1. TABLET MANUFACTURE FORMULATION AND PROCESSING

2. TABLET MANUFACTURE FORMULATION AND PROCESSING
Why are tablets the most popular dosage form for medicines?
Tablet compression
What is a ‘good’ tablet?
Tablet constituents
Direct Compression
Granulation
Sieving/milling
Blending
Common Tablet Problems
Questions

3. WHY TABLETS?
90% of medicines are taken orally with the majority being tablets. Other routes of administration include injections, inhalation, rectal and topical. Why are tablets the most common means of drug delivery?

4. WHY TABLETS? Can be self administered Painless Accurate dose delivery
Portable and discreet
Can be packaged to aid patient compliance
Easily identifiable (colour, shape, size, logo etc)
Simple to use
Low cost of manufacture
Normally stable to heat and moisture
Not easily contaminated with micro-organisms
Good bioavailability for most drugs
Release can be modified

5. TABLET MANUFACTURE
In order to make a ‘good’ tablet the powder to be compressed must have the correct characteristics:
The powder must be able to flow freely
The powder must be compressible (bind together to form a tablet)
The powder must be homogenous (uniform mix of active and excipient)
The tablet must be able to be ejected freely from the die without damage

6. TABLET COMPRESSION Lower punch drops as die passes feed frame
Powder fills to ‘over-fill’
Lower punch rises to expel excess (weight control)
Upper punch enters die
Pass between compression roller
Upper punch withdraws and lower punch rises
Tablet ejected by tablet take-off plate

7. What Is A ‘Good’ Tablet? Must contain the correct amount of active
This is measured during the process by ATW and U of W measurements
Have suitable physical properties
Hardness
Friability
Thickness/Diameter
Disintegration/dissolution
In order to ensure a good tablet is made the granule may need pre-conditioning and addition of excipients will be necessary

8. GRANULE MANUFACTURE
Three principle methods of preparing powder formulations for compression
Direct Compression
Wet Granulation
Dry Granulation

9. DIRECT COMPRESSION
This is the ideal option but is rarely achievable due to:
Active particle size/density mismatch with excipients causing poor homogeneity
Large quantity per tablet of poorly compressible active resulting in weak friable tablets

10. DIRECT COMPRESSION Process flow for direct compression Dispense
Security Sieve
Lubricant Blend
Compress

11. Problems Associated With Direct Compression
If the material is a powder rather than a granule:
it will have poor flow characteristics, which can lead to uneven tablet weights.
The pressure transmission through a powder mass is poor, due to low packing density. Consequently particles do not ‘knit’ together very readily.
Powders, especially fine ones tend to blow out of the die at the top and seep out at the bottom
Dusty powders tend to mix with oil/grease and eventually cause sticking of the punches in the dies or turret bores.
Powders containing two or more components may segregate. The heavier or smaller particle size components separate to the bottom of the bulk, this is made worse by the vibration of the Tablet Press.
Direct compression materials are more expensive than non-DC equivalents

12. Advantages of Direct Compression
Few stages involved
Low handling costs
Losses near zero
No water or heat involved
Reduces the risk of degradation of the active

13. PROCESS AIDS
Regardless of whether a tablet is manufactured by direct compression or granulation, processing aids will be required:
These materials are called excipients and are either:
Diluents
Lubricants
Disintegrants
Glidants
Binders
Direct compression formulations will contain as a minimum diluents, disintegrants and lubricants.
N.B. some excipients have more than one function

14. DILUENTS
A diluent is simply an ingredient that is used as a bulking agent to make tablets large enough to handle and swallow.
Diluents must therefore be:
Pharmacologically inert
Cheap
No supply issues
Compatible
Stable
Processable
Diluents are commonly easily compressible especially in DC formulations.
Examples include:
Micro-crystalline cellulose
Lactose
Di-calcium phosphate

15. LUBRICANTS
Lubricants are materials that lubricate powder mixes and aid tablet ejection.
Without lubrication powder may stick to the punches especially if is too moist.
Lubricants are typically added at a late stage and blended for the shortest possible time as they have adverse effects.
Adverse effects if over-blended are poor compressibility and increased dissolution due to waxy layer covering the surface of the granule
Examples include:
Magnesium Stearate
Stearic Acid
Talc

16. GLIDANTS Glidants are materials that improve the flow of powder mixes
An example is Colloidal Silicon Dioxide
Most powders, without the aid of flow agents, simply cannot flow at speeds required for high speed tabletting.
Flow agents can decrease the capacity of powders to form bridges, create rat holes and stick to contact surfaces.
Good flow into the die will lead to
uniform tablet weight as the volume of
material flowing into the die will be constant

