TABLET MANUFACTURE
FORMULATION AND
PROCESSING
TABLET MANUFACTURE
FORMULATION AND PROCESSING
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Why are tablets the most popular dosage form for medicines?
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Tablet compression
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What is a ‘good’ tablet?
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Tablet constituents
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Direct Compression
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Granulation
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Sieving/milling
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Blending
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Common Tablet Problems
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Questions
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?
WHY TABLETS?
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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
TABLET MANUFACTURE
In order to make a ‘good’ tablet the powder to be compressed must
have the correct characteristics:
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The powder must be able to flow freely
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The powder must be compressible (bind together to form a tablet)
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The powder must be homogenous (uniform mix of active and excipient)
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The tablet must be able to be ejected freely from the die without damage
TABLET COMPRESSION

Lower punch drops as
die passes feed frame
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Powder fills to ‘over-fill’
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Lower punch rises to
expel excess (weight
control)
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Upper punch enters die
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Pass between
compression roller
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Upper punch withdraws
and lower punch rises
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Tablet ejected by tablet
take-off plate
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
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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
GRANULE MANUFACTURE
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Three principle methods of preparing powder
formulations for compression
1. Direct Compression
2. Wet Granulation
3. Dry Granulation
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
DIRECT COMPRESSION
• Process flow for direct compression
Dispense
Security Sieve
Lubricant
Blend
Compress
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
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
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:
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Diluents
Lubricants
Disintegrants
Glidants
Binders
 Direct compression formulations will contain as a
minimum diluents, disintegrants and lubricants.
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N.B. some excipients have more than one function
DILUENTS
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A diluent is simply an ingredient that is used as a bulking agent to make
tablets large enough to handle and swallow.
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Diluents must therefore be:
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Pharmacologically inert
Cheap
No supply issues
Compatible
Stable
Processable
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Diluents are commonly easily compressible especially in DC formulations.
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Examples include:
– Micro-crystalline cellulose
– Lactose
– Di-calcium phosphate
LUBRICANTS
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Lubricants are materials that lubricate powder mixes
and aid tablet ejection.
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Without lubrication powder may stick to the punches
especially if is too moist.
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Lubricants are typically added at a late stage and
blended for the shortest possible time as they have
adverse effects.
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Adverse effects if over-blended are poor
compressibility and increased dissolution due to waxy
layer covering the surface of the granule
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Examples include:
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Magnesium Stearate
Stearic Acid
Talc
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
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:
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Starch
Croscarmellose
Sodium Starch Glycollate
Crospovidone
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:
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Hydroxy propyl methyl cellulose (HPMC in water)
Starch paste in warm water
Gelatin
Polyvinyl pyrrolidone (PVP)
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.
TRADITIONAL WET
GRANULATION
Dispense
Security Sieve
Granulate
Dry
Sieve/Mill
Lubricant
Blend
Compress
Moisture Test
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 100500rpm
› Chopper blade up to 3000rpm
› Main blade mixes and chopper
breaks wet mass to form
granules
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.
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
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)
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
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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
DRYING
• The removal of water or liquid to form a dry solid
• It is necessary as too much residual water can result in:
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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)
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
FLUIDISED BED DRYING
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Heated air is pulled through the bed of material in a
removable bowl.
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Filters prevent fines from escaping
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Temperature can be controlled by probes monitoring
input, output and bed temperatures
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Airflow is adjusted according to particle size and density
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Most efficient drying (minutes vs. hours)
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.
MILLING
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Comills (cone mills) produce
granule of more uniform size and
shape than Apex or Tornado mills
with a smaller proportion of fines
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Fines are powders that are very small
and ‘dusty’, which will pass through
a 200 mesh screen.
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Fines impede the flow, do not compress
well
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Mills may also be used to ‘de-lump’
granules without reducing particle size.
MILLING
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Apex mills have the rotational shaft
in a horizontal orientation vs
Tornado that is vertical
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Tornado mills have 360° mill screens and
consequently produce marginally less fines
than an Apex mill that has a 180° screen.
