INTRODUCTION:
Pellets are small free flowing, spherical
particulate, manufactured by the agglomeration of fine powder or granules1.
Fig.1. Pellets formation
In recent years, there has been a growing
interest in the field of pelletization to produce spherical pellets which can
be 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 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
process have been used over the years. These processes have major limitation
such as use of granulating liquid which causes stability problems during
processing and storage. In recent years hot melt extrusion and freeze
pelletization have been used to produce spherical pellets without the use of
water7.
The word pellet is used to describe a
variety of systematically product geometrically defined agglomerates obtained
from diverse starting material.2,5
In the pharmaceutical industry, pellets can be defined as agglomerates of fine
powders or granules of bulk drugs and excipients. They consist of small,
free-flowing, spherical or semi-spherical solid units, typically from about 0.5
mm to 1.5 mm, and are intended usually for oral administration.2 It
consist of small discrete unit and exhibit some derived characteristics produced
by agglomeration of fine powder with binder solution normally the size of the
pellets varies from 0.5 – 1.5 mm for oral dosage form (Kulkarni P.A et. al,
2010). An innovative use of pellet in pharmaceutical field are given as (I.
Ghebre-Sellassie, 1989)
§ Improve aesthetic appearance of
products.
§ Achieve control release rate of
drugs when coated with polymers.
§ Improve flow properties and
flexibility in formulation development and manufacturing.
§ It has less variance in
transient time through the gastro intestinal tract (GIT) than a single unit
dosage form like tablet.
Application of spherical crystallization in
pharmaceuticals6,7:
•
For increasing solubility and dissolution rate of poorly soluble
drug.
•
For masking bitter taste of drug.
•
Improve flow ability and compressibility.
•
Reduces cost of production7
Pellets can be defined as small, free
flowing, spherical particulates manufactured by the agglomeration o fine powder
and granules of drug substances and excipients typically from about 0.5mm to
1.5mm, by using appropriate processing equipment.8
The pelletized products can improve the
safety and efficacy of the active agent. These multiple-unit doses are usually
formulated in the form of suspensions, capsules or disintegrating tablets,
showing a number of advantages over the single-unit dosage system. 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.
This is apparent in sustained release (SR) single-unit dosage forms, where a
failure may lead to dose-dumping of the drug.2
Historical
development
A major breakthrough occurred in 1949 when
a pharmaceutical scientist SmithKline and French (SKF) realized the potential
application of candy seeds in sustained release preparation and embarked on the
development of tiny drug pellets that could be loaded in capsule. (Hirjau M. et
al, 2011)
In 1964, a new pelletization technique that
provided sustained release pellets ranging in size between 0.25–2.0 mm was
patented by SKF at the same time marumerizer or spheronizer was commercially
introduced. The new machine was developed in Japan and could produce large
quantity of spherical pellets in short time. The marumerizer and variation of
it were subsequently patent in USA. Direct pharmaceutical application of the
process for the development of pellets was first published in literature in the
early 1970 and the process has been the subject of intensive research ever
since. Although pellets have been used in the pharmaceutical industries for
more than 4 decades, it has only been since the late 1970s, with the advent of
controlled release technology, that the advantages of pellets over single –
unit dosage forms have been realized 8-10.
Pelletization:
Pellets can be prepared by a special
technique called Pelletization. This technique is referred to an agglomeration
process that convert fine powder or granules of bulk drug or excipient in to small , free flowing , spherical or semi
spherical pellets .This technique is needed to produce pellets of uniform size
with high drug loading capacity and also prevent segregation and dust11.
Advantages of
Pelletization Technique5-11
§ When formulated as modified
release dosage forms, pellets are less susceptible to dose dumping than
reservoir type single unit formulations.
§ Pellets are recommended for
patients with difficulty in swallowing and dysphasia like in case of children
and aged people.
§ Pelletization reduces intra and
inters subject variability of plasma profiles by reducing variations in gastric
emptying rates and overall transit times.
§ Pelletization produces spheroids
with high loading capacity of active ingredient without producing extensively
large particles.
§ Pellets exhibit better roundness
than the commercial non-pareil seeds and have excellent flow and packing
properties.
§ Pellets composed of different
drugs can be blended and formulated in single unit dosage form that facilitates
delivery of two or more chemically compatible or incompatible drugs at the same
or different site in GI tract.
§ Incompatible drugs processed
separately and mixed later, or pellets with different release mechanisms can be
mixed to give a new modified release profile.
§ Pellets reduce peak plasma
fluctuations and minimize potential side effects without appreciably lowering
the drug bioavailability.
§ Pellets disperse freely in the
GI tract and hence greater absorption of the active drug occurs.
