problem and remedies in tableting.pdf

Section 5

Tablet Problems and Remedies By George E. Reier, PhD

Table of Contents Tablet Problems and Remedies.............. Remedies............................ ............................. ............................. ............................ ............................. .............................. ..................1 ...1 Table of Contents .............. ............................ ............................. ............................. ............................. ............................. ............................ .............................. .....................1 .....1 Part A. Specific Tableting Problems and Remedies (Process Format) ............. ........................... ...........................5 .............5 Dry Blending ............. ........................... ............................. ............................. ............................. ............................. ............................. ............................. .........................5 ...........5 Particle agglomeration ............... ............................. ............................ ............................. ............................. ............................. ............................. ..................5 ....5 Nonuniformity of mix ............. ........................... ............................. ............................. ............................. ............................. ............................ .......................5 .........5 Segregation Segregati on after blending ............... ............................. ............................. ............................. ............................. ............................. .........................6 ...........6 Wet Granulation (Massing) .............. ............................ ............................. ............................. ............................. ............................. ............................. ..................7 ...7 Doughy mass............. mass........................... ............................. ............................. ............................. ............................. ............................ ............................. .....................7 ......7 Moisture Moistur e sensitive drugs .............. ............................ ............................. ............................. ............................. ............................. ............................. ................7 .7 Wet Screenin Screening.................. g................................. ............................. ............................. ............................. ............................. ............................. ............................. ..................8 ...8 Screen clogging.............. clogging............................ ............................. ............................. ............................ ............................. ............................. ............................. ................8 .8 Drying ............... ............................. ............................. ............................. ............................. ............................. ............................ ............................. .............................. ..................9 ...9 Nonuniform drying ............. ............................ ............................. ............................. ............................. ............................. ............................. .........................9 ...........9 Granule case hardening (hard crust forms with incomplete drying inside granule) .......... ................ ...... 9 Color migration .............. ............................ ............................ ............................. ............................. ............................. ............................. ............................. ................9 .9 Drug migration ............... ............................. ............................ ............................. ............................. ............................. ............................. ............................1 ..............10 0 Dry Screening (Dry Granulation) ............. ............................ ............................. ............................ ............................. ............................. .......................11 .........11 Excess fines .............. ............................ ............................. ............................. ............................. ............................. ............................ .............................. ...................11 ...11 Difficult to screen....... screen..................... ............................. ............................. ............................. ............................. ............................. .............................. ..................11 ...11 Poor color distribution ............... ............................. ............................ ............................. ............................. ............................. ............................. ................12 ..12 Feed Hopper .............. ............................. ............................. ............................. ............................. ............................. ............................. ............................. .....................13 ......13 Poor flow.......... flow........................ ............................. ............................. ............................. ............................. ............................. ............................. ............................1 ..............13 3 Flooding.............. Flooding ............................ ............................ ............................. ............................. ............................. ............................. ............................. ..........................14 ...........14 Particle segregatio segregation...................... n.................................... ............................. ............................. ............................. ............................. ............................1 ..............14 4 Tablet Weight .........................................................................................................................15 Weight variation outside limits ............. ............................ ............................. ............................. ............................. ............................. ...................15 ....15 Punches and Dies.......... Dies........................ ............................. ............................. ............................. ............................. ............................ .............................. ...................16 ...16 Punch binding (powder adheres to punch edges and dies; punches may bind in dies) ......16 Punch filming or sticking (picking)—(powde (picking)—(powderr adhesion to punch faces, usually upper) ......17 Punch and die abrasion ............. ........................... ............................. ............................. ............................ ............................. ............................. ................18 ..18 Capping and laminating laminating............. ........................... ............................ ............................. ............................. ............................. ............................. ................18 ..18 Chipping/splitting Chipping/s plitting ............. ........................... ............................. ............................. ............................. ............................. ............................. ..........................19 ...........19 Score line or tablet imprint not sharp ............. ............................ ............................. ............................. ............................. .......................19 .........19 Layered Layere d tablets splitting splitting............... ............................. ............................. ............................. ............................. ............................. ............................2 ..............20 0 Layers not sharply defined ............... ............................. ............................. ............................. ............................. ............................. .......................20 .........20

1

Low hardne hardness ss ............. ........................... ............................. ............................. ............................. ............................. ............................ ............................. ......................20 .......20 Varia V ariable ble hardn hardness ess .... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... ......... .....21 .21 High friability ............... ............................. ............................. ............................. ............................ ............................. ............................. .............................. ......................21 ......21 Disintegration Disintegrati on too long ............. ........................... ............................. ............................. ............................. ............................. ............................. ......................22 .......22 Mottling ............. ........................... ............................. ............................. ............................. ............................. ............................. ............................. ............................. .................22 ..22 Tablets contain “dirty” specks ............. ............................ ............................. ............................ ............................. ............................. ........................23 ..........23 Tablets uniformly discolored...................................................................................................23 Part B. General Tableting Problems and Remedies (Alphabetical Order Format) ......................24 Active Acti ve ingred ingredient ients s .... ......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... ......... .....24 .24 Adsorben Adso rbents ts .... ........ ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... ......... .....24 .24 Agglomer Aggl omeration ation of particle particles s ..... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .....24 24 Aging Agin g of tablets. tablets...... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... .......24 ..24 Air entrap entrapment ment.... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... ......... .....25 .25 Antiadhe Anti adheren rentt .... ......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... .......25 ..25 Attractio Attr action n of particle particles s (aggregation or agglomeration) ............... ............................. ............................. ............................. ................25 ..25 Binder .............. ............................. ............................. ............................ ............................. ............................. ............................. ............................. ............................. .................25 ..25 Binding (bonding or compressibilit compressibility) y) ............. ........................... ............................. ............................. ............................ ............................. .................26 ..26 Binding in the die (punches) ............. ........................... ............................ ............................. ............................. ............................. ............................. ..............26 26 Bioavailability Bioavailabil ity .............. ............................ ............................ ............................. ............................. ............................. ............................. ............................. ......................26 .......26 Bisected or debossed tablets (not sharp or well-define well-defined) d) ............. ............................ ............................. ........................26 ..........26 Blending ............. ............................ ............................. ............................. ............................. ............................. ............................. ............................. .............................2 ..............27 7 Bonding ............. ............................ ............................. ............................. ............................. ............................. ............................. ............................. .............................2 ..............27 7 Bridging .............. ............................. ............................. ............................. ............................. ............................. ............................. ............................. .............................2 ..............27 7 Brittle fracture ............. ........................... ............................. ............................. ............................ ............................. ............................. ............................. ......................28 .......28 Bulk density ............. ............................ ............................. ............................. ............................. ............................ ............................. ............................. ........................28 ..........28 Capping and laminating ............. ............................ ............................. ............................. ............................. ............................. ............................. ...................28 .....28 Case harden hardening................ ing.............................. ............................ ............................. ............................. ............................. ............................. ............................. .................29 ..29 Chipping/splitting Chipping/sp litting ............. ........................... ............................. ............................. ............................. ............................. ............................ .............................3 ...............30 0 Clogging of screen (wet mass) ............. ............................ ............................. ............................. ............................. ............................. ........................30 .........30 Coarse particles.............. particles............................. ............................. ............................. ............................. ............................. ............................. ............................. .................31 ..31 Color distribution ............... ............................. ............................. ............................. ............................. ............................. ............................ .............................3 ...............31 1 Color migraton migraton.............. ............................ ............................. ............................. ............................. ............................. ............................. .............................. ...................31 ....31 Compressibility Compress ibility ............. ........................... ............................. ............................. ............................. ............................. ............................. .............................. ...................31 ....31 Content uniformity uniformity............. ........................... ............................. ............................. ............................. ............................. ............................ .............................3 ...............31 1 Density, bulk (loose density) ......... ................... .................... .................... .................... ..................... ..................... .................... .................... .................... ...............32 .....32 Density,, tapped.................... Density tapped................................... ............................. ............................. ............................. ............................. ............................. ..........................32 ............32 Die fill (nonuniform) (nonuniform)............. ............................ ............................. ............................ ............................. ............................. ............................. ............................. ..............32 32 Diluent .............. ............................. ............................. ............................ ............................. ............................. ............................. ............................. ............................. .................33 ..33 Dilution potential......................... potential........................................ ............................. ............................. ............................. ............................. .............................. ...................33 ....33 Direct compress compression.............. ion............................. ............................. ............................. ............................. ............................. ............................. ..........................33 ............33 Disintegrantt ............. Disintegran ............................ ............................. ............................. ............................. ............................ ............................. .............................. ........................33 .........33 Disintegration Disintegrati on too long or incomplete......... incomplete........................ ............................. ............................ ............................. ............................. .................34 ...34 Disintegration Disintegrati on during coating ............... ............................. ............................. ............................. ............................. ............................. ........................34 ..........34 Dissolution ............. ........................... ............................. ............................. ............................. ............................. ............................ ............................. ...........................35 ............35

