Technology of Making Tablets

Murat Kizaibek
• Tablets are solid dosage fo
rms consisting of active ingr
edient(s) and suitable phar
maceutical excipients. They
may vary in size, shape, wei
ght, hardness, thickness, di
sintegration and dissolution
characteristics, and in other
aspects. They may be class
yfied, according to the meth
od of manufacture, as comp
ressed tablets or molded ta
blets.
 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 pharmac
eutical adjuncts, known as excipients, in addition to the m
edicinal substance. The use of appropriate excipients is i
mportant in the development of the optimum tablets. Exci
pients determine the bulk of the final product in dosage fo
rms such as tablet, capsule, etc., the speed of disintegrati
on, rate of dissolution,release of drug, protection against
moisture, stability during storage, and compatibility . Exci
pients should have no bioactivity, no reaction with the dru
g 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 cellu-
lose 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 formul

ation. Such adhesion enables preparation of granules a
nd maintains the integrity of the final tablet. As listed in
the Table, Commonly used binding agents include: star
ch, 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 tablet’s ejection from the tablet
machine.
• 4. Lubricants give a sheen to the finished tablets.
• Commonly used lubricants include: talc, magnes
ium stearat, calcium stearate ,stearic acid, hydro
genated 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 disinte-
grating 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

wet granulation: suitable for drugs that are stable to moistur

granulation e and heat
dry granulation: suitable for drugs that are sensitive to moi
sture and heat
powder compression : suitable for drugs that are sensitive
direct to moisture and heat, fill material possessing, good flowabilit
compression y and compressibility
crystal compression ： suitable for drugs with prope
r crystal form and good flowability
 wet granulation

drug adhesive

smash sieving mix prilling

excipients

lubricant
processing press
dry mix
granule
 dry granulation

adhesive
drug
press processing
smash sieving mix smash
cake granule
excipient

mix press
 powder compression

adhesive
drugs
mix press
smash sieving mix
excipients
 • crystal compression

drugs adhesive
smash sieving

mix mix press

excipients
• wet granulation technology
• ( 一 )wet granulation methods and equipment:

• 1.Extrusion grain methods and equipment: first prescripti

on drug powder and the auxiliary materials mixed evenly
to join adhesive soft material system, then with soft mate
rial 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)
(liquid
binder)
preparing a damp mass Internal( 内加
法)
screening the damp mass into pellets or granules

drying the granulation

sizing the granulation by dry screening External( 外加

法)

adding lubricant and disintegrant, and blending

tableting by compression
 The classification of tablet presses
• Tablet presses:

a. single-punch presses

b. multi-station rotary presses

The main components of single-punch
tablet presses
t a b l e t
h o p p e r

h a r d n e s s

a d j u s t o r

Core components:
f e e d

s h o e

die d i e

u p p e r

c a v i t y

lower punch up p u n c h

per punch d i e

l o w e r

p u n c h

t a b l e t e j e c t o r

a d j u s t o r

t a b l e t w e i g h t

a d j u s t o r
 The basic mechanical process of tableting
with single-punch presses
a) filling material
u p p e r

a ) b ) c )

p u n c h

b) scraping away the excessive t a b l e t

granulation

c) forming a tablet by compression

f i l l

m a t e r i a l

d) pushing up the tablet to stage l

p
o

u
w

n
e

c
r

h
d i e

surface d ) e ) a

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 lacto

se, sucroseinvert ,sugar – corn starch mixtures, microcrystalline cellulos
e, crystalline malt and dicalcium phosphate;

d) disintegrants, as direct-compression starch, sodium carboxymethyl star

ch, cross-linked carboxymethylcellulose fiber, and cross-linked polyvinyl
pyrrolidone;

c) lubricants, as magnesium stearate and talc;

d) glidants, fumed silicon dioxide

• Sophora Alopecuruldes L ． Seed Tablet
optimization
 excipient

prilling 、
powder of sophora processing mix
AIopecuroides L ． Seed mix 制软材
granule

