MICROMERITICS & ITS

APPLICATION IN PHARMACY
Micromeritics:

Definition: It is the science and technology of small

particles.
*The unit of particle size used is the micrometer,( μm),
micron, (μ), and equal to 10-6 m.
As particle size decreases , the surface area increases
Micromeritics Applications
The knowledge and control of the size of particles is of
importance in pharmacy and materials science. The
size & hence the surface area of a particle can be
related to the physical, chemical & pharmacologic
properties of drugs.
1- Release & dissolution:
Particle size & surface area influence the release of a
drug from a dosage form. Higher surface area allows
intimate contact of the drug with the dissolution fluids
in vivo & increases the drug solubility & dissolution.
Micromeritics (Cont.):

2- Absorption & drug action:

Particle size & surface area influence the drug
absorption & subsequently the therapeutic action.
Higher the dissolution, faster the absorption & hence
quicker & greater the drug action.

3- Physical stability:
The particle size in a formulation influences the
physical stability of the suspensions & emulsions.
Smaller the size of the particle, better the physical
stability of the dosage form.
Micromeritics (Cont.):

4- Dose uniformity:
Good flow properties of granules & powders are
important in the manufacturing of tablets & capsules.
Methods for determining particle size:

1- Optical microscopy (range: 0.2 -100 μm):

The microscope eyepiece is fitted with a micrometer by
which the size of the particles may be estimated.
 Optical microscopy
(Range: 0.2-100 μm)

• According to the optical microscopic method,

an emulsion or suspension is mounted on ruled
slide on a mechanical stage.
• The microscope eyepiece is fitted with a
micrometer by which the size of the particles
can be estimated.
• The ordinary microscope used for
measurement the particle-size in the range of
0.2 to about 100 μm.
 Electron Microscopy

An electron microscope is a dynamic instruments that uses highly

energetic electrons of beam for the determination of very fine scales of
particles (up to 0.2 μm). It has a higher resolving power (0.3 nm) than
an optical microscope that allows the examination of very small
objects. The clear surface features of biological or any other materials
can be observed under electron microscopy, e.g., histopathological
studies, the shape and size of an organelles, and it is useful in the
investigation of clinical specimens like renal diseases, tumor
processes, storage disorders, and infectious agents. This method
provides numerous advantages such as high magnification (310,000
and high resolution of 0.3 nm), individual particle examination, and
particle shape measurement. However, this method is expensive and
a trained operator is required.
 Disadvantage of
microscopic method

1. The diameter is obtained from only two

dimensions of the particle.

2. The number of particles that must be counted

(300-500) to obtain a good estimation of the
distribution makes the method somewhat
slow and tedious.
 Sieving (range: 40 - 9500μm ):

-Standard sized sieves are available to cover a

wide range of sizes. These sieves are designed to
sit in a stack so that material falls through smaller
and smaller meshes until it reaches a mesh which
is too fine for it to pass through.
-The stack of sieves is mechanically shaken to
promote the passage of the solids.
-The fraction of the material between pairs of sieve
sizes is determined by weighing the residue on
each sieve.
-The result achieved will depend on the duration of
the agitation and the manner of the agitation.
 Air-jet Sieving

Air-jet sieving overcomes the problem of the formation of

clumps on the sieve, which is a common problem associated
with the simple sieving method. In this method, a series of
plates are fitted with a reduced pressure stream of air which
blows the particles that creates the blockage during sieving
process. This method is suitable for particles having size
below 40 μm. The sample is introduced into the sieve and
covered with a lid. Sieves fitted with a powerful vacuum
cleaner create a strong jet of air, which helps to disperse the
clogged particles present on the sieve through the slotted
nozzle rotating below the sieve mesh .
Sedimentation (range: .08 -300μm):

The sedimentation method is based on the

principle of gravity that deals with the
measurement of the rate of settling of the
particles of powders which are uniformly
dispersed in a fluid. This method is used for the
measurement of particle size in the range of 1200
μm. In this method, the particle size is expressed
via Stokes diameter (dst) which is referred to as
the diameter of an equivalent sphere having the
same rate of sedimentation of the irregular
particles. Sedimentation of particles can be
studied by using Andreasen pipette, balance
method, and hydrometer method.
Particle volume measurement (range 0.5 -
300 um):

- In this type of machine the powder is

suspended in an electrolyte solution . This
suspension is then made to flow through a
short insulated capillary section between
two electrodes and the resistance of the
system is measured.
- When a particle passes through the
capillary there is a momentary peak in the
resistance, the amplitude of the peak is
proportional to the particle size. Counting is
done by a computer.
 Dynamic Light Scattering

Dynamic light scattering, also called Photon correlation

spectroscopy or quasi-elastic light scattering, is a popular,
noninvasive method used for measuring submicron particles to 1
nm. This method is used for evaluation of samples such as
proteins, polymers, micelles, carbohydrates, nanoparticles, colloidal
dispersions, and emulsion. This technique typically provides
information such as intensity-weighted average (i.e., z average)
and polydispersity index, which is a useful quantification of
distribution width. When compared with laser diffraction or
microscopy, the results of mean values are transformed into
volume-based or number-based distributions
Schematic representation of working principle of dynamic light scattering. Effect of particle
size on final peak pattern. For example, the intensity of photon arriving at the detector
depends on the particle size of a particular sample. The peak pattern varies with change in
particle dimension.
Electronic Scanning Zone

