Particle Size Analysis AM Healy

Particle Size Analysis

• Why measure particle size of pharmaceuticals???

• Particle size can affect

– Final formulation: performance, appearance, stability
– “Processability” of powder (API or excipient)

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Methods for determining particle size

• Microscopy
• Sieving
• Sedimentation techniques
• Optical and electrical sensing zone method
• Laser light scattering techniques
• (Surface area measurement techniques)

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Choosing a method for particle sizing

• Nature of the material to be sized, e.g.

estimated particle size and particle size range
solubility
ease of handling
toxicity
flowability
intended use
• Cost
capital
running
• Specification requirements
• Time restrictions

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Microscopy

Optical microscopy (1-150µm)

Electron microscopy (0.001µ-)

• Being able to examine each particle individually has led to

microscopy being considered as an absolute measurement of
particle size.
• Can distinguish aggregates from single particles
• When coupled to image analysis computers each field can
be examined, and a distribution obtained.
• Number distribution
• Most severe limitation of optical microscopy is the depth of
focus being about 10µm at x100 and only 0.5µm at x1000.
• With small particles, diffraction effects increase causing
blurring at the edges - determination of particles < 3µm is less
and less certain.

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For submicron particles it is necessary to use either

• TEM (Transmission Electron Microscopy) or
• SEM (Scanning Electron Microscopy).
• TEM and SEM (0.001-5µm)

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Types of Diameters
• Martin's diameter (M)
The length of the line which bisects the particle image. The lines may be
drawn in any direction which must be maintained constant for all image
measurements.
• Feret's diameter (F)
is the distance between two tangents on opposite sides of the particle,
parallel to some fixed direction.
• Projected area diameter (da or dp)
is the diameter of a circle having the same area as the particle viewed
normally to the plane surface on which the particle is at rest in a stable
position.

Others:
• Longest dimension:
a measured diameter equal to the maximum value of Feret's diameter.
• Perimeter diameter:
the diameter of a circle having the same circumference as the perimeter of the particle.
• Maximum chord:
a diameter equal to the maximum length of a line parallel to some fixed direction and
limited by the contour of the particle .

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Manual Optical Microscopy

Advantages
• Relatively inexpensive
• Each particle individually examined - detect aggregates, 2D
shape, colour, melting point etc.
• Permanent record - photograph
• Small sample sizes required

Disadvantages
• Time consuming - high operator fatigue - few particles
examined
• Very low throughput
• No information on 3D shape
• Certain amount of subjectivity associated with sizing -
operator bias
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Transmission and Scanning Electron Microscopy

Advantages
• Particles are individually examined
• Visual means to see sub-micron specimens
• Particle shape can be measured

Disadvantages
• Very expensive
• Time consuming sample preparation
• Materials such as emulsions difficult/impossible to prepare
• Low throughput - Not for routine use

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Automatic and Image Analysis Microscopes

Advantages
• Faster and less operator fatigue than manual
• No operator bias

Disadvantages
• Can be very expensive
• No human judgement retained e.g. to separate out
aggregates, select or reject particles etc. (unlike semi-
automatic)

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Sieving
• Sieve analysis is performed using a nest or stack of sieves
where each lower sieve has a smaller aperture size than that
of the sieve above it.
• Sieves can be referred to either by their aperture size or by
their mesh size (or sieve number).
• The mesh size is the number of wires per linear inch.
• Approx. size range : 5µm - ~3mm
– Standard woven wire sieves
– Electroformed micromesh sieves at the lower end or range (< 20µm)
– Punch plate sieves at the upper range.

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• Sieving may be performed wet or dry; by machine or by

hand, for a fixed time or until powder passes through
the sieve at a constant low rate
• Wet sieving
• Air-jet sieving
• Weight distribution

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Particle Size Analysis AM Healy

Advantages
• Easy to perform
• Wide size range
• Inexpensive

Disadvantages
• Known problems of reproducibility
• Wear/damage in use or cleaning
• Irregular/agglomerated particles
• Rod-like particles : overestimate of under-size
• Labour intensive

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British Pharmacopoeia Volume IV

Appendix XVII A. Particle Size of PowdersParticle size classification of
powders
(Ph. Eur. method 2.9.12, Sieve test)

The degree of fineness of a powder may be expressed by reference to sieves

that comply with the specifications for non-analytical sieves (2.1.4).
Where the degree of fineness of powders is determined by sieving, it is defined
in relation to the sieve number(s) used either by means of the following terms
or, where such terms cannot be used, by expressing the fineness of the powder
as a percentage  m/m passing the sieve(s) used.
The following terms are used in the description of powders:
Coarse powder: Not less than 95% by mass passes through a number 1400
sieve and not more than 40 % by mass passes through a number 355 sieve.
Moderately fine powder: Not less than 95% by mass passes through a
number 355 sieve and not more than 40% by mass passes through a number
180 sieve.
Fine powder: Not less than 95% by mass passes through a number 180 sieve
and not more than 40% by mass passes through a number 125 sieve.

etc., etc….

