TABLET DESIGN AND FORMULATION

PART 5

Industrial pharmacy

5th class

1st semester
 TABLET DESIGN AND FORMULATION

Conventional oral tablets for ingestion

usually contain the same classes of
components in addition to the active
ingredients, which are one or more agents
functioning as:
(1) Diluent
(2) Binder or an adhesive
(3) Disintegrant
(4) Lubricant.

Some tablet formulations may additionally

require:
➢ Flow promoter
➢ Colorants
➢ And in chewable tablets:
flavors and sweeteners.
 DILUENTS
Diluents are fillers designed to make up the
required bulk of the tablet when the drug dosage
itself is inadequate to produce this bulk.
Note: The dose of some drugs is sufficiently high that
no filler is required (e.g., aspirin and certain antibiotics).

 Round tablets for ingestion are usually in a size

range of 3/16 to ½ inch (tablet weight range
of perhaps 120 to 700 mg for standard
density organic materials.
 Tablets below 3/16 inch may be difficult for the
elderly to handle, and those larger than ½ inch
become difficult to swallow.

 Oval tablets, weighing up to 800 mg or more

may be produced.

 A diluent for secondary reason:

improved cohesion: to permit use of direct
compression manufacturing, or to promote flow.
Diluents and all other tablet excipients must meet certain
criteria in the formulation. These include the following:

1. They must be non toxic.

2. They must be commercially available in an acceptable

grade.

3. Their coast must be acceptably low.

4. They must not be contraindicated by themselves (e.g.,

sucrose) or because of a component (e.g., sodium).

5. They must be physiologically inert.

 6. They must be physically and chemically stable themselves
and in combination with the drug(s) and other tablet
components.

7. They must be free of any unacceptable microbiologic

“load”.

8. They must be color-compatible (not produce any off-color

appearance)

9. If the drug product is also classified as a food, (certain

vitamin products), the diluent and other excipients must be
approved direct food additives.

10. They must have no deleterious effect on the bioavailability

of the drug(s) in the product.
 Cases
Case 1: pharmaceutical manufacturers actually
producing products in which an excipient reduced
the bioavailability of a drug, or in which chemical
incompatibilities existed.

The former situation occurred with the

marketing of an antibiotic that utilized a
calcium salt as the diluent.

Ex: The tetracycline product made with a

calcium phosphate filler had less than half the
bioavailability of the standard product.
Mechansim: (Divalent and trivalent cations form
insoluble complexes and salts with a number of
amphoteric or acid functionality antibiotics,
which greatly reduces their absorption (which is
also why should not be coadministered with
these drugs).
Case 2: A classic case of a chemical incompatibility;
interaction of certain amine drugs with the commonly
used diluent lactose, in the presence of a metal
stearate lubricant (such as magnesium stearate);

The resulting tablets were gradually discolored with

time.

Important note: Physical and chemical

interactions between formulation components
may be promoted by the intimate contact
between potential reactants that are tightly
compressed together in a tablet compact.

Ex: materials that are capable of forming a eutectic

mixture, may pose no problem when loosely packed as a
powder in a capsule, while the same formulation when
compressed in a tablet forms a compact that quickly
soften and becomes unacceptable.
 EXAMPLES OF DILUENTS

1. DIBASIC CALCIUM PHOSPHATE

AND CALCIUM SULFATE

Advantage: possessing low concentrations

of unbound moister and having a low affinity for
atmospheric moisture. These are required
features for any excipient material to be
combined with water-sensitive drug.

Mechansim: this diluent exist in salt form

as hydrates, containing appreciable
bound water as water of crystallization,
may nevertheless be excellent for very
water-sensitive drugs, provided that the
bound water is not released under any
elevated storage condition to which the
product might be exposed (but released in
80°C).
 2. LACTOSE
Most widely used diluent in tablet formulation.

Properties:
1. It is an excipient that has no reaction with most
drugs, whether it is used in the hydrous or
anhydrous form.