2

Low hardne hardness ss ............. ........................... ............................. ............................. ............................. ............................. ............................ ............................. ......................20 .......20 Varia V ariable ble hardn hardness ess .... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... ......... .....21 .21 High friability ............... ............................. ............................. ............................. ............................ ............................. ............................. .............................. ......................21 ......21 Disintegration Disintegrati on too long ............. ........................... ............................. ............................. ............................. ............................. ............................. ......................22 .......22 Mottling ............. ........................... ............................. ............................. ............................. ............................. ............................. ............................. ............................. .................22 ..22 Tablets contain “dirty” specks ............. ............................ ............................. ............................ ............................. ............................. ........................23 ..........23 Tablets uniformly discolored...................................................................................................23 Part B. General Tableting Problems and Remedies (Alphabetical Order Format) ......................24 Active Acti ve ingred ingredient ients s .... ......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... ......... .....24 .24 Adsorben Adso rbents ts .... ........ ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... ......... .....24 .24 Agglomer Aggl omeration ation of particle particles s ..... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .....24 24 Aging Agin g of tablets. tablets...... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... .......24 ..24 Air entrap entrapment ment.... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... ......... .....25 .25 Antiadhe Anti adheren rentt .... ......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... .......25 ..25 Attractio Attr action n of particle particles s (aggregation or agglomeration) ............... ............................. ............................. ............................. ................25 ..25 Binder .............. ............................. ............................. ............................ ............................. ............................. ............................. ............................. ............................. .................25 ..25 Binding (bonding or compressibilit compressibility) y) ............. ........................... ............................. ............................. ............................ ............................. .................26 ..26 Binding in the die (punches) ............. ........................... ............................ ............................. ............................. ............................. ............................. ..............26 26 Bioavailability Bioavailabil ity .............. ............................ ............................ ............................. ............................. ............................. ............................. ............................. ......................26 .......26 Bisected or debossed tablets (not sharp or well-define well-defined) d) ............. ............................ ............................. ........................26 ..........26 Blending ............. ............................ ............................. ............................. ............................. ............................. ............................. ............................. .............................2 ..............27 7 Bonding ............. ............................ ............................. ............................. ............................. ............................. ............................. ............................. .............................2 ..............27 7 Bridging .............. ............................. ............................. ............................. ............................. ............................. ............................. ............................. .............................2 ..............27 7 Brittle fracture ............. ........................... ............................. ............................. ............................ ............................. ............................. ............................. ......................28 .......28 Bulk density ............. ............................ ............................. ............................. ............................. ............................ ............................. ............................. ........................28 ..........28 Capping and laminating ............. ............................ ............................. ............................. ............................. ............................. ............................. ...................28 .....28 Case harden hardening................ ing.............................. ............................ ............................. ............................. ............................. ............................. ............................. .................29 ..29 Chipping/splitting Chipping/sp litting ............. ........................... ............................. ............................. ............................. ............................. ............................ .............................3 ...............30 0 Clogging of screen (wet mass) ............. ............................ ............................. ............................. ............................. ............................. ........................30 .........30 Coarse particles.............. particles............................. ............................. ............................. ............................. ............................. ............................. ............................. .................31 ..31 Color distribution ............... ............................. ............................. ............................. ............................. ............................. ............................ .............................3 ...............31 1 Color migraton migraton.............. ............................ ............................. ............................. ............................. ............................. ............................. .............................. ...................31 ....31 Compressibility Compress ibility ............. ........................... ............................. ............................. ............................. ............................. ............................. .............................. ...................31 ....31 Content uniformity uniformity............. ........................... ............................. ............................. ............................. ............................. ............................ .............................3 ...............31 1 Density, bulk (loose density) ......... ................... .................... .................... .................... ..................... ..................... .................... .................... .................... ...............32 .....32 Density,, tapped.................... Density tapped................................... ............................. ............................. ............................. ............................. ............................. ..........................32 ............32 Die fill (nonuniform) (nonuniform)............. ............................ ............................. ............................ ............................. ............................. ............................. ............................. ..............32 32 Diluent .............. ............................. ............................. ............................ ............................. ............................. ............................. ............................. ............................. .................33 ..33 Dilution potential......................... potential........................................ ............................. ............................. ............................. ............................. .............................. ...................33 ....33 Direct compress compression.............. ion............................. ............................. ............................. ............................. ............................. ............................. ..........................33 ............33 Disintegrantt ............. Disintegran ............................ ............................. ............................. ............................. ............................ ............................. .............................. ........................33 .........33 Disintegration Disintegrati on too long or incomplete......... incomplete........................ ............................. ............................ ............................. ............................. .................34 ...34 Disintegration Disintegrati on during coating ............... ............................. ............................. ............................. ............................. ............................. ........................34 ..........34 Dissolution ............. ........................... ............................. ............................. ............................. ............................. ............................ ............................. ...........................35 ............35

