Micromeritics

Liknaw W.
(MSc in
Pharmaceutics)
 Objectives

 Define Micromeritics

 Analyze particle size and size distribution

 Discuss methods for determining particle size

 Identify particle shape and surface area

 Determine properties of powders

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Micromeritics
 Definition:
• Micromeretics is the science and technology of small
particles deals with fundamental and derived
properties of individual and collection of particles

• It is thus the study of the fundamental and derived

properties of individual as well as collection of
particles

• It Brought together information on particle size

measurement, size distribution, and packing
arrangements.
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• In the field of pharmacy, micromertics has become an
important area of study because it influences a large
number of parameters

• Research and development

• Manufacturing of dosage forms such as
 suspension to be reconstituted
 tablet
 capsule

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 Study of particle size and size distribution has many
application in pharmacy

 Physical properties of powder are dependent on particle size

and size distribution
• bulk density, compressibility, porosity

 Flow properties of the powder

• Spherical particles have good flow property
• Asymmetrical particles have poor flow property

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 Release & dissolution

• Higher surface area allows intimate contact of the

drug with the dissolution fluids in vivo & increases
the drug solubility & dissolution

 Absorption & drug action

• Higher the dissolution, faster the absorption & hence

quicker & greater the drug action

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 Physical stability

• Suspensions & emulsions; Smaller the size of the particle,

better the physical stability of the dosage form.

 Dose uniformity

• Good flow properties of granules & powders are

important in the manufacturing of tablets & capsules

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 Particle size and size distribution

• Particle shape plays an important role in particle size

determination

• Particles possess different shapes, for example, rod, cubical,

granular, etc

• The size of a spherical particle can be easily expressed in

terms of its diameter

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Denoted in micrometers

1 m = 1000 mm

1 mm = 1000 μm

1 μm = 1000 nm

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Particle diameter in pharmaceutical systems

Particle size Disperse system

0.5 - 10.0 µm Suspension, fine emulsion

10.0 - 50.0 µm Coarse emulsion, flocculated

suspension

50.0 - 100.0 µm Fine powder range

150.0 - 1000.0 µm Coarse powder range

1000.0 - 3360.0 µm Average granule size

 Particle size and size distribution…………
• Particles can be asymmetric and symmetric
• The size of a spherical particle can be easily expressed in terms
of its diameter

• So, for a perfect sphere;

• surface area,

• Volume, S  d2

 d3
V
6
• Non-spherical particles also has a definite surface area and
volume but being asymmetric its apparent length varies with its
orientation

• Hence, it is not possible to express its size in terms of its

diameter
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 A B C

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• Various equivalent diameters have been developed to relate
the size of such particles to that of a sphere with identical
diameter, surface area, or volume.

• Surface diameter , ds the diameter of a sphere having the

same surface area as that of the asymmetric particles in
question.

• Volume diameter, dv the diameter of a sphere having the

same volume as that of the asymmetric particles in question.
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• Projected diameter, dp the diameter of a sphere having the same
observed area as that of the asymmetric particles in question
• when viewed normal to its most stable plane.
• Usually determined using microscopic techniques

• Stock diameter, dst the diameter of a sphere with the same density
as the asymmetric particles in question and which undergoes
sedimentation at the same rate as the asymmetric particles in a
given fluid
• dst is usually determined using sedimentation methods

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 Monodisperse system
• Particles of approximately uniform size

• Polydisperse System
 mixture of particles with varying size and shape

• Thus, we need an estimate of the size range present and the

number or weight fraction of each particle size.

• This is called the particle size distribution and from this the
average particle size of the collection of particles can be derived.
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Particle size and size distribution

Monodisperse Polydisperse
 Methods of particles determination

• Particle size determinations are complicated by the fact that

particles are not uniform in shape.

• Particle-size analysis methods can be divided into different

categories based on several different criteria:
• size range of analysis
• wet or dry methods
• manual or automatic methods
• speed of analysis
Hence,
 Microscopic
 Sieving technique
 Sedimentation
 Coulter counter
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 Microscopy
• The microscope eyepiece is fitted with a micrometer by
which the size of the particles may be estimated.
 The effective size range for analyzing particles is about
0.25 to 100 µm.
• Dilute suspension of the particles whose size are to be
determined is prepared in a liquid in which it is insoluble.
• A drop of suspension is placed on the slide
• The eyepiece of the microscope is fitted with micrometer
• The particles observed are counted , and can be projected
or photographed

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• Average diameter of a
particulate system is obtained
by measuring the particles at
random along a given fixed
line

• At least 300-500 particles must

be counted in order to obtain a
good size distribution analysis
of data.