2. Anhydrous lactose has advantage over lactose in

that it does not undergo the Maillard reaction,
which can lead to browning and discoloration
with certain drugs.

3. The anhydrous form, pick up moisture when

exposed to elevated humidity. Such tablet may
have to be carefully packaged to prevent
moisture exposure.

2. When a wet granulation process is employed, the

hydrous form of lactose should generally be used.
5. Two grades of lactose are available
commercially: a 60-80 mesh
(coarse) and a 80-100 (regular)
grade.

6. Lactose formulations show good

drug release rates, their
granulations are readily dried, and
the tablet disintegration times of
lactose tablets are not strongly
sensitive to variation in tablet
hardness.

7. Lactose is a low cost diluent but it

may discolor in the presence of
amine bases or salts of alkaline
compounds.
 3. STARCH
Starch, which may come from corn,
wheat or potatoes used as a tablet
diluent.
Types:
 The USP grade of starch, has four flow
and compression characteristics and
possesses a high typical moisture
content of between 11 and 14%.

 Specially dried types of starch that have

a standard moisture level of 2 to 4% are
available, but at a premium price.
Use of such starches in wet granulation is
wasteful since their moisture levels increase to 6
to 8% following moisture exposure.
 Directly compressible starches are now
available commercially. Ex: Sta-Rx 1500

Properties:
1. Free-flowing

2. Directly compressible

3. Used as a diluent, binder, disintegrating agent.

4. Also used as self-lubricating, (it may be compressed

alone, but when combined with as little as 5 to 10%
of drug, it typically requires addition of a lubricant,
and possibly a flow promoter such as 0.25% of a
colloidal silicone dioxide).

5. Contains about 10% moisture and is prone to

softening when combined with excessive amount
(more than 0.5%) of magnesium stearate.
 Two hydrolyzed starches are
Emdex and Celutab, which are
basically 90 to 92% dextrose and
about 3 to 5% maltose.

Properties:
1. Free-flowing and directly compressible.
2. Used in place of mannitol in chewable
tablets because of their sweetness and
smooth feeling in the mouth.
3. Contain about 8 to 10% moisture and
may increase in hardness after
compression.
 4. DEXTROSE

Used as a tablet diluent.

 It is available under the
name Cerelose

Types: hydrate, and in

anhydrous form for when low
moisture contents are required.

Properties: combined in
formulation to replace some of
the spray-dried lactose, which
may reduce the tendency of the
resulting tablets to darken.
 4. MANNITOL
Most expensive sugar used as a tablet
diluent.

Properties:
1. Because of its negative heat of solution, slow
solubility, and its pleasant feeling in the
mouth, it is widely used in chewable tablets.

2. It is relatively nonhygroscopic and can be used

in vitamin formulation, in which moisture
sensitivity may be a problem.

Disadvantage: Mannitol formulations typically

have poor flow characteristics and usually require
fairly high lubricant levels.
 5. SORBITOL

Optical isomer of mannitol

Properties:
1. Combined in mannitol
formulations to reduce diluent
cost.
2. Both sorbitol and mannitol
have a low caloric content and
are noncariogenic.

Disadvantage: hygroscopic at
humidities above 65%.
 6. SUCROSE
Sucrose, or sugar, and various sucrose-based
diluents are employed in tablet making.

Disadvantage:
a) Some manufacturers avoid their use in products that
would subject a diabetic to multiple gram quantities of
sugar.
b) Pick up moisture when exposed to elevated humidity.

Types:
1. Sugartab (90 to 93%) sucrose plus 7 to 10% invert sugar).
2. diPac (97% sucrose plus 3% modified dextrins
3. Nu tab (95% sucrose and 4% invert sugar with a small
amount of corn starch and magnesium stearate).

Properties:
i. Available for direct compression
ii. Employed with or without mannitol in chewable tablets
 7. MICROCRYSTALLINE CELLULOSE

Referred to by the trade name Avicel, It

is a commonly employed excipient.

Types:
1. PH 101 (powder)
2. PH 102 (granules).

