1 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 Section 5 Tablet Problems and Remedies By George E. Reier, PhD Table of Contents
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Tablet Problems and Remedies........................................................................................................1Table of Contents .........................................................................................................................1Part A. Specific Tableting Problems and Remedies (Process Format) ........................................5
Dry Blending .............................................................................................................................5Particle agglomeration .........................................................................................................5Nonuniformity of mix ............................................................................................................5Segregation after blending ..................................................................................................6
Drying ......................................................................................................................................9Nonuniform drying ...............................................................................................................9Granule case hardening (hard crust forms with incomplete drying inside granule) ................9Color migration ....................................................................................................................9Drug migration ...................................................................................................................10
Dry Screening (Dry Granulation) ..............................................................................................11Excess fines .......................................................................................................................11Difficult to screen................................................................................................................11Poor color distribution .......................................................................................................12
Punches and Dies...................................................................................................................16Punch binding (powder adheres to punch edges and dies; punches may bind in dies) ......16Punch filming or sticking (picking)—(powder adhesion to punch faces, usually upper) ......17Punch and die abrasion .....................................................................................................18Capping and laminating .....................................................................................................18Chipping/splitting ...............................................................................................................19Score line or tablet imprint not sharp ................................................................................19Layered tablets splitting .....................................................................................................20Layers not sharply defined ................................................................................................20
Section 5
Tablet Problems and RemediesBy George E. Reier, PhD
Table of Contents
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Low hardness .........................................................................................................................20Variable hardness ...................................................................................................................21High friability ...........................................................................................................................21Disintegration too long ...........................................................................................................22Mottling ...................................................................................................................................22Tablets contain “dirty” specks ...............................................................................................23Tablets uniformly discolored...................................................................................................23
Part B. General Tableting Problems and Remedies (Alphabetical Order Format) ......................24Active ingredients ...................................................................................................................24Adsorbents ............................................................................................................................24Agglomeration of particles .....................................................................................................24Aging of tablets.......................................................................................................................24Air entrapment ........................................................................................................................25Antiadherent ..........................................................................................................................25Attraction of particles (aggregation or agglomeration) ............................................................25Binder ....................................................................................................................................25Binding (bonding or compressibility) .......................................................................................26Binding in the die (punches) ...................................................................................................26Bioavailability ..........................................................................................................................26Bisected or debossed tablets (not sharp or well-defined) ....................................................26Blending .................................................................................................................................27Bonding .................................................................................................................................27Bridging ..................................................................................................................................27Brittle fracture .........................................................................................................................28Bulk density ............................................................................................................................28Capping and laminating .........................................................................................................28Case hardening.......................................................................................................................29Chipping/splitting ..................................................................................................................30Clogging of screen (wet mass) ...............................................................................................30Coarse particles......................................................................................................................31Color distribution ....................................................................................................................31Color migraton........................................................................................................................31Compressibility .......................................................................................................................31Content uniformity ..................................................................................................................31Density, bulk (loose density) .........................................................................................................32Density, tapped.......................................................................................................................32Die fill (nonuniform) ..................................................................................................................32Diluent ....................................................................................................................................33Dilution potential.....................................................................................................................33Direct compression.................................................................................................................33Disintegrant ............................................................................................................................33Disintegration too long or incomplete....................................................................................34Disintegration during coating .................................................................................................34Dissolution ..............................................................................................................................35
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Dosage variation.....................................................................................................................35Doughy mass..........................................................................................................................36Drug migration ........................................................................................................................36Dry blending............................................................................................................................36Dry granulation (by slugging or compaction)...........................................................................37Dry screening..........................................................................................................................37Dye migration..........................................................................................................................38Ejection problem.....................................................................................................................38Elastic material........................................................................................................................38Entrapment of air ....................................................................................................................38Excess fines (wet granulation) .................................................................................................38Expanding tablets...................................................................................................................39Filler ....................................................................................................................................39Filming of punches .................................................................................................................39Fines (direct