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  Advantages
 Providing a direct visual representation of the particles
 Requires an extremely small amount of sample
The equipment is relatively inexpensive to acquire and
maintain
 It can provide details about shape, crystal habit, and
homogeneity within the sample in addition to size
Contamination and agglomeration of the particles can be
detected.
Simple to count the particles.
It is the simplest method for particle size analysis.

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• Disadvantage

 The measured diameter of the particles represents two

dimensions only/ the depths of the particle are not
accessible.

 Testing of ultrafine particles not possible.

 Slow and tedious process

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 Sieving
 Sieve analysis is used to obtain the particle size distribution of a
solid material by determining the amount of powder retained on
a series of sieves with different sized apertures.

 A sample is added to the top of a nest of sieves arranged in

decreasing size from top to bottom. As the sieves are vibrated,
the sample is segregated onto the different sized sieves.

 The weight of sample retained on each sieve is then used to

determine the particle size distribution as well as the mean
diameter of the sample.

 Useful for coarse particles (>50m)

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In determining particle size by this method,

• The powder is classified as having passed through one

sieve and being retained on the adjacent finer sieve.

 Mass, collected on each sieve

 Percentage of sample, collected on each sieve

 Cumulative percentage of sample retained on each

sieve

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Sieve Sieve Sieve no Sieve size in Arthim Weight Weight Commul Weight
no size (passed/ µm atic (g)retai retaine ative size
retained) (passed/ret mean ned on d % Frequen n*d
ained) size in sieve(n) cy %
µm (d)

08 2000 8/10 2000/1700 1850 2.4 2.51 2.51 4440

10 1700 10/16 1700/1000 1350 7.5 7.83 10.34 10125

16 1000 16/25 1000/600 800 18.59 19.41 29.75 14872

25 600 25/60 600/250 425 44.67 46.64 76.39 18984

60 250 60/85 250/180 215 13.4 13.99 90.35 2881

85 180 85/100 180/150 165 6.02 6.29 96.67 993

100 150 100/pan 150/pan 75 3.2 3.34 100 240

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• Disadvantage
 aggregation- due to electrostatic charge or moisture
actual size is not determined
 Attrition- size reduction
 Sieve loading and duration of mechanical shaking can
influence the results

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Sedimentation

• Andreason pipette is used for particle size distribution

determination

• The particle size in sub-sieve range can be obtained by

gravity sedimentation as expressed in Stokes’s law (0.8
to 300µm)

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 Andreason pipette
• The particles to be examined (e.g. a powder ) are
first suspended in a suitable liquid and distributed
evenly.

• At first it can be assumed that the suspended

particles are equally concentrated in all transverse
layers of the suspension.

• With the passage of time, however, the particles

sediment, with the larger particles sedimenting
more quickly than the smaller ones according to
Stokes' equation .

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• The Andreasen pipette has a device for
withdrawing the liquid and a scale that provides
information about the filling level of the liquid, so
the height of the liquid level after each sample
withdrawal and the withdrawal time result in a rate
of descent that can be equated with the rate of
descent in Stokes' equation is.
• 10 ml sample is drawn at various time interval
• The samples are evaporated and weighed
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• The particle diameter corresponding to the various time
period is calculated using the Stocks equation

V= h = d2st(ρs – ρo)g
t 18ηo
 V is the rate of settling
 H is the distance of fall in time
 dst is the mean diameter of the particles based on the
velocity of sedimentation
 ρs is the density of the particles
 ρo is the density of dispersion medium
 ηo is the viscosity of the medium
 g acceleration due to gravity
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• Advantage
i. the apparatus is inexpensive and the technique is simple
ii. The results obtained are precise provided the technique is
adequately standardized

• Disadvantages

1. Method is laborious since separate analysis are required for

each experimental point on the distribution curve
2. Very small particles cannot be determined accurately since
their settling is unduly prolonged

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Stokes Diameter
• A sample of powdered zinc oxide, density 5.60 g/cm3 is allowed to
settle under the acceleration of gravity, 981 cm/sec2 at 25 C. The
rate of settling v is 7.30 x 10-3 cm/sec; the density of the medium
is 1.01 g/cm3, and its viscosity is 1 centipoise = 0.01 poise or 0.01
g/cm sec. Calculate the Stokes diameter of the zinc oxide Powder.