§ Particles less than 2-3 mm
rapidly pass the pylorus regardless of the filling level of the stomach or the size
and density of chyme. Also, GI irritations are limited spread as the particles spread
in the intestine.
Pelletization
Technique:6-9
1.
Powder Layering technique
2. Suspension / Solution layering technique
3.
Extrusion and Spheronization1
I. Dry mixing
II. Wet Massing
III. Extrusion
IV. Spheronization
V.
Drying
VI. Screening
i. Screw fed extruders
a) Axial screw extruders
b) Radial screw extruders
ii. Gravity-fed extruders
a) The Rotary Cylinder
b) Rotary-Gear Extruder
iii. Ram Extruders
iv. Marumerizer
a) Static cylinder or stato
b) Rotating friction plate.
4.
Spherical Agglomeration
Liquid-induced agglomeration
Melt-induced agglomeration
5.
Spray Drying and Spray Congealing
6.
Extrusion spheronization1
7.
Cryopelletization
8. Hot Melt Extrusion
9. Freeze pelletization
HOT MELT
EXTRUSION:
In order to overcome the problems
associated with the pellets produced by layering and extrusion spheronization
technique, melt agglomeration and hot melt extrusion technique are in used in
pharmaceutical industries. This method eliminates instability problem during
processing and storage due to presence of water. Furthermore, pellets produced
by these techniques do not require additional film coating since drug release
is diffusion controlled. There is slight difference between these two methods.
Melt agglomeration is a process by which the solid fine particles are bound
together into agglomerates, by agitation, kneading, and layering, in the
presence of a molten binding liquid. Dry agglomerates are obtained as the
molten binding liquid solidifies by cooling.3
Researchers have investigated a
new modified method for preparing matrix pellets for controlled release drug
delivery system to overcome the disadvantages associated with wet mass
extrusion and spheronization process which is called as a Hot Melt Extrusion
(HME) method where a thermal agent softens or gets melted during the process to
obtain matrix pellets. HME has been widely used technique in plastic industries
and now it is used in pharmaceutical industries for formulation of sustained
release, controlled release and transdermal as well as transmucosal drug
delivery system. HME consists of thermal agent or polymer, an active
ingredient, release modifying agents, bulking agents and processing agents. The
HME offers some advantage over a wet mass extrusion and spheronization method,
like; it is a simple, efficient and continuous process requires fewer
processing stages. HME is continuous process as it does not require a lengthy
drying stage since it does not involve addition of water or other solvent. The
absence of water may prevent drug degradation as many drugs are unstable in
presence of water. It produces a spherical shape pellets with narrow range particle
size distribution. Reduce the loss of coating material during the coating
process associated with wet mass extrusion process. It is a convenient
technology for preparation of solid dispersion and solid solution for delivery
of poorly soluble drug as it offers an advantage of solvent free formulation of
solid dispersion. It helps to mask the bitter taste of the active ingredient.
Poorly compatible materials can be incorporated into tablets produced by
cutting an extruded rod. Key Factors affecting Hot melt extrusion:
Pharmaceutical grade polymer which is functional at low temperature and its
selection depends on drug polymer miscibility, polymer stability, function of
final dosage form and thermal stability of drug as well as excipients. Hot melt
extrusion is classified as the molten system under control and semisolid
viscous system, in former case heat is applied to material in order to control
its viscosity and enable it to flow through the die, while the later case is a
multiphase concentrated dispersion where high solid content portion is mixed
with liquid phase. Hot melt extrusion equipment consist of an extruder,
auxiliary equipment for downstream processing and monitoring tool for
performance and product quality evaluation26. HME process is divided in to four
sections namely, feeding of extruder, conveying of mass [mixing and reduction
of particle size], flow through the die and exit from the die and downstream
processing.
In hot melt extrusion process,
extrusion channel is conventionally divided into three sections that are feed
zone, transition zone, and metering zone. The monitor and controlling parameter
in HME are barrel temperature, feed rate, screw speed, motor load and melt
pressure. Extruder consist of two rotating screw inside a stationary cylindrical
barrel. And an endplate die connected to the end of barrel determines the shape
of extruded products28. Various studies have been conducted using this
technique to produce sustained release pellets of diltiazem HCl, using polymers
such as ethyl cellulose, cellulose acetate butyrate, poly ethylene co vinyl
acetate. The resulting pellets exhibited smooth surface, low porosity and
showed slow drug release. Fabrication of a transdermal patch have been done
using Killion melt extruder for HPMC films employing PEG 8000, 2% triethyl
citrate, 2% acetyl tributyl citrate, 2% PEG 400 using 1% hydrocortisone and 1%
chlorpheniramine maleate as a model drug. Utilization of a ram extruder in the
preparation of fast release dosage form with uniform shape and density,
containing carbamazepine as poorly soluble model drug and PEG 4000 as a
hydrophilic carrier and low melting binder, revealed that the 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 heating jacket above
the melting point of the binder. Alternatively, the melt agglomeration process
exploits an extremely high shear input, of a high-shear mixer, where 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.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.3. Process of HME1
Types of hot melt extrusion equipment
Single screw extruder
Fig.4. Single screw
extruder1
Twin screw extruder
Screws can either rotate in the co-rotating
extruder or the counter-rotating extruder direction.
