The Development Of Pharmaceutical Drug Products Engineering Essay

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Powder granulation is a process of size enlargement Litster Ennis, 2004 Swarbrick Boylan, 2006 that incorporate the small particles to agglomerate together to make a larger particles in a way that the main components can still be detected (Ennis, 2005).

Generally, each tablet contains different types of ingredient but the active ingredients are more important one. During the combination of all components, it should be guaranteed that active ingredients are distributed equally in different portion. While sometimes during the blending or compression, the ingredients separate from each other; according to their difference in particle size, density, compressibility and flow characteristics. So to achieve a regular result the powders must flow constantly therefore particles should be granulated (D.Tousey, 2002)

The definition of granulation granulation contain

particle-size distribution and density to attain proper flow and

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

powders must flow consistently to attain consistent results.

The chief reasons to granulate powders for the

manufacture of pharmaceutical dosage forms are

described by Kristensen and Schaefer.[1]

. To improve powder flow properties for dosage filling

and compression processes.

. To eliminate wet granulation induced degradants and

to improve product stability.

. To prevent active product ingredient from segregating.

. To reduce bulk volume thereby minimizing storage

and enhancing transport.

. To reduce potential environmental and safety hazard (16,2806)

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

whereby small particles are agglomerated, compacted, or otherwise brought together

into larger, relatively permanent structures in which the original particles can still be

Distinguished . Granulation technology and size-enlargement processes have been

used by a wide range of industries, from the pharmaceutical industry to fertilizer

or detergent production to the mineral processing industries. Size enlargement generally

encompasses a variety of unit operations or processing techniques dedicated to

particle agglomeration. These processes can be loosely broken down into agitation

and compression methods.(10,31)

Powder granulation is a process of powder size

enlargement that incorporates small particles into larger

ones. The definition of granulation comprises a range of

different size enlargement methods that can be classified

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

used to agglomerate the small powder particles into a

mass. The wet mass is subsequently dried and sized for

further down-stream processing needs. Wet granulation

methods have been the most widely used powder

granulation technology in the production of pharmaceutical

products, particularly in modern pharmaceutical

manufacturing.

Traditionally, tablets have been made by granulation, a

process that imparts two primary requisites to formulations:

compactibility and fluidity. Both wet granulation

and dry granulation (slugging or roll compaction) are used

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

compression or granulation, the first steps, milling and

mixing, are the same; the subsequent steps differ.

The wet massing of powders is typically carried out in

high-shear mixers prior to wet screening. The wet

granules are often dried in fluidized-bed equipment,

enhancing the efficiency of the process. Alternatively, wet

granulation may be carried out in fluid-bed driergranulators

in which the liquid phase is sprayed onto

fluidized powders while the hot air flow dries the granules.

This process reduces the number of handling steps and the

time and space needed for granulation; it can be

automated(16,3165)

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Granulation

-Nonhomogeneous distribution of binder and drug

substance gives drug-rich or drug-poor fines

-Decomposition of drug substance due to residual

moisture

-Uneven granule size (too many or to few fines) leads

to compaction or uniformity problems

Naturally tablets only possess these advantages if they

are properly formulated and manufactured. A wellprepared

tablet should possess the following qualities:

1. It should, within permitted limits, contain the stated

dose of drug.

2. It should be sufficiently strong to withstand the stresses

of manufacture, transport, and handling so as to reach

the patient intact.

3. It should deliver its dose of drug at the site and at the

speed required.

4. Its size, taste, and appearance should not detract from

its acceptability by the patient.(16,3174)

The process of granulation is essentially

one of size enlargement, and it serves several purposes in

the tablet manufacturing process:

1. It improves flow by increasing particle size, since large

particles flow more readily than small ones.

2. It improves compression characteristics, adding to the

cohesive strength of the tablet.

3. Once a homogeneous mixture has been achieved,

segregation is prevented, since particles that are stuck

together cannot separate.

4. It reduces dust.

Both wet and dry granulation techniques are available

The first stage in the wet granulation process is often a dry

mixing stage in which the active component is mixed with

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

only a few milligrams or even less, yet a tablet that weighs

less than about 50 mg is difficult for the patient to handle

conveniently. It is therefore necessary to increase the bulk

of such a tablet with a diluent. Some commonly used

diluents are listed in Table 1.

The ideal diluent would be both chemically and

physiologically inert, and would not interfere with the

bioavailability of the active ingredient. It should also be

inexpensive and be easily tabletted since, if the proportion

of active ingredient is small, the overall tabletting

properties of the mixture are largely governed by those

of the diluent.

