17

PELLETIZATION TECHNIQUES USED

IN PHARMACEUTICAL FIELDS
Mircea Hirjau, MD, Anca Cecilia Nicoara, MD, Victoria Hirjau, MD, PhD,
D. Lupuleasa, MD, PhD
Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy,
University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania

ABSTRACT
Pelle za on is a technique that enables the forma on of spherical beads or pellets with a mean diameter usually
ranging from 0.5 to 2.0 mm. These pellets can evantually be coated and very o en used in controlled-release dosage
forms. The use of pelle za on and pellets leads to an improvement in the flowability, appearance and mixing proper es,
thus avoiding excessive dust and reducing segrega on and, generally, elimina ng undesirable proper es and improving
the physical or chemical proper es of fine powders. Pellets are prepared by different techniques, such as extrusion and
spheronisa on, rotogranula on, solu on, suspension or powder layering, spray-drying or spray-congealing. The aim of
this paper is to review some general aspects about pellets and pelle za on and some common techniques used in the
pharmaceu cal industry. Several alterna ve methods are currently being developed, such as: hot-melt extrusion, freeze
pelle za on, emulsion / solvent evapora on, granula on using foamed aqueous binders, etc. (1-7).

Key words: Pelle za on, pellets

INTRODUCTION “Pelletization” is often referred to as a size-en-

largement process that involves the manufacture of
Pelletization can be defined as an agglomeration
agglomerates with a relatively narrow size range,
(size-enlargment) process that converts fine pow-
usually with mean size from 0.5 to 2.0 mm, named
ders or particles of bulk drugs and excipients into
“pellets”. Pellets have free-flowing properties and a
small, free-flowing, more or less spherical units,
low porosity (about 10 %).
called pellets (7).
The term “spheronization” is more specific, usu-
Granulation is also known as pelletization, ag-
ally associated with spherical units formed by a
glomeration or spheronization, and the units ob-
size-enlargement process that includes a spheroni-
tained are referred to as granules, pellets, agglomer-
zation step where extrudates or agglomerates are
ates or spheroids (8).
rounded as they tumble on a rotating frictional base
The general terms “granulation” and “pelletiza-
plate, being named “spheroids” (9).
tion” are sometimes used synonymously and no
clear distinction is made between them.
Generally, if a size-enlargement process produc- A SHORT HISTORY OF PELLETS
es agglomerates of a size distribution within the Although various industries have routinely uti-
range of 0.1 to 2.0 mm and a high porosity (about lized pelletization processes since the turn of the
20-50%), the process may be called “granulation”, XXth century in order to manufacture particles with
and the resulting agglomerates are called “granu- defined sizes and shapes, it was only in the early
lates”. 1950’s, in response to a desire to sustain the release

Adresa de corespondenţă:
Prof. Dr. Victoria Hirjau, Faculty of Pharmacy, University of Medicine and Pharmacy ”Carol Davila”, Traian Vuia Street, No 6, District 2,
Bucharest
e-mail: victoriahirjau@[Link]

