particle size analysis

What does particle size affect 

• Physiochemical and pharmacological properties e.g dissolution rate ( higher the dissolution rate, faster the onset of action)

• Processing properties of powders e.g flowability, mixing ( good flow and mixing properties manufacture process easier, less energy + costs)

• Formulation performance e.g stability of dispersed systems 

How does particle size affect dissolution rate and how does this affect what type of tablet you have

Increased particle size decreases the dissolution rate 

If you want a slow release tablet you may increase the particle size

What is the median size of a coarse powder and a microionised powder

Give examples of the different equivalent diameters

How is Martins diameter and Ferets diameter measured

Martins diameter : cut the shape in the middle and measure it, the length of the line which bisects the image of the particle

Ferrets diameter : measure the two furthest points of the particles, distance between two tangents on opposite sides

What is the issue when taking martins diameter and Ferets diameter

How do you fix this issue

you get different values if the shape is oriented in different ways

you must measure the values for all the different orientations ( orientate it 18 degrees each time and measure it 10 times) and then take an average to get a statistical mean 

What equivalent diameter would you use for measuring particles in a

• suspension

• Inhaled particles

Suspensions - sedimentation properties: Stokes’ diameter 

Inhaled particles - aerosol deposition in the lungs : aerodynamic diameter

Can you explain what the cumulative % frequency undersized and oversized is from the table

Cumulative frequency undersize example 

You add all the particles which are smaller than a certain number. E.g for 1-2 column, it is all the particles which are smaller than 2um

Cumulative frequency oversize is : 100 - the cumulative frequency undersized 

What are incremental histograms used for in particle size analysis

To show how many particles fall within a given size increment

This reflects the distribution of particle sizes

Presents an interpretation of the particle size distribution

Enables determination of the percentage of particles having equivalent diameters

Allows different particle size distributions to be compared

What are the three different types of distribution you can get from the histograms

Normal distribution

Skewed distribution: either positive skew or negative skew and that is determined by the tail, if the tail is to the left it is negative. If it is to the right it is positive

Bimodal : there are two peaks

What are the two different shapes distributions can have

What is Kurtosis

What are the two different kurtosis

Distributions may have a pointed or rounded shape

Kurtosis focuses on the peak of the distribution

Leptokurtic: pointed, very distinct peak, shows that the distribution is narrow 

Platykurtic : flattened shape for the histogram, you can’t really see where the peak is fr, not obvious 

What is a cumulative size distribution

It shows the fraction of particles that are smaller or bigger than a certain particle sizs

depending on if it is undersized or oversized

How do you get the median particle size on a cumulative graph

Look at the particle size at 50%

As it is a percentage undersize plot 

The % of particles below 0.2mm is 15%

The % of particles above 0.2mm is 85%

What is the different between incremental and cumulative data

General distribution and quick info of the particle size, what % of the powder falls into a specific size increment : incremental 

% of particles smaller or larger : cumulative 

What is central tendency in histograms

The tendency of the particle size to cluster around a particular value. Such values are evident as a peak in the particle size distribution. These values are normally known as ‘averages) or ‘means’ of set of data

How do you perform sieve analysis

• Weigh the powder and each individual sieve 

• Add the powder to the top sieve 

• Seal the sieve ( close the lid)

• Move sieve to the sieve shaker which causes agitation, particles will go through the sieves they are able to travel through due to the gravitational pull

• Separates by size 

In what way is the sieve arranged 

Arrange the sieve so the bigger apertures are on the top and smaller aperture are on the bottom 

What is the sieve equivalent diameter (d_s)

Sieve equivalent diameter (d_s) :the minimum square aperture through which the particle will pass. This is a two-dimensional value 

Why is sieving rarely complete 

Sieving is rarely complete as some particles take a long time to orientate themselves over the sieve apertures to pass through. 

What is the recommended time for sieving 

It is recommended that sieving be continued until <0.2% of material passes a given aperture in any 5 minutes interval

Does sieving overestimate or underestimate particle size

sieving underestimates particle size 

What size range is sieving used for

What type of diameter is measured

What type of distribution is it

How much of the sample is necessary

How long is the measurement time

5pum to > 5000 pum ; intended for use where at least 80% of the particles are larger than 75pum

Equivalent sieve diameter

Distribution by weight

0.5g to a few kg

5-30 mins for dry sieving

What are the advantages of sieving

• inexpensive

• Easy to perform

• Well-established

What are the disadvantages of sieving

• Time consuming

• Problems of reproducibility

• Humidity, static electricity and powder cohesivity can affect the results

• Particles may break or agglomerate during sieving

• 2D measurements

What can microscopy give you additionally to the particle size

Microscopy can give you additional information e.g morphology ( shape and size)

What particle sizes can

Light microscopes allow you to see

Electron microscopes allow you to see

Light microscope (1-1000pum)

Electron microscope (0.01-1000pum) - staining/coating is required

(Sieve analysis is preferred for particles larger than 200pum)

