Tablet Manufacturing By Wet Granulation Method

Tablets are one of the most widely used dosage forms and are manufactured in pharmaceutical industries by the process of granulation or direct compression.

When we talk about granulation then there may be the dry granulation or wet granulation & in this article we will discuss the manufacturing of tablets by using the wet granulation method.




What Is Wet Granulation?

Wet granulation is the size enlargement process where the fine powder particles are brought closer or are agglomerated with the help of binders &  granulating fluid like water or IPA to form large, strong & permanent structures known as granules.

The granulating fluid can be used alone or it can be used as a solvent containing binder or granulating agent.

Selection of Granulating Fluid

The choice of granulating fluid mainly depends on the materials to be granulated.

Following are main types & properties of the granulating fluid used for the process of wet granulation

Organic Solvent

  • Organic solvents are used as a granulating fluid for those products which are moisture sensitive.
  • Organic solvent is volatile in nature & has less drying time.
  • Cost Of Organic solvents is high as compared to the aqueous solution.
  • Organic solvent is  environmentally less safe  as compared to water. 
  • Most commonly used organic solvent are
    • Isopropyl Alcohol (IPA)
    • Rectified Spirit
    • Dichloromethane 

Aqueous Granulating Fluid 

  • Aqueous granulating fluid is cost effective and non flammable.
  • Aqueous granulating fluid is environment friendly.
  • Drying time to evaporate aqueous granulating fluid is long.
  • Example is water




Binders In Wet Granulation 

Binders are powder excipients used in the wet granulation process to give adhesion to the powder particles along with the granulating fluid.

Most commonly used binders in wet granulation are,

  • Kollidon (PVP)
  • HPC (Klucel)
  • HPMC
  • Starch
  • Gelatin
  • Gums

Reasons For Granulation

There are many reasons for which we convert fine powders into granules & some are given as,

  • To enhance flow.
  • To prevent dust generation.
  • To prevent cross contamination.
  • To reduce line loss.
  • To enhance compaction
  • To prevent segregation 

Ideal Characteristics Of Granules

To ensure a trouble free tablet compression process following are some ideal characteristics of granules produced by wet granulation method.

  • Granules should have spherical shape to ensure good flow during the tablet compression process.
  • All the ingredients of formulation must be uniformly distributed in the granules.
  • There must be a suitable ratio of fine along with granules to fill the void spaces in dies during tablet compression.
  • The granules must not be too fragile & have sufficient strength to form good hardness tablets.
  • Granules of different sizes should not segregate in machine hoppers under the influence of compression machine vibrations.
  • The granules formed by wet granulation must disintegrate within a defined period of time.
  • The granules must be properly lubricated to prevent sticking or picking.




Mechanism Of Granules Formation In Wet Granulation 

The process of granules formation by wet granulation method was explained by Ennis & lister in 1980 & it is known as the Ennis mechanism of granulation or droplet nucleation mechanism.It is explained by the following stages,

Wet granulation method

1. Wetting & Nucleation

Wetting is the first stage of granule formation where liquid binder spreads over the surface of powder particles.The purpose of wetting is to ensure that binder properly coats the powder particles for effective binding & agglomeration.

Nucleation is the process where small nuclei or clusters are formed from the wet particles due to formation of small liquid bridges between wet powder particles.

Nucleation occurs when liquid binder is distributed over powder particles resulting in localized wetting & formation of liquid bridges between adjacent particles 

The wetting process is required for nucleation because the wetting process enables particles to come into close contact & adhere with each other to form granules.

The process of wetting & nucleation occurs simultaneously & is affected by the factors like viscosity & surface tension of binder, particle size of powder,spray rate, mixing time & speed.

By optimizing the above factors the process of wetting & nucleation is smooth & results in formation of uniform & robust granules.

2. Coalescence Or Ball Growth 

Coalescence is the main step of granules formation in wet granulation where small nuclei which are formed from wet powder particles collide,adhere & merge to form large granules.

These nuclei combine & encourage the growth of granules through adhesive forces like van der waal & capillary forces.

During the process of granulation the continuous collision & aggregation results in formation of large & more cohesive granules.



Due to continuous agitation & coalescence the granules grow in size & become more spherical in shape.The liquid binder facilitates the binding of more powder particles to grow in size & form cohesive structures.The growth of granules is facilitated by the addition of more liquid binder solution.

3. Consolidation

Consolidation is one of the most important stages of wet granulation where granules undergo compaction & densification.

The granules formed are subjected to the pressure during the subsequent processing which results in more closely packing of particles within the granules,reducing the inter particles void spaces & enhance cohesion.

Consolidation results in improvement of granules strength, durability & flow properties.

4. Breakage Or Attrition

In attrition due to further agitation the granules break into fragments & these fragments bind with other granules to form a layer of material on the remaining granules.

Steps In Wet Granulation Of Tablet Manufacturing 

Tablet manufacturing by using wet granulation method is a multi step process & explanation of these steps is given below,

Steps of tablet manufacturing by wet granulation

Image Credit:Ansel’s Pharmaceutical dosage form

Step 1: Weighing Of Product Formulation Ingredients

The first step of wet granulation is weighing where all the ingredients used for tablet manufacturing by using wet granulation are weigh to ensure their exact quantities according to the manufacturing order & batch manufacturing record (BMR).

