Problems During Tablet Manufacturing & Its Solution

Section 5
Tablet Problems and Remedies

By George E. Reier, PhD
Table of Contents
Tablet Problems and Remedies........................................................................................................1
Table of Contents .........................................................................................................................1
Part A. Specific Tableting Problems and Remedies (Process Format) ........................................5
Dry Blending .............................................................................................................................5
Particle agglomeration .........................................................................................................5
Nonuniformity of mix ............................................................................................................5
Segregation after blending ..................................................................................................6
Wet Granulation (Massing) ........................................................................................................7
Doughy mass........................................................................................................................7
Moisture sensitive drugs ......................................................................................................7
Wet Screening...........................................................................................................................8
Screen clogging....................................................................................................................8
Drying ......................................................................................................................................9
Nonuniform drying ...............................................................................................................9
Granule case hardening (hard crust forms with incomplete drying inside granule) ................9
Color migration ....................................................................................................................9
Drug migration ...................................................................................................................10
Dry Screening (Dry Granulation) ..............................................................................................11
Excess fines .......................................................................................................................11
Difficult to screen................................................................................................................11
Poor color distribution .......................................................................................................12
Feed Hopper ..........................................................................................................................13
Poor flow.............................................................................................................................13
Flooding ..............................................................................................................................14
Particle segregation............................................................................................................14
Tablet Weight .........................................................................................................................15
Weight variation outside limits ..........................................................................................15
Punches and Dies...................................................................................................................16
Punch binding (powder adheres to punch edges and dies; punches may bind in dies) ......16
Punch filming or sticking (picking)(powder adhesion to punch faces, usually upper) ......17
Punch and die abrasion .....................................................................................................18
Capping and laminating .....................................................................................................18
Chipping/splitting ...............................................................................................................19
Score line or tablet imprint not sharp ................................................................................19
Layered tablets splitting .....................................................................................................20
Layers not sharply defined ................................................................................................20
1 www.pharmatechbd.blogspot.com
Low hardness .........................................................................................................................20
Variable hardness ...................................................................................................................21
High friability ...........................................................................................................................21
Disintegration too long ...........................................................................................................22
Mottling ...................................................................................................................................22
Tablets contain dirty specks ...............................................................................................23
Tablets uniformly discolored...................................................................................................23
Part B. General Tableting Problems and Remedies (Alphabetical Order Format) ......................24
Active ingredients ...................................................................................................................24
Adsorbents ............................................................................................................................24
Agglomeration of particles .....................................................................................................24
Aging of tablets.......................................................................................................................24
Air entrapment ........................................................................................................................25
Antiadherent ..........................................................................................................................25
Attraction of particles (aggregation or agglomeration) ............................................................25
Binder ....................................................................................................................................25
Binding (bonding or compressibility) .......................................................................................26
Binding in the die (punches) ...................................................................................................26
Bioavailability ..........................................................................................................................26
Bisected or debossed tablets (not sharp or well-defined) ....................................................26
Blending .................................................................................................................................27
Bonding .................................................................................................................................27
Bridging ..................................................................................................................................27
Brittle fracture .........................................................................................................................28
Bulk density ............................................................................................................................28
Capping and laminating .........................................................................................................28
Case hardening.......................................................................................................................29
Chipping/splitting ..................................................................................................................30
Clogging of screen (wet mass) ...............................................................................................30
Coarse particles......................................................................................................................31
Color distribution ....................................................................................................................31
Color migraton........................................................................................................................31
Compressibility .......................................................................................................................31
Content uniformity ..................................................................................................................31
Density, bulk (loose density) .........................................................................................................32
Density, tapped.......................................................................................................................32
Die fill (nonuniform) ..................................................................................................................32
Diluent ....................................................................................................................................33
Dilution potential.....................................................................................................................33
Direct compression.................................................................................................................33
Disintegrant ............................................................................................................................33
Disintegration too long or incomplete....................................................................................34
Disintegration during coating .................................................................................................34
Dissolution ..............................................................................................................................35
Dosage variation.....................................................................................................................35
Doughy mass..........................................................................................................................36
Drug migration ........................................................................................................................36
Dry blending............................................................................................................................36
Dry granulation (by slugging or compaction)...........................................................................37
Dry screening..........................................................................................................................37
Dye migration..........................................................................................................................38
Ejection problem.....................................................................................................................38
Elastic material........................................................................................................................38
Entrapment of air ....................................................................................................................38
Excess fines (wet granulation) .................................................................................................38
Expanding tablets...................................................................................................................39
Filler ....................................................................................................................................39
Filming of punches .................................................................................................................39
Fines (direct compression) .......................................................................................................39
Fines (wet granulation).............................................................................................................39
Flooding ..................................................................................................................................39
Flow problem ..........................................................................................................................40
Friability (high) .........................................................................................................................40
Glidant ....................................................................................................................................41
Granulation, dry ......................................................................................................................41
Granulation, wet .....................................................................................................................41
Hard tablets ............................................................................................................................41
Hardness increases with time ................................................................................................42
Hardness, variable ..................................................................................................................42
High friability ...........................................................................................................................42
High relative humidity .............................................................................................................42
Hopper flow ............................................................................................................................42
Hygroscopic ingredients.........................................................................................................43
Hygroscopic tablets................................................................................................................43
Laminating ..............................................................................................................................43
Layered tablets splitting (poor bonding between layers; layers peel or split apart) .................43
Loss of hardness (with time) ...................................................................................................44
Loss of hardness ....................................................................................................................44
Low to medium level of active (in direct compression)...........................................................45
Lubricants ...............................................................................................................................45
Mixing ....................................................................................................................................45
Modified direct compression..................................................................................................46
Moisture sensitive actives ......................................................................................................46
Mottling ...................................................................................................................................46
Nonuniform die fill...................................................................................................................46
Nonuniform drying (tray drying) ..............................................................................................46
Nonuniformity of mix ..............................................................................................................46
Oleaginous or sticky actives ..................................................................................................47
Ordered mixing (adhesive blending) ........................................................................................47
Overblending ..........................................................................................................................48
Oven drying ............................................................................................................................48
Overwetting of wet mass .......................................................................................................48
Partial direct compression......................................................................................................48
Particle density variation .......................................................................................................48
Particle size distribution .........................................................................................................49
Picking ....................................................................................................................................49
Poor binding ...........................................................................................................................49
Poor color distribution ............................................................................................................49
Poor flow (rat-holing or bridging) .......................................................................................49
Poor granule disintegration ....................................................................................................50
Poor layer demarcation ..........................................................................................................50
Poor tablet finish/appearance ................................................................................................50
Postgranulation addition ........................................................................................................50
Powder separation .................................................................................................................50
Precompression......................................................................................................................51
Punch and die abrasion .........................................................................................................51
Punch binding (powder adheres to punch edges and dies; punches may bind in dies) ..........52
Punch filming or sticking (picking)(powder adhesion to punch faces, usually upper) ..........52
Rat-holing ..............................................................................................................................53
Relative humidity (RH).............................................................................................................53
Roll compacting......................................................................................................................54
Score line or tablet imprint not sharp ....................................................................................55
Screen clogging (wet mass)....................................................................................................55
Segregation.............................................................................................................................55
Slugging ..................................................................................................................................55
Soft tablets ............................................................................................................................56
Splitting (tablets)......................................................................................................................56
Sticking to punch face ...........................................................................................................56
Sticky ingredients ...................................................................................................................56
Tablet binding in the die .........................................................................................................57
Tablets contain dirty specks ...............................................................................................57
Tablets uniformly discolored...................................................................................................57
Underblending .......................................................................................................................57
Variable hardness ...................................................................................................................57
Weight variation (outside limits)...............................................................................................58
Wet granulation.......................................................................................................................58
Part A. Specific Tableting Problems and remedies (Process Format)
Dry Blending
Problem/Concept Cause/Definition Remedy/Suggested Solution

