1. 1.8 Manufacturing methods
1.8.1 Direct compression(1-3,5,17)
What
will you gain?
1.8.1.1 Introduction.
1.8.1.2 The events that
motivates the industry people to use direct compression technique.
1.8.1.3 Merits
1.8.1.4 Merits over wet granulation process
1.8.1.5 Demerits
1.8.1.6 Manufacturing steps for direct compression
1.8.1.7 Direct compression Excipients
1.8.1.7.1 An ideal direct
compression excipient should possess
the following attributes.

2. 1.8.1.7.2 Major excipients required in direct
compression.
1.8.1.1 Introduction
In early days, most of the tablets require granulation of the powdered Active
Pharmaceutical Ingredient (API) and Excipients. At the availability of new
excipients or modified form of old excipients and the invention of new tablet
machinery or modification of old tablet machinery provides an ease in
manufacturing of tablets by simple procedure of direct compression.
Amongst the techniques used to prepare tablets, direct
compression is the most advanced technology. It involves only blending and
compression. Thus offering advantage particularly in terms of speedy
production. Because it requires fewer unit operations, less machinery, reduced
number of personnel and considerably less processing time along with increased
product stability.
Definition:
The term “direct compression” is defined as the process
by which tablets are compressed directly from powder mixture of API and
suitable excipients. No pretreatment of the powder blend by wet or dry
granulation procedure is required.
1.8.1.2 The events that motivates the industry people to use direct compression technique

3. I.Commercial availability of the directly compressible excipients possessing both good
compressibility and good flowability.
For example,
Spray dried lactose, Anhydrous lactose, Starch-1500, microcrystalline
cellulose, Di-PacÒ, Sorbitol
II.Major advances
in tablet compression machinery:
i)Improved positive die feeding,
ii)Precompression of powder blend.
1.8.1.3 Merits
i)Direct compression is more efficient and economical process as compared to other
processes, because it involves only dry blending and compaction of API and
necessary excipients.
ii)The most important advantage of direct compression is
economical process.
Reduced
processing time, reduced labor costs, fewer manufacturing steps, and less
number of equipments are required, less process validation, reduced consumption

4. of power.
iii)Elimination of heat and moisture, thus increasing not
only the stability but also the suitability of the process for thermolabile and
moisture sensitive API’s.
iv)Particle size uniformity.
v)Prime particle dissolution.
In case of directly compressed tablets after
disintegration, each primary drug particle is liberated. While in the case of
tablets prepared by compression of granules, small drug particles with a larger
surface area adhere together into larger agglomerates; thus decreasing the
surface area available for dissolution.
vi)The chances of batch-to-batch variation are negligible,
because the unit operations required for manufacturing processes is fewer.
vii)Chemical stability problems for API and excipient would be avoided.
viii)Provides
stability against the effect of aging which affects the dissolution rates.
1.8.1.4 Merits over wet granulation process
The variables faced in the processing of the granules
can lead to significant tableting problems. Properties of granules formed can
be affected by viscosity of granulating solution, the rate of addition of
granulating solution, type of mixer used and duration of mixing, method and
rate of dry and wet blending. The above variables can change the density and
the particle size of the resulting granules and may have a major influence on

5. fill weight and compaction qualities. Drying can lead to unblending as soluble
API migrates to the surface of the drying granules.
1.8.1.5 Demerits
Excipient Related
i)Problems in the
uniform distribution of low dose drugs.
ii)High dose drugs having high bulk volume, poor
compressibility and poor flowability are not suitable for direct compression.
For example, Aluminium Hydroxide, Magnesium Hydroxide
iii) The choice of excipients for direct compression is
extremely critical. Direct compression diluents and binders must possess both
good compressibility and good flowability.
iv) Many active ingredients are not compressible either
in crystalline or amorphous forms.
v) Direct compression blends may lead to unblending
because of difference in particle size or density of drug and excipients.
Similarly the lack of moisture may give rise to static charges, which may lead
to unblending.

6. vi) Non-uniform distribution of colour, especially in
tablets of deep colours.
Process Related
i)Capping, lamination, splitting, or layering of tablets is sometimes related to air
entrapment during direct compression. When air is trapped, the resulting
tablets expand when the pressure of tablet is released, resulting in splits or
layers in the tablet.
ii)In some cases require greater sophistication in
blending and compression equipments.
iii) Direct compression equipments are expensive.
1.8.1.6 Manufacturing steps for direct compression
Direct compression involves
comparatively few steps:
i)Milling of drug and excipients.
ii) Mixing of drug and excipients.
iii) Tablet compression.

