Micromeritics

By: Bedilu. A
 Contents

 Particle Size and Size Distribution

 Methods for determining particle size
 Density and Flow properties of powders

2
 Objective
o After completion of this chapter, the student will be able to

➢ Describe the concept of particle size as it applies to pharmaceutical

sciences.

➢ Discuss the common particle size of pharmaceutical preparation and

their impact on pharmaceutical processing/preparation.

➢ Differentiate the method of determining particle size.

➢ Discuss the role and importance of particle shape and surface area.

➢ Understand the methods for determining particle surface area.

➢ Describe derived properties of a powder and their importance.

3
 Micromeritics

Definition:

 It is the science and technology of small particles.

 The unit of particle size used in the micrometer (µm), micron (µ) and equal to

10-6 m.

 As particle size decreases , area increases 

4
 Micromeritics

 Knowledge and control of the size and the size range of particles have

significant importance in pharmacy

 because the size and surface area of a particle are related to the:-

 physical
 chemical and
pharmacologic properties of a drug

 The particle size of a drug can affect its release from dosage forms that are

administered orally, parenterally , rectally and topically.

5
 Cont…

 The successful formulation of suspensions, emulsions, and

tablets, from the viewpoints of both physical stability and

pharmacologic response, also depends on the particle size
achieved in the product.

 In the area of tablet and capsule manufacture, control of the

particle size is essential in achieving the necessary flow

properties and proper mixing of granules and powders.

6
 Cont…
Particle Size and Size Distribution

 In a collection of particles of more than one size (in a polydisperse sample) ,

some properties are important,

 The shape and surface area of the individual particles

 The particle size and size distributions

✓ The size range and number or weight of particles

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 Particle Shape

 Particles of drugs or pharmaceutical excipients are

seldom uniform spheres even after size reduction and

classification

 particles may exist in various shapes, ranging from

simple to irregular geometries

 Their aggregation behavior produces an even greater

variety of shapes and structures

8
 Cont….
 If powders consisted of spherical particles, a simple statement of

diameter would describe the particles

 However, pharmaceutical powders consist of particles with varying

nonspherical shapes and sizes, and any size measurement has to

account for this

 Shape is an important factor along with size

9
 Cont…
 The more spherical the particle, the easier its processing

 Particle shape also influences the measurement of particle size through

orientation effects of the particle during measurement.

 This is an interesting mathematical and statistical problem,

 which leads to the utilization of a variety of descriptors based on

geometrical relationships.
 for example, using surface area or volume, of the particle under

measurement and a nominally equivalent ideal sphere.

10
 Cont…

 In size reduction of relatively large solids

 resulting fine particles would be irregular with different numbers of faces

 it would be difficult or impractical to determine more than a single

dimension.

 For this reason a solid particle is often considered to approximate to a sphere

which can then be characterized by determining its diameter

 Because measurement is then based on a hypothetical sphere

 Which represents only an approximation to the true shape of the particle

 The dimension is referred to as the equivalent diameter of the

particle
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 Equivalent diameters
 Relates the size of the particle to the diameter of a sphere having the same
surface area, volume, or diameter
 It is possible to generate more than one sphere which is equivalent to a given
irregular particle shape
 The size of a sphere is readily expressed in terms of its diameter
 The Surface diameter, ds, is the diameter of a sphere having the same
surface area as the particle. A = 4πr2
 The Volume diameter, dv , is the diameter of a sphere having the same
volume as the particle. V = 4/3πr3
 The Projected diameter, dp , is the projected diameter of a sphere having
the same observed area as the particle.
 The Stokes diameter, dst , is the diameter which describes an equivalent
sphere undergoing sedimentation at the same rate as the asymmetric
particle.

