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– This step is important to control the particle size distribution, which not only
improves the ow property of granules but also determines the size of tablet. In
general, the granule size decreases as the tablet size decreases.
Lubrication
• Lubricants are mixed with the granules in nal step before compression. It
improves the ow of granules and reduces friction of tablet with punches and
walls of the die.
– Same equipment can be used which were employed for mixing of powders at the
start of the process. However, tumbling mixers, e.g., cone mixer and cube mixer
etc. are more common (detailed in Sect. 2.4.6.2).
– Yield is calculated at this stage as well.
Tableting (Compression)
• Granules ow to the die cavity and compressed by the upper and lower punches
therein.
8.1.2.3 Dry Granulation Technique
Similar to wet granulation technique, the granules are subjected to compression
subsequent to preparation of granules. However, no solvent is used in dry granula-
tion technique. High stresses are applied to powder to convert it into aggregated
particles and hence granules [7]. There are two methods of formation of granules,
i.e., slugging and roller compaction.
Slugging:In slugging method, the powders after mixing are compressed into a big
sized tablet (termed as slugs). The slugs are milled to the required size granules
using conventional milling equipment.
Roller Compaction: The drug and excipients are mixed together (similar to the
previous method), subsequently pressed through two rollers (rotating in opposite
direction), to produce a thin compressed sheet of material, which is then converted
into desired size granules using conventional milling equipment, as described
previously.
The main advantages and limitations of wet granulation and dry granulation are
summarized in Table8.4.
Table 8.3 Mesh size required for powder to pass thorough and the corresponding tablet sizes [6]
Tablet size Mesh size
Up to 4.8mm 20
Up to 7mm 16
Up to 10mm 14
11mm or above 12
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8.1.3 Tablet Compression Process
Compression originates from the Latin word compressare, meaning “to press
together.” It is an important step in tablet manufacturing, in which a pharmaceutical
powder is pressed in a conned space (called die) using two metal rods (called
punches). Compression usually involves two phenomena, i.e., compaction and con-
solidation, diagrammatically shown in Fig.8.1.
8.1.3.1 Compaction
Compaction is the process by which the porosity of a given powder is decreased as
a result of being squeezed together by mechanical means.
Pharmaceutical powder contains air spaces; therefore, the bulk volume decreases
when external force is applied. The reduction in volume can be due to:
Particle close repacking: The particles rearrange due to external force; hence the
bulk volume reduces.
Particles Deformation: The geometry of individual particles changes. If the
deformation is reversible (i.e., particles behave like rubber), it is said to be elastic
deformation. Though, all solids experience some extent of elastic deformation.
However, in some material, the deformation is no more reversible after a certain
elastic limit (yield point). This type of deformation is called plastic deformation,
which happens in material where breaking (tensile) strength is higher than shear
strength, i.e., the material squeezes rather than it breaks.
Table 8.4 Advantages and limitations of wet granulation and dry granulation processes
Wet granulation Dry granulation
Advantages Advantages
Reduced separation of ingredients
during storage and/or processing
Common grades of excipients are used
Useful for low doses of therapeutic
agent
The absence of solvent omits the use of heat
Usually, common excipients are used
for manufacturing
Tablets prepared by wet granulation
are suitable for coating.
Limitations Limitations
Often involves several processing
steps
Roller compaction requires special equipment for
granulation
The presence of solvent may
degrade the drug during processing
The components may segregate after mixing
Heat is required to remove the
solvent
Tablet prepared is comparatively softer, hence having
difculty in processes after compression, e.g.,
coating
There may be reduction in the yield of tablets due to
over dusting
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However, materials with tensile strength˂shear strength (e.g., sucrose) break as
a result of applied load (termed as brittle fracture). The smaller fragments ll the
vacant air spaces in bulk powder.
The abovementioned phenomena contribute to the reduction in bulk volume of
powder during tableting. However, in lling of hard gelatin capsules, repacking is
the primary mechanism for bulk volume reduction and negligible amount of particle
deformations is observed.
8.1.3.2 Consolidation
When two particles approach each other by a distance less than 50nm, their exists
a strong attractive force, and this process is called cold welding [8]. The bonds
formed resemble those of internal structure of single particle. This is considered to
be one of the mechanisms responsible for increasing mechanical strength of mate-
rial during compression.
Being irregular in shape, most particles have many points of contacts. When load
is applied to particles, the force is transmitted through these contact points, which
results in generation of considerable amount of heat due to fraction. This conse-
quently melts the contact area of the particles, which upon solidication results into
fusion bonding [9]. This in turn increases the mechanical strength of material.
Fig. 8.1 Effect of
compression on powder
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The phenomenon of cold welding and fusion bonding can be inuenced by
several factors, such as chemical composition of the material, available surface area,
and surface contamination.
Tablet is formed by the compression of powder using two punches and die. The
machine used for tablet compression is called tablet press. Tablet compressing pro-
cesses (schematically shown in Fig.8.2) can be divided into four distinct steps:
(a) Die lling
(b) Metering
(c) Compressing
(d) Ejection and takeoff
Die Filling
It involves the ow of powder from hopper into the feed frame and hence into dies.
