Tablet Preparation

Drug + excipients

Granulation

Compression
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Methods of formulating tablets

Direct compression

Dry granulation (slugging)

Wet granulation

DIRECT COMPRESSION

It is a simple procedure
As a result of: 1. Availability of new excipients

2. New forms of old excipients, particularly fillers and binders,

3. Invention of new (or the modification of old) tablet machinery

Economic

No moisture or heat needed

Advantages

Moisture free process fewer instabilities

Less processing steps less variation

Dry procedure

Disintegration can be optimised

Less variation in dissolution profile over time

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Not all material can be compressed directly

Materials have weak intermolecular bonds

Problems

Materials have adsorbed gases on surface

Content uniformity with low dose drugs

Not suitable for high doses

Specialty DC excipients needed

DC tablet diluents are considerably more expensive

Problems (contd)

Reworking is difficult DC excipients lose their structure

Difference in particle size and densities stratification

Static charges may build up non uniformity of blend

Mottling

Lubrication is difficult as powders tend to separate

Sr. no. 1

Method Chemical modification

Advantages and limitations Relatively expensive Requires toxicology data Time consuming

Examples HPMC, EC from cellulose Cyclodextrin from startch Sorbitol Dextrates DCP

2 3

Physical modification Grinding and/or sieving

Simple Economical Compressibility maybe altered due to change in surface area and surface activation Imparts flowability but not binding Requires stringent control on conversion of polymorphic forms and processing conditions

Crystallisation

-lactose

Sr. no.

Method

Advantages and limitations

Examples

Spray drying

Spherical shape Uniform size Good flowability Poor re-workability

Transformation of small, cohesive, poorly flowable powders into flowable and DC form Increased binding properties by thermal and chemical dehydraion

Spray dried lactose (DCL)

Granulation/ agglomeration

Granulated lactitol, Tablettose

Dehydration

Anhydrous lactose

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Examples of directly compressible excipients

S.No
1 2

Name
Cellulose and cellulose derivatives Inorganic materials Calcium phosphate, dibasic dihydrate Calcium sulphate

Trade name
Avicel, Emcocel , Vivacel Calstar, Dicafos, Emcompress, Di-Tab Compactrol Xylitab Pearlitol

Polyols Xylitol Mannitol

Sorbitol
4 5 Starch and starch derivatives Starch, pregelatinized Sugars

Neosorb
Starch 1500, Starx 1500

Compressible sugar
Lactose 6 Mixtures and co-processed products Calcium sulphateMCC Lactosepovidone

Destab, Dipac, Nutab

Tablettose, Pharmatose DCL, Fast-Flo, Zeparox Cel-O-Cal Ludipress
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Granulation

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Introduction
Granulation may be defined as a size enlargement process which converts small particles into physically stronger & larger agglomerates.

Dry granulation

Wet granulation
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Reasons to granulate
Improve flow Improve density

Improve content uniformity

Improve compression characteristics Control the rate of drug release

Facilitate dispensing
Decrease dust generation Decreased employee exposure to drug

Improve appearance of tablets

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Controlled size distribution Content uniformity Large surface area

Ideal properties
Good flow

Specific bulk density

Physical strength

Structural stability
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1.

Particle size of granules affects average tablet weight, weight

variation, disintegration time, granule friability, flowability and drying time.

2.

Surface area of granules is important because it can affect the

solubility of poorly soluble compounds

3.

Granule density affects the compactibility, tablet porosity &

dissolution.
Dense hard granules: Require higher compression loads

Make hard, difficult to dissolve tablets; and

Wear and tear of punches
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4.

Strength and friability of granules is important as they affect the

changes in particle size distribution, of granulations and consequently compressibility into tablets.
Granules can break into smaller particles during various stressful
conditions of tablet manufacturing

5.

Particles of size , 150m show poor flow due to increased area

of contact between particles and due to development of electrostatic surface charges.

Bigger particles also show poor flow due to irregular shape, friction and surface tension
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Factors affecting granulation

Particle size of drug and excipients Type of binder (strong or weak) Volume of binder (less or more) Wet massing time (less or more) Amount of shear applied to distribute drug, binder and moisture. Drying rate ( Hydrate formation and polymorphism)
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Problems encountered due to poor flow

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DRY GRANULATION

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Introduction
Components of powder are aggregated under high pressure, typically a pressure of 3070 bar Bonding forces develop at high pressure By direct contact between the solid surfaces High pressure serves to improve contact area between surfaces Sometimes a binding agent is needed to provide additional bonding

strength
However, it is not the first choice of granulation
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Compression of tablet components to form compacts Milling of compact to obtain granules

Final compression to form tablets

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Tablet press Methods Roller compactor (Chilsonator)

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Slugging
Powder mixture is forced into large capacity die cavities of tablet press or specially designed machinery Powder blend is compacted using flat faced punches

Compacted masses are called slugs

The process is called slugging Slugs are approximately 1 inch in diameter Slugs are sometimes screened and slugged again and screened once more
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 Slugging is roughly equivalent to extended dwell

time during compression in a tablet machine If the screened slugs are slugged again, it strengthens the bonds that hold the tablet together