17. DISINTEGRANTS
A material to promote disintegration of the tablet when swallowed
Enhances water penetration by wicking effect
Increases porosity
Swells in contact with water and breaks cohesive bonds
Examples include:
Starch
Croscarmellose
Sodium Starch Glycollate
Crospovidone

18. BINDERS A material that imparts cohesiveness to the formulation
Helps bind powder particles into granules during granulation
Helps bind granules together during the compression process
Examples include:
Hydroxy propyl methyl cellulose (HPMC in water)
Starch paste in warm water
Gelatin
Polyvinyl pyrrolidone (PVP)

19. WHY GRANULATE? To improve powder flow. To improve compressibility.
To reduce fines.
To control the tendency of powders to segregate.
To control density.
To capture and fuse small quantities of active material.

20. TRADITIONAL WET GRANULATION
Dispense Security Sieve Granulate Dry Moisture Test Sieve/Mill Lubricant Blend Compress

21. TRADITIONAL WET GRANULATION
Most commonly performed using a high shear mixer e.g. ‘Fielder’ but can be performed using low shear e.g. ‘Hobart’.
Fielder Granulator:
Two blades, main blade and chopper
Main blade speed is typically rpm
Chopper blade up to 3000rpm
Main blade mixes and chopper breaks wet mass to form granules

22. TRADITIONAL WET GRANULATION
Powders are loaded into the bowl and mixed for a defined time before granulation starts
Granulating solution added at defined rate or sprayed (binder is usually incorporated into the solution)
Wet mass is chopped to form granule
Granulation end point can be measured by current draw on main blade
Process is controlled by the mixing times/speeds before and after addition of the granulating solution and the amount of solution added.
Process relies on the binder and/or water soluble elements dissolving upon granulation, then on drying forming a solid bridge between particles.

23. ADVANTAGES OF WET GRANULATION
Increases cohesiveness
Good for high dose/poorly compressible drugs
For example Kalms has large amount of poorly compressible Hops
Good for distributing soluble low dose drugs
For example in Kwells the hyoscine is added to the granulating solution
Prevents segregation of actives

24. DISADVANTAGES OF WET GRANULATION
Processing parameters are derived by trial and error
Mixing time varies with batch size and can be sensitive to variation in starting materials
Danger of over granulation
Cost (multi-stage process)
Incompatibilities (chemical instability with moisture or subsequent drying)

25. A TYPICAL WET GRANULATION FORMULATION
Wet Binder
Polyvinyl pyrrolidone (PVP)
Increases granule size strength and compressibility
Enhances dissolution relative to DC
Granulation process aid
Micro-crystalline cellulose
Reduces water/energy requirements
Reduces process sensitivity
Less risk of over granulation
Easier wet massing and screening
Intra granular filler
Lactose
Better wet binding than insoluble fillers
Intra-granular disintegrant
Croscarmellose sodium

26. DRYING The removal of water or liquid to form a dry solid
It is necessary as too much residual water can result in:
Poor flow
Poor lubrication (sticking to punches)
Chemical instability
Susceptibility to microbial growth
2 main methods
Tray drying
Fluidised Bed Drying
Others include microwave and vacuum drying
(not commonly used)

27. TRAY DRYING Fan assisted convection of hot air over loaded trays
Not commonly used due to:
Large floor space
Manual handling
Labour intensive
Long drying times (up to 24 hours)
Can get non-uniform drying
Can result in hard caked product

28. FLUIDISED BED DRYING
Heated air is pulled through the bed of material in a
removable bowl.
Filters prevent fines from escaping
Temperature can be controlled by probes monitoring
input, output and bed temperatures
Airflow is adjusted according to particle size and density
Most efficient drying (minutes vs. hours)

29. SIEVING AND MILLING
Sieving of the granule may be performed to remove large particles that may then be milled to reduce size
Oversize or all of the dried granule may be milled.
Various types of mill are usually used depending upon the process requirements
Mills used routinely at GR Lane include Comill (Cone mill), Apex and Tornado.

30. MILLING Comills (cone mills) produce granule of more uniform size and
shape than Apex or Tornado mills
with a smaller proportion of fines
Fines are powders that are very small
and ‘dusty’, which will pass through
a 200 mesh screen.
Fines impede the flow, do not compress
well
Mills may also be used to ‘de-lump’
granules without reducing particle size.

