Adoption Pathway
This is the key to
Growth
RED
GAP
A B C
Rule
DO NOT RECEIVE
DO NOT MAKE
DO NOT PASS ON
Bad Quality
© 2002 Kaizen Institute
To gain Understanding of the following:
Advantages, Limitations of Tablets
Tablet Production Methods
Tools
Excipients
In-Process Controls
Problems in Tableting
Trouble Shooting
A tablet is a compressed preparation that
contains:
5-20% of the drug (active substance)
~80% of fillers, binders and lubricants
~10% of compounds which ensure easy
disintegration
For the Patient:
Release of precise drug dosage
At the correct rate
At the correct site of absorption
Easy to administer
Small bulk
For the Manufacturer:
High volume production
Capability for individual design
Embossing identification on both sides
Relatively low cost production
Drug stability usually good (better than in
liquid formulations)
For the Patient:
Can be mistaken as sweets or candy
Cannot be administered if patient is
vomiting or unconcious
Some patients have difficulties swallowing
tablets
Large doses lead to very large tablets
Possible technical Problems:
Sticking
Laminating, capping
Friability, disintegration problems
Dissolution rate increase(decrease)
Weight variations, hardness problems etc.
Tablets are made by compressing a powder
which needs to be:
dry
well mixed
of uniform particle size
with good flow properties
to ensure weight and content uniformity
Step 1: Need for Milling
1. Milling: API‘s, excipients
Granules („calibration“ of granules)
2. Blending: Powders for granulation
Powders for direct tabletting
granules + admix for tabletting
3. Sieving: fractionation of granules, pellets
Milling
and Particle Sizes
1. Milling API‘s , excipients
1.1. Dry milling
• Hammer mill 300 – 2000 µm
• Pin mill 20 – 200 µm
• Mortar mill 20 – 200 µm
• Air jet mill 1 – 30 µm
1.2. Wet milling
• Corundum disc mill 1 – 30 µm
• Pearl mill 1 – 30 µm
Fluid Bed Granulation:
Fluid Bed Granulation
Manufacturing Methods for Granules
* High Shear Granulation
* Fluid Bed Granulation
wet granulation
dry
granulation
tablets
tablets
direct
compression
of powders
USP 23 / NF 18
Fluid Bed Granulation:
Formulation and Process Parameters
Formulation
atomization air
product: pressure /
process air volume + moisture spray rate
temperature + temperature
moisture
Agglomeration
– Spray drying
drying
fluidization
capacit
pattern
y
Fluid Bed Granulation
Key parameters of granulation
porosity
density
particle size distribution
in vitro dissolution kinetics
Fluid Bed Granulation
Production Unit
expansion chamber
MicroPx module
air classifier
GPCG 120/200
GPCG 30/60
Blending and Blenders
1. Mechanical Blenders: Planetary Mixer
High Shear Mixer
2. Free fall blenders: Gymwheel blender
V – Blender
Double cone blender
Bin blender (Container
blender)
Blending parameters must be adjusted for every single
technology for every single formulation !!
Blending:
Planetary Mixer + High
Shear Mixer
Blending:
Drum
blender
Blending:
V-Blender + Double + Ploughshare Blender
Cone
blender
Blending
V - Blender
Blending:
Double Cone Blenders
Blending
Weighing Blending Mechanism
Blending:
Mechanis
m
not blended arbitrary blend controlled blend
Tablets are made by compressing a powder
mix between two punches in a die of a tablet
press.
Direct Compression
Possible if a homogeneous powder is obtained after mixing all
components resulting in tablets with equal amounts of avtive
ingredients
Granulate Compression
Necessary if a homogeneous powder is not obtained by
simple mixing. There are several methods of granulation:
Dry Granulation Wet Granulation
Spray Granulation
Direct Dry Granulation Wet Granulation
Compression
1 Mixing / Blending Mixing / Blending of Mixing / Blending of API &
of API & Excipients API & Excipients Excipients
2 Compression Slug Compression Prep Binder Solution
3 Slug size reduction Massing: mix 1 with
& sieving solution 2
4 Mixing with further Wet screening of mass
excipients
5 Compression Drying of granulate
6 Resieving, blending with
outer phase
7 Compression
High Speed Production Rotary
Tablet Press
55 stations
495,000 tabs/hour
Way of compressing
Description of the
position:
1 2 3 4
1. Upper punch pushes
down
2. Pre-press station
3. Pre-compression
4. Main compression
Stages of Compression
Single-Ended Compression
Elastic limit
exceeded
Rearrangement Plastic
Deformation
(and/or
viscous flow)
Brittle
Ejection of tablet
Ejection of
1 2 3 4 tablet
1.Upper and lower
punch move up
2.-3. Lower punch pushes
the core upwards
4. Ejector releases the
tablet
Compaction of granules
View of Punch Train
Tools
Punch
Should be cleaned directly after using
Cleaning with soap suds or in the ultrasonic bath
Drying after cleaning
Lubricate with grease [eg. Vaseline or
Paraffin] (should be FDA conform,
because it has direct contact with the next
product)
Storage under safe condition
Clean before use next time
Tablets are made by compressing a powder mix between
two punches in a die of a tablet press.
For satisfactory quality, the formulation must have three
essential attributes:
1. Flow must be rapid and in a reproducible manner
2. Particles must cohere when subjected to a compressing force,
and coherence should remain after removal of force
3. Removal of tablet after compression without damage must be
possible
Very few active ingredients possess all three
of these essentials and some possess none of
them. Hence the addition of excipients for
increase of flowability and binding capacity is
almost invariably necessary.