2

Dosage variation........................ variation...................................... ............................. ............................. ............................. ............................. ............................ .....................35 .......35 Doughy mass........................ mass...................................... ............................. ............................. ............................. ............................. ............................. ..........................36 ...........36 Drug migration migration............... ............................. ............................. ............................. ............................. ............................. ............................ .............................. ...................36 ...36 Dry blending....... blending..................... ............................. ............................. ............................. ............................. ............................ ............................. .............................. ................36 .36 Dry granulation (by slugging or compaction ) ).... ......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .........3 ....37 7 Dry screeni screening ng.............. ............................. ............................. ............................. ............................. ............................. ............................. ............................. .....................37 ......37 Dye migration.......... migration........................ ............................ ............................. ............................. ............................. ............................. ............................. ..........................38 ...........38 Ejection problem.............. problem............................. ............................. ............................. ............................. ............................. ............................. ............................. ................38 .38 Elastic material.......... material........................ ............................. ............................. ............................. ............................. ............................. .............................. .......................38 ........38 Entrapment of air ............. ............................ ............................. ............................. ............................. ............................ ............................. .............................. ................38 .38 Excess fines (wet granulation) .............. ............................ ............................. ............................. ............................ ............................. ..........................38 ...........38 Expanding tablets........................ tablets....................................... ............................. ............................. ............................. ............................ .............................. ...................39 ...39 Filler ............... ............................. ............................. ............................. ............................. ............................. ............................ ............................. .............................. ................39 .39 Filming of punches ............. ........................... ............................ ............................. ............................. ............................. ............................. ............................3 ..............39 9 Fines (direct compression) ............... ............................. ............................. ............................. ............................. ............................. ............................. ................39 .39 Fines (wet granulation) .............. ............................ ............................. ............................. ............................ ............................. ............................. .......................39 .........39 Flooding ............. ........................... ............................. ............................. ............................. ............................. ............................ ............................. .............................. ................39 .39 Flow problem problem............... ............................. ............................ ............................. ............................. ............................. ............................. ............................. .....................40 ......40 Friability (high) .............. ............................ ............................ ............................. ............................. ............................. ............................. ............................. .....................40 ......40 Glidant ............... ............................. ............................. ............................. ............................. ............................. ............................ ............................. .............................. ................41 .41 Granulation,, dry ............. Granulation ........................... ............................. ............................. ............................. ............................. ............................ .............................. ...................41 ...41 Granulation,, wet .............. Granulation ............................. ............................. ............................. ............................. ............................ ............................. .............................. ................41 .41 Hard tablets .............. ............................ ............................. ............................. ............................. ............................. ............................. .............................. .......................41 ........41 Hardness increas increases es with time ............... ............................. ............................. ............................. ............................. ............................. .......................42 .........42 Hardness,, variable Hardness variable.............. ............................ ............................. ............................. ............................ ............................. ............................. ............................4 ..............42 2 High friability ............. ........................... ............................. ............................. ............................. ............................. ............................. .............................. .......................42 ........42 High relative humidity humidity............. ............................ ............................. ............................. ............................. ............................. ............................. .......................42 .........42 Hopper flow .............. ............................ ............................. ............................. ............................. ............................. ............................. ............................. .......................42 .........42 Hygroscopic Hygroscop ic ingredie ingredients.............. nts............................. ............................. ............................ ............................. ............................. ............................. ...................43 ....43 Hygroscopic Hygroscop ic tablets......... tablets........................ ............................. ............................ ............................. ............................. ............................. .............................. ................43 .43 Laminating .............. ............................ ............................ ............................. ............................. ............................. ............................. ............................. ..........................43 ...........43 Layered tablets splitting (poor bonding between layers; layers peel or split apart) .................43 Loss of hardness (with time) ............. ............................ ............................. ............................. ............................. ............................. ............................4 .............44 4 Loss of hardnes hardness s ............. ............................ ............................. ............................. ............................. ............................ ............................. .............................. ................44 .44 Low to medium level of active (in direct compression).............. compression) ............................. ............................. ............................. ................45 .45 Lubricants ............... ............................. ............................ ............................. ............................. ............................. ............................. ............................. ..........................45 ...........45 Mixing ............... ............................. ............................. ............................. ............................. ............................. ............................ ............................. .............................. ................45 .45 Modified direct compres compression............ sion........................... ............................. ............................ ............................. ............................. ............................4 ..............46 6 Moisture sensitive actives ............. ............................ ............................. ............................. ............................. ............................. ............................. ................46 ..46 Mottling .............. ............................ ............................. ............................. ............................. ............................. ............................ ............................. .............................. ................46 .46 Nonuniform die fill................. fill............................... ............................. ............................. ............................. ............................. ............................. ..........................46 ...........46 Nonuniform drying (tray drying) ............. ............................ ............................. ............................ ............................. ............................. .......................46 .........46 Nonuniformity of mix .............. ............................. ............................. ............................. ............................. ............................. ............................. .......................46 .........46 Oleaginous or sticky actives .............. ............................. ............................. ............................. ............................. ............................ ..........................47 ............47

3

Ordered mixing (adhesive blending) .............. ............................ ............................. ............................. ............................ ............................. .................47 ..47 Overblending Overblend ing .............. ............................ ............................. ............................. ............................ ............................. ............................. ............................. ......................48 .......48 Oven drying ............. ............................ ............................. ............................. ............................. ............................. ............................. ............................ ........................48 ..........48 Overwetting Overwettin g of wet mass .............. ............................ ............................. ............................. ............................. ............................. ............................. .................48 ..48 Partial direct compress compression.................. ion................................ ............................. ............................. ............................. ............................. ..........................48 ............48 Particle density variation .............. ............................ ............................. ............................. ............................. ............................. ............................. .................48 ..48 Particle size distribution ............. ............................ ............................. ............................. ............................. ............................. ............................. ...................49 .....49 Picking .............. ............................ ............................. ............................. ............................. ............................. ............................. ............................. ............................. .................49 ..49 Poor binding ............... ............................. ............................. ............................. ............................ ............................. ............................. ............................. ......................49 .......49 Poor color distribution.......................... distribution........................................ ............................. ............................. ............................. ............................. ........................49 ..........49 Poor flow (“rat-holing” or “bridging”) ............. ........................... ............................. ............................. ............................ ............................. .................49 ..49 Poor granule disintegration ............. ............................ ............................. ............................. ............................. ............................ .............................5 ...............50 0 Poor layer demarcatio demarcation n ............... ............................. ............................ ............................. ............................. ............................. ............................. ...................50 .....50 Poor tablet finish/appe finish/appearance arance.............. ............................ ............................. ............................. ............................. ............................. ........................50 ..........50 Postgranulation Postgranula tion addition ............... ............................. ............................. ............................. ............................ ............................. ............................. .................50 ...50 Powder separation .............. ............................. ............................. ............................. ............................. ............................. ............................. ..........................50 ............50 Precompression...................... Precompr ession.................................... ............................. ............................. ............................. ............................. ............................ ........................51 ..........51 Punch and die abrasion .............. ............................ ............................ ............................. ............................. ............................. ............................. ...................51 .....51 Punch binding (powder adheres to punch edges and dies; punches may bind in dies) ..........52 Punch filming or sticking (picking)—(pow (picking)—(powder der adhesion to punch faces, usually upper) ..........52 Rat-holing ............. ........................... ............................. ............................. ............................. ............................. ............................ ............................. ...........................53 ............53 Relative humidity (RH) (RH)............. ........................... ............................. ............................. ............................. ............................. ............................. ........................53 .........53 Roll compacting............ compacting.......................... ............................. ............................. ............................. ............................. ............................. .............................. ...................54 ....54 Score line or tablet imprint not sharp .............. ............................. ............................. ............................ ............................. ...........................5 ............55 5 Screen clogging (wet mass) .............. ............................ ............................ ............................. ............................. ............................. ............................. ..............55 55 Segregation..................... Segregati on.................................... ............................. ............................. ............................. ............................. ............................. ............................. .................55 ..55 Slugging.............. Slugging ............................. ............................. ............................. ............................. ............................. ............................. ............................. .............................5 ..............55 5 Soft tablets ............. ............................ ............................. ............................. ............................. ............................ ............................. .............................. ........................56 .........56 Splitting (tablets) (tablets)............... ............................. ............................. ............................. ............................ ............................. ............................. ............................. .................56 ..56 Sticking to punch face ............. ........................... ............................. ............................. ............................. ............................. ............................. ......................56 .......56 Sticky ingredien ingredients ts .............. ............................ ............................. ............................. ............................. ............................. ............................. .............................5 ..............56 6 Tablet binding in the die ............. ............................ ............................. ............................. ............................. ............................. ............................. ...................57 .....57 Tablets contain “dirty” specks ............. ........................... ............................. ............................. ............................. ............................. ........................57 ..........57 Tablets uniformly discolored...................................................................................................57 Underblending Underblend ing ............. ............................ ............................. ............................ ............................. ............................. ............................. .............................. ...................57 ....57 Varia V ariable ble hardn hardness ess .... ......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... .......... .......... .......... .......... ......... ......... .......... .......... .......... ......... ......... ......... .....57 .57 Weight variation (outside limits)............. limits) ............................ ............................. ............................. ............................. ............................. ........................58 .........58 Wet granulation............... granulation.............................. ............................. ............................. ............................. ............................. ............................. ............................. .................58 ..58

4

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

Problem/Concept

Cause/Definition

Remedy/Suggested Solution

Particle agglomeration

• Occurs with fine cohesive powders, which cause “balling up” and poor distribution

• Fine-screen cohesive compound into bulk mix • Use a more effective mixer (one with increased shearing action) • Blend Blend the the cohes cohesive ive powd powder er with 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

• Impr Improper oper blen blender der load

• Use rec recomme ommended nded powd powder er load in blender

• Insufficient mixing

• Increase mixing time

• Inefficient (improper) mixer

• Use alternative mixer with increased shearing action

• Wide particle size distribution

• Select more uniform particle sizes of components

• Overblending

• Reduce blending time • Establ Establish ish opt optimu imum m mix mixing ing conditions

