Granulation and theories of granulation Flashcards
What is granulation?
Granulation is a pharmaceutical technology unit operation or process which involves the size enlargement of fine or coarse particles wherein primary powder particles are made to adhere to form physically stronger, larger, multi-
particulate entities or agglomerates called granules using granulating fluid(binder) or by compression.
Bonds between the primary particles are formed by?
compression, or by using a
binding agent.
Granule sizes range from?
0.2 and 0.5 mm
Give 5 advantages of granulation
- It helps prevent the separation or segregation of the primary ingredients in the powder mixture as well as
improves the flow of the properties of the mixture. - Granulation leads to larger more homogenous particles with better flow characteristics, improving the
tablet making process. - Compacted granules occupy less volume/unit weight compared with powder and is easier to store and ship.
- It improves the compression of the materials
- It improves the appearance of the product
- The granulation process can modify or improve the drug release profile.
Granulation techniques are classified based on?
The type of binder and process used.
Common granulation
techniques include?
Wet granulation, dry granulation, and hot melt granulation.
Explain wet granulation
In wet granulation, a liquid, generally a binder solution, is added to facilitate wetting and agglomeration of a
powder blend (Kristensen & Schaefer, 1987). The wet mass subsequently is dried and screened to obtain
granules with desired size.
Explain dry granulation
Dry granulation involves granulation using dry binders without the aid of any liquid and is particularly useful
for drugs that are sensitive to moisture or heat and, therefore, cannot be processed using wet granulation. In
this technique, powder particles are agglomerated under high pressure either by using the process of slugging
or roller compaction. The slugs or compacts then are milled to the desired size range granules
What is hot melt granulation?
Hot melt granulation is used as an alternate to wet granulation and employs binders that facilitate granulation
in their molten form (Passerini, Calogera, Albertini, & Rodriguez, 2010). After granules are formed, they are
cooled and screened to achieve proper size. The process is carried out in a high-shear granulator fitted with
heating device or using the relatively new technique of hot melt extrusion.
What are the advantages of wet granulation?
- More uniform mixing is achieved than dry
granulation - More binding is achieved with less quantity of
binder - Has better content uniformity
- Is suitable for very low to very high drug content
- Reduces sticking of blend to compression tooling
Advantages of dry granulation
- Suitable for moisture and temperature sensitive APIs
- Suitable for low to high drug contents
- Time and cost effective, as unit operation of drying
not involved - High force is involved in compaction
Give advantages of hot melt granulation
- Intimate mixing sometimes up to molecular
level, can produce solid dispersions and lead
to improvement in solubility and
bioavailability - It is time and cost effective, unit operation of
drying not involved
What are disadvantages of wet granulation?
- Not favourable for moisture sensitive products
- Time consuming due to involvement of additional
unit operation of drying
What are the disadvantages of dry granulation
- Results in greater chances of generation of dust and
environmental contamination - High force is involved in compaction
What are disadvantages of hot melt granulation
- It is not suitable for thermo-labile drugs
- It is a non-traditional process that requires
greater effort in polymer screening and
training on instrument - Binders with low melting points, which can
soften during storage and handling are
utilized
Bonds between particles can be created either by or what?
By the presence of
appropriate liquid (binder) or forces due to application of pressure
Agglomerated granules are formed by
solid bridges, sintering, chemical
reaction, crystallization and deposition of colloidal particles
What are the five recognized bonds that form between particles
- Adhesive and cohesive forces in the immobile liquid between particles
- Interfacial forces in mobile liquid films within granules
- Formation of a solid bridge after subsequent solvent evaporation – the main mechanism
in dry granulation - Attractive forces between solid particles – presence of liquid not required
- Mechanical interlocking of particles often between fibrous or flat particles
What is the first and most important phase in granule formation.
Wetting and Nucleation
Wetting and nucleation involves?
It involves the initial wetting of powder bed and existing granules by the
granulating fluid to form nuclei.
Wetting and Nucleation is largely influenced by
spray rate, fluid distribution, feed formulation properties,
The nucleation process is?
the initial coalescence of primary particles in the
immediate vicinity of the larger wetting drop
What is involved in the coalescence or ball growth stage
Partially wetted primary particles and
larger nuclei come together to form granules composed of several particles. Further collision (coalescence) of two granules could occur to form a new
and larger granule.
The extent of the consolidation depends on?
The agitation in the granulation
equipment and the resistance of the granules to deformation.
What happens in the Consolidation stage?
As granules increase in size, they are consolidated by compaction forces due
to bed agitation.