Particle agglomeration Occurs with fine Fine-screen cohesive compound
cohesive powders, into bulk mix
which cause balling
up and poor Use a more effective mixer (one
distribution with increased shearing action)
Blend the cohesive powder with a

portion (5% to 10%) of an excipient;
screen (mill) if necessary; reblend
and add to the bulk; blend normally
Note: For direct compression excipient

blends do not use a screen size or a
mixer, which will change the excipient
particle size distribution
Nonuniformity of mix Improper blender load Use recommended powder load in

blender
Insufficient mixing Increase mixing time
Inefficient (improper) Use alternative mixer with

mixer increased shearing action
Wide particle size Select more uniform particle sizes

distribution of components
Overblending Reduce blending time
Establish optimum mixing

conditions
Low-dosage actives Use a more effective mixer (one

with increased shearing action)
Nonuniformity of mix Low-level excipients Blend the low-level component
(continued) with a portion (5% to 10%) of an
excipient; screen (mill) if
necessary; reblend; add to an
equal quantity of excipient and
mix; screen or mill if necessary;
blend normally with remainder
of bulk
Dissolve drug in a suitable solvent

and add or spray onto a portion
of the bulk or an excipient; blend;
remove solvent
Note: For direct compression

excipient blends do not use a screen
size or a mixer, which will change the
excipient particle size distribution
Segregation after Particle size Use a narrower particle size range

blending distribution too wide of components
Wet Granulation (Massing)

Doughy mass Too much water Add granulating water slowly;
(often seen on scaleup) mix well after each addition
Overmixing during Reduce water or mixing time

granulation step
Wrong binder Change binder
Component of mix If possible, use alcohol/water or

(e.g., active drug or alcohol as granulating fluid - select
excipient) appropriate binder; use of Avicel
PH-101 gives 1) less sticky or
doughy mass which is easier to
screen; and 2) allows a wider
range of solvent volume
Moisture sensitive Instability with water If possible, use ethyl alcohol

drugs or isopropyl alcohol (if latter,
determine acceptable residual
solvent by GC or other appropriate
method) as granulating fluids,
ethyl cellulose and PVP as binders
Try slugging or roller compaction

as dry granulation methods
Wet Screening

Screen clogging Doughy or sticky wet Avoid oscillating granulator
mass
Use extrusion-type granulator
or Fitz Mill without screens
Reduce granulation time
Add 5% to 20% Avicel PH-101

(gives less sticky or doughy mass,
easier to screen)
Too much water in Reduce water content; add water

mass gradually and mix well after each
addition
Mass sensitive to Incorporate 5% to 20% Avicel

water content PH-101 (allows a wider range
of solvent volume)
Gummy binder Change binder
Component or active Use diluted or anhydrous ethyl

ingredient or isopropyl alcohol (if latter,
solvent level by GC or other
appropriate method); change
binder
Drying

Nonuniform drying Poor air circulation Have oven air circulation checked
(tray dryer) and corrected
Dryer overload Reduce number of trays
Reduce thickness of wet mass

on the trays (tray load)
Try fluid bed dryer
Granule case hardening Too rapid evaporation Try recirculating oven air (damper
(hard crust forms with of water closed) for initial 15 to 30 minutes,
incomplete drying then open damper partially for a
inside granule) Oven drying short period, and finally open
conditions too efficient damper fully
Reduce drying temperature
Add Avicel PH-101 to formulation

(gives more even water
evaporation and uniform granule
moisture content)
Use a fluid bed dryer
Color migration Colors migrate to Use lakes instead of soluble dyes

granule surfaces (wet (will minimize but not eliminate)
granulation); tablets
have mottled Decrease the size of the wet
appearance granules
Decrease thickness of granulation

bed; stir granulation bed frequently
during drying to expose fresh
surfaces at the top of the wet
mass
Use Avicel PH-101- reduces or

eliminates dye migration in wet
granulation
Drug migration Drug migrates to See remedies under Color
granule surfaces; migration
content uniformity
problems may result
as drug becomes part
of fines after dry
screening, or there is
a loss of drug with
subsequent low tablet
assays
Dry Screening (Dry Granulation)

Excess fines Granulation overdried Decrease drying time/temperature
Establish optimum moisture

content
Screen size too small Use larger screen size
Rotor/screen clearance Adjust rotor clearance

too close
Overloading of mill or Slow feed of material to mill

granulator or granulator
Weak granules Increase granulating fluid
Increase binder content
Increase wet massing time
Difficult to screen Granules too hard Decrease drying temperature

(case hardening)
Decrease water content

(use alcohol/water)
Decrease binder content
Use weaker binder
Moisture in granulation Increase drying time

content
Poor color distribution Dye migration to Use lakes instead of soluble dyes
granule surface (will minimize but not eliminate
(nonuniformity of problem)
color throughout
granule) Decrease the size of the wet
granules
Decrease thickness of granulation

mass
Use Avicel PH-101- reduces or

eliminates dye migration in wet
granulation
Feed Hopper

Poor flow Too many fines in wet Reduce fines (see Dry screening:
granulation Excess fines)
rat-holing
bridging In direct compression, Select larger particle size; use

particle size of drug or Avicel PH-102 or PH-200 in place
excipients too small of PH-101 or other excipient
and/or of shape that
will not flow Add glidant (0.1% to 0.5%)
(e.g., Cab-O-Sil, Aerosil
Use induced or force-feed

mechanism on press
Change particle shape of active

ingredient to one that is more likely
to flow
Poor inherent flow Add 0.1% to 0.5% glidant
Dry granulate (by slugging or roller

compacting) with a mixture of
Avicel PH-101, Cab-O-Sil ,
and magnesium stearate
Atmospheric moisture Process in low humidity