• Low-dosage actives

5

• Use a more effective mixer (one with increased shearing action)

Problem/Concept

Cause/Definition


Nonuniformity of mix (continued)

• 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

Segregation after blending

• Particle size distribution too wide

6

• Use a narrower particle size range of components

Wet Granulation (Massing)

Problem/Concept

Cause/Definition


Doughy mass

• Too much water (often seen on scaleup)

• Add granulating water slowly; mix well after each addition

• Overmixing during granulation step

• Reduce water or mixing time

• Wrong binder

• Change binder

• Component of mix (e.g., active drug or excipient)

• If possible, use alcohol/water or alcohol as granulating fluid - 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

• Instability with water

• If possible, use ethyl alcohol or isopropyl alcohol (if latter, determine acceptable residual solvent by GC or other appropriate method) as granulating fluids, ethyl cellulose and PVP as binders

Moisture sensitive drugs

• Try slugging or roller compaction as dry granulation methods

7

Wet Screening

Problem/Concept

Cause/Definition


Screen clogging

• Doughy or sticky wet mass

• Avoid oscillating granulator • 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 mass

• Reduce water content; add water gradually and mix well after each addition

• Mass sensitive to water content

• Incorporate 5% to 20% Avicel ® PH-101 (allows a wider range of solvent volume)

• Gummy binder

• Change binder

• Component or 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

8

Drying

Problem/Concept

Cause/Definition


Nonuniform drying

• Poor air circulation (tray dryer)

• Have oven air circulation checked 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 (hard crust forms with incomplete drying inside granule)

• Too rapid evaporation of water • Oven drying conditions too efficient

• Try recirculating oven air (damper closed) for initial 15 to 30 minutes, then open damper partially for a short period, and finally open 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 granule surfaces (wet granulation); tablets have mottled appearance

• Use lakes instead of soluble dyes (will minimize but not eliminate) • 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

9

Problem/Concept

Cause/Definition


Drug migration

• Drug migrates to granule surfaces; 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

• See remedies under “Color migration”

10

Dry Screening (Dry Granulation)

Problem/Concept

Cause/Definition


Excess fines

• Granulation overdried

• Decrease drying time/temperature • Establish optimum moisture content

• Screen size too small

• Use larger screen size

• Rotor/screen clearance too close

• Adjust rotor clearance

• Overloading of mill or granulator

• Slow feed of material to mill 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 • Establish optimum moisture content

11

Problem/Concept

Cause/Definition


Poor color distribution

• Dye migration to granule surface (nonuniformity of color throughout granule)

• Use lakes instead of soluble dyes (will minimize but not eliminate problem) • 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

12

Feed Hopper

Problem/Concept

Cause/Definition


Poor flow

• Too many fines in wet granulation

• Reduce fines (see “Dry screening: Excess fines”)

• In direct compression, particle size of drug or excipients too small and/or of shape that will not flow

• Select larger particle size; use Avicel ® PH-102 or PH-200 in place of PH-101 or other excipient

“rat-holing” “bridging”

• 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 adsorption

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

13

Problem/Concept

Cause/Definition


Flooding

• Excessive flow properties (fluidization) of one or more components (could be from an excess of glidant or lubricant)

• Identify causative component and exclude or modify particle size

Particle segregation

• Select narrow range of particle sizes; avoid excess fines

• Flow is erratic and feed frame is flooded at times

• Use an induced or force-feed mechanism on press, which may control flow

• Particle size range of mix too wide

• Use a narrower particle size range of ingredients • See “Dry screening: Excess fines”

• Too wide a density difference in mix particles

• Control differences in density of particles

• Mixer too vigorous; produces fines

• Use a mixer with a gentler mixing action

• Use of vibrators (to promote flow from hopper)

• Use force-flow feed mechanisms rather than hopper vibrators

• Excessive machine vibration

• Isolate hopper from tablet machine

14

Table Weight

Problem/Concept

Cause/Definition


Weight variation outside limits

• Poor or erratic powder flow, flooding

• Correct powder flow problem (See “Feed hopper”)

• Particle size range too wide

• Narrow the particle size range; avoid excess fines • Use Avicel® PH-200 to minimize weight variation

• Particle size not suitable for die diameter

• Adjust particle size range to recommended optimum for die diameter

• Punches not within specifications

• Examine punch length dimensions

• Particle segregation as press RPM’s increase

• Narrow the particle size range • Compress at slower RPM

• Lower punch “hang up” • Clean; improve dust collection (material between lower punch and die wall or • Check for proper clearance lower punch and punch between die wall and lower punch guide) • Increase lubricant concentration in formulation • Remove below 200 mesh fines

15

Punches and Dies

Problem/Concept

Cause/Definition


Punch binding (powder adheres to punch edges and dies punches may bind in dies)

• Poor finish or worn punches and dies

• Polish, reface, or replace tooling

• Inadequate lubrication

• Increase or change lubricant; use microfine lubricants; screen into mix

• Increase lubricant blending time • Too many fines or coarse particles in mix

• Design better particle size range; use tapered dies

• Wet granulation insufficiently dried

• Dry granulation to satisfactory moisture limits

• Hygroscopic ingredients

• Process under low humidity conditions • Use moisture scavengers (e.g., calcium silicate, Syloid ®, Cab-O-Sil® )

• Adhesive components

• Increase lubricant level • Add 0.5% Cab-O-Sil® or Syloid® • Add 5% to 10% low moisture grades Avicel® PH-112 and PH-113

16

Problem/Concept

Cause/Definition


Punch filming or sticking (picking)— (powder adhesion to punch faces, usually upper)

• Poor finish on punch faces

• Polish punch faces; refinish

• Embossed letters

• Avoid using certain letters (e.g., “A”, “B”, “P”, “R”)

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

• Refinish or replace

• Punch concavity too great

• Reduce punch concavity or use flat face punches

• Poor binding between surface granules or particles

• Increase binder (wet or dry)

• Low melting point ingredient

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


• Increase or change lubricant • Use microfine lubricants, screen into mix • Increase lubricant mixing time

• Insufficiently dried wet granulation

• Dry granulation and establish moisture limits

• Hygroscopic components

• Process under low humidity conditions • Use moisture adsorbent (e.g., calcium silicate, Syloid ® )


• Increase lubricant level • Add 0.5% Cab-O-Sil® or Syloid® or 5% to 10% Avicel ® PH-101

• Tablets too soft

• Increase compression pressure

17

Problem/Concept

Cause/Definition


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

Capping is separation of the top or bottom from the main body of the tablet.

• Inadequate bonding of the powder particles (direct compression) or granules (wet granulation) to form cohesive tablets

• Use a stronger binder or additional binder


• Polish, reface, or replace

Laminating is transverse cracking and separation of the tablet into two or more layers.