compression) .......................................................................................................39Fines (wet granulation).............................................................................................................39Flooding ..................................................................................................................................39Flow problem..........................................................................................................................40Friability (high) .........................................................................................................................40Glidant ....................................................................................................................................41Granulation, dry ......................................................................................................................41Granulation, wet .....................................................................................................................41Hard tablets ............................................................................................................................41Hardness increases with time ................................................................................................42Hardness, variable ..................................................................................................................42High friability ...........................................................................................................................42High relative humidity .............................................................................................................42Hopper flow ............................................................................................................................42Hygroscopic ingredients.........................................................................................................43Hygroscopic tablets................................................................................................................43Laminating ..............................................................................................................................43Layered tablets splitting (poor bonding between layers; layers peel or split apart) .................43Loss of hardness (with time) ...................................................................................................44Loss of hardness ....................................................................................................................44Low to medium level of active (in direct compression)...........................................................45Lubricants ...............................................................................................................................45Mixing ....................................................................................................................................45Modified direct compression..................................................................................................46Moisture sensitive actives ......................................................................................................46Mottling ...................................................................................................................................46Nonuniform die fill...................................................................................................................46Nonuniform drying (tray drying) ..............................................................................................46Nonuniformity of mix ..............................................................................................................46Oleaginous or sticky actives ..................................................................................................47
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Ordered mixing (adhesive blending) ........................................................................................47Overblending ..........................................................................................................................48Oven drying ............................................................................................................................48Overwetting of wet mass .......................................................................................................48Partial direct compression......................................................................................................48Particle density variation .......................................................................................................48Particle size distribution .........................................................................................................49Picking ....................................................................................................................................49Poor binding ...........................................................................................................................49Poor color distribution............................................................................................................49Poor flow (“rat-holing” or “bridging”) .......................................................................................49Poor granule disintegration ....................................................................................................50Poor layer demarcation ..........................................................................................................50Poor tablet finish/appearance................................................................................................50Postgranulation addition ........................................................................................................50Powder separation .................................................................................................................50Precompression......................................................................................................................51Punch and die abrasion .........................................................................................................51Punch binding (powder adheres to punch edges and dies; punches may bind in dies) ..........52Punch filming or sticking (picking)—(powder adhesion to punch faces, usually upper) ..........52Rat-holing ..............................................................................................................................53Relative humidity (RH).............................................................................................................53Roll compacting......................................................................................................................54Score line or tablet imprint not sharp ....................................................................................55Screen clogging (wet mass)....................................................................................................55Segregation.............................................................................................................................55Slugging ..................................................................................................................................55Soft tablets ............................................................................................................................56Splitting (tablets)......................................................................................................................56Sticking to punch face ...........................................................................................................56Sticky ingredients ...................................................................................................................56Tablet binding in the die .........................................................................................................57Tablets contain “dirty” specks ...............................................................................................57Tablets uniformly discolored...................................................................................................57Underblending .......................................................................................................................57Variable hardness ...................................................................................................................57Weight variation (outside limits)...............................................................................................58Wet granulation.......................................................................................................................58
Particle agglomeration • Occurs with fine • Fine-screen cohesive compoundcohesive powders, into bulk mixwhich cause “ballingup” and poor • Use a more effective mixer (onedistribution 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 inblender
• Insufficient mixing • Increase mixing time
• Inefficient (improper) • Use alternative mixer withmixer increased shearing action
• Wide particle size • Select more uniform particle sizesdistribution of components
• Overblending • Reduce blending time
• Establish optimum mixingconditions
• Low-dosage actives • Use a more effective mixer (onewith increased shearing action)
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Part A. Specific Tableting Problems and remedies (Process Format)
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 rangeblending distribution too wide of components
Doughy mass • Too much water • Add granulating water slowly; (often seen on scaleup) mix well after each addition
• Overmixing during • Reduce water or mixing timegranulation 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 residualsolvent by GC or other appropriatemethod) as granulating fluids,ethyl cellulose and PVP as binders
• Try slugging or roller compactionas dry granulation methods
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 ainside 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 “Colorgranule 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
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 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
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 excipientand/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 humidityadsorption atmosphere
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 particlefrom 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 rangemix 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 mixingproduces 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
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 tosuitable 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 punchguide)
Punch binding (powder • Poor finish or worn • Polish, reface, or replace toolingadheres to punch punches and diesedges and dies • Increase or change lubricant; usepunches 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
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 separationof the tablet into two ormore layers.
