Granulation

Granulation is the process where in individual dry powder particles are bound together to form larger multiparticulate structures known as granules (Fig. 1.0).In pharmaceutical applications, these granules typically range in size from 0.2 mm to 4.0 mm, depending on their intended use. Granules destined for tablet production generally fall towards the smaller end of this range (around 0.2 mm to 0.5 mm), while those intended as standalone dosage forms tend to be larger (approximately 1 mm to 4 mm). It’s crucial for granules to possess appropriate mechanical properties. Those meant for use as dosage forms must be durable enough to withstand handling and transportation, while also being able to deform and bond together during compression to ensure the formation of a compact tablet.

Fig. 1.0: Illustration of how granulation produces by wet granulation

Reasons for granulation  

  1. Prevention of segregation:

    Segregation in powder mixes is caused by differences in size and density of components, leading smaller or denser particles to concentrate at the bottom. Ideal granulation prevents segregation by evenly distributing all components in each granule. Controlling granule size distribution is crucial to prevent segregation in filling machines, ensuring consistent dose units.

  2. Enhance powder mix flow properties:

    Due to factors like small size, irregular shape, and surface characteristics, many powders are cohesive and have poor flow properties. This can lead to significant weight variation in the final product, such as tablets, due to inconsistent fill in tablet dies. However, granules formed from irregular particles tend to be larger and more isodiametric, which improves flow properties.

  3. Enhancing the compaction properties of the powder mix:

    Compacting certain primary powder particles into tablets can be challenging, even with a compactable adhesive. However, granules of the same formulation are usually easier to compact and yield stronger tablets due to their production method and resulting structure. Solute migration during post-wet granulation drying can lead to granules having a binder-rich outer layer, facilitating direct binder-binder bonding and aiding the consolidation of weakly bonding materials.

  4. Minimizing Exposure to Toxic Materials:

    Granulating powdered toxic materials reduces the risk of generating toxic dust during handling. However, precautions are necessary during the granulation process, especially in the dry state, such as during mixing and drying, to prevent dust hazards. The resulting granules should be non-friable and possess adequate mechanical strength.

  5. Prevention of caking through granulation:

    Granulation can mitigate the risk of materials with slight hygroscopic properties forming cakes when stored as powders. Granules can absorb moisture while maintaining flowability due to their size, reducing the hazard of caking.

Pharmaceutical granulation processes

Granulation methods can be categorized into two types: wet methods, involving the use of a liquid in the process, and dry methods, which do not require any liquid.

Dry granulation

Dry granulation methods involve aggregating primary powder particles under high pressure. Two main intermediate processes are utilized: the production of a large tablet (referred to as a ‘slug’) using a heavy-duty tableting press (known as slugging), or the compression of powder between two rollers to create a sheet or flakes of material (roller compaction). In both cases, the intermediate product is broken down using appropriate milling techniques to yield granular material, typically sieved to separate the desired size fraction. Any unused fine material may be recycled to minimize waste. This dry method is suitable for drugs that do not compress well after wet granulation or those sensitive to moisture.

Wet granulation

Wet granulation involves binding powders with an adhesive solution, suspension, or slurry instead of compaction. The process progresses through stages illustrated in (Fig. 2.0) initial wetting, pendular state with low mechanical strength, funicular state with modest strength, capillary state with maximum strength, and droplet formation with weaker structures. Granulation equipment often uses torque measuring devices to optimize the process by ensuring the capillary state is reached.

Fig. 2.0: Stages in the formation of moist granules as the liquid proportion is increased.

The presence of liquid is crucial in the granulation process, facilitating the formation of bridges between particles whose tensile strength improves with increasing liquid content. Surface tension forces and capillary pressure are the main drivers of initial granule formation and strength. Mixing continues until a homogeneous dispersion is achieved and the binder is fully activated.

Wet Granulation Process

During granulation, particles and agglomerates undergo consolidation due to machine action and interparticulate forces. Granulation in large blenders typically takes 15 minutes to an hour, depending on the wetting properties of the powder mixture, the granulating fluid, and mixer efficiency. A simple test to determine the endpoint involves pressing a portion in the palm of the hand; if the ball crumbles under moderate pressure, it’s ready for the next stage: wet screening.

The wet screening process transforms the moist mass into coarse, granular aggregates using equipment like a hammer mill or oscillating granulator with large perforated screens. Its purpose is to further consolidate granules, boost particle contact points, and expand surface area to aid in drying. Excessive moisture can result in slow drying and the formation of hard aggregates prone to powdering during subsequent dry milling. Skipping wet milling can often save time.

Drying is essential to eliminate the solvent used in forming the aggregates and to lower the moisture content to an optimal concentration within the granules. During drying, interparticulate bonds form through fusion or re-crystallization and curing of the binding agent, with Van der Waals forces exerting a significant influence. Following drying, the granulation undergoes another round of screening. The size of the screen is determined by the grinding equipment utilized and the desired size of the tablet to be produced.


Reference
:

  • Aulton, M. (2018). Aulton’s pharmaceutics, the design and manufacture of medicines. Edinburgh. : Elsevier
  • Khar, R.,Vyas, S., Ahmad, F., & Jain, G. (2016). Lachman/Lieberman’s The Theory and Practice of Industrial Industrial Pharmacy. New Delhi, ND: CBS Publishers & Distributors Pvt Ltd