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 Equiv. D
Diameter Definition Equation Determination Method

13
 Cont…

 The projected area diameter is based on a circle of equivalent area to that of

the projected image of a solid particle

 The projected perimeter diameter is based on a circle having the same

perimeter as the particle

 Unless the particles are unsymmetrical in three dimensions then these two

diameters will be independent of particle orientation

 These are statistical diameters which are averaged over many different

orientations to produce a mean value for each particle diameter

 The projected diameter is obtained by microscopic techniques

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  In general, the method used to determine particle size

dictates the type of equivalent diameter that is measured

 although interconversion may be carried out and this is

sometimes done automatically as part of the size analysis

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 Particle Size

 Any collection of particles is usually poly disperse

 It is necessary to know not only the size of a certain particle,

 but also how many particles of the same size exist in the sample

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

number or weight fraction of each particle size

 This is the particle-size distribution and from it we can calculate

an average particle size for the sample

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 Particle Size Distribution………

 A particle population which consists of spheres or equivalent spheres with

uniform dimensions is monosized and

 its characteristics can be described by a single diameter or equivalent

diameter

 It is unusual for particles to be completely monosized

 In order to be able to define a size distribution or compare the characteristics

of two or more powders

 the size distribution can be broken down into different size ranges, which

can be presented in the form of a histogram plotted from data

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18
 Particle Size Distribution…….
 Such a histogram presents an interpretation of the particle size distribution

 and enables to determine the percentage of particles having a given

equivalent diameter

 Also it allows different particle size distributions to be compared

 When the number or weight of particles lying within a certain size range is

plotted against the size range or mean particle size

 a so-called frequency distribution curve is obtained

 This is important because it is possible to have two samples with the same

average diameter but different distributions

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 most powder particles will not exhibit a normal distribution

 Their curves are usually skewed to one side depending on which size range

occupies a larger portion of the powder solids

✓ the smaller particles

✓ the larger particles.

➢ Positively skewed

▪ A frequency curve with an elongated tail towards higher size ranges

➢ Negative skewed:

20 ▪ the reverse case exhibits.

 a positively skewed size negatively skewed size
distribution distribution;

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 Micromeritics Applications
1. Release and dissolution
 Particle size and 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 and increases the drug solubility and

dissolution.

2. Absorption and drug action

 Particle size and surface area influence the drug absorption and

subsequently the therapeutic action.

 Higher the dissolution, faster the absorption and hence quicker and greater
22 the drug action.
 Cont…

3. Physical stability
 The particle size in a formulation influences the physical stability of the

suspensions and emulsions

 Smaller the size of the particle, better the physical stability of the

dosage form.

4. Dose uniformity
 Good flow properties of granules and powders are important in the

manufacturing of tablets and capsules.

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 Methods for determining particle size
 Microscopy methods (light, electron microscope)
 Separation methods (sieving, impaction)
 Sedimentation methods
 Electrical stream sensing (coulter counter)
 Specific surface area (adsorption, permeability) A0= 10-10 m

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 Range of particle sizes

A guide to range of particle sizes applicable to each method

Particle size Method

1 m Electron microscope, ultracentrifuge, adsorption

1 – 100 m Optical microscope, sedimentation, coulter counter, air

permeability

50 m Sieving

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 Microscopic Method
• The microscope eyepiece is fitted with a micrometer by which the size of

the particles may be estimated

• Often used to verify another particle sizing method, during development

and validation of a particle sizing method

• Microscopy measures the projection of the particles, rather than the

particles themselves to describe the size of the particles

✓ For spherical particles, the particle size descriptor is the diameter

✓ For irregularly shaped particles, the diameter of a sphere

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 Microscopy…

Principle:
• Analysis of images of projected particles on a projection screen
✓ The projected particles are compared with circles that are generated by the
graticule of the microscope.
✓ The diameter of the circle, which corresponds most similarly to the projected
particle, is used to describe the size of the particle.

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 Microscopy…
Semi-automatic methods of microscopic Analysis
 Pre-calibrated variable distance to split particles into diferent size ranges

1. Optical microscopic method (2-D particle image)

 Used for measurement of the particle-size 0.2 to about 100 µm

 Number of particles must be counted (300-500) to obtain a good estimation

2. Alternative techniques to light microscopy
SEM and TEM
 SEM: appropriate when a 3-D particle image is required
✓ providing information about particle shape and thickness
 Both SEM and TEM analysis allow the lower particle-sizing limit

