Monday, November 30, 2020

Advance Granulation Techniques

 Advance Granulation Techniques

The process of converting fine powders into granules is called granulation. Granulation process is used to manufacture tablets in pharmaceutical industries. Conventionally two granulation methods are used which are as follow,

  •   Wet granulation 

  •    Dry granulation

In wet granulation method solvent or binder solution is added in powders to convert powders into granules.

In dry granulation fine powders are converted into granules by application of pressure without addition of solvent or binder solution.

With advancements in technology many advanced granulation techniques are developed some of them are as follow,


  1.  Hot Granulation Technique

  2. Foam Binder Granulation Technique

  3. Steam granulation technique

  4. Moisture activated dry granulation technique.

  5. Freeze Granulation technique.

  6. Reverse wet Granulation

  7. Pneumatic Dry Granulation Technique


  1. Hot Granulation Technique

 Hot granulation or hot meltable granulation technique is opposite to wet granulation method.In wet granulation method solvent or binder solution is added into fine powders and the process of drying is used to remove excessive moisture.

In hot meltable granulation technique solvent or binder solution is not added and the drying process is also eliminated. In hot meltable granulation method, a solid binder is used which melts on heat usually at 40-90°C.Commonly used binder for hot meltable granulation  technique is Macrogol 6000.

Steps of Hot Metlable granulation

Following are steps of hot meltable granulation technique.

  1. Weighing 

  2. Sieving

  3. Mixing

  4. Melting+Mixing

  5. Cooling

  6. Screening/Sieving

  7. Final Blending

Weighing

In this step the ingredients are weigh according to Manufacturing Order or dispensing order to ensure exact quantities of all APIs and excipients.

Sieving

All the ingredients are sieved to ensure uniform size and to remove any foreign objects like rubber band etc if mistakenly added during packaging of materials.

Mixing

In mixing step API,diluent and binder are mixed in a blender to ensure uniform mixing.

Melting+Mixing

For hot granulatiom technique, steam jacket high-speed mixer is used.The premixed powder which contains API, diluent and meltable binder is added into a steam-jacketed mixer and heat is applied for 4-5 minutes.Then it is mixed at high temperature to ensure proper melting and mixing  of the binder. The molten binder converts the fine powers into granules.

Cooling

After ensuring proper granulation the hot product is removed from the mixer in SS trays and it is cooled at temperature 20-25 °C for 6-7 hours.

Screening/Sieving

When the product is cooled it is sieved through a proper mesh to produce uniform size granules.Sieve number is selected according to tablet weight and dissolution profile.

Precaution

Do not sieve the granules it they are not properly cooled because if we'll sieve hot granules it will result in sticking and picking during compression.

Final Blending

In this step the cooled sieved granules are mixed with remaining excipients like lubricants and the product is removed in containers after blending.Now this product is ready for compression.

           2) Foam Binder Granulation               Technique

Foam binder granulation technique is a modification of the wet granulation method.In wet granulation method, binder solution or solvent is added but in foam granulation technique binder solution is converted into foam and then this foam is applied to the fine powders to convert powders into granules.

Steps of Foam Binder Granulation

Following are steps of foam binder granulation technique.

  1. Weighing

  2. Sieving

  3. Dry mixing

  4. Wetting with Foam binder

  5. Wet sieving

  6. Drying

  7. Sieving of dried Mass 

  8. Final blending

Weighing

In this step all the ingredients are weigh to ensure that materials are dispensed according to the dispensing order.

Sieving

In this step materials to be granulated are sieved to ensure uniform particle size by breaking the lumps.

Dry Mixing

In this step of dry mixing materials to be granulated are mixed in a high shear or low shear mixer to ensure uniform mixing.

