problem and remedies in tableting.pdf

8/21/2019 problem and remedies in tableting.pdf

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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

Wet Granulation (Massing) ........................................................................................................7

Doughy mass........................................................................................................................7Moisture sensitive drugs ......................................................................................................7

Wet Screening...........................................................................................................................8Screen clogging....................................................................................................................8

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

Feed Hopper ..........................................................................................................................13Poor flow.............................................................................................................................13Flooding..............................................................................................................................14Particle segregation............................................................................................................14

Tablet Weight .........................................................................................................................15Weight variation outside limits ..........................................................................................15

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 Remedies

By George E. Reier, PhD

Table of Contents


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Low hardness .........................................................................................................................20 Variable hardness ...................................................................................................................21High friability ...........................................................................................................................21Disintegration too long ...........................................................................................................22Mottling...................................................................................................................................22

Tablets contain “dirty” specks ...............................................................................................23Tablets 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) ............................................................25Binder ....................................................................................................................................25

Binding (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 )...........................................................................37

Dry 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).............................................................................................................39

Flooding ..................................................................................................................................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......................................................................................................48

Particle 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 .................................................................................................................50

Precompression......................................................................................................................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 .......................................................................................................................57

Variable hardness ...................................................................................................................57Weight variation (outside limits)...............................................................................................58Wet granulation.......................................................................................................................58


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Dry Blending

Problem/Concept Cause/Definition Remedy/Suggested Solution

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 aportion (5% to 10%) of an excipient;screen (mill) if necessary; reblendand add to the bulk; blend normally

Note: For direct compression excipientblends do not use a screen size or amixer, which will change the excipientparticle size distribution

Nonuniformity of mix • Improper blender load • Use recommended powder load inblender

• 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 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)


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Nonuniformity of mix • Low-level excipients • Blend the low-level component(continued) with a portion (5% to 10%) of an

excipient; screen (mill) ifnecessary; reblend; add to anequal quantity of excipient andmix; screen or mill if necessary;blend normally with remainderof bulk

• Dissolve drug in a suitable solventand add or spray onto a portionof the bulk or an excipient; blend;remove solvent

Note: For direct compressionexcipient blends do not use a screen

size or a mixer, which will change theexcipient particle size distribution

Segregation after • Particle size • Use a narrower particle size rangeblending distribution too wide of components


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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 timegranulation step

• Wrong binder • Change binder

• Component of mix • If possible, use alcohol/water or(e.g., active drug or alcohol as granulating fluid - selectexcipient) appropriate binder; use of Avicel®

PH-101 gives 1) less sticky ordoughy mass which is easier to

screen; and 2) allows a widerrange of solvent volume

Moisture sensitive • Instability with water • If possible, use ethyl alcoholdrugs 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


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Wet Screening


Screen clogging • Doughy or sticky wet • Avoid oscillating granulatormass• 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 rangeof solvent volume)

• Gummy binder • Change binder

• Component or active • Use diluted or anhydrous ethylingredient or isopropyl alcohol (if latter,

determine acceptable residualsolvent level by GC or otherappropriate method); changebinder


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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 masson 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 openconditions too efficient damper fully

• Reduce drying temperature

• Add Avicel® PH-101 to formulation(gives more even waterevaporation and uniform granulemoisture content)

• Use a fluid bed dryer

Color migration• Colors migrate to • Use lakes instead of soluble dyesgranule surfaces (wet (will minimize but not eliminate)

granulation); tabletshave mottled • Decrease the size of the wetappearance granules

• Decrease thickness of granulationbed; stir granulation bed frequentlyduring drying to expose freshsurfaces at the top of the wetmass

• Use Avicel® PH-101- reduces or

eliminates dye migration in wetgranulation


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Drug migration • Drug migrates to • See remedies under “Colorgranule surfaces; migration”content uniformityproblems may resultas drug becomes partof “fines” after dryscreening, or there isa loss of drug withsubsequent low tabletassays


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Dry Screening (Dry Granulation)