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 Microscopy…

Automatic methods microscopic Analysis

 The particle comparator or a double-prism arrangement

 Automatic microscopy is usually associated with microprocessor-controlled

manipulation of an analogue signal derived from some form of video monitor

 used to image particles directly from a light microscope or from

photomicrographs of particles

 Alternatively, the signal from an electron microscope can in some cases be

processed directly without an intermediate video imaging system

 Automatic microscopy allows both image analysis and image processing to be

carried out

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 Separation Methods
I. Sieving or screening (range: 40-9500 µm)

 Standard size sieves are available to cover a wide range of size

 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

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 Separation Methods…

Sieve diameter

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 Separation Methods….
II. Impaction

 Commonly used to measure the aerodynamic diameter of aerosols

 Aerosols are characterized by aerodynamic diameter, rather than geometric

diameter

 Aerodynamic diameter is an expression of a particle’s aerodynamic behavior

and diameter,
 as if it was a regularly shaped sphere with uniform density, which has the

same terminal velocity

 Larger particles will impact on the collection surface

 Smaller particles will keep flowing in the air stream, until they interact

32 with the correct surface.

33
 Sedimentation Methods
▪ Stokes diameter, the diameter of a particle measured under the influence of
gravitational and centrifugal forces
✓ during sedimentation at constant rate in laminar flow conditions
▪ Used for measurement of the particle-size range 0.08-300 µm

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 1. Gravitational sedimentation

✓ By measuring the terminal settling velocity of

particles through a liquid medium in a gravitational

centrifugal environment

-using Andreasen apparatus

✓ The particle size can be calculated according to

Stokes’ equation

✓ One can also calculate a cumulative distribution

from samples removed at appropriate time intervals

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 Separation Methods…
2. Centrifugal sedimentation

 used to measure the particle size b/n about 5–10 μm in diameter

 Upon centrifugation of a liquid medium containing the powder particles, the

fraction of the total suspended powder that reaches the bottom of the
centrifugation tube at different times is measured.

 The times are converted to their corresponding diameters

 using equations based on the Stokes’ equation, describing spherical

particles moving through viscous media NB:Vst=H/t

Vst- =rate of sedimentation

36 H= sed. Height
t= sed. time
 The particle diameter corresponding to the various time period is calculated using the
Stocks equation

V= h /t= d2st(ρs – ρo)g

18ηo
✓ V is the rate of settling
✓h the height of the liquid above the lower end of the pipette at the time each
sample is removed.
✓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
 The equation holds exactly only for spheres falling freely without hindrance and at a
constant rate.
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Example

 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 × 10-3 cm/sec; the density of the medium is 1.01 g/cm3, and its
viscosity is 0.01 g/cm sec, Calculate the Stokes diameter of the zinc oxide
powder?

Answer 5.4 x 10-4 cm or 5.4 µm

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 Electrical Sensing Zone Method

Coulter counter

 Equivalent diameter:Volume diameter, dv

 Powder samples are dispersed in an electrolyte to form a very dilute

suspension,
 which is usually subjected to ultrasonic agitation for a period to

break up any particle agglomerates.

Particle ranges 0.5-100µm

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 Principle
➢ when a particle suspended
in a conducting liquid
passes through a small
orifice (opening), on
either side of which are
electrodes, a change in
electric resistance occurs

Schematic diagram of a Coulter counter

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 Surface Area Methods
 Specific surface area refers to the surface area of particles expressed per unit weight

or volume
 the particle size can be calculated from the specific surface area of a powder

1. Gas adsorption method (0.03-1 μm)

 Particles with a large specific surface are good adsorbents for the adsorption of gases
and of solutes from solution
NB Vm = intercept of isotherm I

 where V is volume of gas adsorbed at pressure P; P is partial pressure of adsorbate;

Vm is volume of gas absorbed in monolayer; P0 is saturation pressure of adsorbate

at experimental temperature; and C is a constant relating to the heats and
condensation of the adsorbate
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  The adsorbed layer is monomolecular at low pressures and becomes
multimolecular at higher pressures.