The resultant granules have better flow

properties

This technology is not used anymore and roller

compaction is preferred
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Advantages
Moisture sensitive drugs Heat sensitive drugs Better disintegration Less equipment and space Bypasses time consuming drying step Minimal energy to operate

Improves process cycle time

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Uses less raw material Prevents particle segregation Does not require explosion proof room/ equipment Facilitates continuous manufacturing

Reproduces consistent particle density

Reduces need for excessive lubrication

The process can be easily scaled up

High production rates upto 500kg/hr
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Disadvantages
Excessive air and sound pollution

Frequent maintenance changeover

Increased use of storage containers It does not permit uniform colour distribution Increased needs of manufacturing space Process tends to create more dust increasing potential contamination

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Chilsonator

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Principle of roller compaction

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Working of roller compactor

The basic concept of compaction is to force fine powders between two counter rotating rolls. Compression: Stress from the rollers compresses the powder mass into compacts, Miling: Compacts are milled to form small granules Screening: The granules are screened to select desired size range Recycle System - In order to eliminate fines; Overs a recycle system is installed.
This provides control of final particle size distribution and density
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Principle of roller compactor

1. Two rollers that revolve towards each other

2.
3. 4.

Powdered material is fed between the rollers by screw conveyor

system Horizontal screw picks up material from the vertical feed screw and

provides a continuous delivery of powder to compaction rollers

A fixed pressure can be applied with a hydraulic ram forcing one roller against other

5.
6.

After passing through the rollers a compacted ribbon like mass is

obtained This ribbon like mass is milled and screened
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Variables of roller compactor

1. The hydraulic pressure exerted on the rolls 2. The rotational speed of the compression rollers 3. Rotational speed of feed screw

These parameters are set for each operation

Any variation in the above parameters leads to changes in density and hardness of the compact.
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Modifications of roller compactor

Rollers are available in variable designs for

1. Increased production capacity

2. Greater control of compaction pressure and dwell time

Available designs 1. Smooth or sign curved and serrated

2. Shapes and sizes of screw feed assembly

3. Liquid cooled rolls and chambers
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WET GRANULATION

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Introduction
Most widely used process of agglomeration 1. Involves wet massing of the powder blend

with a granulating liquid,

2. Wet sizing
3. Drying In wet granulation, bonding properties of liquid binders available is usually sufficient to produce bonding with a minimum of additives
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Advantages
High dose drugs with poor flow and/or poor compactibility can be granulated to obtain suitable flow and cohesion for compaction Content uniformity in tablets can be increased for low dose drugs Cohesiveness and compressibility of powders is improved due to the added binder Lower pressures are needed to compress tablets
resulting in improvements in tooling life and decreased machine wear
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Wide variety of powders can be processed together in a single batch

Bulky and dusty powders can be handled without producing a great deal of dust and airborne contamination
Composition of each granule is fixed and remains same as that of the powder mixture at the time of wetting Dissolution rate of an insoluble drug may be improved by wet granulation with proper choice of solvent and binder Controlled release dosage forms can be accomplished by the selection of a suitable binder and solvent
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Limitations
i) 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) Any incompatibility between formulation components is aggravated

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vi) Requires a large area with temperature and humidity control

vii) Greater possibility of cross-contamination than with the direct-compression method viii) Material transfer problems involving processing of sticky masses

ix) Use of volatile and inflammable solvents for granulations causes fire hazard
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Safety precautions
1. Work area should be large and well ventilated to maintain solvent vapour concentration below explosion level

2. All equipments should be electrically grounded

3. Explosion proof or explosion resistant motors should be used 4. Facility should be regularly inspected by safety engineers

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5. Exhausting of solvent vapour into atmosphere should be in accordance with EPA regulatory requirements

Recovery and burning up of solvent vapour

6. Ovens and other drying equipment should have

high air flows appropriate controls to prevent explosion due to accumulated vapour
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Steps in wet granulation

Sieving and Weighing Dry mixing Preparation of binder

Drying

Wet screening

Granulation

Dry screening

Lubrication

Compression

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Stages in wet granulation

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Granulation time
Granulation time varies from 15 min 1 hour

Depends upon
Wetability of the powder mix - Surface Tension Ability of granulation fluid to penetrate into the powder mix to form a wet mass Capillary action Efficiency of the mixer
Overly wet material dries slowly Gives hard granules Breaks during subsequent sizing

Test for complete granulation

Press a small mass of powder blend within palms Crumbles under moderate pressure
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Wet Screening
Wet Mass

Coarse sieves

granular aggrega tes

Hammer mill or oscillating

Sieves

Finer granules

Purpose: 1. To further consolidate particles 2. To increase particle contact 3. To increase surface area for drying
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Drying and screening

1. Drying is essential in all wet granulation process Removes solvent Reduced it to required level Strengthening of inter-particulate bonds By fusion or crystallization of solvent bridges Curing of bonding agent

2. Screening is performed to select granules of optimum size for

compression into tablets
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A comparative processing chart of different granulation techniques

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