Appropriate volume of powder must be lled to ensure size, weight, and content
uniformity of the tablets.
Metering
It involves the removal of excess powder so that exact weight (volume) of powder is
compressed into tablets. The metering ramp (also called the dosage ramp) adjusts
the position of lower punches and hence determines the amount of powder to be
lled in each die. The excess powder is scraped off from the die table.
Fig. 8.2 Major steps in tablet compressing process
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Compression
The upper and lower punches are directed toward the compression zone using cam
tracks, where they are pushed by upper and lower compression rolls, hence com-
pressing the conned powder into tablet. The thickness and hardness of tablet are
determined by the distance between upper and lower punches
Ejection and Takeoff
It involves removal of tablet from the die. After compression the upper punch
retracts while lower punch rises within the die cavity, hence moving the tablet
upward to the surface of die table. Subsequently, the tablet is directed toward dis-
charge chute by a scraper (also called takeoff blade).
8.1.4 Tablet Compression Machines
Pharmaceutical tablets are usually manufactured by rotary tablet presses.
8.1.4.1 Rotary Tablet Press
Tablet press can be of two types, i.e., single-punch tablet press or rotary tablet press
(depending upon the number of punches it has). However, rotary presses are more
common these days. The main parts of rotary tablet press are summarized in
Table8.5.
The rst commercial rotary press was designed by engineer Frank J. Stokes
(from Pennsylvania, USA) in the late 1800s. Stokes collaborated with Thompson
and Capper (English company) to manufacture the Stokes tablet press and tooling.
At the start of World War II, Stokes relocated to Pennsylvania and focused on manu-
facturing facilities there. The trained staff left in England started competing with
Stokes in the name of Manesty Machines Ltd., which has been one of the leading
manufacturers of rotary tablet presses all over the world [10].
Ever since the tablet presses have tremendously been evolved. For instance,
initially, the single-punch presses could produce 100 tablets per minute, which was
increased to 640 tablets per minute with rotary tablet press. Today high-speed
presses are capable to produce up to 24,000 tablets per minute [11].
8.1.5 Defects inTablets andTheir Remedies
The tablets can undergo defects during compression process. The causes and
remedies of problem associated with compression process are explained in
Table.8.6.
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8.1.6 Tablet Coating
Coating of pills was rst introduced by Muhammad ibn Zakariya al-Razi (Rhazes)
(850–923). Ibn-Sina (Avicenna) had used gold and silver coating for tablets. Gelatin
coating of pills was introduced by Garot in 1838. The rst lm-coated tablet was
marketed by Abbott in 1959, ever since a paradigm shift has been observed in coat-
ing technologies [12]. For lm coating the polymer is rst dissolved/dispersed in a
suitable solvent and then sprayed on the tablet surface in the form of ne mist. The
polymer in the form of droplets spreads over the surface of tablets and forms a thin
lm upon drying [13]. Tablet coating is typically performed in a rotating pan. The
coating solution or dispersion is sprayed simultaneously with drying using hot air.
Hot air stream removes solvent, leaving behind a thin layer of coating material on
tablet surface. Therefore, some of the prerequisites are that the tablets must have
sufcient hardness (not less than 8kp) and must not chip or break during coating.
The friability of tablets to be coated should not be more than 0.5%. Moreover, no
formulation component should be affected by elevated temperature and humidity
during the coating.
8.1.6.1 Purpose ofTablet Coating
Tablets are coated for many purposes:
– For protection of drug from extreme conditions in GIT (an enteric coating)
– For prevention of adverse effect on the stomach caused by the drugs like NSAIDs
Table 8.5 Main components of rotary press
Component Function(s)
Hopper Containing powder
Turret Portion of the head which holds the punches
Upper and lower Punches Compress the powder
Eject the compressed tablet
Feed frame Distributes power on die table and hence into dies
Die table Holds dies
Die Accepts powder from feed frame and retains it until
compression occurs
Scrape-off blade Scrapes the excess powder off the die table
Feed cam Lowers the lower punch to allow powder to come in
Compression rolls upper/
lower
Force upper and lower punch to compress
Ejection cam Lifts the lower punch and pushes tablet above the turret
Takeoff blade Removes tablet off die table
Hydraulic Provides hydraulic pressure
Instrumentation Monitors force, speed, and distance
Air handling Provides exhaust
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Table 8.6
Defects in tablet compression and their remedies
Problem Causes and remedies
Sticking and picking Causes
Sticking, when powder adheres to the
face of the punch tips or to the dies
Rough or damaged punches or dies
Excessive moisture in granules
Excessive relative humidity in environment
Insufcient lubricant
Insufcient compaction force
Sharp angles in letters or logos
Picking: describes sticking within the
letters, logos, etc., on punches
Remedies
Polish or change punches or dies
Dry the granules
Dehumidify the environment
Adjust lubricants
Increase compaction force
Sharp angles should be avoided in the engraving
style
“Shocking the press,” i.e., the compression force is
increased to make a few very hard tablets; this
causes the stuck granules at the punch face to
adhere with the tablet
