Problems During Granulation|Granulation Defects

Granulation is a process of converting fine powders into large agglomerates by using binder solution, solvent or application of pressure.Granulation is the most widely used method in pharmaceutical industries for manufacturing tablets.

The process of granulation in which we use binder solution or solvent to convert fine powders to granules is known as wet granulation and the process in which we convert fine powder into granules by applying pressure is known as dry granulation.

In this article, we will discuss the common problems which may occur during granulation and affect product quality.

To read details of wet granulation and dry granulation read following

Wet & Dry  Granulation in pharmaceutical industries.

Problems/Defects Of Granulation

Here we will discuss the common problems or defects or challenges of granulation according to the steps or stages of granulation so that we make it easy to learn and understand the problems of each and every step.

First, we will discuss wet granulation and as we know steps of wet granulation are as follow,

  • Weighing
  • Sieving
  • Pre-Mixing
  • Kneading(Wetting)
  • Sieving Of Wet Mass
  • Drying Of Wet Mass
  • Sieving Of Dried Mass
  • Final Mixing/Blending

Problems During Weighing

Weighing is the first step of wet granulation and in this step, we verify the weight of all excipients and API according to the manufacturing order and BMR.

Common Problem/Defects

The most common problems which may occur during weighing are as follow,

  • Weight of excipients not accurate.
  • Weight of API not Accurate.

Reasons

  • Personnel Error
  • Weighing Balance Error
  • Rupturing of polythene Bags

Solution

  • As we know in this step we are verifying the weight of excipients and API which are dispensed in the raw material store.
  • If the weight of any excipient or API  is not according to BMR, make deviation and return it to the raw material store and adjust the weight according to BMR.
  • Ensure calibration of weighing balance before weighing of ingredients.
  • Use double polythene bags to reduce the chances of material loss due to rupturing of polythene bags.

Problems During  Sieving

Sieving is also an important step of wet granulation and it is done to ensure uniform particle size.

Common Problem

Following defects may occur during sieving,

  • Too hard to Sieve manually.
  • Material  loss due to dusty environment.
  • Large size granules mixed in sieved material.

Solution

  • 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.

Problems During Pre-Mixing

Premixing is a step in which all the materials which require kneading are mixed before kneading to ensure uniform mixing.

Common Problem

Following problems or challenges may occur during pre-mixing

Non Uniform Mixing

Non-uniform mixing may occur because of the following,

  • Mixer load is not according to capacity.
  • Blending speed may be very high or very low
  • Blending time may be very high.
  • Blending time may be very low.
  • Very low quantity of API.
  • Segregation of particles.

Solution

  • Load the blend according to the recommended capacity of the mixer
  • Determine optimum blending speed by validating the results.
  • Determine the optimum mixing time by validating the results.
  • A lower quantity of API should be used by the geometrically mixing method to ensure uniform mixing.
  • Use a narrow range of particle sizes to avoid segregation.
  • Over blending may also result in segregation so use optimum blending time

Problems during Kneading

The process in which we add binder solution into a premix of fine powders to convert powder into granules is known as kneading.

Common Problem

Following problems may occur during Kneading

Over Wetting/Doughy Mass

As the name indicates, in over-wetting our mass is over wet and it appears like a doughy mass.

Reason

Following and  maybe the reasons for over wetting

  • More Binder solution/solvent is added.
  • Mixing time after addition of binder is increased.
  • Binder addition time may be very fast

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.

Add binder slowly for uniform distribution.

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.

Also Read:

Biopharmaceutics FAQ

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

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

As discussed earlier try to avoid over-wetting during the kneading stage and for this use less binder solution.

Problems during Drying Of Wet Mass

Drying is the step in which we use an FBD fluid bed dryer to remove the excessive moisture from our product.

Common Problem

Following problems may occur during the drying stage,

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.

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.

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.

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 tray dryer, 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:

Quick Review of 40 Dosage Forms

 

Mottling/Color Migration

Mottling or colour migration is a defect that occurs during the drying of granules in which we use colour.

