2. What is a Tablet ?
A tablet is a pharmaceutical dosage form. It comprises a
mixture of active substances and excipients, usually
in powder form, pressed or compacted from a powder into a
solid dose.
The excipients can include diluents, binders or granulating
agents, glidants (flow aids) and lubricants to ensure efficient
tabletting; disintegrants to promote tablet break-up in the
digestive tract; sweeteners or flavours to enhance taste; and
pigments to make the tablets visually attractive.
A polymer coating is often applied to make the tablet
smoother and easier to swallow, to control the release rate of
the active ingredient, to make it more resistant to the
environment (extending its shelf life), or to enhance the
tablet's appearance.
3. Classification
The compressed tablet is the most popular dosage form in use
today.
A tablet can be formulated to deliver an accurate dosage to a
specific site; it is usually taken orally, but can be
administered sublingually, buccally, rectally or intravaginally.
Medicinal tablets were originally made in the shape of a disk of
whatever color their components determined, but are now
made in many shapes and colors to help distinguish different
medicines.
Tablets are often stamped with symbols, letters, and numbers,
which enable them to be identified.
4. Sizes of tablets to be swallowed range from a few
millimeters to about a centimeter.
Some tablets are in the shape of capsules, and are
called "caplets". Other products are manufactured in
the form of tablets which are designed to dissolve or
disintegrate; e.g. cleaning and deodorizing products.
Medicinal tablets and capsules are often called
"pills", though originally, "pill" referred specifically
to a soft mass rolled into a ball shape, rather than a
compressed powder.
5. Tabletting formulations
In the tablet-pressing process, it is important that all ingredients be
fairly dry, powdered or granular, somewhat uniform in particle size,
and freely flowing.
Mixed particle sized powders can segregate during manufacturing
operations due to different densities, which can result in tablets with
poor drug or active pharmaceutical ingredient (API) content
uniformity but granulation should prevent this.
Content uniformity ensures that the same API dose is delivered with
each tablet.
Some APIs may be tableted as pure substances, but this is rarely the
case; most formulations include excipients.
6. Compounding
Compounding of tablets requires following additives, in addition to the
drug substance.
Diluents:
Diluents are substances to increase bulk and convert in the compressible
form, when drug material is potent or inadequate to provide a suitable
shape and size to tablet.
A tablet diluent must be compatible, inert, economic, easily available and
organoleptically acceptable, should not affect the bioavailability of a drug
adversely.
Examples of tablet diluents include dibasic calcium phosphate, calcium
sulphate, lactose, lactose anhydrous, lactose spray dried, mannitol,
sorbitol, sucrose, dextrose etc.
Examples of directly compressible diluents include Sta-Rx-1500, Emdex
(contains dextrose 90 to 92% a maltose 3 to 5%), Celutab (dextrose &
maltose), Avicel (Microcrystalline cellulose), Di-C (Dicalcium phosphate
dihydrate), Cab-O-Sil (Colloidal silica).
7. Binders and Adhesive:
These materials are used in dry or liquid form to reduce the amorphous
nature of substance and convert into compressible form (wet granulation).
Example include acacia, tragacanth, gelatin, alginates, methylcellulose,
hydroxypropyl- methylcellulose, hydroxypropylcellulose, PVP, Starch,
sorbiol, ethylcellulose, pregelatinized starch, glucose, iris moss, ghatti
gum, arabogalactan, waxes, etc.
Lubricants:
Lubricants reduce inter-particular friction. It improves the ejection of
tablet from die wall and reduces the sticking problems and smooth
tablets are produced. Examples include Talc, magnesium stearate,
calcium stearate, stearic acid, polyethyleneglycols, starch derivative
Glidants:
Glidants act as a flow promoter and reduce the friction between
particles. It improves the flow properties of granules or powder
through hopper to die. It is not deformed compression pressure of
the tablet machine. Examples include talc, starch, magnesium
stearate, calcium stearate, boric acid, sugar, lycopodium and sodium
chloride.