press

1 ％ Magnesium
stearate
 table 1 the influence of different adhesive to Tablet hardness

formula 1 2 3 4

adhesive 10% 10%PVP （ 10%CMC-Na 10%PVP

Starch water ） (Ethanol)
Hardness 0.68 0.83 0.75 particles de
（ Kg ） formed
table 2 the influence of different fillers to Tablet hardnes
s

formula 5 6 7 8
fillers starch Pregelati lactose 10%PVP
( Ethanol)
nized star
ch
Hardnes 0.68 0.77 3.14 3.55
s（K
g）
 table 3 factor level
Factor level
A [The amount of Microcrstallin 80 120 160
e cellulose(g)]

A [Concentration of PVP solutio 10 15 20

n （ % ， g/ml)]
 table 4 Result of Orthogonal test
A×B Result
Total
Test NO. 　　 A 　　 B Ⅰ Ⅱ
1 2

1 1 1 1 1
2 1 2 2 2 3.1 2.9 6.0
3 1 3 3 3 2.8 3.1 5.9
4 2 1 2 3 3.2 2.7 5.9
5 2 2 3 1 4.1 4.4 8.5
6 2 3 1 2 4.0 4.1 8.1
7 3 1 3 2 4.2 3.4 8.5
8 3 2 1 3 4.0 3.8 7.8
9 3 3 2 1 3.9 4.2 8.1
K1 17.8 23.0 21.4 22.2
K2 24.2 21.8 22.5 22.0
K3 24.4 21.6 22.5 22.2

1.1 0.2
R×6 6.6 1.4 0.6
 table5 Analysis of variance table
variance source SS V MS F P

total variance 5.658

A 4.698 2 2.349 33.562 0.0001

B 0.191 2 0.096 1.366 0.3034

A×B 0.139 4 0.035 0.993 0.4077

error 0.630 9 0.070

table ６　微晶纤维素用量影响苦豆子片硬度的ｑ检验（ｎ＝６）
Comparison 两均数之 value of q Number
group 差 error of
ｑ界值
standard P
group
α =0.05 α= 0.01

A1andA3 -1.1 0.1074 -10.241 3 4.34 6.33 <0.01

A1andA2 -1.0 0.1074 -9.310 2 3.46 5.24 <0.01

A2andA3 -0.1 0.1074 -9.310 2 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
片芯 ——包层隔离——包粉衣层——包糖衣层——包有色糖衣层——打光
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 am
ounts 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 am
ounts 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: Average Weight

weight variation
sample amount 20 tablets
limit
 Tablets should comply
Less than ± 7.5%
with the following 0.3 g
requirements stated in
the table below. 0.3 g or ± 5%
more
电子称量仪
 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 w
eight, then weigh individually each of the 20 tablets. Com
pare the weight of each tablet with the labelled tablet (if n
o labelled weight is stated, compare the weight of each t
ablet with the average weight calculated). No more than
2 of the individual weights exceed the weight variation li
mit 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 tablet’s 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%

硬度检测仪
片剂脆碎度检测仪
溶出仪
自动溶出取样机
 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 product’s in vivo
bioavailability.

Basis: The combinations of a drug’s 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 ves
sel and allowed to come to 37℃±0.5℃.
b) The stirrer is rotate at the specified speed.
c) At stated intervals, samples of the medium are withdraw
n for chemical analysis
5) Requirement for rate of dissolution
The specific required rates of dissolution are different for ta
blets containing different medicinal agents.
e.g. not less than 85% of the labeled amount is dissolved i
n 30 minutes
6) Inconsistencies in dissolution

occur not between dosage units from the same production

batch, but rather between batches or between products f
rom different manufacturers.

Pooled dissolution testing has emerged. This process reco

gnizes the concept of batch characteristics and allows po
oled specimens to be tested.