In Process Quality
control
Part 7
Industrial pharmacy
5th class
1st semester
In-Process Quality Control
• During the compression of tablets, in-process
tests are routinely run to monitor the process,
including tests:
• The in-process tests are performed by
production and/or quality control (QC)
Processing Problems
The source of the problem:
1. Formulation
2. Compression equipment
3. Combination of the two.
Capping and Lamination.
Capping: describe the partial or complete separation of the top or
bottom crowns of a tablet from the main body of the tablet.
Lamination: is the separation of a tablet into two or more-distinct
layers.
Appear immediately after compression or occur hours or even
days, later.
Detection of these problems: subjecting tablets to friability test.
Causes of the problems:
1. During the compression process, air is entrapped among
the particles or granules and does not escape until the
compression pressure is released.
2. Capping and lamination are due to the deformational
properties of the formulation during and immediately
following compression.
Mechansim:
I. During compaction, particles undergo sufficient plastic
deformation to produce die-wall pressures greater than
can be relieved by elastic recovery when the punch
pressure is removed.
II. In some materials, this die-wall pressure causes enough
internal stress to cause a crack to propagate and initiate
fracture of the compact in the die.
III. Ifthe excess stresses do not initiate fracture upon
decompression in the die, the compact may laminate or
cap upon ejection from the die.
IV.The emerging portion of the compact expands while
the confined portion cannot, thus concentrating shear
stresses at the edge of the die and causing a break to
develop.
Rapid decompression results in tablets that fracture.
While tablets that do not fracture have the ability to
relieve shear stress (stress relaxation) which is time-
dependent; therefore, the occurrence of tablet fracture is
also time dependent.
Elimination of capping and
lamination:
1. Precompression
2. Slowing the tabletting rate
3. Reducing the final compression pressure.
I. As the stress relaxation time is increased
II. The amount of stress needing to be
relieved is reduced
III. Allowing an intact compact to be formed.
Problem: deep concave punches
produce tablets that cap (curved part of
such tablets expands radially while the body of
the tablet cannot, which establishes a shear
stress that produces the fracture).
Solution: Flat punches may eliminate this
additional shear stress.
Problem: A granulation that is too dry tends to
cap or laminate for lack of cohesion.
Solution: A certain percentage of moisture is often
essential for good compaction (in moisture-critical
granulations, the addition of a hygroscopic substance,
e.g., sorbitol, methylcellulose, or PEG 4000, can help to
maintain a proper moisture level).
Problem: Capping and lamination in direct
compression product (powder or fine particulate
materials may not be compressible or may have poor
compression properties).
Solution: Relative compressibility of various materials
may be reflected by their degree of consolidation
(crown thickness) when compressed in standard tooling
under identical compression conditions.
Problem: Tablet tooling is a cause of capping.
Causes:
1. The concave or beveled edge faces of punches
(gradually curve inward with use and form a "claw"
that can pull off the crowns of a tablet).
2. Wear in the upper punch (accelerates this claw
formation by permitting the punch tips to strike the
edges of the die hole).
3. The greater the radius of curvature of the punch
face (greater is the force exerted on the edges and
the less on the center of the tablet at the moment
of compression).
Problem: Dies develop a wear "ring" in the area of
compression.
As the ring develops, and enlarges, the tablets that are
compressed in the rings have a diameter that is too large to pass
easily through the narrower portion of the die above the ring.
Upon ejection, this constriction causes the tablet to cap or
laminate.
Cause:
Wear on tablet tooling increases as the hardness of the
material being compressed increases (most organic
materials are soft; certain inorganic materials such as
magnesium trisilicate are relatively hard and abrasive).
Solution:
1. Turn the die over so that compression occurs in an
unworn area above the ring.
2. On some presses, the depth of penetration of the upper
punch can be regulated so that compression may be
performed over some range of locations within the die.
3. Using dies with tungsten carbide inserts. The carbide is so
durable that the casing wears out before the insert
does.
Problem: The punch remains below the face of the die, so sweep-
off blade cuts off the tablet, leaving the bottom in the die) and can
also result in tablet fracture.
Causes:
1. Incorrect setup of the press causes a capping (the edge of
the tablet catches on the die and chip).
2. The blade is adjusted too high (tablets can start to travel
under it, become stuck, and break off).
The resulting broken pieces of tablets then enter the feed
frame; if they are large enough, they can cause a disruption of
the granulation feed, as well as affect the weight and hardness
of subsequent tablets.
Solution:
Adjust a compressed tablet ejection from the die so the lower punch
must rise flush with or protrude slightly above the face of the die at
the point where the tablet strikes the sweep-off blade.
Sticking: refers to tablet material adhering to the die wall.
Additional force is required to overcome the friction between the tablet and
the die wall during ejection.
Serious sticking at ejection can cause chipping of a tablet’s edges and can
produce a rough edge.
Also, a sticking problem does not allow the lower punch free movement and
therefore can place unusual stress on the cam tracks and punch heads, resulting
in their damage.
Sticking can also apply to the buildup of material on punch faces.
Solution:
1. Lettering should be designed as large as possible,
particularly on punches with small diameters. The
tablet can perhaps be reformulated to a larger size.
2. Plating of the punch faces with chromium (produce a
smooth, nonadherent face).
3. Colloidal silica added to the formula (acts as a
polishing agent and makes the punch faces smooth so
that material does not cling to them). Frictional nature
of this material may require additional lubrication to
facilitate release of the tablet from the die.
4. Additional binder or a change in binder (make granules
more cohesive, less adherent than before).
