Particle Size Reduction, Mixing, Granulation and Drying Flashcards
Define toughness
It is a measure of a material’s resistance to fracture.
What is the difference between elastic deformation and plastic deformation?
Elastic deformation is reversible once stress is removed, unlike plastic deformation which is permanent.
What is an example of crack propagation?
Fracture of a birttle material under stress.
Why is particle size reduction not an efficient process?
As only a small portion of the energy provided to the system is used to reduce particle size; most of the energy is lost through heat, friction, vibration, crack initiation or elastic/plastic deformation.
Give an example of materials that become brittle when cooled at low enough temperatures (often well below freezing)
Rubber and other waxy or sticky materials.
What are the 4 different types of mechanical stress that can be used to break down particles?
What is the size range, principle and method when using cutting mills method?
Method:Cutting
Size range: 500-50,000 microns
Principle:Particles are fractured between two sets of knives. A stationary set on the mill casing and set attached to the rotor.
What is the size range, principle and method when using roller mills method?
Method: Compression
Size range: 1,000-100,000 microns
Principle: Powder is compressed between two rotating cylinders
What is the size range, principle and method when using hammer mills method?
Method: Impact
Size range: <100 -10,000 microns
Principle: Particle size is reduced upon impact driven by 4 (or more) rotating hammers
What is the size range, principle and method when using Ball mill method?
Method: Impact & Attrition
Size range: 1 to just above 100 microns
Principle: A rotating cylinder filled to 30-50% with balls. The mill can be filled with a variety of ball sizes to improve the size reduction process.
What is the size range, principle and method when using Fluid energy mill method?
Method: Impact & Attrition
Size range: 1 - 50,000 microns
Principle: 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.
What do you need to consider when selecting to produce very coarse powders ( > 1000 microns)?
- Cutting methods for tough/soft particles
- Roller or hammer mill for harder particles
What do you need to consider when selecting to produce coarse powders ( 50-1000 microns) ?
- Soft/tough materials: size reduction performed under liquid nitrogen
- Cutting still possible for soft materials, under liquid nitrogen
What do you need to consider when selecting to produce fine powders ( >50 microns) ?
- Ball or vibration mill (under liquid nitrogen for soft materials)
Size seperation can be used using which methods?
- Sieving methods with or without aid.
- Agitation
- Brushing
- Centrifugation
- Sedimentation
* Based on a similar principle as sedimentation-based particle size analysis - Elutration
* Seperation under an fluid layer moving in an upwards direction
A cutter mill can be used to produce fine particles from a hard material
TRUE or FALSE
FALSE
They are suitable for size reduction of soft to medium-hard fibrous and tough materials, plastics and heterogeneous mixtures.
What is meant by the neutral mixture category?
- Mixing is NOT spontaneous
- Demixing is NOT spontaneous
- Energy input will be required for the powders to mix or demix
What is positive mixing?
- Simplest situation.
- Spontaneous mixing, energy only required if time constraint. Between liquids, gases (air).
- You only input energy if you want to speed up the process
What is Neutral mixture?
- Non-spontaneous mixing and non-spontaneous demixing.
- Energy input would be required to start the mixing process, unless we disturb the mix it will not demix.
- Examples: Pastes, powders.
What is negative mixing?
- Energy input is required.
- Spontaneous demixing. Fast or slow.
- e.g, emulsion that doesnt contain a stabuliser.
- input energy required to make the oil and water mix.
What are the 2 mechanisms for mixing?
Small scale and Large scale mixing
What is the equipment needed to peform small scale mixing?
- Mortar and pestle
- Glass tile
- Closed container
How is large scale mixing achieved?
- Convection
- Shear
- Diffusion
What is convection mixing?
When the powder is moved in bulk from one part of the powder to another
What are the pros and cons of Ribbon mixers?
Pros:
- Ability to mix powders with poor flow properties
- Lower risk of segregation(demixing) vs tumble mixer
Cons:
- Dead spots in hard-to-reach corners are hard to avoid
What are ribbon mixers?
These mixers achieve macromixing, which is large scale mixing under stirring
What is shear mixing?
In shear mixing, layers of bulk powder are moved during the mixing process.
The mixing achieved is semi-micromixing, an intermediate between the macromixing of agitators and micromixing of diffusion methods.
What are the pros and cons of shear mixing?
Pros
- Good for free flowing powders
Cons
- Lower efficieny for cohesive powders with poor flow
- Risk of segragation/demixing
What is the main mechanism for Tumbling agitators?
Shear mixing
Pros and cons High-shear mixer granulators?
Pros
- Allows mixing and granulation in the same equipment
Cons
- Not the best choice for mixing lubricant into powders
- Potentially issues with very firable materials
What is diffusion mixing?
In diffusion mixing, individual particles are moved during the mixing process. This allows micromixing as particles rearrange as they mix.
Pros and cons of diffusion mixing?
Pros
- Allows mixing and granulation in the same bowl
- True random mix
Cons
- Low mxing rate
What is demixing?
