1

Tableting : Tablet manufacturing

Wet granulation method
Dry granulation method (slugging)
Direct compression
2
Powder properties to make
tablet
The powder must be compressible and
compactible
The particles must flow well (tablet
uniformity)
The particle surfaces must wet well
3
Granulation
Two main advantages do granules show,
That of compressibility and good powder
flow!
4
Wet granulation
Compressibility is improved by the addition
of a binder
Flowability is attained due to a particle size
increase
Hydrophobic surfaces are made hydrophilic
by use of a hydrophilic binder
5
Manufacture of granules
Blend
powders
Moist
mass
Moist agglomerates
Dried granules
Properly sized
Dry granules
Add binder
solution
Pass through
screen
dry
Pass through
screen
-large cohesion force
-low viscosity
-Inert
-Should blend easily
-High solubility
-Non-hygroscopic
6
Wet granulation: Binders
Sugars / Natural binders
Sucrose
Liquid glucose
Acacia
Tragacanth
Gelatin
Starch paste
Pregelatinized starch
Alginic acid
Cellulose
Synthetic / Semisynthetic
polymers
Methyl cellulose (MC)
Ethyl cellulose (EC)
Hydroxypropylmethyl cellulose
(HPMC)
Hydroxypropyl cellulose (HPC)
Na-carboxymethyl cellulose
(CMC)
Polyvinyl pyrrolidone (PVP)
Polyethylene glycol (PEG)
Polyvinyl alcohol (PVA)
Polymethacrylates (PMA)
7
Granule formation
pendular funicular
capillary droplet
Nucleation Transition Ball growth
8
Why granules
Flow better than powder
Less surface area per unit weight than
powders (more stable, less likely to cake in
the container than powders)
Wet granulation provides content
uniformity
Wet granulation may improve drug
dissolution
9
Disadvantages of Wet Granulation
Quality: Effects on disintegration times
Cost: Granulation is an expensive process because
of labor, time, equipment, energy and space
requirements
Loss of material during various stages of
processing
Stability may be major concern for moisture
sensitive or thermo labile drugs
Multiple processing steps add complexity and
make validation and control difficult
Incompatibilities between formulation components
can be aggregated
10
High shear mixture granulation
Blending and wet massing is carried out using an
impeller and a chopper. Mixing, densification and
agglomeration are achieved through shear and
compaction force exerted by the impeller.
Advantages:
Short processing time
Less liquid binder is required
compared with fluid bed
granulation
Highly cohesive material can
be granulated
11
Fluid bed granulation
Fluid bed granulation is a process by which
granules are produced in a single step by spraying
a binder solution onto a fluidized powder bed.
Advantages:
Single step process
Fine, homogenous particles
Free flowing powders
Disadvantages:
Producing too much dust
Segregation and loss of fine particles
Generation of static electricity charges
12
Spray drying granulation
A granulation technique that converts liquids into
dry powders in a single step. This method removes
moisture instantly.
Advantages:
Rapid process
Ability to be operated
continuously
Suitable for heat sensitive
products
13
Drying
Important process - last stage before packaging
moisture low enough - prevent degradation, allow
free flow
pharmaceutical powders contain some moisture -
vary with air they are exposed to
drying -removal of all or most of the liquid by
supplying latent heat to cause thermal vaporization
14
To dry a material following points
should be considered
Heat sensitivity of the material being dried
Physical characteristics of the material
The necessity for asepsis
Nature of the liquid to be removed
The scale of the operation
Available sources of heat
15
Drying problems (solute migration)
Air flow
drug
On compression
16
Consequences of solute migration
Loss of active ingredient
Mottling of coloured tablets
Intragranular migration of colour
To reduce mottling, use insoluble colour
(aluminum lake)
use small granules for tableting
Migration of soluble binders
To make harder granules
Binder-binder interaction rather than drug-drug or
drug-excipient contact
this can be beneficial
17
Dry granulation
Advantages
I deal for moisture sensitive
material
I deal for heat sensitive material
I deal for improved disintegration
(no binder)
Disadvantages
Requires a specialized heavy duty
tablet press to form slug
Poor color distribution uniformity
Tends to create more dust,
increasing the potential of
contamination
Blend powders
Slug
Granules
Sized granules
Mill
Sieve
Compression
18
Operations in tablet manufacturing
Wet granulation Dry granulation Direct compression
1. Weighing 1. Weighing 1. Weighing
2. Sizing 2. Sizing 2. Sizing
3. Blending 3. Blending 3. Blending
4. Wet massing 4. Slug compression -
5. Wet screening 5. Milling -
6. Drying - -
7. Dry screening 6. Dry screening -
8. Blending w/ lubricant
& disintegrant
7. Blending w/ lubricant
& disintegrant
-
9. Tablet compression 8. Tablet compression 4. Tablet compression
19
Choice of Method Depends on
Several Factors
Size of Dose
Compactibility and/or Fluidity of Drug
Stability Characteristics of the Drug
20
A Consideration of the Dose of Drug
is the Starting Point
LOW DOSE (<25 mg)
(Most of the tablet will be excipients)
