Dosage form

Dosage form
Dosage forms are the means by which drug molecules /
APIs are delivered to sites of action within the body to
produce optimum desired effects and minimum
adverse effect.
The need for dosage forms:
• To provide safe and convenient delivery of accurate dosage
Examples: Tablets, Capsules, syrups
• For the protection of a drug substance from the destructive
influence of atmospheric oxygen or moisture. Examples: coated
tablets, sealed ampules
• For the protection of a drug substance from the destructive
influence of gastric acid after oral administration. Example: enteric
coated tablets
• To conceal the bitter taste, salty obnoxious or odor of a drug
substance. Examples: Capsules, coated tablets, flavored syrups
• To provide liquid preparations of substances that are
either insoluble or unstable in the desired vehicle.
Example: suspension
• To provide liquid dosage forms of substances soluble
in desired vehicle. Example: solution
• To provide extended drug action through controlled
release mechanisms Examples: controlled release
tablets, capsules, suspensions
• To provide optional drug action from topical
administration sites Examples: ointments, creams,
ophthalmic, ear and nasal preparations
• To provide for insertion of a drug into one of
the body’s orifices Examples: rectal and
vaginal suppositories
• To provide for the placement of drugs within
body tissues. Examples: Implants
• To provide for the optimal drug action through
inhalation therapy. Examples: inhalants and
inhalations
• In addition, many dosage forms permit ease of
drug identification through distinctiveness of
color, shape, or identifying markings
• To provide for insertion of a drug into one of
the body’s orifices Examples: rectal and
vaginal suppositories
• To provide for the placement of drugs within
body tissues. Examples: Implants
• To provide for the optimal drug action through
inhalation therapy. Examples: inhalants and
inhalations
• In addition, many dosage forms permit ease of
drug identification through distinctiveness of
color, shape, or identifying markings
Drug substance and Pharmaceutical Preparation
• Active drug substance (active pharmaceutical ingredient - API)
– Chemical compound with pharmacological (or other direct effect ) intended for
used in diagnosis, treatment or prevention of diseases
• Excipients (inactive pharmaceutical ingredients)
– Technological, biopharmaceutical and/or stability reasons
– Diluents/fillers, binders, lubricants, desintegrants, coatings, preservants and
stabilizers, colorants and flavourings
• Pharmaceutical dosage form
– is a drug delivery system which is formed by technological processing (drug
formulation)
– determines the physical form of the final pharmaceutical preparation
• Pharmaceutical preparation (PP)
– particular pharmaceutical product containing active and inactive pharmaceutical
ingredients formulated into the particular dosage form.
– Packed and labelled appropriately
– Two major types of PP according the origin:
• Manufactured in large scales by pharmaceutical industry (original and generic
preparations)
• Compounded individually in compounding pharmacies
Types of Dosage forms
They are classified according to-

Route of administration Physical form

• Oral • Solid
• Topical • Semisolid
• Transdermal • Liquid
• Parenteral • Gases
• Inhalation
• Buccal and sublingual
• Opthalmic
• Otic
• Rectal
• Vaginal
Solid dosage forms
– Tablet, Capsules, Implants, Transdermal patches
– Powder for external/internal use
Semisolid dosage forms
– Suppositories (for rectal administration), Pessaries (vaginal
suppositories),
– Gels, Creams, Ointments, Pastes
Liquid dosage forms
– Monophasic-Solutions (Syrups, Spirits, elixirs, Tinctures)
– Biphasic- Emulsions, suspension
– External solutions:- Lotions, Liniments, Collodions
Gaseous dosage forms
– Medicinal gases- Aerosols: inhalation/ volatile anaesthetics
– Aerodispersion- Antisthanatic sprays
Types of dosage forms: Route of Administration
Enteral
• Oral: Tablets, Capsules, syrups, suspension, emulsion etc.
Dry Powder Inhaler (DPI) pressurized
Metered Dose Inhaler (pMDI) • Nebulizer • Vaporizer
• Sub-lingual/Buccal: Orally Disintegrating Tablet (ODT)
• Lozenges • Chewing tablets, Mouthwash
• Toothpaste • Ointment • Oral spray
• Rectal: Ointment • Suppository • Enema •Nutrient enema

Parenteral (injections & infusions)

Intravenous • Intramuscular • Intracardiac
• Intraosseous • Intraperitoneal • Intracerebral
• Intrathecal • Intradermal • Subcutaneous
Topical
• Dermal: Ointment • Liniment • Paste • Cream • Lotion •
Lip balm • Medicated shampoo • Dermal patch

• Mucosal: Ear drops • Eye drops • Nasal spray • Ointment •

Hydrogel • Nanosphere suspension • Mucoadhesive microdisc
(microsphere tablet), pessaries.

• Percutaneous: Transdermal patch etc

Dosage form design
Drug substances are seldom administered in their
natural or pure state, but rather as part of a
formulation in combination with one or more
non-medicinal agents that serve varied and
specialized pharmaceutical functions.
Through selective use of these non-medicinal
agents, referred to as pharmaceutical aids,
pharmaceutical ingredients, adjuncts or
necessities, pharmaceutical preparations of
various type result.
