problemas de tabletas

1

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) ........................................................................................................7Doughy 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 RemediesBy George E. Reier, PhD

Table of Contents

2

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

3

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

4

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

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 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)

5

Part A. Specific Tableting Problems and remedies (Process Format)

6


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


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

7

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 - 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

8

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 water mass gradually and mix well after each

addition

• Mass sensitive to • Incorporate 5% to 20% Avicel®water content PH-101 (allows a wider range

of solvent volume)

• Gummy binder • Change binder

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

determine acceptable residual solvent level by GC or other appropriate method); change binder

9

Drying


Nonuniform drying • Poor air circulation • Have oven air circulation checked(tray dryer) and corrected

• Dryer overload • Reduce number of trays

• Reduce thickness of wet mass on the trays (tray load)

• Try fluid bed dryer

Granule case hardening • Too rapid evaporation • Try recirculating oven air (damper(hard crust forms with of water closed) for initial 15 to 30 minutes,incomplete drying then open damper partially for 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

10


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

11

Dry Screening (Dry Granulation)


Excess fines • Granulation overdried • Decrease drying time/temperature

• Establish optimum moisture content

• Screen size too small • Use larger screen size

• Rotor/screen clearance • Adjust rotor clearancetoo close

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

• Weak granules • Increase granulating fluid

• Increase binder content

• Increase wet massing time

Difficult to screen • Granules too hard • Decrease drying temperature (case hardening)

• Decrease water content (use alcohol/water)

• Decrease binder content

• Use weaker binder

• Moisture in granulation • Increase drying time


12


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

13

Feed Hopper


Poor flow • Too many fines in wet • Reduce fines (see “Dry screening: granulation Excess fines”)

“rat-holing”

“bridging” • In direct compression, • Select larger particle size; use particle size of drug or Avicel® PH-102 or PH-200 in place excipients too small of PH-101 or other 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

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

14


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

15

Table Weight


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

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

• Use Avicel® PH-200 to minimize weight variation

• Particle size not • Adjust particle size range 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)

• Increase lubricant concentration in formulation

• Remove below 200 mesh fines

16

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 into dies) mix

• Increase lubricant blending time

• Too many fines or • Design better particle size range;coarse particles in mix use tapered dies

• Wet granulation • Dry granulation to 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 moisture grades Avicel® PH-112 and PH-113

17


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

• Use shallow embossing with tapered edges rather than edges directly perpendicular to punch face

• Punch tips burred • Refinish or replace

• Punch concavity too • Reduce punch concavity or use great flat face punches

• Poor binding between • Increase binder (wet or dry) surface granules or particles

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

higher melting point ingredient

• Inadequate lubrication • Increase or change lubricant

• Use microfine lubricants, screen into mix

• Increase lubricant mixing time

• Insufficiently dried wet • Dry granulation and establishgranulation moisture limits

• Hygroscopic • Process under low humidity components conditions

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



or 5% to 10% Avicel® PH-101

• Tablets too soft • Increase compression pressure

18


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

19


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 concave deep or flat face punches

• Punch edges worn or • Refinish or replace damaged

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

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

• Excessive tableting • Decrease pressurepressure

• Die wall binding • Use sufficient lubricant

• Use tapered dies

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

• Lower punch setting • Adjust lower punch flush with too low at tablet die face takeoff

• Tablet sweep-off • Adjust settingblade on feed frame set too high

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

• Chrome-plate punch face

• Granulation too • Reduce particle size of granulationcoarse

• Binder not strong • Use a stronger binder enough

20


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 time required; do not blend for long periods 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)


• Blend lubricant for minimal timerequired; establish optimum mixingtime

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

• Granulation too soft • Use additional binder

• Direct compression - use additional Avicel® PH

• Excipient (i.e., too • Reduce level of causative much starch can give excipient a soft tablet)

21


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 moisture low (granulation content overdried or low humidity 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 change of the tablet mix to stronger binder

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

• Avicel® PH gives low friability at lower hardness/machine pressures

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



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

22


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 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

23


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.