8. Disintegrants:
Most of the tablets contain disintegrating agent. Disintegrating agents
facilitate the disintegration of the tablet in small particles in the
gastrointestinal tract. Breaking of tablet' based on the swellability, adsorption
of water or chemical reaction.
Examples include soluble starch, pre-gelatinized starch (PGS), veegum HV,
bentonite, microcrystalline cellulose, sodium carboxy methylcellulose, PVP,
guar gum, Isapgul, primogel, explotab, aerosil, natural spon citrus pulp,
Alginic acid and alginates, Ion exchange resin, magnesium aluminium silicat
modified corn starch, sodium dodecyl sulphate, sodium starch glycollate, etc.
Antiadhesives or Antisticking agents:
These materials are used to reduce the adhesion of the tablet surface to dies
and punches during the compression of tablets. The pressure of the machine
deforms these materials. It reduces sticking, picking and chipping problems.
Examples include paraffin, stearic acid, cocoa butter, soaps, starch derivatives.
Sweeteners:
Chewable tablets have sweetening agents because such tablets remain in the
mouth and are not swallowed. Examples include saccharin sodium,
aspartame, sugar, etc.
9. Coloring agent:
Colours are selected from 'permitted' list and are added to promote elegance and also
to mask differences in colour or speckling when either the drug or an additive is off
white.
Pastel shades are commonly used as these shades help in achieving uniform colour
distribution. Coloring materials or dyes are used in tablet formulation mainly for three
purposes; disguising of off color drugs, product identification and production of more
elegant products. Colours may be added either to the vehicle used for granulation or to
the mixture of powders prior to granulation.
The first approach is known to give better results provided migration of dye to the top
of granules along with solvent during drying does not occur. When wet granulation is
not to be employed, lake dyes (dyes adsorbed on alumina or aluminium hydroxide)
are recommended.
Fading of the colour on standing and exposure to light leading to mottling of tablets is
the common problem with dyes. Examples include water soluble dyes and many other
FD&C approved colors or dyes.
Flavoring agent:
These substances are not necessary for the formulation of compressed tablets. The
proportion of flavours should generally be limited to 0.5% because excessive amounts
may interfere with the free flow or cohesion of the granules.
Special tablets require flavoring agents such as chewable tablet, lozenges, etc.
Examples include flavoring oils like cinnamon, coriander, and caraway etc.
10. Advantages
They provide an accurately measured dosage of the active ingredient in
a convenient portable package, and can be designed to protect unstable
medications or disguise unpalatable ingredients.
Colored coatings, embossed markings and printing can be used to aid
tablet recognition.
Manufacturing processes and techniques can provide tablets special
properties, for example, sustained release or fast dissolving
formulations.
11. Limitations
Some drugs may be unsuitable for administration by the oral route. For
example, protein drugs such as insulin may be denatured by stomach acids.
Such drugs cannot be made into tablets.
Some drugs may be deactivated by the liver when they are carried there from
the gastrointestinal tract by the hepatic portal vein (the "first pass effect"),
making them unsuitable for oral use.
Drugs which can be taken sublingually are absorbed through the
oral mucosae, so that they bypass the liver and are less susceptible to the
first pass effect.
The oral bioavailability of some drugs may be low due to poor absorption
from the gastrointestinal tract. Such drugs may need to be given in very high
doses or by injection.
For drugs that need to have rapid onset, or that have severe side effects, the
oral route may not be suitable. For example salbutamol, used to treat
problems in the pulmonary system, can have effects on the heart and
circulation if taken orally; these effects are greatly reduced by inhaling
smaller doses direct to the required site of action.
A proportion of the population have difficulties swallowing tablets because
their medical condition makes it difficult for them (dysphagia, vomiting)
13. Dispensing (weighing and measuring)
Dispensing may be done by purely manual
by hand scooping from primary containers and weighing each ingredient by hand on a
weigh scale.