The consolidation phase in granule formation controls?
Internal granule porosity, and
therefore final properties of the granules e.g., granule strength, hardness, or
dissolution.
What are the Steps involved in the wet granulation
Mixing of the drugs and excipients
Preparation of binder solution
Mixing of binder solution with powder mixture to form wet mass.
Coarse screening of wet mass using a suitable sieve (6-12 screens)
In wet granulation, Granules are formed by the addition of ______________ onto a _________
which is under the influence of _____
a granulation liquid (usually an aqueous solution), powder bed, an impeller(in a high-shear granulator), screws (in a twin screw granulator) or
air (in a fluidized bed granulator).
Name three types of granulators
a high-shear granulator, a twin screw granulator, or a fluidized bed granulator
What produces bonding between the primary powder
particles to produce wet granules.
Agitation of the particles along with the added liquid
Give three examples of volatile liquids added in wet granulation
water, ethanol or isopropanol
Organic solvents are safer to use than aqueous liquids. T or F?
False. aqueous liquids are safer to use than organic solvents.
Why are Aqueous binder solutions are preferred to aqueous solutions alone
because of better binder capacity
Give exaples of aqueous binder solutions
polyvinyl pyrollidone (PVP), starch mucilage
tragacanth, acacia
In wet granulation the added liquid to the powder system causes what?
a thin and immobile film of
liquid to form between particles.
a thin and immobile film of
liquid forming between particles causes what?
an effective decrease in inter-particulate distance and an increase in contact area
between particles.
The shortening of the inter-particulate distance causes what?
increases the Van der Waals forces of attraction.
More liquid is usually added in wet granulation to form what?
a mobile liquid film.
The three states that can describe the distribution of liquid between particles are:
Pendular state
Funicular state –
Capillary state
what is the Pendular state
this usually occurs at low moisture level, this is when the particles are held
together by lens-shaped rings of liquid, but it is mainly air between the particles.
what is the Funicular state –
this is an intermediary state where air starts to displace from between particles
what is the Capillary state
this is when all air has been displaced from between the particles.
What happens In the capillary state,
liquid penetrate the pores of the particles to form solid bridges
between particles, giving the strongest form of adhesion, when the liquid evaporates.
Nucleation of granules in wet granulation starts with?
a number of particles joining
together in the pendular state.
What happens if agitation is continued too far?
the granules will coalesce to form unusable over-massed
spheres of material.
What affects the
required mixing time, as well as the type of mixer.
The amount of liquid added and the nature of the starting materials
High shear mixers often require less liquid than low–shear mixers. True or false?
True
High impeller
rotation speeds can cause what?
local heating of the mixture and loss of solvent by evaporation
What are The primary advantages of dry granulation?
- its simplicity and low cost.
- The powder mixture is compressed without the use of heat and solvent.
There are three common methods of dry granulation. They are?
Direct compression
Slugging
Roller compaction
What is Direct compression:
This method simply combines the drug-substance powder with the excipient
powders in a blender.
The blend is then directly compressed to a tablet or filled into a capsule
what is Slugging.
In this method, 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.”
Slugs are typically 1 inch in diameter or larger, and there is little attention 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.
what is 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.
What are the advantages of roller compaction?
In addition to its ability to process poor-flowing and moisture-sensitive materials, roller
compaction entails low labor costs and can be adapted for continuous production
What are the characteristics of dry granulation?
It is characterized by granule formation without using liquid solution.
Therefore, it requires compacting and densifying the powders.
Used for materials sensitive to heat and moisture
In this process the primary powder particles are aggregated under high
pressure.
Dry Granulation is characterized by two types of irresistible attractive physical forces between particles :
Electrostatic forces – there are generally weak but may cause cohesion when the material is mixed initially.
Van der Waals forces – these are stronger than electrostatic forces and they increase as the inter-particulate
distances decrease during the compression of powders.
The pressure applied in dry granulation increases and decreases what?
The pressure applied in dry granulation increases the contact area between the adsorption layers of particles
and decreases the inter-particulate distances, thereby contributing to the final strength of the material.
What will cause the particles will bind together and crystallization may take place in dry granulation?
The pressure applied may also melt low melting-point materials where the particles touch and high pressures
are developed. When this happens the particles will bind together and crystallization may take place when the pressure is
relieved.
