Micromeritics

Micromeritics & Powder

Rheology
The branch of science and technology concerned with the study of small particle
behavior is known as Micromeritics. The term was introduced by the American
scientist J.M. Dalla Valle. Understanding micromeritics is vital for analyzing the
characteristics of pharmaceutical dispersions.

The dimensions and surface area of particles influence the physical, chemical, and
therapeutic attributes of drugs. In clinical settings, the particle size of a drug plays
a critical role in how it is released from dosage forms. The effectiveness of a
formulation—both in terms of physical performance and pharmacological activity—
relies heavily on the particle size in the final product. Managing this size is
especially crucial in tablet and capsule production to ensure good flow
Micromeritics
characteristicsincludes the study
and uniform of:of powders and granules.
mixing
1. Distribution and measurement of particle size
2. Techniques used to determine particle dimensions
3. Shape of particles and their surface area
4. Size and structure of pores
Significance of Micromeritics
Understanding and controlling particle size is crucial in pharmacy and materials science.
The dimensions and surface characteristics of particles directly influence the physical,
chemical, and therapeutic behavior of drugs.

Drug Release and Solubility:

The size and surface area of particles play a key role in how a drug is released from
various dosage forms—such as oral, rectal, injectable, or topical forms. A larger surface
area promotes better interaction between the drug and body fluids, which improves the
solubility and rate of dissolution of the medication.

Absorption and Therapeutic Effect:

Particle size and surface area also affect how well a drug is absorbed into the body and
how effectively it performs its therapeutic role. Increased dissolution leads to faster
absorption, which can result in a more rapid and effective drug response.
Formulation Stability:
The physical integrity of suspensions and emulsions depends on particle size. Smaller
particles generally provide greater stability in formulations by reducing the chances of
sedimentation or separation, improving the overall shelf-life and performance.

Uniform Dosage:
Proper flow of powders and granules is essential for producing tablets and capsules. During
manufacturing, consistent volume filling ensures accurate dosing. Any variation in flow or
fill can lead to inconsistent drug content in each unit, which may reduce the dose accuracy
and reliability of the medicine.

Approximate size ranges of methods used for particle size analysis:

Optical Microscopy
Optical microscopy uses visible light and lenses to magnify small objects, allowing scientists
to observe details invisible to the naked eye. It allows for the evaluation of particle
diameters.

Principle:
Optical microscopy is carried out in the following steps:
1. Mounting an emulsion/suspension (diluted/undiluted) on a mechanical stage
2. Fitting the microscope eyepiece with a micrometre using which the particle size can be
estimated
3. Projecting the field onto a screen to make measuring easier

To obtain a value for the dimensions of irregular particles, numerous approaches can be
used:
4. Martin’s diameter: The length of a lien that bisects the particle image
5. Feret’s diameter: Distance between two tangs on opposite sides of the particle parallel
to some fixed direction
6. Projected area diameter: Diameter of a circle with the same area as that of the particle
observed perpendicular to the surface on which the particle rests
Sieving Method
Sieving is a particle size analysis method that separates solid particles by passing them
through a mesh with specific sized openings.

Principle:
SIeve analysis is based on vibratory principle and uses a set of standard sieves calibrated
by National Bureau of Standards. The steps of sieve analysis are as follows:
1. Selected number & size of sieves are stacked upon one another from largest to
smallest. (Stacks of 6-8 with √2 or 2√2 change in diameter)
2. Known amount of powder is then placed on top and the set is vibrated in a mechanical
device. (Usually for 20 minutes)
3. Results are obtained by weighing the amount of retained particles on each sieve and
collecting pans.
Disadvantages of this
Advantages of this method are - method are -
- Simple - Not precise enough
- Inexpensive - Not applicable for
- Easily operable disperse systems
Based on the size of the particles, powders can be divided into three
categories:
1. Coarse powder: >95% mass passes through a number 1400
seive, <40% passes through number 355 sieve.
2. Moderately fine powder: >95% masses through number 355
sieve and <40% passes through number 180 sieve.
3. Fine powder: >95% passes through a number 180 sieve <40%
passes through a number 125 sieve.
Sedimentation method:
In the sedimentation method, particle size is measured by the terminal settling velocity of
particles through a liquid medium in a gravitational centrifugal environment using
Andreasen apparatus.