Lactose is by far the most frequently used diluent for

solid dosage forms. An inexpensive disaccharide obtained

as a by-product of the cheese industry. Probably the second most commonly used diluent in the

wet granulation process is dibasic calcium phosphate. This

substance is virtually insoluble in water and hence is

always used in conjunction with a disintegrating agent

The purpose of the mixing stage is to ensure that the

powder blend and hence the resulting tablets are

homogeneous in content. A random mixture is defined as

one where the probability of sampling a given type of

particle is proportional to the number of such particles in

the total mixture. Thus, the aim is to produce a mixture

such that when a sample is removed, the relative

proportions of the components of that sample are the

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

components can lead to segregation, a situation where

there is a large difference in sizes between components

may be beneficial. In such circumstances, small particles

of one component can become trapped in irregularities in

the surface of the larger component. These are not random

mixtures, as the particles of the two components cannot

behave independently. This concept is called "ordered

mixing" and it has found applicability in the manufacture

of solid dosage forms containing small quantities of highly

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

and Blending in this encyclopedia).

The underlying process of size enlargement in wet

granulation is achieved by either one or both of two

different mechanisms. Firstly, adjacent solid particles may

be stuck together using an adhesive. Such substances are

known as binders or granulating agents. Secondly,

dissolution of the solid in the granulating liquid can

occur, followed by evaporation of the liquid phase of the

latter. This will result in the deposition of dissolved

material on particle surfaces, forming so-called crystal

bridges. The occurrence of this mechanism will depend on

the solubility of the solids in the liquid phase.

The traditional piece of granulating apparatus is the

shear granulator. Its function is to homogeneously

incorporate an adhesive and viscous liquid such as starch

paste into a mass of dry powder to form agglomerates. It

follows that a considerable shearing force needs to be

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

mixer, and the liquid added with agitation. The damp solid

is then forced through a relatively coarse screen (about

1-2 mm), often by means of oscillating bars, to give discrete granules.

the wet granulation process is a

long and hence expensive procedure, which has been

improved by the introduction of high-speed mixer

granulators. These have agitator and chopping blades,

which enable mixing, wet massing, and granulation to take

place in the same piece of apparatus. In such devices, the

granulation process takes place extremely rapidly.

A further technique is fluid-bed granulation. Air is

passed into the powder bed from below. This causes the

particle, of powder to form a suspension in the air and

gives effective mixing. The granulating fluid is then

sprayed over the particles, which adhere on collision and

they are then dried in the heated air stream.

The wet granulation process, apparatus, and pharmaceutical

applications have been comprehensively reviewed

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

Granulation in this encyclopedia).

After the process of granulation, the product exists as a wet

mass from which the liquid must be removed, since the

presence of water leads to the impairment of flow properties,

and perhaps to chemical instability

The fluidized bed drier is the most commonly 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 neighbors. The air provides an

effective means of heat transfer, as well as of removing

water vapor. The speed of the drying process is governed

by the distance that water molecules must diffuse before

they arrive at the evaporative surface. Since the wet

granules are present as individual units, the maximum

distance over which diffusion occurs is equal to the radius

of a granule. Hence, fluidized bed drying is a rapid process. The temperature of the bed can be precisely controlled, and a free-flowing product results.

Second mixing stage

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

product will have cohered into relatively large masses,

especially if tray drying has been used. The dried material

is therefore passed through a sieve (usually 250-700 mm)

to break up aggregates and to give a relatively uniformly

sized granule. A second mixing stage now follows in which

several important ingredients of the formulation are added

The lubricant

When the tablet formulation is compressed, the sides of the

tablet are brought into intimate contact with the die wall.

The tablet must then be ejected from the die, involving the

movement of the side of the tablet relative to the die wall.

Therefore, friction between the tablet and the die wall

must be overcome. With materials such as lactose, friction

resistance can be considerable, and it may be impossible to

remove the tablet from the die without damage to the tablet

or to the tablet press. Therefore, a lubricant is almost

invariably included in a tablet formulation. A lubricant is a

substance that deforms easily when sheared between two

surfaces, and hence when interposed between the tablet

and the die wall, provides a readily deformable film (

The mixing process is

extremely important here, and mixing time, mixer type,

and batch size (16) have all been shown to influence

tablet properties. Thus, there is a need to establish a

minimum lubricant concentration and an optimum

mixing time within which adequate lubrication is

achieved without the development of undesirable tablet

characteristics. To ensure batch-to-batch uniformity, the

parameters of the mixing process such as type of mixer,

batch size, and mixing time must be kept as constant

as possible. A mixing time of 2-5 min usually suffices

to give adequate lubrication

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