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Pelletization Technology: Methods and Applications-A Review

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 Research J. Pharm. and Tech.8 (2): February 2015

ISSN 0974-3618 www.rjptonline.org

REVIEW ARTICLE

Pelletization Technology: Methods and Applications -A Review

Amita A. Ahir1*, Sachin S. Mali2, Ashok A. Hajare1, Durgacharan A. Bhagwat1,

Prasad V. Patrekar2
1
Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy, Near Chitranagari, Kolhapur,
416 013, Maharashtra, India
2
Department of pharmaceutics, Adarsh Institute of Pharmacy, Vita, 415 311, Maharashtra, India
*Corresponding Author E-mail: amita.ahir88@gmail.com, sachinmali143@gmail.com,
aahajare@rediffmail.com

ABSTRACT:
Pellets are small free flowing; spherical particulates manufactured by the agglomeration of fine powder or granules.
Different types of techniques used to produce pellets are referred to as pelletization techniques. In relation to
pharmaceuticals, pellets offer high degree of flexibility in design and development of oral dosage form. They offer
desired dose strength, can be blended to deliver incompatible bioactive agents and can be blended to provide different
release profiles. The most commonly use pelletization processes are Extrusion spheronization, Hot melt extrusion,
Solution or suspension layering, Powder layering, High shear pelletization, Freeze pelletization, Cryopelletization,
Crystallo-co-agglomeration, Wet spherical agglomeration, Spherical crystallization etc. In present review we will be
explaining widely used pelletization techniques especially are Extrusion Spheronization and Hot Melt Extrusion in
detail with methods and applications in pharmaceutical industries because these techniques represent an efficient
pathway for novel drug delivery system today.

KEYWORDS: Pellets, Extrusion spheronization, Hot melt extrusion, Current product portfolio etc.

INTRODUCTION:
Pellets are small free flowing, spherical particulate, In recent years, there has been a growing interest in the field
manufactured by the agglomeration of fine powder or of pelletization to produce spherical pellets which can be
granules1. changed into several dosages forms like tablet and capsule
or can be administered as such. Pelletization involves size
enlargement process and if the final agglomerates are
spherical in shape in the size range of 0.5-2.0 mm, they are
called pellets2,3,4. Pellets have numerous therapeutic as well
as technical advantages such as enhanced drug absorption
due to involvement of large GI surface in absorption
process, less gastric irritation by limiting localized buildup
and dose dumping, good flow ability due to uniform size
and shape, high tensile strength, low friability, narrow
particle size distribution, and uniform packing
characteristics.1-5

The pelletized products can improve the safety and efficacy

Fig.1. Pellets formation
Received on 20.12.2014
Accepted on 12.01.2015
Research J. Pharm. and Tech. 8(2): Feb. 2015; Page 131-138
Modified on 05.01.2015
© RJPT All right reserved
of the active agent. The pellets are directly filled into
capsule and can also be compressed into tablets.The
compression of pellets into tablets is much more ideal than
enclosing them in a hard gelatin capsule6. In multiple-unit
systems, the total drug dose is divided over many units.
Failure of a few units may not be as consequential as failure
of a single-unit system. Manufacturing of pellets using
layering process such as solution layering, suspension
layering or powder layering and extrusion-spheronization

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 Research J. Pharm. and Tech.8 (2): February 2015