Excess fines • Granulation overdried • Decrease drying time/temperature

• Establish optimum moisturecontent

• Screen size too small • Use larger screen size

• Rotor/screen clearance • Adjust rotor clearancetoo close

• Overloading of mill or • Slow feed of material to millgranulator 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



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Poor color distribution • Dye migration to • Use lakes instead of soluble dyesgranule surface (will minimize but not eliminate(nonuniformity of problem)color throughoutgranule) • Decrease the size of the wet

granules

• Decrease thickness of granulationbed; stir granulation bed frequentlyduring drying to expose freshsurfaces at the top of the wetmass

• Use Avicel® PH-101- reduces oreliminates dye migration in wetgranulation


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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; useparticle size of drug or Avicel® PH-102 or PH-200 in placeexcipients too small of PH-101 or other excipientand/or of shape thatwill 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 activeingredient to one that is more likelyto flow

• Poor inherent flow • Add 0.1% to 0.5% glidant

• Dry granulate (by slugging or rollercompacting) with a mixture of

Avicel® PH-101, Cab-O-Sil® ,and magnesium stearate

• Atmospheric moisture • Process in low humidityadsorption atmosphere

• Add moisture absorber (e.g.,0.1% to 0.5% calcium silicate,Cab-O-Sil®, Syloid® )


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Flooding • Excessive flow • Identify causative component andproperties (fluidization) exclude or modify particle sizeof one or morecomponents (could be • Select narrow range of particlefrom an excess of sizes; avoid excess finesglidant or lubricant)

• Flow is erratic and • Use an induced or force-feedfeed frame is flooded mechanism on press, which mayat 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 ofdifference in mix particlesparticles

• 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 vibratorshopper)

• Excessive machine • Isolate hopper from tablet machinevibration


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Table Weight


Weight variation • Poor or erratic powder • Correct powder flow problemoutside limits flow, flooding (See “Feed hopper”)

• Particle size range too • Narrow the particle size range;wide avoid excess fines

• Use Avicel® PH-200 to minimizeweight variation

• Particle size not • Adjust particle size range tosuitable for die recommended optimum for diediameter diameter

• Punches not within • Examine punch length dimensionsspecifications

• Particle segregation as • Narrow the particle size rangepress RPM’s increase

• Compress at slower RPM

• Lower punch “hang up” • Clean; improve dust collection(material between lowerpunch and die wall or • Check for proper clearancelower punch and punch between die wall and lower punchguide)

• Increase lubricant concentrationin formulation

• Remove below 200 mesh fines


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Punches and Dies


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 intodies) 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 satisfactoryinsufficiently dried moisture limits

• Hygroscopic • Process under low humidityingredients 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 moisturegrades Avicel® PH-112 andPH-113


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Punch filming or • Poor finish on punch • Polish punch faces; refinishsticking (picking)— faces(powder adhesion to • Avoid using certain letterspunch faces, usually • Embossed letters (e.g., “A”, “B”, “P”, “R”)upper)

• Use shallow embossing withtapered edges rather than edgesdirectly perpendicular to punchface

• 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 orparticles

• Low melting point • Adsorb low melting pointingredient ingredient on Avicel®, replace with

higher melting point ingredient

• Inadequate lubrication • Increase or change lubricant

• Use microfine lubricants, screeninto mix

• Increase lubricant mixing time

• Insufficiently dried wet • Dry granulation and establishgranulation moisture limits

• Hygroscopic • Process under low humiditycomponents conditions

• Use moisture adsorbent(e.g., calcium silicate, Syloid® )



or 5% to 10% Avicel® PH-101

• Tablets too soft • Increase compression pressure


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Punch and die abrasion • Abrasive components • Exclude or reduce to a fine particlesize

• Increase lubricant level

• Blend abrasive component directlywith the lubricant

• Use minimum tableting pressurepossible

• Use more wear-resistant tooling(harder metal)

Capping and laminating • Inadequate bonding • Use a stronger binder or additionalof the powder binder

