Technology of Making Tablets

Murat Kizaibek

Tablets are solid dosage

forms consisting of active
ingredient(s) and suitable
pharmaceutical excipients.
They may vary in size,
shape, weight, hardness,
thickness, disintegration and
dissolution characteristics,
and in other aspects. They
may be classyfied,
according to the method of
manufacture, as
compressed tablets or
molded tablets.

Advantages

Production aspect
Large scale production at
lowest cost
Easiest and cheapest to
package and ship
High stability
User aspect (doctor,
pharmacist, patient)
Easy to handling
Lightest and most compact
Greatest dose precision &
least content variability

Disadvantages

Some drugs resist

compression into dense
compacts
Drugs with poor wetting, slow
dissolution, intermediate to
large dosages may be difficult
or impossible to formulate and
manufacture as a tablet that
provide adequate or full drug
bioavailability
Bitter taste drugs, drugs with
an objectionable odor, or
sensitive to oxygen or moisture
may require encapsulation or
entrapment prior to
compression or the tablets
may require coating

Types of tablets

1)compressed tablets
2)sugar coated tablets
3)film coated tablets
4)enteric coated tablets
5)effervescent tablets
6)chewable tablets
7)dispersible tablets
8)sustained release tablets

9)multilayer tablets
10)sublingual tablets
11)toroches
12)buccal tablets
13)implant tablets
14)hypodermic tablets
15)solution tabletc
16)vaginal tablets

EXCIPIENTS FOR COMPRESSED

TABLETS
Compressed tablets usually contain a number of
pharmaceutical adjuncts, known as excipients, in addition
to the medicinal substance. The use of appropriate
excipients is important in the development of the optimum
tablets. Excipients determine the bulk of the final product
in dosage forms such as tablet, capsule, etc., the speed
of disintegration, rate of dissolution,release of drug,
protection against moisture, stability during storage, and
compatibility . Excipients should have no bioactivity, no
reaction with the drug substance, no effect on the
functions of other excipients, and no support of
microbiological growth in the product .

A. DILUENTS
Diluents increase the volume to a formulation to
prepare tablets of the desired size. Widely used
fillers are lactose, dextrin, microcrystalline cellulose starch, pregelatinized starch, powdered
sucrose, and calcium phosphate.

 The diluent is selected based on various factors, such as

the experience of the manufacturer in the preparation of
other tablets, its cost, and compatibility with other
formulation ingredients. For example, in the preparation
of tablets or capsules of tetracycline antibiotics, a
calcium salt should not be used as a diluent since
calcium interferes with absorption of the antibiotics from
the GI tract.

B.BINDERS
Binders promote the adhesion of particles of the
formulation. Such adhesion enables preparation of
granules and maintains the integrity of the final tablet.
As listed in the Table, Commonly used binding agents
include: starch, gelatin and sugars (sucrose, glucose,
dextrose, and lactose).

Examples of Binders
Carboxymethylcellulose, sodium

Karaya gum

Cellulose,microcrystalline(Avicel) Starch, pregelatinized

Ethylcellulose

Tragacanth gum

Hydroxypropyl methylcellulose

Poly(acrylic acid)

Methylcellulose

Polypvinylpyrrolidone

Acacia gum

Gelatin

Agar

Dextrin

Algin acid

Glucose

Guar gum

Molasses

C. LUBRICANTS
Lubricant is a substance capable of reducing or
preventing friction, heat, and wear when introduced as a
film between solid surfaces. It works by coating on the
surface of particles, and thus preventing adhesion of the
tablet material to the dies and punches.
Glycerylmonostearate(USP/NFCH2(OH)CH(OH)CH2O2
CC17H35) is one example of a lubricant. Lubricants play
more than one role in the preparation of tablets as
described below.