Principle:
Sedimentation method can be divided into two main categories according to the method of
measurement:
● Based on particle measurement in a retention zone.
● Based on particle measurement in a non-retention zone (e.g. pipette method).

One of the most popular

Here, pipette methods was developed by and named after Andreasen &
Lundberg. Methods depend V on the fact
= Rate that the terminal velocity of a particle in a fluid
of settling
increases with size.
X - distance of fall in t-time
D - mean diameter or
particle
Ps= density of particle
Pf= Density of medium
Stoke’s diameter is defined as the diameter of the sphere that would settle at the same rate as the particle.

Stoke’s law is dependent on a few conditions:

1. The law is applicable to irregularly shaped particles of various sizes as long as one realises that the
diameter obtained is a relative particle size equivalent to that of a sphere falling at the same velocity
as that of the particle under consideration.
2. The particles must not be aggregated or clumped together in the suspension.
3. The rate of sedimentation of a particle must not be so rapid that turbulence is set up.
4. The turbulent flow is indicated by Reynolds number.
Coulter Counter Method : A popular instrument for measuring the volume of
particles
The main components of a Coulter Counter include:
● Orifice (Aperture): A tiny hole through which
particles pass.
● Electrodes: Placed on both sides of the orifice to
detect changes in resistance.
● Diluent Reservoir: Contains the suspension of
particles in a conductive electrolyte.
● Pumping System: Drives the suspension through
the orifice.
● Voltage Source: Maintains a constant voltage
across the electrodes.
● Pulse Amplifier and Analyzer: Detects and
measures the voltage pulses.
● Display/Recording System: Shows particle size and
count data.
Working Principle:
The Coulter Counter works based
on the electrical sensing zone
principle. When a particle
suspended in an electrically
conductive liquid (electrolyte)
passes through a small aperture
between two electrodes, it displaces
its own volume of electrolyte,
causing a temporary increase in
A constantresistance.
electrical voltage is applied across the electrodes.
Each particle creates a voltage pulse, and the height (amplitude) of this pulse is
proportional to the volume of the particle.
By analyzing these pulses, the number and size of particles in a suspension can
be determined.
Working Mechanism:
- A dilute suspension of particles in an electrolyte is prepared.
- The sample is drawn through the orifice using a vacuum or pump system.
- As each particle passes through the orifice, it displaces the electrolyte, increasing the
resistance.
- This increase produces a voltage pulse whose height is proportional to the particle's
volume.
- These pulses are amplified and analyzed to determine:
* Number of particles
* Volume (and hence approximate diameter) of each particle
Data can be converted into particle size distribution graphs.
Advantages: Disadvantages:
With proper calibration, data can also be converted from volume to weight distribution.
● High accuracy in particle size and count ● Requires dilute suspension
● Rapid analysis – up to 4000 particles/sec ● Only works in conductive liquids
● Works well for small particle size range ● Cannot measure dry powders
(0.5–400 µm) ● Orifice can clog with large or
● Provides both size distribution and count aggregated particles
● Non-optical – suitable for opaque particles ● Assumes particles are spherical
● Air bubbles can affect accuracy
 Pipette Method –
The pipette method is a sedimentation technique used to determine particle size
distribution based on Stokes' Law, which relates particle size to the rate at which particles
settle in a fluid under gravity.
Principle:
When a suspension of fine particles is allowed to stand in a cylindrical container, particles
begin to settle due to gravity.
Larger particles settle faster.
Smaller particles settle slower.
By withdrawing samples (aliquots) from a specific depth at set time intervals using a
pipette, we can analyze the concentration of particles of different sizes.
Materials Required:
- Sedimentation cylinder (1000 mL
usually)
- Pipette (25 mL or suitable size)
- Stopwatch
- Balance
- Drying oven
 Procedure:
1. Prepare a uniform suspension of the sample in a dispersing medium (e.g., water +
dispersant).
2. Pour the suspension into a graduated sedimentation cylinder.
3. Allow the suspension to settle undisturbed.
4. At predetermined time intervals (based on Stokes' Law), use a pipette to withdraw a
sample from a fixed depth.
5. Transfer the sample to a dish and evaporate or dry it.
6. Weigh the dried residue to determine the mass of particles of a specific size range.
7. Repeat for different time intervals to analyze the complete size distribution.
Applications:
- Analysis of fine powders in pharmacy
- Soil particle size distribution
- Suspension formulations (e.g., syrups,
emulsions)
Advantages: Disadvantages:
● Accurate for fine particles ● Time-consuming
● Simple and inexpensive ● Assumes particles are spherical
● Useful when other methods ● Results can be affected by
(like sieving) fail temperature, viscosity, and
flocculation
● Not suitable for coarse particles
Aspects of drug designing in medicine :
Micromeritics deals with the study of small particles, crucial in drug formulation and
design. Key aspects and their significance:

