Granulation is the process of creating granules by combining one or more powder particulates through compression activities and/or with a binding agent. In this process primary powder particles are made to adhere to form larger multi-particle entities called granules. Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm, depending on the subsequent use of the granules. Formed granules then allow the products and excipients to be easily moulded as a tablets or part of capsule manufacture. Since these two are the most common drug dosage forms, granulation is one of the most important unit operations in drug manufacturing.
Granules which are used as a dosage form consists of powder particles that have been aggregated to form a larger particle, which is usually 2-4 mm in diameter, sufficiently resistant to withstand handling. This is much larger than granules prepared as an intermediate for tablet manufacture.
Granulation normally commences after initial dry mixing of the necessary powdered ingredients so that a uniform distribution of each ingredient through the mix is achieved. After granulation, the granules will either be packed (when used as a dosage form) or they may be mixed with other excipients prior to tablet compaction or capsule filling.
Advantages of granules:
- Prevents powder segregation: prevents weight variation possibilities.
- Enhances powder flowability: higher flowability provides better filling to the dies.
- Produces uniform mixtures: prevents segregation during transport or handling as it ensures similarity in particle size, shape, and density.
- Produces dust-free formulations: this characteristic also reduces possible occupational exposure to the drug product.
- Eliminates poor content uniformity
- Improves compaction characteristics of the mixture
Methods of Granulation
- Dry Granulation: Dry granulation converts primary powder particles into granules using the application of pressure without the intermediate use of liquid. It therefore avoids heat/ temperature combinations which may cause degradation of the product for APIs and excipients sensitive to moisture and heat. In order to form granules, compacting and densifying powders is done via:
Slugging: This is an old process that is being replaced by the modern roller compaction. In this, dry powders can be compacted using a convectional tablet machine or a large heavy-duty rotary press.
Atablet press machine uses a mechanical device that compresses powders into tablets of uniform size, shape, and weight containing the same quantity of API and excipients. It is comprised of two punches and a die, wherein the upper and lower punches come together in the die which contains the tablet formulation.
Meanwhile, the use of a large or heavy-duty rotary press, normally referred to as slugging, creates compacts typically 25 mm diameter in size (by about 10-15 mm thick); better known as ‘slugs’. However, many pharmaceutical tableting materials suffer from ‘work hardening’ which results in poor recompaction of these already compacted granules.
- Roller compactor: consistently and uniformly deliver powders between two pressure rollers where they are compacted into a ribbon or small pellets. It is composed of three major units: the feeding system (converts powder to the compaction area), the compaction unit (powder is compacted between two counter rotating rolls via applying force), and the size reduction unit (mils the ribbons to desired particle size).
This is an alternative gentler method wherein the powder mix is squeezed between two counter-rotating rollers to form a compressed sheet. The roller rotation speeds can be adjusted to allow variation in the compression time as the material passes between the rollers.
Additionally, roller pressure can be adjusted and maintained during a run via a hydraulic control system to yield resulting granules of constant crushing strength.
The sheet formed is normally weak and brittle and breaks immediately into flakes, and these need gentler treatment to break them into granules.
Some advantages of the roller compaction process are:
- The process is economical as it dispenses with the intermediate stages of wet massing and drying, and thus the associated energy and other processing cost
- It can cope with a wide range of materials, particle size, bulk density and flowability. However, experience has shown that not all materials respond to roller compaction as they do not possess suitable deformation or cohesion properties
- The process is easily scaled up
- Wet Granulation: very applicable to most formulations which causes aggregation of particles. This happens by incorporating a liquid solution with a binder into the powders (via granulating fluid). Such liquid must be non-toxic and volatile so that it can be removed via drying process.
In this method, once a wet mass is formed, it will be forced through a sieve to produce wet granules which will afterwards be subjected to drying and screening processes; this will allow breakage of formed agglomerates of granules.
Since direct compression is not applicable for a number of active pharmaceutical ingredients (APIs) in the market, wet granulation is still the preferred method.
- High-shear Wet Granulation: In comparison to older shear granulators, high-shear wet granulation processing makes use of efficient high-speed mixer/granulators.
In the traditional shear or planetary granulation process, there should be a separate, initial, dry-powder blending operation using different powder-mixing equipment. However, this older process suffered from a number of major disadvantages such as:
- Longer duration
- Need for several pieces of equipment
- High material losses incurred during transfer stages between the different equipment
The process served the industry well for many years but with the advantages of modern mixer/granulators, pharmaceutical companies were compelled to take the next best step.
The different unit operations composing the granulation process may give rise to possible generation of airborne particulates, but modern designs offer granulators with varying containment mechanisms. For handling hazardous substances with high OEL
levels, integrating granulators with barrier technologies is the ultimate solution. This design will reduce emission and promote operator, product, and environmental protection. Modern technologies also allow the integration of other mechanical equipment such as elevated platforms, lift tables, and drum tippers/lifters, to assist workers during heavy lifting activities.
Esco Pharma’s experienced team of designers and engineers can help in designing a completely integrated equipment from the granulation part of tablet manufacture, even until final product stages.
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