Fig.5. Twin screw extruder1
Advantages:
§ Any solvent or water is not used
in this process.
§ Drying steps are eliminated,
processing steps are short.
§ Entire procedure is simple,
continuous and efficient.
§ 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
Applications:
Table No. 2: Applications1
|
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
Shaping the wet
mass into cylinders called extrusion. Breaking up the extrudate and rounding of
the particles into spheres called spheronization.
Fig.6. Process of ES
Equipment used in ES Techniques
Screw fed extruder
A.
Axial extruder
Fig.7. Axial extruder
B. Radial extruder
Fig.8. Radial extruder
Gravity fed
extruder
A.
Rotary cylinder extruder
Fig.9. Rotary cylinder extruder
B.
Rotary gear extruder
Fig.10. Rotary gear extruder
Ram extruder
Piston displaces and forces the material
through a die at the end. Ram extruders are preferentially used in the
development phase.
Fig.11. Ram extruder
MECHANISM OF SPHERONIZATION PROCESS1
Fig.12. Mechanism
of spheronization process
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.
§ Easy to coat.
Disadvantages
§ Spheres fracturing.
§ Extrudate not densified
sufficiently.
§ 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
|
|
Self emulsifying
pellets
|
Aceclofenac
|
|
Colon targeting
pellets
|
Ibuprofen
|
Example
Three layered pellets of budesonide were
prepared for colon delivery by ES method.
Fig.13. Multi
layer film coated pellet
FACTOR AFFECTING
PELLETIZATION TECHNIQUE25-29
§ Moisture Content
§ Rheological characteristics
§ Solubility of excipients and
Drug in granulating fluid
§ Composition of Granulating Fluid
§ Physical Properties of Starting
Material
§ Speed of the Spheronizer
§ Drying technique and drying
temperature
§ Extrusion Screen
EVALUATION OF
PELLETS25-29
§ Size Distribution
§ Pellets Shape
§ Surface Morphology
§ Specific Surface Area
§ Friability
APPLICATIONS1.16
§ Taste masking
§ Immediate release
§ Sustained release
§ Chemically incompatible products
§ Varying dosage without
reformulation
CURRENT PRODUCT PORTFOLIO12, 29-31
I: “PELLETS FOR CAPSULE/TABLET DOSAGE
FORMS”
|
A
|
ENTERIC
COATED/DELAYED RELEASE PELLETS
|
|
|
Name
of drug(s)
|
|
1.
|
Aspirin
|
|
2.
|
Diclofenac
Sodium
|
|
3.
|
Esomeprazole
Magnesium
|
|
4.
|
Lansoprazole
|
|
5.
|
Omeprazole
|
|
6.
|
Pantoprazole
|
|
7.
|
|
|
8.
|
|
|
9.
|
|
|
10.
|
|
|
11.
|
|
|
B
|
|
EXTENDED
RELEASE/TIME RELEASE/SUSTAINED RELEASE AND CONTROLLED RELEASE PELLETS
|
|
|
12
|
|
|
13
|
|
|
14
|
|
|
C
|
|
Taste
Masked Micro Pellets
|
|
|
15
|
|
|
16
|
|
|
17
|
|
Ciprofloxacin
Hydrochloride
|
|
|
D
|
|
IMMEDIATE
RELEASE COATED Pellets
|
|
|
18
|
|
|
19
|
|
|
20
|
|
|
21
|
|
II: Oral Cephalosporins (API)
CONCLUSION:
Pelletization lays the scope for different
oral immediate or controlled delivery system. Due to its simple design,
efficiency of producing spherical pellets and fast processing; it has found a
special place in the pharmaceutical industry and moreover its use in production
of multiparticulate oral controlled release dosage forms overtaking
granulation. Today extrusion spheronization and melt extrusion spheronization
represents an efficient pathway for novel drug delivery system. Using these
pelletization techniques we can formulate suitable dosage forms of drugs that
will have more patient compliance, safety and efficacy.
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