Wetting with Foam binder

In foam binder technique solution of binder is perepared and this binder solution is converted into foam by a foam generator.  By generating foam surface area of foam is increased.This foam is then added to the fine powder to convert powders into granules.With foam binder less amount of binder is used and over wetting does not occur because foam is not absorbed by powders instead foam adhere to the surface of powders and form granules.In foam binder granulation usually aqueous binder solution is used.

Wet sieving

The wet mass is sieved through the wet mill to increase surface area of wet granules and the wet mass is dried in FBD to remove excessive moisture.

Sieving of Dried Mass

The dried product is then sieved through the proper mesh to form uniform size granules.

Final Blending

In final blending step, sieved granules and remaining excipients are mixed and the product is collected in containers after blendind.Now this product is ready for compression. 

               3) Steam Granulation Technique

In steam granulation method we use steam in place of water. 

Steps of Steam Granulation

Following are the steps of wet granulation technique,

Weighing

Weigh all the materials to ensure the correct dispensing of materials.

Sieving of ingredients 

All the materials to be granulated are sieved through a proper mesh  to break down the lumps and to ensure uniform particle size of product.

Dry mixing

 Dry mixing ensures uniform mixing of ingredients which are to be granulated.

Steam Wetting

In this step a stream of steam is introduced into the powder mix and this steam activates the binder which converts powders into granules.

Steam is produced by a steam generator and after condensation of steam, a layer of water is formed around the granules which is removed by drying.

Drying

Excessive moisture is removed by the drying process using a suitable dryer.

Dry Sieving

 Dry granules are passed through a sieve to obtain uniform size granules.

Final blending

In final blending dry sieved  granules are mixed with remaining excipients in the final blending step and the product is collected in containers.The product is ready for compression.

         4) Moisture Activated Dry Granulation Technique(MADG)

This is also known as moist granulation technique.In this method of moist granulation,little quantity of water is added into dry mixed ingredients which activate granules formation.It is a time saving technique.

Steps Of MADG

Following are steps of moisture activated dry granulation method.

Weighing 

All the materials are weight according to the  Manufacturing Order.

Sieving & Mixing

Materials to be granulated are sieved through a mesh to ensure uniform size and  are mixed in a mixer to ensure uniform mixing.

Moisture Activation

A little amount of water is added to facilitate the granulation process. For MADG starch and cellulose-based fillers or diluents are not used because they absorb moisture and retain it.70-80% materials of MADG are added in activation stage of moist granulation.

Up to 5% of water is used as a granulating solvent.The water added converts fine powders into granules.

Moisture Absorbent

In this step moisture absorbing excipients like cellulose are added in moist mass after moisture activation and this absorbing material  absorbs excessive moisture.No drying and wet mill sieving is required in moist granulation method.

Final blending

In this stage other excipients like disintegrants and lubricants are added.After final blending product is removed in containers and is ready for compression.

            5) Freeze Granulation technique

In this granulation technique, the suspension or slurry is sprayed into the liquid nitrogen.In liquid nitrogen particles of slurry or suspension are frozen into granules.The drying process is carried out by sublimation of ice.

           6) Reverse Wet Granulation

In this technique, the drug and excipients are added to the solution of the binder.

Steps Of Reverse Wet Granulation

Following are steps of reverse wet granulation method.

Weighing,Sieving & Mixing

First of all, ingredients to be granulated are weight according to manufacturing order and are sieved through a mesh and then  are mixed in a mixer to ensure uniform mixing.

Binder solution

The solution of binder in water or solvent is prepared and it is added into the high shear granulator.

Reverse Granulation

The mixed dry material is added into the granulator contaning binder solutiom with continous mixing to form a wet mass.

Wet sieving and Drying

The wet mass formed is passed through the wet mill and is dried in a dryer to remove excessive moisture.

Dry Sieving 

The dried mass is passed through a sieve to produce uniform size granules.

Final Blending

In this step the dried sieve granules are mixed with remaining excipients and after blending product is removed in containers.Now the product is ready for compression.

