Pelletization Flashcards
Advantages of pellets as a multi-unit dosage form
Therapeutic advantages:
1) Minimize local irritation
- Distributed all over GIT –> no high local concentration (VS single unit dosage form –> released at single site )
2) Maximize absorption/bioavailability
- Distributed all over GIT –> no saturation (VS single unit dosage form –> released at single site)
3) Less susceptible to dose dumping
4) Not restricted by GER
Technological advantages:
1) Superiority for coating
2) Uniformity in packing
3) Round/spherical –> minimize friction during motion
4) Good flowability
5) Low friability
Direct pelletization
Single step pelletization methods
Examples of direct pelletization
1) Fluid bed layering
2) Disc/Rotary drum pelletizer
Fluid bed layering
Pellitization by layering onto starter seeds
- Deposition of successive coats onto seed particles without agglomerative growth
Coating material: Solution/Suspension containing active
Disc/Rotary drum pelletizer - How it works
1) Powder mass added to spheronizer, on a frictional base –> powder is rotated
2) Agglomerative media sprayed directly onto powder mass –> pellets formed in-situ
3) Pellets formed can be directly coated & dried simultaneously
- Change spray media to coating media & introduce drying air
Disc/Rotary drum pelletizer - Limitations
1) Generally expensive due to complexity
2) Variation in pellet quality –> wide size distribution
Disc/Rotary drum pelletizer - Applications
Used to produce:
1) Nonpareils
- Used in production of sustained release products (used as starter seed, drug and then sustained release polymer coated over it)
- Generally for low dose products
2) Industrial/Agricultural pellets
Extrusion-spheronization - Applications
Method of choice to produce pharmaceutical pellets
- Generally used for pellets with high % composition of drug (difficult to layer large amount of drug)
Extrusion-spheronization - Advantages
Pelletization process:
1) Ease of operation
2) High throughput, low wastage
3) High efficiency
Pellets formed:
1) Highly spherical
2) Narrow size distribution
3) Smooth surface
4) Low friability
Extrusion-spheronization - Steps
1) Dry massing
- Ensure powder is well mixed
2) Wet massing
- Add liquid to obtain wet mass
3) Extrusion
4) Spheronization
5) Coating & drying
- Can by carried out in fluid bed
Extrusion - How it works
Wet mass passed through a screen (extruder) with specific aperture size –> forms high density, cylindrical extrudates
Aperture size selected should be similar to desired pellet size
Extrusion - Types of extruders
1) Radial extruder
2) Axial extruder
- Forms extrudates that are jagged, with regular spaced shark-skinned protuberances –> easily broken up –> ideal for spheronization
Spheronization - How it works
1) Extrudates are broken into uniform lengths
2) Broken extrudates are rounded in spheronizer with rotating frictional plate to produce pellets
3) Rounding occurs in a ‘rope-like’ motion
- Important for ensuring good flow & even distribution
Extrusion-spheronization - Pellets produced
With optimized processes & formulation variables, pellets produced are:
1) Highly spherical
2) Narrow size distribution
3) Close in size to screen aperture size
Extrusion-spheronization - Specific requirements for formulation
Extrusion:
1) Cohesive, plastic wet mass with sufficient fluidity & self-lubricating properties
- Fluidity: Able to flow
- Self-lubricating: Ensures no problems when going through screen
- Else, liquid content may be squeezed out (not ideal) during extrusion
Spheronization:
1) Must be brittle enough to be broken up BUT have sufficient plasticity (for deformation/rounding)
Extrusion-spheronization - Basic raw materials needed
1) Drug
2) Filler
3) Pelletization aid
4) Moistening liquid (to form solid bridges between particles)
Pelletization aid - Types
1) Microcrystalline cellulose (MCC)
2) Cross-linked polyvinyl pyrrolidone
3) Powdered cellulose
4) Hydroxypropyl methylcellulose / Hypromellose
5) Hydroxyethyl cellulose
6) Carrageenan
7) Chitosan
Successful in forming good quality pellets:
1) MCC
- Pelletization aid of choice
2) Cross-linked polyvinyl pyrrolidone
- More expensive
Remaining pelletization aids are less successful
Microcrystalline cellulose (MCC) - Advantages
1) Good binding property
2) Good cohesiveness
3) Large surface area
4) High internal porosity
Microcrystalline cellulose (MCC) - How it works
1) Molecular sponge model
- Extrusion: Absorbs water –> forms cohesive yet plastic wet mass
- Spheronization: Helps in binding & lubrication –> increase surface plasticity, helps in rounding
2) Crystallite gel model
- MCC particles broken down into single crystallites of colloidal size & immobilise liquid –> improves plasticity, provide lubricative properties
Extrusion-spheronization - Factors affecting pellet quality
1) Extrudates formed
2) Particle size
3) Packing
4) Moisture
5) Migratable stickiness
Factors affecting pellet quality - Extrudates formed
Poorly formed extrudates (e.g. uneven)
- Breaks into uneven fragments
- Slow rounding
- Pellets with wide size distribution formed
Well formed extrudates
- Breaks into fragments of similar length
- Rapid rounding
- Pellets with narrow size distribution formed
Factors affecting pellet quality - Particle size
Small particles
- Able to produce agglomerates that are more spherical, smoother, narrow size distribution
- BUT too fine particles won’t agglomerate well (trap a lot of air, poor flow)
Large/Rough particles
- Pellets formed will take shape of particles, with rougher surface
Ideal particle size: 1/6 - 1/8 of desired pellet size
Factors affecting pellet quality - Moisture
Moisture requirement measured using mixer torque rheometer (MTR)
How it works:
1) Add moistening liquid (water) in small amounts to powder mass in mixer bowl of MTR
2) Mix & record torque experienced
3) Plot graph of torque against liquid added
4) Moisture requirement for pellet making: 80 - 90% Tmax
Factors affecting pellet quality - Packability
Packing depends on:
1) Particle size
- Coarser particles –> loosely packed extrudates –> friable pellets
- Small particles –> well packed extrudates –> strong pellets (but more effort needed to form as small particles are very cohesive)
2) Size distribution
- Wide size distribution –> well-packed extrudates –> strong pellets
Overcoming issues in spheronization due to packability
Cohesive forces (in extrudate) < Forces during spheronization:
Pellets formed: Irregular shape, wide size distribution
Overcome by:
1) Decrease spheronization speed
2) Repeat extrusion step
3) Reduce component particle size
4) Widen component particle size distribution
Cohesive forces (in extrudate) > Forces during spheronization:
Pellets formed: Elongated
Overcome by:
1) Increase spheronization speed
Extrusion-spheronization - Migratable stickiness
Avoid binders/materials that can migrate
- Result in pellets that can keep growing, with varying sizes
Use immobile adhesive particles
- E.g. MCC, micronized powders
