Instrumentation in Granule Manufacturing

The reasons for granulating a pharmaceutical compound are listed as follows:

 To increase the uniformity of drug distribution in the product
 To densify the material
 To enhance the flow rates and rate uniformity
 To facilitate metering or volumetric dispensing
 Improve the dissolution characteristics of the finished tablets.
 Narrow the particle size distribution of the powder mixture
 To reduce dust
 To improve the appearance of the product.
Granulation Mechanisms:
Four key mechanisms or rate processes contribute to granulation
These include wetting and nucleation, coalescence or growth, consolidation, and attrition
or breakage. Initial wetting of the feed powder and existing granules by the binding fluid is
strongly influenced by spray rate or fluid distribution as well as feed formulation properties, in
comparison with mechanical mixing. Wetting promotes nucleation of fine powders, or coating in
the case of feed particle size in excess of drop size.
In the coalescence or growth stage, partially wetted primary particles and larger nuclei coalesce
to form granules composed of several particles. As granules grow, they are consolidated by
compaction forces due to bed agitation.
Formed granules may be particularly susceptible to attrition if they are inherently weak or if
flaws develop during drying.

Excipients for granulation

 Bulking agents or filler (e.g. lactose, dicalcium phosphate, starch, and microcrystalline
cellulose)
 Functional additives (binders, disintegrants, lubricants, colorants, and stabilizing agents).
Spray drying:

Atomizer Types and Designs:

 Centrifugal Atomizers.
  Kinetic Energy Nozzles.
 Pressure Nozzles.

 Sonic Energy Atomizers.

Granulation techniques:
The three commonly used granulation methods (categorized based on the type of binder and the
process employed during granulation) include:
  wet granulation
 dry granulation
 Hot-melt granulation.

The equipment that is used during the granulation processes is classified into the following three
major categories, based on the shearing strength it generates on the powder bed:

1. Low-shear granulators—twin shell (Peterson Kelly, PK) with an agitator bar, dough mixer
or planetary mixer, ribbon blenders, and fluid bed granulator without the rotogranulator
2. Medium-shear granulators—fluid bed granulators with a rotogranulator attachment
3. High-shear granulators.

HIGH-SHEAR GRANULATION PROCESS

Wet Granulation

A high-shear wet-granulation process includes the following steps:

1. Loading all the ingredients into the mixing bowl, which can be accomplished by either of
the following methods:
 gravity feeding with manual or pneumatic valve, and
 vacuum feeding.

2. Mixing of dry ingredients such as API, filler, and disintegrant, at high impeller and
chopper speeds for a short period of time (2–5 min).
3. Addition of a liquid binder (either binder solution or solvent) into the powder mixture,
while both the impeller and the chopper are running at a low speed.
4. Wet massing with both the impeller and the chopper running at a high speed.
5. Removal of the resulting wet granules from the granulator bowl, and drying them by
using an appropriate drying technique such as fluid-bed or tray drying.
6. Sieving the dried granules.

Dry granulation:
Briefly, in dry pharmaceutical granulation processing, the powder particles are
aggregated under high pressure, typically a pressure of 30–70 bar.
In the pharmaceutical industry, dry granulation processing favored a process called
slugging (where the powder is compressed into large tablets or slugs).The tablet slugs
were subsequently milled by a separate sizing machine to an appropriate particle size
distribution.

Hot-Melt Granulation

Hot-melt granulation utilizes a binder, which is a solid or semisolid at room temperature and
melts at a temperature below the melting point of API. Generally, the melting point of such
binders is between 30°C and 100°C. The binder, when heated near its melting point, liquifies or
becomes tacky. This tacky and liquified form of binder agglomerates the powder mixture, which
upon cooling forms a solid granulated mass.
MECHANISM OF HIGH SHEAR WET GRANULATION
The high-shear wet-granulation process can be divided into five stages:

 mixing,
 adding binder solution,
 wetting and nucleation,
 consolidation and growth,
 and granule attrition and breakage.