adsorption atmosphere
Add moisture absorber (e.g.,

0.1% to 0.5% calcium silicate,
Cab-O-Sil, Syloid)
Flooding Excessive flow Identify causative component and
properties (fluidization) exclude or modify particle size
of one or more
components (could be Select narrow range of particle
from an excess of sizes; avoid excess fines
glidant or lubricant)
Flow is erratic and Use an induced or force-feed

feed frame is flooded mechanism on press, which may
at times control flow
Particle segregation Particle size range of Use a narrower particle size range
mix too wide of ingredients
See Dry screening: Excess fines
Too wide a density Control differences in density of

difference in mix particles
particles
Mixer too vigorous; Use a mixer with a gentler mixing

produces fines action
Use of vibrators Use force-flow feed mechanisms

(to promote flow from rather than hopper vibrators
hopper)
Excessive machine Isolate hopper from tablet machine

vibration
Table Weight

Weight variation Poor or erratic powder Correct powder flow problem
outside limits flow, flooding (See Feed hopper)
Particle size range too Narrow the particle size range;

wide avoid excess fines
Use Avicel PH-200 to minimize
weight variation
Particle size not Adjust particle size range to

suitable for die recommended optimum for die
diameter diameter
Punches not within Examine punch length dimensions

specifications
Particle segregation as Narrow the particle size range

press RPMs increase
Compress at slower RPM
Lower punch hang up Clean; improve dust collection

(material between lower
punch and die wall or Check for proper clearance
lower punch and punch between die wall and lower punch
guide)
Increase lubricant concentration
in formulation
Remove below 200 mesh fines
Punches and Dies

Punch binding (powder Poor finish or worn Polish, reface, or replace tooling
adheres to punch punches and dies
edges and dies Increase or change lubricant; use
punches may bind in Inadequate lubrication microfine lubricants; screen into
dies) mix
Increase lubricant blending time
Too many fines or Design better particle size range;

coarse particles in mix use tapered dies
Wet granulation Dry granulation to satisfactory

insufficiently dried moisture limits
Hygroscopic Process under low humidity

ingredients conditions
Use moisture scavengers (e.g.,

calcium silicate, Syloid,
Cab-O-Sil)
Adhesive components Increase lubricant level
Add 0.5% Cab-O-Sil or Syloid
Add 5% to 10% low moisture

grades Avicel PH-112 and
PH-113
Punch filming or Poor finish on punch Polish punch faces; refinish
sticking (picking) faces
(powder adhesion to Avoid using certain letters
punch faces, usually Embossed letters (e.g., A, B, P, R)
upper)
Use shallow embossing with
tapered edges rather than edges
directly perpendicular to punch
face
Punch tips burred Refinish or replace
Punch concavity too Reduce punch concavity or use

great flat face punches
Poor binding between Increase binder (wet or dry)

surface granules or
particles
Low melting point Adsorb low melting point

ingredient ingredient on Avicel, replace with
higher melting point ingredient
Inadequate lubrication Increase or change lubricant
Use microfine lubricants, screen

into mix
Increase lubricant mixing time
Insufficiently dried wet Dry granulation and establish

granulation moisture limits
Hygroscopic Process under low humidity

components conditions
Use moisture adsorbent

(e.g., calcium silicate, Syloid)

or 5% to 10% Avicel PH-101
Tablets too soft Increase compression pressure
Punch and die abrasion Abrasive components Exclude or reduce to a fine particle
size
Increase lubricant level
Blend abrasive component directly

with the lubricant
Use minimum tableting pressure

possible
Use more wear-resistant tooling

(harder metal)
Capping and laminating Inadequate bonding Use a stronger binder or additional

of the powder binder
Capping is separation of particles (direct
the top or bottom from compression) or Avicel PH-101 and PH-102
the main body of the granules (wet are particularly effective direct
tablet. granulation) to form compression binders (15% to
cohesive tablets 25%) and as auxiliary binders
Laminating is transverse in wet granulation (5% to 15%)
cracking and separation
of the tablet into two or
more layers.
Poor finish or worn Polish, reface, or replace
punches and dies
Chrome plate punch faces
Too many fines in
granulation Modify granulation process for
minimum fines
Granulation too dry
Adjust moisture level and establish
optimum moisture limits
Granulation too wet Continue to dry and establish

(usually associated optimum moisture limit
with sticking or
picking)
Overlubrication of Decrease lubricant level

final tableting mix
Blend lubricant for minimal time
required; establish optimum mixing
time
Capping and laminating High level of Use precompression on tablet
(continued) ingredient with poor press
compression
properties (also Slow the speed of the tablet
sometimes ascribed machine
to air-entrapment by
powder bed)
Punch concavity too Change to standard concave

deep or flat face punches
Punch edges worn or Refinish or replace

damaged
Lower punch too low Adjust lower punch flush with

at tablet take-off die face
Compression too low Compress in upper portion of

in die cavity die
Excessive tableting Decrease pressure

pressure
Die wall binding Use sufficient lubricant
Use tapered dies
Chipping/splitting Poor finish or worn Polish, reface, or replace punches

punches and dies and dies
Lower punch setting Adjust lower punch flush with

too low at tablet die face
takeoff
Tablet sweep-off Adjust setting

blade on feed frame
set too high
Score line or tablet Faulty punch Redesign using tapered sides

imprint not sharp debossing design on the punch debossing
Chrome-plate punch face
Granulation too Reduce particle size of granulation

coarse
Binder not strong Use a stronger binder

enough
Layered tablets Poor bonding Use a stronger binder or higher
splitting between layers concentration
Compression Compress at lower pressures

pressure too high
Overlubrication Decrease lubricant level

required; do not blend for long
periods of time
Layers not sharply Granulation too Reduce particle size of granulation

defined coarse - less than 16 mesh
Too many fines Remove fines below 200 mesh
Low hardness Compression force Increase pressure (caution: do not

(pressure) too low exceed recommended pressure
for punch size used)

time
Replace metallic stearates with

other lubricants (e.g., stearic acid)
Granulation too soft Use additional binder
Direct compression - use

additional Avicel PH
Excipient (i.e., too Reduce level of causative
much starch can give excipient
a soft tablet)
Low hardness Moisture consent too Determine optimum moisture
(continued) high (granulation content
underdried or high
humidity in Use moisture adsorbent (e.g.,
compressing area) calcium silicate, Syloid)
Moisture content too Determine optimum moisture
low (granulation content
overdried or low
humidity in Add additional moisture
compressing area)
Variable hardness Tooling Examine punch lengths
Uneven diefill See Table Weight: Weight

variation
Overblending Optimize blending time to

minimize creation of fines
High friability Inadequate bonding Increase binder level or change

of the tablet mix to stronger binder
Add or increase Avicel PH-101

or PH-102 (10% to 20%)
Avicel PH gives low friability at

lower hardness/machine pressures
Too much or too little Adjust pressure for acceptable

compression pressure friability

time

Disintegration too long Tablet hardness too Reduce machine pressure for
high acceptable tablets
Use less binder in granulation