31. MILLING Apex mills have the rotational shaft
in a horizontal orientation vs
Tornado that is vertical
Tornado mills have 360° mill screens and
consequently produce marginally less fines
than an Apex mill that has a 180° screen.
Both tornado and apex mills can be used
with varying numbers of blades that throw
material against the mesh that controls the
maximum particle size
Hammers may also be used. These pulverise
the material to a finer particle size

32. SPRAY GRANULATION
This is when granulation and drying is combined in a one-pot process
Granulation solution is sprayed into a fluidised bed
There is a greater degree of control over the size of granules formed.
Control is via spray rate, inlet temperature and air flow.
There are less losses by this method
Granule has an even moisture distribution
However
Higher attrition may lead to fines
Control of rates is critical
Longer process time (may lead to de-mixing)

33. DRY GRANULATING Dry granulating, also called slugging, or roller
compaction, involves the pressing of mixed
powders into an object to be reground into a
precise powder.
This action increases particle density, improves
powder flow and captures fines.
Useful for materials which are sensitive to heat
and/or moisture.
Can be performed on tablet press followed by milling
or by using specialised equipment
However pressure during dry granulation can
result in:
granules with low porosity
Weaker tablets
May produce tablets with longer disintegration time
Dusty process

34. BLENDING There are many different types of blenders
Y cone blenders
Double cone blenders
Drum blenders
IBC blenders
Majority are low shear tumble blenders. GR Lane has
opted for IBC blending to reduce handling
Blend studies are performed to
determine the determine the
optimum endpoint
Given enough time, components
will pass from an unblended state
to a relatively homogenous blend and
back to an unblended state.

35. COMMON TABLET PROBLEMS
Weight variation
Friability variation
Capping
Laminating
Chipping
Cracking
Sticking/Filming
Picking
Binding

36. WEIGHT VARIATION
Weight variation can be caused by a number of factors:
Poor flow of granule
Granule too wet
Insufficient glidant
Poor granule homogeneity
Over or under-blended
Material has settled over time
Separation of fines in hopper
Poor formulation
Tablet press set-up
Dropping punches
Sticking punches
Feed frame speed
Uneven wear or damaged tooling

37. POOR FRIABILITY Poor friability can be caused by a number of factors:
Low hardness
Tablet press set-up
Overblending
Poor granule
Too dry
undergranulated
insufficient binder
too many fines
Inappropriate tablet shape

38. CAPPING
Capping is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling.
Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.
Causes related to the formulation are
Large amount of fines
Granule too dry
Granule too wet
Insufficient lubricant
Causes related to the press:
Ringing in dies
Lower punch remains below the face of die during ejection.
Incorrect adjustment of take-off blade.
High turret speed
Possible remedial actions are:
Move position of compression in die
Adjust take-off blade
Slow down press

39. LAMINATION
Lamination is the separation of a tablet into two or more distinct horizontal layers.
Reason: Air–entrapment during compression and subsequent release on ejection
Causes related to the formulation:
Over lubrication of formula
Oily material in formula
Causes related to the tablet press:
Rapid relaxation of the peripheral regions of a tablet, on ejection from a die.
Rapid decompression
Possible remedial action:
Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°.
Use pre-compression step. Reduce turret speed and reduce the final compression pressure.

40. CHIPPING There are number of causes of chipping that can be due to:
Machine setup
Insufficient dwell time
Compression force too low
Tooling wear
worn punches
Poor granule
too much fines
Granule too dry
Insufficient binder
Excessive lubricant
Not homogenous mix
Possible remedial actions
If clawed tooling, remove claws
Increase pressure
Slow down press

41. CRACKING
Cracking is where small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall
Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used
Causes related to the granule:
Large size of granules.
Too dry granules
Causes related to the tablet press:
Tablet expands on ejection due to air entrapment
Deep concavities cause cracking while removing tablets
Too much pressure
Possible remedial action:
Use tapered die
Use special take-off plate
Reduce compression force

42. STICKING/FILMING
Sticking refers to the tablet material adhering to the die wall.
Filming is a slow form of sticking and is largely due to excess moisture in the granulation.
Reason: Improperly dried or improperly lubricated granules.
Possible remedial action:
Increase pressure.
Reduce speed.

43. PICKING
Picking is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face.
The problem is more prevalent on the upper punch faces. The problem worsens with time into the run because more and more material is added to the already stuck material on the punch face.
Common causes related to the granule:
Excessive moisture in granules
Too little or improper lubrication
Too warm granules when compressing.
Too much binder.
Common causes related to the tablet press:
Rough or scratched punch faces
Unpolished tooling
Insufficient pressure
Possible remedial actions:
Increase compression pressure
Polish tooling by hand
Reduce press speed

44. BINDING
Binding in the die, is the term used when the tablets adhere or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and they may crumble apart
Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.
Causes due to worn dies:
Poorly finished dies
Rough dies due to abrasion
Possible remedial action:
Clean the dies properly
If worn die is due to abrasion investigate use of other steels
Reducing pressure in the tablet press may decrease binding.

45. Thank You
Any Questions