Unit Processes - Granulation

What is granulation?

The process of combining smaller powder particles into larger, more cohesive particles called granules

The individual powder particles are held together by bonding forces

Uses:

• Final pharmaceutical dosage form

• Intermediate step for tablets/capsules

Size ranges:

• 0.2-4 mm

• Intermediate (tableting): 0.2-0.5 mm

• Dosage form: 1-4 mm

Why is granulation important in pharmaceutical manufacturing?

Granulation is used to improve the processing properties of powders and make them more suitable for manufacturing solid dosage forms, particularly tablets

It can improve:

• Flowability

• Compressibility

• Content uniformity

• Handling

• Feeding into tablet presses

• Reduction of dust

• Control of segregation

Granules

• They must have suitable mechanical properties

• Those manufactured to be used as a dosage form must be sufficiently robust to withstand handling (packaging and transportation)

• Those intended to be compressed into tablets must also be robust and nonfriable but must also deform and bond during compression to ensure that a compact is formed

How does granulation improve powder flow?

Granulation increases particle size and can produce particles that are more regular and free-flowing.

Therefore:

Fine powder → granules → improved flow

This allows the material to flow more reliably into tablet-die cavities

Reasons for granulation

• Preventing segregation of the constituents of the powder mix

• Improvement of the flow properties of the mix

• Improvement of the compression characteristics of the mix

• The granulation of powdered toxic materials will reduce the hazard associated with the generation of toxic dust during handling

• Increasing the stability of slightly hygroscopic materials as granules will be able to absorb some moisture and yet retain their flowability because of their size

Why is good powder flow important during tablet manufacture?

Good flow helps ensure that the correct quantity of powder enters each tablet die

Poor flow can cause:

• Inconsistent tablet weight

• Variable drug content

• Problems with tablet production

• Irregular die filling

2 types of granulation methods

1. Wet methods

2. Dry methods

What is dry granulation?

Dry granulation forms granules without adding a liquid

• Powder particles are compressed together to form larger aggregates, which are then broken down into granules of an appropriate size using high pressure

What are the two main methods of dry granulation?

1. Slugging

2. Roller compaction

In both cases, products need to be:

• Broken using a suitable milling technique

• Sieved to separate the desired size fraction

The unused fine material may be reworked to avoid waste

When to use the dry method?

• For drugs which don’t compress well after wet granulation

• For drugs which are sensitive to moisture or heat

What is slugging?

Powder is compressed under high pressure to form large compacted masses called slugs - the slugs are then broken down and screened to produce granules

What is roller compaction?

Powder is fed between two rotating rollers

• The rollers apply pressure and form a continuous compacted sheet/ribbon

• The ribbon is then milled and screened to produce granules

Advantages and disadvantages of dry granulation

Advantages:

• No liquid required

• No drying step

• Suitable for moisture-sensitive materials

• Suitable for heat-sensitive materials

• Fewer processing stages than wet granulation

Disadvantages:

• High compaction pressure can affect powder properties

• May produce weaker or less porous granules

• Can generate fines during milling

• May affect dissolution

• Requires additional milling/sizing

What is wet granulation?

Involves adding a liquid, usually containing a binder, to a powder mixture

• The liquid causes particles to adhere to one another and form wet granules

• The granules are then dried to remove the liquid

The granulating fluid contains a solvent that must be:

• Volatile, so that it can be removed from drying

• Non-toxic

Typical suitable liquids include: water, ethanol and 2-propanol

• The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent; i.e. cellulose derivatives), which is used to ensure particle adhesion once the granule is dry

• In the traditional wet granulation method, products need to be: sieved, dried, checked for agglomerates, separated from fine material, which can be recycled

What are the basic steps of wet granulation?

Powder mixing → binder/liquid addition → wet massing → granule formation → drying → sizing

The dried granules may then be mixed with additional excipients before compression

Advantages and disadvantages of wet granulation

Advantages:

• Good granule strength

• Improved flow

• Improved compressibility

• Reduced dust

• Reduced segregation

• Good distribution of low-dose APIs

• More uniform granules

Disadvantages:

• More processing steps

• Longer processing time

• Requires drying

• Higher energy requirements

• Possible degradation of moisture-sensitive drugs

• Possible degradation of heat-sensitive drugs during drying

• More complex equipment

Granulation mechanisms - what are the primary bonding mechanisms?

