In the dry granulation methods, particle adhesion occurs cause by compaction pressure. A compact or sheet is produced which is larger than the granule size required, and therefore the required size can be attained by milling and sieving.

In wet granulation methods, liquid added to dry powders has to be distributed through the powder by the mechanical agitation created in the granulator. The particles adhere to each other because of liquid films, and further agitation and/or liquid addition causes more particles to adhere.

The precise mechanism by which a dry powder is transformed into a bed of granules varies for each type of granulation equipment.

The granulation mechanism can be divided into three stages.
1. Nucleation
2. Transition
3. Ball growth



Nucleation
Granulation starts with adhesion among particles due to liquid bridges and the formation of agglomerates at capillary state. A number of particles will join to form the pendular state. Further agitation densifies the pendular bodies to form the capillary state, and these bodies act as nuclei for further granule growth.

Transition
Nuclei can grow in two possible ways:
  • single particles added to the nuclei by pendular bridges, or
  • combining two or more nuclei
The combined nuclei will be reshaped by the agitation of the bed. This stage is characterized by the presence of a large number of small granules with a fairly wide size distribution. Providing that this distribution is not excessively large, this is a suitable end-point for granules used in capsule and tablet manufacture, as relatively small granules will produce a uniform tablet die or capsule fill. Larger granules may give rise to problems in small-diameter dies owing to bridging across the die and uneven fill.

Ball growth
Further granule growth produces large, spherical granules and the mean particle size of the granulating system will increase with time. If agitation is continued, granule coalescence will continue and produce an unusable, overmassed system, although this is dependent upon the amount of liquid added and the properties of the material being granulated.

Although ball growth produces granules that may be too large for pharmaceutical purposes, some degree of ball growth will occur in planetary mixers and it is an essential feature of some spheronizing equipment.
The four possible mechanisms of ball growth are :
  1. Coalescence : Two or more granules join to form a larger granule.
  2. Breakage Granules : break into fragments which adhere to other granules, forming a layer of material over the surviving granule.
  3. Abrasion transfer : Agitation of the granule bed leads to the attrition of material from granules. This abraded material adheres to other granules, increasing their size.
  4. Layering : When a second batch of powder mix is added to a bed of granules the powder will adhere to the granules, forming a layer over the surface and increasing the granule size.

There will be some degree of overlap between these stages and it will be very difficult to identify a given stage by inspection of the granulating system.

Using the slower processes, such as the planetary mixer, there is usually sufficient time to stop the process before overmassing occurs. With faster granulation equipment the duration of granulation can only be used as a control parameter when the formulation is such that granule growth is slow and takes place at a fairly uniform rate.

The transition from a non-granulated to an overmassed system is very rapid, and monitoring equipment by operator is necessary to stop the granulation at a predetermined point, known as granulation end-point control. But, if validation has been established, granulation process could be done over and over again without monitoring the mass.

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