Double impression Causes
Punches having engraving on them may
make new impression on the table
Free rotation of the upper or lower punch during
compression
Remedies
Add keys on round punches
Use punch retainers
Mottling Causes
An unequal color distribution, i.e.,
tablets have light and dark areas
Different drug and excipient colors
Dye may migrate to the surface of particles during
drying
Colored binder solution may not distribute evenly
Remedies
Use homogeneous material
Change the solvent system
Reduce the temperature for drying
Overmixing or over wetting of hot paste. However,
care should be taken not to affect disintegration
time
(continued)
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Table 8.6 (continued)
Problem Causes and remedies
Dark spots Causes
Dirt-like spots on tablets
Dirt, dust, or press lubrication
Excessive lubrication of upper punch
Punch tips worn
Worn die bore
Remedies
Frequently clean punches
Replace punches
Replace dies
Chipping Causes
Breaking of tablet edges Upper punch misalignment
Punch tips worn
Remedies
Replace punches
Inspect turret for excessive punch guide wear and
die pocket wear
Thickness/weight variation Causes
Less/more quantity of granules is lled
into the die
Too high speed of compression
Powder lost/gained after die lling due to worn
bores
Worn scraper or improper scraper adjustment
Nonuniform lower punch length/seat or
inconsistent lower punch ight
Dirt bellow weight adjustment
Incorrect setting of feeder
Inconsistent granules, i.e., variation in size
distribution
Poor powder ow (bridging or rat holing) leads to
empty feed frame
Remedies
Adjust the speed
Replace the dies
Adjust/replace scrapper
Replace lower punch/seat
Clean the weight adjustment cam
Adjust feeder properly
Narrow size distribution
Introduce vibration mechanism in the hopper
Reduce the machine speed
Capping and lamination Causes
(continued)
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– For controlling the drug release in GIT (pH-dependent coating)
– For site-specic drug targeting in GIT, e.g., colon targeted drug delivery
– For masking of bitter and nauseating taste of the drug
– For improving appearance of tablets
8.1.6.2 Types ofTablet Coating
Based on the purpose of coating and functionality of formulation components,
tablet coating has been classied into sugar coating and lm coating.
Sugar Coating
Sugar coating involves covering of tablets with a coat of sugar, applied as sugar
solution containing other ingredients like color.
Sugar coating was introduced in the mid of 1800s [15] on the basis of the idea
taken from the candy industry. Tablets were rotated in a rotating pan where a thick
layer of aqueous solution of sugar was applied to them. Nowadays the sugar coating
is mostly replaced by polymeric lm coating. It involves several steps (Fig.8.3):
– Sealing
– Sub-coating
– Smoothing (or grossing)
– Coloring/color coating
Table 8.6 (continued)
Problem Causes and remedies
Capping, the partial or complete
separation of the top or bottom of tablet
from main body of the tablet
Air entrapment
Ringed die bore
Lamination, separation of a tablet into or
two distinct layers
Worn punches
Too dry granules
Insufcient binder
Too much nes in the granules
Remedies
Reduce press speed
Reduce nes in granules
Reverse the dies
Replace the worn punches
Adjust moisture and binder ratio
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– Polishing (or glossing)
– Printing (if needed)
Seal coating (sealing):It is performed in order to prevent moisture penetration into
the tablet, since absorbed moisture might soften the tablet or disintegrate the
tablet. Shellac is the most commonly applied sealant agent; however, it some-
times increases disintegration and dissolution time of tablet during storage
because shellac polymerizes with time. Moreover, zein is also used as sealant.
Sub-coating: It involved the application of sticky binder solution followed by a
dusting with sub-coating powder and then drying. Gelatin/acacia solution is typi-
cally used as binder. This process is repeated until the entire tablet is covered and
sufcient thickness is achieved. Generally, the weight of tablet is increased by
50–100%.
Syrup (smoothing/color) coating:In this step the irregular surface of tablet is lled.
Smoothing is the most technical and skillful step that involves repeated coating
with syrup solution containing the dye.
Polishing: The sugar-coated tablets are subjected to lustering using beeswax or
carnauba in standard coating pan or polishing pan.
Film Coating
Film coating involves application of a thin layer/coat of a polymer on to the tablets
or particles. Film coating was rst introduced in the 1950s and proved to be an
alternative for sugar coating. It can be classied on the basis of solvent used, i.e.,
organic coating and aqueous coating. However, a more common classication is on
the basis of its functions, i.e., nonfunctional coating (e.g., immediate-release lm
coating) and functional coating (e.g., modied-release lm coating).
Immediate-release lm coating: Itis also known as nonfunctional lm coating or
conventional lm coating and is applied only for taste masking, aesthetic pur-
poses, product safety, and identication. It has no effect on dissolution rate of
the drug.
Modied-release lm coating: It is also called functional lm coating. It is used for
modifying the release characteristics of drug, for instance, delaying the release to
surpass the deleterious effect of gastric uid. This type of coating is called enteric
coating. Similarly, extended-release lm coating is intended to sustain the release
Fig. 8.3 Schematic representation of different steps involved in sugar coating process
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