206 Practica Farmaceutică – Vol. 4, Nr. 3-4, An 2011

 Practica Farmaceutică – Vol. 4, Nr. 3-4, An 2011

of drugs over an extended period of time, that the Aditionally, the production of controlled-release
pharmaceutical industry developed a keen interest multiparticulate oral dosage forms using spheroids,
in the technology. designed to deliver drugs at a specific site within
In 1949, pharmaceutical scientists at Smith Kline the gastrointestinal tract or over an extended period
& French (SKF) realised the potential of candy of time, leads to a series of therapeutic advantages
seeds in developing sustained-release preparations over conventional oral dosage forms (tablets or
and began the development of tiny drug pellets that capsules) (11), such as:
could be loaded into capsules. – pellets can disperse freely throughout an area
In time, extensive research was conducted to de- of the gastrointestinal tract after administra-
velop pelletization techniques and major ressources tion and consequently the drug absorbtion is
were allocated towards exploring methods that were maximized as a large gastrointestinal surface
faster, cheaper and more efficient, both in terms of can be involved in this process;
formulation and processing equipment (8). – peak plasma level of the drug can be reduced
The trend is expected to continue in the forsee- by the use of spherical particles with different
able future. release rates; potential side effects are mini-
Also, the role of pellets, especially of spheroids, mized without markedly lowering drug bio-
in oral dosage form design and development has in- availability;
creased substantially during recent decades. – the wide distribution of spherical particles in
Currently, pellets containing the active ingredi- the gastrointestinal tract limits localized
ents are administered in the form of suspensions, build-up of the drug, avoiding the irritand ef-
capsules or tablets, a great number of this kinds of fect of some drugs on the gastric mucosa;
pharmaceutical products being available on the – modified-release multiparticulate delivery
market. systems are less susceptible to dose dumping
Also, pelletization is used in various industries, than single-unit dosage forms.
such as agriculture (fertilizers and herbicides), min- But pellets also present some disadvantages:
eral processing (iron ore pelletization), food and – often pellets can not be pressed into tablets
detergent industry. because they are too rigid. In that case, pellets
have to be encapsulated into capsules.
RE SONS FOR PELLETIZATION – the production of pellets is often an expen-
sive process and / or requires highly special-
The pharmaceutical industry has developed a
ised equipment.
great interest in pelletization due to a variety of rea-
– the control of the production process is diffi-
sons (10):
cult (e.g. the amount of water to be added is
– prevention of segregation of co-agglomerated
critical for the quality of the pellets and over-
components, resulting in an improvement of
wetting can occur very easily).
the uniformity of the content;
– prevention of dust formation, resulting in an
improvement of the process safety, as fine pow- METHODS OF PELLETIZATION
ders can cause dust explosions and the respira- Pelletization methods used in the pharmaceuti-
tion of fines can cause health problems; cal industry can be grouped by various criteria, e.g.
– increasing bulk density and decreasing bulk by the type of equipment used, the intensity of the
volume; mechanical forces involved or the techniques em-
– the defined shape and weight improves the ployed for the production of pellets.
appearance of the product; The success of these methods depends on the
– improvement of the handling properties, due complex relations between the equipment, the for-
to the free-flowing properties; mulation and process variables (12 – 14).
– improvement of the hardness and friability of
pellets; Extrusion / Spheronisation
– controlled release application of pellets due Extrusion / spheronisation is a multistage pro-
to the ideal low surface area-to-volume ratio cess for obtaining pellets with uniform size from
that provides an ideal shape for the applica- wet granulates (extrudates).
tion of film coatings. The method involves the following main steps:
All these aspects can be considered as techno- – the dry mixing of the ingredients, in order to
logical advantages of pelletization. achieve homogenous powder dispersions;

