Guidelines* |
Solid Orals
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Blending of lubricant
Compression
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WET GRANULATION
DRY GRANULATION
DIRECT COMPRESSION
Improved flow by increasing particle size and sphericity Uniform
distribution of API, colour etc. – improved content uniformity Good
for bulky powders, less dust and environmental contamination Lower
compression pressure, less wear and tear on tooling
Improved flow by increasing particle size Improved uniformity of
powder density Improved cohesion during compression Granulation
without addition of liquid
Fewer processing steps – blending and compression -reduced
processing time Processing without moisture and heat – fewer
stability problems Rapid and most direct method of tablet
compression Changes in dissolution less likely on ageing since
there are less formulation variables
Satish Mallya January 20-22, 2010
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WET GRANULATION
DRY GRANULATION
DIRECT COMPRESSION
Large number of processing steps More equipment Wetting and drying
stages are time consuming Greater possibility of cross
contamination
Possible over compaction of slugs/compacts – impact on dissolution
Possible particle segregation
Possibility of lot to lot variations due to differences in psd,
flowability and moisture of excipients Higher risk of content
uniformity failure in low dose products (geometric granulation
indicated) Lack of moisture can create static charges that can
result in un-blending Differences in particle size/density between
API and excipient can result in un-blending in hopper
Satish Mallya January 20-22, 2010
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One of the most critical steps in pharmaceutical
manufacturing
manual weighing on a weight scale with material lifting assistance
like vacuum transfer and bag lifters
automated weighing
weighing accuracy
multiple lots of active ingredient with different assays, moisture
and residual solvent content
cross contamination
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Considerations
Theoretical quantity of API [100% assay (anhydrous) and nil water]
= 30 Kg
January 19-22, 2011
January 18-21, 2012
Actual Assay (%) (B)
Water content (% w/w) (C)
Equivalent quantity on 100% assay and nil water basis (Kg)
(D)
Equivalent quantity on as is basis (Kg) (E)
1
AP-18
23.50
99.4
0.34
23.28
23.50
2
AP-22
60.00
99.1
0.50
6.72
6.815
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Milling/Screening
Principle: Mixing or blending is more uniform if ingredients are of
similar size
January 18-21, 2012
Why do it
What are the equipment
What are the problems
Increased surface area - may enhance rate of dissolution Improved
content uniformity due to increased number of particles per unit
weight Enhanced flow properties of raw materials Uniformly sized
wet granules promotes uniform drying
Fluid energy mill Comil Ball mill Hammer mill Cutting mill
etc.
Possible change in polymorphic form An increase in surface area may
promote the adsorption of air - may inhibit wetting of the drug –
could be the limiting factor in dissolution rate
World Health Organization
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Date
1.1
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Blending
Blending is the most difficult operation in the manufacturing
process since perfect homogeneity is practically impossible due to
differences in size, shape and density of particles
January 18-21, 2012
Why do it
What are the equipment
What are the problems
To achieve optimum mixing of different ingredients in
powder/granules at pre granulation and/or post granulation stages
of tablet manufacturing
Diffusion Mixers (V,double cone, bin,drum blenders) Convection
Mixers (ribbon, planetary blenders) Pneumatic Mixers
Segregation Possible over mixing of lubricant Blend uniformity/
Content uniformity
Satish Mallya January 20-22, 2010
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Principle: A size enlargement process that converts small particles
into physically stronger & larger agglomerates
January 18-21, 2012
Why do it
Dry Granulator (roller compactor, tabletting machine) Wet
High-Shear Granulator (horizontal, vertical) Wet Low-Shear
Granulator (planetary, kneading, screw) Fluid Bed Granulator, Spray
Dry Granulator, RMG
Loss of material during various stages of processing Multiple
processing steps - validation and control difficult Incompatibility
between formulation components is aggravated
Satish Mallya January 20-22, 2010
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January 19-22, 2011
January 18-21, 2012
Date
2.1
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2.2
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Date
3.1
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Recent Advances in Granulation Techniques
Steam Granulation: Modification of wet granulation; steam is used
as a binder instead of water; granules are more spherical and
exhibit higher rate of dissolution
Melt Granulation / Thermoplastic Granulation: Granulation is
achieved by the addition of meltable binder i.e. binder is in solid
state at room temperature but melts in the temperature range of 50
– 80C [e.g. PEG (water soluble), stearic acid, cetyl or stearyl
alcohol (water insoluble)] - drying phase unnecessary since dried
granules are obtained by cooling them to room temperature
Moisture Activated Dry Granulation (MADG): Involves distribution of
moisture to induce agglomeration – drying time is reduced
January 18-21, 2012
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Recent Advances in Granulation Techniques
Moist Granulation Technique (MGT): A small amount of granulating
fluid is added to activate dry binder and to facilitate
agglomeration. Then a moisture absorbing material like
Microcrystalline Cellulose (MCC) is added to absorb any excess
moisture making drying step unnecessary. Mainly employed for
controlled release formulations
Thermal Adhesion Granulation Process (TAGP): Granules are prepared
by moisturizing excipient mixtures with very little solvent in a
closed system (tumble mixing) with low heating – mainly employed
for preparing direct compression formulations
Foam Granulation: Binders are added as aqueous foam
January 18-21, 2012
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January 18-21, 2012
Why do it
What are the equipment
What are the problems
To keep the residual moisture low enough (preferably as a range) to
prevent product deterioration Ensure free flowing properties
Direct Heating Static Solids Bed Dryers Direct Heating Moving
Solids Bed Dryers Fluid Bed Dryer Indirect Conduction Dryers
Over drying (bone dry) Excess fines Possible fire hazard
Satish Mallya January 20-22, 2010
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January 18-21, 2012
Date
3.2
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January 19-22, 2011
January 18-21, 2012
Date
4.1
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4.2
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Date
5.1
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5.2
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Compression
Principle: Powder/granules are pressed inside a die and compressed
by two punches into required size, shape and embossing
January 18-21, 2012
Why do it
Multiple Stations (Rotary) and High Speed Tablet Presses
Poor flow in hopper Inadequate lubrication Capping, chipping,
cracking, lamination, sticking, picking, binding, mottling Double
compression
Satish Mallya January 20-22, 2010
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Hardness tester no.: Friability tester no.:
Disintegration tester no.:
January 19-22, 2011
January 18-21, 2012
55
55
1
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4.10mm +0.15mm (3.95 – 4.25mm)
Width
Disintegration time
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Every hour by production and every two hours by QA
Hardness, thickness, length, width
Wt. variation
Every half hour by production and every hour by QA
DT
Satish Mallya January 20-22, 2010
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Coating/Polishing
Principle: Application of coating solution to a moving bed of
tablets with concurrent use of heated air to facilitate evaporation
of solvent
January 18-21, 2012
Why do it
Enhance appearance and colour Mask taste and odour (film/sugar)
Improve patient compliance Improve stability Impart enteric,
delayed, controlled release properties
Pan (standard/perforated) Coating Machines Fluidized Bed Coating
Machines Spray Coating Machines Vacuum, Dip & Electrostatic
Coating Machines
Blistering, chipping, cratering, picking, pitting Color variation
Roughness
Satish Mallya January 20-22, 2010
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Date
6.1
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