                7) Pneumatic Dry Granulation Technique (PDGT)

Pneumatic Dry Granulation Technique  is the modification of dry granulation method. It is same as conventional dry granulation  method but modification is done by attachment of the pneumatic system.

Powders are compressed into powder sheets by roller compactor and then are sieved or milled by dry mill.The fine particles produced during this procedure are captured by an air system are  are recycled by again passing through the roller compactor.So in this way desired  size granules are produced without excessive fine.And the granules formed are ready for compression.


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Friday, November 27, 2020

Reasons of tablet Sticking and Picking

  Tablet Sticking and Picking 

Sticking and picking are two common problems which may occur during the tablet compression operation. Most of the operators and pharmacists are confused with the term sticking and picking and they use common term sticking for all cases. But there is a big difference between sticking and picking.

What is tablet sticking?

Tablet sticking is defined as 

The defect in which powder or granules adhere to the surface of the punch tip or walls of the die.


What is tablet picking?

Tablet picking is defined as

The defect in which powder or granules adhere to the letters or logo embossed or debossed on the surface of the punch tip.


Reasons for Sticking and picking

There are many reasons which may result in sticking and picking during the tablet compression operation. Some main reasons for sticking and picking are as follow,

  • Formulation Related

  • Machine Related

  • Environment Related 

Formulation Related

  • Moisture content

  • Case hardening

  • The ratio of fine powder

  • Hygroscopic materials

  • Lubricant

    • Quantity of lubricant

    • Blending of lubricant

    • Sieving of lubricant


Compression Machine Related

  • Condition of punches

  • Condition of dies

Environment Related

  • Relative Humidity(RH)

  • Temperature

Formulation Related

Formulation of tablets plays an important role in manufacturing.

A good formulation helps to avoid many problems like sticking and picking.

Following are some main formulation related problems which may result in sticking and picking.

Moisture content

The moisture content of the product is the major reason for sticking and picking.

Majority of products in pharmaceutical industries are manufactured by wet granulation method in which solvent is added to form granules and the process of drying is used to remove the excessive moisture content. If granules are not properly dried during the drying process high moisture level is retained in the granules.

When these granules are compressed they stick to the punch surface,  die walls or are picked by the punch-tip logo because of high moisture level.

Solution

  • Granules should be dried properly during the drying stage.

  • The high moisture level should not be present in granules.

  • To prevent sticking and picking the optimum level of moisture should be present in granules which is determined by validation.

Important Note

If powder or granules stick to the inner side of the die bore then more pressure is exerted by the punches to clear the inside of the die bore. This increases the machine load. Sound of the machine is changed due to overloading and machine accident may occur resulting in tooling damage.

If powder or granules stick to the neck of the punch tip it takes more load to enter into the die bore and it may also result in a machine accident.


Read More

Reasons for compression machine accidents.


Case hardening

Case hardening is a defect which may occur during wet granulation method and may lead towards sticking and picking during compression.

During wet granulation, binder solution is added in powders and powder particles adhere with each other to form granules.

Sometime during local over-wetting, some large lumps are formed which are broken down by wet mills of the granulator.

Wet mill reduces the lump size but some large size granules may be left behind in which more binder is present.

During drying, the solvent is evaporated and forms a  cover around the entrapped binder and prevents heat penetration inside the large granule so granules are dried from outside but binder inside is still wet it is called case hardening and during tablet compression, it results in sticking and picking. Case hardening may also occur if rapid drying is carried out.

Solution

Binder solution should be sprinkled at a uniform rate during wet granulation.

Try to avoid direct or manual addition of binder solution and ensure proper working of the chopper and wet mill.

During drying fan motor speed should be optimized for proper fluidization. Product trolley with a rotating rod should be used in FBD. Rotation of the rod after a specified time interval breaks large lumps. If required, break down large lumps manually during drying to ensure proper drying. Do not perform rapid drying because it may result in case hardening.

