Unit Processes - Particle size reduction and Size separation

What are some of the processes required for the production of solid dosage forms?

• Particle size reduction and size separation

• Mixing

• Granulation

• Drying

Reasons for reducing particle size

• Essential for manufacturing process

• Controls properties of final products

Pharmaceutical formulation includes API, excipients

• Good mix-homogeneous distribution

• Uniformity of content, dissolution rate, etc

• Flow properties

Initial powder size:

• Could be larger than pharmaceutical requirements

• Aggregates - flow properties

Why is particle size reduction important in pharmaceutical manufacturing?

• Increase surface area

• Improve dissolution rate

• Improve drug absorption and bioavailability

• Improve mixing and content uniformity

• Improve powder flow in some formulations

• Produce particles of a suitable size for the dosage form

• Improve extraction of active ingredients

• Make powders easier to process and handle

Aims of particle size reduction

Reducing particle size can:

• Improve mixing

• Size distribution

• Increase the total surface area, flow properties and dissolution rate

The quality and stability of some formulations i.e. suspensions is affected by particle sizes

The impact of particle size on organoleptic properties is clearer with semi-solids such as pastes

Size reduction also affects the distribution of sizes of the powdered material

How does particle size affect dissolution?

Smaller particles have a larger surface area exposed to the dissolution medium

Therefore:

↓ particle size → ↑ surface area → ↑ dissolution rate

This can be particularly important for poorly soluble drugs

How can particle size reduction affect drug absorption?

If dissolution is the rate-limiting step for absorption, reducing particle size can increase dissolution and therefore potentially increase the amount/rate of drug available for absorption

However, particle size reduction does not automatically increase bioavailability because absorption also depends on factors such as permeability and drug stability

How can particle size affect powder flow?

Very fine particles often have poorer flow because their high surface area increases:

• Interparticle attraction

• Cohesion

• Electrostatic forces

Therefore, very small particles can form aggregates and resist movement

What other powder properties are affected by particle size?

• Bulk and tapped density

• Flowability

• Compressibility

• Cohesion

• Dustiness

• Electrostatic behaviour

• Dissolution rate

• Segregation

• Uniformity of the final dosage form

Definitions - toughness & hardness

Toughness is the ability of a material to absorb the applied energy and deform without fracturing

Or toughness is the strength with which the material opposes rupture

• Tough material (i.e. steel, iron) undergo plastic deformation and absorb a lot of energy before breaking

• Brittle material (i.e. glass, ceramic) experience breakage easily - they have little elasticity and don’t stretch easily

• Tough materials break through crack propagation

Tough materials are resistant to fracturing, measured by the amount of breaking energy they can withstand

Hardness = resistance to surface wear, scratches, cuts or permanent deformation

Mohs scale

A minerals hardness is a measure of its relative resistance to scratching, measured by scratching the mineral against another substance of known hardness on the Mohs Hardness Scale

• Mohs scale is used to help identify minerals

• Diamonds are at the top of the table while talc is at the bottom

Definitions - elasticity & plasticity

Elasticity is the property of a solid material that allows it to restore its shape after an external load is removed

• Elastic materials that are subject to external stresses beyond the elastic limit, will not return to the original shape

Plasticity is the property of a solid substance that allows it to keep its deformed shape even when the external load is removed

• Reversible vs irreversible deformation

• No fracture in both

• Ductile materials are easily stretched and clearly show plastic deformation under pressure

• Brittle materials, experience little elastic or plastic deformation - they break through crack propagation rather than stretch

• Elastic materials such as rubber, are extremely soft yet difficult to size-reduce

Influence of material properties

Size reduction of solid materials occurs by a process of crack propagation, whereby localised stresses produce strains in the particles that are large enough to cause bond rupture and thus propagate the crack

• It is hard to break (reduce particle sizes) tough and hard materials

How about soft materials?

Materials such as rubber that are soft under ambient conditions, waxy substances such as stearic acid that soften when heated, and ‘sticky’ materials such as gums are capable of absorbing large amounts of energy through elastic and plastic deformation without crack initiation and propagation

• These materials can be more easily size-reduced when temperatures are lowered below the glass transition point of the material

• At these lower temperatures the material undergoes a transition from plastic to brittle behaviour, and crack propagation is facilitated

• The glass transition point is the temperature at which a material change in properties - below this temperature, the material is brittle while above this temperature, the material is rubbery

What are the main mechanisms of particle size reduction?

