Granulation II Flashcards
Dr. Ologunagba
What are the three common methods of dry granulation?
- Direct compression
- Slugging: poor-flowing blends are compressed using a rotary tablet press fitted with a die much larger than the die used to make the final tablet to form “slugs”, which are typically 1 inch in diameter or larger. Little attention is paid to weight variation or compression properties. Slugs are passed through a mill, blended with other excipients and transferred to a tablet press or
capsule filling machine. - Roller compaction: Typically used with moisture-sensitive drug substances and formulations with poor flow characteristics. The material flows between two rollers that compact it. The rollers come in a variety of designs so the formulator can produce compacts of the correct hardness.
The compacts are subsequently milled, blended, and made into tablets or filled into capsules.
Roller compaction entails low labor costs and can be adapted for continuous production.
Dry Granulation is characterized by two types of irresistible attractive physical forces between particles. They are:
i. Electrostatic forces: they are generally weak but may cause cohesion when the material is mixed initially.
ii. Van der Waals forces: these are stronger than electrostatic forces and they increase as the inter-particulate distances decrease during the compression of powders
Mention 10 advanced methods of granulation.
i. Melt agglomeration / thermoplastic granulation
ii. Foam granulation
iii. Freeze granulation
iv. Moisture-activated dry granulation
v. Extrusion-spheronization granulation
vi. Fluidized bed granulation
vii. Spray drying granulation
viii. Steam granulation
ix. Thermal adhesion granulation
x. Pneumatic dry granulation
Explain melt agglomeration.
This technique involves the use of binders which melt or soften at relatively low temperature (50-90℃)
Solid fine particles are bound together into agglomerates by agitating, needing or layering the powder in the presence of a molten binder.
Once cooled, the binder solidifies, leaving granules
Describe the two methods of melt agglomeration.
i. Spray on method: involves spraying of the molten binder onto the powder cooling the product at room temperature, followed by milling to obtain dried granules.
ii. In situ method: employs a solid binder which is
heated above its melting point by hot air, when it is processed in fluidized bed processor
Highlight the advantages and disadvantages of melt agglomeration.
Advantages
i. Less time consuming and economical process.
ii. No requirement of any solvent either aqueous or non-aqueous.
iii. Uniform dispersion of fine particle.
iv. Release profile of drugs can be controlled and modified.
v. Suitable for enhancing dissolution profile and bioavailability of poorly water soluble drugs by forming solid dispersion.
Disadvantages
i. Not suitable for thermo-labile materials.
ii. There is need of high energy input.
iii. During handling and storage of agglomerates melting or softening of binder may occur.
Describe foam granulation.
Highlight its advantages.
This is similar to spray agglomeration, but it involves the addition of liquid or aqueous binder as foam instead of spraying or pouring liquid onto the powder bed.
Adding the binder solution as foam rather than a spray eliminates the issue of inconsistent and unpredictable binder distribution that can affect tablet hardness and drug release.
A foam generator is used in the binder solution tank with a high-shear granulator or fluid bed granulator to introduce the binder as foam.
Advantages
i. No need for a spray nozzle.
ii. Less water required
iii. Economical process
iv. Suitable for water-sensitive formulations.
Describe freeze granulation.
Highlight its advantages.
A suspension containing the granules is sprayed into liquid nitrogen such that he drops are instantly frozen into granules.The granules are then dried by freeze-drying. This results in spherical, free flowing granules, with optimal homogeneity.
Advantages
i. Granule density can be controlled by the solids content of the suspension.
ii. Cavities in the granules can be avoided.
iii. High yield, less wastage of material.
iv. Easy cleaning of equipment.
v. Organic solvents can be recycled.
Describe moisture-activated dry granulation.
This technique is a variation of conventional wet granulation. It is used in the granulation of moisture-sensitive APIs.
This process uses very little granulating fluid to activate granule formation and it also eliminates the drying steps by using moisture-absorbing materials like microcrystalline cellulose, potato starch, or a mixture of microcrystalline cellulose and potato starch (50:50) to remove excess moisture present in the granules. The moisture absorbents absorb the moisture from the agglomerates, resulting in moisture redistribution within the powder mixture, leading to relatively dry granule mixture.
It involves two major steps:
i. agglomeration
ii. Moisture distribution
Highlight the advantages and disadvantages of moisture-activated dry granulation.
Advantages
i. It utilises very little granulating fluid.
ii. It produces granules with more uniform particle size distribution (particle size range of 150–500 μm) and excellent flowability.
iii. It is economical and time efficient, as it requires less energy and eliminates drying step.
iv. It is suitable for continuous processing.
v. It is used for preparation of sustained release products.
vi. It is applicable to more than 90% of the granulation need for pharmaceutical, and food and nutritional industry.