● Particle Size & Distribution: Affects dissolution rate, bioavailability, and dose
uniformity.
● Surface Area & Shape: Influences solubility, adsorption, and reaction rates.
● Porosity & Density: Important for tablet packing, disintegration, and storage.
● Flow Properties: Ensures uniform filling in tablets/capsules and smooth
manufacturing.
● Compaction Behavior: Affects tablet strength and need for excipients.
 Particle Shape and Surface Area
⮚ Knowledge of particle shape and surface area is essential in
powder and pharmaceutical science because:
⮚ Particle shape affects:
o Flow properties of the powder
o Packing behavior of the particles
o Surface area of the material
⮚ Surface area per unit weight or volume is crucial in:
o Surface adsorption studies
o Dissolution rate studies
 Particle shape
🔹 What is Particle Shape?
∙ Particle shape refers to the external form or geometry of a particle.
∙ It affects how particles flow, pack, and how much surface area they
expose.
Particle shape and surface area are correlated as:
⮚ A sphere has minimum surface area per unit volume.
⮚ The more asymmetric a particle, the greater is the surface area per
unit volume.
⮚ Spherical particles are defined by diameter; asymmetrical ones need
equivalent diameters.
⮚ The shape affects how much surface area is exposed, influencing
processes like adsorption, dissolution rate, and flow properties of
powders.
Formula For Spherical
Particles:

where d is the diameter of the particle.

For spheres, surface area increases with the square of the diameter, and volume with the
cube.

Formula for Irregular Particle Shapes,

If using projected diameter (dp) from microscopic observation,
For a
sphere,

•The ratio αs/αv helps describe particle shape.

•For a spherical particle, this ratio equals 6.0.
•As the particle becomes more asymmetric, the ratio
increases above 6.
🔹 Specific surface is the surface area per unit volume (Sv) or
Specific Surface

per unit weight (Sw) of particles.

✅ General Equations:
•Surface area per unit volume• Surface area per unit weight
(Sv): (Sw):

Where:
o ρ = true density of the particles
•Substituting
gives: o dvs = volume-surface diameter
o αs and αv = shape factors
🔹 For Spherical
Particles:

