PELLETS
AND INNOVATIONS IN
PELLETS
Prepared by:
Dr. Kunal N. Patel
SSPC Zundal
LIST OF CONTENT
• Definition
• Characteristics / properties of pellets
• Advantages and disadvantages of pellets
• Pelletization process
• Newer techniques
• Recent innovation
What is pellet?
Pellets are defined as small, spherical particulates
produced by the agglomeration of fine powders or
granules of drug substances and excipients using
appropriate equipments.
They are usually free flowing.
The size of pellets vary from formulation to
formulation but usually lies between 1 and 2 mm.
Relationship of pharmaceutical solid
dosage forms
CHARACTERISTICS PROPERTIES
OF PELLETS
Uncoated pellets:
• Uniform Spherical Shape
• Uniform Size
• Good Flow Property
• Ease of Packing (E.G. Into A Hard Gelatin Capsule)
• High Mechanical Strength
• Low Friability
• Ease of Coating
Coated pellets:
• All above and desired drug release characteristics
according to the type of coat material.
ADVANTAGES OF PELLETS
They can be dispensed as such, filled into a capsule as well as
can be compressed into a tablet.
They can be also used to dispense incompatible bioactive
agents together into a single formulation.
They can be divided into desired dose strengths without
formulation or process changes.
Different release profiles in a single formulation can be met.
Release of drugs at different sites in the GIT.
Upon oral administration, they maximize absorption as they
freely disperse in GIT.
DISADVANTAGES OF PELLETS
If the pellets are volume filled, for example in capsules, it
may lead to the problems of content uniformity and
differences in dosing.
If the pellets are coated, then upon compression into a tablet,
there are chances that the coat of pellets may rupture.
Pronounced surface roughness of pellets may hinder the filling
process.
If the pellets are coated with an ethyl cellulose film, the
batches could not be filled to an acceptable standard because
electro-static charges develop that lead to blocking during
the filling process.
Examples of commonly used excipients
Filler Microcrystalline cellulose, starch,
sucrose, lactose, mannitol
Binder Ethyl cellulose, sucrose, starch,
povidone.
Lubricant Calcium stearate, Magnesium stearate
Surfactant Polysorbate, Sodium lauryl sulpfate
Spheronization Microcrystalline cellulose
enhancer
Glidants Talc, starch, Magnesium stearate.
Anti sticking Magnesium stearate, glyceryl-1-
agent manostearate
Solvent Ethanol, Isopropyl alcohol
Dye Yellow
PELLETIZATION PROCESSES
Direct pelletizing
Pelletization by layering
Extrusion-spheronization
Sugar spheres
DIRECT PELLETIZING
Manufacture of pellets directly from powder.
Round pellets, defined surface
Ideal flow behaviour and dosability
Narrow particle size distribution
Low abrasion
Process principle
Powder is mixed and moistened and the powder bed set into
centrifugal motion. The impact and acceleration forces that occur
in this process result in the formation of agglomerates, which
become rounded out into uniform and dense pellets.
PALLETIZING BY LAYERING
Layer-by-layer pellet build up around a given starting
core.
Layered pellet Round pellets
Ideal dosability
Low hygroscopicity
Dense, even surface
Narrow grain size distribution
Low wear
Principle of powder layering process
• This 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.
• Generally this process requires specialized equipment
because powder layering involves the simultaneous
application of the binding liquid and dry powder.
• As per requirement in this process, the primary
equipment is that the product container should have
solid walls with no perforations to avoid powder loss
beneath the product chamber before the powder is
picked up by the wet mass of pellets that is being
layered on.
• The first equipment used to manufacture pellets on a
commercial scale was the conventional coating pan.
• During powder layering, a binding solution and a finely
milled powder are added to a bed of starter seeds at a
controlled rate.
• In the initial stages, the drug particles are bound to the
starter seeds and the forming pellets with the help of
liquid bridges originated from the sprayed liquid.
• After some period of time, these liquid bridges are
replaced by solid bridges. These solid bridges are
derived either from a binder in the application medium
or from any material that is soluble in the liquid.
• The drug and binder solution continuously and
successively make layer until the desired pellet size is
reached.
• It is most important to deliver the powder accurately at
a predetermined rate and in a manner that maintains
equilibrium between the binder liquid application rate
and the powder delivery rate throughout the process.
• Toward the end of the layering process, sometimes fines
may be generated due to potential inter particle and wall
to particle friction and appears in the final product,
thereby lowering the yield.
• This problem can be overcome by increasing the
moisture level at the pellet surface by spraying the
application medium on the cascading pellets. It
facilitates layering of the fines onto the pellets.