24


Active ingredients • See “Sticky ingredients”

• See “Low to medium level of active”

• See “High percent active”

• See “Attraction of particles”

• See “Dosage variation”

• See “Density”

• See “Elastic material”

Adsorbents • Materials used to • Use starch, Avicel® PH-101, overcome oiliness or silicon dioxide (Syloid®) or stickiness of tablet tribasic calcium phosphate ingredients

Agglomeration of • Occurs with fine • Fine-screen cohesive 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


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

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

25


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)

• Static electricity • Mechanically disperse

• Drain off static charge

• Low relative humidity • Slightly increase moisture level

• See “Blending”

• Densify as last resort

Binder • Wet granulation - • See Section 4 for a description substances which are of excipients and their uses added in solution (usually) or sometimes dry, followed by granulating solvent to “glue” a powder mix into granules for solid dose preparation

• Direct compression - substances which give compressibility or cohesiveness to the powder mix

26


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)

• Increase binder in formulation

27


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

28


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


29


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)

• Use a fluid bed dryer

30


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

31


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

• See “Segregation”

32


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

33


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

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

• Process in low humidity atmosphere


Diluent • Inert material(s) • See Section 4 for a description added to give the of excipients and their uses necessary bulk for solid dosage preparation

Dilution potential • The percent of an • Avicel® PH has a very high dilution active (usually poorly potential when used as a binder compressible such as ascorbic acid or APAP) that can be compressed with an excipient to form a tablet having 1% or less friability

Direct compression • Method of • See Sections 2 - 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

34


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

• Replace metallic stearates withother 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 allow low 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 of aqueous coating

35


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"

• See “Flow problem”


• See “Die fill (nonuniform)”

• See “Nonuniformity of mix”

36


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 blending • See Section A: “Dry blending”

37


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


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

compressibility

38


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, “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

• Weak granules • Increase binder content/granulating fluid

• Increase wet massing time

• Use stronger binder

39


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 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

40


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


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

• Add or increase Avicel® PH-101 or PH-102 (10% to 20%), which give low friability at lower hardness/machine pressures

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

41


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

required; establish optimum blending time


Glidant • Excipient used to • See Section 4improve fluidity of powders • 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/diebinding 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 - also to reduce tablet friability

• See “Binding (bonding orcompressibility)”

• Decrease compressing speed to increase tablet hardness

42


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

Hardness, variable • Tooling • Examine punch lengths

• Uneven die fill • See “Weight variation”

• Overblending • Optimize blending time to minimize creation of fines

High friability • See “Friability (high)”

High level of active • Direct compression • High percentages of actives can 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

High relative humidity • See “Relative humidity”

Hopper flow • See “Die fill”

• See “Flow Problem”


43


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 time required; establish optimum mixing times


• See “Lubricants”

44


Loss of hardness • Tablets with Avicel® PH • See “Hygroscopic ingredients”(with time) lose some hardness

with time at high • See “Hygroscopic tablets” humidity, but most of the hardness is quickly regained at normal humidity

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

punch size used)


• Blend lubricant for minimal time required; establish optimum mixing times


• Granulation too soft • Use additional binder

• Direct compression - use additional Avicel® PH

• Excipient (i.e., too • Reduce level of causative excipient much starch can give a soft tablet)

• Moisture content too • Granulation underdried high

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

• Moisture content too • Granulation overdriedlow

• Low humidity-direct compression excipients too low in moisture content

45


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)

Mixing • See “Blending”

• See Section A, “Dry blending”

46


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

• Overblending • Reduce blending time

• Establish optimum mixing conditions

47


Nonuniformity of mix • Low-dosage actives • Use a more effective mixer (one(continued) with increased shearing action)

• Low-level excipients • Blend the low-level component with a portion (5% to 10%) of an excipient; screen (mill) if necessary; reblend; add to an equal quantity of excipient and mix; screen or mill if necessary; blend normally with remainder of bulk

• Dissolve drug in a suitable solvent and add or spray onto a portion of the bulk or an excipient; blend; remove solvent

Note: For direct compression excipient blends do not use a screen size or a mixer which will change the excipient particle size distribution

Oleaginous or sticky • See “Punch binding”actives

• See “Sticky ingredients”