•Since αs/αv=6.0 for

spheres:
Surface Area
Math
 Adsorption Method for Measuring Surface Area
∙ Particles with large specific surface area are effective adsorbents for gases and
solutes.
∙ To measure surface area, the volume of gas adsorbed (in cm ³/g) is plotted against
gas pressure at constant temperature to form a Type II isotherm.
∙ At low pressures, gas forms a monomolecular layer; at higher pressures, it forms
multimolecular layers.
∙ The point where the monolayer is complete is marked as point B on the isotherm.
✅ BET Equation (Brunauer, Emmett, and
Teller)
Where:
•V: Volume of gas adsorbed (cm³/g)
•p: Pressure of gas
•p0: Saturation vapor pressure
•Vm: Volume of gas forming a
monolayer
•b: Constant related to heat of
adsorption
🔹 Instrument Used: Quantasorb QS-16
∙ Measures adsorption and desorption of nitrogen
using a thermal conductivity detector.
∙ Nitrogen: Adsorbate gas
∙ Helium: Inert carrier gas
Results are shown as a bell-shaped curve; area under
the curve is proportional to gas adsorbed.

🔹 Advantages of Quantasorb Instrument

∙ Highly sensitive – requires only small powder samples for accurate analysis.
∙ Replaces older vacuum systems made of glass tubing, which were: Time-consuming
& Prone to leakage and breakage
o True density
∙ Versatile – can also measure:
o Pore size and pore volume distributions
o Works with variety of gases and
 Reasons for Producing Free-Flowing Pharmaceutical Powders
∙ Uniform flow from bulk storage containers or hoppers into the feed mechanisms of
tableting or capsule-filling equipment, allowing uniform particle packing and a
constant volume-to-mass ratio in order to maintain tablet weight uniformity.
∙ Reproducible filling of tablet dies and capsule dosators to improve weight
uniformity and allow tablets to be produced with more consistent
physicomechanical properties.
∙ Uneven powder flow can result in excess entrapped air within powders, which in
some high-speed tableting conditions may promote capping or lamination.
∙ Uneven powder flow can result from excess fine particles in a powder, which
increases particle die-wall friction, causing lubrication problems, and increased
dust contamination risks during powder transfer.
Porosity:
Suppose a nonporous powder, is placed in a graduated cylinder:
a. The total volume occupied is known as the bulk volume Vb.
b. The volume of the spaces is the void volume.
c. The true volume of particles is Vp.
Bulk volume, Vb = True volume + Volume of spaces between particles
(Void volume).
Void volume, V = Vb -Vp

The porosity (ε) or voids of powder is determined as the ratio of void

volume to bulk volume:
𝜀 = 𝑉𝑏 − 𝑉𝑝/𝑉𝑏
Porosity is frequently expressed in percent, ε x 100
Calculate Porosity:
A sample of calcium oxide powder with a true density of 3.203 and
weighing 131.3 g was found to have a bulk volume of 82.0 cm3 when
placed in a 100 mL graduated cylinder.
Ans:
The volume of the particles articles is,
131.3 g/(3.203 g/cm3)
= 41.0 cm3

From equation (18–25), the volume of void space is,

v = 82.0 cm3 − 41.0 cm3 = 41.0 cm3

and from equation (18–26) the porosity is

ε =82-41/82
= 0.5 or 50%
Densities of particles:

Density is defined as weight per unit volume (W/V).

Types of densities:
1. True density: The true density, or absolute density, of a sample excludes the volume of
the pores and voids within the sample.

2. Bulk density: The bulk density value includes the volume of all of the pores within the
sample.During tapping, particles gradually pack more efficiently, the powder volume
decreases and the tapped density increases.

