INTRODUCTION

Pellets are spherical or nearly spherical, free- flowing granules with a narrow size distribution,
typically varying between 500 and 1500 µm for pharmaceutical applications. They are generally
produced via a pelletization process whereby a powder blend consisting of an API and excipient
particles is agglomerated into spherical granules.
After being processed, pellets are usually filled into hard gelatin capsules or compressed into tablets.
Furthermore, they can be formulated as immediate release dosage form or in sustain drug release
over a long duration time or can be coated also to deliver a drug to a specific site of action in the
gastrointestinal tract.
Pellets provide the development scientist with a high degree of flexibility during the design and
development of oral dosage forms. They can be divided into desired dose strengths without
formulation or process changes, and also be blended to deliver incompatible bioactive agents
simultaneously or particles with different release profiles at the same site or at different sites
within gastrointestinal tract. Pellets provide development of formulation with high degree of
flexibility due to free- flowing characteristic. So they are packed easily without any difficulties. The
spherical shape and a low surface area to volume ratio of pellets made uniform film coating. Pellets
eliminate the dose dumping effect, which gives smoother plasma concentration profile and gradual
absorption of drug than tablet, which further decrease the adverse effect of drugs.

Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs
and excipients into small, free flowing, spherical or semi-spherical units, referred to as pellets.

Advantages
1.Uniformity of dose- Layering techniques and extrusion- spheronization offers great accuracy with drug
delivery the pellets.
2. Spheres have excellent flow properties and this becomes very useful in automated processes or in
processes where exact dosing is required, e.g. tableting, capsule filling, and packaging.
3. Prevention of dust formation: fine powders can cause dust explosions and the respiration of fines can
cause health problems and these can be reduced by using pellets.
4. Controlled release application of pellets due to the ideal low surface area-to-volume ratio that provides an
ideal shape for the application of film coatings.
5. They can be blended to deliver incompatible bioactive agents simultaneously and/or to provide different
release profiles at the same or different sites in the gastrointestinal (GI) tract.
Therapeutic Advantages
1. Pellets can disperse freely throughout the GIT after administration and consequently the drug
absorption is maximized.
2. The wide distribution of spherical particles in the gastrointestinal tract limits localized build-up of the
drug, avoiding the irritant effect of some drugs on the gastric mucosa.
3. Reduce inter- and intra-patient variability.
4. Modified-release multi-particulate delivery systems are less susceptible to dose dumping than single-unit
dosage forms.
Disadvantages
1. Pellets filling involve capsule filling which can increase the costs.
2. Tableting of pellets destroy film coating on the pellets.
3. The size of the pellets may vary formulation to formulation but usually is in range of 0.05 mm and 2 mm.
4. It is difficult to compress pellets into tablets as they are too rigid. Therefore, they are often delivered
encapsulated in hard gelatin capsule shells.
 5. Pelletization demands highly sophisticated and specialized equipment, thereby increasing the cost of
manufacturing.
Desirable Properties of Pellets
1. For Uncoated pellets
• Uniform spherical size
• Narrow particle size distribution
• Good flow property
• Low friability
• Even surface
• Low dust formation
• Reproducible packing

2. For Coated pellets

• Maintain all above properties
• Desirable drug release characteristics
 Different techniques of Pelletization
Pelletization techniques
1. Drug Layering
It includes deposition of successive layers of drug entities from solution, suspension or dry powder on
nuclei which may be crystals or granules of the same material. In solution/suspension layering, drug
particles are dissolved or suspended in the binding liquid. In powder drug layering, a binder solution is
first sprayed onto previously prepared inert seeds, followed by the addition of powder.

2. Powder Layering
Powder layering is similar to the solution or suspension layering. Instead of these dispersions, the
layering is performed using a drug powder. The process involves the deposition of successive layers
of dry powder of drug or excipients or both on preformed nuclei or cores with the help of a binding
liquid. Usually, the process is carried out in conventional coating pans.
Initially, the nonpareils or starter seeds are charged into a rotating pan, and then wetted by
spraying an adhesive solution. As the wet seeds reach the front end of the pan, the powder added in
the vortex adheres to them.
Inert cores were intermittently treated with micronized drug powder and adhesive solution. This
treatment led to the formation of multiple layers of drug particles around an inert core resulting in
the production of pellets that can further be coated by different polymers to obtain modified
release formulations.
 3. Solution and Suspension Layering: Layering a solution/suspension of a drug on a ‘starter
seed’ material (usually, a coarse crystal or nonpareil) can produce pellets that are uniform in size
distribution and generally possess very good surface morphology. These characteristics are
especially desirable when pellets will be coated for the purpose of achieving a controlled
release. The Wurster coating process had evolved through elaborate design
modifications and refinement into ideal equipment for the manufacture of pellets by solution
and suspension layering.