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 Average particle size
• The particle size of a powder is analyzed microscopically
and the number of particles in each size range is
determined
Size range (µm) Mean size range No particle in each nd
(in µm ) (d) size range (n)

0.5-1.0 0.75 4 3
1.0-1.5 1.25 18 22.5
1.5-2.0 1.75 39 68.25
2.0-2.5 2.25 73 164.25
2.5-3.0 2.75 24 66
3.0-3.5 3.25 14 45.5
3.5-4.0 3.75 2 7.5
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n=174
Liknaw W.
nd=377 33
• From the data the average particle size (dmean) of the
powder may be calculated as

• Average particle size =

=377/174

= 2.16 µm

, where n is the number of particles and d is the diameter

of particles

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Particle size distribution (PSD)

The PSD of a powder, or granular material, or particles dispersed

in fluid, is a list of values or a mathematical function that defines
the relative amount, typically by mass, of particles present
according to size.

The particle size distribution in a powder may be quantified by

1. Determining the number of particles present in each size range

2. Determining the weight of particles present in each size range

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• When this number /weight of particles lying within a
certain size range is plotted against size range or mean
particle size
 frequency distribution curve is obtained

 number frequency distribution curve

number of particles vs mean particle size
 weight frequency distribution curve
weight of particles vs mean particle size

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6/10/2022 A frequency distribution
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• Particle size can be expressed in two
ways
1. Monodisperse particle size
• its characteristics can be described
by a single diameter or equivalent
diameter

% frequency
2. Polydisperse particle size- common
encounter in pharmaceutical powder
• A poly dispersed powder system is
said to have a normal distribution if a
typical bell shaped frequency
Particle size
distribution curve is obtained
Fig. normal or Gaussian size frequency distribution
curve

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• However, normal distribution is not common in
pharmaceutical powder which are commonly processed by
milling or precipitation

• More commonly asymmetric or skewed distribution is

obtained

• A frequency curve with an elongated tail towards higher

size ranges is positively skeiwed; the reverse case
exhibits negative skewness.

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Fig. Frequency distribution curves corresponding to
(a) a normal distribution,
(b) a positively skewed distribution, and
(c) a bimodal distribution.
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• Such a curve can be converted to a normal bell shaped curve
by plotting frequency vs the logarithm of the particle size
diameter
log-normal distribution curve

% frequency

Log particle size

Fig. log normal distribution curve obtained for a polydisperse powder

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• Types of Diameter
particle size (diameter) can be described by different expression

 A mean particle diameter

the sum of all individual diameter divided by the total number
of particles .
 sensitive to extreme value
 represent the size present in the greatest number

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• Median diameter
a diameter for which 50% of the particles are less the stated
size.

• Mode diameter
represent the particle size occurring most frequently in the
sample
• Mean volume surface diameter
used to express powder particle size in terms of surface area
per unit volume.
 nd 3
dave =  n 2

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 Derived properties of powders
1. Porosity of powder
The quality or state of being
porous
• Powders can be
i. Porous (most pharmaceutical
solids are porous, i.e., they have
internal pores or capillary)
 Bulk volume > true
volume
ii. Non-porous

When a powder, is placed in a graduated

cylinder: the total volume occupied is
known as the bulk volume Vb .
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• Bulk volume (Vb) = true volume (Vp) + volume of spaces b/n
particles.
The volume of the spaces, the void volume, V = Vb – Vp

The porosity (ε) of powder is determined

as the ratio of void volume to bulk volume.

• Porosity = ε = Vb – Vp = 1 - Vp
Vb Vb
• frequently expressed in percent, ε x 100

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• Packing Arrangement in Powder Beds
• Two types of packing are possible

• Cubic packing Rhombohedral packing

 Most open/ Loosest packing closest packing (=26%)
(=48%)

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• pharmaceutical powders have porosity range from 30 and 50%.

