Nanosuspension

INTRODUCTION

More than 40% of drugs are poorely soluble in water, so they

show problems in formulating them in conventional dosage
forms.

For class ii drugs which are poorely soluble in aqueous and

organic media, the problem is more complex.

Various approaches to resolve problems of low solubility and

low bioavailability micronization, co-solvancy, oily solution, salt
formation- some other techniques are liposomes, emulsions,
microemulsion, solid dispersion, - cyclodextrin inclusion
complex etc.

Many of these techniques are not universally applicable to all

drugs or are not applicable to drugs which are not soluble in
both aqueous & organic media.

A different but simple approach is needed to tackle the

Definition
Nanosuspension can be defined as a biphasic
system consisting of pure drug particles
dispersed in a aqueous vehicle in which the
diameter of the suspended particle is less than
1m in size.
Nanosuspension consist of the poorly water soluble
compound without any matrix material suspended in
dispersion.

Need for Nanosuspension

Most of the drugs coming from high-screening are
poorly water soluble.
Formulation of poorly water soluble drug is
always being a challenge.
One of the major problem associated with them is
low bioavailability due to less absorption.
This problem can be overcome by using
nanosuspension.
In nanosuspension technology, the drug is
maintained in the required crystalline state
with reduced particle size, leading to an
increased dissolution rate and therefore
improved bioavailability.

NANOSUSPENSION vs NANOPARTICLES
A pharmaceutical nanosuspension is defined as very
finely dispersed solid drug particles in an aqueous or
organic vehicle for either oral, topical, parenteral and
pulmonary administration.
The particle size distribution of the solid particles in
nanosuspensions is usually less than one micron with an
average particle size ranging between 200 and 600 nm.
Nanosuspensions differ from nanoparticles.
Nanoparticles are commonly polymeric colloidal carriers
of drugs whereas solid lipid nanoparticles are lipidic
carriers of drugs.

Advantages
Applicable to poorly water soluble as well as poorly
water and lipid soluble drugs.
Increased bioavailability
Increased saturation solubility due to larger surface area of
nanoparticles.
Increased dissolution raterelated to increased saturation solubility
according to Noyes-Whitney equation
Absorbed by endocytosis.

Adhesivenesscompared to microcrystal
Can be given by various routes of administration
I.V.route.
Useful in drug targetingpassive targeting.
Ease of manufacture and scale-up
Decrease in dose.
Decrease in food effect.

Stability Issues

Stability Issues

a. Deflocculate
d
b. Flocculated.
c. Nanosuspen
sion

Formulation

METHOD OF PREPARATION OF NANOSUSPENSION

BOTTOM UP
TECHNOLOGY

NANOPRECIPITATI
ON

TOP DOWN
TECHNOLOGY

MEDIA
MILLING

Liquid Antisolvent Precipitation

Liquid Emulsion Technique
Sonoprecipitation

High
pressure
homogeniza
tion in
water/
DISSOCUBES

High
pressure
homogeniza
tion in nonaqueous
solvent/
NANOPURE

NANOEDE
GE

1.Bottom up Technology
Bottom up Technology
In Bottom up technology the drug is
dissolved in a solvent, which is then
added to nonsolvent that causes
precipitation of the fine drug particles.
Simple and low expenditure.
In this technique, the drug needs to be
soluble in at least one solvent which is
miscible with nonsolvent.

Main advantage is the use of simple and low cost

equipments.
Basic challenge is that during the precipitation
procedure growing of the crystals need to be controlled
by addition of surfactant to avoid formation of
microparticles.

Limitation of this precipitation technique is that

the drug needs to be soluble in at least one solvent and
the solvent needs to be miscible with non-solvent.

Moreover , It is not applicable to the drugs, which are

poorly soluble in both aqueous and non-aqueous
media.

PREPARATION TECHNIQUES

Bottom up Approach
Liquid Antisolvent Precipitation
Liquid Emulsion Technique
Sonoprecipitation

Preparation: liquid antisolvent

precipitation
Drug is dissolved in an organic solvent and this
solution is mixed with a miscible anti-solvent for
precipitation.
In the water-solvent mixture the solubility is low
and the drug precipitates.
Precipitation has also been coupled with high
shear processing.[6,7]

Preparation: Liquid emulsion

Applicable for drugs that are soluble in either volatile
organic solvents or partially water miscible solvents.
This technique includes an organic solvent or mixture
solvent loaded with the drug dispersed in an aqueous
phase containing suitable surfactants to form an
emulsion.
The organic phase is evaporated under reduced
pressure
to
make
drug
particles
precipitate
instantaneously to form the Nanosuspensions which is
stabilized by surfactants.[6]

Preparation: sonoprecipiation
Drug is dissolved in organic solvent and
stabilizer, surfactants other ingredients is
dissolved in Aqueous solution.
Organic phase is added to aqueous phase then
sonicate for 5 second at 5 second interval for a
total of sonication time of 10 minutes.
Keep under vacuum for 1 hour to remove
organic solvent.[8]

2.Top Down Technology

1. MEDIA MILLING
2. DISSOCUBES : High pressure
homogenization in water.
3. NANOPURE : High pressure
homogenization in non-aqueous
solvent.
4. NANOEDEGE.