• However, care should be taken that the product bed
should not be over wetted because the powder-liquid
equilibrium that has been established will change and will
need to be adjusted accordingly.
• In an ideal process, there should not be agglomeration
of particles. At the end of the process the difference
should observe only in the size of the pellets and thus in
the total mass in the pan.
Disadvantages:
•The degree of mixing is very poor, and the drying process is not
efficient.
•The powder layering process requires a great deal of repetition of
wetting and powdering operations and is thus time consuming;
moreover, undesired agglomeration and adhesion of the pellets to
the wall of the coating equipment can occur.
•If the powder delivery rate is not maintained at predetermined
equilibrium levels, over wetting or dust generation may occur.
•The powder layering technique requires specialized equipment such
as a rotary tangential fluidized bed or modified rotating pans.
•At the end of the layering process, it is likely that fines may be
generated due to potential inter particle and wall to particle friction
and appears in the final product, thereby lowering the yield.
Principle of solution/suspension layering process
Used when the desired drug loading of the pellets is low.
Involves the deposition of successive layers of solution and/or suspension of
drug substances and binder on starter seeds, which may be inert materials or
crystal/granules of the same drug.
EQUIPMENT USED FOR THIS PROCESS:
Conventional coating pans
Fluid-bed Centrifugal granulators.
Wurster coaters
tangential spray process
Top coating Wurster coating Tangential spray
coating (rotor
pellet coating)
An important factor that needs to be considered when
suspensions are used (as compared to solutions) is the particle
size of drug.
Micronized drug particles tend to provide pellets that are
smooth in appearance, a property that is extremely desirable
during subsequent film coating, particulary for controlled-
release applications.
If the particle size of the drug in the suspension is large, the
amount of binder required to immobilize the particles onto the
cores will be high and consequently, pellets of low potency are
produced. The morphology of the finished pellets also tends to
be rough and may adversely affect the coating process and the
coated product.
An important factor that needs to be considered when
suspensions are used (as compared to solutions) is the particle
size of drug.
Micronized drug particles tend to provide pellets that are
smooth in appearance, a property that is extremely desirable
during subsequent film coating, particulary for controlled-
release applications.
If the particle size of the drug in the suspension is large, the
amount of binder required to immobilize the particles onto the
cores will be high and consequently, pellets of low potency are
produced. The morphology of the finished pellets also tends to
be rough and may adversely affect the coating process and the
coated product.
PALLETIZING BY
SPHERONIZING
• Dry mixing of ingredient to achieve homogenous
powder dispersion followed by wet massing to produce
a sufficient plastic mass.
• Extrusion to form rod shaped particles of uniform
diameter called extrudates.
• Spheronization to round off these rod shaped
particles into spherical particles with narrow size
distribution.
• Drying to achieve desired final moisture content and
finally screening to obtain desired size of
spheres/pellets.
• Extrusion-spheronization is a multistep process
involving a number of unit operations and equipments.
• The most critical pieces of processing equipments are
the extruders and spheronizers.
• First, the materials are dry mixed (a) to achieve a
homogeneous powder dispersion and then wet
granulated (b) to produce a sufficiently plastic wet
mass.
• The wet mass is extruded (c) to form rod-shaped
particles of uniform diameter that are charged into a
spheronizer and rounded off (d) into spherical
particles.
• The spherical particles are then dried (e) to achieve
the desired moisture content and optionally screened
(f) to achieve a targeted size distribution.
Product produced by the first four extrusion spheronization process steps: (a) powder
from dry mixing, (b) granules from granulation, (c) extrudate from extrusion, and (d)
spheres from spheronization.
PALLETIZING BY SPHERONIZING
Granulate spheronizing process
EXTRUDERS used for this process are:
Screw-Fed Extruder
Gravity-Fed Extruder
Ram Extruder
Extruded product spheronizing process
APPLICATIONS OF EXTRUSION SPERONIZATION TECHNIQUE:
High drug loading is possible.
Extended release pellets can be produced.
Type of pharmaceutical extruders
[Link]. Extruder Examples
1 Screw fed extruders Axial or End Plate, Dome,
Radial
2 Gravity feed Cylinder Roll, Gear roll,
extruders Radial
3 Piston feed Ram
extruders
Screw fed extruders
Gravity feed extruders
Piston feed extruders
Spheronizers
Factors affecting pellet quality in ES
Drug substance
Excipients
Amount of solvent used
Extruder factors:
Type of extruder
Extruder speed
Thickness of the die plate
Extruder screen size
Spheronizer factors:
Load
Speed
Time
SUGAR SPHERES
Sugar spheres are produced, preferably using layered sugar-
coating structure.
