Tablet manufacturing

• There are 3 main methods of producing tablets:

– Direct compression
– Wet granulation
– Dry granulation

• In all of these methods the active ingredient is

usually mixed with other inactive ingredients
(excipients).

• Excipients improve the physical properties of the

tablet.
What can go wrong?
• Problems in attaining acceptable content
uniformity (accuracy and precision of unit dose
content) for low dose drugs.

• Large dose drugs usually lack th properties to

be formed into tablets

• Compromised bioavailability (poor drug

solubility; malformulation)
Design and Formulation of
Compressed Tablets
• Minumum running characteristics
– Compactibility
– Fluidity
– Lubricity

Excipients and the method of manufacture

are selected to provide these characteristics.
The process of tablet compaction
The process of tablet compaction
Manufacturing Methods
• Granulation
A complex process of first forming granules from the mix and
then tableting the granules.
– Wet
– Dry (Slugging)

• Direct Compression
– Simply mix and compress.

• Novel Methods
– Fluid- bed processing
– Hot melt extrusion

Choice of Method Depends on Several Factors

• Size of Dose
• Compactibility and/or Fluidity of Drug
• Stability Characteristics of the Drug
A Consideration of the Dose of
Drug is the Starting Point...
• LOW DOSE
(Most of the tablet will be excipients)
– Content Uniformity

• High DOSE
(Most of the tablet will be drug)
– Compactibility
– Fluidity

Is drug solubility also an important consideration? Why?

Is it equally important in each case?
Lower Dose Drugs Generally Can
Be Directly Compressed

Blend Compress

• Can compensate for any lack of compactibility and/or lack

of flowability by the use of special direct compression
fillers (aka: filler-binders)
– Can provide lubricity by addition of die wall lubricant
– Can help fluidity by adding a glidant
– Can assure rapid disintegration by adding disintegrant
Direct compression
• The drug itself is compressible and/or it can be
mixed with a filler that is compressible (e.g.
lactose).

• Compressible filler should:

– Have good flow and compression properties
– Inert
– Tasteless
– Able to desintegrate
– inexpensive
Direct compression

Tablet production by direct compression

Direct compression

1-Weighing

2-Blending (two steps)

3-Compaction of tablets
General Formula for a Direct
Compression Tablet

• DRUG 1 PART
• FILLER-BINDER 2 - 3+ PARTS
• DISINTEGRANT
– STARCH 10 - 20%
OR
SUPER DISINT. 2 - 5%
• GLIDANT
– COLLOIDAL SILICA 0.5 - 1%
• LUBRICANT
– MAG. STEARATE 0.5 - 1%
Direct compression

Direct compression diluents (fillers)

Advantages of Direct
Compression over Granulation
• More economical (less time, space, materials,
personnel, fewer steps)
• Avoids heat and moisture of wet granulation
• Disintegrate more directly into primary particles
Disadvantages of Direct Compression

• Problem of content uniformity for low dose drugs

• Not practical for large dose poorly
compactible/poorly flowing drugs
• Requires tight control over physical properties of
filler-binder

Generally, direct compression Filler-Binders

are common fillers that have been physically
modified.
Examples of Direct Compression
Filler-Binders
• Microcrystalline Cellulose (MCC) (isolated from
cellulose fibers by acid hydrolysis) [Avicel]
– Most compactible material available for pharmaceutical
use
– When made from mostly MCC, tablets self-disintegrate
and require little lubricant.

• Spray processed lactose [Fast Flo Lactose]

– minigranulation of lactose crystals glued together by
small amount amorphous lactose
Examples of Direct Compression
Filler-Binders

• Dicalcium phosphate dihydrate, unmilled

[Ditab, Emcompress]
– minigranules made up of agglomerated
crystallites

• Spray processesd sucrose [Dipac]

– Used in chewable tablets
– minigranulation of sugar crystals "glued"
together with amorphous dextrins
When Direct Compression Is Not
Practical*...
• Granulate
– Granulation is a size enlargement process:
Improves Flowability
– Addition of a BINDER that "glues " the particles
together into granules helps to hold the overall
tablet together: Improves Compactibility

*i.e. large-dose, poorly compactible and/or

poorly flowing drugs
Introduction

• What is Granulation?
– Granulation may be considered as a size enlargement
process during which primary particles are formed
into larger, physically strong agglomerates wherein
the primary particles can still be identified.

• Objectives of granulation:
 To improve the flow properties
 Densification
 To improve compression characteristics
 Prevention of segregation of the constituents
The Traditional Granulation Method is
Wet Granulation
• Involves wetting the powders with binder solution
("glue") and then a drying step.
– Wet Massing Techniques
• Low Shear Granulation
• High Shear Granulation
– Fluid Bed Granulation

• Not practical for drugs sensitive to water or heat.

