Wet granulation is the process by which powders are converted to granules with the desired properties to ensure good tablet production.

Important consideration are :
  1. Type and quantity of Binder
  2. Compatibility
  3. Characteristics of drugs and other excipients
  4. Spreading of Binder
  5. Temperature and Viscosity
  6. Method of Addition of Binder
  7. Mixing Time
  8. Material of Construction of Granulator
  9. Type of Granulator
  10. Process Variables
  11. Apparatus Variables
  12. Impeller Movement

Type and quantity of 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

The uniformity of the particle size, hardness, disintegration and compressibility of the granulation depends on type and quantity of binder added to formulation.

As for example hard granulations results due to stronger binder or a highly concentrated binder solution which require excessive compression force during tableting. On the other hand, fragile granulations results due to insufficient quantity of binder which segregates easily. Larger quantities of granulating liquid produce a narrower particle size range and coarser and hard granules i.e. The proportion of fine granulates particle decreases. Therefore the optimum quantity of liquid needed to get a given particle size should be known in order to keep a batch to batch variations to a minimum.

The primary criteria is the compatibility of binder with the API & other tablet components. This is traditionally found by choosing appropriate stability study design.

Characteristics of drugs and other excipients
The drugs characteristics like its compressibility, particle size, surface area, porosity, hydrophobicity, solubility in binder are important in granulation process.

Strong binder such as liquid glucose and sucrose need to be added to drug that exhibits poor compressibility while the drugs that exhibit good compressibility can be using a weak binder such as starch paste.

Fine and porous particles requires higher amount of liquid binder as compared to coarse particles. Hydrophilic drug/excipients exhibiting absorption characteristics require higher volume of binder as compared to hydrophobic drug/excipients. The granule quality (size , friability) is governed by the solubility of the drug in the granulation solution.

Spreading of Binder
A binder that spreads easilyon particles is superior as compared to that which shows poor wetting quality. For example HPMC is a superior binder for paracetamol as compared to PVP.

Temperature and Viscosity
Fluid (less viscous) binder exhibit good spreading behavior.

Method of Addition of Binder
The method of addition of binder is also important. PVP can be used as solution as a binder or it may be dry blended with powders and later activated by adding water. Distribution of binder is favored if it is dispersed instead of pouring it.

Mixing Time
The mixing time also determines quality of granules. If the wet massing time is higher (resulting into hard granules), the tablets may fail the dissolution test in certain cases since drug release from hard granules is altered.

Material of Construction of Granulator
The material of construction of granulator determines the volume of binder required and also granule size distribution. Higher volume of binder is needed if vessel wall are wetted easily by binder.

Vessel wall made up of Stainless Steel require higher volume of binder as compared to vessel made up of plastics (PMMA/Polymethylmethacrylate and PTFE/Polytetrafluoroethylene/Teflon). In case of PMMA and PTFE due to high contact angle, all granulating liquid is forced immediately into the powder bed and gives narrow particle size distribution. While in case of steel, due to less contact angle liquid layer formed on the wall surface which in turn causes inhomogeneous distribution of liquid over the powder bed resulting into broader granule size.

Type of Granulator
Fluidized Bed Granulator produces porous granules as compared to High Shear Granulators.

Process Variables
Higher degree of densification of the granules results due to higher impeller speed as well as longer wet massing time. If liquid saturation increases tendency of agglomeration may occurs. Consequently, impeller speed and wet massing time affect the granule size.

Apparatus Variables
The apparatus variables in High Shear Mixer have a larger effect on granule growth than in FBD because the shear forces are dependent on the mixer construction. The size and shape of the mixing chamber, impeller and chopper vary in different High Shear Mixers.

Impeller Movement
If impeller movement is helical adhesion of wetted mass to the vessel is less. This gives a narrower granule size and few lumps. In case of High Shear Mixers, adhesion of wetted mass to the vessel is a problem which can be reduced by proper construction of the impeller or by coating the vessel with Polytetrafluoroethylene i.e. Teflon.