(waterproofing) Blend lubricant for minimal time
time

Requires additional Consider a super disintegrant

disintegrant or a (e.g., Ac-Di-Sol, 2% to 5%)
different disintegrant
Include Avicel PH-101 or PH-102
(added dry), about 10% as an
auxiliary disintegrant
Consider adding a surfactant (e.g.,

DOSS, 0.1%)
Tablet hardness too Increase hardness to allow

low swellable disintegrant to function
Mottling Uneven distribution of Increase mixing time or use high

the dye in colored shear mixer
tablets
Dye migration during See Drying: Color migration

drying process
See Dry screening: Poor color
distribution
Preferential Replace causative component

absorption of soluble
dye by component of Replace soluble dye with microfine
mix lake pigment
High level of Reduce quantity of additives

uncolored additives
(e.g., fillers, lubricants, Color additives with soluble dye
disintegrants) or mix with lake pigment
Mottling In direct compression, Use microfine lake dye
(continued) uneven distribution of
lake dye Increase blending time
Mill lake dye with 5% excipient,

then blend with bulk
Reduce size of larger particles

of excipient or active
Use lower drying temperature
Tablets contain dirty Misaligned upper cam Check alignment of upper cam
specks tracks - rubbing of tracks
punches on cam
actually rubs off metal
which is introduced
into material being
compressed
No lubrication on
upper cam tracks
Excessive or improper Use dust caps on upper punches

lubrication on upper
punch shanks (no dust
caps on punches) -
dust mixes with excess
oil or grease and falls
into material being
compressed
Tablets uniformly Feed frame rubbing Check clearance between feed

discolored on die table frame and die table
Feed hopper rubbing Check clearance between feed

on turret hopper and turret
Abrasive materials Check for presence of abrasive

wearing screens, materials
scooper, etc.
Part B. General Tableting Problems and Remedies
(Alphabetical Order Format)

Active ingredients See Sticky ingredients
See Low to medium level

of active
See High percent active
See Attraction of particles
See Dosage variation
See Density
See Elastic material
Adsorbents Materials used to Use starch, Avicel PH-101,

overcome oiliness or silicon dioxide (Syloid) or
stickiness of tablet tribasic calcium phosphate
ingredients
Agglomeration of Occurs with fine Fine-screen cohesive compound

particles cohesive powders into bulk mix
causing "balling" or
lump formation and Use a more effective mixer (one
poor distribution of with increased shearing action)
the powder
Blend the cohesive powder with
a portion (5% to 10%) of an
excipient; screen (mill) if
necessary; reblend and add to
the bulk; blend normally
Note: For direct compression

excipient blends do not use a
screen size or a mixer, which will
change the excipient particle size
distribution
Aging of tablets See Loss of hardness (with time)
24
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Air entrapment Very low density See Capping and laminating
materials with very
high porosity See Binding
(sometimes ascribed
as cause for tablet
capping, splitting,
or laminating)
Antiadherent Materials that aid in See Section 4 for a description

preventing the tablet of excipients and their uses
mix from sticking to
punch faces
Attraction of particles Fine cohesive Modify particle size distribution

(aggregation or powders
agglomeration)
Static electricity Mechanically disperse
Drain off static charge
Low relative humidity Slightly increase moisture level
See Blending
Densify as last resort
Binder Wet granulation - See Section 4 for a description

substances which are of excipients and their uses
added in solution
(usually) or sometimes
dry, followed by
granulating solvent to
glue a powder mix
into granules for solid
dose preparation
Direct compression -
substances which give
compressibility or
cohesiveness to the
powder mix
25
Binding (bonding or Relative degree of See Blending
compressibility) cohesiveness
between particles or Be careful not to overblend or
granules overlubricate
Compressibility of Optimize particle size and particle

active ingredients size distribution of active and
determines (to some excipients
extent) the percent
that can be Use excipients which are
incorporated into a compressible and designed for
direct compression direct compression process
formulation
Determine that granulation and/or
Particular binder and other excipients have proper
concentration moisture content
influences degree of
binding and tablet
hardness
Binding in the die See Punch binding

(punches)
Bioavailability The rate and extent to See Dissolution

which an active
ingredient is absorbed Use up to 50% soluble filler
in-vivo (lactose, dextrose) with insoluble
drugs (direct compression)
May or may not be

correlated with
dissolution
Bisected or debossed Poor design on Redesign tooling, consult tooling

tablets (not sharp or tooling supplier
well-defined)
Increase binder in formulation
26
Blending Mixing of powders to Optimize blending or mixing time
obtain a homogeneous
mixture (for
compression)
Optimized blending
may depend on type
of mixer (low shear,
high shear, etc.)
Overblending is
probably more
common than
underblending
Overblending causes
overdistribution of the
lubricant which can
result in poor
disintegration/
dissolution, poor
compressibility,
demixing
(segregation)
Bonding See Binding
Bridging Lack of powder See Die fill

fluidity; actual
stoppage of powder See Flow problems
flow as powder
compacts in hopper
or feed-frame
27
Brittle fracture Bonding mechanism See Section 2 for a discussion
of some materials of compression mechanisms
(e.g., lactose), in which
single particles fracture
under pressure to
produce multiple
particles having clean
surfaces, which then
bond with each other
to form a compact
Bulk density See Density, bulk
Capping and laminating
Capping is separation of Inadequate bonding Use a stronger binder or additional

the top or bottom from of the powder binder
the main body of the particles (direct
tablet. compression) or Avicel PH-101 and PH-102 are
granules (wet particularly effective direct
Laminating is transverse granulation) to form compression binders (15% to
cracking and separation cohesive tablets 25%) and as auxiliary binders in
of the tablet into two or wet granulation (5% to 15%)
more layers. Poor finish or worn
punches and dies Polish, reface, or replace
Chrome-plate punch faces
Too many fines in Modify granulation process for

granulation minimum fines
Granulation too dry Adjust moisture level and establish

optimum moisture limits
Granulation too wet Continue to dry and establish

(usually associated optimum moisture limit
with sticking or
picking)
Overlubrication of Decrease lubricant level

final tableting mix
time
28
Capping and laminating High level of Use precompression on tablet
(continued) ingredient with press
poor compression
properties (also Slow the speed of the tablet
sometimes ascribed machine
to air-entrapment by
powder bed)
Punch concavity too Change to standard concave or

deep flat-face punches
Punch edges worn or Refinish or replace

damaged
Lower punch too low Adjust lower punch flush with
at tablet take-off die face
Compression too low Compress in upper portion of die

in die cavity
Excessive tableting Decrease pressure

pressure
Die wall binding Use sufficient lubricant
Use tapered dies
Case hardening Rapid evaporation of Try recirculating oven air (damper

water, which forms closed) for initial 15 to 30 minutes
hard outer crust often then open damper partially for a
associated with short period and finally open
incomplete drying damper fully
inside granules
Reduce drying temperature
Oven drying
conditions too efficient Add Avicel PH-101 to formulation
(gives more even water evaporation
and uniform granule moisture
content)
Use a fluid bed dryer
29
Chipping/splitting Poor finish or worn Polish, reface, or replace punches
punches and dies and dies
Lower punch setting Adjust lower punch flush with

too low at tablet take- die face
off
Tablet sweep-off Adjust setting

blade on feed frame
See Capping and laminating
See Binding/bonding
Clogging of screen Doughy or sticky wet Avoid oscillating granulator