 1. Lubricants improve the flow of granules in the hopper

to the die cavity.
2. Lubricants prevent sticking of tablet formulation to the
punches and dies during formulation.
3. Lubricants reduce the friction between the tablet and
the die wall during the tablets ejection from the tablet
machine.
4. Lubricants give a sheen to the finished tablets.

 Commonly used lubricants include: talc,

magnesium stearat, calcium stearate ,stearic
acid, hydrogenated vegetable oils and (PEG).

D. DISINTEGRATORS

The breakup of the tablets to smaller particles is important for

dissolution of the drug and subsequent bioavailability.
Disintegrators promote such breakup. To rupture or breakup of
tablets, disintegrating agents must swell or expand on exposure to
aqueous solution. Thus, the most effective disintegrating agents in
most tablet systems are those with the highest wa-ter uptake
property. In general, the more hydrophilic, the better disintegrating agents are therefore highly hydrophilic. A list of typical
disinte-grants is tabulated in Table

E. WETTING AGENTS
Water molecules attract each other equally in all directions. Water
molecules on the surface, however, can only be pulled into the bulk water
by water molecules underneath, since there are no water molecules to
pull in the opposite direction. The surface tension of water is strong
enough to support the weight of tiny insects such as water striders. The
surface ten-sion in action can be visualized by placing a small drop of
alcohol on a thin layer of water. Alcohol with lower surface tension mixes
with water causing reduction in the surface tension in the local region.
Owing to the higher surface tension of water in the neighbor, water is
pulled from the alcohol dropped region into the neighbor, and this leads
to the formation of a dry spot in the middle of the water layer.

Compressed tablet manufacture

The classification of manufacturing methods

granulation

wet granulation: suitable for drugs that are stable to

moisture and heat
dry granulation: suitable for drugs that are sensitive to
moisture and heat

direct
compression

powder compression : suitable for drugs that are sensitive

to moisture and heat, fill material possessing, good
flowability and compressibility
crystal compression suitable for drugs with
proper crystal form and good flowability

wet granulation

adhesive

drug
smash

sieving

mix

prilling

excipients

lubricant
dry

processing
granule

mix

press

dry granulation
adhesive

drug
smash
excipient

mix

press

sieving

mix

press
cake

processing
smash
granule

powder compression
adhesive

drugs
smash
excipients

sieving

mix

mix

press

 crystal compression

drugs

smash

adhesive

sieving
mix

excipients

mix

press

 wet granulation technology

( )wet granulation methods and equipment:
1.Extrusion grain methods and equipment: first
prescription drug powder and the auxiliary materials
mixed evenly to join adhesive soft material system, then
with soft material compulsory extrusion way through has
a certain size screen hole and granulating method.

wet granulation

Compressed tablet manufacture

wet granulation

The steps of wet granulation

weighing and blending the ingredients(disintegrant)

preparing a damp mass

(liquid
binder)
Internal( )

screening the damp mass into pellets or granules

drying the granulation
sizing the granulation by dry screening
adding lubricant and disintegrant, and blending
tableting by compression

External( )

The classification of tablet presses

Tablet presses:
a. single-punch presses
b. multi-station rotary presses

The main components of single-punch

tablet presses
Core components:
die
lower punch
upper punch

The basic mechanical process of tableting

with single-punch presses
a) filling material
b) scraping away the excessive
granulation
c) forming a tablet by compression
d) pushing up the tablet to stage
surface
e) shoving the tablet aside

A picture of multi-station rotary press

hopper
feed-frame
head: upper turret, lower turret, die table
upper turret
die table
lower turret

The core components and compression

cycle of rotary presses

A: upper punch
B: die cavity
C: die
D: lower punch
The compression
is applied by both
the upper punch
and the lower
punch.
The compression cycle of a rotary tablet press

Compressed tablet manufacture

Direct compression tableting
Suitable for
1) granular chemicals possessing free flowing and
cohesive properties
e.g. potassium chloride
2) chemicals added with special pharmaceutical
excipients which impart the necessary qualities for the
production of tablets by direct compression