7. Manufacturing Steps For Direct Compression
Figure.23. Manufacturing Steps For Direct Compression
1.8.1.7 Direct compression Excipients
Direct compression excipients mainly include
diluents, binders and disintegrants. Generally these are common materials that
have been modified during the chemical manufacturing process, in such a way to
improve compressibility and flowability of the material.
The physicochemical properties of the ingredients
such as particle size, flowability and moisture are critical in direct
compression tableting. The success of direct compression formulation is highly
dependent on functional behavior of excipients.
1.8.1.7.1 An ideal direct compression excipient should possess the following attributes
i)It should have
good compressibility.
ii)It should possess good hardness after compression,
that is material should not possess any deformational properties;
otherwise this may lead to capping and
lamination of tablets.

8. iii) It should have good flowability.
iv) It should be physiologically inert.
v) It should be compatible with wide range of API.
vi) It should be stable to various environmental
conditions (air, moisture, heat, etc.).
vii) It should not show any physical or chemical change in
its properties on aging.
viii) It should have high dilution potential. i.e. Able to incorporate high amount of API.
ix) It should be colourless, odorless and tasteless.
x) It should accept colourants uniformity.
xi) It should possess suitable organoleptic properties
according to formulation type, that is in case of chewable tablet diluent
should have suitable taste and flavor. For example mannitol produces cooling
sensation in mouth and also sweet test.
xii) It should not interfere with bioavailability and
biological activity of active ingredients.

9. xiii)It should be
easily available and economical in cost.
1.8.1.7.2 Major excipients required in direct
compression
I.Diluents
II.Binders
III.Disintegrants
Diluents
Selection
of direct compression diluent is extremely critical, because the success or
failure of direct compression formulation completely depends on characteristics
of diluents. There are number of factors playing key role in selection of
optimum diluent. Factors like- Primary properties of API (particle size and
shape, bulk density, solubility), the characteristics needed for processing
(flowability, compressibity), and factors affecting stability (moisture, light,
and other environmental factors), economical approach and availability of material.
After
all, one can say that raw material specifications should be framed in such a

10. way that they provide an ease in manufacturing procedures and reduce chances of
batch to batch variation. This becomes possible only when the raw material
specifications reflect most of properties of diluents as mentioned in section
1.5.
Binders (56)
Binders are the agents used to impart cohesive qualities
to the powdered material. The quality of binder used has considerable influence
on the characteristic of the direct compression tablets. The direct compression
method for preparing tablets requires materials which are not only free flowing
but also sufficiently cohesive to act as binder.
Key Phrases
Ø Direct
compression is one of the most advanced technologies to prepare tablets.
Ø It requires
only blending and compression of excipients.
Ø It is an
economical process.
Ø It is suitable

11. for heat and moisture sensitive API.
It is not
suitable for very low and very high dose drugs.
1.8.2 Granulation (1,4,5,57)
What will you gain?
1.8.2.1
Introduction
1.8.2.2
Wet granulation
1.8.2.2.1 Introduction
1.8.2.2.2 Important steps involved in the wet
granulation
1.8.2.2.3 Limitation of wet granulation
1.8.2.2.4 Special wet granulation techniques
1.8.2.2.4.1 High shear mixture granulation

12. 1.8.2.2.4.2 Fluid bed granulation
1.8.2.2.4.3 Extrusion and Spheronization
1.8.2.2.4.4 Spray drying granulation
1.8.2.2.5 Lists of equipments for wet granulation
1.8.2.2.6 Current topics related to wet
granulation
1.8.2.3
Dry granulation
1.8.2.3.1 Introduction
1.8.2.3.2 Advantages
1.8.2.3.3 Disadvantages
1.8.2.3.4 Steps in dry granulation
1.8.2.3.5 Two main dry granulation processes
1.8.2.3.5.1Slugging process

13. 1.8.2.3.5.2 Roller compaction
1.8.2.3.6 Formulation for dry granulation
1.8.2.3 Advancement in Granulations
1.8.2.3.1 Steam Granulation
1.8.2.3.2 Melt Granulation/Thermoplastic
Granulation
1.8.2.3.3 Moisture
Activated Dry Granulation
1.8.2.3.4 Moist
Granulation Technique (MGT)
1.8.2.3.5 Thermal Adhesion Granulation Process
(TAGP)
1.8.2.3.6 Foam Granulation
1.8.2.1 Introduction
Granulation may be defined as a size enlargement process