Capping is separation of particles (directthe top or bottom from compression) or • Avicel® PH-101 and PH-102the main body of the granules (wet are particularly effective directtablet. granulation) to form compression binders (15% to

cohesive tablets 25%) and as auxiliary bindersLaminating 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 orpicking)

• Overlubrication of • Decrease lubricant levelfinal tableting mix

• Blend lubricant for minimal timerequired; establish optimum mixingtime


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Capping and laminating • High level of • Use precompression on tablet(continued) ingredient with poor press

compressionproperties (also • Slow the speed of the tabletsometimes ascribed machineto air-entrapment bypowder bed)

• Punch concavity too • Change to standard concavedeep or flat face punches

• Punch edges worn or • Refinish or replacedamaged

• Lower punch too low • Adjust lower punch flush withat tablet take-off die face

• Compression too low • Compress in upper portion ofin die cavity die

• Excessive tableting • Decrease pressurepressure

• Die wall binding • Use sufficient lubricant

• Use tapered dies

Chipping/splitting • Poor finish or worn • Polish, reface, or replace punchespunches and dies and dies

• Lower punch setting • Adjust lower punch flush withtoo low at tablet die facetakeoff

• Tablet sweep-off • Adjust settingblade on feed frameset too high

Score line or tablet • Faulty punch • Redesign using tapered sidesimprint not sharp debossing design on the punch debossing

• Chrome-plate punch face

• Granulation too • Reduce particle size of granulationcoarse

• Binder not strong • Use a stronger binderenough


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Layered tablets • Poor bonding • Use a stronger binder or highersplitting between layers concentration

• Compression • Compress at lower pressurespressure too high

• Overlubrication • Decrease lubricant level

• Blend lubricant for minimal timerequired; do not blend for longperiods of time

Layers not sharply • Granulation too • Reduce particle size of granulationdefined 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)



• Replace metallic stearates withother lubricants (e.g., stearic acid)

• Granulation too soft • Use additional binder

• Direct compression - useadditional Avicel® PH

• Excipient (i.e., too • Reduce level of causativemuch starch can give excipienta soft tablet)


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Low hardness • Moisture consent too • Determine optimum moisture(continued) high (granulation content

underdried or highhumidity in • Use moisture adsorbent (e.g.,compressing area) calcium silicate, Syloid® )

• Moisture content too • Determine optimum moisturelow (granulation contentoverdried or lowhumidity in • Add additional moisturecompressing area)

Variable hardness • Tooling • Examine punch lengths

• Uneven diefill • See “Table Weight: Weightvariation”

• Overblending • Optimize blending time tominimize creation of fines

High friability • Inadequate bonding • Increase binder level or changeof the tablet mix to stronger binder

• Add or increase Avicel® PH-101or PH-102 (10% to 20%)

• Avicel® PH gives low friability atlower hardness/machine pressures

• Too much or too little • Adjust pressure for acceptablecompression pressure friability





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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


• 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 anauxiliary 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 dyedisintegrants) or mix with lake pigment


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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 particlesof excipient or active

• Use lower drying temperature

Tablets contain “dirty” • Misaligned upper cam • Check alignment of upper camspecks tracks - rubbing of tracks

punches on camactually rubs off metal

which is introducedinto material beingcompressed

• No lubrication onupper cam tracks

• Excessive or improper • Use dust caps on upper puncheslubrication on upperpunch shanks (no dustcaps on punches) -dust mixes with excessoil or grease and falls

into material beingcompressed

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.