List the ADVANCED GRANULATION
TECHNIQUES
Melt Agglomeration/ Thermoplastic Granulation
Foam Granulation
Freeze Granulation Technology
Moisture Activated Dry Granulation
Extrusion-Spheronization Granulation
Fluidized Bed Granulation
Spray Drying Granulation
Steam Granulation
Thermal Adhesion Granulation
Pneumatic Dry Granulation
Explain the process of Melt Agglomeration/ Thermoplastic Granulation
This technique consists of the agglomeration of powder particles using binders that,
which melts or softens at relatively low temperature (50–90°C).
Solid fine particles are bound together into agglomerates by agitation, kneading, and
layering in the presence of molten binding liquid.
After cooling of the agglomerated powder and the consequent solidification of the
molten or soften binder complete the formation of the granules.
Melt Agglomeration/ Thermoplastic Granulation utilizes two methods which are?
- spray on method that involves spraying of the molten
binder onto the powder and by simple cooling of the product at room temperature
followed by milling to obtain dried granules. - In situ melt granulation method that employs a solid binder which is
heated above its melting point by hot air, when it is processed in fluidized bed
processor.
List the advantages of Melt Agglomeration/ Thermoplastic Granulation
Less time consuming and economical process.
No requirement of any solvent either aqueous or non-aqueous.
Uniform dispersion of fine particle.
Release profile of drugs can be controlled and modified.
Suitable for enhancing dissolution profile and bioavailability of poorly water soluble
drugs by forming solid dispersion.
Improved product stability.
List the disadvantage of Melt Agglomeration/ Thermoplastic Granulation
Not suitable for thermo-labile materials.
There is need of high energy input.
During handling and storage of agglomerates melting or softening of binder may occur.
Explain the process of Foam Granulation
This technique is analogous to spray agglomeration; it involves the addition of liquid/ aqueous
binder as foam instead of spraying or pouring liquid onto the powder particles.
Adding the binder solution as foam rather than a spray eliminates the problems 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 high-shear granulator or fluid bed
granulator to introduce the binder as foam rather than spraying or pouring in binder onto the
moving powder particles.
List the advantages of Foam Granulation
No need of spray nozzle.
Less water required
Economical process
Suitable for water sensitive formulations.
Explain the process of Freeze Granulation Technology
This technique enables preservation of the homogeneity from suspension to dry granules.
The powder suspension are sprayed into liquid nitrogen such that the drops are instantly
frozen into granules, and by freeze drying process, the granules are dried by sublimation of ice
without any segregation effects.
This results into spherical, free flowing granules, with optimal homogeneity.
List the advantages of Freeze Granulation Technology
Advantages
Granule density can be controlled by the solids content of the suspension.
Cavities in the granules can be avoided.
High yield, less wastage of material.
Easy cleaning of equipment.
Organic solvents can be recycled.
Explain the process of Moisture Activated Dry Granulation
This technique is a variation of conventional wet granulation technique. This technology is
widely used in granulation of moisture sensitive active pharmaceutical ingredients.
This process involves the utilization of 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, a mixture of MCC and potato starch (50% w/w to
remove excess of moisture present in the granulate.
The moisture absorbents absorb the moisture from the agglomerates, resulting in moisture
redistribution within the powder mixture, leading to relatively dry granule mixture.
The process of Moisture Activated Dry Granulation is accomplished by what two major steps
agglomeration and moisture distribution.
List the advantages of Moisture Activated Dry Granulation
A simple, clean, lean process that utilizes very little granulating fluid.
Produce granules with more uniform particle size distribution (particle size range of 150–500
μm) and excellent flowability.
Economical and time efficient, as requires less energy and eliminates drying step.
Suitable for continuous processing.
Used for preparation of floating and sustained release products.
Applicable to more than 90% of the granulation need for pharmaceutical, food and Nutritional
industry.
Explain the process of Extrusion-Spheronization Granulation
This technique involve in production of granules or pellets of uniform size with high drug
loading capacity.
It consists of multiple steps of wet mass extrusion followed by spheronization to produce
uniform sized spherical particles with narrow size distribution.
It is mainly used in multi particulates for oral controlled drug delivery system.
List the disadvantage of Moisture Activated Dry Granulation
- Unsuitable for thermo-labile, moisture sensitive, high moisture absorbing substances.
- Formulations with high drug loading are difficult to develop.
What are the steps involved in Extrusion-Spheronization Granulation
Dry mixing of materials for homogeneous dispersion.
Wet granulation of the mixture to form wet mass.
Extrusion of wet mass to form rod shaped particles.
Rounding off the rod shaped particles using spheronizer.