The direct compression tableting excipients include:

a) fillers, as spray-dried lactose, microcrystals of alphamonohydrate
lactose, sucroseinvert ,sugar corn starch mixtures, microcrystalline
cellulose, crystalline malt and dicalcium phosphate;
d) disintegrants, as direct-compression starch, sodium carboxymethyl
starch, cross-linked carboxymethylcellulose fiber, and cross-linked
polyvinylpyrrolidone;
c) lubricants, as magnesium stearate and talc;
d) glidants, fumed silicon dioxide

 Sophora Alopecuruldes L Seed Tablet

optimization

excipient

powder of sophora
AIopecuroides L Seed

press
1 Magnesium
stearate

mix

prilling
processing
granule

mix

table 1

the influence of different adhesive to Tablet hardness

formula

adhesive

10%
Starch

Hardness
Kg

0.68

2
10%PVP
water
0.83

3
10%CMC-Na
0.75

4
10%PVP
(Ethanol)
particles
deformed

table 2

the influence of different fillers to Tablet hardness

formula
fillers

5
starch

6
7
Pregelati lactose
nized
starch

Hardnes
s Kg

0.68

0.77

3.14

8
10%PVP
( Ethanol)

3.55

table 3 factor level

level

Factor
A [The amount of
Microcrstalline cellulose(g)]

80

120

160

A [Concentration of PVP
solution % g/ml)]

10

15

20

table 4 Result of Orthogonal test

AB
Test NO.

1
2
3
4
5
6
7
8
9
K1
K2
K3

R6

1
1
1
2
2
2
3
3
3
17.8
24.2
24.4

1
2
3
1
2
3
1
2
3
23.0
21.8
21.6

6.6

1.4

Result

1
2
3
2
3
1
3
1
2
21.4
22.5
22.5

1
2
3
3
1
2
2
3
1
22.2
22.0
22.2

1.1

0.2
0.6

3.1
2.8
3.2
4.1
4.0
4.2
4.0
3.9

2.9
3.1
2.7
4.4
4.1
3.4
3.8
4.2

Total

6.0
5.9
5.9
8.5
8.1
8.5
7.8
8.1

table5
variance source

SS

total variance

5.658

Analysis of variance table

V

MS

4.698

2.349

33.562

0.0001

0.191

0.096

1.366

0.3034

AB

0.139

0.035

0.993

0.4077

error

0.630

0.070

table
Comparison
group

standard

value of q Number

error
of
group
=0.05
= 0.01

A1andA3

-1.1

0.1074

-10.241

4.34

6.33

<0.01

A1andA2

-1.0

0.1074

-9.310

3.46

5.24

<0.01

A2andA3

-0.1

0.1074

-9.310

3.46

5.24

>0.05

Tablet coating
The reasons for tablet coating
1) to protect the medicinal agent against destructive exposure to air
and/or humidity;
2) to mask the taste of the drug;
3) to provide special characteristics of drug release;
4) to provide aesthetics or distinction to the product;
5) to prevent inadvertent contact by nonpatients with the drug
substance

The general methods involved in coating tablets are as follows

1) sugarcoating tablets
2) film-coating tablets
3) enteric coating
4) pan coating
5) fluid-bed or air suspension coating
6) compression coating

The sugarcoating of tablets may be divided into the

following steps:
1) waterproofing and sealing (if needed)
2) subcoating
3) smoothing and final rounding
4) finishing and coloring (if desired)
5) polishing

film-coating machine

1) waterproofing and sealing (if needed)

aim: to prevent the components from being adversely
affected by moisture; one or more coats; shellac , zein , or
a polymer as cellulose acetate phthalate
2) Subcoating aim: to bond the sugar coating to the tablet
and provide rounding
a) 3 to 5 subcoats of a sugar-based syrup are applied. The
sucrose and water syrup also contains gelatin, acacia, or
PVP.

b) When the tablets are partially dry they are sprinkled with
a dusting powder, usually a mixture of powdered sugar
and starch but sometimes talc, acacia, or precipitated
chalk as well.
c) Then drying the tablets. Repetition (15 to 18 times) the
subcoating process until the tablets are of the desired
shape and size.