4. Extrusion-Spheronization
Extrusion / spheronization is a multistage process for obtaining pellets with uniform size from wet
granulates (extrudates).
 The dry mixing of the ingredients, in order to achieve homogenous powder dispersions;

 Wet massing, in which the powders are wet mixed to form a sufficiently plastic mass.

 An extrusion stage, in which the wet mass is shaped into cylindrical segments with a uniform
diameter.
 The spheronization stage, in which the small cylinders are rolled into solid spheres (spheroids);
 The drying of the spheroids, in order to achieve the desired final moisture content;
 Screening (optional), to achieve the desired narrow size distribution.

Extrusion consists in applying pressure to a wet mass until it passes through the calibrated openings
of a screen or die plate of the extruder and further shaped into small extrudate segments. The
extrudates must have enough plasticity in order to deform, but an excessive plasticity may lead to
extrudates which stick to each other. The diameter of the segments and the final size of the
spheroids depend on the diameter of the openings in the extruder screen.

Spheronization refers to the formation of spherical particles from the small rods produced by
extrusion. The essential part of the spheronizer is the friction plate. In order to form spheroids,
the extrudates are brought onto the rotating friction plate of the spheronizer, which imparts a
rolling motion to the material. Following the collisions between the extrudates with each other and
with the friction plate and the stationary walls of the spheronization chamber, the cylindrical
segments change their shape and size. The movement of the product along the chamber and
transition from the almost cylindrical segments to spheres during the spheronization process.
MCC is considered as golden standard for extrusion-spheronization. Based on its good binding
properties, it is able to provide the appropriate rheological conditions the process needs. Moreover,
by controlling the movement of water through the plastic mass, it prevents phase separation during
extrusion or spheronization.

5. Cryopelletization
Pellets here can be produced by allowing droplets of liquid formulation such as solution, suspension or
emulsion to come in contact with liquid nitrogen at -160˚C in which liquid nitrogen used as solidifying
medium. The procedure permits freezing of the material being processed due to rapid heat transfer
that occurs between the droplets and the liquid nitrogen for manufacturing a given quantity depends
on the solid content and temperature of solution or suspension being processed. The pellets are dried
in conventional freeze dryers to remove water or organic solvents.

6. Compression
Compression is one type of compaction technique for preparing pellets. Pellets of definite sizes and
shapes are prepared by compacting mixtures or blends of active ingredients and excipients under
pressure.

7. Balling
Balling, otherwise known as spherical agglomeration, is a pelletization technique in which powders are
converted into spherical pellets by a continuous rolling or tumbling motion.

8. Hot-Melt Extrusion technology (HME)

This is a newly modified variation of extrusion- spheronization method. Here a drug substance and
excipients are converted into a molten or semi-molten state and subsequently shaped using
appropriate equipment to provide solid spheres or pellets. This is a simple, efficient and continuous
process which requires fewer processing stages. It does not require a lengthy drying stage since it
does not involve addition of water or other solvent.

9. Freeze pelletization
In this technique, a molten-solid carrier/matrix is introduced as droplets into an inert column of
liquid in which the molten solid is immiscible. The molten solid moves in the liquid column as droplets
and solidifies into spherical pellets. The molten solid droplets can move upward or downward in the
liquid column depending on the droplet’s density with respect to the liquid in the column. If the
density of the molten-solid carrier/matrix is less than that of the liquid in the column, then droplets
are introduced from top of the column and pellets solidify in the bottom portion of the column.
 Conversely, if the density of molten- solid carrier/matrix is less than that of the liquid in the column,
then the droplets are introduced from the bottom of the column and pellets solidify at the top
portion of column.

10. Spray-drying and Spray-congealing

1. Spray-Drying
During spray drying, drug entities in solution or suspension are sprayed, with or without excipients,
into a hot stream of air to generate dry and highly spherical particles. As the atomized droplets come
in contact with hot air, evaporation of the application medium occurs. This drying process continues
through a series of stages whereby the viscosity of the droplets constantly increases until finally
almost the entire application medium is evaporated and solid particles are obtained. Though the
technique is suitable for the development of controlled-release pellets, it is generally employed to
improve the dissolution rates and the bioavailability of poorly soluble drugs. Also, this method is
applied for processing heat sensitive pharmaceuticals, such as: amino acids, antibiotics, ascorbic acid,
liver extracts, pepsin and similar enzymes. The spray-dried powder particles are homogenous,
approximately spherical and nearly uniform in size.