3. Tapped density: Tapped density is an increased bulk density attained after

mechanically tapping a container containing the powder sample. It is the ratio of the
mass of the powder to the volume occupied by the powder after it has been tapped for
a defined period of time
 Bulkiness
In Micrometrics, bulkiness is the reciprocal of bulk density.
Where bulk density is the mass of a powder divided by the bulk volume it occupies.
Bulkiness= Specific bulk volume= Reciprocal of bulk density:1/bulk density = bulk
volume/mass of powder

Bulkiness is inversely proportional to particle size. For example, micronized Calcium

Carbonate has high bulkiness because the fine particles trap more air and pack
loosely,while precipitated
Characterization of PowderCalcium
Flow Carbonate has low bulkiness due to better packing and
reduced void space.
Characterization of powder flow is crucial for the design and manufacture of solid dosage
forms like tablets and capsules.
In general,methods of measuring powder flow must be
practical,useful,reproducible,sensitive and must yield meaningful results.
Hence, following standardized test methods are used to characterize the various aspects of
powder flow:
1. Angle of Repose;
2. Compressibility index and Hausner Ratio;
3. Flow Rate through an Orifice and
Measurement of Cohesive-Adhesive Properties
Cohesive force refers to attraction between similar particles (e.g., powder to powder) and
Adhesive force means attraction between dissimilar surfaces(e.g., powder to container).
Measuring cohesive and adhesive properties of powders is essential in understanding how
particles interact. This includes-
1. Shear Strength (e.g.,Jenike Shear Cell);
2. Tensile Strength and
3. Angle of Repose.

Shear Strength
Shear stress it the force per unit area requiring to cause one layer of powder particles to
slide over another. This is used to determine the resistance to flow caused by
adhesion,cohesion or friction and can be measured using a shear cell (e.g.,Jenike Shear
Cell).
Shear strength is used to measure cohesive properties of a bed of powder.
In pharmaceutical context of powder rheology,
- High shear strength = High cohesion= Poor flow
- Low shear strength = Powder is free flowing
 Tensile Strength

Tensile strength is defined as the maximum tensile stress a material (such as a bed of
powder) can resist before failure due to tension.
It too is used to measure cohesive properties of a bed of powder.
In pharmaceutical context of powder rheology,
- High tensile strength = Strong interparticulate bonds (good tablet quality)
- Low tensile strength = Weak bonding (may cause tablet cracking or friability)
Tensile strength, σt, of the powder can be determined from,

Where,
M = Mass of the mobile half plate+powder;
Θ = Angle of the tilted table at the point of failure;
A = Cross -sectional area of the powder bed.
 Angle of Repose

An Angle of Repose or a critical angle of repose of a granular material is the steepest angle
of descent or dip relative to the horizontal plate on which the material can be piled without
slumping.
Angle of repose is an indirect method of quantifying powder flowability that assess cohesion
and adhesion.
In pharmaceutical context of powder rheology,
- Lower angle = Better flow = Less cohesive
- Higher angle = Poor flow = Better cohesion
While,
φ is the maximum angle possible between the surface of powder and
Horizontal plate=Coefficient of friction, μ between the particles,
tanθ = μ,
tanθ= h/r
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.
Bulk density = weight / bulk volume; Tapped density = weight / true volume.

Hausner ratio

Hausner ratio was related to inter-particle 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.
Improvement of Powder Flowability:
1. Particle Size and Distribution
2. Particle Shape and Texture
3. Surface Forces
4. Flow Activators

Alteration of Particle’s size & Distribution

1. There is a certain particle size at which powder’s flowability is optimum.
2. Coarse particles are more preferred than fine ones as they are less cohesive.
3. 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.
Alteration of Particle Shape & texture
1.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 crystallisation.
2.Particle's texture:Particles with very rough surfaces will be more cohesive and have a
greater tendency to interlock than smooth surfaced particles.
Alteration of Surface Forces
1. Reduction of electrostatic charges can improve powder flowability.Electrostatic charges
can be reduced by altering process conditions to reduce frictional contacts.
2. Moisture content of particles greatly affects powder’s flowability.
3. Drying the particles will reduce the cohesiveness and improve the flow.
4. Hygroscopic powders, stored and processed under low humidity conditions.

Formulation additives ( Flow activators)

1. Flow activators are commonly referred to as glidants.
2. Flow activators improve the flowability of powders by reducing adhesion and cohesion.
3. e.g. talc, maize starch and magnesium stearate.