Content Uniformity
High DOSE (>250 mg)
(Most of the tablet will be drug)
Compactibility
Fluidity
21
Lower Dose Drugs Generally can
Be Directly Compressed
Can compensate for any lack of compactibility
and/or lack of flowability by the use of special
direct compression fillers (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.
Blend Compress
22
Advantages of direct compression
Efficient and economical
Elimination of heat and moisture = increased stability
Particle size uniformity
Increased particle dissolution rate (each primary
particle is released upon tablet disintegration as
opposed to granules)
Batch-to-batch variation is negligible (fewer process
steps)
Fewer excipients = less chance of chemical
interaction between API and excipient
No aging effects
23
Direct compression limitations
Uniform blending and prevention of unblending of
low-dose drugs
Fillers often are more expensive than filler used in
granulation
Limitation in producing coloured tablets
Dust problems
Limitations in the dilution capacity of excipients
More sensitive to lubricant softening and
overmixing than granulations
24
Requirements for a directly
compressible filler
Good flowability
Good blending properties
Low lubricant sensitivity
High compactibility
Inertness
Constant quality
Relatively cost effective
25
Examples of Direct Compression
Filler-Binders
Microcrystalline Cellulose (MCC)
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.
26
POTENTIAL PROBLEMS
IN TABLETING
27
Manufacturing problems
Capping and Laminating or Splitting
Sticking, Picking and Filming
Chipping and Cracking
Binding
28
Potential problems in tableting
Tablet presses have become more complex, however,
the compaction of material between punches remains
essentially the same
The main differences in speed of compaction,
mechanical feeding of the materials from the hopper into
the die and electronic monitoring of the press
Large presses can produce as many as 10000
tablets/min
All these advancements and innovations have not
decreased the problems often encountered in
production, and in fact have increased the problems
because of the complexities of the presses and the
greater demands on quality
29
Capping
Capping occurs when the upper segment of the
tablet separates from the main portion of the tablet
and comes off as a cap.
Top tablet falls off
Elasticity in combination with poor bonding
30
Capping: reasons
Due to air entrapped in the granulation and then
expands when the pressure is released
Due to a large amount fine particles in the
granulation
Due to a lack of sufficient clearance between the
punch and the die wall
It is often due to new punches and dies that are
tight fitting
Due to too much or too little lubricant
Due to an excessive moisture
31
Causes and remedies of capping related to formulation
CAUSES REMEDI ES
1.
Large amount of fines in the
granulation
Remove some or all fines
2.
Too dry (leading to loss of
proper binding action).
Moisten the granules or add a
hygroscopic substance e.g.:
sorbitol, methyl cellulose or PEG-
4000
3.
Granules not dry enough Dry the granules properly
4.
Insufficient amount of binder or
improper binder.
Increase the amount of binder or
add a dry binder such as acacia,
sorbitol, PVP
5.
Insufficient or improper
lubricant
Increase the amount of lubricant or
change the type of lubricant
6.
Granular mass too cold to
compress firmly
Compress at room temperature
32
Causes and remedies of capping related to
the machinery
CAUSES REMEDIES
1. Poorly finished dies Polish dies properly, investigate
other steels or materials
2. Deep concave punches or
beveled-edge faces of
punches
Use flat punches
3. Lower punch remains below the
face of die during ejection
Make proper setting of lower
punch during ejection
4. Incorrect adjustment of sweep-
off blade
Adjust sweep-off blade correctly
to facilitate proper ejection
5. High compression speed Reduce speed of compression
(increase dwell time)
33
Lamination
Lamination is the separation of the
tablet into two or more distinct layers.
Elasticity in combination with poor bonding
34
35
Causes and remedies of lamination
related to formulation
CAUSES REMEDIES
1. Oily or waxy materials
in granules
Modify mixing process. Add
adsorbent or absorbent.
2. Too much of
hydrophobic
lubricant e.g.:
Magnesium-stearate.
Use a lower amount of
lubricant or change the
type of lubricant.
36
Causes and remedies of lamination
related to the machinery
CAUSES REMEDIES
1. Rapid relaxation of the
peripheral regions of a
tablet, on ejection from a
die.
Use tapered dies, i.e. upper part
of the die bore has an
outward taper of 3 to 5.
2. Rapid decompression Use pre-compression step.
Reduce turret speed and
reduce the final
compression pressure.
37
Sticking, picking and filming
Sticking is usually due to improperly dried or lubricated
granulations causing the tablet surface to stick to the punch
faces
Picking is a form of sticking in which a small portions of
granulations sticks to the punch face and grows with each
revolution of the press, picking out a cavity on the tablet
face
Filming is a slow form of picking and is largely due to