It is the pharmaceutical adjuncts that serves to
solubilized, suspend, thicken, dilute, emulsify,
stabilize, preserve, color, flavor and fashion the many
and varied medicinal agents into effective and
appealing pharmaceutical preparations.
The term “Pharmaceutics” which is the study that
concerns itself with the physical, chemical and
biological factors which influence the formulation,
manufacture, stability and effectiveness of
pharmaceutical dosage forms.
Drug Consideration In Dosage Form Design
1. Characteristics of Drug Substances
2. Drug Stability
3. Determining Drug Formulation Stability
4. Prevention Against Microbial Contamination
5. Appearance and Palatability
Therapeutic Considerations In Dosage Form Design
1. Nature of the disease or illness
2. Age of the Patient
Biopharmaceutics Considerations
1. Biopharmaceutics
2. Concept of Bioavailability
Tablets
Tablets are solid unit dosage forms usually
containing active pharmaceutical ingredient and
excipients in powder, crystalline or granular form
with or without diluents which is prepared either
by moulding or compression process. They are
solid, biconvex or flat in shape and vary in size,
shape and weight which is depends on the
medicaments which are used for preparation.
Tablets are the most widely used solid dosage forms
because of their advantages and popularity
increasing day by day. Tablet usually contains
filler, diluents, binders, lubricants, glidants,
disintegrants, antiadherent, colouring agents and
flavouring agents as excipients.
Advantages of tablets
• Unit dosage forms with accurate, stable dose and great
precision and least variability.
• Most stable with respect to physical, chemical and
microbiological attributes.
• Cheapest oral dosage form, easy to handle, use and carry
out with attractive and elegant appearance.
• Cheap, easy to swallow and production does not require
and additional processing steps.
• Provide protection of medicaments from atmospheric
conditions like air, moisture and light, etc.
• Provide prolonged stability to medicaments.
• Low manufacturing cost as compare to other solid
dosage forms and large scale production is possible.
• Administration of minute dose of drug in
accurate amount.
• Unpleasant taste can be masked by sugar
coating.
• Easy to divide into halves and quarters
whenever fraction dose is required.
• Formulate as a special release products such
as enteric or delayed release products.
• Packing and production is cheap and does not
require more space for storage.
Disadvantages of tablets
• Drugs which are amorphous and low density character
are difficult to compress into tablet.
• Hygroscopic drugs are not suitable for compressed
tablets.
• Drugs with low or poor water solubility, sloe
dissolution, high absorbance in GI tract may be difficult
to formulate.
• Sensitive to oxygen drugs may require special coating.
• Cost of production may be increase because of coating
and encapsulation to remove bitter and unpleasant
taste.
• Some tablet may cause problem in bioavailability.
• Difficult to formulate liquid in tablet and swallowing is
difficult especially for children and ill patients.
Types of Tablets:
Tablets are classified according to their route of
administration or function. The following are the
5 main classification groups.
1. Tablets ingested orally
• Compressed tablets
• Multiple compressed tablets
I. Multilayered tablets
II. Inlay tablets
• Sustained action tablets
• Enteric coated tablets
• Sugar coated tablets
• Film coated tablets
• Chewable tablets
2. Tablets used in the oral cavity
2.1. Buccal tablets
2.2. Sublingual tablets
2.3. Lozenge tablets and torches
2.4. Dental cones
3. Tablets administered by other routes
3.1. Implantation tablets
3.2. Vaginal tablets
4. Tablets used to prepare solutions
4.1. Effervescent tablets
5. Molded tablets or tablet triturates (TT)
5.1. Dispensing tablets (DT)
5.2. Hypodermic tablets (HT)
Compressed tablets:
These tablets are uncoated and made by
compression of granules. These tablets are
usually intended to provide rapid
disintegration and drug release. These tablets
after swallowing get disintegrated in the
stomach, and its drug contents are absorbed
in the gastrointestinal tract and distribute in
the whole body.
Multiple compressed tablets:
Multiple compressed tablets are prepared by
compressing the material more than once.
These are known as multiple layered tablets or
tablet within tablet. Layered are depends on
number of fills. Layered tablets are prepared
by compaction of fill material in die followed
by additional of fill material and compression.
Inlay Tablet:
A type of layered tablet in which instead the core
tablet being completely surrounded by coating,
top surface is completely exposed. While
preparation, only the bottom of the die cavity is
filled with coating material and core is placed
upon it. When compression force is applied,
some coating material is displaced to form the
sides and compress the whole tablet. It has some
advantages over compression coated tablets-
i) Less coating material is required.
ii) Core is visible, so coreless tablets can be easily
detected.
iii) Reduction in coating forms a thinner tablet and thus
freedom from capping of top coating.
Delayed action and Enteric coated tablets: These types of
tablets contain a coating which resist dissolution of tablets
in Gastro Intestinal Track (GIT) and disintegrate in
intestinal fluids thus rendering delayed release features.