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Problem/Concept Cause/Definition Remedy/Suggested Solution Active ingredients • See “Sticky ingredients”

• See “Low to medium levelof 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® ) orstickiness of tablet tribasic calcium phosphateingredients

Agglomeration of • Occurs with fine • Fine-screen cohesive compoundparticles cohesive powders into bulk mix

causing "balling" orlump 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 anexcipient; screen (mill) ifnecessary; reblend and add tothe bulk; blend normally

Note: For direct compressionexcipient blends do not use ascreen size or a mixer, which willchange the excipient particle sizedistribution

Aging of tablets • See “Loss of hardness (with time)”

Part B. General Tableting Problems and Remedies(Alphabetical Order Format)


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Air entrapment • Very low density • See “Capping and laminating”materials with veryhigh porosity • See “Binding”(sometimes ascribedas cause for tabletcapping, splitting,or laminating)

Antiadherent • Materials that aid in • See Section 4 for a descriptionpreventing the tablet of excipients and their usesmix from sticking topunch faces

Attraction of particles • Fine cohesive • Modify particle size distribution(aggregation or powdersagglomeration)

• 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 descriptionsubstances which are of excipients and their usesadded in solution

(usually) or sometimesdry, followed bygranulating solvent to“glue” a powder mixinto granules for soliddose preparation

• Direct compression -substances which givecompressibility orcohesiveness to thepowder mix


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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 percentthat 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 content

influences degree ofbinding and tablethardness

Binding in the die • See “Punch binding”(punches)

Bioavailability • The rate and extent to • See “Dissolution”which an activeingredient is absorbed • Use up to 50% soluble fillerin-vivo (lactose, dextrose) with insoluble

drugs (direct compression)

• May or may not becorrelated withdissolution

Bisected or debossed • Poor design on • Redesign tooling, consult toolingtablets (not sharp or tooling supplierwell-defined)

• Increase binder in formulation


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Blending • Mixing of powders to • Optimize blending or mixing timeobtain a homogeneousmixture (forcompression)

• Optimized blendingmay depend on typeof mixer (low shear,high shear, etc.)

• Overblending isprobably morecommon thanunderblending

• Overblending causes

overdistribution of thelubricant which canresult in poordisintegration/dissolution, poorcompressibility,demixing(segregation)

Bonding • See “Binding”

Bridging • Lack of powder • See “Die fill”fluidity; actual

stoppage of powder • See “Flow problems”flow as powdercompacts in hopperor feed-frame


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Brittle fracture • Bonding mechanism • See Section 2 for a discussionof some materials of compression mechanisms(e.g., lactose), in whichsingle particles fractureunder pressure toproduce multipleparticles having cleansurfaces, which thenbond with each otherto 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 binderthe main body of the particles (directtablet. compression) or • Avicel® PH-101 and PH-102 are

granules (wet particularly effective directLaminating is transverse granulation) to form compression binders (15% tocracking and separation cohesive tablets 25%) and as auxiliary binders inof 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 orpicking)

• Overlubrication of • Decrease lubricant levelfinal tableting mix



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Capping and laminating • High level of • Use precompression on tablet(continued) ingredient with press

poor compressionproperties (also • Slow the speed of the tabletsometimes ascribed machineto air-entrapment bypowder bed)

• Punch concavity too • Change to standard concave ordeep flat-face punches

• Punch edges worn or • Refinish or replacedamaged

• Lower punch too low • Adjust lower punch flush withat 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 (damperwater, which forms closed) for initial 15 to 30 minuteshard outer crust often then open damper partially for a

associated with short period and finally openincomplete drying damper fullyinside granules

• Reduce drying temperature• Oven drying

conditions too efficient • Add Avicel® PH-101 to formulation(gives more even water evaporationand uniform granule moisturecontent)

• Use a fluid bed dryer


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Chipping/splitting • Poor finish or worn • Polish, reface, or replace punchespunches and dies and dies

• Lower punch setting • Adjust lower punch flush withtoo 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 ofwater volume, gives “shorter”,less doughy, less sticky mass)

– Gummy binder • Change binder

– Active ingredient • Use diluted or anhydrous ethylor isopropyl alcohol (if latter,determine acceptable residualsolvent level by GC or otherappropriate method); changebinder


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Coarse particles • Mottled appearance • Design particle size distribution forin 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 dyesoluble 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 withcase hardening • Decrease thickness of granulation

bed; stir granulation bed frequentlyduring drying to expose freshsurfaces at the top of the wet

mass

• Use Avicel® PH-101- reducesor eliminates dye migration

Compressibility • See “Binding (bonding orcompressibility)”

