To form granules, a strong bonds must be formed between powder particles so that they adhere not easily breakdown in subsequent handling operations.

There are five primary bonding mechanisms between particles:
  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;
  5. Mechanical interlocking.
Different types of mechanism were identified in each group and the ones discussed below are those that are relevant to pharmaceutical granulations.

Adhesion and cohesion forces in immobile films

If sufficient liquid is present in a powder to form a very thin and immobile layer, there will be an effective decrease in interparticulate distance and an increase in contact area between the particles. The bond strength between the particles also increased, as the van der Waals forces of attraction are proportional to the particle diameter and inversely proportional to the square of the distance of separation. This situation will arise with adsorbed moisture and accounts for the cohesion of slightly damp powders.

In dry granulation, the pressures used will increase the contact area between the adsorption layers and decrease the interparticulate distance, and this will contribute to the final granule strength.

Thin, immobile layers may also be formed by highly viscous solutions of adhesives, and so the bond strength will be greater than that produced by the mobile films. This type of film produce my starch mucilage.


Interfacial forces in mobile liquid films

During wet granulation liquid is added to the powder mix and will be distributed as films around and between the particles. Sufficient liquid is usually added to exceed that necessary for an immobile layer and to produce a mobile film. There are three states of water distribution between particles.

At low moisture levels, termed the pendular state, the particles are held together by lens-shaped rings of liquid. These cause adhesion because of the surface tension forces of the liquid/air interface and the hydrostatic suction pressure in the liquid bridge. When all the air has been displaced from between the particles the capillary state is reached, and the particles are held by capillary suction at the liquid/air interface, which is now only at the granule surface. The funicular state represents an intermediate stage between the pendular and capillary states. Moist granule tensile strength increases about three times between the pendular and the capillary state.

It may appear that the state of the powder bed is dependent upon the total moisture content of the wetted powders, but the capillary state may also be reached by decreasing the separation of the particles. In the massing process during wet granulation, continued kneading/mixing of material originally in the pendular state will densify the wet mass, decreasing the pore volume occupied by air and eventually producing the funicular or capillary state without further liquid addition.
 
Water distribution between particles of a granule during formation and drying

This will be important in the process of granulation by spray drying of a suspension. In this state, the strength of the droplet is dependent upon the surface tension of the liquid used. 

These wet bridges are only temporary structures in wet granulation because the moist granules will be dried. They are, however, a prerequisite for the formation of solid bridges formed by adhesives present in the liquid, or by materials that dissolve in the granulating liquid.

Solid bridges

These can be formed by:
  1.  partial melting
  2. hardening binders
  3. crystallization of dissolved substances.
Partial melting the pressures used in dry granulation methods may cause melting of low melting-point materials where the particles touch and high pressures are developed. The particlers will bind together and crystallization will take place when the pressure is relieved.

Hardening binders when an adhesive is included in the granulating solvent,  the liquid will form liquid bridges,  and the adhesive will harden or crystallize on drying to form solid bridges to bind the particles. 

Crystallization of dissolved substances The solvent used to mass the powder during wet granulation may partially dissolve one of the powdered ingredients. When the granules are dried, crystallization of this material will take place and the dissolved substance then acts as a hardening binder. 

The rate of drying of the granules influence the size of the crystals produced in the bridge, larger particle size will occurs if drying time longer/slower. It is therefore important that the drug does not dissolve in the granulating liquid and recrystallize, because it may adversely affect the dissolution rate.

Attractive forces between solid particles
In the absence of liquids and solid bridges formed by binding agents, there are two types of attractive force that can operate between particles in pharmaceutical systems.
Electrostatic forces may be important in causing powder cohesion and the initial formation of agglomerates, e.g. during mixing. In general they do not contribute significantly to the final strength of the granule.
Van der Waals forces, however, are about four orders of magnitude greater than electrostatic forces and contribute significantly to the strength of granules produced by dry granulation. The magnitude of these forces will increase as the distance between adjacent surfaces decreases, and in dry granulation this is achieved by using pressure to force the particles together.

Mechanical interlocking

The mechanical interlocking theory of adhesion states that good adhesion occurs only when an adhesive penetrates into the pores, holes and crevices and other irregularities of the adhered surface of a substrate, and locks mechanically to the substrate. The adhesive must not only wet the substrate, but also have the right rheological properties to penetrate pores and openings in a reasonable time.


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