process have been used over the years. These processes development of tiny drug pellets that could be loaded in
have major limitation such as use of granulating liquid capsule. (Hirjau M. et al, 2011)
which causes stability problems during processing and
storage. In recent years hot melt extrusion and freeze In 1964, a new pelletization technique that provided
pelletization have been used to produce spherical pellets sustained release pellets ranging in size between 0.25–2.0
without the use of water7. mm was patented by SKF at the same time marumerizer or
spheronizer was commercially introduced. The new
The word pellet is used to describe a variety of machine was developed in Japan and could produce large
systematically product geometrically defined agglomerates quantity of spherical pellets in short time. The marumerizer
obtained from diverse starting material.2,5 In the and variation of it were subsequently patent in USA. Direct
pharmaceutical industry, pellets can be defined as pharmaceutical application of the process for the
agglomerates of fine powders or granules of bulk drugs and development of pellets was first published in literature in
excipients. They consist of small, free-flowing, spherical or the early 1970 and the process has been the subject of
semi-spherical solid units, typically from about 0.5 mm to intensive research ever since. Although pellets have been
1.5 mm, and are intended usually for oral administration.2 It used in the pharmaceutical industries for more than 4
consist of small discrete unit and exhibit some derived decades, it has only been since the late 1970s, with the
characteristics produced by agglomeration of fine powder advent of controlled release technology, that the advantages
with binder solution normally the size of the pellets varies of pellets over single – unit dosage forms have been
from 0.5 – 1.5 mm for oral dosage form (Kulkarni P.A et. realized 8-10.
al, 2010). An innovative use of pellet in pharmaceutical
field are given as (I. Ghebre-Sellassie, 1989) Pelletization:
Pellets can be prepared by a special technique called
 Improve aesthetic appearance of products. Pelletization. This technique is referred to an agglomeration
 Achieve control release rate of drugs when coated with process that convert fine powder or granules of bulk drug or
polymers. excipient in to small , free flowing , spherical or semi
 Improve flow properties and flexibility in formulation spherical pellets .This technique is needed to produce
development and manufacturing. pellets of uniform size with high drug loading capacity and
 It has less variance in transient time through the gastro also prevent segregation and dust11.
intestinal tract (GIT) than a single unit dosage form
like tablet. Advantages of Pelletization Technique5-11
 When formulated as modified release dosage forms,
Application of spherical crystallization in pellets are less susceptible to dose dumping than reservoir
pharmaceuticals6,7: type single unit formulations.
• For increasing solubility and dissolution rate of poorly  Pellets are recommended for patients with difficulty in
soluble drug. swallowing and dysphasia like in case of children and aged
• For masking bitter taste of drug. people.
• Improve flow ability and compressibility.  Pelletization reduces intra and inters subject variability
• Reduces cost of production7 of plasma profiles by reducing variations in gastric
Pellets can be defined as small, free flowing, spherical emptying rates and overall transit times.
particulates manufactured by the agglomeration o fine  Pelletization produces spheroids with high loading
powder and granules of drug substances and excipients capacity of active ingredient without producing extensively
typically from about 0.5mm to 1.5mm, by using appropriate large particles.
processing equipment.8  Pellets exhibit better roundness than the commercial
non-pareil seeds and have excellent flow and packing
The pelletized products can improve the safety and efficacy properties.
of the active agent. These multiple-unit doses are usually  Pellets composed of different drugs can be blended and
formulated in the form of suspensions, capsules or formulated in single unit dosage form that facilitates
disintegrating tablets, showing a number of advantages over delivery of two or more chemically compatible or
the single-unit dosage system. In multiple-unit systems, the incompatible drugs at the same or different site in GI tract.
total drug dose is divided over many units. Failure of a few  Incompatible drugs processed separately and mixed
units may not be as consequential as failure of a single-unit later, or pellets with different release mechanisms can be
system. This is apparent in sustained release (SR) single- mixed to give a new modified release profile.
unit dosage forms, where a failure may lead to dose-  Pellets reduce peak plasma fluctuations and minimize
dumping of the drug.2 potential side effects without appreciably lowering the drug
bioavailability.
Historical development  Pellets disperse freely in the GI tract and hence greater
A major breakthrough occurred in 1949 when a absorption of the active drug occurs.
pharmaceutical scientist SmithKline and French (SKF)  Particles less than 2-3 mm rapidly pass the pylorus
realized the potential application of candy seeds in regardless of the filling level of the stomach or the size and
sustained release preparation and embarked on the
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 Research J. Pharm. and Tech.8 (2): February 2015