Content uniformity • See “Dosage variation”

Demixing • Segregation/ • Optimize blending times specificseparation, usually to mixer (blender) employedcaused by overmixingrather than • See “Overblending”undermixing

• See “Segregation”


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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 volumeon 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 flowespecially at highdosage (active)

Density, tapped • Usually defined as the • See “Segregation”ratio of weight of apowder (or mixture ofpowders) to its volume

after being tapped orcaused to consolidate(“settle”) in some way

• Too dense — cancause 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; use Avicel® 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


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Die fill (nonuniform) • Dry granulate (by slugging or roller(continued) compacting) with a mixture of

Avicel®, Cab-O-Sil® and magnesiumstearate

• Process in low humidity atmosphere

• Add moisture absorber (e.g.,0.1% to 0.5% calcium silicate,Cab-O-Sil®, Syloid® )

Diluent • Inert material(s) • See Section 4 for a descriptionadded to give the of excipients and their usesnecessary bulk forsolid dosagepreparation

Dilution potential • The percent of an • Avicel® PH has a very high dilutionactive (usually poorly potential when used as a bindercompressible suchas ascorbic acid or

APAP) that can becompressed with anexcipient to form atablet having 1% orless friability

Direct compression • Method of • See Sections 2 - 4manufacturing tablets

by compressingdirectly a dry blend ofactive and excipientpowders; the powdersare neither wet or drygranulated

Disintegrant • Material added to • See Section 4 for a descriptiontablets to aid them in of excipients and their usesbreaking apart so thatparticles of drug candissolve


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Disintegration too long • Tablet hardness too • Reduce machine pressure foror incomplete high acceptable tablets

• Use less binder in granulation

• Overlubrication • Decrease lubricant level(waterproofing)

• Blend lubricant for minimal timerequired; establish optimumblending 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 anauxiliary disintegrant

• Consider adding a surfactant(e.g., DOSS, 0.1%)

• Tablet hardness too • Increase hardness to allowlow swellable disintegrant to function

Disintegration during • Caused by soft cores • Increase tablet strength (increasecoating or rapidly binder, add better binder,

disintegrating tablets compress harder)

• Apply a seal coat(Aquacoat® ECD)

• If possible, lower spray rate ofaqueous coating


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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 particlesolution 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 studiesto 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, overblendingmixing/segregation and demixing"

• See “Flow problem”


• See “Die fill (nonuniform)”

• See “Nonuniformity of mix”


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Doughy mass • Too much water • Add granulating water slowly;(often seen on mix well after each additionscaleup)

• Overmixing during • Reduce water or mixing timegranulation 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 stickyor doughy mass, which is easierto screen; and 2) allows a widerrange of solvent volume

Drug migration • Drug migration to • See “Color migration”surface of granulation

• May lead to contentuniformity problemsas drug becomes partof “fines” after dryscreening, or there isa loss of drug withsubsequent low tabletassays

Dry blending • See Section A: “Dry blending”


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Dry granulation • Method for • See Section 2(by slugging or compacting powderscompaction) by slugging or roller • See “Slugging”

compaction and thensize reducing the • See “Roll compaction”compacts to thedesired particle sizefor tableting

• Often preferred when1) it is difficult orimpossible to directlycompress; and 2) theactives are unstablewhen subjected to wetgranulation

Dry screening • Granules too hard • Decrease drying temperature(case hardening)

• Decrease water content (usealcohol/water)

• Decrease binder content

• Use weaker binder

• Moisture in • Increase drying timegranulation


Drying • Overdrying can cause • Set in-process moisturestatic flow, case specifications on wet granulatedhardening, drug/color materialsmigration, lamination/ capping/splitting • See Section A: “Drying”

• Underdrying can • See Section A: “Drying”cause weak granulesfilming, and sticking • Control moisture in directof punches compression excipients for proper

compressibility


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Dye migration • See “Color migration”

Ejection problem • See “Punch binding”

