Particle size Flashcards
Why is particle size measurement
important?
• Size influences physical properties of pharmaceutical materials
– Powder flow, tablet formation
• It tells us if a process has been successful
– Milling of a solid; homogenization of emulsions
• Gives an indication of product stability
– Emulsion droplet size on storage
- Quality control of products – Increases confidence that a product is same as previous batches
- Indicative of in-vivo behavior – Absorption rate of insulin from IM injection depends on crystal size – Nanosized particles can accumulate in ‘leaky’ cancerous tissues via EPR effect (enhanced permeability and retention)
Equivalent diameters
- We need to find a way of defining a single size for a particle that may be irregularly shaped
- To do this we use the concept of equivalent diameter – the diameter of a sphere that is in some unique way similar to the particle in question
- Simplest to do this by volume
What is dV
Simplest is Volume Equivalent Diameter (dV) – the diameter of a sphere that has the same volume as the irregular particle – it’s unambiguous, as particles have a well-defined volume
Distributions of particle size - mode
Size with most particles is called the mode
Distributions of particle size - mean
the weighted arithmetic mean size
Distributions of particle size - median
the size with half the particles on each side
Distributions of particle size - standard deviation
The width can be defined as the standard deviation
Cumulative frequency representation
This is the percentage of particles above or below a given size
Techniques for measuring particle size
– Sieving
– Sedimentation
– Microscopy
– Light scattering
Choice of technique to measure particle size depends on
– Applicable size range for sample – Cost – Time taken – Skill required – Precision – Quantity of material needed – How much data they provide (e.g. full distribution or just an average)
Sieving
• Oldest method, inexpensive, widely available
• Separates fine material from course material by means of a series of woven or perforated surfaces. The proportion of different size particles are recorded and analysed.
• Sieves are precision-woven square mesh, from steel or
bronze wire
• Smallest size is about 50 µm – smaller particles don’t pass through readily, fine meshes are easily damaged and clogged
• Method defines a ‘sieve equivalent diameter’ – the size of the sphere which will pass through the square hole
Sieving method
• Standard size sieves stacked into a ‘nest’ of decreasing mesh size – bottom is a closed tray
• Sample put in top and shaken - particles fall through until mesh size is too small – at which point the particles
will be retained
• When shaking is completed, the amount of particles in each sieve is weighed
Errors in sieving
• Errors are readily visualised with sieving.
– Sieve holes may vary in size due to manufacture or damage – Powder may coat the wires leading to sieve apertures being reduced
– Particles may be cohesive – stick together so that they don’t pass through the mesh
– Vibration from shaking may damage the particles leading to erroneous ‘fines’
– Stack may not be shaken for long enough to get particles to their final sieve
– Sieve may be overloaded – only works well for a light load
– Particle shape may cause problems (e.g. needle-like particles)
Sedimentation - theory
- The rate at which suspended particles settle has long been used for size measurement
- The connection between particle size and settling rate or ‘sedimentation velocity’ is given by Stokes’ law
equation
v = 2r2 (ρ2-ρ1)g/9η
Sedimentation in practice
- Settling velocity is not measured directly
- Can measure the amount of material settled in a particular time (e.g. on to an immersed balance pan) – a sedimentation balance
- Can measure the amount remaining in suspension vs time by passing a beam of light or x-rays through the sample
How does gravity effect settling
Because settling can be slow under gravity, instruments usually use centrifugal sedimentation to speed things up - g in Stokes’ law is then replaced by r2ω, where r is the centrifuge radius and ω the angular velocity
Andreasen pipette
Remove samples over time (hours/days) and analyse for particle content; calculate size distribution
Sedigraph III
Insert sample and push button
Microscopy and image analysis
- More sophisticated and expensive technologies
- Many different types of microscopy e.g.. Light, electron, atomic force etc.
- Uses very small volume of sample
- Measures 1 nm – millimetres depending on technique
- Computer thresholds image then simply counts pixels in each region, constructs histogram, computes statistics as required
Disadvantage and advantage of Microscopy
Disadvantage- Measures relatively few particles
Advantage - One of the few methods of getting
shape information
Particle size analysis by light scattering and its advantages
• Light scattering methods now account for the majority of size measurements and instruments
• Advantages: – Rapid – Easy to use – Wide applicability – Wide size range
The diffraction pattern
determined by the particle size and shape
Given the particle size we can compute the scattering
pattern – its not a simple calculation!
Disadvantage for light scattering
- Measuring the diffraction pattern
* Finding the particle size distribution from it
Operation of a laser diffraction sizer
- Particles in dilute suspension Scattering is measured from many particles - Laser light source High intensity Single colour single direction - Array detector Similar to digital camera sensor Measures light intensity at each point
How does the calculation work?
- It guesses the size distribution! (The ‘trial’ distribution)
- It calculates the scattering pattern of the trial distribution
- It compares the trial distribution scattering pattern with the measured scattering pattern (of course they don’t match at first)
- It adjusts the trial distribution
- Recalculates scattering pattern of trial distribution
- Goes round loop, adjusting trial distribution until its scattering pattern is the same as the measured scattering pattern
- The size measured is a representation of the hydrodynamic radius, this is defined as the size of a sphere that moves at an identical rate to the particle
Particle counting
- Problem with previous methods is that they tell you the size distribution, but do not tell you how many particles are present.
- For some applications, the number of particles is critical (e.g. cell counting, or particle contamination in injections).
- The classic instrument for this is the Coulter Counter or electrical zone sensing (EZS) technique
Electrical zone sensing
- The volume of suspension drawn through the aperture is determined by the suction potential created
- Now lets put an electrode in each chamber and add a battery; the only way we could pass a current through the circuit would be if it goes through the aperture:
- If a particle is sucked through the aperture, it will briefly occlude the hole and stop part of the current reducing the electrical current.
- We can suck a known amount of suspension (e.g. 1 ml or 10 ml) through the aperture and the instrument will count the number of times the current is blocked.
- From the amount of blockage we can also measure the size of each particle, and the instrument can build up a size distribution
- Sufficiently small apertures (15 micrometres is the smallest commercially supplied aperture)
Optical particle counting
• A similar particle counter can be made using optical sensing of particles
• Particles in dilute suspension are passed through a narrow beam of light
• As they pass they cast a shadow which is measured by a
photodetector
• This is the principle of the Hiac counter which is the method used in pharmacopoeial tests for particles in injections