excess moisture in the granulation, high humidity, high
temperature or loss of highly polished punch faces due to
wear
38
Causes and remedies of
sticking/filming related to formulation
CAUSES REMEDIES
1. Granules not dried
properly
Dry the granules properly. Make
moisture analysis to determine
limits.
2. Too little or improper
lubrication
Increase or change lubricant.
3. Too much binder Reduce the amount of binder or use a
different type of binder.
4. Hygroscopic granular
material
Modify granulation and compress
under controlled humidity.
5. Oily or waxy materials Modify mixing process. Add an
absorbent.
6. Too soft or weak granules Optimize the amount of binder and
granulation technique.
39
Causes and remedies of sticking/filming
related to the machinery
CAUSES REMEDIES
1. Concavity too deep for
granulation.
Reduce concavity to
optimum.
2. Too little pressure. Increase pressure.
3. Compressing too fast. Reduce speed.
40
Causes and remedies of picking related to
formulation
CAUSES REMEDIES
1. Excessive moisture in granules. Dry the granules properly
2. Too little or improper lubrication. Increase lubrication; use colloidal
silica as an antiadherant
3. Low melting point substances may
soften from the heat of
compression
Add high melting-point materials. Use
high meting point lubricants.
4. Low melting point API in a high
concentration.
Refrigerate granules and the entire
tablet press
5. Granules too warm during
compression
Compress at room temperature. Cool
sufficiently before compression.
6. Too much binder Reduce the amount of binder, change
the type or use dry binders.
41
Causes and remedies of picking related to the
machinery
CAUSES REMEDIES
1. Rough or scratched punch faces Polish faces to high luster.
2. Embossing or engraving letters
on punch faces such as B, A,
O, R, P, Q, G
Design lettering as large as
possible. Plate the punch faces
with chromium to produce a
smooth and non-adherent face.
3. Bevels or dividing lines too deep Reduce depths and sharpness.
4. Pressure applied is not enough;
tablets too soft
Increase pressure to optimum.
42
Chipping and cracking
Chipping = The breaking of tablet edges as the tablet
leaves the press or during subsequent handling and coating
operations
Cracking = Small, fine cracks observed on the upper and
lower central surface of tablets, or very rarely on the side
walls
43
Causes and remedies of
chipping/cracking related to formulation
CAUSES REMEDIES
1. Sticking to
punch faces
Dry the granules
properly or
increase
lubrication.
2. Granules too
dry
Moisten the granules.
Add hygroscopic
substances.
3. Too much
binder
Optimize binding, or
use dry binders.
CAUSES REMEDIES
1. Large size of
granules
Reduce granule
size. Add fines.
2. Granules too
dry
Moisten the
granules and add
binder.
3. Tablet
expansion
Improve
granulation. Add
dry binders.
4. Granules too
cold
Compress at room
temp.
44
Causes and remedies of chipping/
cracking related to the machinery
CAUSES REMEDIES
1. Groove of die
worn
Polish to open end,
reverse or
replace the die.
2. Barreled die
(center of the
die wider
than ends)
Polish the die to
make it
cylindrical
3. Edge of punch
face turned
inward
Polish the punch
edges
4. Concavity too
deep to
compress
properly.
Reduce concavity
of punch faces.
Use flat punches.
CAUSES REMEDIES
1. Tablet expands
on ejection due
to air
entrapment.
Use tapered die.
2. Deep concavities
cause cracking
during tablet
removal
Use special
removal
equipment
45
Causes and remedies of binding
related to formulation
CAUSES REMEDIES
1. Granules too moist, extrudes
around lower punch
Dry the granules properly
2. Insufficient or improper
lubricant
Increase the amount of lubricant or use a
more effective lubricant.
3. Granules too coarse Reduce granule size, add more fines, and
increase the quantity of lubricant.
4. Granules too hard for the
lubricant to be effective
Modify granulation. Reduce granule size.
5. Granules are very abrasive
and are cutting into dies
Reduce granule size. Use wear-resistant
dies.
6. Granules too warm, they stick
to the die
Reduce temperature.
46
Causes and remedies of binding
related to the machinery
CAUSES REMEDIES
1. Poorly finished dies Polish the dies properly.
2. Rough dies due to abrasion,
corrosion
Investigate other steels or other
materials or modify granulation.
3. Undersized dies. Too little
clearance
Rework to proper size.
Increase clearance.
4. Too much pressure in the tablet
press
Reduce pressure OR
modify granulation.
47
Mottling
Mottling = an unequal distribution of color
with light or dark spots standing out in an
otherwise uniform surface
Causes: Use of colored drug with neutral
excipients, dye migration to the surface during
granule drying process, improper mixing
48
Tablet testing (uncoated tablets)
Uniformity of weight
Hardness
Disintegration time
Friability
Dissolution test (similarity factor)
Content uniformity
49
Uniformity of weight
Weight control is based on a sample of 20 tablets
[B.P 1998].
The USP needs 10 Tablets
Danish and Switzerland require 100 tablets
The USP XXII: has made content uniformity the
principal attribute. Weight uniformity still
applies, where the product contains > 50mg