Elastic material • Actives or excipients • Use materials that have plasticthat are deficient in flow (low in elasticity) and that,plastic flow properties, once compressed, “stayand therefore lack compressed” (do not “springbonding or binding back”), such as Avicel® PHproperties

• Often are springy orspongy and have“spring back”:characteristics (i.e.,return to original

size/shape)

• Results in capping,lamination, splitting,and lack ofcompressibility ingeneral

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

• Weak granules • Increase binder content/ granulating fluid

• Increase wet massing time

• Use stronger binder


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Expanding tablets • See “Elastic material”


• See “Active ingredients”

• See “Binding”

Filler • Inert material(s) • See Section 4 for a descriptionadded to give the of excipients and their usesnecessary bulk forsolid dosagepreparation

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 oleaginousones or those with elastic

• Poor binding deformation properties, and aids inin bonding and filling voids withinthe tablet

• Too many cause segregation

Fines (wet granulation) • See “Excess fines (wet granulation)”

• See “Fines (direct compression)”above

Flooding • Excessive flow • Identify causative component andproperties exclude or modify particle size(fluidization) of one ormore components • Select narrow range of particle(could be from an sizes; avoid excess finesexcess of glidant orlubricant) • Induced or force-feed mechanism

on press may control flow• Flow is erratic and

feed frame is flooded • See “Flow problem”at times


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Flow problem • Too many fines in wet • Reduce fines (see “Dry Screening-granulation Excess fines”)

• In direct compression, • Select larger particle size; useparticle size of drug or Avicel® PH-102 or PH-200 in placeexcipients too small of PH-101 or other excipientand/or of shape thatwill not flow • 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 morelikely to flow

• Poor inherent flow • Add 0.1% to 0.5% glidant

• Dry granulate (by slugging or rollercompacting) with a mixture of

Avicel®, Cab-O-Sil®, andmagnesium stearate

• Atmospheric moisture • Process in low humidityabsorption atmosphere

• Add moisture absorber (e.g.,0.1% to 0.5% calcium silicate,

Cab-O-Sil®, Syloid® )

Friability (high) • Inadequate bonding • Increase binder level or change toof the tablet matrix stronger binder

• Add or increase Avicel® PH-101or PH-102 (10% to 20%), whichgive low friability at lowerhardness/machine pressures

• Too much or too little • Adjust pressure for acceptablecompression pressure friability


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Friability (high) • Overlubrication • Decrease lubricant level(continued) • Blend lubricant for minimal time

required; establish optimumblending time


Glidant • Excipient used to • See Section 4improve fluidity ofpowders • Add 0.1% to 0.5% Cab-O-Sil® or

Aerosil® fumed silica to improveflow

• Small increase in lubricant may benecessary 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 tabletswith low machine pressure - alsoto reduce tablet friability

• See “Binding (bonding orcompressibility)”

• Decrease compressing speedto increase tablet hardness


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Hardness increases • Probably more • Optimize moisture consentwith 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

Hardness, variable • Tooling • Examine punch lengths

• Uneven die fill • See “Weight variation”

• Overblending • Optimize blending time to minimizecreation 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, and

compressibility properties

• Dry/wet granulation • If unable to compress directly, drygranulation or wet granulation arepossible alternatives depending onactive's physical properties

High relative humidity • See “Relative humidity”

Hopper flow • See “Die fill”

• See “Flow Problem”



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Hygroscopic • Moisture pick-up • Process under low humidityingredients conditions

• Compress with low moisture grades Avicel® PH-112 and PH-113


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


• Blend lubricant for minimal timerequired; establish optimum mixingtimes


• See “Lubricants”


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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 ofthe hardness is quicklyregained at normalhumidity

Low hardness • Compression force • Increase pressure (caution - do not(pressure) too low exceed recommended pressure for

punch size used)


• Blend lubricant for minimal timerequired; establish optimum mixing

times


• Granulation too soft • Use additional binder

• Direct compression - use additional Avicel® PH

• Excipient (i.e., too • Reduce level of causative excipientmuch starch can givea soft tablet)