This method is also commonly known as the Coulter counter

method and is also considered to be the most accurate
method for analyzing the particle size of a method is capable
of counting the particles within the range of 0.11000 μm.
However, for sample. This this method the sample is to be
suspended in appropriate dilution in a electrolyte solution
followed by ultrasonication so as to break the agglomerates,
if formed.
Principle of Coulter counter. This technique is based on calculable alterations in
electrical impedance generated by nonconductive particles suspended in an electrolyte.
A small opening (aperture) between electrodes is the sensing zone via which suspended
particles pass.
Cascade Impactor

This method works on the principle of the law of inertia and, when
sedimentation technique is inadequate for measurement of small
particles, a cascade impactor is used. Cascade impactor is
mostly used for particles in the range of about 0.1100 μm. In
principle, during the operation of the cascade impactor, the
particles in the sample move and classify themselves according
to the size of particles. Then, particles are collected in series on
collecting plates. The deposition of the particles on each plate
depends on the impact velocity of the gas stream.
Schematic representation of cascade impactor. Material arrives at a sequence of discs
intended to accumulate particulate matter and it is collected as it passes through the disc
series. The size of the discs is graduated, to properly determine the size of the
particulate matter at each stage of the impactor.
 Laser Diffraction

Laser diffraction is most popular in particle size measurement of samples that

ranges from 0.00011000 μm in size. Laser diffraction is widely used for of the
determination of particle size distribution by measuring the angular variation in
intensity of light scattered when a laser beam enters across a dispersed
sample. Larger particles scatter light at a smaller angle than smaller particles.
Laser diffraction works on the Mie theory of light scattering to measure the
particle size distribution by determining particle size as a volume equivalent
sphere diameter The Mie theory requires knowledge of optical properties of the
sample, i.e., refractive index and imaginary component, but the most
commercial light scattering instrument uses Fraunhofer diffraction which does
not require knowledge of optical properties of sample and dispersant. The
principle of Fraunhofer diffraction is also known as static light scattering and it
is mostly applied to large particles.
Principal of dynamic light scattering. The measurement is based on the intensity
of light that is detected by the detector after the interaction with particle in suitable
medium. This technique in physics that can be used to determine the size,
polydispersity index, and zeta potential.
 Elutriation

Elutriation is a method used for the separation of

particles depending on their particle size, shape, density.
This method follows the process of reverse gravity
sedimentation.
This is a physical process to separate fine and coarse
particles from overflow liquid or fluid and suspended
liquid or fluid. The particle size less than 1 μm can be
determined successfully using the elutriation method. In
this methodology, the particle size is determined
principally by using a stream of gas or liquid flowing in an
opposite direction to the direction of sedimentation.
Showing elutriator and elutriator process. (A) Schematic diagram of elutriator and (B) elutriation
process for separating particle based on their size, shape, density, using gas or liquid flow
which usually opposite to sedimentation direction (particle smaller than 1 μm).
Acoustic Spectroscopy

Acoustic spectroscopy is one of the emerging techniques for the

measurement of particle size with a maximization of the quality
and ensuring the safety of pharmaceutical formulation.
Acoustic spectroscopy, sometimes referred as“electroacoustics,”
can analyze particles in the range of about 0.0110 μm. The main
principle of operation of acoustic spectroscopy is based on the
measurement of ultrasound pulse and phase after its
propagation into the sample. When a pulsed electrical field is
applied to the sample, particles start vibrating and thus creates
ultrasonic sound waves of a range of frequencies, and the
attenuation at each frequency is accurately measured.
Acoustic resonance spectroscopy work based on principles of
sonication. Where electric field applied to sample and sound
interacts with samples. The resultant attenuation is converted to
size.
Derived properties of powders:
Derived properties of powders:

1- Porosity:
Suppose a nonporous powder, is placed in a graduated cylinder:
• the total volume occupied is known as the bulk volume Vb.
• bulk volume = true volume + volume of spaces between
particles.
• The volume of the spaces, the void volume, V = Vb - Vp
• Vp is the true volume of particles.
• The porosity or voids ε of powder is determined as the ratio of void
volume to bulk volume.
• Porosity = ε = Vb - V p = 1 - Vp
Vb Vb
• Porosity is frequently expressed in percent, ε x 100 .
Porosity
Derived properties of powders (Cont.):

2- Densities of particles:
- Density is defined as weight per unit volume (W/V).
Types of densities:
A- true density
The true density, or absolute density,
of a sample excludes the volume of the
pores and voids within the sample.