To form granules, bonds must be formed between powder particles so that they adhere, and these bonds must be sufficiently strong to prevent breakdown of the granule to powder in subsequent handling operations

The primary bonding mechanisms between particles are:

1. Adhesion and cohesion forces in the immobile liquid films between individual primary powder particles

2. Interfacial forces in mobile liquid films within the granules

3. The formation of solid bridges after solvent evaporation

4. Attractive forces between solid particles

Granulation: bonding mechanism 1 - adhesive and cohesive forces

• Facilitated through adsorbed moisture, a thin liquid layer, immobile layer

• Immobile layer decreases the interparticulate distances & increases the contact area

• Increases attractive forces i.e. Van der Waals forces

• These bonds are relatively weak, and unlikely to contribute to the final granule’s strength

• Immobile layer can be formed by highly viscous solutions of adhesives i.e., starch mucilage

• Bonds of immobile layer of viscous adhesives solutions are stronger than that of mobile films (next bonding mechanism)

Granulation: bonding mechanism 2 - interfacial forces in mobile liquid films within the granules

The granulation liquid, in wet granulation method, distributed around and between the particles

• The granulation liquid form mobile film, liquid bridges

• The granulation liquid must be added gradually

Particles can be in three states depending on the total moisture content of the wetted powders

• Pendular state

• Funicluar state

• Capillary state

Moist granule tensile strength increases by approximately three times from the pendular state to the capillary state

Liquid bridges are temporary structures as they will be dried

This mechanism is called the Interfacial Forces in Mobile Liquid Films

Granulation: bonding mechanism 3 - formation of solid bridges after solvent evaporation

Solid bridges

• The temporary liquid bonds need to be replaced by strong solid bridges which can be formed by:

Partial melting

• Occurs during dry granulation method

• Melting of low-melting point materials

• Releasing pressure will induce crystallisation that binds particles together

Hardening binders

• Adding adhesives (i.e. Polyvinylpyrrolidone, Cellulose derivatives, pregelatinized starch) to the granulation fluid

• Adhesives will crystallise upon drying, binding particles together

Crystallization of dissolved substances

• Granulation fluid does not include adhesives

• Granulation fluid “partly” dissolves one powder component

• The dissolved component will act as an adhesive (i.e. Lactose when water is used as granulation fluid)

• There is a risk of dissolving the API

Granulation: bonding mechanism 4 - attractive forces between solid particles

Electrostatic forces:

• Weak forces

• Initiate agglomeration between particles

• Do not contribute to the strength of the final granules

Van der Waals forces:

• Stronger than electrostatic forces

• Important for granule strength during dry granulation

• Stronger at short interparticular distances

What is granule formation?

The precise mechanism by which a dry powder is transformed into a bed of granules varies for each type of granulation equipment but the mechanism discussed in the following sections serves as a useful broad generalization of the process. The proposed granulation mechanism can be divided into three stages: nucleation, transition and ball growth.

Granule formation: nucleation, transition and ball growth

Nucleation:

• Individual particles adhesion due to liquid bridges

• Individual particles → pendular state → capillary state: nuclei

Transition:

In transition nuclei grow through:

• Individual particles bind nuclei

• 2 or more nuclei combine together

• Transition stage is characterised by the wide size distribution

• Granules at this stage can be used for the preparation of tablets and capsules

Ball Growth

Coalescence, breakage, abrasion transfer, layering

Coalescence:

• A group of granules join to form a larger granule

Breakage:

• Some granules might break down to smaller fragments

• Fragments might adhere to the surface of other granules

• Layers of materials on surface of granules (growing granules)

Abrasion transfer:

• Agitation of granule bed leads to attrition

• Abraded materials adhere to other intact granules

Layering:

• Powder particles added to a granule bed

• New particles adhere to the surface of the existing granules

• Layering occurs at production of coated granules (spheronizing)