Issues like weighing accuracy, dust control (laminar air flow booths, glove boxes),
during
manual handling, control of each ingredient, material movement into and out
of dispensary should be considered during dispensing.
Sizing
It increases surface area, which may enhance an active ingredient’s dissolution
rate and hence bioavailability.
Improved the tablet-to-tablet content uniformity by virtue of the increased number of
particles per unit weight.
Controlled particle size distribution of dry granulation or mix to promote better flow
of
mixture in tablet machine.
Improved flow properties of raw materials.
Improved colour and/or active ingredient dispersion in tablet excipients.
Uniformly sized wet granulation to promote uniform drying.
14. Disadvantages associated with sizing if not controlled
properly:
A possible change in polymorphic form of the active ingredient,
rendering it less or totally inactive, or unstable.
A decrease in bulk density of active compound and/or excipients,
which may cause flow problem and segregation in the mix.
An increase in surface area from size reduction may promote the
adsorption of air, which may inhibit wettability of the drug to the extent
that it becomes the limiting factor in dissolution rate.
A number of different types of machine
may be used for the dry sizing or milling process depending on whether
gentle screening or particle milling is needed.
The ranges of equipment employed for this process includes Fluid
energy mill, Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller
mill, Conical mill, etc.
15. Powder Blending
In practice, problems of mixing of granules arise due to the inherent
cohesiveness and resistance to movement between the individual
particles.
The process is further complicated by the presence of substantial
segregation influencing the powder mix. They arise because of
difference in size, shape, and density of the component particles.
The powder/granules blending are involved at stage of pre granulation
and/or post granulation stage of tablet manufacturing.
Each process of mixing has optimum mixing time and so prolonged
mixing may result in an undesired product. So, the optimum mixing
time and mixing speed are to be evaluated.
Blending step prior to compression is normally achieved in a simple
tumble blender.
16. V Blender
Oblicone Blender Container Blender
Ribbon Blender
Agitator Blender
The various blenders used include :
17. Now a days to optimize the
manufacturing process
particularly in wet granulation
the various improved
equipments which combines
several of processing steps
(mixing, granulation and/or
drying) are used. They are
“Mixer granulator” or
“High shear mixing
machine”.
18. Manufacture of the tableting blend : Granulation
The ingredients must be granulated prior to compression to assure an even
distribution of the active compound in the final tablet. Two basic techniques are used
to granulate powders for compression into a tablet: wet granulation and dry
granulation. Powders that can be mixed well do not require granulation and can be
compressed into tablets through direct compression.
Wet granulation
Wet granulation is a process of using a liquid binder to lightly agglomerate the powder
mixture. The amount of liquid has to be properly controlled, as over-wetting will cause
the granules to be too hard and under-wetting will cause them to be too soft and friable.
Aqueous solutions have the advantage of being safer to deal with than solvent-based
systems but may not be suitable for drugs which are degraded by hydrolysis.
Procedure
The active ingredient and excipients are weighed and mixed.
The wet granulate is prepared by adding the liquid binder–adhesive to the powder blend
and mixing thoroughly. Examples of binders/adhesives include aqueous preparations of
cornstarch, natural gums such as acacia, cellulose derivatives such as methyl
cellulose, gelatin, and povidone.
Screening the damp mass through a mesh to form pellets or granules.
Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most
commonly used.
After the granules are dried, they are passed through a screen of smaller size than the
one used for the wet mass to create granules of uniform size.
19. Dry granulation
Dry granulation processes create granules by light compaction of the
powder blend under low pressures.
The compacts so-formed are broken up gently to produce granules
(agglomerates). This process is often used when the product to be
granulated is sensitive to moisture and heat.
Dry granulation can be conducted on a tablet press using slugging
tooling or on a roll press called a roller compactor.
Dry granulation equipment offers a wide range of pressures to attain
proper densification and granule formation.
Dry granulation is simpler than wet granulation, therefore the cost is
reduced.
However, dry granulation often produces a higher percentage of fine
granules, which can compromise the quality or create yield problems
for the tablet.