Media Milling
The nanosuspensions are prepared by using high
shear media mills.
The milling chamber charged with milling media,
water, drug & stabilizer is rotated at very high shear
rate under controlled temp.
The milling medium is composed of glass, zirconium
oxide or highly cross-linked polystyrene resin.
The high energy shear forces are generated as a
result of impaction of milling media with the drug
resulting into breaking of microparticulate drug to
nanosized particles.
The major concern with this method is the residues
of milling media remaining in the finished product

Media Milling
In this method the nanosusensions are
produced using highshear media mills or
pearl mills.
Milling chamber consist of
1. Milling chamber
2. Milling shaft
3. Recirculation
4. Chamber
. Process is done under controlled
temperature.

ADVANTAGES OF MEDIA MILLING

1. Applicable to the drugs that are poorly soluble in both
aqueous and organic media.
2. Very dilute as well as highly concentrated
nanosuspensions can be prepared by handling 1mg/ml to
400mg/ml drug quantity.

DISADVANTAGES OF MEDIA MILLING

1. Nanosuspensions contaminated with materials eroded
from balls may be problematic when it is used for long
therapy.
2. The media milling technique is time consuming.
3. Some fractions of particles are in the micrometer range.
4. Scale up is not easy due to mill size and weight.

High pressure Homogenisation in Water

(Dissocubes)
Homogenization involves the forcing of the suspension
under pressure through a valve having a narrow aperture.
Most of the cases require multiple passes or cycles through
the homogenizer
Examples of Commercial homogenizers :
APV micron LAB 40 (APV Deutschland GmbH, Lubeck,
Germany)
Pistongap homogenizers from Avestin (Avestin Inc., Ottawa,
Canada)
Stansted (Stansted Fluid Power Ltd, Stansted, UK) 11

Advantages
Drugs that are poorly soluble in both aqueous and
organic media can be easily formulated into
nanosuspensions.
Ease of scale-up and little batch-to-batch variation
Narrow size distribution of the nanoparticulate drug
present in the final product.
Allows aseptic production of nanosuspensions for
parenteral administration.
Flexibility in handling the drug quantity, ranging from
1 to 400mg/mL, thus enabling formulation of very
dilute as well as highly concentrated nanosuspensions.

Disadvantages
Preprocessing like micronization of drug is required.
Prerequisite of micronized drug particles.
Prerequisite of suspension formation using high-speed
mixers before subjecting it to homogenization.
High cost instruments are required that increases the cost of

Homogenisation In Nonaqueous
Media (Nanopure)
The drugs that are chemically labile can be
processed in such non-aqueous media or
water-miscible liquids like
polyethyleneglycol-400 (PEG), PEG1000
etc.
The homogenization can be done at room
temperature, 0o C and below freezing point
(-20o C).

Combined Precipitation And Homogenization

(Nanoedege)

So the precipitated particle suspension is

subsequently homogenized which preserve
the particle size obtained after the
precipitation step.

Precipitate
d drug
particle
(nanosize)

Contineou
s to grow
till
microcrys
tal size

Nanoedege
Principle: same that of the
precipitation and homogenization
techniques.
In this technique the precipitated
suspension is further homogenized to
get smaller particle size and to avoid
crystal growth.
NON-solvent, such as methanol,
ethanol, and isopropanol added

Potential Benefits Of Various

Routes
ORAL - Rapid onset, Improved
bioavailability
INTRAVENOUS - Rapid dissolution
OCULAR - Higher bioavailability, More
consistent dosing
INHALATION - Higher bioavailability, More
consistent dosing
SUBCUTANEOUS/ INTRAMUSCULARHigher bioavailability, Rapid onset, Reduced
tissue irritation.


Evaluation Parameters:

A. Evaluation Parameters In-vitro

Evaluation
. 1. Particle size and size distribution
. 2. Zeta potential
. 3. Crystalline state and morphology
. 4. Entrapment Efficiency.
. 4. Saturation solubility and dissolution
velocity.
B. In-vivo Evaluation

Mean particle size and Size Distribution:

Mean particle size and Size Distribution:- The most
important characterization parameter Governs the
physicochemical properties like saturation solubility,
dissolution velocity, physical stability and even biological
performance.
Methods for determining particle size distribution:
Photon correlation spectroscopy (PCS),
Laser diffraction (LD),
Coulter counter multisizer.