Enteric coating is generally apply when drug substance is
unstable in gastric fluid and may destroyed or may cause
irritation in gastric mucosa or to extent absorption of drug
from intestine. Normally coating materials mixed with acid
and acid functionality or modified natural polymers. Most
commonly used coating polymers are: Cellulose acetate
phthalate (CAP), polyvinyl acetate phthalate (PVAP) and
hydroxyl propyl methyl cellulose phthalate.
Sugar coated tablet: Compressed tablets may be coated
with coloured or uncoloured sugar coating and the
coater is water soluble and dissolve quickly after
swallowing. Sugar coat protects drug from
environment, remove bitter taste and odour, enhance
the appearance of tablet and permit identifying
information. Sugar coating has some disadvantages like
increase coat of production, require expertise for
coating, increase size and weight.
Film coated tablets: Tablets are compressed
with a thin layer of polymer which forms a
skin like film over tablet. The film is usually
coloured, more durable and less bulky. The
coating is designed to rupture and expose of
tablet at desired location within GIT. Most
commonly used polymers are Hydroxy propyl
cellulose, Hydroxy ethyl and propyl methyl
cellulose.
Chewable tablet: Chewable tablets are an oral
dosage form intended to be chewed and then
swallowed by the patient rather than swallowed
whole. They should be designed to be palatable
and be easily chewed and swallowed. These
types of tablets have smooth surface, creamy
base and usually flavoured and coloured These
types mostly useful for administration of large
dose to children and adults.
2. Tablet used for oral cavity:
Buccal tablets and sublingual tablets: Buccal and
sublingual tablets are flat in shape and intended
to dissolve drug in buccal cavity or beneath the
tongue for mucosa absorption. These techniques
useful for drugs which are destroyed by gastric
fluid or poor absorption in GIT. Buccal tablets
erode slowly and sublingual tablets dissolve
quickly and produce rapid effect.
2. Tablet used for oral cavity:
Troches and Lozenges: They are
intended to slowly dissolution
mostly for local effect but
sometimes for systemic
absorption. Troches and
Lozenges are disc shaped which
contain active ingredient and
flavouring agent in hard candy or
sugar base.
Dental cones: dental cones are
designed to place in the empty
socket for prevention of bacterial
growth and sometime bleeding
by containing coagulant. Dental
cones release slowly for long
duration.
3. Tablets for other routes
Vaginal tablet: Vaginal tablets are prepared by
compression and shaped to fit snugly on plastic
inserter devices in uncoated bullet shaped or
ovoid tablets which are inserted into vagina for
local effects with slow dissolution. They contain
anti bacterial effect and also called vaginal inserts.
Implantation tablet: Implantation tablets are
injected under the skin by giving a small surgical
cut into the skin. A special injector a hallow needle
and plunger may require for administration.
Purpose of these tablets is to prolong drug effect
from month to year. These tablets are implanted
intramuscularly or subcutaneous so they must be
sterile and packed in sterile container.
4. Tablets for solution
• Effervescent tablet: Effervescent tablets prepared
by compression of granular salts which release in
contact with water.
• Dispensing tablets: These types of tablets are no
longer use because they had dangerous potential.
They might be termed compounding tablets
because it contain highly potent drug and
pharmacist use it for compound prescription.
• Hypodermic tablets: Hypodermic tablets are soft
moulded tablets which contain soluble ingredient
and used for extemporaneous parenteral
preparation by physician. They are no longer in
use because it is difficult to achieve sterility and
availability of stable liquid.
4. Tablets for solution
Tablet triturates: tablet triturates are rarely use
now a days because they are obsolete. They
are small, cylindrical, molded which contain
small amount of potent drug. They must be
readily soluble in water and minimum amount
pressure require during manufacture.
Triturates inserted into capsules or dissolved in
liquid to provide accurate potent drug.
Tablet Excipients:
Excipients are substance other that active
ingredient in formulation of tablet. The roles of
excipients are to ensure tabletting operation
satisfactory and ensure that tablets of specified
quality are prepared. Depend on intended use;
they are subcategorised in different groups.
However excipients affect properties of tablets.
Diluents or filler
Diluents or filler are designed to make up the
required bulk of the tablet when the drug dosage
itself is inadequate to produce this bulk. The dose
of some drugs is sufficiently high that no filler is
required. Tablet formulation may contain a diluent
for secondary reasons: to provide better tablet
properties such as improved cohesion, to permit
use of direct compression manufacturing, or to
promote flow.
The ideal dilute should have following properties-
cheap, chemically inert, acceptable taste, good
compactability and dilution capacity,
biocompatible, good biopharmaceutical properties
and non hygroscopic.
A single substance cannot fulfil all these requirements so
different substance have gained use as diluents mainly
carbohydrates and inorganic salts sometimes. The most
common diluent is lactose because it possess a sires of
good properties like dissolves readily in water, has a
pleasant taste, non hygroscopic is fairly non reactive and
shows good compact ability. Its main limitation is that
some people have intolerance to lactose. Basically
lactose exists in two forms crystalline and amorphous.
Other sugar and sugar alcohols such as glucose, sucrose,
and mannitol have been used as alternative fillers,
mostly in chewable tablets or lozenges because of their
pleasant taste. Other important example of the filler is
an inorganic substance, dicalcium phosphate dehydrate.