Disadvantages
i. It is unsuitable for thermolabile, moisture sensitive and high moisture-absorbing substances.
ii. Formulations with high drug loading are difficult to develop.
Describe extrusion-spheronisation granulation. Highlight its advantages and disadvantages.
The powder materials are first mixed for homogenous dispersion. They then undergo wet granulation to form wet a mass, which is extruded to form rod-shaped particles. Then the rod-shaped particles are rounded off using a spheronizer. The resulting granules are dried.
Advantages
i. It is suitable for higher levels of active ingredients without production of larger particles.
ii. It is suitable for combination of two or more active agents within the same unit, in any ratio.
iii. It produces spherical particles with high bulk density, low hygrscopicity, narrow particle size distribution and smoother surface.
Disadvantages
i. It is time-consuming and requires more labour.
ii. It is not suitable for moisture-sensitive and thermolabile materials
Describe fluidized bed granulation.
The powder particles are fluidized by introducing air from the bottom of the granulator. A liquid binder solution is then sprayed onto the fluidized particles, causing them to adhere and form granules. The product is finally dried to the required end moisture content. Granulation in fluidized state can be achieved either by batch process or continuous process.
This fluidized bed processor contains air handling unit, product container, air distributor, spay
nozzle, process filters, exhaust blower/fan, control system, and solution delivery systems
Describe the spray drying granulation process and highlight its advantages.
A solution of the active agent along with excipient is fed into the drying system where the feed is atomized and dried with a heated gas stream, followed by separation of granular product from the gas stream to obtain dry granules.
This process differs from other methods in that it is a continuous process in which a dry granular product is made from a solution or a suspension rather than initially dried the primary powder particles.
The spray drying process involves three fundamental steps:
- Liquid feed’s atomization into fine droplets
- Mixing of droplets with a heated gas stream to evaporate the liquid.
- Separation of dried powder from the gas stream.
Advantages
i. It is a rapid and a continuous process
ii. It reduces overall cost by eliminating labor intensive drying and granulation steps.
iii. Less exposure to dust.
iv. Suitable for heat-sensitive materials
Describe steam granulation.
This process is simply a modification of the conventional wet granulation method. In this technique, water steam is used as a binder instead of a liquid.
Steam provides a higher diffusion rate into the powder and a more favorable thermal balance during the drying step.
After condensation of the steam, water forms a hot thin film on the powder particles, requiring only a small amount of extra energy for its elimination, so it evaporates more easily.
Highlight the advantages and disadvantages of steam granulation.
Advantages
i. It results in more spherical granule formation
ii. It has a higher diffusion rate
iii. It is environment friendly, safe for working operator.
iv. It maintains sterility
Disadvantages
i. There is need of special equipment for steam generation and transportation.
ii. Need of high energy inputs
iii. Not suitable for thermolabile materials
Describe thermal adhesion granulation and granulation and highlight its advantages.
This technique involves granulation of the powder blend by addition of very little amount of solvent.
In this process the blend is first moisturised by spraying water or ethanol, and then transferred into a pre-warmed glass bottle and sealed.
It is then heated properly by an infrared lamp to raise surface temperature of the vessel to 90ºC-105ºC (in case of water) or 70ºC-90ºC (in case of ethanol), and mixed under tumble rotation for 3-20 minutes until the granules are formed.
This method utilizes less water or solvent when compared to conventional wet granulation technique.
Describe pneumatic dry granulation and highlight its advantages.
This method involves production of granules from powder particles by applying mild compaction force by roller compactor to produce a compacted mass comprising a mixture of fine particles and granules.
The granules are then separated and the rejected fraction recycled theusing a fractionating device.
Granules pass through the fractioning chamber to be compressed into tablets.
Advantages
i. High drug loading is possible.
ii. Faster development (within weeks).
iii. Suitable for thermo-labile and moisture-sensitive drugs
iv. Improved stability with increased shelf-life.
v. Compatible with other technologies like coating, sustained release.
vi Produces soft and porous granules with improved flow property and compressibility.
vii. Taste masking can be achieved.
viii. Sterile products and toxic materials can be handled.
ix. Reduces cost of final product by minimizing waste through recycling
What are the effects of granule properties on tablets?
i. Granules prevent segregation of components in the powder blend
ii. It promotes content uniformity and compressibility
iii. Granule size affects the hardness of the tablet.
iv. Increase in granuke size causes an increase ub weight variation and a decrease in hardness and friability.
