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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1.2
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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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Date
5.1
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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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