Properties:
a) The flow properties are good.
b) Direct compression are excellent.
c) Producing cohesive compacts.
d) Acts as a disintegrating agent (added to tablet
formulation for several possible function.

Disadvantage: a relatively expensive material

when used as a diluent in high concentration and
is thus typically combined with other materials.
 BINDERS AND ADHESIVES
The reason behind adding these materials :
1. Dry or in liquid form during wet granulation
to form granules
2. Promote cohesive compacts for directly
compresses tablets.

1. Acacia and tragacanth

Natural gums, and are employed in solutions
ranging from 10 to 25% concentration, alone
or in combination.

Properties: These materials are much more

effective when they are added as solution in the
preparation of granulations than when they are
added dry to a direct compression formula.
Disadvantages:
1. Variable in their composition
and performance based on
their natural origin,
2. Fairly heavily contaminated
with bacteria.
Ex: wet granulation masses should
be quickly dried at a temperature
above 37°C to reduce microbial
proliferation.
 2. GELATIN

natural protein and is

sometimes used in
combination with acacia.

Properties:
1. More consistent material than
the two natural gums,
2. Easier to prepare in solution
form
3. Forms tablets equally as hard
as acacia or tragacanth.
 3. STARCH PASTE

One of the most common granulating

agents.

Preparation: dispersing starch into

water, which is then heated for some
prescribed time.
During heating

The starch undergoes hydrolysis to dextrin

and to glucose.

Made paste that is translucent rather than

clear (which would indicate virtually
complete conversion to glucose) and
produces cohesive tablets that readily
disintegrate when properly formulated.
 4. MODIFIED NATURAL POLYMERS

➢ As the alginates and cellulose

derivatives (methylcellulose,
hydroxypropyl methylcellulose,
and hydroxypropyl cellulose),
are common binders and
adhesives.
Uses:
1. Dry for direct compression (binder
capabilities)
2. Aqueous solutions (adhesive properties.

➢ Hydroxypropyl cellulose
Used as an alcohol solution to provide an
anhydrous adhesive.
➢ Ethylcellulose
used only an alcoholic solution
(expected to retard disintegration
and dissolution time of drugs in the
resulting tablets when wet
granulation is employed).

➢ Polyvinylpyrrolidone is a
synthetic polymer
(Used as an adhesive in either an
aqueous solution or alcohol. It also
has some capabilities as a dry
binder).
 DISINTEGRANTS
A disintegrant is added to most tablet formulations
to facilitate a breakup or disintegration of the tablet
when it contacts water in the gastrointestinal tract.
Mechanism

Disintegrant may function by drawing water into the

tablet, swelling, and causing the tablet to burst
apart.
 1. STARCH USP AND VARIOUS STARCH DERIVATIVES

Properties:
1. Most common disintegrating agents.
2. Lowest cost.

Types:
i. Starch is typically used in a conc.
range of 5 to 20% of tablet weight.
ii. Modified starches as Primogel and
Explotab, which are low substituted
carboxylmethyl starches, are used in
lower conc. (1 to 8%, with 4% usually
reported as optimum).
iii. Various pregelatinized starches are
also employed as disintegrants,
usually in a 5% conc.
2. CLAYS SUCH AS VEEGUM HV AND BENTONITE

used as disintegrants at about a 10% level.

Disadavantages:
Limited unless the tablet are colored
1. Produce off-white appearance
2. Less effective as disintegrant

3. AC-DI-SOL
New material known as (related to cellulose
class) is now available and is effective in low
concentration levels.
It is internally cross-linked form of sodium
carboxymethylcellulose.
 LUBRICANTS, ANTIADHERENTS, AND GLIDANTS

These three classes of materials are

typically described together because they
have overlapping functions.

A material that is primarily described as

an antiadherent is typically also a
lubricant, with some glidant properties as
well.