• Avicel ® PH-101 and PH-102 are particularly effective direct compression binders (15% to 25%) and as auxiliary binders in wet granulation (5% to 15%)

• Chrome plate punch faces • Too many fines in granulation

• Modify granulation process for minimum fines

• Granulation too dry • Adjust moisture level and establish optimum moisture limits • Granulation too wet (usually associated with sticking or picking)

• Continue to dry and establish optimum moisture limit

• Overlubrication of final tableting mix

• Decrease lubricant level • Blend lubricant for minimal time required; establish optimum mixing time

18

Problem/Concept

Cause/Definition


Capping and laminating (continued)

• High level of ingredient with poor compression properties (also sometimes ascribed to air-entrapment by powder bed)

• Use precompression on tablet press • Slow the speed of the tablet machine

• Punch concavity too deep

• Change to standard concave or flat face punches

• Punch edges worn or damaged


• Lower punch too low at tablet take-off

• Adjust lower punch flush with die face

• Compression too low in die cavity

• Compress in upper portion of die

• Excessive tableting pressure

• Decrease pressure

• Die wall binding

• Use sufficient lubricant • Use tapered dies

Chipping/splitting

Score line or tablet imprint not sharp


• Polish, reface, or replace punches and dies

• Lower punch setting too low at tablet takeoff


• Tablet sweep-off blade on feed frame set too high

• Adjust setting

• Faulty punch debossing design

• Redesign using tapered sides on the punch debossing • Chrome-plate punch face

• Granulation too coarse

• Reduce particle size of granulation

• Binder not strong enough

• Use a stronger binder

19

Problem/Concept

Cause/Definition


Layered tablets splitting

• Poor bonding between layers

• Use a stronger binder or higher concentration

• Compression pressure too high

• Compress at lower pressures

• Overlubrication

• Decrease lubricant level • Blend lubricant for minimal time required; do not blend for long periods of time

Layers not sharply defined

Low hardness


• Reduce particle size of granulation - less than 16 mesh

• Too many fines

• Remove fines below 200 mesh

• Compression force (pressure) too low

• Increase pressure (caution: do not exceed recommended pressure for punch size used)

• Overlubrication

• Decrease lubricant level • Blend lubricant for minimal time required; establish optimum mixing time • Replace metallic stearates with other lubricants (e.g., stearic acid)

• Granulation too soft

• Use additional binder • Direct compression - use additional Avicel ® PH

• Excipient (i.e., too much starch can give a soft tablet)

20

• Reduce level of causative excipient

Problem/Concept

Cause/Definition


Low hardness (continued)

• Moisture consent too high (granulation underdried or high humidity in compressing area)

• Determine optimum moisture content

• Moisture content too low (granulation overdried or low humidity in compressing area)

• Determine optimum moisture content

• Tooling

• Examine punch lengths

• Uneven diefill

• See “Table Weight: Weight variation”

• Overblending

• Optimize blending time to minimize creation of fines

• Inadequate bonding of the tablet mix

• Increase binder level or change to stronger binder

Variable hardness

High friability

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

• Add additional moisture

• 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 compression pressure

• Adjust pressure for acceptable friability

• Overlubrication


21

Problem/Concept

Cause/Definition


Disintegration too long

• Tablet hardness too high

• Reduce machine pressure for acceptable tablets • Use less binder in granulation

• Overlubrication (waterproofing)


• Requires additional disintegrant or a different disintegrant

• Consider a “super disintegrant” (e.g., Ac-Di-Sol ®, 2% to 5%) • Include Avicel® PH-101 or PH-102 (added dry), about 10% as an auxiliary disintegrant • Consider adding a surfactant (e.g., DOSS, 0.1%)

Mottling

• Tablet hardness too low

• Increase hardness to allow swellable disintegrant to function

• Uneven distribution of the dye in colored tablets

• Increase mixing time or use high shear mixer

• Dye migration during drying process

• See “Drying: Color migration” • See “Dry screening: Poor color distribution”

• Preferential absorption of soluble dye by component of mix

• Replace causative component

• High level of uncolored additives (e.g., fillers, lubricants, disintegrants)

• Reduce quantity of additives

22

• Replace soluble dye with microfine lake pigment

• Color additives with soluble dye or mix with lake pigment

Problem/Concept

Cause/Definition


Mottling (continued)

• In direct compression, uneven distribution of lake dye

• Use microfine 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” specks

• Misaligned upper cam tracks - rubbing of punches on cam actually rubs off metal which is introduced into material being compressed

• Check alignment of upper cam tracks

• No lubrication on upper cam tracks

Tablets uniformly discolored

• Excessive or improper lubrication on upper punch shanks (no dust caps on punches) dust mixes with excess oil or grease and falls into material being compressed

• Use dust caps on upper punches

• Feed frame rubbing on die table

• Check clearance between feed frame and die table

• Feed hopper rubbing on turret

• Check clearance between feed hopper and turret

• Abrasive materials wearing screens, scooper, etc.

• Check for presence of abrasive materials

23

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

Cause/Definition

Remedy/Suggested Solution • See “Sticky ingredients”

Active 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 overcome oiliness or stickiness of tablet ingredients

• Use starch, Avicel ® PH-101, silicon dioxide (Syloid ® ) or tribasic calcium phosphate

Agglomeration of particles

• Occurs with fine cohesive powders causing "balling" or lump formation and poor distribution of the powder

• Fine-screen cohesive compound into bulk mix • Use a more effective mixer (one 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 • See “Loss of hardness (with time)”

Aging of tablets

24

Problem/Concept

Cause/Definition


• Very low density materials with very high porosity (sometimes ascribed as cause for tablet capping, splitting, or laminating)

• See “Capping and laminating”

Antiadherent

• Materials that aid in preventing the tablet mix from sticking to punch faces

• See Section 4 for a description of excipients and their uses

Attraction of particles (aggregation or agglomeration)

• Fine cohesive powders

• Modify particle size distribution

• Static electricity

• Mechanically disperse

Air entrapment

• See “Binding”

• Drain off static charge • Low relative humidity

• Slightly increase moisture level • See “Blending” • Densify as last resort

Binder

• Wet granulation substances which are added in solution (usually) or sometimes dry, followed by granulating solvent to “glue” a powder mix into granules for solid dose preparation • Direct compression substances which give compressibility or cohesiveness to the powder mix

25


Problem/Concept

Cause/Definition


Binding (bonding or compressibility)

• Relative degree of cohesiveness between particles or granules

• See “Blending”

• Compressibility of active ingredients determines (to some extent) the percent that can be incorporated into a direct compression formulation • Particular binder and concentration influences degree of binding and tablet hardness

• Optimize particle size and particle size distribution of active and excipients • Use excipients which are compressible and designed for direct compression process • Determine that granulation and/or other excipients have proper moisture content

• See “Punch binding”

Binding in the die (punches) Bioavailability

• Be careful not to overblend or overlubricate

• The rate and extent to which an active ingredient is absorbed in-vivo

• See “Dissolution” • Use up to 50% soluble filler (lactose, dextrose) with insoluble drugs (direct compression)

• May or may not be correlated with dissolution Bisected or debossed tablets (not sharp or well-defined)

• Poor design on tooling

• Redesign tooling, consult tooling supplier • Increase binder in formulation

26

Problem/Concept

Cause/Definition


Blending

• Mixing of powders to obtain a homogeneous mixture (for compression)

• Optimize blending or mixing time

• 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) • See “Binding”

Bonding Bridging

• Lack of powder fluidity; actual stoppage of powder flow as powder compacts in hopper or feed-frame

27

• See “Die fill” • See “Flow problems”

Problem/Concept

Cause/Definition


Brittle fracture

• Bonding mechanism of some materials (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

• See Section 2 for a discussion of compression mechanisms

• See “Density, bulk”

Bulk density Capping and laminating

Capping is separation of the top or bottom from the main body of the tablet. Laminating is transverse cracking and separation of the tablet into two or more layers.