• Moisture content too • Granulation underdriedhigh

• High humidity-use moisturescavenger or moisture adsorbent(e.g., calcium silicate, Syloid® )

• Moisture content too • Granulation overdriedlow

• Low humidity-direct compressionexcipients too low in moisturecontent


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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 useless magnesium stearate, since

Avicel® PH is self-lubricating

• At low-dosage level-blend or millactive with part (e.g., 10% ofexcipient) and then blend withremainder of formulation

• At very low-dosage levels (


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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 granulatingsolvent (flammability and residualsolvent 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 loadin 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

• Overblending • Reduce blending time

• Establish optimum mixingconditions


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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 witha portion (5% to 10%) of anexcipient; screen (mill) if necessary;reblend; add to an equal quantity ofexcipient and mix; screen or mill ifnecessary; blend normally withremainder of bulk

• Dissolve drug in a suitable solventand add or spray onto a portion ofthe bulk or an excipient; blend;remove solvent

Note: For direct compression excipientblends do not use a screen size or amixer which will change the excipientparticle 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 oflarger-sized

(excipient) particles

• Segregation does notoccur

• Usually requires ahigh-intensity mixer


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Overblending • Can cause powder • Optimize mixing timesseparation(segregation or • See “Blending”demixing)

• Can cause particlesize reduction leadingto other problems

• Can cause“waterproofing” oftablet by lubricant

Oven drying • See “Drying”

Overwetting of • A common problem in • See “Clogging of screen”

wet mass wet granulation

• Some actives aloneand in combinationwith excipients aremore sensitive thanothers (due tosolubility)

Partial direct • See “Modified direct compression”compression

Particle density • See “Density, bulk (loose density)”

variation• See “Density, tapped”


• See “Punch binding”


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Particle size • See “Binding (bonding ordistribution compressibility)”


• See “Fines (direct compression)”

• See “Flooding”

• `See “Flow problem”


• See “Ordered mixing (cohesiveblending)”


Picking • Tablet surfaces • See “Punch filming or sticking”“pitted”

• Small areas ofcompressed powderleft on punch faces(mostly upper) aftercompression - tabletsurface is “picked”

• Often associated with

punch filming andsticking

Poor binding • See “Binding (bonding orcompressibility)”

Poor color distribution • See “Color distribution”

• See “Color migration”

Poor flow (“rat-holing” • See “Flow problem”or “bridging”)


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Poor granule • Wet granulation • Granules must be disintegrateddisintegration for prompt and full drug release

(dissolution)

• Include a portion (50%) of thedisintegrant (Ac-Di-Sol® ) for thispurpose in the materials beinggranulated (disintegrant “inside”the granulation)

Poor layer demarcation • Granulation too • Reduce particle size ofcourse 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 4addition drying the granules

and screening them

Examples: disintegrant,lubricant, additionalbinder

Powder separation • See “Coarse particles”

• See “Demixing”

• See “Fines (direct compression)”

• See “Flow problem”


• See “Overblending”



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Precompression • Application of a • See Section 3relatively smallamount of tabletingpressure immediatelyprior to application ofmain tabletingpressure

• Aids in removingentrapped air

• Aids in preventing/ minimizing capping/ laminating of difficult-to-compress materialsby allowing time for

relaxation betweencompressions

• Requires a rotarytablet machineequipped forprecompression

Punch and die abrasion • Abrasive components • Exclude or reduce to a fine particlesize

• Increase lubricant level

• Blend abrasive componentseparately with the lubricant

• Use minimum tableting pressurepossible

• Use more wear-resistant tooling(harder metal)


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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 intoin 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 satisfactoryinsufficiently dried moisture limits

• Hygroscopic • Process in low humidity conditionsingredients


• Use low moisture grades Avicel® PH-112 and PH-113

• Adhesive or • Increase lubricant leveloleaginouscomponents • 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 orparticles

