Common problems, defects, or challenges of granulation according to the steps or stages involved. This structured approach simplifies the understanding of issues specific to each step.
The key steps of wet granulation include:
- Weighing
- Sieving
- Pre-Mixing
- Kneading (Wetting)
- Sieving of Wet Mass
- Drying of Wet Mass
- Sieving of Dried Mass
- Final Mixing/Blending
1. Problems During Weighing
Weighing is the initial step of wet granulation, where the weight of all excipients and active pharmaceutical ingredients (API) is verified as per the manufacturing order and batch manufacturing record (BMR).
Common Problems
- Inaccurate weight of excipients.
- Inaccurate weight of API.
Reasons
- Human error.
- Weighing balance malfunction.
- Ruptured polythene bags.
Solutions
- Verify the weight of excipients and API dispensed in the raw material store.
- If any discrepancies in weight occur, document the deviation, return the material to the raw material store, and adjust the weight according to the BMR.
- Ensure proper calibration of the weighing balance before weighing ingredients.
- Use double polythene bags to minimize material loss due to bag rupture.
2. Problems During Sieving
Sieving is a crucial step in wet granulation to ensure uniform particle size.
Common Problems
The following defects may occur during sieving:
- Blockage of sieve openings.
- Particle size inconsistency.
- Equipment damage or improper functioning.
- Too hard to Sieve manually.
- Material loss due to dusty environment.
- Large size granules mixed in sieved material.
- Do not use manual sieving for hard materials.
- Use an oscillating granulator or other size reduction mill to sieve the hard
- materials.
- Cover the hopper of the granulator or mill with a lid to prevent dusting.
- Large size granules are mixed with sieved granules if our sieve is damaged during sieving so critically observe the sieve condition.
3. Problems During Pre-Mixing
Premixing ensures uniform distribution of materials before kneading.
Common Problems
- Non-uniform mixing.
Reasons
Non-uniform mixing may occur due to:
- Mixer load exceeding or falling below the recommended capacity.
- Inappropriate blending speed (too high or too low).
- Excessive or insufficient blending time.
- Very low quantity of API.
- Segregation of particles.
Solutions
- Load the mixer according to its recommended capacity.
- Validate and determine the optimal blending speed.
- Validate and determine the optimal blending time.
- Use geometric mixing for small quantities of API to ensure uniform distribution.
- Use a narrow range of particle sizes to reduce segregation.
- Avoid over-blending to minimize segregation.
4. Problems During Kneading
Kneading involves adding a binder solution to a premix of fine powders to form granules.
Common Problems
A. Over-wetting/Doughy Mass
Reasons
Over-wetting may occur due to:
- Excessive binder solution.
- Improper binder solution composition.
- Extended kneading time.
Solutions
- Measure the exact quantity of binder solution as required.
- Validate the binder solution composition to ensure optimal consistency.
- Control kneading time to avoid over-wetting the mass.
- Validate the amount of solvent used during the kneading process and always use a validated quantity.
- Adjust the kneading time according to physical monitoring of granules quality.
- Add binder slowly for uniform distribution.
ALSO READ: Granulation Process in Pharmaceutical
B. Under Wetting
As the name indicates, in under wetting our product mass is not properly wet and all fine powder is not converted into granules.
Reasons
Following may be the reasons for under wetting wetting
- Less Binder solution/solvent is added.
- Mixing time after addition of binder is less.
- Binder addition time may be very slow.
Solution
- Validate the amount of solvent used during the kneading process and always use a validated quantity.
- Adjust the kneading time according to physical monitoring of granules quality.
- Enhance binder addition rate for uniform distribution.
5. Problems during Sieving of Wet Mass
Sieving of wet mass is the step in which we pass the wet mass formed after kneading through a wet mill to break large lumps and to reduce particle size.
Following problems may occur during wet sieving
A. Sieve Clogging
One commonly observed problem during this stage is sieve blockage or clogging.
Reason
Sieve clogging or blockage occurs due to over wet mass.
Solution
Try to avoid over-wetting during the kneading stage and for this use less binder solution.
6. Problems during Drying of Wet Mass
Drying is the step in which we use an FBD to remove the excessive moisture from our product.
Common Problem
Following problems may occur during the drying stage,
A. Over Drying
- As the name indicates in this defect our product is excessively dried.
- Moisture content is low or beyond the defined range.
Reason
Over drying occur because of following,
- Drying time is increased
- Drying Temperature is high
Solution
- Determine the optimum drying time and drying temperature by validating the moisture content.
B. Under Drying
- As the name indicates in this defect our product is not dried properly.
- Moisture content is higher than the defined range.
Reason
Under drying occur because of following,
- The drying time is low.
- The temperature used for drying is low.
Solution
- Determine the optimum drying time and drying temperature by validating the moisture content.
C. Case Hardening
Case hardening is a defect in which a binder is entrapped inside the granules and it is not properly dried although grain is dried from outside but inside is wet.
Reason
Case Hardening may occur because of the following,
- Too rapid drying may result in case hardening because rapid drying evaporates moisture from outside and makes granules hard so hot air is not able to penetrate inside and the inside binder remains moist.
- During wet granulation fast binder addition rate may result in local over wetting and the binder may entrap inside large granules.
- Large granules are not properly broken down by a chopper or wet mill.
Solution
- Do not apply rapid heat to dry the granules and increase the temperature slowly.
- Sprinkle binder solution slowly.
- Reduce the size of wet granules during wet sieving.
D. Non Uniform Drying
Non-uniform drying is a defect in which our product is not dried uniformly. In the case of FBD, the product is not properly lifted or fluidized in the product trolley and in the case of the Tray dryer the product is dried from the bottom but not from the surface.
Reason
- In the case of a try dyer, the trays may be overloaded with the product.
- Hot air circulation in the tray dryer may be poor.
- In the case of Fluid bed dryer product trolleys may be overloaded.
- Fan motor speed for fluidization may be low.
- Filters to exhaust air may be choked so results in a pressure drop
Solution
- In the case of a tray dryer, reduce the tray load or in other words reduce the thickness of the product layer in trays.
- Improve Hot air circulation in tray dryer for uniform drying for this check blower speed.
- Load the product trolley according to its capacity
- In FBD Increase fan motor speed for proper fluidization.
- Use stirrer to properly mix granules in product trolley for uniform drying
- Use shakers or blowback systems to prevent filter clogging during drying.
ALSO READ: Tablet Manufacturing Method - Granulation
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