Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
PELLETS
Definition: In the pharmaceutical industry, pellets can be defined as small, free-flowing, spherical
particulates manufactured by the agglomeration of fine powders or granules of drug substances
and excipients using appropriate processing equipment.
Introduction: The general terms “granulation” and “pelletization” are sometimes used
synonymously, the units obtained are referred to as granules, pellets, agglomerates or spheroids
without making any clear distinction among them.
Generally, if a size-enlargement process produces agglomerates of a size distribution
within the range of 0.1mm to 2.0 mm and a high porosity (about 20-50%), the process may be
called “granulation”, and the resulting agglomerates are called “granulates”. “Pelletization” is
often referred to as a size-enlargement process that
involves the manufacture of agglomerates with a
relatively narrow size range, usually with mean size
from 0.5 to 2.0 mm, named “pellets”. Pellets have free-
flowing properties and a low porosity (about 10 %). The
term “spheronization” is usually associated with
spherical units formed by a special process that includes a spheronization step where extrudates or
agglomerates are rounded as they tumble on a rotating frictional base plate.
Pelletization is one of the most promising technique for the multiparticulate drug delivery
systems. The interest in pellets as dosage forms (filled into hard gelatin capsules or compressed
into disintegrating tablets) has been increasing continuously, since their multiparticulate nature
offers many important pharmacological as well as technological advantages over conventional
single-unit solid dosage forms. They can be divided into desired dose strengths without
formulation or process changes and also 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. When taken orally, they disperse freely in the GI tract, maximize drug
absorption, minimize local irritation of the mucosa by certain irritant drugs, and reduce inter- and
intra-patient variability.
Because of these enormous advantages, pelletization has become focus of extensive
research, on refining & optimizing the existing techniques, as well as on the development of novel
manufacturing approaches.
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Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
Advantages: Pellets offer a significant number of advantages over conventional unit-dose
systems.
Technological advantages:
1. Uniformity of dose: Layering techniques and extrusion-spheronization technique offers
great accuracy with uniform drug delivery to the pellets.
2. Spheres have excellent flow properties: This becomes very useful in automated processes
or in processes where exact dosing is required, e.g. tableting, molding operations, capsule
filling, and packaging.
3. Prevention of dust formation, resulting in an improvement of the process safety, as fine
powders can cause dust explosions and the respiration of fines can cause health problems.
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:
6. Pellets can disperse freely throughout the GIT after administration and consequently the
drug absorption is maximized.
7. 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;
8. Reduce inter-and intra-patient variability.
9. Modified-release multiparticulate delivery systems are less susceptible to dose dumping
than single-unit dosage forms.
Disadvantages:
1. It is difficult to compress pellets into tablets as they are too rigid. Therefore, they are often
delivered encapsulated in hard gelatin capsule shells.
2. Pelletization demands highly sophisticated and specialized equipment, thereby increasing
the cost of manufacturing.
3. The control of manufacturing process is complicated with too many process variables as
well as formulation variables.
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Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
Ideal properties of a good pellet:
• Spherical shape and smooth surface are considered as desired characteristics for uniform
film coating.
• The particle size of pellets should be in range of 600- 1000μm.
• The quantity of the active ingredient in pellets should be maximum in order to maintain
size of pellet.
Pelletization Techniques:
The most commonly used and intensively investigated pelletization technique include
extrusion-spheronization, powder layering and solution/suspension layering. There are other
methods available which can be used for preparing pellets.
1. Extrusion-Spheronization: (Refer Video)
Extrusion / spheronization is a multistage process for obtaining pellets with uniform size from
wet granulates (extrudates). The method involves the following main steps
• 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.
a. 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.
b. 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.
The indentation pattern on the plate can have various designs, which correspond to
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Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
specific purposes. The most common design is the cross-hatch pattern with grooves
intersecting each other at 90° angles.
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 occurs in several stages shown in figure below.
Figure: Different steps involved in the Extrusion- Spheronization process.
2. Hot Melt Extrusion: (Refer Video)
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, in disparity to granulation process.
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Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
3. Layering Techniques: (Refer Video)
Solution &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, which was
invented about 30 years ago, had evolved through
elaborate design modifications and refinement into
ideal equipment for the manufacture of pellets by
solution and suspension layering. The primary
features that distinguish Wurster equipment from
other fluid-bed equipment are the cylindrical partition
located in the product chamber and the configuration
of the air distributor plate, also known as the orifice
plate. This plate is configured to allow most of the
fluidization or drying air to pass at high velocity
around the nozzle and through the partition, carrying with it the particles to the expansion chamber
(figure 3). In the large expansion chamber, the velocity of air becomes slower, thereby causing the
particles to fall back again to area surrounding the partition (down bed). The down bed is kept
aerated by the small fraction of air that passes through the small holes on the periphery of the
orifice plate. The particles in the down bed are transported horizontally through the gap between
the air distributor plate and the partition by suction generated by the high air velocity that prevails
around the nozzle and immediately below the partition. Thus, a constant and well-organized
motion of particles is formed inside the chamber, helping a uniform coating on the particles to
form.