Problem: low-melting-point substances, either active
ingredients or additives such as stearic acid and polyethylene
glycol, may soften sufficiently from the heat of compression to
cause sticking.
Solution:
1. Dilution of the active ingredient with additional higher-
melting-point materials consequent increase in the size
of the tablet that may help.
2. The level of low-melting-point lubricants may be reduced, or
higher-melting-point replacements may be substituted.
3. When a low-melting-point medicament is present in high
concentration, refrigeration of the granulation and the press
may be in order.
4. Excessive moisture may be responsible for sticking, and
further drying of the granulation is then required.
Mottling is an unequal distribution of color on a
tablet, with light or dark areas standing out in an
otherwise uniform surface.
Mottling.
Cause of mottling: is a drug whose color differs
from the tablet excipients or a drug whose
degradation products are colored.
Solution: use of colorants may solve the above
problem but can create others.
• A dye can cause mottling by migrating to the
surface of a granulation during drying.
• To overcome this difficulty, the formulator may
(change the solvent system, change the
binder system, reduce the drying
temperature, or grind to a smaller particle
size).
Note: The use of colorants in direct compression
formulations can lead to mottling if the dye is not well
dispersed or if its particle size is too large.
Problem: Certain colored adhesive gel solutions may not be
distributed well because they must be hot when added to
much cooler powder mixtures. The adhesive then precipitates
from solution and carries most of the color with it.
Temporary solution: Further wetting, even overwetting,
is needed to disperse the binder and the color. The
additional mixing and increased activation of the binder,
however, may result in tablets with increased disintegration
times.
Permeant solution: Therefore, a better practice may be to:
1- incorporate fine powder adhesives such as acacia and
tragacanth into the product before adding the granulating
fluid,
2- or disperse a dry color additive during the powder blending
step.
Weight Variation.
The weight of a tablet being compressed is determined by
the amount of granulation in the die prior to compression.
Anything that can alter the die-filling process can alter
tablet weight and weight variation.
Granule Size and Size Distribution
Before Compression.
Variations in the ratio of small to large granules and in the
magnitude of difference between granule sizes
Influence how the void spaces between particles are filled.
• If large granules are used to fill a small die cavity (relatively
few granules are required) the average may represent
a high percentage weight variation.
• If hundreds of granules are required on the average for die fill,
(variation of a few granules around the average would
produce a minor weight variation, given a narrow particle size
range).
Poor Flow.
The die-fill process is based on a continuous and uniform flow of
granulation from the hopper through the feed frame.
Problem:
a. When the granulation does not flow readily, it tends to move
spasmodically through the feed frame so that some dies are
incompletely filled.
b. Similarly, dies are not filled properly when machine speed is in
excess of the granulation's flow capabilities.
Solution:
1. Addition of a glidant (talcum or colloidal silica), or an increase in the
amount already present, may be helpful.
2. Induced die feeders, which mechanically "force" the granulation
down into the die cavities as they pass beneath the feed frame.
Problem: Poor flow through the feed frame (a sign that the granulation is
not flowing properly out of the hopper).
As particulate solids move under the force of gravity through progressively
smaller openings; they are subjected to uneven pressures from the mass
above and alongside.
Depending on the geometry of the hopper, this situation may give rise to
one or another of two causes for poor flow: "arching" or "bridging,“ and "rat-
holing.
When poor hopper flow occurs, it may be controllable with vibrators
attached to the hopper sides to induce the granulation flow.
Another problem arise: most tablet granulations consist of
materials with a range of particle sizes.
Vibration or mixing action of the flow promoting devices may
induce segregation and stratification of the particles.
The larger particles tend to drift upward while the smaller
particles sift downward.
Changes in tablet weight and weight variation but it can also
lead to poor content uniformity, since drug is often not uniformly
distributed between the larger and smaller particles.
A new feed frame design that accommodated excessive flow
from the hopper without compromising uniform weight
variation.
Poor Mixing.
Problem 1: lubricants and glidants are not thoroughly
distributed.
The flow of particles is then impaired, and the granules
do not move efficiently into the dies.
Problem 2: a tendency to minimize the mixing time
during lubricant addition to prevent or reduce granule
friability
Inadequate mixing during this stage can result in
unsatisfactory granulation flow.
Punch Variation.
Problem: When lower punches are of unequal lengths-
the difference may be only a few thousandths of an inch-
the fill in each die varies because the fill is volumetric.
Solution: Only a good punch and die control program can
provide tooling of uniform dimensions.
Hardness Variation.
Hardness variation weight variation.
Hardness depends on:
1. Weight of material
2. Space between the upper and lower punches at the
moment of compression.
If the volume of material or the distance between
punches varies hardness is inconsistent.
Double Impression.
This involves only punches that have a monogram or
other engraving on them.
Problem: At the moment of compression, the tablet receives
the imprint of the punch. On some machines, the lower punch is
free to drop and then travel uncontrolled for a short distance
before it rides up the ejection cam to push the tablet out of the
die.
During its free travel, it rotates.
At this point, the punch may make a new, although lighter,
impression on the bottom of the tablet, resulting in a double
imprint.
Problem: Similar problems can be encountered with
engraved upper punches and tablet machines that utilize two
compression stages to compress a tablet.
The first stage (precompression) uses a lower compaction force
than the final compression stage
But the tablet does receive the imprint of the punch.
If the upper punch is uncontrolled, it can rotate during the short
travel to the final compression stage and thus create a double
imprint.
Solution for both problems: The newer presses have
anti-turning devices as an integral part of their design and
construction.
