Through the pelletization process, pellets are generally prepared by compressing the powders or granules that consist of active pharmaceutical ingredients (APIs) and excipients. In this article, I will discuss palletization as well as different types of pelletization Processes.
Pelletization Process
Pelletization is an agglomeration process through which granules of bulk drugs or fine powders as well as excipients are transformed into pellets. Many pelletization techniques can be achieved by formulating spherical agglomerates.
Mechanism of Pellet Formation and Growth
Nucleation Phase
A stage of the pelletization process is called nucleation. In the nucleation stage, the powder particles are wetted with binder liquid.The preparation of pellets includes sticking fine powders or solid particles to each other because of attractive forces like magnetic forces, molecular forces, and electrostatic forces.
The binder solution filled into the void spaces between the primary particles.
Because of this reason, the formation of a three-phase-air-water-liquid nuclei system occurs that is bound by liquid bridges that are pendular in nature.
Read more - Pellets
Pendular State
In the Pendular state, the level of moisture is low.
The liquid surface tension and the negative suction pressure which is generated at the liquid bridges cause the attraction between the powder particles. It occurs due to the air between the particles.
Funicular State
It is an intermediate state where the air starts to be scattered continuously throughout the agglomerate.
Capillary state
In agglomerate, the void space is fully occupied by liquid. Due to this the formation of strong bonds occurs between the particles.
As the liquid evaporates these bonds also disappear.
In this state, the liquid can not form nuclei and does not completely surround the agglomerate.
Droplet
Droplet is the stage where it is identified when liquid completely surrounds the agglomerate.
The rate of nuclear formation depends on the moisture content, particle size, substrate wettability, the viscosity of the binding particles, and processing conditions.
During this operation, the total mass of the system remains unchanged but the number of nuclei is lowered.
The particles and fines are produced during a collision.
The consecutive addition of fragments on the surface of already-formed nuclei is called layering.
In the layering phase, the number of particles remains constant but the total mass of nuclei increases by increasing particle size with time.
The final step of pellet formation is the ball growth phase.
The mechanism used in the ball growth phase is abrasion transfer.
It comprises the transfer of materials from one granule formed to another.
In the ball growth phase, there is no change in the total number or mass of the particles.
There are two types of steps which are constituted in the manufacturing process of multiple unit pellet system;
1) Manufacturing of pellets
2) Tablets containing pellets manufacturing.
Stages of Nucleation
In the Pendular state, the level of moisture is low.
The liquid surface tension and the negative suction pressure which is generated at the liquid bridges cause the attraction between the powder particles. It occurs due to the air between the particles.
Funicular State
It is an intermediate state where the air starts to be scattered continuously throughout the agglomerate.
Capillary state
In agglomerate, the void space is fully occupied by liquid. Due to this the formation of strong bonds occurs between the particles.
As the liquid evaporates these bonds also disappear.
In this state, the liquid can not form nuclei and does not completely surround the agglomerate.
Droplet
Droplet is the stage where it is identified when liquid completely surrounds the agglomerate.
The rate of nuclear formation depends on the moisture content, particle size, substrate wettability, the viscosity of the binding particles, and processing conditions.
Coalescence Phase
The process of the formation of large-sized particles due to the random collision of well-formed nuclei is known as coalescence.During this operation, the total mass of the system remains unchanged but the number of nuclei is lowered.
The particles and fines are produced during a collision.
Layering Phase
Layering is a slow-growth mechanism.The consecutive addition of fragments on the surface of already-formed nuclei is called layering.
In the layering phase, the number of particles remains constant but the total mass of nuclei increases by increasing particle size with time.
Ball Growth Phase or Abrasion Transfer Phase
The mechanism used in the ball growth phase is abrasion transfer.
It comprises the transfer of materials from one granule formed to another.
In the ball growth phase, there is no change in the total number or mass of the particles.
Read more - Soft gelatin capsules
In the preparation of controlled-release as well as the sustained-release delivery system extrusion spheronization is a very widely used technique.
The purpose of the extrusion spheronization is to formulate uniform sizes of pellets with the capacity of high drug loading.
Commonly used granulators are Hobart mixer sigma blade mixer or planetary mixer and high shear mixer.
