MANUFACTURING DEFECTS/ PROCESSING PROBLEMS
• During routine production of tablets many defects arise with the finished tablets
which may be due to either some fault in tablet formulation or in the tableting
equipment and sometimes due to both reasons.
• The defects are as follows:
Capping and Lamination
Picking and Sticking
Mottling
Weight variation
Hardness variation
Double impression
Capping and Lamination
• Capping is 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. Usually,
these processing problems are readily apparent immediately after compression;
however, capping and lamination may occur hours or even days later. Subjecting
tablets to the friability test is the quickest way of revealing such problems.
Reasons:
Due to the entrapment of air among the particles or granules during the
compression and does not escape until the compression pressure is removed.
• Too much pressure on compression.
• Presence of either excess fine powders or less amount of fine powders in
granules.
• A granulation that lack of cohesion due to excessive dryness.
• Use of deep concave punches.
• Wear and tear of punches and dies.
• Wrong setting of dies or punches.
Solution:
• Slowing the tableting rate or reducing the speed of the machine.
• Reducing the final compression pressure.
• Applying precompression.
• Granulating the material.
• Addition of hygroscopic substance, e.g. sorbitol, to maintain the proper moisture
level.
• Using proper granules and required amount of fine powders.
• Replacing the worn out dies and punches.
• Correcting the level of the top of the lower punch so as to coincide with the level
of the upper surface of the die.
Picking and Sticking
• In picking a small surface of the tablet material is removed by the punches
and
adheres to the surface of punches therefore the resulting tablets show a pitted
surface instead of smooth surface.
• In sticking the tablet materials adhere to the die
wall.
Reasons:
• Presence of scratches or engraving or embossing on the punches.
• Use of damp granules.
• Presence of excessive moisture.
• Use of worn out dies and punches.
• Presence of low melting point substances (either active ingredient or additives)
which may soften from compression heat.
Solution:
• Letters of the engraving or embossing should be as large as possible.
• Using chromium plated punches for producing a smooth non-adherent face.
• Using dry granules and by adding lubricant to the granules.
• Replacing the worn out dies and punches.
• Using higher melting point material as diluents.
• In case of excessive moisture, further drying of the granules.
• In some cases, colloidal silica added to the formula acts as a polishing agent and
makes the punch faces smooth.
• Sometimes additional binder or change in binder makes the granules more
cohesive and therefore less adherent.
Mottling
• Mottling is an unequal distribution of color on a tablet, with light or dark
areas standing out in an otherwise uniform surface.
Reasons:
• Difference of colors in the drugs and the added excipients.
• Occurrence of colored degraded products of the drug.
• Migration of dyes during drying of granules.
• Use of colorants in direct compression formulation (if the dye is not well dispersed
or if its particle size is too large)
Solution:
• Using a dye which can mask the color of tablet ingredient.
• Changing the solvent system.
• Changing the binder system.
• Drying the granules at a low temperature.
• Grinding to a smaller particle size.
Weight variation
• The weight of a tablet being compressed is determined by the amount of
granules in the die prior to compression. Therefore, anything that can alter
the die
filling process can alter tablet weight.
Reasons:
• Poor flow of granules to the die.
• Size separation of granules i.e. small and large size granules.
• Presence of too fines in granules.
• Separation of mixed ingredients of granules.
• Less quantity or poor mixing of lubricants.
• Unequal length of lower punch.
Solution:
• Proper granulation with good flow property.
• Removing the too fines from the granulation.
Hardness variation
• Tablet should not be harder than required. The hard tablets may not
disintegrate in the required period of time and to soft tablets may not
withstand the shocks during handling,
transporting and dispensing.
Reasons:
• Hardness variation has the similar causes as weight variation.
• Apart from these reasons other factors include:– Weight of the material.– Space between the upper and lower punches at the time of compression.– Inappropriate pressure applied by the punches.
Solution:
• Correcting the causative factors.
Double impression
• This involves only punches that have a monogram or other engraving on them to
produce an impression on the tablet during compression.
• On some machines, the lower punch moves downwards then travels uncontrolled
upward to a short distance to push the tablet out of the die. During its free travel it
rotates and makes second impression on the tablet. This impression is generally
lighter than the original impression.
• Similar problem 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 receives 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.
• The newer tablet presses are fitted with devices which prevent the
rotation/turning of the punches.
Quality Attributes of Tablets
• Should include the drug with correct dose and uniform distribution
• Should be an elegant product having its own identity while being free of defects
such as chips, cracks, discoloration, and contamination etc.
• Should have accurate and uniform weight & size
• Should have the strength to withstand the rigors of mechanical shocks encountered
in its production, packaging, shipping, and dispensing
• Should be chemically, physically and microbiologically stable during the lifetime of
the product.
• Must be able to release the medicinal agent (s) in the body in a predictable and
reproducible manner
• Incompatibility should be absent
• Should be easy and economical in production
Quality Evaluation of a Tablet
General Appearance :
The control of the general appearance of a tablet involves the measurement of a number
of attributes such as a tablets,
size
shape
color
presence or absence of an odor
taste
surface texture
physical flaws and consistency and
legibility of any identifying markings
Size and shape:
• A compressed tablets shape and dimensions are determined by the tooling during
the compression process.
• The crown thickness of individual tablets may be measured with a micrometer
which permits accurate measurement and provides information on the variation
between tablets. Other techniques employed in production control involving
placing 5 to 10 tablets in a holding tray, where their total crown thickness may be
measured with a slide caliper scale.