What diameter do microscopes measure 

Projected area diameter (equivalent circle diameter), also Feret’s diameter or Martin’s diameter 

Can single particles and aggregated be distinguished in microscopes 

Yes

How many particles are needed to be measured using a microscope 

600 or more particles to be measured to get a statistical representative size 

What type of distribution is being measured using a microscope 

Distribution by size, computational tools are used to do it 

What are the advantages for microscopes for particle sizes analysis (4)

• inexpensive ( light microscope)

• Small sample size

• Individual particle sizes can be measured

• Images can be captured

What are the disadvantages of microscopes (5)

• Expensive (electron microscope)

• Time consuming

• Low throughput ( slow/little bit of data)

• 2D measurement

• Operator dependent

How does sedimentation analysis work to distinguish particle size generally

The first few particles that are taken out of the pipette will be larger as the larger particles sediment faster, after time is passed the smaller particles will start to sediment 

So it works y collecting samples at different time points

What diameter is being measured in sedimentation analysis + what do you actually measure 

What do you assume about the particles

Stokes’ diameter, particles with different sizes settle at different velocities 

The sedimentation velocity by measuring the time which particles require to settle 

(Assume all particles have the same density)

What is the normal size range for sedimentation analysis 

5-200 pum 

What type of distribution is measured for sedimentation analysis 

Distribution by weight 

What type of formulations are usually measured by sedimentation analysis 

suspensions or emulsions 

What are the advantages of sedimentation analysis (2)

• low cost

• Useful for cases where sedimentation is key

What are the disadvantages of sedimentation analysis (4)

• labour intensive

• Particles must be insoluble in the dispersion medium

• Temperature control is required

• Particle shape also affects settling rate

When doing sedimentation analysis for particle size, what is important for the liquid medium the particles are in

It’s important the medium doesn’t dissolve the particles

How does the coulter counter work

What type of measurement does it do

What happens to the particles as they pass through the aperture

It is a measurement by conductivity, a type of electrical sensing zone method

As particles pass through the aperture opening , they bend the current flux lines around the particles

This causes a longer length for the current to pass and a higher resistance to the current

The amplitude of this current pulse is directly proportional to the volume of the particle that produced it

What diameter is being measured in the coulter counter 

The volume equivalent diameter 

What is the size range for the coulter counter 

0.5 - 1000pum (large size range)

What is the type of distribution 

distribution by number 

What it’s important for the liquid medium in a coulter counter

How much drug quantity do you need

liquid must be able to conduct electricity and it can’t dissolve the particles 

You need mg to gram quantities depending on particle size 

What are the advantages of the coulter counter (4)

• rapid measurement

• Large number of particles counted + reproducible and reliable

• Simple to use

• Wide range of sizes measured

What are the disadvantages of the coulter counter (5)

• particles have to be suspended in an electrolyte liquid

• Limited choice of liquid media

• There can be blockage of the orifice by oversized particles

• Needs calibration

• Expensive

What is laser diffraction analysis

A technique based on laser diffraction to derive particle size information from patterns of angular light scattering of the sample

(Good for aerosols)

What type of diameter is being measured in laser diffraction

Equivalent volume diameter 

What is the size range of particles used 

0.01 to 3000pum

What do larger particles do to light (laser diffraction)

They scatter light at smaller angles with higher intensity 

What do smaller particles do to light (laser diffraction)

They scatter light at bigger angles with lower intensity 

What type of distribution does laser diffraction show

Distribution by volume

How much do you need in your sample to get a good measurement 

Mg to gram quantities 

What are the advantages of laser diffraction (6)

• quick and simple

• no calibration required

• high reproducibility

• testing is non-destructive and non-intrusive

• the entire sample is measured

• Suitable for a wide range of samples (in gas or liquid)

What are the disadvantages of laser diffraction

• refractive index should be known

• Refractive index difference is required between particles and the dispersion medium

• Expensive

What is dynamic light scattering (DLS)

Photon correlation spectroscopy used to measure nanoparticles

It measures the fluctuations in the intensity of scattered light that are due to the random Brownian motion of particles suspended in a suspending medium

(Brownian motion depends on particle size)

For dynamic light scattering,

How does larger particles affect it

How do smaller particles affect it

Larger particles means the change of the scattering intensity is slower 

Smaller particles means the change of the scattering intensity is faster

What are the advantages of dynamic light scattering (DLS) (6)

• quick and simple

• No calibration required

• High reproducibility

• Testing is non-destructive and non-intrusive

• The entire sample is measured Suitable

• Nanoparticle size range

What are the disadvantages of DLS

• samples must be dispersed in liquid

• Particle-particle interaction at increased concentration

• Multiple scattering at increased concentration

• Expensive

What diameter does DLS measure

What is the size range of the particles measured

What type of distribution is it

What formulations is it good for

• hydrodynamic diameter - using stokes - Einstein equation

• 1nm to 3pum

• Distribution by intensity

• Suspension emulsions