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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
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Hammers may also be used. These pulverise
the material to a finer particle size
SPRAY GRANULATION
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This is when granulation and drying is combined in a one-pot process
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Granulation solution is sprayed into a fluidised bed
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There is a greater degree of control over the size of granules formed.
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Control is via spray rate, inlet temperature and air flow.
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There are less losses by this method
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Granule has an even moisture distribution
However
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Higher attrition may lead to fines
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Control of rates is critical
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Longer process time (may lead to de-mixing)
DRY GRANULATING
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Dry granulating, also called slugging, or roller
compaction, involves the pressing of mixed
powders into an object to be reground into a
precise powder.
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This action increases particle density, improves
powder flow and captures fines.
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Useful for materials which are sensitive to heat
and/or moisture.
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Can be performed on tablet press followed by milling
or by using specialised equipment
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However pressure during dry granulation can
result in:
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granules with low porosity
Weaker tablets
May produce tablets with longer disintegration time
Dusty process
BLENDING
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There are many different types of blenders
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Y cone blenders
Double cone blenders
Drum blenders
IBC blenders
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Majority are low shear tumble blenders. GR Lane has
opted for IBC blending to reduce handling
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Blend studies are performed to
determine the determine the
optimum endpoint
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Given enough time, components
will pass from an unblended state
to a relatively homogenous blend and
back to an unblended state.
COMMON TABLET PROBLEMS
• Weight variation
• Cracking
• Friability variation
• Sticking/Filming
• Capping
• Picking
• Laminating
• Binding
• Chipping
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
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Dropping punches
Sticking punches
Feed frame speed
Uneven wear or damaged tooling
POOR FRIABILITY
• Poor friability can be caused by a number of factors:
– Low hardness
• Tablet press set-up
• Overblending
– Poor granule
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Too dry
undergranulated
insufficient binder
too many fines
– Inappropriate tablet shape
CAPPING
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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.
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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.
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Causes related to the formulation are
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Causes related to the press:
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Large amount of fines
Granule too dry
Granule too wet
Insufficient lubricant
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:
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Move position of compression in die
Adjust take-off blade
Slow down press
LAMINATION
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Lamination is the separation of a tablet into two or more distinct horizontal layers.
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Reason: Air–entrapment during compression and subsequent release on ejection
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Causes related to the formulation:
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Causes related to the tablet press:
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Over lubrication of formula
Oily material in formula
Rapid relaxation of the peripheral regions of a tablet, on ejection from a die.
Rapid decompression
Possible remedial action:
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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.
CHIPPING
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There are number of causes of chipping that can be
due to:
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Machine setup
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Tooling wear
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worn punches
Poor granule
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Insufficient dwell time
Compression force too low
too much fines
Granule too dry
Insufficient binder
Excessive lubricant
Not homogenous mix
Possible remedial actions
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If clawed tooling, remove claws
Increase pressure
Slow down press
CRACKING
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Cracking is where small, fine cracks observed on the upper and lower central surface
of tablets, or very rarely on the sidewall
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Reason: It is observed as a result of rapid expansion of tablets, especially when deep
concave punches are used
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Causes related to the granule:
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Causes related to the tablet press:
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Large size of granules.
Too dry granules
Tablet expands on ejection due to air entrapment
Deep concavities cause cracking while removing tablets
Too much pressure
Possible remedial action:
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Use tapered die
Use special take-off plate
Reduce compression force
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.
PICKING
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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.
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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.
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Common causes related to the granule:
› Excessive moisture in granules
› Too little or improper lubrication
› Too warm granules when compressing.
› Too much binder.
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Common causes related to the tablet press:
› Rough or scratched punch faces
› Unpolished tooling
› Insufficient pressure
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Possible remedial actions:
› Increase compression pressure
› Polish tooling by hand
› Reduce press speed
BINDING
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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
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Reason: Binding is usually due to excessive amount of moisture in granules,
lack of lubrication and/or use of worn dies.
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Causes due to worn dies:
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Possible remedial action:
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Reducing pressure in the tablet press may decrease binding.
– Poorly finished dies
– Rough dies due to abrasion
– Clean the dies properly
– If worn die is due to abrasion investigate use of other steels
Thank You
Any Questions