• Poor finish or worn • Polish, reface, or replacepunches and dies
• Chrome plate punch faces• Too many fines in
granulation • Modify granulation process forminimum fines
• Granulation too dry• Adjust moisture level and establish
optimum moisture limits
• Granulation too wet • Continue to dry and establish(usually associated optimum moisture limitwith sticking or picking)
• Overlubrication of • Decrease lubricant levelfinal tableting mix
• Blend lubricant for minimal time required; establish optimum mixing time
Disintegration too long • Tablet hardness too • Reduce machine pressure forhigh acceptable tablets
• Use less binder in granulation
• Overlubrication • Decrease lubricant level(waterproofing) • Blend lubricant for minimal time
required; establish optimum mixingtime
• Replace metallic stearates with other lubricants (e.g., stearic acid)
• 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 allowlow swellable disintegrant to function
Mottling • Uneven distribution of • Increase mixing time or use highthe dye in colored shear mixertablets
• Dye migration during • See “Drying: Color migration”drying process
• See “Dry screening: Poor colordistribution”
• Preferential • Replace causative componentabsorption of solubledye by component of • Replace soluble dye with microfinemix lake pigment
• High level of • Reduce quantity of additivesuncolored 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 feeddiscolored on die table frame and die table
• Feed hopper rubbing • Check clearance between feedon turret hopper and turret
• Abrasive materials • Check for presence of abrasivewearing screens, materialsscooper, etc.
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 compoundparticles 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)”
Part B. General Tableting Problems and Remedies(Alphabetical Order Format)
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 powdersagglomeration)
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
Binding (bonding or • Relative degree of • See “Blending”compressibility) cohesiveness
between particles or • Be careful not to overblend orgranules overlubricate
• Compressibility of • Optimize particle size and particleactive ingredients size distribution of active anddetermines (to some excipientsextent) the percent that can be • Use excipients which areincorporated into a compressible and designed fordirect compression direct compression processformulation
• Determine that granulation and/or• Particular binder and other excipients have proper
concentration moisture contentinfluences degree ofbinding and tablethardness
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 toolingtablets (not sharp or tooling supplierwell-defined)
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
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 directLaminating 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 establishoptimum moisture limits
• Granulation too wet • Continue to dry and establish(usually associated optimum moisture limitwith 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 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 replacedamaged
• Lower punch too low • Adjust lower punch flush with at tablet take-off die face
• Compression too low • Compress in upper portion of diein die cavity
• Excessive tableting • Decrease pressurepressure
• 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)
Chipping/splitting • Poor finish or worn • Polish, reface, or replace punchespunches and dies and dies
• Lower punch setting • Adjust lower punch flush with too low at tablet take- die faceoff
• Tablet sweep-off • Adjust settingblade 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
• Add 5% to 20% Avicel® PH-101 (gives less sticky or doughy mass, easier to screen)
– Too much water in • Reduce water content; add watermass 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, determine acceptable residual solvent level by GC or other appropriate method); change binder
Coarse particles • Mottled appearance • Design particle size distribution for in direct compression optimum flow, color distribution,
binding
• Segregation • Some fines are needed for goodbinding
Color distribution • Dye migration leading • In direct compression, preblend orto mottling mill color with portion of excipient
• In wet granulation, use a dye soluble in the granulating solution
• May help to use a lowertemperature for tray drying; use afluid bed dryer
• See “Color migration”
Color migration • Colors migrate to • Use lakes instead of soluble dyesgranule surface (will minimize but not eliminate)(wet granulation); will cause mottling • Decrease the size of the wettablets; often granulesassociated with case hardening • 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
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
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 topowder flow into dies, recommended optimum for diecausing variations in diametertablet weight, hardness,and disintegration/ • Reduce finesdissolution
• Select larger particle size; useAvicel® PH-102 or PH-200 in placeof PH-101 or other excipient
• Add glidant (0.1% to 0.5%) (e.g.,Cab-O-Sil®, Aerosil®)
• Use induced or force-feedmechanism on press
• Change particle shape of activeingredient to one that is more likelyto flow
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 - 4manufacturing 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 usesbreaking apart so that particles of drug can dissolve
Dissolution • Measure of the rate • Use most soluble form of drugand extent to whichan active component • Micronize insoluble drugs - inis released into general, use smallest particle solution from a drug size possibleproduct
• Consider using a wetting agent
• May or may not be • Add additional disintegrant or acorrelated with different disintegrant - granulesbioavailability must disintegrate for good
dissolution
• Poor dissolution • Optimize tablet hardness versusfriability and disintegration/dissolution
• Conduct preformulation studies to be certain there is noactive/excipient interaction(binding)