Starch (various origins)
Acts as dry binder and increases flowability
Is also suitable as disintegration agent
Concentration 5%
Cheap, commonly available
Lactose monohydrate
(Preferably in spray-dried form, spherical shape, good flowability, good
binding capacity for micronized API‘s)
Excellent physical and chemical stability,
water solubility
Compatibility with active ingredients and
other excipients
Cost effectiveness, availability, bland taste,
low hygroscopicity
Concentration as filler 60% and more
Microcrystalline cellulose (MCC)
Good binder with excellent compaction properties but
unsufficient flowability (→ Aerosil addition!)
Concentration: 20 -30%
Also used as disintegration agent
Grades (particle size)
Avicel 101 and 102 (50 and 90 µm, resp.)
Note: commonly, the coarser 102 grade is used, but the
finer grade 101 may be used with an API with low
particle size
Aerosil (0.3 – 1.0%)
High specific surface of 200 m2/g; absorbs
humidity and improves flowability
Higher concentrations (> 1%) reduce lubricant
action (esp. of magnesium stearate)
Other Binding Agents
Polyethylene glycole (4000 - 8000),
Polyvinyl pyrrolidone and
Dicalcium phosphate
Sugars used as binders:
Sucrose / Saccharose
Mannitol
Sorbitol
Glucose
Xylitol
Disintegration Process
DISINTEGRATION
PRIMARY
DRUG
DEAGGREGATION
PARTICLES GRANULES
DRUG IN SOLUTION
Lubricants
In a general sense
Lubricant Typical True Anti- Level Glidant
Lubricant adherent Activity
Activity Activity
Metallic 0.5 - 1% Excellent Good Poor*
Stearates
e.g. mag. st.,
calcium st.
Stearic Acid 1-5% Good Good Nil
Colloidal Silicas <1% Nil Good Excellent
Talc 1-5% Poor Excellent Good
Formulation depends heavily on API properties e.g.
particle size, hygroscopicity, flow properties etc.
and needs to be adapted accordingly!
General Formula
API 5-10%
Starch 5%
Cellulose 20 – 30%
Aerosil 200 max 1%
Lactose 60 – 70%
Mg-Stearate 0.5-1%
In-process controls prior to compression
Reposography
Sharp cone → poor flow properties
Good spread →superior flow properties
Particle size & distribution
Has to match particle size of API
Broad based distribution ensures even compression and good
disintegration time
Bulk density
Ratio tapped to un-tapped density →“compressibility index“
Acceptable range 1.3 to 1.6
In-process controls after compression
(as in compression after dry or wet granulation)
Appearance
Weight
Hardness
Friability
Disintergration
Dissolution
Friabilator
Drop
Measuring Hardness
(Breaking Force)
Fixed
Possible technical Problems:
Sticking
Laminating, capping
Friability & Disintegration problems
Dissolution rate increase(decrease)
Weight variations, Hardness problems etc.
A B C
Rule
DO NOT RECEIVE
DO NOT MAKE
DO NOT PASS ON
Bad Quality / Wrong quantity
© 2002 Kaizen Institute
Trouble shooting
Weight Variation
Punch working lengths out of tolerance
(For example: Manufactured to a total
variation of 0,02 mm)
If the Machine speed is too high the dies will
not be completely filled
Incorrect Compression Force
A too high compression force could have
some impacts for your drug:
- Increased dissolution time
- Increased disintegration time
- Punch tip breakage or damage
- Damage to machine
Incorrect Compression Force
• Compression force too high or too low
– Incorrect drug release from controlled release
tablets
– Incorrect tablet thickness (packaging
problems)
• Solution
– Define and set operating limits
(to state of the art)
Crushing Strength and Friability
• Low crushing strength, tablets breaking easily
• High friability, Tablet crumbling at the edges
Causes:
Compression force too low
Insufficient binder
Insufficient moisture
Excessive lubricant
Insufficient dwell time
Crushing Strength and Friability
Solution:
- Increase compression force
- Increase or change binder, or improve
binder distribution
- Optimize moisture and lubricant levels
- Reduce granule size
- Reduce machine speed, increase
dwell time
Sticking and Picking
Granule sticks to punch face
Causes:
• Punch face deteriorating
• Incorrect embossing design
• Excessive moisture in compression
• Inadequate lubrication in formulation
• Temperature and/or humidity
Sticking and Picking
• Granule sticks to punch face
Solution:
- Polish punch face
- Decrease moisture content of granule
- Adjust or change lubricant
- Change punch
Capping and Laminating
Definition of capping:
Upper section of tablet splits away
Definition of laminating:
Tablet splits into several layers
Capping Lamination
Elastic recovery in combination with poor
bonding
Capping and Laminating
Causes:
• Air entrapment at compression stage
• Punch tip to die clearance
• Clawed punch tips
• Moisture content too high/ too low
• Lubricant content too high/ too low
• Insufficient binder
• Highly elastic formulation components
(e.g Paracetamol)
Possible cause of
capping/lamination
The structure formed must be
strong enough to withstand the
stresses of decompression,
as well as those induced by
ejection.
Capping and Laminating
Solution:
• Use pre-compression on tablet press
• Re-condition or replace tooling
• Reduces fines in compression mix
• Optimize moisture and lubricant levels
• Increase, or improve binder distribution
A B C
Rule
DO NOT RECEIVE
DO NOT MAKE
DO NOT PASS ON
Bad Quality
© 2002 Kaizen Institute
Questions