Dry granulation requires drugs or excipients with cohesive properties,
and a 'dry binder' may need to be added to the formulation to facilitate
the formation of granules.
20. WET GRANULATION DRY GRANULATION DIRECT COMPRESSION
1.
Milling
and mixing of drugs and excipients
1.
Milling
and mixing of drugs and excipients
1. Milling and mixing of drugs and
excipients
2.
Preparation
of binder solution
2.
Compression
into slugs or roll compaction
2.
Compression of tablet
3.
Wet
massing by addition of binder solution
or granulating solvent
3.
Milling
and screening of slugs and compacted
powder
4.
Screening
of wet mass
4.
Mixing
with lubricant and disintegrant
5.
Drying
of the wet granules
5.
Compression
of tablet
6.
Screening
of dry granules
7.
Blending
with lubricant and disintegrant to produce
“running powder”
8.
Compression
of tablet
Typical Unit Operation Involved In Wet Granulation, Dry Granulation And
Direct Compression
21. Granule lubrication
After granulation, a final lubrication step is used to ensure that the tableting
blend does not stick to the equipment during the tableting process. This usually
involves low shear blending of the granules with a powdered lubricant, such as
magnesium staerate or stearic acid.
Drying
It is important to keep the residual moisture low enough to prevent product
deterioration and ensure free flowing properties.
Drying improves the good properties of a material, e.g. flowability,
compressibility.
It reduces the cost of transportation of large volume materials (liquids).
It makes the material more suitable for handling, preservation, storage.
The commonly used dryer includes Fluidized – bed dryer,
Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo – tray dryer,
Pan dryer, etc.
Drying process in
fluidised bed dryer.
22. DRYER EXAMPLE ADVANTAGES LIMITATIONS
Static bed dryer:There is no
relative motion among the
particles during drying.
Tray dryer,
Freeze
dryer
No Attrition Only a fraction of
particles is exposed to
dring process
Moving bed dryer: systems
in which drying particles are
partially separated and flow
over each other.
Drum
dryer
Whole material is
exposed to heating
surface.
Attrition is possible.
Fluidised bed dryer:
particles are suspended in a
moving heated gas system.
Fluidised
bed dryer
Excellent contact b/w
solid particles &
heated gas system.
Attrition is possible.
Pneumatic dryers: drying
particles are entrained at high
velocity using gas stream.
Spray
dryer
Efficient & rapid
drying
Chances of Attrition
Tray Dryer Fluidisedbed
Dryer
Spray Dryer Freeze Dryer
23. Tablet compression
After the preparation of granules (in case of wet granulation) or sized slugs (in
case of dry granulation) or mixing of ingredients (in case of direct
compression), they are compressed to get final product. The compression is
done either by single punch machine (stamping press) or by multi station
machine /rotary press.
The tablet press is a high-speed mechanical device. It 'squeezes' the
ingredients into the required tablet shape with extreme precision.
Common manufacturers of tablet presses include Stokes, Fette Compacting, Korsch,
Kikusui, Manesty, B&D, IMA and Courtoy.
Each tablet is made by pressing the granules inside a die, made up of hardened
steel.
The powder is compressed in the centre of the die by two hardened steel
punches that fit into the top and bottom of the die.
The punches and dies are fixed to a turret that spins round.
As it spins, the punches are driven together by two fixed cams - an upper cam
and lower cam. The top of the upper punch (the punch head) sits on the upper
cam edge .The bottom of the lower punch sits on the lower cam edge.
The shapes of the two cams determine the sequence of movements of the two
punches. This sequence is repeated over and over because the turret is spinning
round.
The force exerted on the ingredients in the dies is very
carefully controlled. This ensures that each tablet is perfectly formed.
24. Common stages occurring
during compression :
Stage 1: Top punch is withdrawn from
the die by the upper cam.
Bottom punch is low in the die so
powder falls in through the hole and
fills the die.