• When the particles of varying sizes are present, porosity lower

than the theoretical minimum of 26% is also possible. Why ?

• If the powder contains floccules or aggregates, the porosity may

go beyond the theoretical maximum of 48%. Why ?

• Highly compressed crystalline materials,  < 1%

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Example
• A sample of calcium oxide powder with a true density of 3.203
and weighing 131.3g was found to have a bulk volume of 82
cm3 when placed in a 100-ml graduated cylinder. Calculate
the porosity ?
• Ans.=50%

• Calculate the percent porosity of TiO2 having a true density of

4.26g/cm3 and 100g sample of which was found to occupy a
bulk volume of 80 mL.
• Ans=70%

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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.
 Methods
 Liquid (water) displacement method
 Gas displacement method (He, H2)-better penetration
ability

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B- bulk density (b)
• It is the ratio of the mass of the powder and its bulk volume

• includes the volume of all of the pores within the sample.

• Weighed quantity of the powder material is introduced into a

graduated measuring cylinder and is tapped mechanically or
manually till a constant volume is obtained, then tapped
density calculated.

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C. Tapped density (T)
• It is the ratio of mass of powder to tapped volume

• This volume, known tapped volume of the powder is noted and

includes the true volume of the powder as well as the volume
occupied by the interparticle and intraparticle spaces.

V1 M
b 
V1
V2

M
T 
V2
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 Tappe densitometer

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3. Flow properties of powders

 Powders may be free-flowing or cohesive (“sticky”).

 Important parameter to be considered in the production
of pharmaceutical dosage forms.

• Example:
 dies filling during tableting
 capsules filling
directly depend on the flow properties of the
powder

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Flow properties of powders depends on;
i. Cohesiveness or stickiness between particles due to
presence of Van der Waals, surface tension and
electrostatic forces.
• Cohesiveness of particles has been found to depend
upon a number of factors
a. Particle size and shape
 Very fine particles tend to be more cohesive due to
their large surface area
b. Density or porosity of the powders
 dense materials tend to be less cohesive than
lighter ones
c. The presence of adsorbed materials on the powder
surface
 Moisture increase cohesiveness of particles

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ii. Adhesion between the particles and the container wall
due to the above forces.

iii. Friction between particles due to surface roughness.

iv. Physical interlocking of particles specially if these are of

irregular shape

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Many common manufacturing problems are attributed
to powder flow:
- Uneven powder flow
• excess entrapped air within powders → capping or
lamination.
• increase particle’s friction with die wall causing
lubrication problems, and
• increase dust contamination risks during powder
transfer.
• non-uniformity of dose
- non-uniformity (segregation) in blending

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Assessment of flow properties of powders
1- Carr’s compressibility index

• Bulk density = weight / bulk volume

• Tapped density = weight / true volume

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• Relationship between powder flowability and %
compressibility

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2- Hausner ratio:
• Hausner ratio was related to interparticle friction:

• Value less than 1.25 indicates good flow

• The powder with low interparticle friction, such as coarse
spheres.
• Value greater than 1.5 indicates poor flow
• more cohesive, less free-flowing powders .
• Between 1.25 and 1.5, added glidant normally improves flow.
> 1.5 added glidant doesn’t improve flow.

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 3.Angle of Repose ()
• 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.

h
tan  
r

where,
, angle of repose, h & r are height and radius of the
powder, respectively

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• Angle of repose is a function of the surface roughness.
The rougher and more irregular the surface of
particles, the more the angle of repose
• As the particles become less and less spherical, the
angle of repose increases while the bulk density and
flowability decreases.

• Angle of repose () Flow properties

<25o excellent
25 – 30o good
30 – 40o satisfactory
40 – 50o poor
>50o very poor

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Factors affecting the flow properties of powders

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.

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Alteration of Particle Shape & texture
• Particle’s shape: generally, more spherical particles have
better flow properties than more irregular particles.

• Particle's texture:
 particles with very rough surfaces will be more
cohesive and have a greater tendency to interlock than
smooth surfaced particles

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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.

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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

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 Assignments
Discuss the following with diagrammatic illustration

Q1. Iontophoresis and Sonophoresis based skin drug delivery?

Q2. Method of particle volume measurement by coulter counter

method?
Q3.
Q4.
Q5.

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