• Low melting point • Adsorb low melting point ingredientingredient on Avicel® PH, replace with higher

melting point ingredient


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Punch filming or • Inadequate lubrication • Increase or change lubricantsticking(continued) • Use microfine lubricants, screen

into mix

• Increase lubricant mixing time

• Insufficiently dried wet • Dry granulation and establishgranulation moisture limits

. • Hygroscopic • Process under low humiditycomponents 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 mixturedirectly 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 remainingpowder, which isaround the hole, mayfall into the hole withthe net result beingan uneven flow ofpowder and/or lumpsfrom the hopper

Relative humidity (RH) • Ratio of the amount of • Keep tableting area


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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 ofconstant, lowers the material being compressed with,relative humidity but perhaps, some loss ofthe absolute amount compressibilityof water present isthe same • See “Hygroscopic ingredients”

• See “Hygroscopic tablets”

Roll compacting • Forcing powder • See Section 2(almost always aformulation containing • Use Avicel® PH-101filler, lubricant, anddisintegrant) between

two oppositely turningrolls in order to form adense compact in theform of a relatively flatsheet as it exits therolls

• The sheet (which oftenbreaks under its ownweight as it exits therolls) is milled to formgranules, which canthen be used for

tableting after addingadditional lubricant,disintegrant, etc.


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Score line or tablet • Faulty punch • Redesign using chamfered edgesimprint not sharp embossing design on the punch embossing

• Chrome-plate punch face

• Granulation too • Reduce particle size of granulationcoarse

• Binder not strong • Use a stronger binderenough

Screen clogging • See “Clogging of screen (wet mass)”(wet mass)

Segregation • Particle size range of • Use a narrower particle size rangemix too wide of ingredients

• Limit the amount of the fines present

• Too wide a density • Control differences in the densitydifference of particles

• Mixer too vigorous, • Use a mixer with a gentler mixingproduces fines action

• Use of vibrators (to • Use force-feed mechanisms ratherpromote flow from than hopper vibratorshopper)

Slugging • Use of relatively large • See “Dry granulation”punches and dies toproduce tablets froma poor flowing powdermix

• Tablets usually notwell-controlled withrespect to weightand hardness


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Slugging (continued) • Tablets milled toproduce granuleswhich can then beused (after addingadditional lubricant,disintegrant, etc.)to produce uniformtablets of desiredsize, weight,hardness, etc.

Soft tablets • See “Binding (bonding orcompressibility)”


• See “Coarse particles”


• See “Elastic material”

• See “Excess fines (wetgranulation)”

• 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 betterflow and tableting

• See “Punch filming or sticking”

• See “Punch binding”


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Tablet binding • See “Punch binding”in the die

Tablets contain “dirty” • Misaligned upper cam • Check alignment of upper camspecks tracks - rubbing of tracks

punches on camactually rubs off metal,which is introducedinto material beingcompressed

• No lubrication onupper cam tracks

• Excessive or improper • Use dust caps on upper puncheslubrication on upper

punch shanks (no dustcaps on punches) -dust mixes with excessoil or grease and fallsinto material beingcompressed

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.

Underblending • See “Blending”

Variable hardness • Tooling • Examine punch lengths

• Uneven die fill • See “Weight variation”

• Overblending • Optimize blending time tominimize creation of fines


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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 tosuitable for die recommended optimum for diediameter diameter

• Punches not within • Examine punch length dimensionsspecifications

• Narrow the particle size range• Particle segregation

as press RPMs • Compress at slower RPMincrease

• Clean; improve dust collection• Lower punch “hangup” (material between • Check for proper clearancelower punch and die between die wall and lower punchwall or lower punchand punch guide) • Increase lubricant concentration

in formulation

• Remove below 200 mesh fines

Wet granulation • Process whereby • See Section 2active drugs andexcipients are wet

massed (wet witha solvent containinga binder in solution,usually), screened,dried, and screenedagain

• Used for high-doseactive drugs whichhave poor flow andeither cannot be orare difficult to directlycompress

• Used for active drugswhich are very fineand/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.

©1998 FMC Corporation. All rights reserved. RS

problem and remedies in tableting.pdf

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