density of chyme. Also, GI irritations are limited spread as delivery system. HME consists of thermal agent or
the particles spread in the intestine. polymer, an active ingredient, release modifying agents,
bulking agents and processing agents. The HME offers
Pelletization Technique:6-9 some advantage over a wet mass extrusion and
1. Powder Layering technique spheronization method, like; it is a simple, efficient and
2. Suspension / Solution layering technique continuous process requires fewer processing stages. HME
3. Extrusion and Spheronization1 is continuous process as it does not require a lengthy drying
I. Dry mixing stage since it does not involve addition of water or other
II. Wet Massing solvent. The absence of water may prevent drug
III. Extrusion degradation as many drugs are unstable in presence of
IV. Spheronization water. It produces a spherical shape pellets with narrow
V. Drying range particle size distribution. Reduce the loss of coating
VI. Screening material during the coating process associated with wet
mass extrusion process. It is a convenient technology for
i. Screw fed extruders preparation of solid dispersion and solid solution for
a) Axial screw extruders delivery of poorly soluble drug as it offers an advantage of
b) Radial screw extruders solvent free formulation of solid dispersion. It helps to
ii. Gravity-fed extruders mask the bitter taste of the active ingredient. Poorly
a) The Rotary Cylinder compatible materials can be incorporated into tablets
b) Rotary-Gear Extruder produced by cutting an extruded rod. Key Factors affecting
iii. Ram Extruders Hot melt extrusion: Pharmaceutical grade polymer which is
iv. Marumerizer functional at low temperature and its selection depends on
a) Static cylinder or stato drug polymer miscibility, polymer stability, function of
b) Rotating friction plate. final dosage form and thermal stability of drug as well as
excipients. Hot melt extrusion is classified as the molten
4. Spherical Agglomeration system under control and semisolid viscous system, in
Liquid-induced agglomeration former case heat is applied to material in order to control its
Melt-induced agglomeration viscosity and enable it to flow through the die, while the
5. Spray Drying and Spray Congealing later case is a multiphase concentrated dispersion where
6. Extrusion spheronization1 high solid content portion is mixed with liquid phase. Hot
7. Cryopelletization melt extrusion equipment consist of an extruder, auxiliary
8. Hot Melt Extrusion equipment for downstream processing and monitoring tool
9. Freeze pelletization for performance and product quality evaluation26. HME
process is divided in to four sections namely, feeding of
HOT MELT EXTRUSION: extruder, conveying of mass [mixing and reduction of
In order to overcome the problems associated with the particle size], flow through the die and exit from the die and
pellets produced by layering and extrusion spheronization downstream processing.
technique, melt agglomeration and hot melt extrusion
technique are in used in pharmaceutical industries. This In hot melt extrusion process, extrusion channel is
method eliminates instability problem during processing conventionally divided into three sections that are feed
and storage due to presence of water. Furthermore, pellets zone, transition zone, and metering zone. The monitor and
produced by these techniques do not require additional film controlling parameter in HME are barrel temperature, feed
coating since drug release is diffusion controlled. There is rate, screw speed, motor load and melt pressure. Extruder
slight difference between these two methods. Melt consist of two rotating screw inside a stationary cylindrical
agglomeration is a process by which the solid fine particles barrel. And an endplate die connected to the end of barrel
are bound together into agglomerates, by agitation, determines the shape of extruded products28. Various
kneading, and layering, in the presence of a molten binding studies have been conducted using this technique to
liquid. Dry agglomerates are obtained as the molten binding produce sustained release pellets of diltiazem HCl, using
liquid solidifies by cooling.3 polymers such as ethyl cellulose, cellulose acetate butyrate,
poly ethylene co vinyl acetate. The resulting pellets
Researchers have investigated a new modified method for exhibited smooth surface, low porosity and showed slow
preparing matrix pellets for controlled release drug delivery drug release. Fabrication of a transdermal patch have been
system to overcome the disadvantages associated with wet done using Killion melt extruder for HPMC films
mass extrusion and spheronization process which is called employing PEG 8000, 2% triethyl citrate, 2% acetyl tributyl
as a Hot Melt Extrusion (HME) method where a thermal citrate, 2% PEG 400 using 1% hydrocortisone and 1%
agent softens or gets melted during the process to obtain chlorpheniramine maleate as a model drug. Utilization of a
matrix pellets. HME has been widely used technique in ram extruder in the preparation of fast release dosage form
plastic industries and now it is used in pharmaceutical with uniform shape and density, containing carbamazepine
industries for formulation of sustained release, controlled as poorly soluble model drug and PEG 4000 as a
release and transdermal as well as transmucosal drug hydrophilic carrier and low melting binder, revealed that the
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 Research J. Pharm. and Tech.8 (2): February 2015

extruded mixture of equal composition exhibited more rapid

release than simple physical mixture. Controlled release
theophylline pellets were prepared by hot melt extrusion
method using eudragit preparation 4135 F, microcrystalline
cellulose and poly ethylene glycol 8000 powder. The
evaluation studies showed that pellet follows diffusion
controlled drug release which is influenced by polymer
swelling and pH dependent dissolution. Sustained release
matrix tablets of chlorpheniramine maleate were prepared
by hot melt extrusion method using polyethylene oxide as
drug carrier, the evaluation studies revealed that drug
release was controlled by erosion of matrix and the
diffusion of drug took place through swollen gel layer at
surface of the tablet.

During a melt agglomeration process, the meltable binder

may be added as molten liquid, or as dry powder or flakes.
In the latter, the binder may be heated by hot air or by a Fig.3. Process of HME1
heating jacket above the melting point of the binder.
Alternatively, the melt agglomeration process exploits an Types of hot melt extrusion equipment
extremely high shear input, of a high-shear mixer, where Single screw extruder
the heat of friction alone raises the temperature of the
binder and effects melting. Typically, the melting points of
meltablebinders range from 50 to 80°C. A lower-melting-
point binder risks situations where melting or softening of
the binder occurs during handling and storage of the
agglomerates. Advantage and disadvantage of these
techniques are given below:11-20

Diagrammatic representation HME

Fig.4. Single screw extruder1

Twin screw extruder

Screws can either rotate in the co-rotating extruder or the

counter-rotating extruder direction.

Fig.2. Diagrammatic representation HME1

The material in which the drug is dispersed is called

thermal carrier. The carrier polymer or low melting point
wax like polyethylene glycol, paraffin wax etc.