Read more - Soft gelatin capsule manufacturing
Pelletization Techniques
Extrusion-Spheronization
The purpose of the extrusion spheronization is to formulate uniform sizes of pellets with the capacity of high drug loading.
(a) Dry Mixing
For achieving the homogeneous powder dispersion by using a twin shell blender, high-speed mixer, planetary mixer, and tumbler mixer the dry mixing of ingredients is to be done.(b) Wet Massing
To produce a sufficient plastic mass for extrusion by using the normal equipment as well as the process that followed in the compaction of wet granulation, wet massing is done.Commonly used granulators are Hobart mixer sigma blade mixer or planetary mixer and high shear mixer.
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During the process of spheronization, different stages can be recognized depending on the shape.
The drying step is very important as it provides more porous pellets by decreasing the pellet density during the process of drying.
Solution or suspension layering and powder layering.
This solution or suspension is sprayed on the surface of the starter core and evenly spread as soon as it strikes or hits on its surface.
Spraying is followed by the drying phase which allows dissolved material to crystallize and hence, between the core and coating layer of the drug materials and also among the consecutive layers of drug and polymers, forms a solid bridge.
The method of drying affects the structural as well as functional properties of pellets.
Like, by increasing the pore diameter the fluidized bed drying increases the dissolution rate of the pellets.
Also, due to the increased porosity of pellets, the lyophilized pellets show increased dissolution.
On the surface of the seed the powder is evenly distributed and with the rolling movement, it gets a spherical shape.
It involves successive deposition of drugs and other components.
With the help of binding liquid that is sprayed on it the drug particles attached to the starter core form a liquid bridge.
After that, this liquid bridge is replaced by the solid bridge which arises either from a binder in the solvent or from any material that is soluble in the solvent.
(c) Extrusion
Extrusion exhibits particles of rod shape that are uniform in size, from the wet mass. The wet mass is forced through the dies and shaped into small cylindrical particles with uniform or unchanged diameters.(d) Spheronization
The spheronization process consists of a static cylinder and a rotating friction plate where the ejected material is broken up into smaller cylinders with a length equal to their diameter and due to the frictional forces these plastic cylinders are rounded.
During the process of spheronization, different stages can be recognized depending on the shape.
(e) Drying
For achieving the desired moisture content drying is required.The drying step is very important as it provides more porous pellets by decreasing the pellet density during the process of drying.
(f) Screening
For achieving the required size screening is necessary and sieves are used for screening purposes.Layering Technique
The layering technique is of two types;
Solution or suspension layering and powder layering.
Solution or Suspension Layering
In Solution or suspension, layering powder feed material as well as other components are dissolved in the solvent.
This solution or suspension is sprayed on the surface of the starter core and evenly spread as soon as it strikes or hits on its surface.
Spraying is followed by the drying phase which allows dissolved material to crystallize and hence, between the core and coating layer of the drug materials and also among the consecutive layers of drug and polymers, forms a solid bridge.
The method of drying affects the structural as well as functional properties of pellets.
Like, by increasing the pore diameter the fluidized bed drying increases the dissolution rate of the pellets.
Also, due to the increased porosity of pellets, the lyophilized pellets show increased dissolution.
Powder Layering
In powder layering, the seeds like sugar spheres are charged into the pelletizer, and on its surface drugs and excipients are sprayed tangentially.On the surface of the seed the powder is evenly distributed and with the rolling movement, it gets a spherical shape.
It involves successive deposition of drugs and other components.
With the help of binding liquid that is sprayed on it the drug particles attached to the starter core form a liquid bridge.
After that, this liquid bridge is replaced by the solid bridge which arises either from a binder in the solvent or from any material that is soluble in the solvent.
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In this technique, liquid nitrogen (at -196°C) is used as a fixing medium which causes the freezing of liquid formulations to droplets into solid spherical particles which after lyophilization provide pellets.
In this technique, the total quantity of nitrogen required totally depends upon the temperature of the solution that is being fixed.