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– wet massing, in which the powders are wet- Following the collisions between the extrudates
mixed to form a sufficiently plastic mass. with each other and with the friction plate and the
– an extrusion stage, in which the wet mass is stationary walls of the spheronization chamber, the
shaped into cylindrical segments with a uni- cylindrical segments change their shape and size.
form diameter; The transition from the almost cylindrical seg-
– the spheronisation stage, in which the small ments to spheres during the spheronisation process
cylinders are rolled into solid spheres (spher- occurs in several stages.
oids); The resulting spherical shape of the pellets is
– the drying of the spheroids, in order to achieve correlated to the peripheral velocity of the plate. As
the desired final moisture content; the spheronisation process begins, the processed
– screening (optional), to achieve the desired material begins to move inside the spheroniser on a
narrow size distribution. trajectory which resembles a woven rope.
Extrusion
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.
As the mass passes through the extruder screen,
the resulting extrudates eventually break under their
own weight. Usually the extrudates have the same
length. The extrudates must have enough plasticity
in order to deform, but an excessive plasticity may
lead to extrudates which stick to each other as they
are collected and further processed in the spher-
oniser. The diameter of the segments and the final
size of the spheroids depend on the diameter of the
openings in the extruder screen. Figure 2. The movement of the product along the chamber
In order to obtain reproductible results, it is rec- wall
ommended to monitor extrusion parameters such
as: feed rate, powder consumption, die temperature In addition, in order to obtain a high yield of
and compression chamber pressure. spherical pellets, it is essential that the extrudates
are non-friable and that they have suitable plastic
Spheronisation properties which allow them to take a spherical
Spheronisation reffers to the formation of spheri- shape.
cal particles from the small rods produced by extru- The process of spheroid formation by extrusion /
sion. The essential part of the spheronizer is the fric- spheronization is similar to the wet granulation pro-
tion plate. The indentation pattern on the plate can cess, claiming the presence of a moistening liquid.
have various designs, which correspond to specific However, there are two major differences in the
purposes. The most common design is the cross-hatch granulation steps:
pattern with grooves intersecting each other at 90° • the amount of granlation fluid required to
angles. In order to form spheroids, the extrudates are obtain pellets with uniform size and sphericity
brought onto the rotating friction plate of the spher- is likely to be higher than for a similar wet
onizer, which imparts a rolling motion to the material. granulation;
• uniform dispersion of the granulation fluid
leads to a product with a good quality.
Extrusion/spheronisation is a versatile process for
producing pellets with useful properties. However, the
process is more labour-intensive and more expensive
than the conventional wet-granulation technique, as its
use should be limited only to the production of spheri-
cal pellets for controlled release of drugs.
Technological advances now allow the produc-
Figure 1. The whirling movement tion of spherical pellets by new processes, such as
of the particles at the chamber wall fluid-bed granulation and rotary granulation.

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In these cases, specialized equipments allow the – bed load,

whole cycle of wet spheronization, drying and coat- – rate of adition of binder,
ing of the pellets to be performed in one closed sys- – temperature in the fluid bed of particles,
tem. – fluidizing air flow rate,
– temperature, volume and humidity of the air,
Fluid-bed Granulation – nozzle type and spray angle,
The process is carried out continuously in a flu- – droplet size.
id-bed granulator. Fluid-bed granulation has several advantages
It consists in the spraying of a granulation solu- over traditional wet granulation: the process is au-
tion onto the suspended particles, which then are tomated, performed in one unit, thus saving costs,
dried rapidly in the hot air stream. transfer losses and time. On the other side, the pro-
The fluid-bed granulation is performed follow- cess requires extensive efforts in the initial formula-
ing these steps (2): tion and in the scale-up from development to pro-
– the preblending of the formulation powder, duction.
including the active ingredients, fillers, disin-
tegrants, in a flow of air; Rotogranulation
– the granulation of the mixture by spraying a Rotogranulation is one of the most recent meth-
suitable liquid binder onto the fluidized (sus- ods for the production of spheroids.
pended) powder bed; The single-unit spheronizing system can be de-
– the drying of the granulated product to the de- scribed using terms like centrifugal granulator, ro-
sired moisture content. tary fluidized-bed granulator, rotary fluid bed, rota-
ry processor or rotor granulator.
Regardless the name of the equipment, they all
have the same main piece, a rotating disc. When the
equipment is operating, this disk provides a cen-
trifugal force which throws the pellets towards the
wall of the processing chamber.
Air via a slit between the disc and the wall of the
chamber moves the particles in a vertical direction.
As the fluidizing force decreases with the distance
above the slit, the pellets fall towards the bottom of
the disc.
The centrifugal force is in relation with the rota-
tion speed of the disc, while the vertical distance for
which the particles move is dependent on the air
velocity and volume.
Figure 3. The schematic representation of a fluid-bed
granulator
The combined action of the three forces gener-
ates a spiral, twisted, rope-like motion of the mate-
rial (7).
There are numerous equipment, processes and
product parameters that can influence the quality of
the final granules, such as:
– equipment parameters:
– the shape of the granulator body,
– the air distribution plate,
– the nozzle height,
– positive or negative pressure operation.
– product parameters:
– the type and quantity of the binder,
– the concentration and temperature of the
granulating solution,
– the properties of the starting materials (fluidi-
zation, hydrophobicity).
– process parameters: Figure 4. The schematic diagram of a rotary processor