• Inadequate bonding of the powder particles (direct compression) or granules (wet granulation) to form cohesive tablets • Poor finish or worn punches and dies

• Use a stronger binder or additional binder • Avicel ® PH-101 and PH-102 are particularly effective direct compression binders (15% to 25%) and as auxiliary binders in wet granulation (5% to 15%) • Polish, reface, or replace • Chrome-plate punch faces

• Too many fines in granulation

• Modify granulation process for minimum fines

• Granulation too dry

• Adjust moisture level and establish optimum moisture limits

• Granulation too wet (usually associated with sticking or picking)

• Continue to dry and establish optimum moisture limit

• Overlubrication of final tableting mix

• Decrease lubricant level • Blend lubricant for minimal time required; establish optimum mixing time

28

Problem/Concept

Cause/Definition


Capping and laminating (continued)

• High level of ingredient with poor compression properties (also sometimes ascribed to air-entrapment by powder bed)

• Use precompression on tablet press • Slow the speed of the tablet machine

• Punch concavity too deep

• Change to standard concave or flat-face punches

• Punch edges worn or damaged • Lower punch too low at tablet take-off


• Compression too low in die cavity

• Compress in upper portion of die

• Excessive tableting pressure

• Decrease pressure

• Die wall binding

• Use sufficient lubricant


• Use tapered dies Case hardening

• Rapid evaporation of water, which forms hard outer crust often associated with incomplete drying inside granules

• Try recirculating oven air (damper closed) for initial 15 to 30 minutes then open damper partially for a short period and finally open damper fully • Reduce drying temperature

• Oven drying conditions too efficient

• Add Avicel ® PH-101 to formulation (gives more even water evaporation and uniform granule moisture content) • Use a fluid bed dryer

29

Problem/Concept

Cause/Definition


Chipping/splitting


• Polish, reface, or replace punches and dies

• Lower punch setting too low at tablet takeoff


• Tablet sweep-off blade on feed frame

• Adjust setting • See “Capping and laminating” • See “Binding/bonding”

Clogging of screen (wet mass)

• Doughy or sticky wet mass

• Avoid oscillating granulator • 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 mass

• Reduce water content; add water gradually and mix well after each addition

– Mass sensitive to water content

• Incorporate 5% to 20% Avicel ® 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

30

Problem/Concept

Cause/Definition


Coarse particles

• Mottled appearance in direct compression

• Design particle size distribution for optimum flow, color distribution, binding

• Segregation

• Some fines are needed for good binding

• Dye migration leading to mottling

• In direct compression, preblend or mill color with portion of excipient

Color distribution

• In wet granulation, use a dye soluble in the granulating solution • May help to use a lower temperature for tray drying; use a fluid bed dryer • See “Color migration” Color migration

• Colors migrate to granule surface (wet granulation); will cause mottling tablets; often associated with case hardening

• Use lakes instead of soluble dyes (will minimize but not eliminate) • 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

Compressibility

• See “Binding (bonding or compressibility)”

Content uniformity

• See “Dosage variation”

Demixing

• Segregation/ separation, usually caused by overmixing rather than undermixing

• Optimize blending times specific to mixer (blender) employed • See “Overblending” • See “Segregation”

31

Problem/Concept

Cause/Definition


Density, bulk (loose density)

• Usually defined as the ratio of weight of a powder (or mixture of powders) to its volume on an “as-is” basis (not tapped)

• See “Flow”

• Low bulk density often related to poor flow especially at high dosage (active) Density, tapped

• Usually defined as the ratio of weight of a powder (or mixture of powders) to its volume after being tapped or caused to consolidate (“settle”) in some way

• See “Die fill” • See “Dry granulation” • Select higher density grades Avicel ® PH-301 and PH-302

• See “Segregation”

• Too dense — can cause segregation Die fill (nonuniform)

• Lack of consistent • Adjust particle size range to powder flow into dies, recommended optimum for die causing variations in diameter tablet weight, hardness, and disintegration/ • Reduce fines dissolution • Select larger particle size; use Avicel® PH-102 or PH-200 in place of PH-101 or other excipient • Add glidant (0.1% to 0.5%) (e.g., Cab-O-Sil®, Aerosil® ) • Use induced or force-feed mechanism on press • Change particle shape of active ingredient to one that is more likely to flow

32

Problem/Concept

Cause/Definition

Remedy/Suggested Solution • Dry granulate (by slugging or roller compacting) with a mixture of Avicel®, Cab-O-Sil® and magnesium stearate

Die fill (nonuniform) (continued)

• 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) added to give the necessary bulk for solid dosage preparation


Dilution potential

• The percent of an active (usually poorly compressible such as ascorbic acid or APAP) that can be compressed with an excipient to form a tablet having 1% or less friability

• Avicel® PH has a very high dilution potential when used as a binder

Direct compression

• Method of manufacturing tablets by compressing directly a dry blend of active and excipient powders; the powders are neither wet or dry granulated

• See Sections 2 - 4

Disintegrant

• Material added to tablets to aid them in breaking apart so that particles of drug can dissolve


33

Problem/Concept

Cause/Definition


Disintegration too long or incomplete

• Tablet hardness too high

• Reduce machine pressure for acceptable tablets • Use less binder in granulation

• Overlubrication (waterproofing)

• Decrease lubricant level • Blend lubricant for minimal time required; establish optimum blending time • Replace metallic stearates with other lubricants (e.g., stearic acid)

• Requires additional disintegrant or a different disintegrant

• Consider a “super disintegrant” (e.g., Ac-Di-Sol ®, 2% to 5%) • Include Avicel® PH-101 or PH-102 (added dry), about 10% as an auxiliary disintegrant • Consider adding a surfactant (e.g., DOSS, 0.1%)

Disintegration during coating

• Tablet hardness too low

• Increase hardness to allow swellable disintegrant to function

• Caused by soft cores or rapidly disintegrating tablets

• Increase tablet strength (increase binder, add better binder, compress harder) • Apply a seal coat (Aquacoat® ECD) • If possible, lower spray rate of aqueous coating

34

Problem/Concept

Cause/Definition


Dissolution

• Measure of the rate and extent to which an active component is released into solution from a drug product

• Use most soluble form of drug • Micronize insoluble drugs - in general, use smallest particle size possible • Consider using a wetting agent

• May or may not be correlated with bioavailability

• Add additional disintegrant or a different disintegrant - granules must disintegrate for good dissolution

• Poor dissolution

• Optimize tablet hardness versus friability and disintegration/ dissolution • Conduct preformulation studies to be certain there is no active/excipient interaction (binding) • Use a soluble filler with insoluble actives • Use less lubricant, establish optimum blending time • See “Bioavailability” • See “Disintegration”

Dosage variation

• Improper mixing/segregation

• See "Blending, overblending and demixing" • See “Flow problem” • See “Segregation” • See “Die fill (nonuniform)” • See “Nonuniformity of mix”

35

Problem/Concept

Cause/Definition


Doughy mass

• Too much water (often seen on scaleup)

• Add granulating water slowly; mix well after each addition

• Overmixing during granulation step

• Reduce water or mixing time

• Wrong binder

• Change binder

• Component of mix (e.g., active drug or excipient)

• If possible, use alcohol/water or alcohol as granulating fluid 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 to surface of granulation

• See “Color migration”

Drug migration

• 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 • See Section A: “Dry blending”

Dry blending

36

Problem/Concept

Cause/Definition


Dry granulation (by slugging or compaction)

• Method for compacting powders by slugging or roller compaction and then size reducing the compacts to the desired particle size for tableting

• See Section 2 • See “Slugging” • See “Roll compaction”

• 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 granulation

• Increase drying time • Establish optimum moisture content

Drying

• Overdrying can cause static flow, case hardening, drug/color migration, lamination/ capping/splitting

• Set in-process moisture specifications on wet granulated materials

• Underdrying can cause weak granules filming, and sticking of punches

• See Section A: “Drying”

37

• See Section A: “Drying”

• Control moisture in direct compression excipients for proper compressibility

Problem/Concept

Cause/Definition


Dye migration

• See “Color migration”

Ejection problem

• See “Punch binding”

Elastic material

• Actives or excipients that are deficient in plastic flow properties, and therefore lack bonding or binding properties

• Use materials that have plastic flow (low in elasticity) and that, once compressed, “stay compressed” (do not “spring back”), such as Avicel ® PH

• 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 • See “Air entrapment”

Entrapment of air Excess fines (wet granulation)

• Low moisture in granulation

• Decrease drying time; establish optimum moisture content

• Screen size too small (dry screening)

• Use larger screen size

• Rotor/screen clearance too close

•

• Overloading granulator or mill

• Feed granulator gradually

• Weak granules

• Increase binder content/ granulating fluid

Adjust clearance of rotor

• Increase wet massing time • Use stronger binder

38

Problem/Concept

Cause/Definition

Remedy/Suggested Solution • See “Elastic material”