Fig.5. Twin screw extruder1

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Advantages:
 Any solvent or water is not used in this process. Equipment used in ES Techniques
 Drying steps are eliminated, processing steps are short. Screw fed extruder
 Entire procedure is simple, continuous and efficient. A. Axial extruder
 Uniform dispersion of fine particle takes place during
processing.
 Good stability of the final product at varying pH and
moisture condition.

Disadvantages:
 Requires high energy input.
 This technique cannot be applied for heat-sensitive
materials owing to the elevated temperatures involved.
 Because melting or softening of the binder occurs
during handling and processing steps so, lower-
melting-point binder risks the situation.
 Higher-melting-point binders require high melting
temperatures and can contribute to instability problems
especially for heat-labile materials.3
Fig.7. Axial extruder
Applications:
1
Table No. 2: Applications B. Radial extruder
Formulation type Drug
Sustained release pellets Diltiazem hydrochloride
Sustained release pellets Chlorpheniramine maleate
Controlled release pellets Theophylline
Controlled release pellets Diclofenac sodium
Targeted local drug delivery Ketoconazole
Mini Matrices pellets Metoprolol tartrate

General applications6,10,11
 Masking the bitter taste of an active drug.
 Formation of polymer drug solutions.
 Increased drug solubility.
 Improving drug dissolution rate.
 Formulation of controlled release dosages.
 Formulation of targeted release dosages.

Extrusion Spheronization1, 12-25 Fig.8. Radial extruder

Shaping the wet mass into cylinders called extrusion.
Breaking up the extrudate and rounding of the particles into
spheres called spheronization.
Gravity fed extruder
A. Rotary cylinder extruder

Fig.9. Rotary cylinder extruder

Fig.6. Process of ES

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 Research J. Pharm. and Tech.8 (2): February 2015

B. Rotary gear extruder ADVANTAGES1:

Therapeutic
 Ability to mix pellets with different release rates.
 Reduced risk of dose dumping.
 Reduced risk of local irritation in GIT.
 Less variable bioavailability.
 Easy mixing of non-compatible products spherical
particles.

Physical
 Improved flow characteristics.
 Uniform packing characteristics.
 Dust free.
 Low friability.
Fig.10. Rotary gear extruder  Easy to coat.

Ram extruder Disadvantages

Piston displaces and forces the material through a die at the  Spheres fracturing.
end. Ram extruders are preferentially used in the  Extrudate not densified sufficiently.
development phase.  Momentum too low.
 Minimum porosity.
 Sticking can occurs on the friction plate and bowl wall.
 Lubricant it will increase the plasticity but also
increase the amount of fine dust.

APPLICATIONS:
Table No. 2: Applications1
Formulation type Drug
Sustained release pellets Omeprazole
Sustained release pellets Pantoprazole
Immediate release pellets Tramadol
Matrix pellets Atenolol
Extended release pellets Verapamil hydrochloride
Fig.11. Ram extruder Self emulsifying pellets Aceclofenac
Colon targeting pellets Ibuprofen
MECHANISM OF SPHERONIZATION PROCESS1
Example
Three layered pellets of budesonide were prepared for colon
delivery by ES method.

Fig.13. Multi layer film coated pellet

Fig.12. Mechanism of spheronization process

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 Research J. Pharm. and Tech.8 (2): February 2015

FACTOR AFFECTING PELLETIZATION D IMMEDIATE RELEASE COATED Pellets

TECHNIQUE25-29 18 Folic Acid
 Moisture Content
 Rheological characteristics 19 Domperidone
 Solubility of excipients and Drug in granulating fluid 20 Itraconazole
 Composition of Granulating Fluid
21 Flurbiprofen
 Physical Properties of Starting Material
 Speed of the Spheronizer
 Drying technique and drying temperature II: Oral Cephalosporins (API)
 Extrusion Screen API (Product List)

EVALUATION OF PELLETS25-29 1. Cefixime

 Size Distribution 2. Cephalexin
 Pellets Shape
3. Cephradin
 Surface Morphology
 Specific Surface Area 4. Cefaclor
 Friability 5. Cefuroxime Axetil
APPLICATIONS 1.16 6. Cefadroxil
 Taste masking 7. cefadinir
 Immediate release
8. Cefopodoxime
 Sustained release
 Chemically incompatible products
 Varying dosage without reformulation CONCLUSION:
Pelletization lays the scope for different oral immediate or
CURRENT PRODUCT PORTFOLIO12, 29-31 controlled delivery system. Due to its simple design,
I: “PELLETS FOR CAPSULE/TABLET DOSAGE efficiency of producing spherical pellets and fast
FORMS” processing; it has found a special place in the
pharmaceutical industry and moreover its use in production
A ENTERIC COATED/DELAYED RELEASE PELLETS of multiparticulate oral controlled release dosage forms
Name of drug(s) overtaking granulation. Today extrusion spheronization and
melt extrusion spheronization represents an efficient
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3. Esomeprazole Magnesium
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