3) smoothing and final rounding

aim: to complete the rounding and smooth the coatings
5 to 10 additional coatings of a thick syrup; This syrup is
sucrose-based with or without additional components as
starch and calcium carbonate.
4) finishing and coloring
aim: to attain final smoothness and the appropriate color
several coats of a thin syrup containing the desired colorant

5) imprinting
aim: to impart identification codes and other distinctive symbols to the
product
The imprint may be debossed, embossed, engraved, or printed on the
surface with ink.
6) polishing
aim: to render the tablets the desired sheen/gloss/luster
a) pans lined with canvas cloth impregnated with carnauba
waxand/or beeswax
b) Pieces of wax may be placed in a polishing pan
c) light-spraying of the tablets with wax dissolved in a nonaqueous
solvent

Tablet coating
film-coating tablets
1) The disadvantages of sugarcoating process
a) time-consuming
b) requiring the expertise of highly skilled technicians
c) doubling the size and weight of the original uncoated tablets
d) may vary in size from batch to batch and within a batch
e) large tablets are not as easily swallowed as are small tablets.

2) The advantages of film-coating process

a) coated tablets having essentially the same weight, shape, and size
as the originally compressed tablet
b) The coating is thin enough to reveal any identifying monograms.
c) far more resistant to destruction by abrasion than are sugar-coated
tablets
d) the coating may be colored to make the tablets attractive and
distinctive.

3) The components of nonaqueous film-coating solutions:

a) film former: e.g. CAP
b) alloying substance: to provide water solubility or permeability to
the film e.g. PEG
c) plasticizer: to render flexibility and elasticity to the coating e.g.
castor oil
d) surfactant: to enhance spreadability of the film e.g.
polyoxyethylene sorbitan derivatives
e) opaquants and colorants: e.g. titanium dioxide, FD&C or D&C
dyes
f) sweeteners, flavors, and aromas: saccharin, vanillin
g) glossant: beeswax
h) volatile solvent: alcohol-acetone mixture

4) The components of a typical aqueous film-coating

solutions:
a) film-forming polymer (7-18%): e.g. cellulose ether
polymers as HPMC, HPC and MC
b) plasticizer (0.5-2.0%): e.g. glycerin, propylene glycol,
PEG, diethyl phthalate, and dibutyl subacetate
c) colorant and opacifier (2.5-8%): FD&C or D&C lakes
and iron oxide pigments
d) water

5) Some problems with aqueous film-coating

a) picking and peeling

the appearance of small amounts or large

amounts of film fragments flaking from the tablet surface

b) orange peel effect

roughness of the tablet surface due to failure of

spray droplets to coalesce

c) mottling

an uneven distribution of color on the tablet surface

d) bridging
filling-in of the score-line or indented logo on the tablet by the film
e) tablet erosion
disfiguration of the core tablet

5) Some problems with aqueous film-coating

a) picking and peeling

the appearance of small amounts or large

amounts of film fragments flaking from the tablet surface

b) orange peel effect

roughness of the tablet surface due to failure of

spray droplets to coalesce

c) mottling

an uneven distribution of color on the tablet surface

d) bridging
filling-in of the score-line or indented logo on the tablet by the film
e) tablet erosion
disfiguration of the core tablet

The reasons for capping,

splitting or laminating of
tablets
1) air entrapment
2) not immaculately cleaned or not perfectly
smoothed punches
3) too great a proportion of fine powder
4) Tablets have aged or have been stored
improperly

quality standards and compendial

requirements
The apparent physical features of compressed tablets:
1) shape: round, oblong, unique