Expanding tablets

• See “Capping and laminating” • See “Active ingredients” • See “Binding” Filler

• Inert material(s) added to give the necessary bulk for solid dosage preparation

• See “Punch filming or sticking (picking)”

Filming of punches Fines (direct compression)


• Poor flow

• An optimum percent of fines serves a useful purpose of dusting the actives, especially oleaginous ones or those with elastic deformation properties, and aids in in bonding and filling voids within the tablet

• Improper die fill • Poor binding

• Too many cause segregation • See “Excess fines (wet granulation)”

Fines (wet granulation)

• See “Fines (direct compression)” above Flooding

• Excessive flow properties (fluidization) of one or more components (could be from an excess of glidant or lubricant) • Flow is erratic and feed frame is flooded at times

39

• Identify causative component and exclude or modify particle size • Select narrow range of particle sizes; avoid excess fines • Induced or force-feed mechanism on press may control flow • See “Flow problem”

Problem/Concept

Cause/Definition


Flow problem

• Too many fines in wet granulation

• Reduce fines (see “Dry ScreeningExcess fines”)

• In direct compression, particle size of drug or excipients too small and/or of shape that will not flow

• Select larger particle size; use Avicel ® PH-102 or PH-200 in place of PH-101 or other excipient • Add glidant (0.1% to 0.5%), e.g., Cab-O-Sil®, Aerosil® • 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 absorption

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

Friability (high)

• Inadequate bonding of the tablet matrix

• Increase binder level or change to 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 compression pressure

40

• Adjust pressure for acceptable friability

Problem/Concept

Cause/Definition


Friability (high) (continued)

• Overlubrication

• Decrease lubricant level • Blend lubricant for minimal time required; establish optimum blending time • Replace metallic stearates with other lubricants (e.g., stearic acid)

Glidant

• Excipient used to improve fluidity of powders

• See Section 4 • Add 0.1% to 0.5% Cab-O-Sil ® or Aerosil® fumed silica to improve flow • Small increase in lubricant may be necessary to offset slight punch/die binding effect of glidant • See “Dry granulation”

Granulation, dry

• See Section 2 • See “Wet granulation”

Granulation, wet

• See Section 2 • Use Avicel® to obtain hard tablets with low machine pressure - also to reduce tablet friability

Hard tablets

• See “Binding (bonding or compressibility)” • Decrease compressing speed to increase tablet hardness

41

Problem/Concept

Cause/Definition


Hardness increases with time

• Probably more prevalent in wet granulated products, although it can happen in directly compressed tablets

• Optimize moisture consent of granulations

• Can be caused by water of crystallization/hydration interacting with ingredients or other kinds of interactions between active materials/excipients Hardness, variable

• Tooling


• Uneven die fill

• See “Weight variation”

• Overblending

• Optimize blending time to minimize creation of fines • See “Friability (high)”

High friability High level of active

• Conduct preformulation studies, even though data at accelerated temperature/ humidity conditions may not always be relevant to shelf-life conditions

• Direct compression

• High percentages of actives can be directly compressed depending on physical form (low density, entrapped air, etc.), flow, and compressibility properties

• Dry/wet granulation

• If unable to compress directly, dry granulation or wet granulation are possible alternatives depending on active's physical properties

High relative humidity

• See “Relative humidity”

Hopper flow

• See “Die fill” • See “Flow Problem” • See “Segregation”

42

Problem/Concept

Cause/Definition


Hygroscopic ingredients

• Moisture pick-up

• Process under low humidity conditions • Compress with low moisture grades Avicel® PH-112 and PH-113 • Use moisture scavengers (e.g., calcium silicate, Syloid ®, Cab-O-Sil® )

Hygroscopic tablets

• Moisture pick-up

• Compress and package underlow humidity conditions (to maintain tablet hardness and active ingredient stability) • Use moisture scavengers (e.g., calcium silicate, Syloid ®, Cab-O-Sil® ) • Keep tablet containers well closed (use adequate closures especially if plastic or blister packed) • See “Capping and laminating”

Laminating Layered tablets splitting (poor bonding between layers; layers peel or split apart)

• Poor bonding between layers

• Use a stronger binder or higher concentration

• Compression pressure too high

• Compress at lower pressures

• Overlubrication

• Decrease lubricant level • Blend lubricant for minimal time required; establish optimum mixing times • See “Capping and laminating” • See “Lubricants”

43

Problem/Concept

Cause/Definition


Loss of hardness (with time)

• Tablets with Avicel ® PH lose some hardness with time at high humidity, but most of the hardness is quickly regained at normal humidity

• See “Hygroscopic ingredients”

Low hardness

• See “Hygroscopic tablets”

• Compression force (pressure) too low

• Increase pressure (caution - do not exceed recommended pressure for punch size used)

• Overlubrication

• Decrease lubricant level • Blend lubricant for minimal time required; establish optimum mixing times • Replace metallic stearates with other lubricants (e.g., stearic acid)

• Granulation too soft

• Use additional binder • Direct compression - use additional Avicel® PH

• Excipient (i.e., too much starch can give a soft tablet)

• Reduce level of causative excipient

• Moisture content too high

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

• Moisture content too low

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

44

Problem/Concept

Cause/Definition

Remedy/Suggested Solution • Use 10% to 20% Avicel ® PH combined with compressible lactose and/or dicalcium phosphate

Low to medium level of active (in direct compression)

• 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 reduce friction between the die wall and the tablet mix, and hence facilitate ejection of the tablets from the die

• See Section 4 for a description of excipients and their uses • See “Punch binding” • Add lubricant at end of blending 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) • See “Blending”

Mixing

• See Section A, “Dry blending”

45

Problem/Concept

Cause/Definition


Modified direct compression

• Modification of direct compression process to assure good dispersion of low-level actives or for other reasons

• Dissolve actives in volatile solvents and spray onto excipients

• Avoids granulation of entire formulation Moisture sensitive actives

• Unstable in the presence of water

• Granulate a small portion of the formulation and directly compress this granulation with the remainder (major part) of the formulation ingredients • Use direct compression or dry 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 (tray drying)

• Poor air flow (circulation)

• Correct air circulation pattern • 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) mixer

• Use alternative mixer with increase shearing action

• Wide particle size distribution

• Select more uniform particle sizes of components

• Overblending

• Reduce blending time • Establish optimum mixing conditions

46

Problem/Concept

Cause/Definition


Nonuniformity of mix (continued)

• Low-dosage actives

• Use a more effective mixer (one 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 • See “Punch binding”

Oleaginous or sticky actives

• See “Sticky ingredients” Ordered mixing (adhesive blending)

• Small-sized (drug) particles adhesively held on the surface of larger-sized (excipient) particles • Segregation does not occur • Usually requires a high-intensity mixer

47

• See Section 2

Problem/Concept

Cause/Definition


Overblending

• Can cause powder separation (segregation or demixing)

• Optimize mixing times • See “Blending”

• Can cause particle size reduction leading to other problems • Can cause “waterproofing” of tablet by lubricant • See “Drying”

Oven drying Overwetting of wet mass

• A common problem in wet granulation

• See “Clogging of screen”

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

• See “Modified direct compression”

Particle density variation

• See “Density, bulk (loose density)”

• See “Density, tapped” • See “Die fill (nonuniform)” • See “Punch binding”

48

Problem/Concept

Cause/Definition

Remedy/Suggested Solution • See “Binding (bonding or compressibility)”

Particle size distribution

• See “Die fill (nonuniform)” • See “Fines (direct compression)” • See “Flooding” • `See “Flow problem” • See “Nonuniformity of mix” • See “Ordered mixing (cohesive blending)” • See “Segregation” Picking

• Tablet surfaces “pitted”

• See “Punch filming or sticking”

• 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” • See “Flow problem”

Poor flow (“rat-holing” or “bridging”)

