tablet preparation
TRANSCRIPT
Tablet Preparation
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Drug + excipients
Granulation
Compression
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Methods of formulating tablets
Direct compression Dry granulation (slugging) Wet granulation
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DIRECT COMPRESSION
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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
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Economic
No moisture or heat needed
Moisture free process – fewer instabilities
Less processing steps – less variation
Dry procedure
Disintegration can be optimised
Less variation in dissolution profile over time
Adva
ntag
es
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Not all material can be compressed directly
Materials have weak intermolecular bonds
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
Prob
lem
s
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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
Prob
lem
s (c
ontd
)
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Sr. no. Method Advantages and limitations Examples
1 Chemical modification
Relatively expensiveRequires toxicology dataTime consuming
HPMC, EC – from celluloseCyclodextrin from startch
2 Physical modification
SimpleEconomical
SorbitolDextrates
3 Grinding and/or sieving
Compressibility maybe altered due to change in surface area and surface activation
DCP
4 Crystallisation Imparts flowability but not bindingRequires stringent control on conversion of polymorphic forms and processing conditions
β-lactose
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Sr. no. Method Advantages and limitations Examples
5 Spray drying Spherical shapeUniform sizeGood flowabilityPoor re-workability
Spray dried lactose (DCL)
6 Granulation/ agglomeration
Transformation of small, cohesive, poorly flowable powders into flowable and DC form
Granulated lactitol, Tablettose
7 Dehydration Increased binding properties by thermal and chemical dehydraion
Anhydrous α-lactose
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Examples of directly compressible excipientsS.No Name Trade name
1 Cellulose and cellulose derivatives Avicel, Emcocel , Vivacel
2 Inorganic materials
Calcium phosphate, dibasic dihydrate Calstar, Dicafos, Emcompress, Di-Tab
Calcium sulphate Compactrol
3 Polyols
Xylitol Xylitab
Mannitol Pearlitol
Sorbitol Neosorb
4 Starch and starch derivatives
Starch, pregelatinized Starch 1500, Starx 1500
5 Sugars
Compressible sugar Destab, Dipac, Nutab
Lactose Tablettose, Pharmatose DCL, Fast-Flo, Zeparox
6 Mixtures and co-processed products
Calcium sulphate–MCC Cel-O-Cal
Lactose–povidone 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 granulateImprove 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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Ideal properties
Controlled size
distribution
Large surface
area
Specific bulk
densityStructural stability
Physical strength
Good flow
Content uniformity
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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 , ≤ 150μm 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 30–70 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
Final compression to form tablets
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Methods
Tablet press
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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AdvantagesMoisture 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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Chils
onat
or
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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. Powdered material is fed between the rollers by screw conveyor system
3. Horizontal screw picks up material from the vertical feed screw and
provides a continuous delivery of powder to compaction rollers
4. A fixed pressure can be applied with a hydraulic ram forcing one roller
against other
5. After passing through the rollers a compacted ribbon like mass is
obtained
6. 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
3. Smooth or sign curved and serrated
4. Shapes and sizes of screw feed assembly
5. 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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High dose drugs with poor flow and/or poor compactibility can be granulated to obtain suitable flow and cohesion for compaction
• resulting in improvements in tooling life and decreased machine wear
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
Advantages
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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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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
Limitations
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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
Granulation
Wet screening Drying
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
• Test for complete granulation
– Press a small mass of powder blend within palms
• Crumbles under moderate pressure
Overly wet material dries slowly
Gives hard granulesBreaks during
subsequent sizing
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Wet Screening
• Coarse sieves
Wet Mass
• Hammer mill or oscillating
granular
aggregates
• Finer granulesSieves
Purpose:
1. To further consolidate particles2. To increase particle contact3. 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