The disadvantage of the Wurster process is the inaccessibility of the nozzles. If the nozzles
are clogged at any time during the layering process, the operation has to be interrupted, and the
spray guns must be removed for cleaning. The problem can be minimized by screening the
formulation or by using a spray gun with a bigger nozzle.
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Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
The importance of various process parameters are very high while layering with Wurster
technique. It is important to identify and optimize various formulation characteristics like
solubility, concentration of binder, viscosity of solution/suspension etc. When suspensions are
used, the size of particles must be very carefully optimized; as smooth and potent pellets can only
be obtained by using small (micron- sized) particles, otherwise the surface of pellets tends to be
rough, which may adversely affect the coating process. Solution/suspension layering is usually
used when the desired drug loading of the pellets is low because production of high- potency pellets
from a low solids content formulation is not economically feasible. In case of suspensions, another
important factor comes into play i.e. the particle size of the drug. Micronized drug particles provide
smooth pellets, and therefore are preferable for controlled-release formulations, where subsequent
film coating is required. A drug with larger particle size requires higher amount of binder solution.
As a result, potency of prepared pellets is reduced, and their surface also tend to be rough.
Dry 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.
4. 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. This can
be done either by adding an appropriate amount of liquid into the powder or subjecting it to high
temperature. Spherical agglomeration can be divided into two categories
a. Liquid-induced agglomerations and
b. Melt-induced agglomerations.
Various instruments are used ranging from conventional horizontal drum pelletizers,
inclined dish pelletizers or tumbling blenders to more advanced rotary fluid-bed granulators and
high-shear mixers. This technique is popularly used in iron ore and fertilizer industries, but its use
in pharmaceutical industries are still very limited.
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Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
During liquid-induced agglomeration, liquid is added to the powder before or during the
agitation step. As powders come in contact with a liquid phase, they form agglomerates or nuclei.
Melt-induced agglomeration processes are similar to liquid-induced processes except that the
binding material is a melt. The rate and extent of agglomerate formation depend on formulation
variables such as particle size and solubility of the powder, the degree of liquid saturation, and the
viscosity of the liquid phase.
5. 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. The formulation and process variables controlling the quality of pellets prepared
are similar to those used in tablet manufacturing.
6. Globulation:
Globulation, or droplet formation, consists of two related processes, spray drying and spray
congealing. They involve atomization of hot melts, solutions, or suspensions to generate spherical
particles or pellets.
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. The design and operation of the spray drier can influence a great number of the
characteristics of the final product, such as particle size and size distribution, bulk density,
porosity, moisture content, flowability and friability.
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Capsules: Pellets MDCP
Spray Congealing:
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.
7. Cryopelletization:
Cryopelletization is a process whereby droplets of a liquid formulation are converted into solid
spherical particles or pellets by using liquid nitrogen as the fixing medium at - 1600°C. The
procedure permits instantaneous and uniform freezing of the material. The rapid heat transfer that
occurs between the droplets and liquid nitrogen is responsible for the same. The pellets are dried
in conventional freeze dryers. Generally, 3-5 kg of liquid nitrogen is required for 25 preparation
of 1 kg pellets.
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 alcohol is 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.
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Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
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 decrease with the presence of water at the extrudate surface.
Evaluation Parameters:
1. Particle size distribution:
a. 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.
b. Sieve analysis using sieve shaker is most widely used method for measuring
particle size distribution.
c. 100 gm of pellets are weighed using electronic weighing balance.
d. 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:
a. 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.
b. It can be calculated from particle-size distribution by measuring the mean diameter,
gas adsorption, and air permeability.
c. 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.
d. 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.
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Formulative Pharmacy I Dr Deepu S
Capsules: Pellets MDCP
e. 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:
a. The porosity of pellets influences the rate of release of drugs from pellets by
affecting the capillary action of the dissolved drug.
b. 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
a) 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.
b) The bulk density of pellets can be measured by an automated tapper. True density
indicates the extent of densification or compactness of substances.
c) Bulk Density= Weight of powder/ Bulk volume
d) Tapped density= Weight of powder/ Tapped volume
5. Hardness and Friability
a) Hardness and friability determination of pellets is necessary because the pellets
have to withstand during handling, shipping, storage and other processes such as
coating.
b) The instrument such as Kaul pellet hardness tester provide relative hardness values
c) Friability of pellets are determined by using Erkewa type tablet friabilator or
Turbula mixer for a fixed
d) 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.
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