2) thickness: thick or thin

3) diameter: large or small

4) flat or convex

5) unscored or scored in halves, thirds and quadrants

6) engraved or imprinted with an identifying symbol and/or code
number
7) coated or uncoated 8)colored or uncolored 9) number of layer.
The die and punches determine the physical features of compressed
tablets.

quality standards and compendial

requirements
Other physical specifications and quality standards:
tablet weight

weight variation

content uniformity

tablet thickness

tablet hardness

tablet disintegration

drug dissolution
in-process controls
verification after the production

quality standards and compendial requirements

tablet weight and Chp weight variation
Chp weight variation:
sample amount 20 tablets
Tablets should comply
with the following

Average
weight

Weight
variation
limit

Less than
0.3 g

7.5%

0.3 g or
more

5%

requirements stated in
the table below.

quality standards and compendial requirements

tablet weight and Chp weight variation
The procedure of weight variation determination in Chp:
Weigh accurately 20 tablets and calculate the average
weight, then weigh individually each of the 20 tablets.
Compare the weight of each tablet with the labelled
tablet (if no labelled weight is stated, compare the weight
of each tablet with the average weight calculated). No
more than 2 of the individual weights exceed the weight
variation limit stated in the table above and none doubles
the limit.

quality standards and compendial requirements

tablet hardness and friability
Tablet hardness
1)The greater the pressure applied, the harder the tablets.
2) The hardness required by different tablets
a) lozenges and buccal tablets: hard (dissolve slowly)
b) the tablets for immediate drug release: soft
3) measurement
a) special dedicated hardness testers
b) multifunctional equipment

quality standards and compendial requirements

content uniformity
applys to potent drug of low dose.
USP method, 10 tablets are individually assayed for their
content.
The amount of active ingredient in each tablet lies within
the range of 85% to 115% of the label claim and the RSD
is less than 6.0%.

quality standards and compendial requirements

tablet hardness and friability
(continued)
Friability
1) It is used to determine a tablets durability
2) Method: allowing the tablets to roll and fall within the
rotating apparatus (friabilator); determine the loss in
weight;
3) requirement: weight loss 1%

quality standards and compendial requirements

tablet dissolution
1)

The importance of in vitro dissolution test

a) to guide the formulation and product development

process toward product optimization
b) to monitor the performance of manufacturing process
c) to assure bioequivalence from batch to batch
d) as a requirement for regulatory approval for product
marketing for products registered with the FDA and
regulatory agencies of other countries.

2) The goal of in vitro dissolution is to provide a

reasonable prediction of the products in vivo
bioavailability.
Basis: The combinations of a drugs solubility and
its intestinal permeability are supposed as a
basis for predicting the likelihood of achieving a
successful in vivo in vitro correlation (IVIVC).

Considered are drugs determined to have:

a) high solubility and high permeability (IVIVC
may be expected.)
b) low solubility and high permeability (IVIVC
may be expected.)
c) high solubility and low permeability
d) low solubility and low permeability

3) The formulation and manufacturing factors

affecting the dissolution of a tablet
a) the particle size of the drug substance
b) the solubility and hygroscopicity of the formulation
c) the type and concentration of the disintegrant,
binder, and lubricant used
d) the manufacturing method, particularly, the
compactness of the granulation and the
compression force
e) the in-process variables

4) Test method
a) A volume of the dissolution medium is placed in the
vessel and allowed to come to 370.5.
b) The stirrer is rotate at the specified speed.
c) At stated intervals, samples of the medium are
withdrawn for chemical analysis
5) Requirement for rate of dissolution
The specific required rates of dissolution are different for
tablets containing different medicinal agents.
e.g. not less than 85% of the labeled amount is dissolved
in 30 minutes

6) Inconsistencies in dissolution
occur not between dosage units from the same production
batch, but rather between batches or between products
from different manufacturers.
Pooled dissolution testing has emerged. This process
recognizes the concept of batch characteristics and
allows pooled specimens to be tested.