active or where the drug constitutes >50% of the
compression weight.
50
Uniformity of weight
(Continued)
Uncoated tablets comply with the following test:
Weigh 20 tablets selected at random and determine
average weight.
Not more than 2 of the individual weights deviate
from the average weight by more than the
percentage deviation shown in table I and none
deviates by more than twice that percentage.
51
Table I: Permitted weight variation
Average weight of tablet [mg] Acceptable Percentage
of deviation
80
80< tablet weight <250
250
10
7.5
5
B.P 1998
52
Average tablet weight
Tablet weight (mg) tablet weight (mg) Tablet weight (mg)
310 83 210
310 80 200
315 83 210
288 82 220
289 88 185
310 73 176
305 75 191
305 74 200
268 82 219
300 80 189
300 mg 80 mg
200 mg
285-315 mg
72-88 mg
185-215 mg
REJECTED
ACCEPTED
REJECTED
300 x 5%=15 mg x 2 = 30mg
53
Uniformity of content
Determine the content of active ingredient of each of 10
tablets taken at random using a suitable analytical
method.
The requirement is met if the individual values obtained
are all within the range [85-115%] of the average value.
The test fails if more than one individual value is
outside the limits 85 to 115%of the average value or if
any individual value is outside the limits 75 to 125%of
the average value.
54
Paracetamol (mg) paracetamol (%)
500 100
510 102
520 104
505 101
490 98
470 94
480 96
530 106
475 95
520 104
mean 500
Content uniformity
85%-115%
ACCEPTED
REJECTED
REJECTED
Content uniformity
Outside 75%-125%
Paracetamol (mg) Paracetamol (%)
500 98.23
545 107.07
520 102.16
505 99.21
490 96.27
420 82.51
480 94.30
590 115.91
530 104.13
520 102.16
Mean 509
Paracetamol (mg) Paracetamol (%)
500 100
490 98
480 96
505 101
490 98
480 96
480 96
630 126
470 94
480 96
Mean 500.5
55
Only 1 individual outside of 85-115% but within 75-125%
More tablets
should be
tested
paracetamol tablets
(mg) paracetamol (%)
500 96
545 104
520 100
505 97
490 94
510 98
480 92
620 119
530 102
520 100
Mean 522
56
Uniformity of content
(Continued)
If one individual value is outside the limits 85-115%
but within the limits 75-125% of the average value,
repeat the determination using another 20 tablets taken
at random.
The requirement is met if in the total sample of 30
tablets not more than one individual value is outside the
limits 85-115% and none is outside the limits 75-125%
of the average value.
57
Paracetamol (mg) paracetamol (%)
1 500 97.81
2 545 106.61
3 520 101.72
4 505 98.79
5 490 95.85
6 510 99.76
7 480 93.89
8 600 117.37
9 530 103.68
10 520 101.72
11 518 101.33
12 500 97.81
13 520 101.72
14 530 103.68
15 515 100.74
16 480 93.89
17 480 93.89
18 460 89.98
19 485 94.87
20 530 103.68
21 500 97.81
22 525 102.70
23 550 107.59
24 535 104.65
25 485 94.87
26 520 101.72
27 495 96.83
28 510 99.76
29 500 97.81
30 500 97.81
mean 511.27
Outside of 85-115%
Within 75-125%
Previous 10 tablets
ACCEPTED
58
Disintegration
The process of disintegration is characterised by two
simultaneous processes:
Fluid penetration and
Particle separation
The method uses a 2.8 cm diameter tube which has a
10# (1700 m) sieve fitted at the base and which is
vertically raised and lowered 30 times a minute, 7.5 cm
through water at 37C.
59
Disintegration apparatus
60
Method
Introduce one tablet or capsule in each tube and, if
prescribed in the appropriate general monograph, add a
disc to each tube.
Suspend the assembly in the beaker containing the
specified liquid.
Operate the apparatus for the specified time.
Remove the assembly from the liquid.
The tablets pass the test if all six have disintegrated.
61
Disintegration testing
Tablet type Standard Conditions
Uncoated <15min Water
Coated [film] <30min Water
Other Coated tablets <60min Water, if no disint. Occurred
repeat the test on a further 6 tablets,
replacing water by 0.1M HCl.
Enteric-coating >120min 0.1 M HCl. No disintegration
<60min pH 6.8 phosphate buffer.
Effervescent <5min 200 ml water at 20C.
Soluble <3min Water at 20C.
Dispersible <3min 2 tablets placed in 100 ml water at
20C and stir until completely dispersed. A smooth dispersion is produced which
passes through a sieve screen 22 # (710 m).
62
Mechanical properties of tablets
robustness & capping propensity
Crushing strength: defined as the compressional force
applied diametrically to a tablet which just fractures it.
Tablet diameter and thickness affect the force
necessary to break it.
Tensile strength:
Where o is the tensile strength, P the crushing
strength, D the diameter and H tablet thickness.
DH
P
t
o
2
=
63
Hardness or Tensile strength
hardness (kg) diameter (mm) Thickness (mm) TS (Mpa)
5 5 3 2.08068
7 8 4 1.36545
11 10 5 1.37325
64
Hardness tester
Schleuniger hardness tester: calibrated in
Strong Cobb units [SCU] as well as
kiloPonds [kP].
1 kP = 9.807N and 1 SCU = 0.714kP.
Tensile strength is expressed in N/m
2
or
Pa, MPa.
65
Resistance to abrasion or
Friability
20 tablets are dedusted, weighed [W
0
] and
placed in a perspex drum (Roche Friabilator)
and tumbled (rotated 100 times [4min]). After
dedusting they are reweighed [W].
Limits of 1% friability are often set but <0.1% is a
realistic goal in development.
100 *
0
0
%
W
W W
F
(

