Pellets - Industrial pharmacy -I as per PCI syllabus...

1. PELLETS

2. CONTENTS
• Introduction
• formulation requirements
• pelletization processes and equipments for manufacture of
pellet
• mechanism of pellet formation and growth

3. INTRODUCTION
These are the small size (0.5-1.5 mm), free flowing spherical units
obtained by agglomeration of fine powder or granules of bulk drugs and
excipients by pelletization techniques. Pellets have low porosity (about
10%)
Pellets either filled in hard gelatin capsules or compressed into
disintegrating tablets. When pellets are intended for oral use, they
quickly liberate their contents in the stomach and gets distributed
throughout the gastrointestinal tract and produce maximal drug
absorption and also minimize local irritation.

4. APPLICATION OF PELLETS
l . They improved aesthetic appearance of products.
2 They offer uniformity of dose.
3. They are used to achieve controlled release rate of drugs by coating
of drug pellets with different polymers.
4.Chemically incompatible products can be formulated into pellets and delivered
in a single dosage form.
5.During formulation of pellets, there is no dust formation. While fine powder cause dust
explosion and cause health problems.

5. 10. They reduce peak plasma fluctuations and minimize potential side effects with improved drug
bioavailability.
6.Pellets have excellent flow properties in formulation development.
7.They reduce inter and intra patient variability.
8.The high bulk density of pellets plays an important role in achieving content and weight uniformity.
9. Pellets provides less risk of dose dumping.
APPLICATION OF PELLETS

6. ADVANTAGES OF PELLETS
1.Improved aesthetic appearance of the product.
2.Coating of drug pellets with different polymers to achieve
controlled release rate of drugs.
3.For immediate release products large surface area of the pellets
enables better distribution, dissolution and absorption.
4.Chemically incompatible products can be formulated into pellets
and delivered into single dosage form by encapsulating them.
5.Pellets ensures improved flow properties and flexibility in
formulation, development, and manufacture.

7. DISADVANTAGES OF PELLETS
1.Preparation of pellets is a complicated and time consuming process.
2.Due to rigid nature, it is difficult to compress pellets into tablets.
Therefore they are dispensed in hard gelatin capsule.
3.Specialized equipments are required for pelletization which raise
manufacturing cost.
4.Due to high specific surface area per dose , more amount of coating
should be given.

8. MECHANISM OF PELLET FORMATION AND GROWTH
Nucleation phase
 Nucleation is a stage of pelletization process in which powder particles are wetted with
binder liquid.
 The Formation of pellet involves adhering of the solid particles or fine powders to each
other due to attractive forces such as molecular forces, electrostatic forces and magnetic
forces.
 The void spaces between the primary particles are occupied by the binder solution .
 This lead to the formation of three-phase -air-water-liquid nuclei system which are held
together by liquid bridges that are pendular in nature.

9. Stages of Nucleation
This state is referred to as pendular state because of low moisture level. The surface tension of the
liquid and the negative suction pressure generated at the liquid bridges causes attraction between
the powder particles. But it is due to air between the particles.
o PENDULAR STATE
The next state in nucleation is funicular state, This is an intermediary
state where air start to dispersed continuously throughout the
agglomerate.
o FUNICULAR STATE
In capillary state, all the void space in agglomerate is fully occupied by liquid. This lead to formation of
strong bonds between the particles. These bonds disappear as the liquid evaporates. In this state, the
liquid does not completely surround the agglomerate and cannot form nuclei.
o CAPILLARY STATE

10. The next state is droplet, identified when liquid completely surrounds onto the agglomerate.
o DROPLET
 The rate and the extent of nuclear formation depends upon the size of the particles, moisture content, the
viscosity of the binding particles, the wettability of the substrate and the processing conditions.
Coalescence phase
Coalescence is defined as process of the formation of large-sized particles due to random collision of
well-formed nuclei. The total mass of the system remains unchanged during this operation. But the
number of nuclei is reduced. During collision, fines and particles are produce

11.  The successive addition of these fines and fragments on surface of already formed nuclei is called
layering. Layering is a slow growth mechanism. In this phase, the number of particles remains constant,
but the total mass of nuclei in the system increases due to increasing particle size with time.
 The subsequent coalescence and layering continues until the number of collisions declines rapidly. This
cause reduction in the rate of growth of the pellets.
Layering phase
Ball growth phase or Abrasion transfer phase
 It is the last step of pellet formation The main mechanism in the ball growth phase is the abrasion
transfer. It involves the transfer of materials from one granule formed to another without any preference
in either direction. This phase does not cause the change in the total number or mass of the particles.

