Granulation Flashcards
Segregation due to particle size - 3 types
• Trajectory segregation
– Larger particles travel greater horizontal distances than smaller particles
• Elutriation Segregation
– Very small particles sediment on top of the larger
particles
• Percolation Segregation
– Smaller particles drop to the bottom of the powder bed (as in hopper where movement of particles can take place)
Segregation due to particle density
- Dense particles have tendency to move to bottom
* Dense particles have greater mass than less dense particles
Reasons for granulation
- Help improve powder flow (increase in particle size) - MAIN REASON
- Help provide a uniform mix of powders
- Increase density of the powder mix
- Reduce risks of dust generation
- Reduces risk of caking of hygroscopic powders (powders draw in water which results in caking)
- As a dosage form
- As intermediate for tableting / capsulation (granules used for tableting - easier)
- Help compaction of powder mix
- Aid wetting of particles (used when its hydrophobic to make it solubilised)
Considerations
• Mixing of powders granule formation
• Segregation of constituents after mixing
• Segregation of constituents after granule formation
• Size distribution of granules
• Tableting and capsulation
– Fill by volume not weight
• Accurate proportions of active ingredient and excipients
Segregation more likely to occur when..
particles are different sizes
Wet granulation (most commonly used)
• Liquids used in granulation process
– Granulating fluid
• Solvents: water, ethanol, isopropanol
• Compatible
• Non-toxic
• Removable by drying
– Binder
• To help particles adhere together after drying
• Aggregation of primary powder particles to form granules using granulating fluid
• Mixing of powders
• Addition of granulating fluid
• Aggregation of powder particles (wet massing) – Controlled by altering fluid volume added and
intensity/duration of mixing
• Wet mass forced through sieve producing wet granules (granulation)
• Drying stage (different methods available)
• Milling stage (selecting desirable size of
particles for application) – Screening
4 stages of wet granulation
- Pendular state
- Funicular state
- Capillary state (ideal)
- Droplet state
Formation of liquid bridges between particles
- Pendular state
– Low liquid levels, discrete liquid bridges at points of contact between particles
– Assumption that there is a uniform distribution of liquid throughout powder bed - Funicular state
– Further liquid content, pendular bonds coalesce and liquid bridges form between non-touching points
– Dependant on degree of liquid (or voidage) saturation, usually 25-80% - Capillary state
- Liquid saturation>80%
- Granule becomes paste-like and unsuitable for wet sieving
- Tensile strength of granule increases x3 between pendular and capillary state - Droplet state
- ↑liquid converts capillary state into droplet state (undesirable)
- Particle completely enclosed in water droplet and mass takes on slurry like properties
What would happen is droplet stage was sieved
if droplet stage was sieved it would go right through and it was dried it would turn into a flat cake
Nature and extent of liquid bridges
- Formation of liquid bridges between particles of powder
- Nature and extent of liquid bridges dependant on amount of liquid added and method of wet massing
- 4 stages of bridge formation
- Agglomerates constantly formed and destroyed
Mechanism of particle-bonding with granulating fluid
- In dry methods particle adhesion takes place due to pressure
- In wet granulation particles adhere because of liquid
- Precise mechanism of powder to granule formation different for all equipment.
Mechanism of particle-bonding with granulating fluid - In general 3 phases of agglomeration occur
– Nucleation
– Transition
– Ball growth
Phases of agglomeration
• Nucleation
– Particle-particle contact and formation of liquid bridges
– Further agitation densifies pendular state which acts as a nuclei for further granule growth
• Transition
– Nuclei can grow by single particles being added via pendular bridges or two or more nuclei can combine
– Wide size distribution exhibited
• Ball growth
– Further granule growth produces large, spherical granules with size
increasing over time.
– Agitation stopped (would promote further coalescence making over- massed particles)
Formation of solid bridges
• Partial melting
– Pressures used in dry granulation may cause melting of low melting point materials ( as mp decreases, pressure increases)
– Crystallisation of the materials helps bond the particles together when the pressure is relieved
• Hardening binders
– Binders used in granulating fluid harden or crystallise on drying
– Synthetic polymers and pre-gelatinised starch
• Crysallisation of dissolved materials
– Some of the powders in the mix may be soluble
and dissolved in the granulating liquid
– Crystallisation of the dissolved substances may happen when the granules are dried eg. Lactose
– Slower drying times result in larger crystals
Advantages and disadvantages of wet granulation (most used for tablets, good for forming hard and less brittle tablets due to binding agent)
• Advantages
– Reduced segregation of formulation components during
storage/processing
– Useful for formulation of tablets with low active ingredient concentrations
– Uses conventional excipients
– Can be post-processed (tablet coating - enteric coating will allow dissolution of the tablet to occur in the small intestine instead of the stomach as its more acidic)
• Disadvantages
– Several processing steps needed
– Solvents used in process lead to concerns i.e. stability of drugs, toxicology of formulation
