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IJRPC 2017, 7(3), 232-238 Sandip Joshi et al. ISSN: 22312781
INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY
Research Article
Available online at www.ijrpc.com
TO STUDY AND UNDERSTAND THE PROCESS OF WET
GRANULATION BY FLUIDIZED BED GRANULATION TECHNIQUE
*
Sandip Joshi and Rohan Kamat
Pravara College of Pharmacy, Ahmednagar, Loni Bk, Maharashtra-413 736, India.
ABSTRACT
Fluidized bed granulation is a widely used wet granulation technique in the pharmaceutical industry to
produce solid oral dosage forms. The process involves the spraying of a binder liquid onto fluidizing
powder particles which results particle- particle collision with each other and form larger permanent
aggregates (granules). After spraying the required amount of granulation liquid, the wet granules are
rapidly dried in the fluid bed granulator. The characteristics of fluid bed granulation processing and
the fundamentals of the mechanisms contributing to wet granule growth are briefly discussed. This
review also discusses the endpoint detection methods in fluidized wet granulation.
Keywords: Fluidized wet granulation, granules, endpoint detection, top spray, fluidization.
INTRODUCTION to 2.0 mm. The use of granulation techniques
Granulation is defined as a particle size in the pharmaceutical industry is driven by the
enlargement process, whereby small powder improvement of one or more powder
particles are gathered into larger, permanent properties generally the powder flow
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structures in which the original particles can be properties which include, increased bulk
distinguished. There are two major granulation density, flowability and solubility, reduced risk
methods are widely applied, namely wet and of size segregation, and dust formation. The
dry granulation. As its name suggests, wet manufactured granules are primarily used for
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granulation involves the use of a binder liquid, tableting, but may also be filled into capsules .
which is introduced onto agitated powder Fluidized bed granulation is a widely applied
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particles, binding these together . During wet granulation technique in the
subsequent drying, the solvent is removed via pharmaceutical industry. Both the spraying of
evaporation, and more permanent bonds are binder liquid onto the fluidized powder bed
formed. The granule strength is then mainly (granulation) and subsequent drying of the
related to the solid bridges, formed by agglomerates are carried out in the same
hardening of binders and the crystallization of equipment. Hence, dry mixing, wetting, and
dissolved particles. Dry granulation methods drying are accomplished in a single operation
are based on the compaction of the powder unit, which simplifies the process and benefits
mass, before it is crushed and fractionated. the GMP requirements. It also saves on labor
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Hence, particle size enlargement is achieved costs, transfer losses, and time . The
without the use of a binder liquid, making this continuous heat and mass transfer between
process particularly suitable for moisture- or the fluidizing air and particles creates a
heat-sensitive drugs. Compared to dry uniform product temperature distribution and
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granulation processes, wet granulation offers a relatively short processing times.
better control of drug content uniformity, Understanding the fundamental physical and
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compatibility and product bulk density . chemical phenomena that contribute to the
However, the process is more complicated to granulation behavior and granule properties
validate and control due to the additional enables to model/predict how a material will
preparation of binder liquid and supplementary granulate given that formulation properties,
drying step. It is also more expensive, equipment type, and operating conditions are
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equipment, energy and space . adequately characterized. Different
Granules are polydispersible, and the size of approaches are considered to model the
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pharmaceutical agglomerates ranges from 0.1 granulation system . Empirical or black-box
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IJRPC 2017, 7(3), 232-238 Sandip Joshi et al. ISSN: 22312781
models are based on actual plant data, and an entrapped air and even liquid binder to the
arbitrary function is fitted to the data. A model particle surface. The rate of consolidation or
structure is selected, and the model densification depends on the properties of the
parameters are fitted to get the best fit of the feed material, such as particle size distribution,
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model to the data. The empirical model is surface roughness and particle shape . The
obtained rather quickly and can be used for final densification level determines end
process optimization and control. However, as product porosity and therefore granule
extrapolation of the model is not strength, hardness, and dissolution. High
recommended, the limited application range porosity granules are weak and friable, but
can be a significant disadvantage. On the display often an advantageous fast dissolution
other hand, mechanistic or white-box models rate, which makes granule porosity an
incorporate the fundamental physical and important product property to control.