• Use a soluble filler with insolubleactives
• Use less lubricant, establishoptimum blending time
• See “Bioavailability”
• See “Disintegration”
Dosage variation • Improper • See "Blending, overblending mixing/segregation and demixing"
Doughy mass • Too much water • Add granulating water slowly; (often seen on mix well after each additionscaleup)
• 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 granulation • Method for • See Section 2(by slugging or compacting powderscompaction) 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 timegranulation
• Establish optimum moisture content
Drying • Overdrying can cause • Set in-process moisture static flow, case specifications on wet granulated hardening, drug/color materialsmigration, lamination/capping/splitting • See Section A: “Drying”
• Underdrying can • See Section A: “Drying” cause weak granulesfilming, and sticking • Control moisture in direct of punches compression excipients for proper
Elastic material • Actives or excipients • Use materials that have plasticthat 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 rotorclearance too close
• Overloading • Feed granulator graduallygranulator or mill
Filler • Inert material(s) • See Section 4 for a descriptionadded 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 finescompression) 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
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®
• 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®, Cab-O-Sil®, and magnesium stearate
• Atmospheric moisture • Process in low humidity absorption atmosphere
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 acceleratedcompressed tablets temperature/ humidity conditions
may not always be relevant to• Can be caused by shelf-life conditions
water of crystal-lization/hydrationinteracting withingredients or otherkinds of interactionsbetween activematerials/excipients
• 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 bedirectly compressed depending onphysical form (low density,entrapped air, etc.), flow, andcompressibility properties
• Dry/wet granulation • If unable to compress directly, drygranulation or wet granulation arepossible alternatives depending onactive's physical properties
Hygroscopic • Moisture pick-up • Process under low humidityingredients conditions
• Compress with low moisture grades Avicel® PH-112 and PH-113
• Use moisture scavengers (e.g., calcium silicate, Syloid®, Cab-O-Sil®)
Hygroscopic tablets • Moisture pick-up • Compress and package underlowhumidity conditions (to maintaintablet hardness and activeingredient stability)
• Use moisture scavengers (e.g.,calcium silicate, Syloid®,Cab-O-Sil®)
• Keep tablet containers well closed(use adequate closures especiallyif plastic or blister packed)
Laminating • See “Capping and laminating”
Layered tablets • Poor bonding • Use a stronger binder or highersplitting (poor bonding between layers concentrationbetween layers; layerspeel or split apart)
• Compression • Compress at lower pressurespressure too high
• Overlubrication • Decrease lubricant level
• Blend lubricant for minimal time required; establish optimum mixing times
Low to medium level • Use 10% to 20% Avicel® PHof active (in direct combined with compressiblecompression) 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)
Modified direct • Modification of direct • Dissolve actives in volatile solventscompression compression process and spray onto excipients
to assure gooddispersion of low-level • Granulate a small portion of theactives or for other formulation and directly compressreasons 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 dryactives 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 increasemixer shearing action
• Wide particle size • Select more uniform particle sizesdistribution of components
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
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
Punch binding (powder • Poor finish or worn • Polish, reface or replace toolingadheres to punch punches and diesedges and dies, • Increase or change lubricant; usepunches 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
• Hygroscopic • Process in low humidity conditions ingredients
• Use moisture scavengers (e.g., calcium silicate, Syloid®, 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®
• Add 5% to 10% Avicel® PH-101
Punchfilming or • Poorfinish on punch • Polish punch faces; refinishsticking (picking)— faces(powder adhesion to • Avoid using certain letters (e.g.,punch faces, usually • Embossed letters “A”, “B”, “P”, “R”)upper)
• Use shallow embossing withtapered edges rather than edgesperpendicular to punch face
• Punch tips burred • Refinish or replace
• Punch concavity too • Reduce punch concavity or usegreat flat-face punches
• Poor binding between • Increase binder (wet or dry) surface granules or particles
• Low melting point • Adsorb low melting point ingredientingredient on Avicel® PH, replace with higher
. • Hygroscopic • Process under low humiditycomponents conditions
• Use moisture adsorbent (e.g., calcium silicate, Syloid®)
• Adhesive components • Increase lubricant level
• Add 0.5% Cab-O-Sil® or 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
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.
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 “Capping and laminating”
• See “Coarse particles”
• See “Die fill (nonuniform)”
• 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
Tablets contain “dirty” • Misaligned upper cam • Check alignment of upper camspecks tracks - rubbing of tracks
punches on cam actually rubs off metal, which is introduced into material being compressed
• No lubrication onupper 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 feeddiscolored on die table frame and die table
• Feed hopper rubbing • Check clearance between feedon turret hopper and turret
• Abrasive materials • Check for presence of abrasivewearing screens, materialsscooper, etc.
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
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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.