– Alternative: Dry Granulation
• Slugging or Roller Compaction
In a more broader way , Granulation methods can be
classified as follows :
Granulation Process Methodology

Wet processes Pan granulation

Spray drying
High shear granulation
(wet massing)
Fluid bed spray granulation

Dry processes Slugging

Roller compaction
 Wet and Dry Granulation

 In wet granulation process, a

granulating liquid is used to
facilitate the agglomeration
process.

 In dry granulation process, dry

powder particles may be brought
mechanically by compression into
slugs or, more frequently these
days, by roller compaction.
Methods of granulation
• Wet granulation
• Dry granulation
Wet granulation
• Wet granulation involves the massing of a mix of dry
primary powder particles using a granulating fluid.

• The fluid contains a solvent which must be volatile so

that it can be removed by drying, and be non-toxic.

• Typical liquids include water, ethanol and isopropanol.

• The granulation liquid is usually used as a solvent

containing a dissolved adhesive (binding agent) to
ensure particle adhesion.
Wet granulation
• Water is usually used in the granulating fluid because
of its non-flammability and economic values.

• However it might affect the stability of the active

ingredient and cause hydrolysis.

• Another disadvantage of water is that it requires

longer drying times which in turn subjects the active
ingredient to prolonged exposure to heat and thus
affects its stability.
Wet granulation
• For those drugs that are water sensitive:
– Use organic solvents
– Use dry granulation methods
Wet granulation

• After mixing the dry particles with the

granulating fluid a wet mass is generated.

• The wet mass is passed through a sieve to

produce wet granules that are dried.

• This is followed by a screening stage that

breaks agglomerates of granules and removes
the fine material, which can than be recycled.
Wet granulation

Tablet production by wet granulation methods

 Wet granulation
1-Weighing
2-Blending of powders
3-Addition of binder fluids
(containing binder)
4-Granulation (agglomeration)
(mixer, fluïd bed)
5-Drying (oven, fluïd bed)
6-Screening (0.5 tot 1.5 mm)
(-> D(50) 70-200 m)
7-Blending with glidants
and lubricants
8-Compaction of tablets

Hot air
Dry granulation
• The primary powder particles are aggregated
under high pressure.

• There are two processes used in dry granulation:

– Slugging: large tablets (slugs) are produced
– Roller compaction: The powder is squeezed between
two rolls to produce a sheet of material
• In both processes a milling and sieving operations are
used to obtain the desired particle size distribution.
Dry granulation

Tablet production by pre-compression (dry granulation methods)

Dry granulation

1-Weighing
2-Blending of powders

3-Compaction (rol/wals)

4-Crushing of compacts

5-Blending with glidants

and lubricants
6-Compaction of tablets
PHARMACEUTICAL
GRANULATION EQUIPMENT
Wet granulators

• Shear granulators
• High-speed mixer/granulators
• Fluidized-bed granulators
Shear granulator

• The dry powder is mixed with the granulating

liquid in a planetary mixer.

• The wet mass is then passed through an

oscillating granulator to obtain the required
granule size.

• Granules can be collected on trays and dried in

a drying oven or can be dried in a fluidized bed
dryer.
Planetary mixer for wet massing.
Oscillating granulator.
Fluidized bed dryer
Shear granulator

• Problems associated with oven drying:

– Takes longer periods of time.
– Dissolved material can migrate to the upper
surface of the bed of granules.
– Granules may aggregate owing to bridge
formation at the points of contact of the
granules.
• To deaggregate the granules and remix them, a
sieving stage is necessary after drying.
Shear granulator

• Advantages:

• Disadvantages:
– long duration
– The need for several pieces of equipment
– High material losses because of the transfer
stages.
 High speed mixer/granulator
• The machines have a stainless steel mixing bowl containing a
three-bladed main impeller, which revolves in the horizontal plane,
and an auxiliary chopper (breaker blade) which revolves either in
the vertical or the horizontal plane.

• The chopper is usually switched on when the moist mass is

formed, as its function is to break up the wet mass to produce a
bed of granular material.

• After the wet granules are collected they pass through a wire mesh
which breaks up any large aggregates and transferred into a
fluidized-bed drier.
Diosna, high-speed mixer/granulator.
Collette–Gral granulator: mixing shafts and bowl.
High speed mixer/granulator

• Advantages:
– mixing, massing and granulation are all
performed within a few minutes in the same
piece of equipment.

• Disadvantages:
– It is necessary to use a suitable monitoring
system to indicate the end of the granulation
process, i.e. when a granule of the desired
properties has been attained.
Fluidized bed granulators
• The powder particles are fluidized in a stream of air.

• Granulation fluid is sprayed from a nozzle on to the

bed of powders.

• The temperature of the stream of air is controlled.