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 Surface Area Methods…
2. Air Permeability Method (1–100 μm)

 The principal resistance to the flow of a fluid such as air through a plug of compacted

powder is the surface area of the powder

 The greater is the surface area per gram of powder, Sw, the greater is the resistance to

flow

 Hence, for a given pressure drop across the plug, permeability is inversely proportional

to specific surface.
 where V is the volume of air flowing through a capillary of internal diameter d and

length l in t seconds under a pressure difference of ΔP. The viscosity of the fluid
(air) is η poise
 where A is the cross-sectional area of the plug, K is a constant (5.0 ± 0.5) and ε is

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the porosity
 Derived properties of powders
 The manufacture of commercial product batches necessitates the handling of large

quantities (kilograms) of drug

 Bulk powder properties are important for processing

 E.g. flow into dies during tablet production

 These properties are primarily controlled by particle size and shape

 A feature that can change during scale-up and

 Should be measured as early as possible to ensure consistency

 Particle shape and size distribution is essential to behavior of powders

 Essential for rational formulation and manufacture of dosage forms

 Contribute to secondary properties of a powder

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 Derived properties of powders…

Powder technology: deals with 20 (derived properties of powder)

 Densities, Porosity, Packing Arrangement, Flowability

1. Powder Densities

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

True density (Absolute density):

 When the volume measured excludes both open and closed pores

 is a fundamental property of a material

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 Derived properties of powders…
Bulk density (Apparent density):
 Volume measured includes intraparticulate pores

 The density of a powder sample is usually referred to as the bulk density

 volume includes both the particulate volume and the pore volume

 The bulk density of a powder depends primarily on

✓ particle-size distribution,

✓particle shape,

✓the packaging arrangement

✓the tendency of the particles to adhere to one another.

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Tap density
 It is the ratio of mass of powder to tapped volume (V2 below)
 is achieved by mechanical tapping a measuring cylinder
containing a powder sample
 The cylinder is mechanical tapping, and volume readings are
taken until little further volume change is observed

V1

V2

M
b =
M T =
V1 V2
 Derived properties of powders…
2. Porosity

 Is the proportion of a powder bed or compact that is occupied by pores, and is

a measure of the packing efficiency of a powder

 If the powder is nonporous, has no internal pores or capillary spaces,

 The bulk volume of the powder consists of the true volume of the solid

particles plus the volume of the spaces between the particles

 The volume of the spaces, known as the void volume (v) V=Vb-Vp

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

volume to the bulk volume of the packing:

 Porosity is frequently expressed in percent, ε × 100

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Derived properties of powders…
Examples:

1. A sample of calcium oxide powder with a true density of 3.203g/ cm3 and

weighing 131.3g was found to have a bulk volume of 82 cm3 when placed in
a 100-ml graduated cylinder.
 Calculate:- The true volume of the particles, Bulk density, The volume of

void space and Porosity

2. The weight of a sodium iodide tablet was 0.3439g and the bulk volume was

measured by use of calipers and found to be 0.0963 cm3. The true density
of sodium iodide is 3.667 g/cm3.
 What is the bulk density and the total porosity of the tablet?
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 Derived properties of powders…
 When granules and tablets are made from fine powders, they tend to be

porous, and the porosity of tablets has a great impact on the disintegration
time

 For tablets with higher porosity, water can penetrate the tablets, more

readily resulting in a faster disintegration time.

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3. Packing Arrangements
 Powder beds of uniform-sized spheres can assume either of
two ideal packing arrangements:
✓closest or rhombohedral
✓most open, loosest, or cubic packing.
 The theoretical porosity of a powder consisting of uniform
spheres in closest packing is 26% and for loosest packing is
48%.
 The arrangements of spherical particles in closest and loosest
packing are shown in Figure .
 Derived properties of powders…
 Particles in real powders are neither spherical in shape nor uniform in size

 It is to be expected that the particles of ordinary powders may have any

arrangement
 most powders in practice have porosities between 30% and 50%

 If the particles are of greatly different sizes, however, the smaller ones may shift

between the larger ones

 to give porosities below the theoretical minimum of 26%

 In powders containing flocculates or aggregates, which lead to the formation of

bridges and arches in the packing

 the porosity may be above the theoretical maximum of 48%

 In real powder systems, any degree of porosity is possible

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 Derived properties of powders…
4. Bulkiness