12. Ball growth phase or Abrasion transfer phase

13. FORMULATION
 They are used to add bulk to products and make very small active components easy for consumer
to take. They are generally water soluble or insoluble substances. The selection of filler depends on
desired dose, physical property of drug and manufacturing process. Example: MCC (Micro
Crystalline Cellulose), Starch, sucrose, lactose, mannitol.
Fillers:
 They are added to bind powder and make pellet integrity. Ex. Sucrose, Starch, Hydro
propyl Methyl Cellulose, Hydroxy Propyl Cellulose, Gelatin, pyrrolidone, Methyl Cellulose,
Polyvinyl.
Binders:
 They are added to reduce friction between particles and surface of equipment. Ex. Glycerin,
Polyethylene Glycol, Magnesium stearate, Calcium stearate
Lubricants:

14.  During manufacturing pellets may develop surface charge and get attracted to each other.
Separating agents promote separation of pellets into unit. Ex. Kaolin, Talc, silicon dioxide
Separating agents:
 Ex. Alginate, cross carmellose sodium.
Disintegrating agents:
 Ex. Citrate, Phosphate, Meglumine
pH adjuster:
 Surfactants are added to the liquid to improve wettability by lowering the interfacial tension between
the liquid and drug particles. Surfactants help to weaken the liquid bridges and results in more friable
pellets. Ex. Sodium Lauryl Sulfate, Polysorbate
Surfactant:

15.  They not only impart plasticity onto the formulation, but also impart binding properties that are
essential for pellet strength and integrity. Ex. Micro Crystalline Cellulose, Sodium Carboxy
Methyl Cellulose.
Spheronization enhancer:
 They reduces the friction between the die wall and material mix either during
the compression process or in ejection phase. hey also play a significant role
in smooth discharge Of the pellets from the Spheronizer
 Ex. Talc, starch, Magnesium stearate
GIidant:
 They are added to possess specific release profiles in a single step. Generally, water soluble low molecular
weight excipients, surfactants and disintegrants are incorporated in formulations to enhance the drug release
kinetics, while water insoluble polymers, hydrophobic substances, inorganic salts, and hydrophilic polymers that
swell and/or form gels are incorporated in pellets that retard release kinetics.
 Ex: Ethyl cellulose, Shellac, Carnauba wax
Release modifier:

16. Others: Include sweetening, coloring and flavoring agents.
PELLETIZATION PROCESS
Pelletization is an agglomeration process in which fine powders or granules of bulk drugs and excipients is
converted into pellets. The preparation of spherical agglomerates can be approached by several
techniques.

17.  This is also known" as spherical agglomeration. In this Pelletization technique, the required
amount of liquid is added before or during the agitation to the finely divided particles. This mass
under a continuous rolling or tumbling motion in pans, discs, drums or mixers gives spherical
particles.
Agitation (Balling)
 In liquid induced agglomeration method, liquid is added to powder to obtain agglomerates while in
Melt induced agglomeration binding material is in melt form.
 This method is mainly used in iron ore and fertilizer industry.
Types of agitation
Liquid induced
agglomeration
Melt induced
agglomeration

18.  Compression: It is a pelletization process in which mixtures or blends of active ingredients and excipients
are compacted by applying pressure to get pellets of definite shape and size which can be filled into
capsules.
 Extrusion — Spheronization: This was introduced in the early 1960s. This process is commonly used in the
pharmaceutical industry to make uniformly sized spheroids roughly 1 mm in diameter. It is especially useful
for making dense spherical pellets of uniform size and shape with high drug loading for controlled-release
oral solid dosage forms.
 It is a multi-step compaction process comprising of following steps.
Compaction:
Granulation :
 The process of using a liquid solution to powders involves the massing opf a mix of dry
primary powder particles using a granulating fluid . The fluid contains a solvent that must
be volatile.
 Meets all the physical requirements od compression .

19.  Dry mixing: Different types of mixers like twin shell blender, high shear mixer, tumbler mixer and planetary
mixer are used to get homogeneous powder dispersion.
 Wet Massing: This is done to produce a plastic mass for extrusion. It is similar to the
conventional wet granulation method with the exception of granulation end point. The
granulation end point is determined by the behavior of the wet mass during the extrusion
operation. The most commonly used granulator is the Planetory mixer or Sigma blade mixer
or the high shear mixer and the Horbat mixer. The planetary mixer is used systematically for
mixing and granulation operations.
 Fluid- bed Granulator:
• The process is carried out continuously in a fluid-bed granulator.
• Spraying of a granulation solution onto the suspended particles which are
then dried rapidly in the hot air stream.
 Advantage over traditional wet massing process :
• Automated, performed in one unit, thus saving costs, transfer losses and
time.
• FBG improves the dissolution efficiency of both nimodipine and
spironolactone and many other pellets based controlled release
formulations.

