Wet Granulation

Question 1

Why wet granulate?

Answer 1

To produce larger agglomerates from fine powders which:

• Improve handling through enhanced flow and reduced dustiness
• Improve product appearance
• Control of solubility and porosity – can moderate release profile
• Increase bulk density for tablet compression and/or storage
• Prevent drug segregation during tablet compression or capsule filling
• Improve compressibility / tablettability

Question 2

Pharmaceutical wet granulators?

Answer 2

1) Vertical axis (batch)

2) Screw (continuous)

Question 3

Granulating liquid can be:

Answer 3

• Plain (purified) water
• An aqueous solution containing a polymer such as hydroxypropyl cellulose (HPC) or polyvinylpyrrolidone (PVP).
• An organic solvent such as ethanol

Question 4

Effect of binders (low level)?

Answer 4

Low level (0-1%) -
Higher water quantity required to achieve a given level of agglomeration.
Shorter disintegration time and faster dissolution rate .
HOWEVER
More attrition during drying could impact flow and weight.

Question 5

Effect of binders (high level)?

Answer 5

High level (4-6%)
Lower water quantity required to achieve a given level of agglomeration.
Easier manufacturing - improved granule flow (due to lack of attrition of large granules) – more consistent product quality.
Longer disintegration time and slower dissolution rate – may be possible to counteract with use of disintegrants.

Question 6

Effect of disintergrants (low level)?

Answer 6

Lower water quantity required to achieve a given level of agglomeration.
Shorter granulation and drying times.

Longer disintegration time and slower dissolution rate.
Typically better long-term storage stability – cheaper, less protective packaging can be used.

Question 7

Effect of disintergrants (high level)?

Answer 7

Higher water quantity required to achieve a given level of agglomeration.
Longer granulation and drying times required.

Faster disintegration and increased dissolution rate.
May cause performance (dissolution) reduction over time due to moisture uptake.

Question 8

Effect of mannitol and lactose as diluents/fillers?

Answer 8

Lower water quantity required (10-20% w/w).
Faster granulation and shorter drying times.
Soluble excipients may aid drug release.
Can be trickier to compress – lower tensile strength of tablets and granules need to be well lubricated if appearance defects are to be avoided.

Question 9

Effect of MCC and starch as diluents/fillers?

Answer 9

Significant levels of water required (30-60% w/w).
Makes process less sensitive to small changes in water quantity.
Long granulation and drying times.
Usually imparts high tensile strength to tablets.
Insoluble and so may be detrimental to drug release for some products.
Can absorb a large amount of water on storage if allowed to do so – not good for performance or microbiological quality.

Question 10

How does water quantity impact the process?

Answer 10

Liquid quantity controls the maximum number of liquid bridges that can form between powder particles – and therefore, ultimately, maximum achievable granule size

Quantity of liquid added affects stickiness of mixture, which can be monitored during granulation by measuring power or torque

The more liquid is added, the more granules are likely to consolidate and grow – the more sticky they become

Question 11

Granule characterisation considerations:

Density/porosity

Answer 11

Can affect tablet hardness and dissolution, remember that granule density can vary with size

Question 12

Granule characterisation considerations:

Moisture content

Answer 12

Residual moisture content after drying can affect tabletting and tablet hardness, moisture content will vary with granule size

Question 13

Granule characterisation considerations:

Size and size distribution

Answer 13

Can affect flow and where granules are dense, can affect tablet hardness and dissolution (compression and dissolution of large, dense granules is difficult). Any ungranulated drug may stick to punches during compression

Question 14

Granule characterisation considerations:

Drug content uniformity

Answer 14

It is desirable to have drug evenly distributed across all granule sizes, especially if drug loading of formulation is low (this makes the tablet or capsule drug content very sensitive to granule size or weight)

Question 15

What are the flow regimes for batch granulation?

Answer 15

Bumping flow and roping flow.

Starts off with bumping flow and an increase in impeller speed = roping flow.

Question 16

Bumping flow characteristics?

Answer 16

• Poor vertical mixing
• Longer dry mix times may be necessary
• Poor liquid distribution during granulation

Question 17

Roping flow characteristics?