(wet mass) mass
Use extrusion-type granulator
or Fitz Mill without screens
Reduce granulation time

(gives less sticky or doughy mass,
easier to screen)
Too much water in Reduce water content; add water

mass gradually and mix well after each
addition
Mass sensitive to Incorporate 5% to 20% Avicel

water content PH-101 (allows a wider range of
water volume, gives shorter,
less doughy, less sticky mass)
Gummy binder Change binder
Active ingredient Use diluted or anhydrous ethyl

or isopropyl alcohol (if latter,
solvent level by GC or other
appropriate method); change
binder
30
Coarse particles Mottled appearance Design particle size distribution for
in direct compression optimum flow, color distribution,
binding
Segregation Some fines are needed for good

binding
Color distribution Dye migration leading In direct compression, preblend or

to mottling mill color with portion of excipient
In wet granulation, use a dye

soluble in the granulating solution
May help to use a lower

temperature for tray drying; use a
fluid bed dryer
See Color migration
Color migration Colors migrate to Use lakes instead of soluble dyes

granule surface (will minimize but not eliminate)
(wet granulation);
will cause mottling Decrease the size of the wet
tablets; often granules
associated with
case hardening Decrease thickness of granulation
mass
Use Avicel PH-101- reduces

or eliminates dye migration
Compressibility See Binding (bonding or

compressibility)
Content uniformity See Dosage variation
Demixing Segregation/ Optimize blending times specific

separation, usually to mixer (blender) employed
caused by overmixing
rather than See Overblending
undermixing
See Segregation
31
Density, bulk Usually defined as the See Flow
(loose density) ratio of weight of a
powder (or mixture of See Die fill
powders) to its volume
on an as-is basis See Dry granulation
(not tapped)
Select higher density grades
Low bulk density often Avicel PH-301 and PH-302
related to poor flow
especially at high
dosage (active)
Density, tapped Usually defined as the See Segregation

ratio of weight of a
powder (or mixture of
powders) to its volume
after being tapped or
caused to consolidate
(settle) in some way
Too dense can

cause segregation
Die fill (nonuniform) Lack of consistent Adjust particle size range to

powder flow into dies, recommended optimum for die
causing variations in diameter
tablet weight, hardness,
and disintegration/ Reduce fines
dissolution
Select larger particle size; use
Avicel PH-102 or PH-200 in place
of PH-101 or other excipient
Add glidant (0.1% to 0.5%) (e.g.,

Cab-O-Sil, Aerosil)

mechanism on press

ingredient to one that is more likely
to flow
32
Die fill (nonuniform) Dry granulate (by slugging or roller
(continued) compacting) with a mixture of
Avicel, Cab-O-Sil and magnesium
stearate
Process in low humidity atmosphere

Cab-O-Sil, Syloid)
Diluent Inert material(s) See Section 4 for a description

added to give the of excipients and their uses
necessary bulk for
solid dosage
preparation
Dilution potential The percent of an Avicel PH has a very high dilution

active (usually poorly potential when used as a binder
compressible such
as ascorbic acid or
APAP) that can be
compressed with an
excipient to form a
tablet having 1% or
less friability
Direct compression Method of See Sections 2 - 4

manufacturing tablets
by compressing
directly a dry blend of
active and excipient
powders; the powders
are neither wet or dry
granulated
Disintegrant Material added to See Section 4 for a description

tablets to aid them in of excipients and their uses
breaking apart so that
particles of drug can
dissolve
33
Disintegration too long Tablet hardness too Reduce machine pressure for
or incomplete high acceptable tablets
Use less binder in granulation

(waterproofing)
required; establish optimum
blending time

Requires additional Consider a super disintegrant

disintegrant or a (e.g., Ac-Di-Sol, 2% to 5%)
different disintegrant
Include Avicel PH-101 or PH-102
(added dry), about 10% as an
auxiliary disintegrant
Consider adding a surfactant

(e.g., DOSS, 0.1%)
Tablet hardness too Increase hardness to allow

low swellable disintegrant to function
Disintegration during Caused by soft cores Increase tablet strength (increase

coating or rapidly binder, add better binder,
disintegrating tablets compress harder)
Apply a seal coat

(Aquacoat ECD)
If possible, lower spray rate of

aqueous coating
34
Dissolution Measure of the rate Use most soluble form of drug
and extent to which
an active component Micronize insoluble drugs - in
is released into general, use smallest particle
solution from a drug size possible
product
Consider using a wetting agent
May or may not be Add additional disintegrant or a

correlated with different disintegrant - granules
bioavailability must disintegrate for good
dissolution
Poor dissolution Optimize tablet hardness versus

friability and disintegration/
dissolution
Conduct preformulation studies

to be certain there is no
active/excipient interaction
(binding)
Use a soluble filler with insoluble

actives
Use less lubricant, establish

optimum blending time
See Bioavailability
See Disintegration
Dosage variation Improper See "Blending, overblending

mixing/segregation and demixing"
See Flow problem
See Segregation
See Die fill (nonuniform)
See Nonuniformity of mix
35
Doughy mass Too much water Add granulating water slowly;
(often seen on mix well after each addition
scaleup)
Overmixing during Reduce water or mixing time

granulation step
Wrong binder Change binder
Component of mix If possible, use alcohol/water

(e.g., active drug or or alcohol as granulating fluid -
excipient) select appropriate binder, use of
Avicel PH-101 gives 1) less sticky
or doughy mass, which is easier
to screen; and 2) allows a wider
range of solvent volume
Drug migration Drug migration to See Color migration

surface of granulation
May lead to content

uniformity problems
as drug becomes part
of fines after dry
screening, or there is
a loss of drug with
subsequent low tablet
assays
Dry blending See Section A: Dry blending
36
Dry granulation Method for See Section 2
(by slugging or compacting powders
compaction) by slugging or roller See Slugging
compaction and then
size reducing the See Roll compaction
compacts to the
desired particle size
for tableting
Often preferred when

1) it is difficult or
impossible to directly
compress; and 2) the
actives are unstable
when subjected to wet
granulation
Dry screening Granules too hard Decrease drying temperature