It is insoluble in water and also non hygroscopic but
have hydrophilic property i.e. easily wetted by water. It
also has good flow ability and therefore it is used mostly
in direct compaction.
Disintegrants:
A disintegrant is added in tablet formulation to
facilitate a breakup or disintegration of the tablet
when it come in contact with water in
gastrointestinal tract. Disintegrants may function
by drawing water into the tablet, swelling and
causing the tablet to burst apart. Such tablet
fragmentation is critical to the subsequent
dissolution of the drug and to attainment of
satisfactory drug bioavailability. Most common
types of disintegrants in tablets are maize, potato
and corn starch.
Binder
Binder is added to the tablet to ensure that tablets and granules
have sufficient mechanical strength. There are several ways to
add it in powder-
• Mixed with powder before wet granulation which completely
or partially dissolves during agglomeration process by
agglomeration liquid.
• Mixed with other ingredient as a dry powder solution before
compaction process
• As a solution used as agglomeration liquid during wet
granulation.
Typically 2-10% of binders or dry binders are used in
formulation. Most common binders are starch, sucrose and
gelatine how ever these days synthetic polymer like
polyvinylpyrrolidone and cellulose derivatives which have
improved adhesive properties are increasingly used. Examples
of dry binders are microcrystalline cellulose and crosslinked
polyvinylpyrrolidone. Solution binders are most effective
therefore it is incorporated in granules.
Glidant
Glidant is added to tablet formulation to improve
the flow ability of the powder during
compression. Glidants are used in formulation
for direct compaction but they are also used in
granulation process before tabletting which
ensure flow ability of tablet mass for high
speed production. Traditionally talc has been
used as glidant about in 1-2% concentration in
formulation but nowadays the most commonly
used glidant is colloidal silica added in very low
proportion about 0.2% by weight.
Lubricant
The function of lubrication is to ensure low friction
between solid and the die wall during tablet formation
and ejection. High friction during tabletting can cause a
series of problems such as inadequate tablet quality and
may even stop production. Lubrication is most
important which included in most of production.
Lubrication can get by mainly two mechanism, fluid
lubrication and boundary lubrication. In fluid
lubrication, liquid is achieved between die surface and
tablet surface which separates the moving surfaces of
the solids from each other and reduces the friction.
While in boundary lubrication, it is considered as a
surface phenomenon, as here moving surface is
separated by a very thin layer of lubricants. Such
boundary lubricants are Stearic acid salts, primarily
Magnesium Stearate which is most widely use due to its
superior lubrication properties.
Besides reducing friction, lubricants may also causes
undesirable changes such as reducing tablet
strength with bonding between the particles
during compaction. Because of hydrophobic
properties of lubricants, tablet disintegration and
dissolution are often retarded by the addition of
lubricants. Thus, minimum amount of lubricants
are used, in order to avoid these negative effects.
More hydrophilic substances have been suggested as
alternatives to the hydrophobic lubricants. For
example, surface active agents and polyethylene
glycols and sometimes a combination of
hydrophilic and hydrophobic substances might
also be used.
Antiadherent
Antiadherent are substance which reduce adhesion
between powder and punch faces which prevent
sticking of particles to punches. The sticking is
mainly affected by moisture content of the
powder. Such adherence especially prone to
happen if the tablet punches have marking or
symbols which lead to a build of thin layer of
powder on the punches which in turn will lead to
an uneven and matt tablet surface with unclear
markings or symbols. Some lubricants such as
Magnesium Stearate have also antiadherent
properties. However, other substances with
limited ability to reduce friction can also act as
antiadherent such as talc and starch.
Sorbents
Sorbents are substances which has capacity of
sorbing some quantities of fluid into dry state.
So oil and oil-drug solutions can be
incorporated into mixture of powder and
compacted into tablets. Most commonly used
sorbents are Microcrystalline Cellulose and
Silica.
Flavouring agents
Flavouring agents are incorporated into a
formulation to remove unpleasant taste of
bitter drug or to make tablet more pleasant or
mask. This can be achieved by coating or by
adding some drug particles. Most of
Flavouring agents are thermolabile so it
cannot be added in process which involve
heating. They are mixed with granules as
alcoholic solution.
Colouring agents
The aim to add colourant is to aid identification
of tablet, improve looks of tablet and patient
compliance. Mostly, colourant are added
during coating of tablet but some of colourant
may be added in formulation prior to
compaction. Colourant may be added as an
insoluble powder or dissolved in granulation
liquid and the latter procedure may produce
colour variation by migration of soluble dye
during drying stage.
Tablet manufacturing
There are three method of tablet preparation-
– Direct compression method
– Wet granulation
– Dry granulation
Direct compression method
Some crystalline substances such as sodium chloride,
sodium bromide and potassium chloride have free
flowing and cohesive properties so they can be
compress directly in a tablet machine without
granulation. However majority of chemicals lacking
of these qualities so some excipients like filler,
disintegrants agents, lubricants and glidants are
used to impart these qualities for production of
tablets by direct compression.
The most important advantage of the direct
compression process is its simplicity, low labor input
and hence economical. Being a dry process, risk of
deterioration of the active ingredient, is decreased.
