Granulation is a process of size enlargement whereby small particles are gathered into larger, permanent aggregates in which the original particles can still be identified.

Granulation methods can be divided into two types:
  1. wet methods (wet granulation) : use a liquid in the process, binders are added in solution/suspension form
  2. dry methods (dry granulation/slugging) : no liquid is used.
In a suitable formulation a number of different excipients will be needed in addition to the drug. The common types used are diluents, to produce a unit dose weight of suitable size, and disintegrating agents, which are added to aid the break-up of the granule when it reaches a liquid medium, e.g. on ingestion by the patient. Adhesives in the form of a dry powder may also be added, particularly if dry granulation is employed. These ingredients will be mixed before granulation.

Dry granulation

The dry granulation process is used to form granules without using a liquid solution because the product to be granulated may be sensitive to moisture and heat. Forming granules without moisture requires compacting and densifying the powders. In this process the primary powder particles are aggregated under high pressure There are two main processes. Either a large tablet (known as a ‘slug’) is produced in a heavy-duty tabletting press (a process known as ‘slugging’) or the powder is squeezed between two rollers to produce a sheet of material (roller compactor or chilsonator). In both cases these intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size fraction. The unused fine material may be reworked to avoid waste.

When a tablet press is used for dry granulation, the powders may not possess enough natural flow to feed the product uniformly into the die cavity, resulting in varying degrees of densification. The roller compactor (granulator-compactor) uses an auger-feed system that will consistently deliver powder uniformly between two pressure rollers. The powders are compacted into a ribbon or small pellets between these rollers and milled through a low-shear mill. When the product is compacted properly, then it can be passed through a mill and final blend before tablet compression.

Roller-compaction or dry-granulation equipment offers a wide range of pressures and roll types to attain proper densification. This equipment is loud and dusty compared with other process machinery. Material feed rates are critical for attaining the final objective. The process may require repeated compaction steps to attain the proper granular end point. Typically, a percentage of product Again, successful compaction depends on the compatibility of the products being compressed. If fines are not removed or reprocessed, then the batch may contain too many of them, a situation that can contribute to capping, laminating, weight, and hardness problems on the tablet press. The need for screening large amounts of fines is common to roller compaction, and the degree to which it can be managed depends on the nature of the ingredients.

Wet granulation (involving wet massing)

Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid (the process of adding a liquid solution to powders). The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. 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) which is used to ensure particle adhesion once the granule is dry. The density of each granule is increased by increasing the amount of binding solution as well as the mechanical action of the mixer. Therefore, controlling the amounts of solution, binder, and mechanical action allows one to control the strength and density of the granule.

Water is commonly used for economical and ecological reasons (safer to nature and operator). Its disadvantages as a solvent are that it may adversely affect drug stability, causing hydrolysis of susceptible products, and it needs a longer drying time than do organic solvents. This increases the length of the process and again may affect stability because of the extended exposure to heat. The primary advantage of water is that it is non-flammable, which means that expensive safety precautions such as the use of flameproof equipment need not be taken. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required.

Water mixed into the powders can form bonds between powder particles that are strong enough to lock them together. However, once the water dries, the powders may fall apart. Therefore, water may not be strong enough to create and hold a bond. In such instances, a liquid solution that includes a binder (pharmaceutical glue) is required. Povidone, which is a polyvinyl pyrrolidone (PVP), is one of the most commonly used pharmaceutical binders. PVP is dissolved in water or solvent and added to the process. When PVP and a solvent/water are mixed with powders, PVP forms a bond with the powders during the process, and the solvent/water evaporates (dries). Once the solvent/water has been dried and the powders have formed a more densely held mass, then the granulation is milled. This process results in the formation of granules.

In the traditional wet granulation method, the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material, which can than be recycled. Variations of this traditional method depend on the equipment used, but the general principle of initial particle aggregation using a liquid remains in all of the processes.
A drying process that is too short will produce granules that have entrapped moisture; if the process is too long, then the granules become very dry and friable. If granules that have been dried only on the outside reach the tablet press, then moisture will escape the granules during compression and cause the granules to stick to the tablet-press tooling, a problem called case hardening.

Air flow and temperature control must be uniform. If the dryer has poor air circulation, then the product on the top will become drier than the product on the bottom. Overly dry product breaks apart easily and is no longer in a granular state. When an overly dry granulation is milled, it produces fine dry particles commonly referred to as fines. Fines do not flow well on a tablet press and thereby cause weight variations. In addition, fines do not compress well and can contribute to capping and lamination, which are common tablet defects.On the other hand, compressing the lower-tray granulations, which may contain too much moisture, can cause granules to stick to the tablet-press tooling, another situation that produces defective tablets. The error that is most common to granulation processes is the mixing of overdried granules, overwetted granules, and good granules. Once this mixture is on the tablet press, the full range of the previously described problems ensues: capping, lamination, picking, sticking, and tablet weight and hardness variation.

Criteria for Selecting a Wet Granulation Binder

Criteria Performance Impact
High cold water dispersibility and solubility Fast solution preparation when binder is added to solution
Low viscosity solutions Ease of handling and pumping of solution
High binding efficiency Lower use levels. Tablets have higher breaking force and/or require lower compaction force
High water solubility No impact on drug dissolution at high use levels

Effect of granulation method on granule structure

The type and capacity of granulating mixers significantly influences the work input and time necessary to produce a cohesive mass, adequate liquid distribution and intragranular porosity of the granular mass. The method and conditions of granulation affect intergranular and intragranular pore structure by changing the degree of packing within the granules. It has been shown that precompressed granules, consisting of compressed drug and binder particles, are held together by simple bonding during compaction. Granules prepared by wet massing consist of intact drug particles held together in a sponge-like matrix of binder. Fluidized-bed granules are similar to those prepared by the wet massing process, but possess greater porosity and the granule surface is covered by a film of binding agent. With spray-dried systems the granules consist of spherical particles composed of an outer shell and an inner core of particles. Thus the properties of the granule are influenced by the manufacturing process.