Pelletization

Question 1

Advantages of pellets as a multi-unit dosage form

Answer 1

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

Question 2

Direct pelletization

Answer 2

Single step pelletization methods

Question 3

Examples of direct pelletization

Answer 3

1) Fluid bed layering

2) Disc/Rotary drum pelletizer

Question 4

Fluid bed layering

Answer 4

Pellitization by layering onto starter seeds
- Deposition of successive coats onto seed particles without agglomerative growth
Coating material: Solution/Suspension containing active

Question 5

Disc/Rotary drum pelletizer - How it works

Answer 5

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

Question 6

Disc/Rotary drum pelletizer - Limitations

Answer 6

1) Generally expensive due to complexity

2) Variation in pellet quality –> wide size distribution

Question 7

Disc/Rotary drum pelletizer - Applications

Answer 7

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

Question 8

Extrusion-spheronization - Applications

Answer 8

Method of choice to produce pharmaceutical pellets

- Generally used for pellets with high % composition of drug (difficult to layer large amount of drug)

Question 9

Extrusion-spheronization - Advantages

Answer 9

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

Question 10

Extrusion-spheronization - Steps

Answer 10

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

Question 11

Extrusion - How it works

Answer 11

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

Question 12

Extrusion - Types of extruders

Answer 12

1) Radial extruder
2) Axial extruder
- Forms extrudates that are jagged, with regular spaced shark-skinned protuberances –> easily broken up –> ideal for spheronization

Question 13

Spheronization - How it works

Answer 13

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

Question 14

Extrusion-spheronization - Pellets produced

Answer 14

With optimized processes & formulation variables, pellets produced are:

1) Highly spherical
2) Narrow size distribution
3) Close in size to screen aperture size

Question 15

Extrusion-spheronization - Specific requirements for formulation

Answer 15

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)

Question 16

Extrusion-spheronization - Basic raw materials needed

Answer 16

1) Drug
2) Filler
3) Pelletization aid
4) Moistening liquid (to form solid bridges between particles)

Question 17

Pelletization aid - Types

Answer 17

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

Question 18

Microcrystalline cellulose (MCC) - Advantages

Answer 18

1) Good binding property
2) Good cohesiveness
3) Large surface area
4) High internal porosity

Question 19

Microcrystalline cellulose (MCC) - How it works

Answer 19

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

Question 20

Extrusion-spheronization - Factors affecting pellet quality

Answer 20

1) Extrudates formed
2) Particle size
3) Packing
4) Moisture
5) Migratable stickiness

Question 21

Factors affecting pellet quality - Extrudates formed

Answer 21

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

Question 22

Factors affecting pellet quality - Particle size

Answer 22

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

Question 23

Factors affecting pellet quality - Moisture

Answer 23

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

Question 24

Factors affecting pellet quality - Packability

Answer 24

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

Question 25

Overcoming issues in spheronization due to packability

Answer 25

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

Question 26

Extrusion-spheronization - Migratable stickiness

Answer 26

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