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Subsequent to the granulation, the coating of the When using a centrifugal granulator, as the pel-
pellets by spraying them with a coating solution or lets rotate in a rope-like fashion, they are first wet-
a dispersion is possible in any of the all-in-one ted by the adhesive solution and the powder is add-
glanulation equipments described above. ed to the wet pellets immediately afterwards. This
cycle continues until the desired pellet size is ob-
Solution and Suspension Layering tained (17).
Layering a suspension or a solution of a drug on
a seed material (usually, a coarse crystal or nonpa- Spray-drying
reil) can produce pellets that are uniform in size dis- Spray-drying represents another process with
tribution and generally posess very good surphace limited application in the development of pharma-
morphology (15). ceutical pelletized products, based on globulation.
These characteristics are especially desirable During spray-drying, a drug solution or suspen-
when pellets will be coated for the purpose of sion is sprayed, with or without excipients, into a
achieving a controlled release. hot-air stream, generating dry and highly spherical
The equipment employed for this kind of pro- particles.
cesses consists of custom modified conventional
coating pans (perforated pans) and various configu-
rations of fluid-bed equipment.
There are many factors that determine the eco-
nomic and performance feasability of pellet coat-
ing.
Besides the process variables mentioned before,
there are other formulation variables, such as the
drug solubility in the media used for solution layer-
Figure 5. The schematic diagram of a spray-drier
ing, or the suspension concentration in solid parti-
cles for the suspension layering of the pellets, which
need to be taken into account. Though the technique is suitable for the devel-
opment of controlled-release pellets, it is generally
Dry Powder Layering employed to improve the dissolution rates and,
hence, the bioavailability of poorly soluble drugs.
This process is similar to the solution or suspen-
Also, this method is applied for processing heat-
sion layering. Instead of these dispersions, the lay-
sensitive pharmaceuticals, such as: amino acids, an-
ering is performed using a drug powder.
tibiotics, ascorbic acid, liver extracts, pepsin and
Usually, the process is carried out in convention-
al coating pans. similar enzimes, protein hydrolysate and thiamine
Initially, the nonpareils or starter seeds (neutral (2).
or innert pellets, beads, spheres) are charged into a The spray-dried powder particles are homoge-
rotating pan, then wetted by spraying an adhesive nous, approximately spherical, nearly uniform in
solution. As the wet seeds reach the front end of the size. The design and operation of the spray drier can
pan, the powder added in the vortex adheres to them influence a great number of the characteristics of
(16). the final product, such as particle size and size dis-
A baffle inserted into the rolling bed enhances tribution, bulk density, porosity, moisture content,
the vortex action, which in turn intensifies the mix- flowability and friability.
ing and shear, improving the adhesion of the of the
powder to the wet seeds. After the wet seeds pick up Spray-congealing
the powder, they are directed back into the upward Spray-congealing (spray-chilling) is a technique
moving bed and the entire process is repeated. In an similar to spray-drying.
intermitent powder layering process, the layering Spray-congealing is a process in which a drug is
solution is added until the bed is wet and tacky. The allowed to melt, disperse or dissolve in hot melts of
drug powder is then added, until the bed is dry. gums, waxes, fatty acids or other melting solids.
Warm drying air may be used after each cycle. The The dispersion is then sprayed into a stream of air
process continues untill all of the drug powder has and other gases with a temperature below the melt-
been added. In a continuous process, the layering ing point of the formulation components. Under ap-
solution and the drug powder are added simultane- propriate processing conditions, spherical con-
ously. gealed pellets are obtained.