In the weighing step we also segregate our formulation ingredients according to the sequence of manufacturing meaning that we separate the ingredients of wetting stage & final blending stage to avoid wrong usage or mix up.



Step 2: Sifting Of Formulation Ingredients

In step 2 the sifting of all the ingredients which are required to be granulated is done.The sieving or sifting step is performed by using Russel sifter,vibro sifter or oscillating granulator.

Step 3: Pre Mixing Of Formulation Ingredients

In this step, all the sieved materials which are required for the wetting stage are mixed in a suitable equipment to ensure uniform mixing.These ingredients can be mixed in bin blender,double cone blender, ribbon mixer or high shear mixer.

Different types of ingredients which are commonly mixed & used for granulation or wetting stage are drug, diluents and disintegrants.

Size of all the ingredients used in this step must be uniform to ensure uniform mixing.A huge difference in particle size may result in segregation or demixing.

Most commonly used diluents for wet granulation are lactose,starch,dextrose, mannitol, microcrystalline cellulose, dibasic calcium phosphate,tribasic calcium phosphate.

The disintegrants used for wet granulation are usually sodium starch glycolate,croscarmellose sodium,starch,and cross linked PVP.

Step 4: Binder Preparation

In this step the binder solution,paste or slurry is prepared using suitable solvent & binder excipient.

Most commonly used binder for wet granulation are starch,kollidon,HPMC & HPC.

Step 5: Preparation Of Wet Mass

In this step the binder prepared is poured or sprinkled to the pre mixed dry powders to form a wet or damp mass.This step is also known as kneading,wetting or granulation stage because in this step we wet our dry powders by adding the granulating fluid.

It is the most critical step & granules quality mainly depends on the successful completion of this step.

To ensure that required granules quality is achieved the end point determination of wet granulation is important & critical.

Read About End Point Determination

The various factors which may affect the process of wetting are given below




  • Amount of binder solution
  • Rate of binder addition
  • Kneading or wetting time
  • Speed of agitation & chopper blades

If the amount of binder solution is high or kneading time is very high it will result in over wetting & production of hard granules.Hard granules result in poor drug release profile & high disintegration Time.

If less granulating fluid is added it may result in under wetting & production of fragile granules which will break during drying & generate more fine.More fine & fragile granules may result in tablet compression problems like capping, lamination,weight variation & low hardness.

Step 6: Size Reduction Of Wet Mass

After formation of wet damp mass the next step is the wet sieving or sieving of damp wet mass.The wet mill is used to reduce the size of wet mass by using 6 to 8 mesh.

The purpose of size reduction of damp mass is to increase the surface area of wet mass & to ensure uniform & rapid drying.

Step 7: Drying Of Wet Sieved Material

The aim of the drying step is to remove the extra solvent from the granulated product.The process of drying is completed by using tray dryers or fluid bed dryers.

Fluid bed dryer is an advanced type of drying equipment which is most commonly used for drying of wet granules during wet granulation method.

An optimum level of moisture content or LOD (loss on drying) is maintained in the final dried granules & it is checked by the moisture analyser.

The temperature of the drying stage is critically monitored because over drying will result in tablet capping and lamination problems & Under drying will result in tablet sticking or picking during the process of tablet punching or compression.

Step 8: Sizing Of Dried Granules

The wet granules dried in tray dryer or fluid bed dryer don’t have uniform size.To get a desired granules size the dried granules are sieved or screened using a suitable mesh size like 12 to 30.

The size of granules is directly related to the tablet compression weight to ensure uniform die filling.

For screening of dried granules the following equipment may be used

  • Co Mill or Multiple Mill
  • Oscillating Granulator




Step 9: Lubrication Of Granules

After sizing of dried granules the next step of wet granulation is lubrication or final blending.

Depending upon the formulation the  ingredients like the remaining portion of disintegrants, diluents, flavors, colorants are also added in this stage after the sizing of granules.

The glidants and lubricants are added at the end of all ingredients.

The final blending or lubrication step is carried out by blending the dried granules with above mentioned excipients in a bin blender or double cone blender.

Step 10: Compression Of Final Blend

After completion of all steps of wet granulation, we collect the final blend of granules in suitable containers & calculate its yield.

Now this blend of granules is compressed into tablets using multi station rotary compression machines.

Step 11: Tablet Coating & Packaging 

After compression,the process of tablet coating is performed depending upon the requirements & tablets are blistered into Alu Alu or Alu PVC.Thess blisters are then packed into unit cartons & these unit cartons are placed in shippers & dispatched to the quarantine area for release.After release from quality control these tablets are dispatched to the finish good store from where these are supplied to the market.

Conclusion

We convert fine powders into granules by using suitable binder & granulating fluid.These granules are then dried,sized & Lubricated.After lubrication the granules are compressed into tablets.Then these tablets are coated,blistered & packed.Quality control testing is performed after packaging & then these tablets are ready to deliver to market.



Image Credit

Image Source – Google | Image By –intechopen

Learn Details About

  1. Tablet Compression Process
  2. Tablet Coating Process
  3. Tablet Blistering Process
  4. Tablet Packaging Process
  5. Defects Of Tablet Granulation



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