14. which converts small particles into physically stronger & larger
agglomerates.
Granulation method can be broadly classified into two
types:
Wet granulation and Dry granulation
Ideal characteristics of granules
The ideal characteristics of granules include spherical
shape, smaller particle size distribution with sufficient fines to fill void
spaces between granules, adequate moisture (between 1-2%), good flow, good
compressibility and sufficient hardness.
The effectiveness of granulation depends on the
following properties
i) Particle size of
the drug and excipients
ii) Type of binder (strong or weak)
iii) Volume of binder (less or more)
iv) Wet massing time ( less or more)

15. v) Amount of shear applied
vi) Drying rate ( Hydrate formation and polymorphism)
1.8.2.2 Wet granulation
1.8.2.2.1 Introduction
The most widely used process of agglomeration
in pharmaceutical industry is wet granulation. Wet granulation process simply
involves wet massing of the powder blend with a granulating liquid, wet sizing
and drying.
1.8.2.2.2 Important steps involved in the wet
granulation
i) Mixing of the
drug(s) and excipients
ii) Preparation of binder solution
iii) Mixing of binder solution with powder mixture to form
wet mass.
iv) Coarse screening of wet mass using a suitable sieve
(6-12 # screens).

16. v) Drying of moist granules.
vi) Screening of dry granules through a suitable sieve
(14-20 # screen).
vii) Mixing of screened granules with disintegrant,
glidant, and lubricant.
1.8.2.2.3 Limitation of wet granulation
i) The greatest
disadvantage of wet granulation is its cost. It is an expensive process because
of labor, time, equipment, energy and space requirements.
ii) Loss of material during various stages of processing
iii) Stability may be major concern for moisture sensitive
or thermo labile drugs
iv) Multiple processing steps add complexity and make
validation and control difficult
v) An inherent limitation of wet granulation is that any
incompatibility between formulation components is aggravated.
1.8.2.2.4 Special wet granulation techniques

17. i) High shear
mixture granulation
ii) Fluid bed granulation
iii) Extrusion-spheronization
iv)Spray drying
1.8.2.2.4.1 High shear mixture granulation
High shear mixture has been widely used in Pharmaceutical
industries for blending and granulation. Blending and wet massing is
accompanied by high mechanical agitation by an impeller and a chopper. Mixing,
densification and agglomeration are achieved through shear and compaction force
exerted by the impeller.
Advantages:
i) Short processing
time
ii) Less amount of liquid binders required compared with
fluid bed.
iii) Highly cohesive material can be granulated.

18. 1.8.2.2.4.2 Fluid bed granulation
Fluidization is the operation by which fine solids are
transformed into a fluid like state through contact with a gas. At certain gas
velocity the fluid will support the particles giving them free mobility without
entrapment.
Fluid bed granulation is a process by which granules are
produced in a single equipment by
spraying a binder solution onto a fluidized powder bed. The material processed
by fluid bed granulation are finer, free flowing and homogeneous.
1.8.2.2.4.3 Extrusion and Spheronization
It
is a multiple step process capable of making uniform sized spherical particles.
It is primarily used as a method to produce multi-particulates for controlled
release application.
Advantages:
i) Ability to
incorporate higher levels of active components without producing excessively
larger particles.
ii) Applicable to both immediate and controlled release

19. dosage form.
1.8.2.2.4.4 Spray drying granulation
It is a unique granulation technique that directly
converts liquids into dry powder in a single step. This method removes moisture
instantly and converts pumpable liquids into a dry powder.
Advantages:
i) Rapid process
ii) Ability to be operated continuously
iii) Suitable for heat sensitive product
1.8.2.2.5 Lists of equipments for wet granulation
High Shear granulation:
i)Little ford Lodgie granulator
ii)Little ford MGT granulator
iii)Diosna granulator
iv)Gral mixer

20. Granulator with drying facility:
i)Fluidized bed granulator
ii) Day nauta mixer processor
iii)Double cone or twin shell processor
iv)Topo granulator
Special granulator:
i)Roto granulator
ii)Marumerizer
1.8.2.2.6 Current topics related to wet granulation
I. Hydrate formation
For example, theophylline anhydrous during
high shear wet granulation transfers to theophylline monohydrate. The midpoint
conversion occurs in three minutes after the binder solution is added.
For online monitoring of the transformation from one form to another, Raman

