Granulation is a process of converting powders into granules to form tablets by using a binder solution/solvent or by application of pressure on powders. In pharma industries, the Granulation method is used to manufacture tablets. The following are commonly used methods of granulation for tablet manufacturing.
- Wet Granulation
- Dry Granulation
There is a difference between these two methods of granulation i.e. wet granulation and dry granulation. The selection of wet granulation or dry granulation depends upon nature of Active Pharmaceutical Ingredients. In wet granulation, we use a solvent or binder solution to convert powders into granules.
Wet granulation is a multistage process and requires more time. Most of the pharmaceutical products are formulated by the wet granulation method because the majority of APIs are compatible with this method.
Wet granulation is used for those products which are not degraded by moisture and heat whereas dry Granulation is used for Moisture sensitive and heat-sensitive products.
Steps of Wet Granulation
Different steps are involved in wet granulation and every step during manufacturing f granules is monitored critically to produce good and high-quality granules.
All steps of wet granulation during manufacturing are followed according to specifications mentioned in Batch manufacturing record.
Following steps are involved in wet granulation,
- Pre Mixing
- Binder solution preparation
- Kneading/Addition of binder
- Sieving of wet Mass
- Drying of wet mass
- Sieving of dried mass
- Final mixing/Blending
The first step in wet granulation is weighing. In this step, all the ingredients of the formulation are weighed on a weighing balance and are checked by production pharmacist after that cross-checked by QA inspector to ensure that all ingredients are according to the Manufacturing order and all the information e.g lot number, batch number, product name, etc on dispensing label are according to the Manufacturing Order.
The second step involved in wet granulation is sieving. In this step, all the ingredients which are required to be granulated according to formulation mentioned in BMR mean batch manufacturing record are sieved through a proper mesh size. The purpose of sieving is to break down the lumps to ensure uniform particle size.
Any foreign material which may be the rubber band or tie clip part mixed in the material during raw material packaging is removed during sieving. Sieving process may be performed manually or by using a vibratory sifter. During the process of sieving, the face should be covered with a face mask to avoid inhalation of powders.
The third step in wet granulation is pre-mixing and in this step, all the ingredients which are required to be granulated according to formulation are mixed in a mixer after sieving. During pre-mixing some factors are observed critically like the mixing time, speed of mixer or impeller blades speed. The equipment used for mixing should be calibrated to ensure uniform mixing at all times.
4. Binder Solution Preparation
To convert powders into granules in wet granulation solvent or binder solution is added in pre-mix powders and this binder solution is prepared by dissolving binders in water or organic solvents. Binder may be added in powders in form of paste as in case of starch paste or gelatin paste or may be in form of solution like PVP k 30 in water/IPA or in form of suspension.
5. Kneading (Addition of binder)
Mixing Of binder solution in powder pre-mix is called kneading. It is the most important step of wet granulation because the quality of granules is greatly affected by this step of kneading. Important and critical factors to be monitored in this step are binder addition rate, mixer blades speed, chopper speed in case of high shear mixing granulator. Endpoint determination of wet granulation also plays an important role in this step of kneading
6. Sieving of Wet Mass
The wet mass-produced after kneading is sieved through a wet mill to break down large lumps formed during wetting and to make uniform size. By wet sieving surface area of granules is increased which helps in, efficient drying and reduce drying time. A critical step during wet sieving is to maintain the optimum speed of the wet mill.
7. Drying of Wet Mass
After wet sieving, the wet granules are dried to remove excess moisture from granules and to maintain an optimum level of moisture in granules. For drying different types of dryers like fluid bed dryer (FBD)or tray dryers are used.
In the case of Fluid bed dryer or FBD during drying critical factors to be monitored critically are Inlet air temperature of the dryer, fan motor speed for Air pressure, product temperature, outlet air temperature, drying time and loss on drying or LOD of product. After drying product yield is calculated and is mentioned in the Batch manufacturing record.
