Development Of Pharmaceutical Drug Products

Powder granulation is a procedure of size expansion ( Litster & A ; Ennis, 2004 ) ( Swarbrick & A ; Boylan, 2006 ) that incorporate the little atoms to agglomerate together to do a larger atoms in a manner that the chief constituents can still be detected ( Ennis, 2005 ) .

By and large, each tablet contains different types of ingredient but the active ingredients are more of import one. During the combination of all constituents, it should be guaranteed that active ingredients are distributed every bit in different part. While sometimes during the blending or compaction, the ingredients separate from each other ; harmonizing to their difference in atom size, denseness, squeezability and flow features. So to accomplish a regular consequence the pulverizations must flux invariably therefore atoms should be granulated ( D.Tousey, 2002 )

The definition of granulation granulation contain

particle-size distribution and denseness to achieve proper flow and

achieve volume of fill ( i.e. , tablet weight ) . In other words, the

pulverizations must flux systematically to achieve consistent consequences.

The main grounds to grain pulverizations for the

industry of pharmaceutical dose signifiers are

described by Kristensen and Schaefer. [ 1 ]

. To better pulverization flow belongingss for dose filling

and compaction procedures.

. To extinguish wet granulation induced degradants and

to better merchandise stableness.

. To forestall active merchandise ingredient from segregating.

. To cut down majority volume thereby minimising storage

and heightening conveyance.

. To cut down possible environmental and safety jeopardy ( 16,2806 )

Wet granulation is a subset of size expansion ( 1-5 ) , which involves any procedure

whereby little atoms are agglomerated, compacted, or otherwise brought together

into larger, comparatively lasting constructions in which the original atoms can still be

Distinguished. Granulation engineering and size-enlargement procedures have been

used by a broad scope of industries, from the pharmaceutical industry to fertilizer

or detergent production to the mineral processing industries. Size enlargement by and large

encompasses a assortment of unit operations or treating techniques dedicated to

atom agglomeration. These procedures can be slackly broken down into agitation

and compaction methods. ( 10,31 )

Powder granulation is a procedure of pulverization size

expansion that incorporates little atoms into larger

1s. The definition of granulation comprises a scope of

different size expansion methods that can be classified

as either dry or wet. In wet methods, a suited liquid is

used to agglomerate the little pulverization atoms into a

mass. The wet mass is later dried and sized for

farther down-stream processing demands. Wet granulation

methods have been the most widely used pulverization

granulation engineering in the production of pharmaceutical

merchandises, peculiarly in modern pharmaceutical


Traditionally, tablets have been made by granulation, a

procedure that imparts two primary necessities to preparations:

compactibility and fluidness. Both wet granulation

and dry granulation ( sloging or turn over compression ) are used

( Table 1 ) . Regardless of whether tablets are made by direct

compaction or granulation, the first stairss, milling and

commixture, are the same ; the subsequent stairss differ.

The wet massing of pulverizations is typically carried out in

high-shear sociables prior to wet showing. The moisture

granules are frequently dried in fluidized-bed equipment,

heightening the efficiency of the procedure. Alternatively, moisture

granulation may be carried out in fluid-bed driergranulators

in which the liquid stage is sprayed onto

fluidized pulverizations while the hot air flow dries the granules.

This procedure reduces the figure of managing stairss and the

clip and infinite needed for granulation ; it can be

automated ( 16,3165 )


-Nonhomogeneous distribution of binder and drug

substance gives drug-rich or drug-poor mulcts

-Decomposition of drug substance due to residual


-Uneven granule size ( excessively many or to few mulcts ) leads

to compression or uniformity jobs

Naturally tablets merely possess these advantages if they

are decently formulated and manufactured. A wellprepared

tablet should possess the undermentioned qualities:

1. It should, within permitted bounds, contain the declared

dosage of drug.

2. It should be sufficiently strong to defy the emphasiss

of industry, conveyance, and managing so as to make

the patient intact.

3. It should present its dosage of drug at the site and at the

velocity required.

4. Its size, gustatory sensation, and visual aspect should non take away from

its acceptableness by the patient. ( 16,3174 )

The procedure of granulation is basically

one of size expansion, and it serves several intents in

the tablet fabrication procedure:

1. It improves flow by increasing atom size, since big

atoms flow more readily than little 1s.

2. It improves compaction features, adding to the

cohesive strength of the tablet.

3. Once a homogenous mixture has been achieved,

segregation is prevented, since atoms that are stuck

together can non divide.

4. It reduces dust.

Both wet and dry granulation techniques are available

The first phase in the wet granulation procedure is frequently a dry

blending phase in which the active constituent is assorted with

a dilutant. Many drugs need to be administered in doses of

merely a few mg or even less, yet a tablet that weighs

less than approximately 50 milligram is hard for the patient to manage

handily. It is hence necessary to increase the majority

of such a tablet with a dilutant. Some normally used

dilutants are listed in Table 1.

The ideal dilutant would be both chemically and

physiologically inert, and would non interfere with the

bioavailability of the active ingredient. It should besides be

cheap and be easy tabletted since, if the proportion

of active ingredient is little, the overall tabletting

belongingss of the mixture are mostly governed by those

of the dilutant.