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The resultant material can be used for the pro- Currently there are several pelletization meth-
duction of prolonged-release dosage forms (2, 8). ods, the most widely used being etxrusion / spher-
onization.
Due to the good technological, pharmacokinetic
CONCLUSIONS and biopharmaceutic characteristics of the pellets
In the later decades, pelletization has gained an and the flexibility of the maufacturing processes in-
increased interest, especially due to the posibilities volved, pellets are expected to continue to play a
to use pellets in the development of modified-re- major role in design and fabrication of solid dosage
lease solid oral dosage forms. forms.

BIBLIOGRAFIE
1. Matei I. E., Pelete în Iuliana Popovici, D. Lupuleasa, Tehnologie 10. L. Gu, C. V. Liew, P. W. S. Heng, Wet Spheronization by Rotary
Farmaceutică, vol. 3, ed. Polirom, 2009, 355-381 Processing – A Multistage Single-Pot Process for Producing Spheroids;
2. Leucuţa S. E., Tehnologie Farmaceutică Industrială, Ed. Dacia, Cluj Drug Dev. Ind. Pharm., vol. 30, No. 2., 111 – 123, 2004;
Napoca, 2001, 269 – 288; 11. *** Caleva processing solutions;
3. Summers M., Aulton M., Granulation, in Pharmaceutics: The science of 12. Bechegaard H., Nielson G. H., Controlled Release Multiple Unit and
Dosage Form Design, ed. by Aulton M., Churchill-Livingstone, 2002, 364 Single Unit Doses, Drug Dev. Ind. Pharm., 1978, 4, 53 – 67;
– 378; 13. Kristensen H. G., Agglomeration of powder, Acta Pharm. Succ., 1988,
4. Kearey M. C., Sheskey P. J., Drug Dev. And Ind. Pharm., vol. 30, No. 8, 25, 187 – 204;
831 – 832, 2004; 14. Schwartz J. B., Granulation, Drug Dev. Ind. Pharm., 1988, 14 (4), 2071
5. Cheboyina S., Walter G. C., Wyandt C. M., A Novel Freeze Pelletization – 2090;
Technique for Preparing Matrix Pellets, Pharm. Technology, Oct., 2004, 15. Kristensen H. G., Schaefer T., Granulations in Encyclopedia of
98; Pharmaceutical Technology, Swabrick J., Boylan J. C., Eds. Marcel
6. Crowley M. M. at all., Pharmaceutical Applications of Hot-melt Extrusion: Dekker Inc., New York, 1993, vol. 7, 121 – 160;
Part I., Drug Dev. Ind. Pharm., 33, 909 – 926, 2007; 16. David M. Jones, Solution and Suspension Layering, in Pharmaceutical
7. Palmieri F. G., Grifantini R., Di Martino P., Martelli S., Emulsion/Solvent Pelletization Technology, ed. by Ghebre-Sellasie I., Ed. Marcel Dekker
evaporation as an Alternative Technique in Pellet Preparation, Drug Dev. Inc., New York, 1989, 145 – 165;
Ind. Pharm., 26 (11), 1151 – 1158, 2000; 17. Sinchaipanit N et all., Influences of Layering Process on Theophylline
8. Sövgren K., Pellet preparation, in Industrial Aspects of Pharmaceutics, Pellet Characteristics, Pharm. Dev. Tech., 9, 136 – 170, 2004;
Ed. Sandell E., Swedish Pharmaceutical Press, Stockholm, 1992, 200 – 18. Goodhart F. W., Jan S., Dry Powder Layering, in Pharmaceutical
212; Pelletization Technology, ed. by Ghebre-Sellasie I., Ed. Marcel Dekker
9. Ghebre-Sellasie I., Pellets: a general view, in Pharmaceutical Inc., New York, 1989, 165 – 187.
Pelletization Technology; Ed. Marcel Dekker Inc., New York, 1989, 1 – 13;

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