There are some limitations of direct compression
1. Differences in particle size and bulk density between the drug and
diluent may lead to stratification within the granulation. The
stratification may then result in poor content uniformity.
2. A large dose drug may present problems with direct compression
if it is not easily compressible by itself.
3. In some instances, the direct compression diluent may interact
with the drug.
4. Because of the dry nature of direct compression, static charge
buildup during mixing which may prevent a uniform distribution of
drug in the granulation.
Some precaution must be taken during direct compression to avoid air
entrapment which cause capping, splitting, or laminating of
tablets. Forced feeders or induced feeders are used to reduce air
entrapment, make filling powder more dense and amenable to
compaction.
Capping also may be caused by punches that are not perfectly clean
and flawlessly smooth or by too much fines granulation. Some aged
or improperly stored tablets also may exhibit splitting and other
physical deformations.
Wet granulation
Granulation is process in which primary powder
particles are made to form large and these
types of multi particle called granules. In
pharmaceutical industry, granules are useful in
production of tablets and capsules in ranges of
particle size between 0.2 to 0.5mm.
Granulation prevents segregation of
constituents of powder, improve flow ability of
powder, improve compaction characteristics
of mixture and reduce toxic dust.
Wet granulation is widely used method for production of
compressed tablets which include flowing steps-
Weighting and blending
In this step, specified quantities of active ingredient,
diluents or fillers, and disintegrating agents are mixed by
mechanical powder blender or mixture until uniform.
Most widely used fillers are lactose, microcrystalline
cellulose, starch, powdered sucrose, and calcium
phosphate. Selections of filler depend on the experience
of manufacture, cost and compatibility with
formulation. Among the fillers, lactose is most preferred
because of its solubility and compatibility, and
microcrystalline cellulose, because of its easy
compaction compatibility and consistent uniformity of
supply.
Disintegrating agents include croscarmellose, corn
and potato starches, sodium starch glycolate,
sodium carboxymethylcellulose, polyvinyl
polypyrrolidone (PVP), cation exchange resins,
alginic acid and other materials which swell or
expand on exposure to moisture and helps to
breakup tablets in gastrointestinal track (GIT).
Mainly croscarmellose and sodium starch
glycolate are used because of their high water
uptake and rapid action. Mostly up to 5-10% of
starch is suitable for formulation, but up to about
20% may be used to facilitate more rapid tablet
disintegration.
Preparation of Damp Mass
A liquid binder is now added to the powder to
facilitate adhesion of powder particles. A
damp mass resembling dough is formed and
used to prepare the granulation. A good
binder is very important for hardness of tablet
and does not hinder the release of drug from
the tablet.
Most widely used binders are povidone, an aqueous
preparation of corn starch (10-20%), methyl cellulose
(3%), carboxymethylcellulose, and microcrystalline
cellulose. Some drugs may be adversely affected by an
aqueous binder then non-aqueous solutions or dry
binder may be used. The amount of binders is a part of
operation which maintains integrity of tablet after
compression. However, care must be exercised not to
over or underwet powder otherwise underwet can
result too hard granules for proper tablet formulation
and overwet can result too soft and tend to crumble in
under wetting. After getting desired dump mass a
colorant or flavorant may be added to prepare a
granulation with an added features.
Screening Damp Mass into Pellets and Granules
The Damp Mass is pressed through 6 or 8 mesh
size to prepare granules. This process may be
done by hand or by special equipment which
prepares granules by extrusion process. The
final product are spread on in trays and dried.
Drying the granulation
Granules may be dried in special drying cabinets which is
thermostatically controlled at constant, temperature,
humidity and time. Fluid bed drier and tray drier are
commonly used for during process.
Sizing the granulation by Dry Screening
After drying, the granules are passed through a screen of a
smaller mess than that used to prepare the original
granulation. The size of granules depends upon the size
of the punches to be used. Usually 12 to 20 mesh sizes
are used for granulation. Sizing of the granules is
necessary so that the die cavities for tablet compression
may be completely or rapidly filled by the free flowing
granules. Voids or air spaces left by too large a
granulation result in production of uneven tablets.
Adding Lubrication and Blending
After dry screening, a dry lubricant is spread over
the granulation through a fine mess screen
which contributes to preparation of
compressed tablets. Among the most
commonly used lubricants are talc, magnesium
stearate, calcium stearate, stearic acid, and
sodium stearyl fumarate in ranges of 0.1% to
5%. Lubricants improve flow property of
granules form hooper ti die, prevent adhesion
during compaction, reduce friction between
die and punch and provide a sheen final
product.
Dry granulation
In this method, powder mixer is compressed in
large pieces and subsequently broken down or
sized into granules. In this method, either
active ingredient or diluent must have cohesive
properties. This method is basically applied to
materials which cannot be prepared by wet
granulation because of moisture degradation
properties or thermolabile properties of
granules. It is carried out by two steps:
Slugging:
After weighing and the mixing of ingredients, the
powder mixture is slugged or compressed into
large flat tablets about one inch in diameter
which are called slug. Slugs are than broken up
hand or mill and passed through a screen of
desired mess for sizing which now flow more
uniformly than the original powder mixture.