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United States Pharmacopeia

General Chapters: <811> POWDER FINENESS

Classification of Powders by Fineness

Classification of Powder d50 Sieve Opening (µm)

Very Coarse > 1000
Coarse 355–1000
Moderately Fine 180–355
Fine 125–180
Very Fine 90–125

d50= smallest sieve opening through which 50% or more of the material passes

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Sedimentation techniques

• Methods depend on the fact that the terminal velocity of a

particle in a fluid increases with size.
• Stokes's Law :
  s   f  gd sph
2

18

18 x
d sph 
 
s   f g t

• Stokes's diameter (dst) is defined as the diameter of the

sphere that would settle at the same rate as the particle

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• The particle size distribution of fine powder can be determined

by examining a sedimenting suspension of the powder.

• 2 categories:
(1) Incremental : changes with time in the concentration or
density of the suspension at known depths are determined.
Can be either fixed time or fixed depth techniques.
(2) Cumulative : the rate at which the powder is settling out
of suspension is determined. i.e the accumulated particles
are measured at a fixed level after all particles between it and
the fluid's surface have settled.

• Weight distribution

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Andreasen Pipette
• Size distribution is determined by
allowing a homogeneous suspension
to settle in a cylinder and taking
samples from the settling suspension
at a fixed horizontal level at intervals of
time.
• Each sample will contain a
representative sample of the
suspension, with the exception of
particles greater than a critical size, all
of which will have settled below the
level of the sampling point.
• The concentration of solid in a sample
taken at time t is determined by
centrifugation of the sample followed
by drying and weighing or simply by
drying and weighing.
• This concentration expressed as a
percentage of the initial concentration
gives the percentage (w/w) of particles
whose falling velocities are equal to or
less than x/t. Substitution in the
equation above gives the
corresponding Stokes' diameter.

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Advantages
• Equipment required can be relatively simple and inexpensive.
• Can measure a wide range of sizes with considerable accuracy
and reproducibility.

Disadvantages
• Sedimentation analyses must be carried out at concentrations
which are sufficiently low for interactive effects between particles
to be negligible so that their terminal falling velocities can be
taken as equal to those of isolated particles.
• Large particles create turbulence, are slowed and are recorded
undersize.
• Careful temperature control is necessary to suppress convection
currents.
• The lower limit of particle size is set by the increasing importance
of Brownian motion for progressively smaller particles.
• Particle re-aggregation during extended measurements.
• Particles have to be completely insoluble in the suspending liquid.

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Electrical sensing zone method – Coulter Counter

• Instrument measures particle

volume which can be expressed as
dv : the diameter of a sphere that
has the same volume as the
particle.
• The number and size of particles
suspended in an electrolyte is
determined by causing them to
pass through an orifice an either
side of which is immersed an
electrode.
• The changes in electric impedance
(resistance) as particles pass
through the orifice generate voltage
pulses whose amplitude are
proportional to the volumes of the
particles.
• Volume distribution
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Optical sensing zone method

• Obscuration of light source relates to particle size (area)

• Advantage of not requiring medium to be an electrolyte

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Laser light scattering techniques

• Laser Diffraction Particle Size Analysis

– (Particle size range 0.02-2000µm)
• Photon Correlation Spectroscopy
– (Particle size range :1nm to 5µm)

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Laser diffraction
• Particles pass through a laser beam
and the light scattered by them is
collected over a range of angles in
the forward direction.
• The angles of diffraction are, in the
simplest case inversely related to
the particle size.
• The particles pass through an
expanded and collimated laser
beam in front of a lens in whose
focal plane is positioned a
photosensitive detector consisting
of a series of concentric rings. • Volume distribution
• Distribution of scattered intensity is
analysed by computer to yield the
particle size distribution.

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Suspension Material

Gas Liquid Solid

Gas Fuel sprays Powders not liquid

Paints dispersible.
Aerosols Pneumatic transport
Inhalers soluble powders

Liquid Bubbles Emulsions Powders easily liquid

2 phase fluids dispersed.
Cohesive powders.

Solid Reference standards

(reticules)

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Particle Size Analysis AM Healy

Advantages:

• Non-intrusive : uses a low power laser beam

• Fast : typically <3minutes to take a measurement and analyse.
• Precise and wide range - up to 64 size bands can be displayed
covering a range of up to 1000,000:1 in size.
• Absolute measurement, no calibration is required. The instrument is
based on fundamental physical properties.
• Simple to use
• Highly versatile

Disadvantages:
• expense
• volume measurement all other outputs are numerical
transformations of this basic output form, assuming spherical
particles
• must be a difference in refractive indices between particles and
suspending medium

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PCS

• Large particles move more slowly than small particles, so that the rate
of fluctuation of the light scattered from them is also slower.
• PCS uses the rate of change of these light fluctuations to determine the
size distribution of the particles scattering light.
• Comparison of a "snap-shot" of each speckle pattern with another
taken at a very short time later (microseconds).
• The time dependent change in position of the speckles relates to the
change of position of the particles and hence particle size.
• The dynamic light signal is sampled and correlated with itself at
different time intervals using a digital correlator and associated
computer software.
• The relationship of the auto-correlation function obtained to time
intervals is processed to provide estimates of the particle size
distribution.

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Advantages:
• Non-intrusive
• Fast
• Nanometre size range

Disadvantages:
• Sample prep critical
• Vibration, temperature fluctuations can interfere with analysis
• Restricted to solid in liquid or liquid in liquid samples
• Expense
• Need to know R.I. values and viscosity

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Particle size distribution

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