The ideally rounded spheres are then coated with the active
substance and sustained release additives.
Sugar spheres characteristically consist of sucrose and corn
starch, which are pharmacologically indifferent, digestible
excipients frequently occurring in normal diet.
Sugar spheres must have adequate mechanical stability to
withstand the loads during subsequent coating, including
contact with solvent.
NEWER TECHNIQUES
Melt spheronization
Spray drying and Spray congealing
Cryopelletization
Freeze pelletization
MELT SPHERONIZATION
• Drug substances and excipients are converted into a
molten or semisolid state and shaped using
appropriate equipment to provide pellets.
• Equipments used are: Blenders, extruders, cutters
and spheronizers.
• The spheronization temperature needs to be high to
partially soften the extrudate and facilitate
deformation eventual spheronization.
• Depending on the characteristics of the formulation
ingredients, pellets that exhibit immediate or
sustained release characteristics can be
manufactured in a single step.
Spray drying and spray congealing:
• These are pelletization processes in which hot
melts, solutions, or suspensions are automized
to generate spherical particles or pellets. It is
also known as globulation process.
• In both process the droplet size is kept small
which maximize the rate of evaporation or
congealing and consequently the particle size of
the pellets produced is very small.
Spray drying :
• During Spray drying, drug entities in solution or
in suspension form are sprayed, with or without
excipients, in to a hot air stream to generate
dry and highly spherical particles.
• When the atomized droplets come in contact
with hot air, evaporation of the application
medium is started.
• 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 driven off and solid
particles are formed. Generally, pellets
prepared by this method are porous in nature.
• Though the technique is suitable for the
development of controlled release pellets, it is
generally employed to improve the dissolution
rates and hence, bioavailability of poorly soluble
drugs.
Spray congealing :
• Spray congealing is a process in which a drug is
allowed to melt, disperse, or dissolve in hot
melts of waxes, fatty acids, etc., and is sprayed
in to an air chamber where the temperature is
below the melting points of the formulation
components, to provide spherical congealed
pellets under appropriate processing conditions.
• A critical requirement in a spray congealing
process is that the formulation components have
well defined, sharp melting points or narrow
melting zones.
• The process does not involve evaporation of
solvents and therefore the pellets produced are
dense and nonporous in nature.
• Depending on the physicochemical properties of
the ingredients and other formulation variables,
pellets with immediate or controlled release
behavior can be produced.
CRYOPELLETIZATION
TECHNIQUE
• It is a process whereby droplets of a liquid formulation
converted into solid spherical particles or pellets by using liquid
nitrogen as fixing medium.
• The procedure permits instantaneous and uniform freezing of
the processed material due to the rapid heat transfer that
occurs between the droplets and liquid nitrogen. The pellets are
dried in conventional freeze dryers.
• The size of the droplets are small which provides the large
surface area and facilitates the drying process.
• During manufacturing of pellets, the required amount of liquid
nitrogen mainly depends on the solids content and temperature
of the solution or suspension being processed. It is usually
between 3 and 5 kg per kg of finished pellets.
• The equipment consists of a container equipped with perforated
plates at the bottom. Immediately below the plates at a
predetermined distance is a reservoir of liquid nitrogen. A
conveyor belt with transport baffles is immersed in that
reservoir.
• The conveyor belt has a variable speed and can be adjusted to
provide the residence time required for freezing the pellets.
The perforated plates generate droplets that fall and freeze
instantaneously as they come in contact with the liquid nitrogen
below.
• The frozen pellets are transported out of the nitrogen bath into
a storage container at -60°C before drying.
• The most critical step in cryopelletization is droplet formation,
which is influenced not only by formulations related variables
such as viscosity, surface tension, and solids content but also by
equipment design and the corresponding processing variables.
FREEZE-PELLETIZATION
Freeze pelletization is a new and simple technique for producing
spherical pellets for pharmaceutical use.
Molten-solid Carrier(Drug+Excipients) as droplets
Liquid in which the
molten solid is immiscible
Depending upon the
differences in the density,
The solidified droplets may
move downwards or
upwards
If the density of molten If the density of molten
droplets is higher than droplets is lower than that
that of liquid, then the of liquid, then the droplets
droplets are passed are passed from
from upwards, and thus downwards, and thus they
they solidify when they solidify when they reach
reach the bottom of the the top of the liquid filled
liquid filled vessel. vessel.
