufficient water to allow the
complete diffusion of acetone into the aqueous phase, thus inducing the formation of
nanospheres.
 This technique does not require an increase in temperature and stirring energy required
for lower particle size. Disadvantage of this technique is exclusive application to
lipophilic drug and the extensive nanoparticles washing steps.
Dialysis
 Dialysis is an effective method for preparation of nanparticles. In this method firstly polymer
(such as Poly(benzyl-l-glutamate)-b-poly(ethylene oxide), Poly(lactide)-b-poly(ethylene
oxide)) and drug dissolved in a organic solvent.
 This solution added to a dialysis tube and dialysis performed against a non-solvent miscible
with the former miscible.
 The displacement of the solvent inside the membrane is followed by the progressive
aggregation of polymer due to a loss of solubility and the formation of homogeneous
suspensions of nanoparticles.

12.  Dialysis mechanism for formation of nanoparticle is not fully understood at present. It may
be based based on a mechanism similar to that of nanoprecipitation.
Evaluation of Nanoparticle
Yield of Nanoparticles
 The yield of nanoparticles was determined by comparing the whole weight of nanoparticles
formed against the combined weight of the copolymer and drug.
Drug Content / Surface entrapment / Drug entrapment
 After centrifugation amount of drug present in supernatant (w) determined by UV
spectrophotometery.
 After that standard calibration curve plotted. Then amount of drug present in supernatant
subtracted from the total amount used in the preparation of nanoparticles (W). (W-w) is the
amount of drug entrapped. % drug entrapment calculated by

13. Particle Size and Zeta Potential
 Value of Particle size and Zeta Potential prepared nanoparticles determined by using Malvern
Zetasizer.
Surface Morphology
 Surface morphology study carried out by Scanning Electron Microscopy (SEM) of prepared
nanoparticle.
Polydispersity index
 Polydispersity index of prepared nanoparticles was carried out by using Malvern Zetasizer.
In-vitro release Study
 In-vitro drug release studies were performed in USP Type II dissolution apparatus at rotation
speed of 50 rpm. The prepared immersed in 900ml of phosphate buffer solution in a vessel,
and temperature was maintained at 37±0.20°C. Required quantity 5ml of the medium was
withdrawn at specific time periods and the same volume of dissolution medium was replaced
in the flask to maintain a constant volume. The withdrawn samples were analyzed using UV
spectrophotometer.
Kinetic Study
 For estimation of the kinetic and mechanism of drug release, the result of in vitro drug
release study of nanoparticles were fitted with various kinetic equation like zero order
(cumulative % release vs. time), first order (log % drug remaining vs time), Higuchi‟s model
(cumulative % drug release vs. square root of time). r2 and k values were calculated for the
linear curve obtained by regression analysis of the above plots.
Stability of Nanoparticles
 Stability studies of prepared nanoparticles determined by storing optimized formulation at
4°C ±1°C and 30°C ± 2°C in stability chamber for 90 days. The samples were analyzed after
a time period like at 0, 1, 2, and 3 months for their drug content, drug release rate (t50%) as
well as any changes in their physical appearance.
References
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10.1080/10837450.2018.1486424

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