Unit 3 - Pellets -Rajesh.pdf

Pellets

1. PELLETS
•Introduction,
•Formulation requirements,
•Pelletization process
•Equipments for manufacture of
pellets.
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2. •Pellets can be defined as small free flowing spherical particles
manufactured by the agglomeration of fine powders or granules of
drug substances and excipients using appropriate equipment.
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•Pelletization is an agglomeration process that converts fine powders
or granules of bulk drugs and excipients into small, free flowing,
spherical or semi spherical units, referred to as pellets.
•Taken orally, pellets generally disperse freely in the gastrointestinal
tract, and consequently maximize the drug absorption, minimize
local irritation of the mucosa by certain irritant drugs because of the
small quantity of drug available in a single pellet.

3. • Pellets are spherical or nearly spherical, free-flowing
granules with a size varying between 500 and 1500 μm for
pharmaceutical applications.
•They are generally produced via pelletization process
whereby a powder blend consisting of an API and excipient
particles is agglomerated into spherical granules.
•After being processed, pellets are usually filled into hard
gelatin capsules or compressed into tablets.
• Furthermore, they can be formulated as immediate release
dosage form or as sustain drug release over a long duration
time or can be coated also to deliver a drug to a specific site of
action in the gastrointestinal tract(enteric coated).

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Advantages of Pellets:
•Spheronization will reduce the amount of fines generated
during handling or transportation. Prevent of dust formation
results in an improvement of the process safety, as fine
powders can cause dust explosions and the respiration of fines
can cause health problems.
•The defined shape and weight improves the appearance of the
product. Attract consumers & marketing.
•Handling is easy, due to the free-flowing of pellets.
• Improved flow characteristics: Spheres have excellent flow
properties which can be used in automated processes or in
processes where exact dosing is required(Drug content
uniformity) E.g. In tabletting & capsule filling.

5. Advantages of Pellets: Cont..
•Spheronization increases the hardness and and reduces the
friability.
•Controlled release application is easy. The easiest shape to
coat is the sphere due to the absence of edges.
•Incompatible drugs can be blended.
•They also provide different release profiles at same site or
different sites in the GIT.
•Pellets offer high degree of flexibility in the design and
development of oral dosage form like suspension, sachet, tablet
and capsule.
•Pellets disperse freely in GI tract, maximize drug absorption,
and minimize local irritation of the mucosa by certain irritant
drugs.

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Therapeutic advantages:
•Pellets can disperse freely throughout the GIT after administration and
hence the drug absorption is maximized.
•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.
•Modified-release multiparticulate delivery systems are less susceptible
to dose dumping than single unit dosage forms like tablets and capsules.
Disadvantages:
•Pellets are difficult to compress into tablets due to rigidness and hence
it is often delivered encapsulated in hard gelatin capsules.
•Pelletization demands highly sophisticated and specialized equipment,
thereby increasing the cost of manufacturing.
•Pellets filling involve capsule filling which can increase the costs.
•Tableting of pellets destroy film coating on the pellets.

7. Desirable Properties of Pellets:
1. For Uncoated pellets:
a. Uniform spherical size & shape
b. Good flow property
c. High strength
d. Low friability
e. Even surface
f. Low dust formation
g. Ease of coating
2. For Coated pellets:
a. Maintain all above properties
b. Desirable drug release characteristics

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Formulation Requirements:
•API:- Variety of drugs are used to develop IR or SR pellets.
•Binders:- For Agglomeration. E.g- Starch paste, gelatin solution, PVP, etc.
•Fillers:-To increase the bulk. E.g-MCC, Lactose, etc.
•Plasticizer:-Improve flexibility. E.g-Glycerol, PG, Castor oil, etc.
•Flavor/Color/Sweetener/ wetting agents/disintegrants/release modifiers:-
E.g-Vanilla/Sunset yellow/Sucrose/SLS/CCS/Eudragit RL & RS.
Various techniques of Pelletization
•Powder layering technique
•Solution / suspension layering technique
•Extrusion - spheronization technique
•Hot melt extrusion technique
•Cryopelletization
•Spray congealing / spray drying

9. 1.Powder Layering Technique: Various steps involved in this
technique are as follows:
1.Sifting/milling the drug and excipients.
2.Loading of non pareil seeds (Dummy granules or sugar pellets) in
the fluid bed coater containing conical rotor. Drug is sprayed through
powder gun and binder solution is sprayed through solution spray gun.
3.Drying.
4.Sizing (Sifting or Milling).
5.Functional coating (Enteric or modified release polymer coating).
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10. •Powder layering involves the deposition of successive layers
of dry powder of drug or excipients or both on cores with the
help of a binding liquid.
•Because powder layering involves the simultaneous
application of the liquid and dry powder, it generally requires
specialized equipment. Equipments for powder layering
processing as a pelletizing techniques are- tangential spray
fluid bed granulators.
•With powder layering, the inner wall is closed so that
simultaneous application of liquid and powder could proceed
until the pellets have reached the desired size. The inner wall
is then raised, and the spheres enter the drying zone where
they are dried.