Zeta Potential (particle charge):

Zeta Potential (particle charge)
Determines the physical stability of
nanosuspension.
In order to obtain a nanosuspension
exhibiting good stability, for an
electrostatically stabilized
nanosuspension a minimum zeta
potential of 30mv is required.
whereas in the case of a combined
electrostatic and steric stabilization, a minimum
zeta potential of 20mV is desirable.

Crystalline state and Particle Morphology:

When nanosuspensions are prepared drug particles get
converted to amorphous form hence it is essential to measure
the extent of amorphous drug generated during the production
of nanosuspensions.
The X-Ray Diffraction (XRD) is also used for determining change
in physical state and extent of amorphous drug.
Differential Scanning Calorimetry (DSC) determines the
crystalline structure.

SEM, TEM
Atomic force microscopy

CHARACTERIZATION
Crystal

structure/ morphology:
Morphological evaluation of drug nanoparticles was
conducted through transmission electron microscopy
(TEM) and scanning electron microscopy (SEM).[9]

Entrapment Efficiency (EE):

Determined by measuring the concentration of free drug in
dispersion medium.
The obtained suspension was centrifuged and drug content
is determined by using spectrophotometer or HPLC.[11]

Saturation solubility and

Dissolution rate:
Nanosuspension increases the dissolution
velocity and saturation solubility.
An increase in solubility that occurs with
relatively low particle size reduction may be
mainly due to a change in surface tension
leading to increased saturation solubility.
Depend upon temperature and properties of
dissolution medium.

Application of
Nanosuspension
Bioavailability enhancement
Ocular administration
Intravenous administration
Pulmonary administration
Targeted drug deliver
Topical formulations

Application
Bioavailability enhancement:
Nanosuspensions resolve the problem of poor
bioavailability by solving problems of poor solubility
and poor permeability across the membrane.[12]

Target drug delivery:

Nanosuspensions can also be used for targeted delivery
as their surface properties and in vivo behaviour can
easily be altered by changing either the stabilizer.[12]

Application
Topical formulations:
Drug nanoparticles can be incorporated into creams and waterfree ointments.
The nanocrystalline form leads to an increased saturation
solubility of the drug in the topical dosage form, thus enhancing
the diffusion of the drug into the skin.[12]

Mucoadhesion of the nanoparticles:

Nanoparticles orally administered in the form of a suspension
diffuse into the liquid media and rapidly encounter the mucosal
surface.
The particles are immobilized at the intestinal surface by an
adhesion mechanism referred to as bioadhesion.[12]

Application
Parenteral administration:
Can be administered via different parenteral routes like intraarticular, intraperitoneal, intravenous injection.
For administration by the parenteral route, the drug either has to
be solubilized or has particle/globule size below 5 m to avoid
capillary blockage.
The current approaches for parenteral delivery include salt
formation, solubilization using co-solvents, micellar solutions,
complexation with cyclodextrin and recently liposomes.[12]

Oral administration:
Nanosizing of drugs can lead to a dramatic increase in their oral
absorption and subsequent bioavailability.[12]

Patented technologies for

Preparation:
NANOCRYSTAL

COMPANY

PATENT/PATENT
APPLICATION
EXAMPLE

HODROSOL

NOVATIS(prev.sando
z)

GB 22 69 536

NANOMORPH

SOLIGS/ABBOTT

GB 22 00 048
D 1963 7517

NANOCRYSTAL

ELAN NANOSYSTEM

US 5,145, 684

DISSOCUBES

SKYPHARMA

US 5,858,410

NANOPURE

PHARMASOL

PCT/EPOO/0635

NANOEDGE

BAXTER

US 6,884,436

MARKETED NANOSUSPENSIONS:
PRODUCT

DRUG
COMPOUND

INDICATION

COMPANY

NANOPARTICE
TECHNOLOGY

RAPAMUNE

Sirolimus

Immunosuppre
sant

Wyeth

ELAN DRUG
DELIVARY
NANOCRYSTAL

EMEND

Aprepitant

Antiemetic

Merck

ELAN DRUG
DELIVARY
NANOCRYSTAL

TRICOR

Fenofibrate

Treatment of
hypercholester
olemia

Abbott

ELAN DRUG
DELIVARY
NANOCRYSTAL

MEGACEE
S

Megestrol
acetate

Appetite
stimulant

PAR
Pharmaceu
ticals

ELAN DRUG
DELIVARY
NANOCRYSTAL

TRIGLIDE

Fenofibrate

Treatment of
hypercholester
olemia

First
horizon
pharmaceu
ticals

SKYEPHARMA IDD
-P TECHNOLOGY

Conclusion:
Nanosuspension solved poor
bioavailability problem of hydrophobic
drugs and drugs which are poorly soluble
in aqueous and organic solutions.
Nanotechnique is simple, less
requirements of excipients, increased
dissolution velocity and saturation
solubility many poor bioavailability drugs
are formulated in nanosuspension form.

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