chemical laws and rules. Conservation However, it creates unwanted dust during
principles (of mass, energy, momentum, and product handling. The third-rate process
particle number) and appropriate constitutive includes two phenomena. Low binding
relations that reflect the key factors in strengths in the moist agglomerates create
granulation are used to mechanistically model weak wet granules that may break in the
a granulation system. This approach is more granulator, influencing the final granule size
complex and time-consuming but more flexible distribution. This breakage is more prominent
compared to empirical models. Especially for in granulation processes displaying high shear
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scale-up, these models can be more efficient forces . Weak dried granules are susceptible
than the traditional method of trial and error to attrition or fracture in the fluid bed
experimentation. They minimize the granulator or during subsequent handling. This
guesswork and offer a more rational approach counteracts the objectives of granulation and
to scaling-up the process. In-between should therefore be avoided.
empirical and mechanistic, a third type of During a fluid bed granulation process, the
models, gray-box models, is classified. This binder liquid addition and evaporation take
model type combines fundamental knowledge place at the same time, making this a unique
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and experimental data with equal importance and effective granulation process . Hence, the
and is most commonly applied in process three rate mechanisms occur simultaneously,
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systems modeling. Cameron et al. reviewed and the contribution of each of them to the
the use of different modeling approaches to developed agglomerates depends on
the integrated understanding of the granulation granulation equipment, process settings, and
phenomena. feed material properties. The end product
quality attributes is determined by combination
Fundamentals of granule growth of the most dominant rate processes
During wet granulation, several different determines the final granule size distribution,
mechanisms take place. In this work, the structure, and porosity.
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classification according to Iveson et al. is According to the relative amount of liquid
considered, viewing the wet granulation phase, a number of different states of the
process as a sets of rate processes or moist agglomerates are described, that is, the
combination of three different mechanisms. pendular, the funicular, and the capillary state
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These include the following: (Figure. 1) . The herewith associated
Wetting and nucleation of particles, increasing amount of liquid phase is
Consolidation and growth by collisions expressed by the liquid saturation, describing
of material in the granulator, the ratio of pore volume occupied by the liquid
Attrition and breakage. to the total pore volume within the
A wetting advances the nucleation of fine agglomerate. In each state, a different type of
powders occur. The nucleation is strongly bonding is holding the particles together. In the
influenced by the distribution of the binding pendular state, liquid bridges at particle
fluid and the powder properties. The contact points are holding the particles
nucleation is followed by granule growth which together, whereas in the capillary state, all the
involves collisions between two (partially) voids are saturated with liquid, and the surface
wetted granules (i.e., coalescence) or granules liquid is drawn into the particle pores under
and feed powder (i.e., layering) resulting in capillary action. The intermediate funicular
larger granules composed of several particles. state is characterized by voids that are not
During granule growth, the agglomerates are completely filled with liquid. In addition to
subjected to compaction forces (due to bed these three stages, a fourth one, the droplet
agitation) causing the granules to gradually state has been defined. This state is
consolidate. This is accompanied by a characterized by the addition of more liquid to
reduction in size and porosity, and forces out the powder mixture than the amount required
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IJRPC 2017, 7(3), 232-238 Sandip Joshi et al. ISSN: 22312781
to completely fill all inter- and intra-particulate generally, too much liquid has been added and
voids. Hence, the liquid completely surrounds results in over granulation. This in contrast to
the solid particles. If the droplet state is the process of granulation by spray-drying of a
achieved during conventional wet granulation suspension, where the droplet state is an
(i.e., fluidized bed and high shear granulation), important stage of the process.
Fig. 1: Overview of the four stages of powder wetting (liquid saturation).
The solid particles are represented by gray circles, and the binding liquid is colored black.