(case hardening)
Decrease water content (use

alcohol/water)
Decrease binder content
Use weaker binder
Moisture in Increase drying time

granulation
content
Drying Overdrying can cause Set in-process moisture

static flow, case specifications on wet granulated
hardening, drug/color materials
migration, lamination/
capping/splitting See Section A: Drying
Underdrying can See Section A: Drying

cause weak granules
filming, and sticking Control moisture in direct
of punches compression excipients for proper
compressibility
37
Dye migration See Color migration
Ejection problem See Punch binding
Elastic material Actives or excipients Use materials that have plastic

that are deficient in flow (low in elasticity) and that,
plastic flow properties, once compressed, stay
and therefore lack compressed (do not spring
bonding or binding back), such as Avicel PH
properties
Often are springy or

spongy and have
spring back:
characteristics (i.e.,
return to original
size/shape)
Results in capping,
lamination, splitting,
and lack of
compressibility in
general
Entrapment of air See Air entrapment
Excess fines Low moisture in Decrease drying time; establish

(wet granulation) granulation optimum moisture content
Screen size too small Use larger screen size

(dry screening)
Rotor/screen Adjust clearance of rotor

clearance too close
Overloading Feed granulator gradually

granulator or mill
Weak granules Increase binder content/

granulating fluid
Increase wet massing time
Use stronger binder
38
Expanding tablets See Elastic material
See Active ingredients
See Binding
Filler Inert material(s) See Section 4 for a description

added to give the of excipients and their uses
necessary bulk for
solid dosage
preparation
Filming of punches See Punch filming or sticking

(picking)
Fines (direct Poor flow An optimum percent of fines

compression) serves a useful purpose of dusting
Improper die fill the actives, especially oleaginous
ones or those with elastic
Poor binding deformation properties, and aids in
in bonding and filling voids within
the tablet
Too many cause segregation
Fines (wet granulation) See Excess fines (wet granulation)
See Fines (direct compression)

above
Flooding Excessive flow Identify causative component and

properties exclude or modify particle size
(fluidization) of one or
more components Select narrow range of particle
(could be from an sizes; avoid excess fines
excess of glidant or
lubricant) Induced or force-feed mechanism
on press may control flow
Flow is erratic and
feed frame is flooded See Flow problem
at times
39
Flow problem Too many fines in wet Reduce fines (see Dry Screening-
granulation Excess fines)
In direct compression, Select larger particle size; use

particle size of drug or Avicel PH-102 or PH-200 in place
excipients too small of PH-101 or other excipient
and/or of shape that
will not flow Add glidant (0.1% to 0.5%), e.g.,
Cab-O-Sil, Aerosil

mechanism on press

ingredient to one that is more
likely to flow
Poor inherent flow Add 0.1% to 0.5% glidant
Dry granulate (by slugging or roller

compacting) with a mixture of
Avicel, Cab-O-Sil, and
magnesium stearate
Atmospheric moisture Process in low humidity

absorption atmosphere

Cab-O-Sil, Syloid)
Friability (high) Inadequate bonding Increase binder level or change to

of the tablet matrix stronger binder
Add or increase Avicel PH-101

or PH-102 (10% to 20%), which
give low friability at lower
hardness/machine pressures
Too much or too little Adjust pressure for acceptable

compression pressure friability
40
Friability (high) Overlubrication Decrease lubricant level
(continued) Blend lubricant for minimal time
required; establish optimum
blending time

Glidant Excipient used to See Section 4

improve fluidity of
powders Add 0.1% to 0.5% Cab-O-Sil or
Aerosil fumed silica to improve
flow
Small increase in lubricant may be

necessary to offset slight punch/die
binding effect of glidant
Granulation, dry See Dry granulation
See Section 2
Granulation, wet See Wet granulation
See Section 2
Hard tablets Use Avicel to obtain hard tablets

with low machine pressure - also
to reduce tablet friability
See Binding (bonding or

compressibility)
Decrease compressing speed

to increase tablet hardness
41
Hardness increases Probably more Optimize moisture consent
with time prevalent in wet of granulations
granulated products,
although it can Conduct preformulation studies,
happen in directly even though data at accelerated
compressed tablets temperature/ humidity conditions
may not always be relevant to
Can be caused by shelf-life conditions
water of crystal-
lization/hydration
interacting with
ingredients or other
kinds of interactions
between active
materials/excipients
Hardness, variable Tooling Examine punch lengths
Uneven die fill See Weight variation
Overblending Optimize blending time to minimize

creation of fines
High friability See Friability (high)
High level of active Direct compression High percentages of actives can be

directly compressed depending on
physical form (low density,
entrapped air, etc.), flow, and
compressibility properties
Dry/wet granulation If unable to compress directly, dry

granulation or wet granulation are
possible alternatives depending on
active's physical properties
High relative humidity See Relative humidity
Hopper flow See Die fill
See Flow Problem
See Segregation
42
Hygroscopic Moisture pick-up Process under low humidity
ingredients conditions
Compress with low moisture grades

Avicel PH-112 and PH-113
Cab-O-Sil)
Hygroscopic tablets Moisture pick-up Compress and package underlow

humidity conditions (to maintain
tablet hardness and active
ingredient stability)

Cab-O-Sil)
Keep tablet containers well closed

(use adequate closures especially
if plastic or blister packed)
Laminating See Capping and laminating
Layered tablets Poor bonding Use a stronger binder or higher

splitting (poor bonding between layers concentration
between layers; layers
peel or split apart)
Compression Compress at lower pressures
pressure too high

times
See Lubricants
43
Loss of hardness Tablets with Avicel PH See Hygroscopic ingredients
(with time) lose some hardness
with time at high See Hygroscopic tablets
humidity, but most of
the hardness is quickly
regained at normal
humidity
Low hardness Compression force Increase pressure (caution - do not

(pressure) too low exceed recommended pressure for
punch size used)

times

Granulation too soft Use additional binder
Direct compression - use additional

Avicel PH
Excipient (i.e., too Reduce level of causative excipient

much starch can give
a soft tablet)
Moisture content too Granulation underdried

high
High humidity-use moisture
scavenger or moisture adsorbent
(e.g., calcium silicate, Syloid)
Moisture content too Granulation overdried

low
Low humidity-direct compression
excipients too low in moisture
content
44
Low to medium level Use 10% to 20% Avicel PH
of active (in direct combined with compressible
compression) lactose and/or dicalcium phosphate
With higher levels of Avicel PH use

less magnesium stearate, since
Avicel PH is self-lubricating
At low-dosage level-blend or mill

active with part (e.g., 10% of
excipient) and then blend with
remainder of formulation
At very low-dosage levels (<1%),

dissolve active in solvent and spray
on excipients
Lubricants Materials added to See Section 4 for a description of

reduce friction excipients and their uses
between the die wall
and the tablet mix, See Punch binding
and hence facilitate
ejection of the tablets Add lubricant at end of blending
from the die operation-do not overblend
Screen into bulk powders through a