49

Problem/Concept

Cause/Definition


Poor granule disintegration

• Wet granulation

• Granules must be disintegrated for prompt and full drug release (dissolution) • Include a portion (50%) of the disintegrant (Ac-Di-Sol® ) for this purpose in the materials being granulated (disintegrant “inside” the granulation)

Poor layer demarcation

Poor tablet finish/appearance

Postgranulation addition

• Granulation too course

• Reduce particle size of granulation - less than 16 mesh

• Too many fines

• Remove fines below 200 mesh

• Picking

• See “Filming of punches”

• Mottling

• See “Color distribution”

• Coarse particles

• See “Coarse particles”

• Excipients added after drying the granules and screening them

• See Sections 2 and 4

Examples: disintegrant, lubricant, additional binder • See “Coarse particles”

Powder separation

• See “Demixing” • See “Fines (direct compression)” • See “Flow problem” • See “Nonuniformity of mix” • See “Overblending” • See “Segregation”

50

Problem/Concept

Cause/Definition


Precompression

• Application of a relatively small amount of tableting pressure immediately prior to application of main tableting pressure

• See Section 3

• Aids in removing entrapped air • Aids in preventing/ minimizing capping/ laminating of difficultto-compress materials by allowing time for relaxation between compressions • Requires a rotary tablet machine equipped for precompression Punch and die abrasion

• Abrasive components

• Exclude or reduce to a fine particle size • Increase lubricant level • Blend abrasive component separately with the lubricant • Use minimum tableting pressure possible • Use more wear-resistant tooling (harder metal)

51

Problem/Concept

Cause/Definition


Punch binding (powder adheres to punch edges and dies, punches may bind in dies)


• Polish, reface or replace tooling


• Increase or change lubricant; use microfine lubricants; screen into mix

• Increase lubricant blending time • Too many fines or coarse particles in mix

• Design better particle size range; use tapered dies

• Wet granulation insufficiently dried

• Dry granulation to satisfactory moisture limits

• Hygroscopic ingredients

• Process in low humidity conditions • Use moisture scavengers (e.g., calcium silicate, Syloid ®, Cab-O-Sil® ) • Use low moisture grades Avicel® PH-112 and PH-113

• Adhesive or oleaginous components

• Increase lubricant level • Add 0.5% Cab-O-Sil ® or Syloid® • Add 5% to 10% Avicel® PH-101

Punchfilming or sticking (picking)— (powder adhesion to punch faces, usually upper)

• Poorfinish on punch faces • Embossed letters

• Polish punch faces; refinish • Avoid using certain letters (e.g., “A”, “B”, “P”, “R”) • Use shallow embossing with tapered edges rather than edges perpendicular to punch face

• Punch tips burred


• Punch concavity too great

• Reduce punch concavity or use flat-face punches

• Poor binding between surface granules or particles

• Increase binder (wet or dry)

• Low melting point ingredient

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

52

Problem/Concept

Cause/Definition


Punch filming or sticking (continued)


• Increase or change lubricant • Use microfine lubricants, screen into mix • Increase lubricant mixing time

.

• Insufficiently dried wet granulation

• Dry granulation and establish moisture limits

• Hygroscopic components

• Process under low humidity conditions • Use moisture adsorbent (e.g., calcium silicate, Syloid ® )


• Increase lubricant level • Add 0.5% Cab-O-Sil® or Syloid® or 5% to 10% Avicel ® PH-101

Rat-holing

• Tablets too soft

• Increase compression pressure

• Limited flow of a powder or mixture directly over the discharge of a hopper, leaving a hole in the center of the powder as flow slows or stops

• See “Bridging” • See “Die fill (nonuniform)” • See “Flow problem” • 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 water the air is holding to the amount it could hold (at saturation) at a given temperature

53

• Keep tableting area <55% RHhigher RH can cause flow problems and sticking depending on materials present

Problem/Concept

Cause/Definition


Relative humidity (RH) (continued)

• Raising the temperature, all other things remaining constant, lowers the relative humidity but the absolute amount of water present is the same

• Keep tableting area >40% to 45% RH - lower humidity can cause flow because of static and drying out of material being compressed with, perhaps, some loss of compressibility • See “Hygroscopic ingredients” • See “Hygroscopic tablets”

Roll compacting

• Forcing powder (almost always a formulation containing filler, lubricant, and disintegrant) between two oppositely turning rolls in order to form a dense compact in the form of a relatively flat sheet as it exits the rolls • The sheet (which often breaks under its own weight as it exits the rolls) is milled to form granules, which can then be used for tableting after adding additional lubricant, disintegrant, etc.

54

• See Section 2 • Use Avicel ® PH-101

Problem/Concept

Cause/Definition


Score line or tablet imprint not sharp

• Faulty punch embossing design

• Redesign using chamfered edges on the punch embossing • Chrome-plate punch face


• Reduce particle size of granulation

• Binder not strong enough

• Use a stronger binder • See “Clogging of screen (wet mass)”

Screen clogging (wet mass) Segregation

• Particle size range of mix too wide

• Use a narrower particle size range of ingredients • Limit the amount of the fines present

Slugging

• Too wide a density difference

• Control differences in the density of particles

• Mixer too vigorous, produces fines

• Use a mixer with a gentler mixing action

• Use of vibrators (to promote flow from hopper)

• Use force-feed mechanisms rather than hopper vibrators

• Use of relatively large punches and dies to produce tablets from a poor flowing powder mix

• See “Dry granulation”

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

55

Problem/Concept

Cause/Definition


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. • See “Binding (bonding or compressibility)”

Soft tablets

• See “Capping and laminating” • See “Coarse particles” • See “Die fill (nonuniform)” • See “Elastic material” • See “Excess fines (wet granulation)” • See “Friability (high)” • See “Hardness, variable” • See “Loss of hardness (with time)” • See “Low hardness” • See “Capping and laminating”

Splitting (tablets)

• See “Chipping/splitting” Sticking to punch face

• See “Punch filming or sticking”

Sticky ingredients

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

• See “Punch filming or sticking” • See “Punch binding”

56

Problem/Concept

Cause/Definition

Remedy/Suggested Solution • See “Punch binding”

Tablet binding in the die Tablets contain “dirty” specks

• Misaligned upper cam tracks - rubbing of punches on cam actually rubs off metal, which is introduced into material being compressed

• Check alignment of upper cam tracks

• No lubrication on upper cam tracks

Tablets uniformly discolored

• Excessive or improper lubrication on upper punch shanks (no dust caps on punches) dust mixes with excess oil or grease and falls into material being compressed

• Use dust caps on upper punches

• Feed frame rubbing on die table

• Check clearance between feed frame and die table

• Feed hopper rubbing on turret

• Check clearance between feed hopper and turret

• Abrasive materials wearing screens, scooper, etc.

• Check for presence of abrasive materials • See “Blending”

Underblending Variable hardness

• Tooling


• Uneven die fill

• See “Weight variation”

• Overblending

• Optimize blending time to minimize creation of fines

57

Problem/Concept

Cause/Definition


Weight variation (outside limits)

• Poor or erratic powder flow, flooding

• Correct powder flow problems (See “Feed Hopper” in Part A)

• Particle size range too wide

• Narrow the particle size range; avoid excess fines

• Particle size not suitable for die diameter

• Adjust particle size range to recommended optimum for die diameter

• Punches not within specifications

• Examine punch length dimensions • Narrow the particle size range

• Particle segregation as press RPMs increase

• Compress at slower RPM • Clean; improve dust collection

• Lower punch “hang up” (material between lower punch and die wall or lower punch and punch guide)

• Check for proper clearance between die wall and lower punch • Increase lubricant concentration in formulation • Remove below 200 mesh fines

Wet granulation

• Process whereby active drugs and excipients are wet massed (wet with a solvent containing a binder in solution, usually), screened, dried, and screened again • Used for high-dose active drugs which have poor flow and either cannot be or are difficult to directly compress • Used for active drugs which are very fine and/or low density

58

• See Section 2

problem and remedies in tableting.pdf

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