8. Sieving of Dried Mass
When granules are dried and loss on drying or LOD according to BMR is achieved then the granules are sieved through a proper mesh size mentioned in BMR to form uniform size granules. Mesh size in this stage play an important role because it may affect tablet dissolution, flow properties and weight variation so it is selected based on tablet final weight and dissolution profile.
9. Final Mixing (Blending)
The final and last step in wet granulation after dry sieving is mixing of sieved granules with remaining excipients. All the remaining ingredients e.g diluents, colourants, disintegrants, flavours etc which are to be mixed with granules according to formulation mentioned in Batch manufacturing record are sieved and then mixed with granules in a mixer.
A the end, Glidents are added and then lubricants are added after the addition of all excipients. The blending time after addition of lubricant is kept minimum that is 3-5 minutes to prevent the effect of lubricant on disintegration and the dissolution profile of tablet. After completion of final blending, the product is removed from the mixer and final yield is calculated against a standard weight mentioned in batch manufacturing record or BMR.
Dry granulation method is used for those pharmaceutical products which are moisture sensitive and heat sensitive. In dry granulation, we manufacture granules without the addition of binder solution or solvent and without using heat. One common question comes in mind that than how we convert powders into granules in dry granulation? the answer to this question is that we use pressure in dry granulation to convert powders into slugs or sheets and then these slugs or sheets are crushed to form granules.
Steps of Dry Granulation
Most of the steps involved in dry granulation are same as that of wet granulation except kneading and drying. In place of kneading and drying here in dry granulation, we use slugging method or roller compaction method.
Following steps are involved in dry granulation,
- Pre Mixing
- Slugging/Roller Compaction
- Sieving/Screening of Slugs
- Final Mixing/Blending
In this step, the weight of all ingredients is checked on weighing balance by production and QA. The same procedure is followed as in wet granulation that is lot number checking, batch number etc are verified.
In this step, all ingredients which are required to be granulated according to formulation mentioned in batch manufacturing record are sieved through proper mesh size. Sieving breaks down lumps and ensures uniform mixing.
All sieved ingredients which are required to be granulated according to formulation mentioned in BMR are properly mixed in a mixer for the period defined in BMR to achieve uniformity of powders. During pre-mixing, the speed of mixer should be observed critically.
4. Slugging/Roller Compaction
Slugging is an important step of dry granulation. Slugging is a pre-compression stage in which all powder mix is compressed using a compression machine into large size tablets called slugs and this process is called slugging.
Slug is a term used for large size tablets usually 25 mm in diameter. By applying pressure on powders in a compression machine powders are converted into slugs.
Roller compaction is an alternative method of slugging in dry granulation. In roller, compaction powder is pressed between two wheels/rollers which press the powder and convert powders into thin paper sheets. The thickness of the powder sheet is controlled by the distance between two wheels/rollers. The equipment used for roller compaction in dry granulation is called roller compactor. The sheets of powder formed in this method are crushed or sieved through oscillating granulator or multi mill attached to the roller compactor.
5. Sieving/Screening of Slugs
The slugs formed in slugging stage are crushed or sieved through oscillating granulator or the multi mill/Fitz mill to form granules. So in this way, fine powders are converted into granules without using binder solution/solvent and heat.
6. Final Mixing/Blending
In final mixing step, all remaining ingredients mentioned in Batch manufacturing record are mixed with sieved granules in a mixer and are mixed for a period specified in BMR or batch manufacturing record. One important and critical point to remember in this stage is that Lubricants are mixed at the end of the mixing process and after completion of mixing, product is discharged from the mixer in containers and final yield is calculated and is mentioned in batch manufacturing record.
- Advancements Granulation Techniques
- End point determination or wet granulation.
- Equipments used for Granulation.
- Working of Rapid Mixing Granulator.
- Working of fluid bed dryer.
- Pharmaceutical Questions and Answers.