Tablet Problems and Remedies: Section 5

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
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
2
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
3
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
4
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)
5
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
6
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
7
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
8
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
9
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
10
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
11
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
12
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®)
13
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
14
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 RPM’s 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
15
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
16
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
17
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
18
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
19
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)
20
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

21
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
22
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.
23
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
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

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 “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

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”
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)”
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”
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

Tablet Problems and Remedies: Section 5

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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

• Add moisture absorber (e.g.,

• Flow is erratic and • Use an induced or force-feed

• See “Dry screening: Excess fines”