The ratio of fine powder

If a higher amount of fine powder is present in the formulation it may adhere to the punch surface or the logo of the punch and may result in sticking and picking.

Solution

Sieve the granules properly to generate less fine powder.

Machine pressure is increased which forces the powders to adhere to the tablet surface instead of adhering to the punch surface or logo.

Hygroscopic materials

During direct mixing or granulation of hygroscopic products, they may take up moisture from the environment and result in sticking and picking.

Solution

Temperature and humidity of the area should be properly maintained.

Lubricant

Lubricants are the excipients which are added in the formulation to prevent sticking and picking.

How lubricants work

Lubricants form a layer around the powders and granules, this layer reduces the friction between the product and machine toolings like punch tip and product and between die wall and product. After the addition of lubricant, machine load is reduced and tooling life is increased.

Lubricants are added in the final stage of blending so that the layer covers all the granules and fine powders and prevent sticking and picking.

Commonly used lubricants

Following are commonly used lubricants

  • Mg Streate

  • Sodium stearyl fumarate

Reason

Sticking and picking is related to

  • Quantity of lubricant

  • Blending of lubricant

  • Sieving of lubricant

Quantity of lubricant

Lower quantities of lubricant in formulation does not form a proper layer of lubrication around particles so sticking and picking may occur.

Solution

The optimum concentration of lubricants should be added in the formulation to prevent sticking and picking.

Lubricants e.g Mg Stearate are added in the formulation as 0.25-5% concentration.

Blending stage of lubricant

Lubricant blending stage plays an important role to prevent sticking and picking.

If lubricants are added in the wetting stage they will lose their lubricant effect.

If lubricants are added in final blending before glidants, diluents or disintegrants they will not work properly and result in sticking and picking.

Solution

Always add lubricants at the last stage of final blending and no excipients should be added after lubricant blending.

Sieving of lubricant

  • It is commonly observed that the sieving of lubricant increases its effect to prevent sticking and picking.

  • Sieving increases the surface area of lubricant.

  • Do not sieve lubricant by mixing it with other excipients.

Compression Machine Related

Compression machine and compression machine tooling may also result in sticking and picking of tablets during the compression operation. Machine related problems are as follow,

  • Condition of punches

  • Condition of dies

Condition of punches

Punches are used to determine the size and shape of the tablet during the compression operation. Most important part of the punch is the surface of the punch tip which is in direct contact with the product.

Two types of punch tip pattern are used

  • Plain tip surface

  • Tip surface with embossing

Plain tip surface

The surface of the punch tip has a chrome polishing layer which prevents sticking of the product to the punch tip. If this polishing layer is damaged, the product sticks with the punch surface during compression.

If the surface of the punch tip becomes rough it also results in sticking.

Solution

  • Polish the punch tip with polishing material.

Tip surface with embossing

In some cases, the surface of the punch tip is embossed or debossed with letters or have some logo.

The embossing or logo may result in picking.

Solution

Deep or close letters should not be used in embossing.

Condition of dies

With passage of time inside of the die bore becomes rough and it results in sticking.

Solution

Replace the dies after regular time intervals.

Environment Related

The environmental conditions of the manufacturing area may also result in sticking and picking defects. Following are two major environmental factors,

  • Relative Humidity(RH)

  • Temperature

Relative Humidity ( RH)

If relative humidity ( RH) is high in the compression area, the hygroscopic materials may take the moisture when they are exposed to a high humidity level. Due to moisture uptake sticking and picking occur in such cases.

Solution

Humidity level of the compression area should be controlled by using a dehumidification system of HVAC.

Silica desiccants should be placed in the containers of the final blended product.

Temperature

The temperature of the compression area may also result in sticking and picking.

In the compression room, heat is also generated by the friction of machine parts. Some formulations containing ingredients like macrogol or Mg treated start to melt at high temperature and result in sticking and picking.

Solution

The temperature of the compression room should be maintained properly by the HVAC system.


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