• Granulating fluid is pumped from a reservoir through

a spray nozzle positioned over the bed of particles.
– The fluid causes the primary powder particles to
adhere when the droplets and powders collide.
– When granules of the required size are reached,
the spray is turned off but the fluidizing air
continued until the granules become dry.
Fluidized-bed granulator.
 Fluidized bed granulators

• Advantages:
– All the granulation processes are
performed in one unit, saving labour
costs, transfer losses and time.
– process can be automated once the
conditions have been optimized.

• Disadvantages:
– The equipment is expensive.
– Optimization of process (and product)
parameters affecting granulation needs
extensive development work.
 Slide from Heni Rahmawati

Proses Fluid Bed Granulator Larutan pengikat

disemprotkan di atas
campuran serbuk dengan
Zat aktif dan eksipien dicampur
arah berlawanan dengan
aliran udara

Campuran massa serbuk diterbangkan dengan

aliran udara yang disemprotkan ke atas melalui
dasar ayakan granulator

Granul terbentuk karena ikatan partikel

padat dengan tetesan pengikat

Pengeringan sebagian terjadi

selama proses granulasi

Pengeringan sempurna dicapai

Proses dilanjutkan sampai semua serbuk
dengan cepat menggunakan aliran
teraglomerasi
udara panas setelah penyemprotan
pengikat berhenti
 Fluid Bed Spray Granulator
Nowadays, spray granulation wherever used is mostly done in a fluid
bed.
Fluid bed granules are very homogeneous. All particles in the powder
mix are sprayed evenly with liquid starting materials. The type of
granulate (size, density, porosity) can be influenced over a wide
range by the adjustment of various parameters.
 Different types of granulators

•Spray Granulator
•The powder to be granulated is suspended
in the heated air of a fluid bed, and a liquid
binder sprayed from nozzles positioned
above

•High-shear Granulator
•The high-shear granulation process
combines the active powder with a binder
solution using a high-speed mixing blade and
chopper.
Dry granulators

• Dry granulation converts primary powder

particles into granules using the application
of pressure without the intermediate use of
a liquid. Thus avoiding exposure of the
product to heat and moisture.

• The process involves compaction followed

by size reduction (milling).
Dry granulators
• Sluggers
• Roller compactors
Sluggers

• The compact made (slug) in a heavy duty

compression machine.

• The typical dimensions of the slugs: 25

mm diameter by about 10–15 mm thick.

• A hammer mill is then used for breaking

the compacts. The granules are then
screened into the suitable size.
Sluggers

• Advantages:
– Requires less equipment and space than
wet granulation.
– The product is not subjected to heat and
moisture.
Roller compactors

• The powder mix is squeezed between

two rollers to form a compressed sheet.

• The sheet is weak and brittle and breaks

immediately into flakes.

• These flakes are broken into granules,

and screened to the desired size.
 Chilsonator roller compaction system
Advantages/disadvantages of different processes:
Wet granulation Dry granulation Direct compression
Good powder flow Good powder flow Simple process?
Limited segregation Limited segregation Few machines needed
Good distribution of Drug not in contact Little process stress
drug and excipients water no water
no high temperatures no high temperatures
Suitable for all Complex process Robust process
concentrations of drug
Compaction behavior Poor process control, Segregation change
determined by process compaction behavior poor distribution
Binder substance in Dust! Limited concentration
the powder range (0.5-25%)

Complicated process Dependence of flow

many ipc’s, and compaction difficult validation behavior of
excipient
Unsuitable for drugs
sensitive to moisture
And heath.
Tablet compression operation
Tablet compression machine
Tablets

• Tablet compression machines (tablet presses)

have the following basic components:
– Hoppers: for holding and feeding granules or
powder to be compressed.
– Dies: that defines the size and shape of the tablet.
– Punches: for compressing the granules or powder
within the dies.
– Cam tracks for guiding the movement of the
punches.
– A feeding mechanism for moving granules or
powder from the hopper into the dies.
Tablet press hopper

Punch and die set

Examples of Tooling
Tabets
• Tablet presses can be classified into:
– Single punch machine
– Multi station rotary press
 Single punch machine
Technical parameter:

DP30 Single Punch Tablet

Model
Press
  Number of top punch (set) 1

  Max tablet diameter (mm) 20

  Max output (tablet /h) 3600

  Max filling depth (mm) 16

  Max press (KN) 30

  Power (kw) 0.55

  Rated power source AC220V/50Hz

  Weight (kg) 160

 Overall dimension (mm) 708x459x740

Stoke Tablet Press
• Tablet Punch Controls
Shape
Single punch
machine

Diagram showing important

sections of a single punch
machine.
Single punch machine
Single punch
machine

Another diagram showing steps

in the compression cycle of a single
punch tablet machine.
 A picture of a single-punch press

manual driving wheel

cylindrical gearing
hopper
cam gearing

belt gearing
feed shoe
electric motor

core components

70
Single-punch tablet press
Multistation press

• Also known as rotary because the head

of the press that holds the upper punch
rotates.