Sometimes lubricant are added and prepared
by compression.
Roller compaction:
On a large scale, Instead of
slugging, powder compactors
may be used to increase the
density of a powder by pressing
it between rollers at 1 ton to 6
tons of pressure. The compact
material is broken up, sized,
and lubricated, and tablets are
prepared by compression.
Commonly used binding agents
are methyl cellulose or
hydroxylmethyl cellulose (6-
12%) which produces good
hardness and friability of
tablet.
Tableting of granulation:
There are different types of tabletting machines
which are used in the production of tablet but
similar in basic function and operation. They all
compress tablet formulation within steel die cavity
by the pressure exerted by the movement of two
steel punches, lower punch and an upper punch.
Problems in manufacture of tablet
Capping and lamination:
Capping means partial and complete separation of the top
or bottom crowns of a tablet from main body of a tablet.
While lamination is term used to describe the separation
of the two or more distinct layers. Some reasons which
are responsible for these problems are as follows:
Air is entrapped among the particles during the
compression process and does not escape until
compression pressure is released.
• Die wall pressure causes enough internal stress to
cause a crack which is due to plastic deformation
of the particles during compaction.
• Sometimes due to deep concave or bevelled edge
punches.
• Development of ‘wear ring’. This problem can
reduced or eliminated by slowing tabletting rate,
granules with sufficient moisture, pre-
compression, using flat punches, correct
adjustment punches.
Weight variation:
This is very important in process control
measurement. If anything that can alter the die
filling process can alter tablet weight, it causes
weight variation because the weight of the
tablet being compressed is determined by the
amount of the granulation in the die prior to
compression. Some causes of variation are
large granules, poor mixing of granules with
lubricants and glidants, poor granulation flow
from hopper, double impression and punch
variation.
Picking
Picking is the term used to describe the
surface material from tablet that is sticking
to being removed from the tablet’s surface
by a punch. It concerns when punching tips
have engraving or embossing

Sticking
Sticking is usually referred to adhesion of tablet
material to die wall. Because of that, lower punch
cannot move freely and additional force is required
to overcome friction between die wall and the
tablet. These problems can be solved by design large
lettering, adding polishing agent such as colloidal
silica or additional lubricants. Some low melting
point substances such as polyethylene glycol may
also cause sticking at the heat of compression. Such
Remedies are addition of high melting point
materials and consequently increasing size of tablet.
Mottling:
Mottling is term used unequal distribution of colour
on a tablet with light and dark areas. It’s due to
colour difference of drug with excipients or drugs
whose degradation product is coloured. Such
problems might be solved by using colorants but it
can cause mottling on the top of surface when
granulation undergoes drying. To overcome
difficulties, it require to change solvent system,
binder system and by reducing temperature.
Tablet coating
Tablet coating is application of coating of
material to the exterior of tablet with some
intentional benefits. It is also intended for
modified release applications.
– Main three types of coating are-
– Film coating
– Sugar coating
– Press coating
Coating of tablets are for following purposes-
– Protection from environment, light and moisture
– To remove bitter taste of some tablets and for easy
swallowing of tablets
– Colour coating mask differences in appearance which
effect on patient compliance
– Rapid identification by manufacturer, pharmacist and
patient
– Functional films can enable sustained and enteric
protection
– Improve looks (elegance), masks and minor difference
in raw material appereance
– Enhance strength, reduce dust and cross
contamination
Film coating
This is more modern and widely used for tablet coating.
Most of newly launched coated products are film coated
rather than sugar coating.
Film coating involves covering of tablet by thin film layer of
coating liquid (polymer). Coating liquid is sprayed in a
rotating tablet bed or bed fluidised tablet which contains
plasticizer, polymer, colourant and solvent. The drying
condition permits removal of solvent and leaves a thin
layer around each tablet. Sometimes aqueous solution or
organic solutions are used to reduce elimination of
volatile organic compound, health and safety and cost
reduction purposes.
Cellulose derivatives like Hydroxypropylmethylcellulosa
(HPMC), methylcellulose, hydroxypropylcellulose (HPC)
and Methacrylate amino ester copolymer are available
polymer for film coating.
Film coating polymer should have following
properties-
• Optimum solubility to facilitate dissolution of final
product. High soluble for immediate release and
low soluble for controlled release.
• Optimum viscosity to permit and trouble free
spraying of solution.
• Optimum permeability to optimize shelf life of
tablet preparation and some tuned to provide an
effective barrier oxygen and water vapour.
• Good mechanical strength to withstand the impact
and abrasion encountered in normal handling
which avoids cracks and imperfections.
Sugar coating
Sugar coating involves the successive application of sucrose based
solutions to tablet cores in suitable equipment. Some stages in
production of sugar coated tablets are-
• Sealing of tablet core- provide water proofing core from
coating process and shellac, cellulose acetate phthalate are
normally used in sealing process.
• Sub coating- it is the actual start of sugar coating which
provides necessary build-up to roundup the tablet edge.
Bulking agents such as calcium carbonate or talc added in
sucrose solution with gum.