 The differentiation between these

terms is as follows:
1. Lubricants: intended to reduce
the friction during tablet ejection
between the walls of the tablet
and the walls of the die cavity in
which the tablet was formed.
2. Antiadherents: have the
purpose of reducing
sticking or adhesion of
any of the tablet
granulation or powder to
the faces of the punches

3. Antiglidants: promote
flow of the tablet
granulation or powder
materials by reducing
friction between the
particles.
EXAMPLES OF LUBRICANT
1. The most widely used lubricants have been stearic acid
salts and derivatives (Calcium and magnesium stearate).

Note: Stearic acid is a less effective lubricant than those

salts and also has a lower melting point.

2. Talc the second most commonly used tablet lubricant.

Note: Most talc samples are found to contain trace quantities

of iron, and talc should be considered carefully in any
formulation containing a drug whose breakdown is catalyzed by
the presence of iron.
EXAMPLES OF LUBRICANT
3. The higher-molecular-weight
polyethylene glycols and certain
polymeric surfactants have been
used as water-soluble lubricants
(These materials are much
less effective as lubricants).

Important note: Since

lubrication is basically a coating
process, the finer the particle size
of the lubricant the more
effective the lubricant action is
likely to be.
EXAMPLES OF ANTIADHERENT AND ANTIGLIDANT

 Most of the materials listed as lubricants,, also function as

Antiadherents (Talc, magnesium stearate, starch
derivatives and various colloidal silicas).

 Materials used as glidants, or flow promoters

Typically talc at a 5% concentration, corn starch at a 5
to 10% concentration, or colloidal silicas such as Cab-O-
Sil, syloid, or Aerosil in 0.25 to 3% concentration.
 (COLORS, FLAVORS AND SWEETENERS)
COLORS
The use of colors and dyes in tablet
making has served three purposes over
the years:
1. Disguising of(mask) off-color drugs
2. Product identification
3. Production of a more elegant product.

 The availability of natural vegetable

colors is limited, and these colors are
often unstable.

Types of dye:
1. FD&C and D&C dyes-applied as
solutions, typically in the granulation agent.
2. Lakes dyes absorbed on a hydrous oxide
and employed as dry powders for coloring.
 Several precautions should be concerned when
colors are employed:

i. When using water-soluble dyes, pastel shades

usually show the least mottling from uneven
distribution in the final tablet.
ii. When wet granulation is employed, care
should be taken to prevent color migration
during drying.
iii. In any colored tablet, the formulation should
be checked for resistance to color changes on
exposure to light.
 FLAVORS
Flavors are usually limited to chewable tablets or other
tablets intended to dissolve in the mouth.

Types of flavors:
A. Water-soluble have little acceptance in tablet making
because of their poor stability.

B. Flavor oils are added to tablet granulations in solvents,

are dispersed on clays and other absorbents, or are
emulsified in aqueous granulating agents.
(maximum amount of oil added to a granulation without
influencing its tabletting characteristics is 0.5 to 0.75%.

C. Various dry flavors for use in pharmaceutical products

are also available from flavor suppliers.
 SWEETENERS

The use of sweeteners is primarily limited to

chewable tablets to exclude or limit the use of
sugar in the tablets.

Examples:
1. Mannitol is about 72% as sweet as sucrose.

2. Saccharin was the only artificial sweetener

available (500 times sweeter than sucrose).
Disadvantages: bitter after taste and reported to be
carcinogenic.
3. Aspartame: new artificial sweetener that is
expected to largely replace saccharin.
Disadvantage: lack of stability in the presence
of moisture (when used in a chewable tablet with
hygroscopic components)

It will be necessary to determine its stability

under conditions in which the product can
adsorb atmospheric moisture.
Important note: excipients are the inactive part of
a tablet formulation, they have a direct influence on the
quality and effectiveness of the final product.
Ex: the influence of compression force on
disintegration time for various direct compression
materials.
i. Some materials have maximum disintegration
time of no higher than 200 to 250 sec,
regardless of the compression force applied
over the range studied.
ii. One material rapidly increased in
disintegration time to over 500 sec at a
compression force of less than 1000kg.