21. spectroscopy is most widely used.
II. Polymorphic transformation
The
drying phase of wet granulation plays a vital role for conversion of one form
to another.
For
example, glycine which exist in three polymorphs that is a, β, g . g
is the most stable form and a
is the metastable form. The stable Glycine polymorph (g) converts to metastable form (a) when
wet granulated with microcrystalline
cellulose.
1.8.2.3 Dry granulation
1.8.2.3.1 Introduction
In dry granulation process the powder mixture is
compressed without the use of heat and solvent. It is the least desirable of
all methods of granulation. The two basic procedures are to form a compact of
material by compression and then to mill the compact to obtain a granules. Two
methods are used for dry granulation. The more widely used method is slugging,
where the powder is precompressed and the resulting tablet or slug are milled
to yield the granules. The other method is to precompress the powder with
pressure rolls using a machine such as Chilosonator.

22. 1.8.2.3.2 Advantages
The main advantages of dry granulation or slugging are
that it uses less equipments and space. It eliminates the need for binder
solution, heavy mixing equipment and the costly and time consuming drying step
required for wet granulation. Slugging can be used for advantages in the
following situations:
i) For moisture
sensitive material
ii) For heat sensitive material
iii) For improved disintegration since powder particles
are not bonded together by a binder
1.8.2.3.3 Disadvantages
i) It requires a
specialized heavy duty tablet press to form slug
ii) It does not permit uniform colour distribution as can
be
iii) Achieved with wet granulation where the dye can be
incorporated into binder liquid.

23. iv) The process tends to create more dust than wet
granulation, increasing the potential contamination.
1.8.2.3.4 Steps in dry granulation
i) Milling of drugs
and excipients
ii) Mixing of milled powders
iii) Compression into large, hard tablets to make slug
iv) Screening of slugs
v) Mixing with lubricant and disintegrating agent
vi) Tablet compression
1.8.2.3.5 Two main dry granulation processes
1.8.2.3.5.1 Slugging process
Granulation by slugging is the process of compressing dry
powder of tablet formulation with tablet press having die cavity large enough
in diameter to fill quickly. The accuracy or condition of slug is not too
important. Only sufficient pressure to compact the powder into uniform slugs
should be used. Once slugs are produced they are reduced to appropriate granule

24. size for final compression by screening and milling.
Factors which determine how well a material may slug
i) Compressibility
or cohesiveness of the mater
ii) Compression ratio of powder
iii) Density of the powder
iv) Machine type
v) Punch and die size
vi) Slug thickness
vii) Speed of compression
viii) Pressure used to
produce slug
1.8.2.3.5.2 Roller compaction
The compaction of
powder by means of pressure roll can also be accomplished by a machine called

25. chilsonator. Unlike tablet machine, the
chilsonator turns out a compacted mass in a steady continuous flow. The powder
is fed down between the rollers from the hopper which contains a spiral auger
to feed the powder into the compaction zone. Like slugs, the aggregates are
screened or milled for production into granules.
1.8.2.3.6 Formulation for dry granulation
The excipients used for dry granulation are basically
same as that of wet granulation or that of direct compression. With dry
granulation it is often possible to compact the active ingredient with a minor
addition of lubricant and disintegrating agent. Fillers that are used in dry
granulation include the following examples: Lactose, dextrose, sucrose, MCC,
calcium sulphate, Sta-Rx® etc .
Examples of some tablet
formulation prepared by dry granulation:
Aspirin tablet Aspirin effervescent
tablet
Rx Rx
Starch Sodium
bicarbonate

26. Cab-o-sil
® Citric
acid
Aspirin Fumaric
acid
Aspirin
Antacid tablet
Rx
Aluminum
hydroxide
Magnesium
hydroxide
Magnesium
carbonate
Sucrose
PEG

27. 1.8.2.3 Advancement in Granulations
1.8.2.3.1 Steam
Granulation
It is modification of wet granulation. Here steam is used as a binder instead
of water. Its several
benefits includes higher
distribution uniformity, higher diffusion
rate into powders, more
favourable thermal balance
during drying step, steam
granules are more spherical, have large surface
area hence increased
dissolution rate of
the drug from
granules, processing time is
shorter therefore more
number of tablets are
produced per batch, compared to
the use of
organic solvent water vapour
is environmentally friendly,
no health hazards
to operators, no restriction
by ICH on