2. Spray-congealing (Spray-chilling)
Spray-congealing is a process in which a drug is allowed to melt, disperse or dissolve in hot melts of
gums, waxes, fatty acids or other melting solids. The dispersion is then sprayed into a stream of air
and other gases with a temperature below the melting point of the formulation components. Under
appropriate processing conditions, spherical congealed pellets are obtained.

Factors affecting pelletization technique

1. Moisture content
Moisture in the wet mass brings cohesiveness to powder so that the wet mass can be extracted and
spheronizer to give spherical shape. High moisture contents lead to agglomeration of pellets during
the process of spheronization.

2. Rheological characteristics
The optimum rheological condition leads to good flow ability in order to extrudate the wet mass. The
rheological variations make improper and non- uniform extrudate.

3. Solubility of excipients and drug in granulating fluid

Soluble drug get dissolve in a granulating liquid. Thus increasing the volume of liquid phase leads to
over wetting of pellets. But increase in wetting liquid increases plasticity but includes sticky mass.

4. Composition of granulating fluid

Besides water, alcohol, water/alcohol mixture, ethyl ether, dilute acetic acid, isopropyl alcoholis
used as a granulating liquid. Aqueous polymer dispersion containing HPMC, PVP, etc can also be used as
granulating fluid.

5. Physical properties of starting material

Quality of pellets depend not only composition but also on different grades of the same product. The
swelling property of material used in pelletization technique decides the release rate of drug in
pellets.
6. Speed of Spheronizer
It affects the size, hardness, sphericity and density of pellets. The high speed gives high sphericity,
lower friability, smooth surface and higher crushing strength.

7. Extrusion screen
The quality of pellets is greatly influenced by the characteristics of orifice of the screen. And
increase in orifice dimension resulted in increased mean pellet size. The increase in orifice depth
decreased with the presence of water at the extrudate surface.

Evaluation parameters
1. Particle size distribution
• Particle size should be as narrow as possible. This will ensure minimum variation in coating,
thickness, facilitate blending process if blending of different types is requires.
• Sieve analysis using sieve shaker is most widely used method for measuring particle size
distribution.
• 100 gm of pellets are weighed using electronic weighing balance. Pellets are then transferred to
set of sieves having different mesh size for particle size analysis. Calculate the % retained on
each sieve.

2. Surface Area
• The characteristics of pellets, those controlling the surface area, are mainly size shape, porosity
and surface roughness. There are three methods of measuring the surface area of pellets.
• It can be calculated from particle-size distribution by measuring the mean diameter, gas
adsorption, and air permeability.
• Mean diameter- This calculation does not account for the contributions of the surface area
arising from other morphologic characteristics such as porosity, surface roughness and shape of
pellets.
• Air permeability method- It is widely used pharmaceutically for specific surface measurement,
for controlling batch to batch variations. The principle for resistance to flow of a fluid such as
air through a plug of compacted material is the surface area of material.
• Gas adsorption method- In this method the volume of nitrogen that is absorbed by the substrate
contained in an evacuated glass blub is measured at different pressures.

3. Porosity
• The porosity of pellets influences the rate of release of drugs from pellets by affecting the
capillary action of the dissolved drug.
• The porosity of pellets can be measured qualitatively by scanning electron microscopy (SEM) and
 quantitatively by mercury porosimetry; optical microscopy and scanning electron microscopy
together with image.

4. Density
• The density of pellets can be affected by changes in the formulation or process, which may
affects other processes or factors, such as capsule filling, coating and mixing.
• The bulk density of pellets can be measured by an automated tapper. True density indicates the
extent of densification or compactness of substances.
• Bulk Density= Weight of powder/ Bulk volume
• Tapped density= Weight of powder/ Tapped volume

5. Hardness and Friability

• Hardness and friability determination of pellets is necessary because the pellets have to
withstand during handling, shipping, storage and other processes such as coating.
• The instrument such as Kaul pellet hardness tester provides relative hardness values.
• Friability of pellets are determined by using Erkewa type tablet friabilator or Turbula mixer for a
fixed period of time combined with glass beads of certain diameter in order to generate abrasion.

6. Tensile Strength
The tensile strength of pellets is determined by using tensile apparatus with a 5 kg load cell; the
pellets are strained until failure occurs. The load is recorded and the tensile strength is calculated
applying the value for the failure load and the radius of pellets.