• Smoothing – it increases tablet size to predetermined
dimension by syrup solution. This solution contains pigments,
starch, gelatine, acacia or opacifier.
• Colouring- dyes or pigments
• Polishing- tablets need to be polished to achieve final elegance
by waxes like beeswax, carnubawax or hard paraffin.
• Printing
Press coating
Press coating involves compaction of granules
material around core of tablet with the use of
compressing equipment like Manesty Drycota.
Today press coating is used in to separate
incompatible placed core and coating layer. This
process requires some care and large or
irregularly sized agglomerate of granules may
cause core to tilt in die. Disadvantages of
process arise from complexities of mechanism
used in compression equipment.
• Techniques/ Methods Used in Tablet
Formulation
Tablets are commonly manufactured by
1. Wet granulation
2. Dry granulation or
3. Direct compression.
One important requirement is that the drug
mixture flows freely from the hopper of the
tabletting machine into the dies to enable
high-speed compression of the powder mix
into tablets.
Wet granulation is a widely used method for the
production of compressed tablet. It is
essentially a process of size enlargement
involving several steps and the use of an
adhesive substance known as binder. The
granules produced using this method of
granulation has a greater probability of
meeting all the physical requirements for
tablet formation.
Manufacture of tablets by wet granulation method
Flowchart of wet granulation process
A stepwise summary of the manufacturing steps
used in the manufacture of tablets by the wet
granulation method are listed below.
1. Weighing, milling and mixing of the APIs with
powdered excipients (excluding the lubricant)
2. Preparation of binder solution
3. Mixing of binder solution with powders to
form a damp mass
4. Screening the dampened powder into pellets
or granules (wet screening) using 6- to 12-
mesh screen
5. Drying of moist granules
6. Sizing the granulation by dry screening using
14- to 20-mesh screen
7. Mixing of the dried granules with lubricant
and disintegrants
8. Compression of granules into tablets.
Tablets manufactured by wet granulation exhibit
sufficient mechanical properties to be
subsequently exposed to other unit
operations, e.g. film coating.
Manufacture of tablets by dry granulation method
The formation of granules by compacting powder
mixtures into large pieces or compacts which are
subsequently broken down or sized into granules
(often referred to as dry granulation or pre-
compression) is a possible granulation method which,
however, is not widely used in the manufacture of
tablets. This method is used when tablet excipients
have sufficient inherent binding properties. The
procedure can also be used as a means to avoid
exposure of drug substances to elevated temperatures
(during drying) or moisture. Dry compression method
eliminates a number of steps but still includes
weighing, mixing, slugging, dry screening, lubrication,
and compression of granules into tablets. Compaction
for the dry granulation process is generally achieved
either by slugging or roller compaction.
Slugging
In this method, the powder mix is compressed into a
soft large flat tablet (about 1 inch in diameter) using
a tablet press that is capable of applying high stress.
Following this, the slugs are broken by hand or
milled using conventional milling equipment to
produce granules of the required size. Lubricant is
added in the usual manner, and the granules then
compressed into tablets.
Aspirin is a good example of where slugging is
satisfactory. Other materials, such as
acetaminophen, thiamine hydrochloride, ascorbic
acid, magnesium hydroxide, and other antacid
compounds, may be treated similarly.
Roller Compaction
Results similar to those accomplished by the
slugging process are also obtained with powder
compactors. In roller compaction method, the
formulation ingredients are mixed and are
passed between high-pressure (oppositely)
rotating rollers that compress the powder at 1
to 6 tons of pressure. The compacted material
is then milled to a uniform granule size and
compressed into tablets after the addition of a
lubricant.
Flowchart of dry granulation process
A stepwise summary of the manufacturing steps
used in the manufacture of tablets by the dry
granulation method are listed below.
1. Weighing and Milling of formulation
ingredients (drug substance and excipients)
2. Mixing of milled powders.
3. Compression of mixed powders into slugs.
4. Milling and sieving of slugs.
5. Mixing with disintegrant and lubricant.
6. Compression into tablets.
Manufacture of tablets by direct compression
method
As its name implies, direct compression involves
direct compression of powdered materials into
tablets without modifying the physical nature
of the materials itself. The technology involved
in this method assumes great importance in the
tablet formulations, because it is often the
cheapest means, particularly in the production
of generics that the active substance permits.
Direct compression avoids many of the
problems associated with wet and dry
granulations.
Flowchart of direct compression process
A stepwise summary of the manufacturing steps used
in the manufacture of tablets by the dry
granulation method are listed below.
1. Milling of therapeutic agent and excipients
2. Mixing of milled powders, disintegrants and
lubricants
3. Compression into tablets.
It is worth noting that tablets produced by direct
compression are often softer than their
counterparts that have been produced by wet
granulation and therefore they may be difficult to
film-coat.