B- bulk density (w/v) the bulk density

value includes the volume of all of the
pores within the sample.
 Densities of particles
• During tapping, particles gradually
pack more efficiently, the powder
volume decreases and the
tapped density increases.
Derived properties of powders (Cont.):

3- Bulkiness = Specific bulk volume = reciprocal of bulk

density:
It is an important consideration in the packaging of powders.
The bulk density of calcium carbonate vary from 0.1 to 1.3, and
the lightest (bulkiest) type require a container about 13 times
larger than that needed for the heaviest variety.
(Bulkiness increases with a decrease in particle size).
In mixture of materials of different sizes,
the smaller particles sift between the larger
ones and tend to reduce bulkiness.
Derived properties of powders (Cont.):

4- Flow properties:
• Powders may be free-flowing or cohesive (“sticky”).
- Many common manufacturing problems are attributed to powder
flow:
1- Powder transfer through large equipment such as hopper.

2- Uneven powder flow → excess entrapped air within powders →

capping or lamination.

3- Uneven powder flow → increase particle’s friction with die wall

causing lubrication problems, and increase dust contamination
risks during powder transfer.
Derived properties of powders (Cont.):
Tablet Defects During
Manufacturing
Derived properties of powders (Cont.):

5- Powder storage- which for example result in caking

tendencies within a vial or bag after shipping or storage
time.
6- Separation of small quantity of the powder from the
bulk- specifically just before the creation of individual
doses such as during tableting, encapsulation and vial
filling which affect the weight uniformity of the dose
(under or over dosage).
powder flow problems
Tests to evaluate the flowability of a
powder:

1- Carr’s compressibility index

A volume of powder is filled into a graduated glass cylinder and repeatedly

tapped for a known duration. The volume of powder after tapping is
measured.

Carr’s index (%) =

Tapped density - Poured or bulk density x 100

Tapped density

Bulk density = weight / bulk volume

Tapped density = weight / true volume

1- Carr’s compressibility index (Cont.):

Flow description % compressibility

Excellent flow 5 - 15
Good 16 - 18
Fair 19 - 21
Poor 22 - 35
Very poor 36 - 40
Extremely poor > 40
Tests to evaluate the flowability of a
powder (Cont.):
2- Hausner ratio:
Tapped density
Hausner ratio =
Poured or bulk density

Hausner ratio was related to interparticle friction:

**Value less than 1.25 indicates good flow ( = 20% Carr ).
The powder with low interparticle friction, such as coarse spheres.

**Value greater than 1.5 indicates poor flow ( = 33% Carr ).

more cohesive, less free-flowing powders such as flakes.

**Between 1.25 and 1.5, added glidant normally improves flow.

** > 1.5 added glidant doesn’t improve flow.

Tests to evaluate the flowability of a
powder (Cont.):

3- The angle of repose φ:

The frictional forces in a loose powder can be
measured by the angle of repose φ.
φ = the maximum angle possible between the surface
of a pile of powder and horizontal plane = coefficient
of friction μ between the particles:
tan φ = μ
tan φ = h / r
r=d/2
3- The angle of repose φ (Cont.):

- The sample is poured onto a horizontal surface and the angle of the
resulting pyramid is measured.
- The user normally selects the funnel orifice through which the powder
flows slowly and reasonably constantly.

Angle of repose less than 20 (excellent flow)

Angle of repose between 20-30 (good flow)
Angle of repose between 30-34 (Pass flow)
Angle of repose greater than 40 (poor flow)

***The rougher and more irregular the surface of the particles,

the higher will be the angle of repose.
Factors affecting the flow properties
of powders:

Improvement
of
Powder
Flowability

Particle’s
size Particle Surface Flow
& Shape forces Activators
Distribution & texture
Factors affecting the flow properties of
powders (Cont.):

Alteration of Particle’s size & Distribution

• There is certain particle size at which powder’s flow ability
is optimum.

Coarse particles are more preferred than fine ones as they are
less cohesive.

The size distribution can also be altered to improve

flowability by removing a proportion of the fine particle
fraction or by increasing the proportion of coarser particles,
such as occurs in granulation.
Factors affecting the flow properties of
powders (Cont.):

Alteration of Particle Shape & texture

Particle’s Shape:
Generally, more spherical particles have better flow properties than
more irregular particles.

Spherical particles are obtained by spray drying, or by temperature

cycling crystallization.

Particle's texture:
particles with very rough surfaces will be more cohesive and have a
greater tendency to interlock than smooth surfaced particles.
Factors affecting the flow properties of
powders (Cont.):

Alteration of Surface Forces

- Reduction of electrostatic charges can improve powder flowability.
Electrostatic charges can be reduced by altering process conditions
to reduce frictional contacts.
- Moisture content of particle greatly affects powder’s flowability.
-Adsorbed surface moisture films tend to increase bulk density and
reduce porosity.
- Drying the particles will reduce the cohesiveness and improve the
flow.

- Hygroscopic powders, stored and processed under low humidity

conditions.
Factors affecting the flow properties of
powders (Cont.):

Formulation additives ( Flow activators)

- Flow activators are commonly referred as glidants.
- Flow activators improve the flowability of powders
by reducing adhesion and cohesion.

e.g. talc, maize starch and magnesium stearate

 References

1. Text book of Physical Pharmaceutics by CVS

Subramanyam.

2. Text book of Physical Pharmacy By Albert

Martin.

3. Text Book of Dosage Form Design Considerations,

pp.599-635

4. https://www.google.com.pk/