11. 2.Solution / suspension
layering technique:
Various steps involved in this
technique are as follows:
1.Sifting / Milling of drug and
excipients.
2.Loading of non pareil seeds.
Conventional coating pan, fluid
bed granulator, Wurster coating
are used in this technique
3.Deposition of solution or
suspension containing drug &
binder on inert core material (drug
and excipients are dissolved or
suspended in binder solution)
4.Drying
5.Sizing
6.Functional coating
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3.Extrusion and Spheronization Technique (Pelletizer):
•It is a multistep process capable of making uniform sized spherical
particles or pellets. Its primary use to produce controlled release or
sustained release granules.
•Extrusion spheronization consists of the following steps:
i. Process of dry blending: Dry blending/mixing of all components is
made to produce a mixture of uniformly blended powder utilizing
distinctive kinds of blenders such as a high shear blender, planetary
blender, twin shell blender, and tumbler blender.
ii. Process of wet massing/ granulation: Wet massing of dry powder is
done to obtain an adequate dense mass for the extrusion process. This
process is the same as a customary wet granulation.
iii.Extrusion: Wet granules are extruded through the extruder which
contains the mesh and form thread like coherent mass.It produces rod
shaped particles of uniform diameter from wet mass.(i.e) The wet mass
is forced through dies and shaped into small cylindrical particles with
uniform diameter.

13. iv. Spheronization:Then it is transferred to the spheronizer,
the thread like granules are cutted through blades and shaped
into spherical shaped granules through the fast moving
centrifugal rotor.
v. Drying (tray dryer), screening (sieves) & coating (coating
pan).
Advantages:
Uniform size pellets formed
Modified release granules are formed
Low dose drug are loaded in the granules easily
Disadvantages:
Multistep process & Expensive

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16. 4.Hot Melt extrusion method:
It is process of pumping raw materials with a rotating screw
under elevated temperature through a die into a product of
uniform shape. Rotating screw impose mixing and agitation
result in the de-aggregation of suspended particles in the
molten polymer resulting in the more uniform dispersion.
Method:
•The drug substance and excipients are converted into a
molten or semi molten state at predetermined temp. and
pumped (extruded) through a die which cuts the extrudates into
uniform cylindrical segments by a cutter and then they are
spheronized to form pellets & the resulting pellets are dried.
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5.Cryo pelletization:
•This is the process whereby droplets of liquid formulations such as
solution, suspension or emulsion are converted into pellets by using
liquid nitrogen as solidifying medium at -160°C.
•The technology which was initially developed for lyophilization of
viscous bacterial suspension can be used to produce drug-loaded pellets
in liquid nitrogen at -160°C.
•The procedure permits instant and uniform freezing of the processed
material which facilitate the drying process.
•The pellets are dried in conventional freeze dryers to remove water or
organic solvents.
•The amount of liquid nitrogen required for depends on the solids
content and temperature of the solution or suspension being processed.
•It is usually between 3 and 5 kg of liquid nitrogen per kilogram of
finished pellets is required.

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20. Spray drying and Spray congealing:
•Both are known as Globulation processes which involve atomization of
hot melts, solutions or suspensions to generate spherical particles of
pellets.
•During spray drying, drug solution or suspension are sprayed with or
without excipients using atomizer, into a hot air stream. As the atomized
droplets come in contact with hot air evaporation chamber, the droplets
converted in pellets. The spray dried powder particles are homogenous,
approximately spherical and nearly uniform in size.
•Spray congealing procedure involves formation of spherical particles by
introduction of molten liquid containing drug particles which is sprayed
into a cooling chamber having air at lowered temperature to get spherical
congealed pellets. (i.e)It 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 stream of air with a
temperature below the melting point of formulation components.
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Evaluation of Pellets:
Flowability:
Density and porosity, Angle of repose, Hausner ratio and Carr index
(% compressibility index) were determined to predict
flowability.
Particle size distribution:
Sieve analysis using sieve shaker is most widely used method for
measuring particle size distribution. 100 gm of pellets are weighed
& transferred to set of sieves having different mesh size for particle
size analysis. Calculate the % retained on each sieve.
Hardness and Friability:
Hardness and friability determination of pellets is necessary because
the pellets have to withstand during handling, shipping, storage and
other processes such as coating. Kaul pellet hardness tester provide
relative hardness values & friability of pellets are determined by
using erweka type tablet friabilator.

23. Morphology of structure:
Morphology of pellets is examined using SEM (Scanning electron microscope).
Drug content:
The concentration of drug can be determined with the help of suitable UV method
or HPLC method or some other suitable analytical methods.
Tensile strength measurement :
The tensile strength of pellets is useful to measure the load require to break the
pellets. It is determined by using tensile apparatus with a 5 kg load.
Disintegration time:
Disintegration time is one of the important test to measure the disintegration of
pellets. This test is usually performed in disintegration apparatus using 0.1N HCl.
In vitro dissolution studies:
Dissolution was conducted in a USP (Method 1, rotating basket) apparatus, at a
speed of 100 rpm, in 900 ml of dissolution media (phosphate buffer at pH 7.2
±0.05), maintained at 37 ± 0.5°C.
Stability study of pellets:
Stability study of pellets was performed as at room temperature, 30°C/70% RH &
40°C/75% RH for three months. Physical and Chemical properties of the pellet
was determined.