MicroPxTM Pelletization technology
The Micro Px™ Technology consists of a continuous fluid bed
process.
After liquid spraying and coating of APIs, generated
micropellets are classified by applying a vertical online air
sifting system.
The Micro Px™ Technology process results in manufacturing of
high drug loaded matrix-type micropellets. Drug loadings of
produced pellets can be up to 95%.
Taste Masking:-
Applying Wurster fluid bed technology, micropellets
with a particle size distribution between 200 to 400
µm were coated with two functional coatings.
Manufactured Micro Px™ core pellets proved to be
extremely mechanically stable, a prerequisite for
application of subsequent functional coatings like
taste masking, enteric coatings, modified release
coating and similar processes.
ADVANTAGES OF THE MICRO PX™
PELLETIZATION TECHNOLOGY
• small particle size
• spherical pellet shape
• manufactured Micro Px™ pellets reach very
homogeneous and narrow particle size
distribution
• drug loads achievable of up to 95%
ProCellTM Technology
Process Technology for the manufacture of very high
concentrated spherical particles
Modified fluid bed granulation process
– in particular performed as melt granulation
– no inert starting beads required
– controlled particle movement
Controlled material circulation through special air
flow design
Special processing chamber design, no bottom sieve
ProCellTM: Spray granulation-Mechanism
ProCellTM: Product characteristics
Very high material concentration (up to 100%)
Particle size range from 50 – 1500 µm
High density, low porosity
Particularly suitable for processing of
products with inherent stickiness
Processing of excipients and drug substances
Fast Dissolving pellets
Fast Dissolving Pellets are manufactured using
proprietary pelletisation techniques.
Fast Dissolving Pellets consist entirely of very
water soluble and/or swellable excipients and
can be compressed into orally dispersible
tablets (ODTs).
Characteristics of Fast Dissolving Pellets
• Narrow particle size distribution, e.g. 100 - 400 µm
• Smooth mouth feel
• Highly water soluble & swellable pharmacopoeial
constituents with low hygroscopic behaviour
• Addition of flavoring agents possible
• Spherical pellets with porous structure; porosity
facilitates disintegration and dissolution
• Mechanically very stable; easy product handling
• Packaging into conventional stick packs feasible
Cellets
Homogenous distribution of the active agent and the controlled
release are two fundamental advantages of this dosage form.
Due to the uniform concentration of highly active agents more
reliable formulations can be achieved.
As an inert, odorless and tasteless excipient, microcrystalline
cellulose is extremely versatile. Therefore Cellets® are made
from certified MCC and water only. Allowing combining the
benefits of neutral pellets with the unique properties of
cellulose.
Advantages of Cellets
• Wide range of particle size fractions
• Inert and water insoluble
• Dense, uniform, spherical shaped pellets
• Narrow particle size distribution
• Better for tablet compaction
• No controlled release collapse
• Higher drug load permits smaller capsule size
• Homogenous distribution of API
Study Questions
WHAT ARE THE CHARACETERISTIC PROPERTIES OF
PELLETS?
STATE THE ADVANTAGES AND DISADVANTAGES OF
PELLETS AS A DOSAGE FORM.
WHAT ARE THE RECENT INNOVATIONS IN PELLETIZATION
TECHNIQUES?
WHAT ARE THE RECENT INNOVATIONS IN PELLETIZED
FORMULATIONS?
CAN INSULIN BE ADMINISTERED BY AN ORAL
FORMULATION? EXPLAIN WITH AN EXAMPLE.
References
• The influence of pellet shape and film coating on the filling of pellets into hard shell
capsules., European journal of pharmaceutical and biopharmaceutics, 2006, 53(3) 327-
333.
• The effect of shape and porosity on the compression behavior and tablet forming ability
of granular materials formed from microcrystalline cellulose. European journal of
pharmaceutics and biopharmaceutics, 2005, 52, 347-357.
• Influence of process variables on physical properties of pellets using extruder
spheronizer. Drug development industrial pharmacy, 25 (!) , 45-61 (1999).
• Encyclopedia of Pharmaceutical technology, Volume 11, Page no-369.
• [Link]
• Physical characteristics of HPMC and HEC and investigation of their use as pelletization
aids, R. Catlapalli, B.D. Rohera, International Journal of Pharmaceutics, 161(1998)179-193.
• Eudragit NE40–Drug Mixed Coating System for Controlling Drug Release of Core Pellets
Drug Development And Industrial Pharmacy, Taylor & Francis Issue: Volume 31
number4-5/2005 Pages: 339 - 347