Reason

  • Dye colours are water-soluble and migrate along with the evaporation of water.
  • Excessive drying without stirring the granules in the product trolley.
  • Most products dried in a tray dryer show a mottling effect.

Solution

  • The use of lake colours prevents colour migration because lakes are not soluble in water.
  • Do not over-dry the granules.
  • Try to use an FBD or fluid bed dryer.
  • Use a stirring mechanism during drying which brings new surfaces in contact with heat.
  • The use of Microcrystalline cellulose in product formulation prevents colour migration.

Problems during Sieving Of Dried Mass

Dry sieving is the process in which we convert dried granules into uniformly sized granules using a specified mesh or sieve in an oscillating granulator or dry mill.

Common Problem

Following problems may occur during the dry sieving stage,

Excessive Fine

The excessive fine is a defect in which  more fine is generated during the dry sieving stage

Reason

  • If we select a wrong sieve mean sieve with a higher number like #60 sieve for sieving of granules then the more fine powder will be generated.
  • Overloading of granulator or dry mill.
  • Over speeding of the dry mill.
  • Rotor sieve clearance(Distance between sieve and rotating arm of granulator) is very low.
  • Granules are over-dried.
  • Less binder is used and granules are not strong.

Solution

  • Use the correct sieve according to validation results to get better quality granules and dissolution profiles.
  • Do not overload the hopper of the granulator or dry mill.
  • Use optimum speed for dry sieving.
  • Adjust rotor screen clearance.
  • Do not over-dry the granules.
  • Adjust binder quantity according to the formulation.

Difficult to sieve

It is the problem in which granules are not easily sieved.

Reason

  • Granules may be hard due to higher binder amount or higher solvent amount used during kneading(Over-wetting)
  • Granules dried at high temperature may become hard.
  • There may be moisture in granules due to improper drying.

Solution

  • Try to avoid the production of hard granules for this use optimum binder and solvent amount.
  • Use uniform drying.
  • Properly dry the granules to get optimum moisture content.

Problems during Final Blending

Final blending is the stage used in granulation where we mix granules with diluents, lubricants and other excipients.

Common Defects

Following defects may occur during the final blending stage

Non Uniform Mixing

Non-uniform mixing may occur because of the following,

  • Mixer load is not according to capacity.
  • Blending speed may be very high or very low
  • Blending time may be very high.
  • Blending time may be very low.
  • Very low quantity of API.

Solution

  • Load the blend according to the recommended capacity of the mixer
  • Determine optimum blending speed by validating the results.
  • Determine the optimum mixing time by validating the results.
  • A lower quantity of API should be used by the geometrically mixing method.

Segregation of particles

Segregation may occur because of 

  • Over mixing
  • Due to the wide range of particle size differences.
  • Wide Density difference in the final mix.

Solution

  • Use optimum blending time.
  • Use a narrow range of particle sizes to avoid segregation.
  • Try to reduce the density differences.

Assay or Content uniformity issue

Assay or content uniformity issue may occur because of the following,

  • If final blending is not uniform there will be variation in the assay or content uniformity.
  • Because of segregation

Solution

  • Ensure uniform mixing.
  • Avoid segregation using narrow particle size.

Defects of Dry Granulation

Dry granulation is a process in which fine powders are converted into granules by application of pressure using the process of slugging or roller compaction.

In dry granulation, we use the following steps,

  • Weighing
  • Sieving
  • Pre blending
  • Slugging
  • Screening of slugs
  • Final blending

Common problem

Defects during weighing, sieving, pre blending, final blending g are the same as we discussed in the upper portion but the difference is in two steps which are as follow,

Defects Of Slugging

Slugging is a process in which fine powders are converted into large size tablets called slugs using punches and dies on a compression machine.

Following defects may occur during slugging,

  • The low hardness of slugs may result in more fine.

Solution

  • Compress the slugs at defined hardness.

Defects During Screening Of Slugs

Common defects during the screening of slugs are as follow,

  • More fine due to wrong selection of sieves.
  • More fine due to the high speed of the dry mill.

Solution

  • Select the sieve according to validation results and use the optimum speed of the mill to crush or screen the slugs.

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