Melted polymers are added with active ingredients along with some other additives through a die that is placed at a controlled temperature, pressure, and screw speed to form products of different sizes and shapes. There are the following steps involved;
a) Extruder feeding with the help of a hopper
b) Then mixing, grinding and kneading occurs
c) Then flow through the die
d) Finally, extrusion from the die and further downstream processing
1) It makes the bitter taste of active drugs.
2) It also modifies the release of the drug.
3) By forming a solid dispersion it improves the dissolution rate as well as the bioavailability of the drugs.
Cryopelletization
In the crystallization technique, pellets are formulated by the freeze-drying method.In this technique, liquid nitrogen (at -196°C) is used as a fixing medium which causes the freezing of liquid formulations to droplets into solid spherical particles which after lyophilization provide pellets.
In this technique, the total quantity of nitrogen required totally depends upon the temperature of the solution that is being fixed.
Hot-Melt Extrusion
In this method, the compaction of powder blend into the uniform shape product occurs.
Melted polymers are added with active ingredients along with some other additives through a die that is placed at a controlled temperature, pressure, and screw speed to form products of different sizes and shapes. There are the following steps involved;
a) Extruder feeding with the help of a hopper
b) Then mixing, grinding and kneading occurs
c) Then flow through the die
d) Finally, extrusion from the die and further downstream processing
Applications of Extrusion in the Pharmaceutical Industry
Melt extrusion is used for any purpose in the pharmaceutical industry;1) It makes the bitter taste of active drugs.
2) It also modifies the release of the drug.
3) By forming a solid dispersion it improves the dissolution rate as well as the bioavailability of the drugs.
Read more - Capsules - What kind of pill is a capsule
Then these droplets solidify into spherical pellets. Depending upon the density of the molten solid carrier about the liquid in the column these pellets can either move upwards or downwards.
If the density of the molten-solid carrier is lower than the liquid in the column then droplets are present from the bottom of the column and get converted into solid pellets at the top of the column.
In the same way, if the density of the molten-solid carrier is more than that of the liquid in the column then droplets are present from the top of the column and get converted into solid pellets at the bottom of the column.
The solid carrier melting point that is used for this process should be below 100°C so that it remains in solid form at room temperature.
To prevent needle blockage as well as to maintain the homogeneity in size and shape of the pellets, the viscosity of the drug mixture should be less.
For achieving the spherical pellets, the minimum viscosity of the liquid in the column should range from 4 to 40 cP at 20°C.
If single dosage forms are formulated multi particulates like filling them into hard gelatin capsules or compressing them into tablet dosage forms is called a multiple unit pellet system (MUPS).
Freeze Pelletization
In the freeze pelletization technique, the drug is uniformly distributed into a molten-solid carrier which is allowed to enter a small droplet into an inert column of liquid in which the molten solid carrier is completely immiscible.Then these droplets solidify into spherical pellets. Depending upon the density of the molten solid carrier about the liquid in the column these pellets can either move upwards or downwards.
If the density of the molten-solid carrier is lower than the liquid in the column then droplets are present from the bottom of the column and get converted into solid pellets at the top of the column.
In the same way, if the density of the molten-solid carrier is more than that of the liquid in the column then droplets are present from the top of the column and get converted into solid pellets at the bottom of the column.
The solid carrier melting point that is used for this process should be below 100°C so that it remains in solid form at room temperature.
To prevent needle blockage as well as to maintain the homogeneity in size and shape of the pellets, the viscosity of the drug mixture should be less.
For achieving the spherical pellets, the minimum viscosity of the liquid in the column should range from 4 to 40 cP at 20°C.
MUPS (Multiple unit pellet system)
Multiple unit pellet system generally has significance on the final dosage form.If single dosage forms are formulated multi particulates like filling them into hard gelatin capsules or compressing them into tablet dosage forms is called a multiple unit pellet system (MUPS).
Read more - Hard Gelatin Capsules | Manufacturing Methods
There are two types of steps which are constituted in the manufacturing process of multiple unit pellet system;
1) Manufacturing of pellets
2) Tablets containing pellets manufacturing.
Pelletization Process Video Tutorial
Conclusion
I hope you have liked the article on the Pelletization Process as well as the techniques involved in Pelletization. If you have any point please ask in the comment. I will be happy to help.
Read More - Solid oral dosage Forms (Tablet or Capsules)
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