HIGH-SHEAR GRANULATORS

Most of the high-shear granulators consist of a mixing bowl, a three-bladed impeller, and an
auxiliary chopper. The shape of the mixing bowl could be cylindrical or conical. The mixing
bowl can be jacketed for heating or cooling the contents in the bowl, by circulating hot or cool
liquid or steam through the jacket. An impeller is employed to mix the dry powder and spread
the granulating fluid. The impeller of the high-shear mixer granulator normally rotates at a speed
ranging from 100 to 500 rpm. The function of the chopper is to break down the wet mass to
produce granules. The rotation speed of the chopper ranges from 1000 to 3000 rpm.
High-shear granulator could be termed as either vertical or horizontal, based on the orientation
and the position of the impeller.
Top driven vertical granulators:

Schematic view of top-driven vertical high shear granulator.

Bottom Driven:

Schematic view of a bottom-driven vertical high shear granulator with horizontal

chopper shaft.
LOW SHEAR GRANULATORS:

 mechanical agitator granulators

The machine classes to be considered under mechanical agitator granulators are;
1. ribbon or paddle blender;
2. planetary mixers;
3. orbiting screw mixers; and
4. sigma blade mixers

 ROTATING SHAPE GRANULATORS

Schematic of the twin-shell blender that allows blending and granulating in a single
vessel.

A true adaptation of the batch, rotating shape granulators is the Patterson-Kelley Zig Zag mixer
Fluid bed granulation:
Fluidization is the unit operation by which fine solids are transformed into a fluid like state
through contact with a gas.
Fluidized bed granulation is a process by which granules are produced in a single piece of
equipment by spraying a binder solution on to a fluidized powder bed. This process is sometimes
classified as the one-pot system.

Types of fluid beds:

Product container with air distributor.

Spray Nozzle
A spray is a zone of liquid drops in a gas, and spraying is the act of breaking up a liquid into a
multitude of these droplets. The general purpose of spraying is to increase the surface area of a
given mass of liquid, in order to disperse it over the product area.
Types of nozzles

Figure 7 Types of nozzle.

1. Pressure nozzle: The fluid under pressure is broken up by its inherent instability and its
impact on the atmosphere, on another jet, or on a fixed plate.
2. Rotating nozzle (rotary atomizer): Fluid is fed at a low pressure to the center of a rapidly
rotating disk, and the centrifugal force breaks up the fluid. These types of nozzles are
used mainly in a spray drying application.

3. Airless spray nozzle: The fluid is separated into two streams that are brought back
together at the nozzle orifice, where upon impingement, they form drops.

4. Gas atomizing nozzle (two-fluid nozzle): The two-fluid (binary) nozzle where the binder
solution (one fluid) is atomized by compressed air (second fluid) is the most commonly
used nozzle for fluid bed granulation
Extrusion:
Extrusion/spheronization is a multiple step process capable of making uniformly
sized spherical particles.

1. Dry mixing:
Same mixer used for the granulation or in separate mixer.
2. Granulation:
Typically carried out in a batch type mixer/granulator including:
 planetary mixers,
 vertical or horizontal high shear mixers,
 sigma blade mixers.

Continuous type MIXER:

Nica M6 instant mixer and high shear twin screw mixer/extruders.

3. EXTRUSION:
The third step is the extrusion step which forms the wet mass into rod-shaped
particles.The wet mass is forced through dies and shaped into small cylindrical particles
having a uniform diameter.
4. Spheronization
Carried out in a relatively simple piece of equipment. The working parts consist of a bowl
having fixed sidewalls with a rapidly rotating bottom plate or disk.
5. Drying
This can be accomplished in any dryer that can be used for conventional type granulations,
including tray dryers, column type fluid beds, and deck type vibratory fluid beds.
Figure 16 Twin spheronizer with extruder.