• During the rotation the punches are

guided up and down by fixed cam tracks
which control the sequence of filling,
compression, and ejection.
Diagram showing the movement of the punch and die sets in a
multistation tablet machine (rotary tablet press).
The core components and compression cycle
of rotary presses
filling and adjustment compression tablet ejection

⑥upper punch raising cam

⑤upper compression track of upper punch
roll

feed-frame
A: upper punch ⑨sweep-off blade

B: die cavity ③wipe-off blade

C: die
D: lower punch

The compression is ①pull-down cam

track of lower punch

applied by both the ②weight control cam

⑧ejector knob
upper punch and the ④lower compression roll
⑦lower punch raising cam

lower punch.
The compression cycle of a rotary tablet press
 A picture of multi-
station rotary press
hopper
feed-frame

head: upper turret, lower turret, die table

upper turret
die table
lower turret

16, 19, 27, 33, 37, 41, 49 stations

ZP19 rotary tablet press

Multistation machines

• Multistation tablet machines are engineered for

fast and economical production of tablets.

• They can produce several thousand tablets per

minute. The speed depends mainly on:
– The number of stations.
– Rotation speed.
• Example Manesty rotapress can produce about
100000 tablets per hour.
 High Speed Production Rotary
View of Punch Train Tablet Press

55 stations
495,000 tabs/hour
 Processing problems
• Capping and lamination:
– Capping: partial or complete separation of the top or bottom
crowns of the tablet.
– Lamination: is the separation of the tablet into two or more distinct
layers.
– Capping and lamination might occurs hours or days after the
tablets are made.
– The friability test is the quickest way of revealing such problems.
– Capping and lamination is mostly due to the deformational
properties of the formulation during and immediately following
compression.
 Processing problems

• Capping and lamination:

– During the elastic recovery of the tablet, and if
interparticulate bonding is not sufficient, a crack might
propagate leading to capping or lamination.

– Deep concave punches often produce tablets that cap

because the concaved part expand radially (horizontally)
while the body of the tablet does not expand radially to the
same extent which leads to capping. Using flat punches
might eliminate this.

Example of lamination
Processing problems

• Capping and lamination:

– A granulation or powder that is too dry might
cap or laminate for lack of cohesion.
Maintaining proper moisture levels facilitates
good interparticulate bonding and could
prevent capping or lamination.

– In direct compression operations if the

powder formulation is not compressible this
leads to capping or lamination.
Processing problems

• Capping and lamination:

– Dies develop wear “ring” in the area of
compression. Tablets compressed in this ring will
have larger diameter than the rest of the die region.
This leads to capping or lamination when the tablet
is ejected from the die.

– Capping and lamination can be eleminated by:

• Double compression (precompression)
• Increasing dwell time (slowing tabletting rate)
Possible cause of capping/lamination
Processing problems

• Picking and sticking:

– Picking: surface material from the tablet becoming
stuck and removed by the punch. This especially a
concern when the punch tips have engraving or
embossing.
• This might lead to accumulation of material at the
punch surface and thus prevent proper operation.

– Sticking: refers to tablet material adhering to the die

wall.
• This could lead to tablet edges chipping during
ejection, or producing rough edges.
Processing problems

• Picking and sticking:

– Sticking might result from the presence of materials of low
melting point (stearic acid) in the formulation which
becomes soft and sticky during the compression process
(generates heat).

– Excessive moisture in the granules or powder might lead

to sticking. Further drying might be necessary in this case.

– Addition of colloidal silica to the formula might reduce this

problem.
• Colloidal silica acts as polishing agent and makes punch
faces smooth.
Processing problems

• Mottling: Unequal distribution of color on a

tablet.
– Might result from the drug having a color that is
different than the excipients.
– Or if the drug’s degradation product is colored.
– Addition of dye can solve this problem but
• The dye can cause mottling by migration to the
surface of the granules during drying. This can be
overcome by proper control of the drying process, or
by changing the granulating fluid.
Processing problems

• Weight variation:
– The weight of the tablet is controlled by the
amount of granules or powder that fills the
die cavity prior to the compression.

– Any alteration to the filling process or the

volume being filled could lead to weight
variation.
Processing problems

• Granule size and size distribution before

compression:
– The size and size distribution of the
granules affects the filling of the die cavity.

– If large granules are used to fill a small die,

then missing few granules could lead to
large weight variation.
Processing problems

• Poor flow:
– If granules or powder have poor flow from
the hopper and around the die cavity this
could affect the filling of the die.
• This could arise if the machine speed is in
excess of the flow capabilities.
• Addition of a glidant such as talc or colloidal
silica improves the flow.
• Mechanical feeders can also be used to force fill
the die cavity.