Demixing is the seperation of a powder blend.
What is the easiest way to avoid demixing?
Since powder blends are neutral mixtures, the easiest way to avoid demixing is by limiting handling of the powder bed.
What casues demixing?
Demixing is more likely in powders with a wide distribution of;
Sizes
Densities
- less likely for pharmaceutical preparations except in fluidised beds
Shapes
- spherical shape = better flow = better mixing BUT also = higher risk of demixing
- irregular shape = more cohesive = lower risk of demixing
- shape may vary as the powder is process/handled.
What causes the seperation of blend components?
- Having a wide size distribution
- Variation of shape
- Difference in density
- Difference in surface properties
What is Percolation?
Accumulation of small particles at the bottom of a powder bed
Increased risk if the powder is disturbed
Can be potentiated if the small particles also have a higher density
What is trajectory segregation?
Accumulation of larger particles at the edge of a powder cone (i.e. powder heap)
Results for a difference in kinetic energy of larger vs. small particles
Can overlap with percolation
Can also occur for particles of similar sizes but different densities
What is dusting out?
Small particles are lifted and settle at the top of the powder bed
It’s also called: fluidisation segregation, eluthation segregation
How do adhesion and cohesion forces effect granulation?
Forms thin layer
- Increases attrctive forces
- Increased contact area
What is the benefit of using viscous adhesive solutions as a granulation fluid?
They have relatively stronger bonds
e.g. Starch mucilage as granulation fluid
In wet granulation, what are the stages as you add granulation fluid?
NB: In most cases you dont want to reach the suspension stage, as this means too much of the granulation fluid has been added.
Having the powder particle in suspension is only used when used for spray-drying to produce granules.
Drying creates more permenant bridges .
How are solid bridges formed during drying?
Crystallisation of solutes
- Dissolution in granulation fluid
- Re-crystalisation upon drying
- Crytsal size will depend on drying rate
Hardening Binders
- Use of biners in wet granulation: hardening/crystallisation during drying
Partial melting:
- Melting of a solid under pressure
- Dry granulation
- Binding upon re-crystallisation
If no solid or liquid bridegs can’t be formed, what other forces can be used?
Electrostatic forces
- Realtively weak interaction
Van der Waals
- Stronger than electrostatic
- Important for granule strength during dry granulation
- Stronger at short interparticular distances
Describe the three steps of granule formation
- nucleation: adhesion from liquid bridges (pendular or capillary state)
- transition: nuclei growth (pendular bridges, nuclear aggregation, wide size distribution)
- ball growth: granule growth
What are the four types of ball growth?
- coalescence: fusion of two granules
- breakage: two granules in contact, weaker one breaks and adsorbed onto other one
- abrasion transfer: friction between two granules, some absorb on surface
- layering: second powder blend absorbed onto surface of granule (spheronisation - controlled release granule)
What is total moisture content the sum of?
- free moisture content
- equilibrium moisture content (harder to remove)
What makes drying efficient?
- large SA
- efficient heat trasnfer
- efficient mass transfer
- efficient vapour removal
What do we need to consider for method selection?
- properties of powder
- sensitivity to heat
- physical properties
- nature of liquid
- amount of powder to dry
- need for sterilitiy
- source of heat
What are the main drying mechanisms?
- convection: bulk movement of heated air
- conduction: heating by contact with hot surface
- radiation: heat transfer by radiation
- spray drying: drying of liquid into a solid particle
- freeze drying: drying through sublimation
What are pros and cons of convection drying?
pros
- high drying rates
- shorter heat exposure
- constant rate
- uniform
- attrition
cons:
- dust production
- segregation
- risk of explosion
Describe conduction drying
- used on substances which are hygroscopic and heat senssiitve
- vacuum oven
- drying at lower temp
- reduction in pressure reduces temp required
What are pros and cons of radiation drying?
pros:
- rapid drying at lower temp
- high thermal efficiency
- reduced solute migration
cons:
- for smaller batches
- hazardous radiation
What are pros and cons of spray drying?
pros:
- efficient mass transfer
- rapid evaporation
- improved flow
cons:
- cost
- low thermal efficiency
What is spray drying used for?
- thermolabile compounds
- dry powder inhalers - keeps taste, flavour and colour
What are three drying issues?
- solute migration (towards surface and any solid dissolved within it moves too)
- surface populated by solid
- intergranular migration
- occurs if short intergranular distance such as tray drying
- intragranular migration
- solute moving to surface of granule
What are three consequences of drying issues?
- solute migration causes
- uniformity of content issues
- loss of drug to granule surface
- mottling in coloured tablets
- intragranular migration of colour
- high colour density on surface
- migration of soluble binder
- surface enriched with binder = harder granules
How can you prevent solute migration?
- add absorbent powder - starch, mycrocrystalline cellulose
- will increase affinity of solute for the granule, rather than granulation fluid
- control solubility
- limit affinity for the fluid
- use viscous granulation fluids
- diffusion rate reduced
- limit initial moisture content
- control granule size
- larger = more issues