• Tablet thickness should be controlled within a ±5% variation. In addition, thickness
must be controlled to facilitate packaging.
Unique identification marking:
Pharmaceutical companies manufacturing tablets often use some type of unique
markings on the tablet in addition to color to aid in the rapid identification of their
products. These marking utilize some form of embossing, engraving or printing.
Organoleptic properties:
• Many pharmaceutical tablets use color as a vital means of rapid identification and
consumer acceptance. The color of a product must be uniform within a single
tablet (non-uniformity is generally referred as mottling), tablet to tablet and lot to
lot.
• The presence of an odor in a batch of tablets could indicate stability
problem, such as the characteristic odor of acetic acid in degrading aspirin
tablet. The presence of an odor could be characteristic of the drug
(vitamin have a characteristic odor), added ingredients (flavoring agents
have pleasant odors) or the dosage form (film coated tablet usually have a
characteristic odor).
• Taste is important in consumer acceptance of chewable tablets.
Weight Variation
• Tablet weight is determined by the amount of fill placed in the die. It is measured
by volume and not by weight and therefore depends on the granule size and the
void space.
• Twenty tablets are weighed individually and average weight is calculated. Then
individual weight of each tablet is compared with the average weight. The
equation for calculation of percentage weight variation is given below:
• The USP has provided tolerance for the average weight of uncoated tablet.
• The tablets are said to be met the specification if–
not more than 2 tablets are outside the percentage limit and
no tablets differ by more than twice the percentage limit.
Tablet hardness /breaking strength /crushing strength
• 3,000 to 40,000 lbs of force can be applied during compression in tablet
manufacture; the greater the pressure applied the harder the tablet.
• Tablets that are intended to dissolve slowly such as lozenges or buccal tablets are
intentionally made hard, whereas tablets intended to dissolve fast such as tablet
triturates are intentionally made soft.
• Generally tablets are made so that they are hard enough to resist breakage during
packaging, shipping and handling yet soft enough to disintegrate and dissolve
properly after administration.
• Hardness measuring devices apply increasing pressure on the tablet until the tablet
breaks (a force of about 4 kilograms is considered to be a minimum for hardness).
• Different types of tablet hardness testers are available:
— The Strong-Cobb Hardness Tester
—
The Pfizer Hardness Tester
—The Stokes-Monsanto Tester
Figure: Monsanto Tablet Hardness Tester
Friability
• This test is performed to evaluate the ability of the tablets to withstand abrasion in packing, handling and transporting. The instrument used for the test is friabilator.
• A number of tablets are weighed and placed in a tumbling chamber which is
rotated for 4 minutes or for 100 revolutions. During each revolution the tablets fall
from a distance of six inches to undergo shock. After 100 revolutions the tablets
are again weighed and the lost in weight indicates the friability.
• The maximum acceptable limit of weight loss is 1%.
Disintegration
Disintegration can be defined the process of breaking down the tablet into smaller
particles. It results in an increase in surface area to provide more surfaces for
dissolution or release of the drug so that the drug can exert its effect.
Figure: Tablet Disintegration Tester
• A disintegration apparatus consists normally of six chambers. One tab is placed in each tube and a plastic disc is placed upon it. Tubes are placed in a water bath and the temperature is raised upto (37±2) °C. The instrument is used to move the
basket containing the tablets up and down through a distance of 5-6cm at a
frequency of 28-32 cycles per minute.
• At the highest position of the tubes, the screen remains below the surface of the
water. The end point of the test, at which all visible parts of the tablets have been
eliminated from their holding tubes during agitation, is recorded.
• According to USP, disintegration time for tablets is,
• If 1 or 2 tablets fail to disintegrate within the time specified, an additional 12
tablets are tested. The requirement is met if not fewer than 16 of the total of 18
tablets tested are disintegrated.
Dissolution
• Dissolution plays an important role in the absorption and physiologically
availability of the drug in the blood stream. USP contains a test that determines
the dissolution characteristics.
• The tablet to be tested is introduced in the basket (basket apparatus, USP Type I) or at the bottom of the dissolution vessel (paddle apparatus, USP type II). The
apparatus is fitted in position in the dissolution medium (as specified in the
monograph) containing vessel.
• The temperature of the surrounding bath is maintained (37±0.5) °C. The motor is
started and its revolutions adjusted according to monograph.
• The samples are withdrawn at specified intervals and filtered immediately
through a suitable filter medium. The samples are tested by chemical analysis
for proportion of drug dissolved which should meet the requirements as stated
in the monograph.
• Dissolution acceptance criteria as per USP,
Content uniformity
• This test is performed to ensure that every tablet coated or uncoated must contain the stated amount of medicaments within the prescribed limits.
• For this purpose 30 tablets are selected randomly and 10 of them are assayed
individually according to the procedure indicated in the monograph. Nine of the 10
tablets must contain not less than 85% and not more than 115% of the labeled
drug content. The 10th tablet may not contain less than 75% or more than 125%. If
this step is failed than remaining 20 tablets are assayed individually. They must
contain 85-115% of drug content.
• Content uniformity may be disturbed by 3 factors:
—Non uniform distribution of ingredients during granulation.
— Segregation of powder mixture of granulation during various manufacturing
process.
—Tablet weight variation (occasionally)