Ordered mixing • Small-sized (drug) • See Section 2(adhesive blending) particles adhesively

held on the surface oflarger-sized(excipient) particles

• Segregation does notoccur

• Usually requires ahigh-intensity mixer

48


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

• Can cause particle size reduction leading to other problems

• Can cause “waterproofing” of tablet by lubricant

Oven drying • See “Drying”

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

• Some actives alone and in combination with excipients are more sensitive than others (due to solubility)

Partial direct • See “Modified direct compression”compression

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

• See “Density, tapped”


• See “Punch binding”

49


Particle size • See “Binding (bonding or distribution 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 of compressed powder left on punch faces (mostly upper) after compression - tablet surface is “picked”

• Often associated with punch filming and sticking

Poor binding • See “Binding (bonding or compressibility)”

Poor color distribution • See “Color distribution”

• See “Color migration”

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

50


Poor granule • Wet granulation • Granules must be disintegrated disintegration 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”


51


Precompression • Application of a • See Section 3 relatively small amount of tableting pressure immediately prior to application of main tableting pressure

• Aids in removing entrapped air

• Aids in preventing/minimizing capping/laminating of difficult-to-compress materials by allowing time for relaxation between compressions

• Requires a rotary tablet machine equipped for precompression

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

• Increase lubricant level

• Blend abrasive component separately with the lubricant

• Use minimum tableting pressure possible

• Use more wear-resistant tooling (harder metal)

52


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

• Wet granulation • Dry granulation to satisfactory insufficiently dried moisture limits

• Hygroscopic • Process in low humidity conditions ingredients


• 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

melting point ingredient

53


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 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

54


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.

55


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

• Chrome-plate punch face

• Granulation too • Reduce particle size of granulationcoarse

• Binder not strong • Use a stronger binder enough

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

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

• Limit the amount of the fines present

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

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

• Use of vibrators (to • Use force-feed mechanisms rather promote flow from than hopper vibrators hopper)

Slugging • Use of relatively large • See “Dry granulation” punches and dies to produce tablets from a poor flowing powder mix

• Tablets usually not well-controlled with respect to weight and hardness

56


Slugging (continued) • Tablets milled to produce granules which can then be used (after adding additional lubricant, disintegrant, etc.) to produce uniform tablets of desired size, weight, hardness, etc.

Soft tablets • See “Binding (bonding or compressibility)”


• See “Coarse particles”


• See “Elastic material”

• See “Excess fines (wet granulation)”

• See “Friability (high)”

• See “Hardness, variable”

• See “Loss of hardness (with time)”

• See “Low hardness”

Splitting (tablets) • See “Capping and laminating”

• See “Chipping/splitting”

Sticking to punch face • See “Punch filming or sticking”

Sticky ingredients • Fines in excipient mix (especially Avicel® PH) aid in “drying up” oleaginous actives, giving better flow and tableting

• See “Punch filming or sticking”

• See “Punch binding”

57


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 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.

Underblending • See “Blending”

Variable hardness • Tooling • Examine punch lengths

• Uneven die fill • See “Weight variation”

• Overblending • Optimize blending time tominimize creation of fines

58


Weight variation • Poor or erratic powder • Correct powder flow problems(outside limits) flow, flooding (See “Feed Hopper” in Part A)

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

• Particle size not • Adjust particle size range to suitable for die recommended optimum for die diameter diameter

• Punches not within • Examine punch length dimensions specifications

• Narrow the particle size range• Particle segregation

as press RPMs • Compress at slower RPM increase

• Clean; improve dust collection• Lower punch “hang

up” (material between • Check for proper clearance lower punch and die between die wall and lower punch wall or lower punch and punch guide) • Increase lubricant concentration

in formulation

• Remove below 200 mesh fines

Wet granulation • Process whereby • See Section 2 active drugs and excipients are wet massed (wet with a solvent containing a binder in solution, usually), screened, dried, and screened again

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

• Used for active drugs which are very fine and/or low density

59

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

problemas de tabletas

Documents

screening dry granulation

dry blending

color migration

incomplete drying

tablet problems

granulation massing

color distribution

remedies process format