Stage 2: Bottom punch moves up to
adjust the powder weight-it raises and
expels some powder.
Stage 3: Top punch is driven into the
die by upper cam.
Bottom punch is raised by lower cam.
Both punch heads pass between
heavy rollers to compress the powder.
Stage 4: Top punch is withdraw by the
upper cam.
Lower punch is pushed up and expels
the tablet.
Tablet is removed from the die
surface by surface plate.
Stage 5: Return to stage 1.
26. Common problems encountered during tablet manufacturing
operations include:
Fluctuations in tablet weight, usually caused by uneven powder flow into the die
due to poor powder flow properties.
Fluctuations in dosage of the Active Pharmaceutical Ingredient, caused by uneven
distribution of the API in the tableting blend (either due to poor mixing or
separation in process.
Sticking of the powder blend to the tablet tooling, due to inadequate lubrication,
worn or dirty tooling, or a sticky powder formulation
Capping, lamination or chipping. This is caused by air being compressed with the
tablet formulation and then expanding when the punch is released: if this breaks
the tablet apart, it can be due to incorrect machine settings, or due to incorrect
formulation: either because the tablet formulation is too brittle or not adhesive
enough, or because the powder being fed to the tablet press contains too much air
(has too low bulk density).
Capping can also occur due to high moisture content.
Tablets that failed due to capping and lamination compared to a
normal tablet
27. Tablet coating
Modern tablet coatings are polymer and polysaccharidebased,
with plasticizers and pigments included.
Tablet coatings must be stable and strong enough to survive the handling of the
tablet, must not make tablets stick together during the coating process, and must
follow the fine contours of embossed characters or logos on tablets.
Coatings are necessary for tablets that have an unpleasant taste, and a smoother
finish makes large tablets easier to swallow.
Tablet coatings are also useful to extend the shelf-life of components that are
sensitive to moisture or oxidation.
Special coatings (for example with pearlescent effects) can enhance brand
recognition.
There are two types of coating
machines used in the pharmaceutical
industry: coating pans and automatic
coaters. Coating pans are used mostly
for sugar coating of pellets. Automatic
coaters are used for all kinds of
coatings; they can be equipped with
remote control panel, dehumidifier,
dust collectors. The explosion-proof
design is required for alcohol
containing coatings. coating pan
28. If the active ingredient of a tablet is sensitive to acid, or is irritant to
the stomach lining, an enteric coating can be used, which is resistant
to stomach acid, and dissolves in the less acidic area of the intestines.
Enteric coatings are also used for medicines that can be negatively
affected by taking a long time to reach the small intestine, where they
are absorbed.
Coatings are often chosen to control the rate of dissolution of the drug
in the gastrointestinal tract.
Some drugs will be absorbed better at different points in the digestive
system.
If the highest percentage of absorption of a drug takes place in the
stomach, a coating that dissolves quickly and easily in acid will be
selected.
If the rate of absorption is best in the large intestine or colon, then a
coating that is acid resistant and dissolves slowly would be used to
ensure it reached that point before dispersing.
29. Pill-splitters
It is sometimes necessary to split tablets into halves or quarters.
Tablets are easier to break accurately if scored, but there are devices
called pill-splitters which cut unscored and scored tablets. Tablets
with special coatings (for example enteric coatings or controlled-
release coatings) should not be broken before use, as this will expose
the tablet core to the digestive juices, circumventing the intended
delayed-release effect.
30. Packaging
The type of packaging will depend on the
formulation of the medicine.
'Blister packs' are a common form of packaging used for a wide
variety of products. They are safe and easy to use and they allow the
consumer to see the contents without opening the pack. Many
pharmaceutical companies use a standard size of blister pack.
Sometimes the pack may be perforated so that individual tablets
can be detached. This means that the expiry date and the name of the
product have to be printed on
each part of the package.
The blister pack itself must remain
absolutely flat as it travels through
the packaging processes, especially
when it is inserted into a carton.
Extra ribs are added to the blister
pack to improve its stiffness.