Drying
List the advantages of Extrusion-Spheronization Granulation
Suitable for higher levels of active ingredients without production of larger particles.
Suitable for combination of two or more active agents within the same unit, in any
ratio.
It produces spherical particles with high bulk density, low hygrscopicity, narrow
particle size distribution and smoother surface.
List the disadvantage of Extrusion-Spheronization Granulation
Time consuming process having requirement of more labour.
Moisture sensitive and thermo-labile materials are not suitable candidates for it.
Explain the process of Fluidized Bed Granulation
It is an air suspension technique in which binder solution is sprayed on to the fluidized powder bed
in order to get finer, free flowing and homogenous granules.
This fluidized bed processor contains air handling unit, product container, air distributor, spay
nozzle, disengagement area, process filters, exhaust blower/fan, control system, and solution
delivery systems.
The particle formation in fluidized bed granulation is influenced by numerous parameters like
moisture content in solids, liquid spray flow rate, airflow rates, and atomization pressure.
Granulation in fluidized state can be achieved either by batch process or continuous process.
For granulation in batch process, the dry starting product is placed in the product container,
where it is mixed vigorously in the heated gas stream, held in the suspension and granulated by
spraying with a suitable bonding material.
The product is finally dried to the required end moisture content.
Explain the process of Spray Drying Granulation
This process is used to produce microcapsules, food ingredients, flavors and various biotechnological preparations.
Dry granular product is obtained by feeding a solution of active agent along with excipients 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.
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.
What are the steps involved in Spray Drying Granulation
Liquid feed’s atomization into fine droplets
Mixing of sprays droplets with a heated gas stream, for liquid evaporation.
Separation of the dried powder from the gas stream.
What are the advantages of Spray Drying Granulation
It is a rapid and continuous process
It reduces overall cost by eliminating labor intensive drying and granulation steps.
Less exposure to dust.
Heat sensitive product are suitable candidates.
Explain the process of Steam Granulation
This process is simply a modification of conventional wet granulation method. In this technique, water steam is used as binder.
Pure form of steam is transparent gas, and it provides a higher diffusion rate into the powder and a more favorable thermal
balance during the drying step.
At standard temperature and pressure, pure steam (unmixed with air, but in equilibrium with liquid water) occupies about 1,600
times the volume of an equal mass of liquid water. 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, and evaporates more easily.
What are the advantages of Steam Granulation
Results in more spherical granule formation
Higher diffusion rate
Environment friendly, safe for working operator.
Maintain sterility
What are the disadvantages of Steam Granulation
There is need of special equipment for steam generation and transportation.
Need of high energy inputs
Not suitable for thermo labile materials.
Explain the process of thermal adhesion granulation
This technique involves granulation of the blend by addition of very less amount of water or solvents. This technique is quite
simple and convenient with low moisture and binder contents in a closed system for preparing highly compressible materials or for
modifying the poor characteristics of excipients.
In this process the binder is first moisturized by spraying water or ethanol, and then this blend is 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 and
70oC-90oC in case of ethanol, and mixed under tumble rotation for 3-20 minutes until the granules are formed.
Thermal adhesion granulation process is performed under low moisture content or low content of pharmaceutically acceptable
solvent by subjecting a mixture of excipients to heating. This method utilizes less water or solvent when compared to
conventional wet granulation technique.
What are the advantages of thermal adhesion
Utilizes less amount of water or solvent.
Granules with good flow properties and binding capacity were obtained even with substances having poor tableting properties.
Minimizes the dust generation during powder processing.
Explain the process of pneumatic dry granulation
This method involves production of granules from powder particles by initially applying mild compaction force by roller
compactor to produce a compacted mass comprising a mixture of fine particles and granules.
To separate the granules and to recycle the rejected fraction, a newly innovated fractionating device is employed.
Granules pass through the fractioning chamber to be compressed into tablets.
Pneumatic dry granulation is suitable for automatic or semi-automatic production of granules.
What are the advantages of pneumatic dry granulation
High drug loading is possible.
Faster development (within weeks).
Suitable for thermo-labile and moisture sensitive drugs. d. Improved stability with increased shelf-life.
Compatible with other technologies like coating, sustained release.
Produce soft and porous granules with improved flow property and compressibility.
Taste masking can be achieved.
Sterile products and toxic materials can be handled.
Reduces cost of final product by minimizing waste through recycling and production cost.
What are the effects of Effects of Granule Properties on Tablets
as granules size increases, there will be respective increase
in tablet weight variation, decreased hardness and increased friability