=
66
Friabilator
Drop
The % Weight loss due to chipping, abrasion and erosion
is reported as % Friability.
67
Dissolution tester
68
Versus
Concern :
In-vitro versus in-vivo dissolution
Reasons for dissolution test:
1. To evaluate the potential effect of formulation
2. To ensure that preparations comply with product specification
3. To indicate the performance of the preparation under in vivo
condition
69
USP Dissolution Apparatus
Apparatus 1 - Basket (37)
Apparatus 2 - Paddle (37)
Apparatus 3 - Reciprocating Cylinder (37)
Apparatus 4 Flow-Through Cell (37)
Apparatus 5 Paddle over Disk (32), Transdermal
Delivery System, use paddle and vessel from Apparatus
2 with a stainless steel disk assembly to hold the
transdermal on the bottom of vessel.
Apparatus 6, Cylinder (32), Transdermal Delivery
System, use Apparatus 1 except replace the basket
shaft with a stainless steel cylinder element.
Apparatus 7, Reciprocating Holder, for transdermal
delivery systems and also a variety of dosage forms
70
71
72
Dissolution specifications
Known drug
New chemicals
Highly
soluble
Poorly
soluble
Single
point
two
points
NLT 80%
In 30 min
15 and 30 min
(carbamazepine)
Highly
soluble
Poorly
soluble
Single
point
two
points
NLT 80%
In 30 min
15 and 30 min
M
i
l
d

c
o
n
d
i
t
i
o
n
s
:
B
a
s
k
e
t

5
0
/
1
0
0

r
p
m
P
a
d
d
l
e

5
0
/
7
5

r
p
m
73
Dissolution Profile comparison
Similarity factor
Difference factor
Time (min)
D
i
s
s
o
l
v
e
d

9
%
)
5 10 20 30
reference
Test
74
Difference Factor
where n is the number of time points, R
t
is the dissolution value of
the reference batch at time t, and T
t
is the dissolution value of the
test batch at time t.
Similarity Factor
f2 > 50 similar
f2 < 50 different
f1 0-15 similar
f1 > 15 different