40- to 60-mesh screen prior to final
mixing
If disintegration/dissolution is a
problem with magnesium stearate,
use stearic acid (1% to 2%)
With higher levels of Avicel PH use

less magnesium stearate (since
Avicel PH is self-lubricating)
Mixing See Blending
See Section A, Dry blending
45
Modified direct Modification of direct Dissolve actives in volatile solvents
compression compression process and spray onto excipients
to assure good
dispersion of low-level Granulate a small portion of the
actives or for other formulation and directly compress
reasons this granulation with the remainder
(major part) of the formulation
Avoids granulation of ingredients
entire formulation
Moisture sensitive Unstable in the Use direct compression or dry

actives presence of water granulation
Use low moisture grades Avicel

PH-112 and PH-113
Use nonaqueous granulating

solvent (flammability and residual
solvent cautions must be observed)
Mottling See Color distribution
Nonuniform die fill See Diefill (nonuniform)
Nonuniform drying Poor air flow Correct air circulation pattern

(tray drying) (circulation)
Reduce number of trays
Overloaded trays Reduce tray load
See Drying
Nonuniformity of mix Improper blenderload Use recommended powder load

in blender
Insufficient mixing Increase mixing time
Inefficient (improper) Use alternative mixer with increase

mixer shearing action
Wide particle size Select more uniform particle sizes

distribution of components
Overblending Reduce blending time
Establish optimum mixing

conditions
46
Nonuniformity of mix Low-dosage actives Use a more effective mixer (one
(continued) with increased shearing action)
Low-level excipients Blend the low-level component with

a portion (5% to 10%) of an
excipient; screen (mill) if necessary;
reblend; add to an equal quantity of
excipient and mix; screen or mill if
necessary; blend normally with
remainder of bulk
Dissolve drug in a suitable solvent

and add or spray onto a portion of
the bulk or an excipient; blend;
remove solvent
Note: For direct compression excipient

blends do not use a screen size or a
mixer which will change the excipient
particle size distribution
Oleaginous or sticky See Punch binding

actives
See Sticky ingredients
Ordered mixing Small-sized (drug) See Section 2

(adhesive blending) particles adhesively
held on the surface of
larger-sized
(excipient) particles
Segregation does not

occur
Usually requires a
high-intensity mixer
47
Overblending Can cause powder Optimize mixing times
separation
(segregation or See Blending
demixing)
Can cause particle

size reduction leading
to other problems
Can cause
waterproofing of
tablet by lubricant
Oven drying See Drying
Overwetting of A common problem in See Clogging of screen

wet mass wet granulation
Some actives alone

and in combination
with excipients are
more sensitive than
others (due to
solubility)
Partial direct See Modified direct compression

compression
Particle density See Density, bulk (loose density)

variation
See Density, tapped
See Punch binding
48
Particle size See Binding (bonding or
distribution compressibility)
See Flooding
`See Flow problem
See Ordered mixing (cohesive

blending)
See Segregation
Picking Tablet surfaces See Punch filming or sticking

pitted
Small areas of
compressed powder
left on punch faces
(mostly upper) after
compression - tablet
surface is picked
Often associated with

punch filming and
sticking
Poor binding See Binding (bonding or

compressibility)
Poor color distribution See Color distribution
See Color migration
Poor flow (rat-holing See Flow problem

or bridging)
49
Poor granule Wet granulation Granules must be disintegrated
disintegration for prompt and full drug release
(dissolution)
Include a portion (50%) of the

disintegrant (Ac-Di-Sol) for this
purpose in the materials being
granulated (disintegrant inside
the granulation)
Poor layer demarcation Granulation too Reduce particle size of

course granulation - less than 16 mesh
Too many fines Remove fines below 200 mesh
Poor tablet Picking See Filming of punches

finish/appearance
Mottling See Color distribution
Coarse particles See Coarse particles
Postgranulation Excipients added after See Sections 2 and 4

addition drying the granules
and screening them
Examples: disintegrant,
lubricant, additional
binder
Powder separation See Coarse particles
See Demixing
See Flow problem
See Overblending
See Segregation
50
Precompression Application of a See Section 3
relatively small
amount of tableting
pressure immediately
prior to application of
main tableting
pressure
Aids in removing
entrapped air
Aids in preventing/
minimizing capping/
laminating of difficult-
to-compress materials
by allowing time for
relaxation between
compressions
Requires a rotary
tablet machine
equipped for
precompression
Punch and die abrasion Abrasive components Exclude or reduce to a fine particle
size
Increase lubricant level
Blend abrasive component

separately with the lubricant
Use minimum tableting pressure

possible
Use more wear-resistant tooling

(harder metal)
51
Punch binding (powder Poor finish or worn Polish, reface or replace tooling
adheres to punch punches and dies
edges and dies, Increase or change lubricant; use
punches may bind Inadequate lubrication microfine lubricants; screen into
in dies) mix
Increase lubricant blending time
Too many fines or Design better particle size range;

coarse particles in mix use tapered dies
Wet granulation Dry granulation to satisfactory

insufficiently dried moisture limits
Hygroscopic Process in low humidity conditions

ingredients
Cab-O-Sil)
Use low moisture grades

Avicel PH-112 and PH-113
Adhesive or Increase lubricant level

oleaginous
components Add 0.5% Cab-O-Sil or Syloid
Punchfilming or Poorfinish on punch Polish punch faces; refinish

sticking (picking) faces
(powder adhesion to Avoid using certain letters (e.g.,
punch faces, usually Embossed letters A, B, P, R)
upper)
Use shallow embossing with
tapered edges rather than edges
perpendicular to punch face
Punch tips burred Refinish or replace
Punch concavity too Reduce punch concavity or use

great flat-face punches
Poor binding between Increase binder (wet or dry)

surface granules or
particles
Low melting point Adsorb low melting point ingredient

ingredient on Avicel PH, replace with higher
melting point ingredient
52
Punch filming or Inadequate lubrication Increase or change lubricant
sticking
(continued) Use microfine lubricants, screen
into mix
Increase lubricant mixing time
Insufficiently dried wet Dry granulation and establish

granulation moisture limits
. Hygroscopic Process under low humidity

components conditions
Use moisture adsorbent (e.g.,

calcium silicate, Syloid)

or 5% to 10% Avicel PH-101
Tablets too soft Increase compression pressure
Rat-holing Limited flow of a See Bridging

powder or mixture
directly over the See Die fill (nonuniform)
discharge of a hopper,
leaving a hole in the See Flow problem
center of the powder
as flow slows or stops See Glidant
Part of the remaining

powder, which is
around the hole, may
fall into the hole with
the net result being
an uneven flow of
powder and/or lumps
from the hopper
Relative humidity (RH) Ratio of the amount of Keep tableting area <55% RH-
water the air is holding higher RH can cause flow problems
to the amount it could and sticking depending on
hold (at saturation) at a materials present
given temperature
53
Relative humidity (RH) Raising the Keep tableting area >40% to 45%
(continued) temperature, all other RH - lower humidity can cause flow
things remaining because of static and drying out of
constant, lowers the material being compressed with,
relative humidity but perhaps, some loss of
the absolute amount compressibility
of water present is
the same See Hygroscopic ingredients
See Hygroscopic tablets
Roll compacting Forcing powder See Section 2