28. traces left in
the granules, freshly distilled
steam is sterile
and therefore the
total count can
be kept under
control, lowers dissolution rate
so can be
used for preparation
of taste masked
granules without modifying
availability of the
drug. But the limitation is that it is unsuitable for thermolabile
drugs. Moreover special equipments
are required and
are unsuitable for
binders that cannot
be later activated
by contact with
water vapour.
1.8.2.3.2 Melt Granulation / Thermoplastic Granulation (24)
Here granulation is achieved by the addition of meltable binder. That is
binder is in solid state at room temperature but melts
in the temperature range of 50 – 80˚C. Melted binder then acts like a binding

29. liquid. There is no need of drying phase since dried granules
are obtained by cooling it to room temperature. Moreover, amount of liquid
binder can be controlled precisely and the production and
equipment costs are reduced. It is useful for granulating water
sensitive material and producing SR granulation or solid dispersion. But this
method is not suitable for thermolabile
substances. When water soluble
binders are needed, Polyethylene Glycol (PEG) is used
as melting binders. When water
insoluble binders are
needed, Stearic acid, cetyl or stearyl
alcohol, various waxes and
mono-, di-, & triglycerides are used
as melting binders.
1.8.2.3.3 Moisture
Activated Dry Granulation (MADG) (58)
It involves moisture distribution and
agglomeration. Tablets prepared using MADG method has better content
uniformity. This method utilizes very little granulating fluid. It decreases
drying time and produces granules with excellent flowability.
1.8.2.3.4 Moist Granulation Technique (MGT) (59)
A small amount granulating fluid is added
to activate dry binder and to facilitate agglomeration. Then

30. a moisture absorbing material like Microcrystalline Cellulose (MCC) is
added to absorb any excess moisture. By adding MCC
in this way drying step is
not necessary. It is applicable for developing a controlled release formulation.
1.8.2.3.5 Thermal
Adhesion Granulation Process (TAGP) (60)
It is applicable for preparing direct tableting formulations. TAGP is
performed under low
moisture content or low content
of pharmaceutically acceptable
solvent by subjecting
a mixture containing
excipients to heating
at a temperature
in the range
from about 30ºC
to about 130ºC
in a closed
system under mixing
by tumble rotation
until the formation
of granules. This
method utilizes less
water or solvent

31. than traditional wet
granulation method. It
provides granules with
good flow properties
and binding capacity
to form tablets
of low friability, adequate hardness
and have a
high uptake capacity
for active substances
whose tableting is
poor.
1.8.2.3.6 Foam
Granulation (61)
Here liquid binders are added as aqueous foam. It
has several benefits
over spray(wet) granulation
such as it
requires less binder
than Spray Granulation, requires less
water to wet
granulate, rate of
addition of foam
is greater than

32. rate of addition
of sprayed liquids, no
detrimental effects on
granulate, tablet, or invitro
drug dissolution properties, no plugging
problems since use
of spray nozzles
is eliminated, no overwetting, useful for
granulating water sensitive
formulations, reduces drying time, uniform
distribution of binder
throughout the powder
bed, reduce manufacturing time, less
binder required for
Immediate Release (IR) and
Controlled Release (CR)
formulations.
Key Phrases
Ø In wet granulation process a granulating liquid is
used to facilitate the agglomeration process. Wet granulation has been and
continues to be the most widely used agglomeration process. Typically wet
massing of pharmaceutical powder is carried out in the high shear mixture
before wet screening and dried in fluidized bed equipment.

33. Ø In the dry granulation process granulation takes
place without utilizing liquid. In this process dry powder particles may be
brought together mechanically by compression into slug or by rolled
compaction.
Ø
Steam Granulation, Melt Granulation, MADG, MGT,
TAGP, Foam Granulation are some of the new advancements in
granulation and show better quality granule formation as compared
to conventional granulation
methods.
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Tablet
Tablets Book Chapter
Tablets Advantages and Disadvantages
Types of tablets
Formulation of tablets
Activie Ingredient
Manufacturing
Manufacturing methods of tablets
Tablet coating
Problems in tablet manufacture and related remedies
Quality Control tests for tablets
References
Tablet Evaluation Tests : Book Chapter
Brief Notes on Evaluation of tablet
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