Granulation Flashcards
Dr. Ologunagba
What is granulation?
Granulation is a pharmaceutical process which involves the size enlargement of fine or coarse particles wherein primary powder particles are made to adhere to form physically stronger, larger 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.
What is the size range for granules?
0.2-0.5mm
Mention 5 advantages of granulation.
i. It helps prevent the segregation of the primary ingredients in the powder mixture.
ii. It improves the flow properties of the mixture.
iii. It improves compression and density of the powder.
iv. Compacted granules occupy less volume/unit weight compared with powder and is easier to store and ship.
v. It improves the appearance of the product
vi. The granulation process can modify or improve the drug release profile.
vii. It reduces the risk of caking of hygroscopic materials as the granules are still able to absorb moisture but retain their ability to flow on account of the large granule size
viii. Handling of toxic material is less hazardous than is the case with fine powder.
Mention 3 common types of granulation.
- Wet granulation: a liquid, generally a binder solution, is added to facilitate wetting and agglomeration of a powder blend. The wet mass subsequently is dried and screened to obtain granules with desired size.
- Dry granulation: involves granulation using dry binders without the aid of any liquid. It is particularly useful for drugs that are sensitive to moisture or heat and cannot be processed using wet granulation. In this technique, powder particles are agglomerated either by using the process of slugging or roller compaction. The slugs or compacts then are milled to the desired size range granules
- Hot melt granulation: used as an alternative to wet granulation and employs binders that facilitate granulation in their molten form. 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.
Highlight the advantages and disadvantages of wet granulation.
Advantages
1. More uniform mixing is achieved than with dry granulation
2. More binding is achieved with less quantity of binder
3. Has better content uniformity
4. Is suitable for very low to very high drug content
5. Reduces sticking of blend to compression tooling
Disadvantages
1. Not favourable for moisture-sensitive products
2. Time consuming due to involvement of additional unit operation of drying
Highlight the advantages and disadvantages of dry granulation.
Advantages
1. Suitable for moisture and temperature-sensitive APIs
2. Suitable for low to high drug contents
3. Time and cost effective, as unit operation of drying not involved
4. Simplicity
DIsadvantages
1. Results in greater chances of generation of dust and environmental contamination
2. High force is involved in compaction
Highlight the advantages and disadvantages of hot-melt granulation.
Advantages
1. Intimate mixing, sometimes up to molecular level, can produce solid dispersions
2. It can lead to improvement in solubility and bioavailability
3. It is time and cost-effective, as unit operation of drying is not involved
Disadvatages
1. It is not suitable for thermo-labile drugs
2. It requires greater effort in polymer screening and training on equipment
3. Uses binders with low melting points, which can soften during storage
Agglomerated granules are formed by solid bridges ____, ____, ____, and ____
Solid bridges
Sintering
Chemical reaction
Crystallisation
Deposition of colloidal particles
What are the 5 recognised bonds that form between particles in granulation?
- 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
Discuss the three phases of granulation.
- Wetting and Nucleation: This is the first and an important phase in granule formation. It involves the initial wetting of powder bed and existing granules by the granulating fluid to form nuclei.
- Coalescence or Ball growth: 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 .
- Consolidation: As granules increase in size, they are consolidated by compaction forces due to bed agitation. The extent of the consolidation depends on the agitation in the granulation
equipment and the resistance of the granules to deformation.
What factors influence the wetting and nucleation phase?
Spray rate
Fluid distribution
Feed formulation properties
____ phase in granule formation controls internal granule porosity, and therefore final properties of the granules e.g., granule strength, hardness, or
dissolution.
Consolidation phase
Highlight the steps involved in 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)
About Wet Granulation. State True or False.
i. Granules are formed by the addition of a granulation liquid (usually an aqueous solution) onto a powder bed, which is under the influence of an impeller (in a high-shear granulator), screws (in a twin screw granulator) or air (in a fluidized bed granulator).
ii. Agitation of the particles along with the added liquid produces bonding between the primary powder particles to produce wet granules.
iii. Typically water, ethanol or isopropanol is
used either alone or in combination.
iv. Organic liquids are safer to use than aqueous solvents.
v. Aqueous solutions alone are preferred to aqueous binder solutions because of better binder capacity.
v. Typically polyvinyl pyrollidone (PVP), starch mucilage are used but other natural polymers such as tragacanth, acacia etc. are also used.
i. True
ii. True
iii. True
iv. False. Aqueous solvents are safer
v. False. Aqueous binder solutions have better binding capacity
vi. True
Describe the mechanism of Granulation in Wet Granulation.
In wet granulation the liquid added to the powder system causes a thin and immobile film of liquid to form between particles.
This causes an effective decrease in inter-particulate distance, and an increase in contact area between particles.
The shortening of the inter-particulate distance increases the Van der Waals forces of attraction.
More liquid is usually added in wet granulation to form a mobile liquid film.
Nucleation of granules in wet granulation starts with a number of particles joining together in the pendular state.
Two or more granules may coalesce to form larger granules, or they may break into fragments that can adhere to other granules. There may also be some mechanical interlocking of powder particles.
If agitation is continued too far, the granules will coalesce to form unusable over-massed
spheres of material
The amount of liquid added and the nature of the starting materials will affect the required mixing time, as well as the type of mixer.
High shear mixers often require less liquid than low–shear mixers, and high impeller
rotation speeds can cause local heating of the mixture and loss of solvent by evaporatio
The three states that can describe the distribution of liquid between particles are:
- 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. - Funicular state: this is an intermediary state where air starts to displace from between particles
- Capillary state: this is when all air has been displaced from between the particles. In the capillary state, liquid penetrates the pores of the particles to form solid bridges between particles, giving the strongest form of adhesion, when the liquid evaporates.