Answer 17

• Good mixing
• Good liquid distribution – more unimodal granule size distribution
• Higher consolidation rates may lead to dense granules

Question 18

What happens if you under fill the bowl: (batch)

Answer 18

Under-filled = <25% working volume):
- Chopper redundant (no breakage of lumps – poor liquid distribution)

• Poor mixing (all powder moves round bowl at close to impeller speed)
• Slower consolidation rates

Question 19

What happens if you over fill the bowl:(batch)

Answer 19

Over-filled level = (>65% working volume):

• Poor water distribution throughout powder bed
• Poor mixing (especially top to bottom)
• Higher consolidation rates

Question 20

What happens in a high shear granulator?

Granule formation mechanisms

Answer 20

Nucleation and wetting:
1) Spray&raquo_space; liquid (solid+liquid= distribution mechanism)

Surface-wet granule nucleus:
Likely to coalesce with other granules or powder particles

2) Solid &laquo_space;liquid
(solid+liquid= immersion mechanism)

Surface-dry granule nucleus:

• Coalescence not likely (no available liquid for bonding)
• More likely to break or consolidate first

Question 21

Consequences of big granules?

Answer 21

Big granules contain lots of liquid. When dried, this liquid is removed leaving a porous structure and crystals of any soluble components

Question 22

Granule Consolidation:

Answer 22

Granule consolidation (or densification) rate depends on liquid saturation level, mixing time and forces acting on the granule (eg, impeller speed, chopper speed)

If high granule porosity is desirable, granulate with small primary powder particles, use low impeller speeds, short mixing times and don’t add too much liquid.

Question 23

Granule coalescence:

Deformation/formation

Answer 23

Granules deform on impact with each other, increasing contact surface area and coalescence probability.
Granules grow at a steady rate, so easy to control.

Granules do not deform on impact with each other, coalescence largely dependent on liquid properties (viscosity).
Granules do not grow until there is an abundance of liquid – then grow rapidly (difficult to control)

Question 24

Attrition and breakage-

Influence on granule homogeneity:

Answer 24

Attrition dominated–>
Limited redistribution of granule components
Granule homogeneity depends on quality of pre-granulation mixing

Fragmentation dominated–>
Extensive redistribution of granule components
Granulation process contributes to granule homogeneity

Question 25

Process characteristics - continuous granulation –>

Answer 25

• The process at macro scale is easier to predict – effect of each screw element can be characterised
• Mixing is more uniform (primarily due to smaller volume of channels)
• Liquid distribution and particle size are more homogeneous and vary mostly with position along the barrel

Question 26

What happens if you under fill a barrel (continuous)?

Answer 26

Under-filled (<25% working volume):
Poor mixing and liquid distribution (limited granule-granule and granule-machine contact restricts amount of breakage that occurs)
Wider granule size distribution – limited breakage to distribute granulation liquid

Question 27

What happens if you over fill a barrel (continuous)?

Answer 27

Over-filled level (>75% working volume):

• Increased granule breakage and consolidation – dense granules likely to be detrimental to tablet compression
• Granule size distribution gets narrower – increased breakage distributes liquid across all material

Question 28

Granulation occurs in a series of compartments along the length of the screw: What are these?

Answer 28

C1 - nucleation to give large initial granules.
C2 – significant consolidation and breakage – size decrease (significant).
C3 – moderate coalescence and breakage – size increase or decrease (depending on materials and conditions).
C4 – coalescence and consolidation – size increase

Question 29

Along the length of the barrel, granules:

Answer 29

• Become more spherical.

- Granule strength increases.

Question 30

Increasing viscosity of granulation liquid results in:

Answer 30

• Increased residence time
• Increased screw torque
• More mono-modal size distribution
• Increasing granule strength
• Improved granule flow (due to mean size increase and narrower size distribution)
• Surface tension of granulation liquid has only minor influence on residence time, torque and granule properties.

Question 31

Downstream Processing.

What is de-lumping and drying?

Answer 31

De-lumping (milling of large, wet granules) is optional and is used to ensure that no excessively large granules remain that would be difficult to dry.

Breakup of lumps post drying can release trapped moisture into the dried granules, which may affect manufacturability (sticking), microbiological quality, assay or degrade the drug substance.

Wet granules require drying before further processing.  The quantity of water added during wet granulation will have the most significant impact on drying times.  
This may have subsequent effects on:
- Extent of granule attrition
- Thermal degradation of components
- Compressibility of dried granules