 Specific bulk volume, the reciprocal of bulk density

 often called bulkiness or bulk

 It is an important consideration in the packaging of powders

 E.g.The bulk density of calcium carbonate can vary from 0.1 to 1.3

 The lightest or bulkiest type would require a container about 13 times

larger than that needed for the heaviest variety

 Bulkiness increases with a decrease in particle size

 In a mixture of materials of different sizes,

 however, the smaller particles shift between the larger ones and tend to

reduce the bulkiness

53
Derived properties of powders…
I. Flow properties of powders

 Flowability refers to the ease with which a powder will flow under a specified set of

conditions

 A bulk powder is somewhat analogous to a non-Newtonian liquid, which exhibits

plastic flow and sometimes dilatancy,

✓ the particles being influenced by attractive forces to varying degrees

 Accordingly, powders may be free-flowing or cohesive (“sticky

54
 Derived properties of powders…

 Many common manufacturing problems are attributes to powder flow

1. Powder transfer through large equipment such as hopper

2. Uneven powder flow

→ Excess entrapped air within powders → capping or lamination

→ Increase particle’s friction with die wall causing lubrication

problems
→ Increase dust contamination risks during powder transfer

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 common manufacturing problems……..
3. Powder storage

→ result in caking tendencies within a vial or bag after shipping or storage time

4. Separation of small quantity of the powder from the bulk

→ just before the creation of individual doses during tableting, encapsulation and
vial filling

→ which affect the weight uniformity of the dose (under or over dosage)

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methods for evaluating flow properties of powders & granules
Hopper flow rate
➢ The simplest method of determining powder flowability directly is to
measure the rate at which powder discharges from a hopper
 A simple shutter is placed over the hopper outlet and the hopper filled
with powder.
 The shutter is then removed and the time taken for the powder to
discharge completely is recorded.
 By dividing the discharged powder mass by this time, a flow rate is
obtained
 which can be used for quantitative comparison of different powders
The angle of repose ()
 The sample is poured onto the 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
 The duration of flow will be recorded and used to calculate the flow rate
 Then, the radius (R) and the height (H) of the pile were determined and the
angle of repose (θ) was calculated as follows.
 The angle of repose ()
Example
• A powder was poured through the funnel and formed a cone 3.3 cm high
and 9 cm in diameter
➢What is the angle of repose?

Pharmacopoeial interpretation
 Angle of repose less than 20 → Excellent flow
 Angle of repose between 20-30 → Good flow
 Angle of repose between 30-40 → Pass flow
 Angle of repose greater than 40 → Poor flow
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 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,Vtab

Poured density= weight/bulk volume

Tapped density=weight/tapped volume

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 Carr’s compressibility index..

Relationship between powder flowability and % compressibility

Flow description Compressibility (%)

Excellent flow 5 – 15
Good 16 – 18
Fair 19 – 21
Poor 22 – 35
Very Poor 36 -40
Extremely poor  40

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 Hausner ratio

 Hausner ratio is related to interparticle friction:

 Value less than 1.25 indicates good flow (=20% CI)

 Value greater than 1.5 indicates poor flow (= 33%CI)

 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

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 Improvement of powders flowbility
 Flow properties can improved by:

 Powder processes into granules of spherical shape

 Choosing optimum size of powders (400-800µm)

 Incorporate optimum amount of fines (15%)

 Incorporate optimum amount of lubricants/glidant

Suggested methodologies
 Alteration of Particle’s size & Distribution
 Alteration of Particle shape & texture
 Alteration of Surface Forces
63  Formulation additives (Flow activators)
 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

➢ increasing the proportion of coarser particle’s such as occurs in

granulation

64
 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

65
 Cont…
Alteration of Particle shape & texture

Particle’s texture

 Particles with very rough surfaces will be more cohesive and have a greater

tendency to interlock than smooth surfaced particles

 altered by control of production methods

66
 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 powder’s stored and processed under low humidity conditions

67
 Cont’…

Formulation additives (Flow activators)

 Flow activators are commonly referred as a 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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 thank you!

69 4/19/2023