(almost always a
formulation containing Use Avicel PH-101
filler, lubricant, and
disintegrant) between
two oppositely turning
rolls in order to form a
dense compact in the
form of a relatively flat
sheet as it exits the
rolls
The sheet (which often

breaks under its own
weight as it exits the
rolls) is milled to form
granules, which can
then be used for
tableting after adding
additional lubricant,
disintegrant, etc.
54
Score line or tablet Faulty punch Redesign using chamfered edges
imprint not sharp embossing design on the punch embossing
Chrome-plate punch face
Granulation too Reduce particle size of granulation

coarse
Binder not strong Use a stronger binder

enough
Screen clogging See Clogging of screen (wet mass)

(wet mass)
Segregation Particle size range of Use a narrower particle size range

mix too wide of ingredients
Limit the amount of the fines present
Too wide a density Control differences in the density

difference of particles
Mixer too vigorous, Use a mixer with a gentler mixing

produces fines action
Use of vibrators (to Use force-feed mechanisms rather

promote flow from than hopper vibrators
hopper)
Slugging Use of relatively large See Dry granulation

punches and dies to
produce tablets from
a poor flowing powder
mix
Tablets usually not

well-controlled with
respect to weight
and hardness
55
Slugging (continued) Tablets milled to
produce granules
which can then be
used (after adding
additional lubricant,
disintegrant, etc.)
to produce uniform
tablets of desired
size, weight,
hardness, etc.
Soft tablets See Binding (bonding or

compressibility)
See Coarse particles
See Elastic material
See Excess fines (wet

granulation)
See Friability (high)
See Hardness, variable
See Loss of hardness (with time)
See Low hardness
Splitting (tablets) See Capping and laminating
See Chipping/splitting
Sticking to punch face See Punch filming or sticking
Sticky ingredients Fines in excipient mix (especially

Avicel PH) aid in drying up
oleaginous actives, giving better
flow and tableting
See Punch filming or sticking
See Punch binding
56
Tablet binding See Punch binding
in the die
Tablets contain dirty Misaligned upper cam Check alignment of upper cam
specks tracks - rubbing of tracks
punches on cam
actually rubs off metal,
which is introduced
into material being
compressed
No lubrication on
upper cam tracks
Excessive or improper Use dust caps on upper punches

lubrication on upper
punch shanks (no dust
caps on punches) -
dust mixes with excess
oil or grease and falls
into material being
compressed
Tablets uniformly Feed frame rubbing Check clearance between feed

discolored on die table frame and die table
Feed hopper rubbing Check clearance between feed

on turret hopper and turret
Abrasive materials Check for presence of abrasive

wearing screens, materials
scooper, etc.
Underblending See Blending
Variable hardness Tooling Examine punch lengths
Uneven die fill See Weight variation
Overblending Optimize blending time to

minimize creation of fines
57
Weight variation Poor or erratic powder Correct powder flow problems
(outside limits) flow, flooding (See Feed Hopper in Part A)
Particle size range too Narrow the particle size range;

wide avoid excess fines
Particle size not Adjust particle size range to

suitable for die recommended optimum for die
diameter diameter
Punches not within Examine punch length dimensions

specifications
Narrow the particle size range
Particle segregation
as press RPMs Compress at slower RPM
increase
Clean; improve dust collection
Lower punch hang
up (material between Check for proper clearance
lower punch and die between die wall and lower punch
wall or lower punch
and punch guide) Increase lubricant concentration
in formulation
Remove below 200 mesh fines
Wet granulation Process whereby See Section 2

active drugs and
excipients are wet
massed (wet with
a solvent containing
a binder in solution,
usually), screened,
dried, and screened
again
Used for high-dose

active drugs which
have poor flow and
either cannot be or
are difficult to directly
compress
Used for active drugs

which are very fine
and/or low density
58
FMC logo, Avicel, Aquacoat and Ac-Di-Sol trademarks of FMC Corporation.
Aerosil trademark of Degussa Aktiengesellschaft.
Cab-O-Sil trademark of Cabot Corporation.
Fitz Mill trademark of Fitzpatrick Company, The Illinois Corporation.
Syloid trademark of W.R. Grace & Co. Connecticut.
1998 FMC Corporation. All rights reserved. RS
59

Problems During Tablet Manufacturing & Its Solution

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Section 5

Tablet Problems and Remedies

Problem/Concept Cause/Definition Remedy/Suggested Solution

Blend the cohesive powder with a

Note: For direct compression excipient

Nonuniformity of mix Improper blender load Use recommended powder load in

Insufficient mixing Increase mixing time

Inefficient (improper) Use alternative mixer with

Wide particle size Select more uniform particle sizes

Overblending Reduce blending time

Establish optimum mixing

Low-dosage actives Use a more effective mixer (one

Dissolve drug in a suitable solvent

Note: For direct compression

Segregation after Particle size Use a narrower particle size range

Problem/Concept Cause/Definition Remedy/Suggested Solution

Overmixing during Reduce water or mixing time

Wrong binder Change binder

Component of mix If possible, use alcohol/water or

Moisture sensitive Instability with water If possible, use ethyl alcohol

Try slugging or roller compaction

Problem/Concept Cause/Definition Remedy/Suggested Solution

Add 5% to 20% Avicel PH-101

Too much water in Reduce water content; add water

Mass sensitive to Incorporate 5% to 20% Avicel

Gummy binder Change binder

Component or active Use diluted or anhydrous ethyl

Problem/Concept Cause/Definition Remedy/Suggested Solution

Dryer overload Reduce number of trays

Reduce thickness of wet mass

Try fluid bed dryer

Reduce drying temperature

Add Avicel PH-101 to formulation

Use a fluid bed dryer

Color migration Colors migrate to Use lakes instead of soluble dyes

Decrease thickness of granulation

Use Avicel PH-101- reduces or

Problem/Concept Cause/Definition Remedy/Suggested Solution

Establish optimum moisture

Screen size too small Use larger screen size

Rotor/screen clearance Adjust rotor clearance

Overloading of mill or Slow feed of material to mill

Weak granules Increase granulating fluid

Increase binder content

Increase wet massing time

Difficult to screen Granules too hard Decrease drying temperature

Decrease water content

Decrease binder content

Use weaker binder

Moisture in granulation Increase drying time

Establish optimum moisture

Decrease thickness of granulation

Use Avicel PH-101- reduces or

Problem/Concept Cause/Definition Remedy/Suggested Solution

bridging In direct compression, Select larger particle size; use

Use induced or force-feed

Change particle shape of active

Poor inherent flow Add 0.1% to 0.5% glidant

Dry granulate (by slugging or roller

Atmospheric moisture Process in low humidity