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
Dry granulation (widely used but not as popular as wet granulation as higher pressures and more machinery needed in dry granulation)
• No liquids
• Suitable for formulation where:
– Product is moisture sensitive
– Drug is heat sensitive
– Poor compression exhibited after wet granulation
• Aggregation of primary powder particles to form granules and subsequently tablets under high pressure
– Compression of dry powders
– Mill used to break up compacts / ‘slug’ into granules
• Slugging
– Process used to compress dry powders into a large
‘oversized’ tablet (slug)
– Around 25 mm in diameter, 10-15 mm thickness
– Large heavy duty tablet press used (dangerous)
– Binder can be used to improve bonding strength in compaction
– Disintegrant can be used as excipient (disintegrants are put into the tablet mix and are bound to swell when they hit the liquid in GI tract)
– Lubricant can be added to prevent compacts sticking to the punches and die
• Roller compaction
– Dry powder mix squeezed between two rollers to
form compressed sheet
– Brittle sheet immediately broken into flakes or milled into correct size
– Flakes ͢ granules
– Can be compacted with binder to improve
bonding strength
– Roller compaction required less lubricant than for slugging (constant movement through a sheet and not hard pressure)
Types of excipients
• Diluent (filler) e.g. lactose, starch
– Bulks up powder mix
• Disintegrant e.g.starch, sodium starch glycolate
– To break up granule / tablet in solution
– Not the same as dissolution
• Binders
– Bind constituents together
• Lubricant e.g. stearates, PEG, SDS
• Glidant e.g. talc, colloidal silicone dioxide
– Anti-adherent properties
Advantages and disadvantages of dry granulation
• Advantages
- Less wastage than wet granulation
– Both roller compaction and slugging require conventional
excipients
– Methods not commonly associated with degradation/alteration of drug molecules during processing
– No heat or solvents required
• Disadvantages
– Roller compaction requires specialist equipment
– Segregation of components may occur post processing
– May be issues regarding powder flow
– Final tablets usually softer than with wet granulation
- Cannot be used for EC tabs
Wet granulators - 3
- Low shear mixers
- High-speed granulators
- Fluidised-bed granulators
Granulating agents (usually polymers)
• Hydroxylpropyl methylcellulose (HPMC) 2-8% – Various MW and viscosities available – Soluble in water and ethanol • Methylcellulose (MC) 1-5% – Low viscosity grades commonly used • Starch5-25% – Requires preparation as a paste • Pre-gelatinised starch 5-10% – Easier to prepare than starch • Acacia 1-5% – Requires preparation as a paste – Can result in prolonged disintegration times at high concentrations • Polyvinylpyreolidone (PVP) 2-8% – Various MW and viscosities available – Dry or in solution – Soluble in water and ethanol
What properties would be desirable in a granulating fluid?
dries at a relatively low boiling point
non-toxic
cheap
upon drying be able to hold crystals together
How does the volume of granulating fluid affect formation of granules?
if you exceed the amount of granulation fluid, particles will never sieve or dry
Spheronisation
• Form of granulation
• Makes uniform sized spherical pellets
• Used when spheres required as dosage form
• Useful for M/R or C/R formulations
– Coating is possible
– Multiparticulate systems
• More labour intensive than other forms of granulation – Only used when other forms inappropriate
• Wet massing important to produce good quality spheres
– Usually higher fluid volumes than in wet granulation
Transition from rod-shaped to spherical particles
- Cylinder
- Cylinder with rounded ends
- Dumbbell
- Ellipsoid
- Sphere
- Water level is critical for optimising the spheronisation process - if you increase water the edges of the cylinder become rounder
Types of extruders
- screw feed
- gravity feed
- piston feed
