W22 Granulation Flashcards
Definition of granulation
A process of size enlargement
- in which particles of varying shape/size are gathered to form larger, uniform, permanent aggregates
- in which the original particles can still be identified
Purpose of granulation (6)
- To improve flowability
- To prevent segregation of the constituents in a powder mix
(ensure same amount of API + excipients) - To increase bulk density
- To reduce dust production (hazard)
- To improve/control dissolution rate
–> disintegrant를 추가하니까 - For control of moisture content
–> heating도 일어나니까
Granulation process
- API + filler (=diluent) + disintegrant + binder mixed to ==> dry blend
[Wet Granulation] - Solvent added to dry mix = wet mix
- Granulate
- Dry to form dry granules ==> dry blend
- Lubricant added
- Compress into tablet
Wet granulation
- Preparation
- Add powders
- mix with impeller blade to prepare uniform powder mix - Start point
- Uniform powder mix - Intermediate stage
- Spray granulation fluid to powder
- As granulation fluid added, nucleation & growth starts to occur
- Turn chopper blade on to prevent large granules - Finish point
- Wet granules placed in oven to cause fluids to evaporate to get dried granules
What holds granules together -during wet granulation process
binder solution
two types
1. immobile liquid bridge= monolayer of binder solution
2. mobile liquid bridge = multiple layers of binder solution
What holds granules together - during dried granulation process
- solid bridges due to
- hardening of liquid binder
- recrystallisation
- spot melting - IMF
- surface tension from residual moisture
- mechanical interlocking
time progression of granulation
- mean particle size increases
- particle size distribution narrows
- granules become closer to spherical
- density increases
- porosity decreases
mds/dp
How big should granules be?
small tablet
large tablet
small tablet < 200mg
- 75-100 microns
large tablet ≥ 600 mg
- larger granules
duration of granulation
- too little granulation fluid
- too much granulation fluid
- undergranulated granule –> very friable
- overwetted granule –> slurry granules.
How to know when to stop granulation
- manual determination
- pressure detection
- light reflectance
- humidity measurement
- mass temp
- conductivity / resistance probs
- power consumption
- acoustic emission
- torque measurement
–> measure of resistance to rotation
Types of granulators
- High shear mixer
- blades and chopper - lower shear granulators
- oscillating rotor bars - fluid bed granulation
- air
variables that can be controlled in fluid bed granulatin
- droplet size
- atomisation air pressure / volume
- spray rate - Evaporation rate
- inlet air temp
- RH
- dew point
- air volume
Dry granulation process
- mix drugs and excipients
- compress to form a big lump
- grind big lump to produce dry granules
Dry granulation techniques
- Roller compaction
- powder feeder
- rotating rolls breaking
- granules produced - slugging
- hammer
Wetting apparatus four equipments
- Impeller blade = rotates slowly (= mixes powder mix)
- Chopper blade = sharper & rotates faster than impeller blade (= prevents granules getting too big)
- Granulation fluid = either water (dry binder) OR solution of water + binder (wet binder)
- Spray nozzle = sprays granulation fluid onto powder
Dried granules
- porous structure
- solid bridges between particles - after binding solution surrounding the particles evaporate
- greater porosity gives faster dissolution but weaker granules
Fluid bed granulation
- (1 ) causes granules to move around in air rather than (2 )
- (3) added into air
- mixes until end of granulation
- measured by (4 and 5), cannot measure using (6) as there is no. (7)
- (8) prevents dust escaping
- air
- blade
- granulation fluid
- temperature
- humidity
- torque - measure of resistance to rotation
- blade
- exhaust filter
Pros (4) and cons of wet granulation
Pros
1) increase granule strength - hard, not friable, easy to coat
2) can use with wide range of API concentration – useful for API with poor flow properties
3) uniform distribution of API and colours - create range of colour intensity
4) prevents component de-mixing (segregation)
cons
1) many stages = higher chance for things to go worng
2) long, expensive, requires large space
3. heat/water sensitive drug cannot
4. safety issues with organic solvents - evaporate to create gas
5. potentially hazardous dust
6. risk of migration of soluble components to granule surface (water moves from inside to outside when drying, carrying components )
Dry granulation pros and cons
pros
1) less equipment, cheaper, no expensive drying process
2) no binder solution
3) no heat and liquid - so heat/water sensitive API can
4) overcome some morphology issues found with powders
cons
1) nultiple processing steps
2) mixing can be problematic - less consistant balance between drug and excipients
3. poor powder flow
4. no solid bridges - non porous, weaker
5. colour distribution poor
6. dust production- hazardous
7. final tablets softer than wet
8. harder to coat
pros and cons of low shear granulators
- high fluid
- longer process
- loss of materials occurs
- cheaper equipment than high shear mixer
Examples of binder
- sucrose
- starch
- PVP
- celluloses (HPMC)
- Gelatin
Properties of binders
- cohesive
- inert
- easily blended
- non-hydroscopic = don’t suck moisture from air
wet granulation process
- powder + binder droplets
- liquid bridge
- solid bridge
- snowball structure
how to measure the particle size & create a graph
- powder containing particles w/ various size range is poured through the stack of sieves
- the frequency of particle size can be represented through a cumulative frequency diagram
- get cumulative frequency undersize & oversize - plot a cumulative frequency graph