Granulation in the fluidized bed visually monitored by the free downward flow
During fluidization, solids are subjected to a of the granules at the windows of the
gas (usually air), which converts the material container. As particles move up and down in
to a dynamic fluid state. At certain gas the container, a binder solution is sprayed (i.e.,
velocities, the gas will support the particles, spraying phase). Binder liquid droplets are
allowing an upward and downward movement, deposited onto the fluidized particles in the
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suspending the material in the gas . spray granulation zone. This wetting causes
Pharmaceutical fluidized bed granulation was the formation of granules. After spraying the
first described by Wurster, when he reported required amount of binder liquid, further
on the use of the air suspension technique to fluidization enables rapid drying of the
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coat tablets . This was followed by a paper granules in the same equipment (i.e., drying
describing the process of granulation and phase). Drying reduces the residual moisture
drying via the air suspension technique to of the granules to a level that ensures the
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prepare tablets . A fluid bed granulation stability of product active(s) and meets the
process involves the suspension of particles in requirements for downstream processing. A
a conical shaped container by use of a good granulation is achieved when particles
(heated) air stream. The applied air velocity are uniformly mixed, and liquid bridges
should allow proper particle movement in the between the particles are strong and easy to
container, but keep the material out of the filter dry.
bags (Figure. 2). Good fluidization can be
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IJRPC 2017, 7(3), 232-238 Sandip Joshi et al. ISSN: 22312781
Fig. 2: Schematic representation of a top-spray fluid bed granulator with assignment of its
different components: (1) control panel, (2) air handling unit, (3) product container, (4) air
distributor plate, (5) top-spray installed nozzle, (6) pump, (7) air expansion chamber, (8) filter
bags, (9) air filter system, and (10) exhaust blower. Arrows indicate the direction of the airflow.
Compared to high shear granulation, the lack independent of flow rate. With this nozzle, the
of shear forces in a conventional fluidized bed binder solution (one fluid) is atomized by
results into the production of more porous and compressed air (other fluid). The spray pattern
less dense granules with better dissolution and and angle can be modified by adjusting the
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compression characteristics . Generally, the position of the air cap surrounding the nozzle
fluidized bed granules exhibit a narrower size needle and by varying the air pressure
distribution of granules. The most common required for atomization of binder liquid.
problems encountered during fluid bed Depending on the location of the spray nozzle,
granulation include the production of different types of fluid bed granulators are
excessively coarse granules, poor fluidization, available. Top-spray fluid bed granulation with
excessive fines, inconsistency of final moisture the nozzle located at the top of the chamber is
content, non-uniformity of finished product and the most frequently studied and used
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low yield . technique for wet granulation . The binder
A fluidized bed granulator consists of several liquid is sprayed from the top down onto the
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key components (Figure. 2, ). A control fluidized bed, counter-currently to the fluidizing
panel (1) allows operating the process and air. During bottom-spray granulation, the
monitoring critical process variables. As nozzle is positioned at the base of the
generally outside air is used to fluidize the chamber, in the middle of the distributor plate,
particles, an air handling unit (2) is essential and liquid is sprayed in the same direction of
for air filtering, heating, cooling, and removal the fluidizing air. The bottom-spray granulator
of humidity. After preconditioning the air, it is can be equipped with a partition column (i.e.,
passed through the bed of solids in the Wurster partition) and a specially designed
product container (3) via the air distributor distributor plate to regulate the fluidization
plate (4). The type of container and air pattern. The plate, with perforation sizes
distributor must be selected accordingly to decreasing from the center to the outer part,
obtain a proper product fluidization. The binder enables a higher air velocity inside the Wurster
liquid is introduced onto the fluidizing particles partition than in the outer region creating a
via a nozzle (5) system. The two-fluid (binary) fountain-like movement. Introducing the spray
nozzle is most commonly applied in fluid bed nozzle at the side of the chamber, embedded
granulation as it can function at very slow in the powder bed during granulation,
liquid rates and offers a controlled droplet size, corresponds to tangential-spray granulation.
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