1. Compression

2. Impact

3. Cutting

4. Combined impact and attrition

Many pharmaceutical mills use a combination of these mechanisms

What is compression as a size-reduction mechanism?

Compression involves applying a force that squeezes a particle until it fractures

It is particularly useful for brittle materials e.g. Roller mill

• Roller mills use 2 cylindrical rollers mounted horizontally and rotated about their long axes - the size reduction range is 1000-100000 microns

What is cutting as a size-reduction mechanism?

Cutting involves sharp blades or edges physically cutting particles into smaller pieces

It is particularly useful for soft, tough or fibrous materials e.g. Cutter mill

• Particles are fractured between 2 sets of knives - a stationary set on the mill casing and a set attached to the rotor

• The size reductions range is 500-50000 microns

• There’s a risk of segregation

What size reduction method uses the end-runner mill?

Compression

• Powder is compressed using a mortar and pestle

• The size reduction range is 50 to 10000 microns

What is attrition as a size-reduction mechanism?

Attrition is size reduction caused by rubbing or friction between particles and/or surfaces

The particles are gradually worn down e.g. Ball mill

What is a hammer mill?

A hammer mill uses rapidly rotating hammers to break particles through impact

Material is fed into the mill and repeatedly struck until particles are small enough to pass through a screen

• Size reduction range is 50 to 10000 microns

Advantages and limitations of the hammer mill

Advantages

• Rapid

• Suitable for many materials

• Can produce relatively fine powders

Limitations:

• Generates heat

• Not ideal for heat-sensitive materials

• Performance depends on material properties

What is a vibration mill?

Size reduction method: Impact

• A cylinder filled to 80% with porcelain or stainless-steel balls. Particle size is reduced upon repeat impact driven by vibration of the whole body of the mill

• The size reduction range is 1 to 1,000 micron

What is a ball mill?

A ball mill consists of a rotating chamber containing balls

Particle size reduction occurs mainly through impact and attrition as the balls collide with and rub against particles

• Size reduction method: combined impact & attrition

• Size reduction range is 1 to 100 microns

• Tumbler, vibratory and planetary mills

What are the advantages and disadvantages of a ball mill?

Advantages:

• Can produce fine particles

• Useful for hard materials

• Can be used for wet or dry milling

Disadvantages:

• Relatively slow

• Can generate heat

• Equipment can be noisy

• Possible contamination from the milling media

What is a fluid energy mill?

Size reduction method: combined impact and attrition

• Air is injected at a high-pressure, creating turbulence which will lead particles to collide with other particles and with the wall of the mill

• Size reduction range: 1-50000 microns

What is a pin mill?

Size reduction method: combined impact and attrition

A pin mill uses two discs containing pins, with one or both discs rotating at high speed

• It can produce fine powders

• Particle size reduction occurs mainly be impaction with the pins and by attrition between pins as the particles travel outwards under the influence of centrifugal force

• Size reduction range: 10-10000 microns

What factors determine which size-reduction method is selected?

• Initial particle size

• Required final particle size

• Material hardness

• Material toughness

• Material brittleness

• Moisture content

• Heat sensitivity

• Required particle-size distribution

• Desired production scale

• Risk of contamination

• Whether wet or dry processing is required

• Cost of the process

Table showing selection of size reduction mills according to particle properties and product size required

Why is heat sensitivity important during milling?

Milling can generate heat through friction and mechanical energy

Heat-sensitive substances may therefore:

• Degrade

• Melt

• Lose potency

Why is moisture content important during drug milling?

Too much moisture can cause particles to:

• Stick together

• Become difficult to mill

• Block screens

• Form agglomerates

Why is particle-size separation performed?

• Remove oversized particles

• Obtain a desired particle-size range

• Improve uniformity

• Control powder properties

• Ensure the material meets a specification

What factors affect sieving efficiency?

• Particle size

• Particle shape

• Particle density

• Moisture content

• Screen aperture size

• Duration of sieving

• Vibration/agitation

• Amount of material on the screen

Size separation by sedimentation

Separating particles based on the differences in settling velocities of particles with different diameters

• The fluid is stationary and the separation of particles of various sizes depends solely on particle velocity

Size separation by elutriation

There is a fluid flow in the opposite direction to the sedimentation movement so that in gravitational elutriators particles move vertically downwards while the fluid travels vertically upwards