Lactose is by far the most often used dilutant for

solid dose signifiers. An cheap disaccharide obtained

as a byproduct of the cheese industry. Probably the 2nd most normally used dilutant in the

wet granulation procedure is dibasic Ca phosphate. This

substance is virtually indissoluble in H2O and hence is

ever used in concurrence with a disintegrating agent

The intent of the commixture phase is to guarantee that the

pulverization blend and therefore the resulting tablets are

homogenous in content. A random mixture is defined as

one where the chance of trying a given type of

atom is relative to the figure of such atoms in

the entire mixture. Therefore, the purpose is to bring forth a mixture

such that when a sample is removed, the relation

proportions of the constituents of that sample are the

same as in the mixture as a whole. Although in general a size difference between

constituents can take to segregation, a state of affairs where

there is a big difference in sizes between constituents

may be good. In such fortunes, little atoms

of one constituent can go trapped in abnormalities in

the surface of the larger constituent. These are non random

mixtures, as the atoms of the two constituents can non

act independently. This construct is called “ ordered

blending ” and it has found pertinence in the industry

of solid dose signifiers incorporating little measures of extremely

potent active ingredients ( 5 ) ( see the article on Blenders

and Blending in this encyclopaedia ) .

The implicit in procedure of size expansion in moisture

granulation is achieved by either one or both of two

different mechanisms. First, next solid atoms may

be stuck together utilizing an adhesive. Such substances are

known as binders or graining agents. Second,

disintegration of the solid in the granulating liquid can

occur, followed by vaporization of the liquid stage of the

latter. This will ensue in the deposition of dissolved

stuff on atom surfaces, organizing alleged crystal

Bridgess. The happening of this mechanism will depend on

the solubility of the solids in the liquid stage.

The traditional piece of graining setup is the

shear granulator. Its map is to homogeneously

integrate an adhesive and syrupy liquid such as amylum

paste into a mass of dry pulverization to organize agglomerates. It

follows that a considerable shearing force demands to be

exerted. The assorted solids are loaded into the bowl of the

sociable, and the liquid added with agitation. The moistness solid

is so forced through a comparatively harsh screen ( about

1-2 millimeter ) , frequently by agencies of hovering bars, to give distinct granules.

the wet granulation procedure is a

long and therefore expensive process, which has been

improved by the debut of high-velocity sociable

granulators. These have fomenter and chopping blades,

which enable commixture, wet massing, and granulation to take

topographic point in the same piece of setup. In such devices, the

granulation procedure takes topographic point highly quickly.

A farther technique is fluid-bed granulation. Air is

passed into the pulverization bed from below. This causes the

atom, of pulverization to organize a suspension in the air and

gives effectual commixture. The granulating fluid is so

sprayed over the atoms, which adhere on hit and

they are so dried in the het air watercourse.

The wet granulation procedure, setup, and pharmaceutical

applications have been comprehensively reviewed

by Kristensen and Schaefer ( 8 ) ( see the article on Tablet

Granulation in this encyclopaedia ) .

After the procedure of granulation, the merchandise exists as a moisture

mass from which the liquid must be removed, since the

presence of H2O leads to the damage of flow belongingss,

and possibly to chemical instability

The fluidized bed desiccant is the most normally used

device for drying tablet granules. The solid is fluidized

from below by a jet of hot air, and so each granule

becomes separated from its neighbours. The air provides an

effectual agencies of heat transportation, every bit good as of taking

H2O vapour. The velocity of the drying procedure is governed

by the distance that H2O molecules must spread before

they arrive at the evaporative surface. Since the moisture

granules are present as single units, the upper limit

distance over which diffusion occurs is equal to the radius

of a granule. Hence, fluidized bed drying is a rapid procedure. The temperature of the bed can be exactly controlled, and a free-flowing merchandise consequences.

Second commixture phase

When the drying procedure is complete, it is likely that the

merchandise will hold cohered into comparatively big multitudes,

particularly if tray drying has been used. The dried stuff

is hence passed through a screen ( normally 250-700 millimeter )

to interrupt up sums and to give a comparatively uniformly

sized granule. A 2nd commixture phase now follows in which

several of import ingredients of the preparation are added

The lubricator

When the tablet preparation is compressed, the sides of the

tablet are brought into confidant contact with the dice wall.

The tablet must so be ejected from the dice, affecting the

motion of the side of the tablet relation to the dice wall.

Therefore, clash between the tablet and the dice wall

must be overcome. With stuffs such as lactose, clash

opposition can be considerable, and it may be impossible to

take the tablet from the dice without harm to the tablet

or to the tablet imperativeness. Therefore, a lubricator is about

constantly included in a tablet preparation. A lubricator is a

substance that deforms easy when sheared between two

surfaces, and therefore when interposed between the tablet

and the dice wall, provides a readily deformable movie (

The commixture procedure is

highly of import here, and blending clip, sociable type,

and batch size ( 16 ) have all been shown to act upon

tablet belongingss. Therefore, there is a demand to set up a

minimal lubricant concentration and an optimum

commixture clip within which equal lubrication is

achieved without the development of unwanted tablet

features. To guarantee batch-to-batch uniformity, the

parametric quantities of the blending procedure such as type of sociable,

batch size, and mixing clip must be kept as changeless

as possible. A mixing clip of 2-5 min normally suffices

to give equal lubrication