Comparison of various steps used in different
methods of tablet manufacturing processes
Tablets defects/ special problem in compressing
tablet process
• Weight variation (granule size and size
distribution)
• Poor mixing
• Poor flow
• Capping and lamination
• Picking of tablets
• Chipping and splitting
• Sticking
• Embossing/print defect
• Low hardness/ low mechanical strength of
tablets/ soft tablets
• Variable hardness/ hardness variation
• Mottling
• Punch variation
• Double impression
Quality control of tablets
Tablets should be subjected to a number of tests
before they are deemed fit for marketing and
consumption. These tests can be divided into two
broad categories namely
1. Pharmacopoeial or official tests
a. Content of active ingredient/ absolute drug content
test/ assay of active ingredient.
b. Weight uniformity test/ weight variation test
c. Content uniformity test
d. Disintegration time test
e. Dissolution test
Non-pharmacopoeial or non-official tests
a. Crushing strength test/ hardness test
b. Friability test.
c. Tensile strength determination.
Packaging and storing of tablets
Before tablets are sent out for distribution, they are
usually packaged using appropriate packaging
materials. The type of packaging material used is
a matter of choice and is dependent on several
factors including:
1. The degree of protection required
2. Compatibility of the packaging material with the
formulation.
3. Customer convenience in terms of size, weight,
method of opening or reclosing legibility of
printing, etc.
4. Filling method and
5. Cost
Tablets are commonly packaged using blister
and strip packs and are kept in places of low
humidity, and protected from extremes
temperature. The packaging provides
excellent environmental protection for each
unit of tablet, coupled with an aesthetically
pleasing and efficacious appearance. Blister
and strip packaging also provide some degree
of tamper resistance to the dosage form.
For larger quantities, glass or plastic bottles,
metal containers, cartons, or paperboard
drums may be used along with polyethylene
liners, where necessary, to give added
protection from moisture. Light sensitive
tablets are packaged in light-resistant
containers.
Evaluation/ quality control of raw materials
used in the manufacture of tablets
Quality control of tablet raw materials (APIs and
excipients) is one of the main tasks of the
quality control unit in any drug manufacturing
industry.
Raw materials described in monograph of
relevant Pharmacopoeia must undergo the
necessary tests as stated in the monograph. It
is often sufficient if identification testing is
conducted on the individual
packages/containers and content and purity
determination in mixed samples.
Starting materials are released only after their
quality are established or judged as
satisfactory. Raw materials that fail the quality
control test are rejected and returned to the
supplier.
Any risks that may come from starting materials
of inappropriate quality must be avoided to
prevent product failure and to ensure a
consistent level of quality, as well as safety in
consumer and industrial products.
Tablet Manufacturing Equipment/ Machines
Common equipment used in pharmaceutical tablet
manufacturing include:
1. Size reduction equipment/ communition
equipment e.g., hammer mill, roller mill, fluidized
energy mill, cutter mill and ball mill.
2. Weighing balance/ balances e.g., bulk weighing
balance (weighs in kilogram), electronic weighing
balance (weighs in grams and milligrams).
3. Mixing equipment e.g.,
– pneumatic mixers (air-mix mixer or air-driven mixer),
– diffusion/ tumbling mixers (e.g., V-blender, double cone
blender, cubic mixer, drum blender),
– convective mixers (e.g., ribbon blenders, orbiting screw
mixers, planetary blenders)
4. Granulators e.g., rotating shape granulators, mechanical
agitator granulators (e.g., ribbon or paddle blender,
sigma blade mixer, planetary mixer, orbiting screw
mixers), high-shear granulator, fluidized bed
granulator, dry granulator etc.
5. Dying equipment e.g., spray dryer, rotary dryer, fluidized
bed dryer etc.
6. Tabletting machine – single punch tablet press and
multi-station/ rotary tablet press (e.g., High-speed rotary
tablet machines and multi-layer rotary tablet machines).
7. Quality control equipment e.g., disintegration
equipment (Manesty single unit disintegrating apparatus,
multiple unit disintegrating apparatus), USP Dissolution
Tester, Tablet Hardness Tester, Tablet Thickness Tester,
Tablet Friability Testers etc.
8. Coating and polishing machines for coated
tablets e.g., standard coating pan, perforated
pan, fluidized bed/ Air suspension coating
system etc.
9. Packaging machines e.g., blister packaging
machines, strip packing machine, aluminium
foil packaging machine, etc.
Steps Involved In Tablet Formulation/ Procedure for
Manufacturing Tablets
1. Dispensing: Each ingredient in the tablet formula is
weighed and accurately dispensed as per dose. This
is one of the critical steps in any type of
formulation process and should be done under
technical supervision.
2. Sizing: Formulation ingredients must be in finely
divided form, otherwise, size reduction should be
carried out for better flow property and easy
mixing.
3. Powder blending: Powders are mixed using a
suitable blender to obtain a uniform and
homogeneous powder mix. The drug substance
and excipients are mixed in geometric dilution.
4. Granulation: Here small powder particles are
gathered together into layers, and permanent
aggregates to render them into free-flowing states.
5. Drying and dry screening: Screened wet granules
need to be dried for a particular time period in tray
dry or fluid bed dryer at controlled temperature
not exceeding 550C. Dried granules are screened
through the appropriate mesh screen.
6. Tablet compression: This step involves the
compression of granules into a flat or convex,
round, oblong, or unique shaped, scored or
unscored tablets; engraved with an identifying
symbol and/ or code number using tablet press.