21.  Extrusion:
In this process, the wet mass passes through the extruder to form rod- shaped particles of
uniform diameter. The extrudate should have sufficient plasticity to deform but not so much that
the extrudate particles adhere to other particles as they are rotating urmgt e sp e process.
It is a process in which Spheronizer is used. In Spheronizer, the extrudate is subjected to rotate at
higher speed by friction plate to break these rod shaped particle in to in to spherical particle with narrow
size distribution.
 Spheronization:

22. STEPS OF EXTRUSTION- SPHERONIZATION

23. Hot melt extrusion
 It is a continuous process of converting raw material into a final product of uniform shape
and density by forcing it through a die under controlled conditions
HOT MELT EXTRUSION EQUIPMENT

25.  The theoretical approach to understand the melt extrusion process is therefore , generally
presented by dividing the process of flow into four sections .
1. Feeding of the extruder
2. conveying of mass ( mixing and reduction of particle size)
3. Flow through the die
4. Exit from the die and down stream processing
 The applications in the pharmaceutical industry:
1. Improving the dissolution rate and bioavailability of the drug by forming a solid
dispersion or solid solution.
2.Controlling or modifying the release of the drug.
3.Masking the bitter taste of an active drug.

26. It is done to achieve the desired size distribution. Sieves are used for this purpose.
 Drying:
 Screening:
It is the stage in which the pellets are dried at room temperature or at a elevated temperature in a tray dryer
or in a fluidized bed dryer to retains the shape and size.
 In this process, drug is layered onto nonpareil or starter seeds in powder, solution or
suspension form. The resulting pellet consist of an inner core region and an outer shell region
of a different composition.
 This process is classified into two categories
A. Powder layering.
B. Solution or Suspension layering
Layering:

27. A. Powder Layering:
 The first equipment used to make pellets on a commercial scale was the conventional coating pan, but it
has a significant limitation, namely that the de ee of mixing is very. low and the drying process is not
efficient. Therefore now a days, tangential spray granulator and a centrifugal bed granulator are used.
 This technique involves the deposition of successive layers of powdered drug and excipient or both
on preformed cores or nucleus with the aid of a binding liquid. The binding solution and the finely
milled powder are added simultaneously in a controlled manner to maintain equilibrium.
 In the initial steps, the drug particle is bound to the starter seeds to
form the pellets using a liquid bridge from a spray binding liquid.
These liquid bridges are replaced by solid bridges during solidification.
This treatment leads to the formation of successive layers of a drug
and the binder solution until the desired pellet size is reached.

28. Powder layer of pellets

29. B. Solution/Suspension Layering:
 Therefore, a conventional coating press; a centrifugal fluidized bed granulator of a Wurster coating
have been successfully used to make pellets. In this technique, solution / layering of neutral pellets
has been achieved by applying a novel fluidized bed technology. Hüettlin's three-component spray
nozzle is a good choice as it prevents excessive spray drying or clogging of the nozzle.
 This technique involves the deposition of successive layers of solution and / or suspension of
drug substances and binders on starter seeds, which may be inert materials or granule crystals
of the same drug:
 In this technique, drug particles and other components are dissolved or suspended in the binding
liquid. The droplets impinge on the starter seeds or cores and spread evenly when the solution or
suspension is sprayed onto the nuclei. During drying, solid bridges are formed between the nuclei
and the initial layer of. drug substances and. between the successive layers of drug substances
or polymers. Continue this process until the desired drug or polymer layer is formed.

30.  Globulation or droplet formation includes spray drying and spray congealing. In this methods,
spherical pellets are produced by atomization of hot melt, solutions or suspension.
Globulation or Droplet formation:
A. Spray drying: It is a process in which drug entities (in or suspension) with or without excipients
are sprayed into a stream of hot air to generate dry, highly spherical . It is generally used to
enhance the dissolution rates and hence, bioavailability of poorly soluble drugs.

31. B. Spray Congealing or spray chilling: It is the process in which a drug is allowed to melt, disperse,
or dissolve in hot melts of gums, waxes, fatty acids, etc. Then it is sprayed into an air chamber where
the temperature is below the melting points of the formulation components. This technique is similar to
spray drying but no source of heat is needed. This process is used to obtain spherical congealed
pellets under appropriate processing conditions. This process is used to get sustained released effect.

32.  It is the process in which liquid droplet is converted into solid spherical particle by using liquid nitrogen.
The conventional freeze dryer is used to dry the pellets. It is used to get free flowing pellets.
Cryopelletization:

33. CHARACTERIZATION OF PELLETS
 Pellet size and size distribution: It is determined by sieve analysis, microscopy
methods like Scanning electron microscopy (SEM) and laser diffraction.
 Shape: The most common method of analysis is scanning electron microscopy (SEM) for qualitative and
quantitative analysis .Visual inspection of pellets by microscope is also used to determine shape of pellets.
 Surface area: The surface area is analyzed by particle size distribution, gas adsorption (BET
method- Brunauer, Emmett & Teller) and air permeability method .

34.  Porosity: It is measured by mercury porosimeter. The sample introduced into the chamber, degassed,
and then completely covered with mercury. Pressure is applied and the volume of mercury that
penetrates into the pores is recorded. Pore radius is given by Washburn equation.
R = 2 g [cos q] / P
Where g = 480 ergs/cm3
q=1400
R = pore radius
P = mercury-intrusion pressure.
 In-vitro Dissolution study: In this, USP I (basket) and USP Il (paddle) apparatus are
used to study the release pattern of the coated pellets.

35. Thank you…