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By Rakesh P. Patel, PhD, and A.M. Suthar, Gnpat University, India Aug 07, 2008
Tablets are the most common drug dosage form today, and thus granulation, which allows
primary powder particles to adhere and form granules, is one of the most important unit
operations in drug manufacturing. Understanding granulation grows more complex each year.
This article reviews the most current methods and mechanisms of pharmaceutical granulation,
including factors that can lead to improved control.
Particle-bonding Mechanisms
a) Adhesion and cohesion forces in immobile films. If sufficient liquid is present in a powder to
form a thin, immobile layer, there will be an increase in contact area between particles. The
bond strength between particles will increase, as the Van der Waals forces of attraction are
proportional to the particle diameter and inversely proportional to the square of the distance of
separation [1].
b) Interfacial forces in mobile liquid films. During wet granulation, liquid is added to the powder
mix and distributed as films around and between the particles. There are three states of water
distribution between particles. At low moisture levels, the pendular state, particles are held
together by surface tension forces of the liquid/air interface and the hydrostatic suction
pressure in the liquid bridge.
When all the air has been displaced from between the particles, the capillary state is reached,
and the particles are held by capillary suction at the liquid/air interface. The funicular state
represents an intermediate stage between the pendular and capillary states. Moist granule
tensile strength increases about three times between the pendular and the capillary state.
These wet bridges are, however, a prerequisite for the formation of solid bridges formed by
adhesives present in the liquid, or by materials that dissolve in the granulating liquid.
Solid bridges can be formed in two ways:
Hardening binders. When an adhesive is included in the granulating solvent it forms liquid
bridges, and the adhesive will harden or crystallize on drying to form solid bridges to bind the
particles.
Crystallization of dissolved substances. The solvent used to mass the powder during wet
granulation may partially dissolve one of the powdered ingredients. When the granules are
dried, crystallization of this material will take place and the dissolved substance then acts as a
hardening binder.
c) Attractive forces between solid particles. In the absence of liquids and solid bridges formed
by binding agents, there are two types of attractive force that can operate between particles in
pharmaceutical systems, electrostatic forces and Van der Waals forces. Van der Waals forces
are about four orders of magnitude greater than electrostatic and add to the strength of
granules produced by dry granulation.
Mechanisms of Granule Formation
a) Nucleation. Granulation starts with particle-particle contact and adhesion due to liquid
bridges. A number of particles will join to form the pendular state. Further agitation densifies
the pendular bodies to form the capillary state, and these bodies act as nuclei for further
granule growth [2].
b) Transition. Nuclei can grow in two possible ways: either single particles can be added to the
nuclei by pendular bridges, or two or more nuclei may combine. The combined nuclei will be
reshaped by the agitation of the bed. This stage is characterized by the presence of a large
number of small granules with a fairly wide size distribution.
c) Ball Growth. If agitation is continued, granule coalescence will continue and produce an
unusable, over-massed system, although this is dependent upon the amount of liquid added
and the properties of the material being granulated
[1].
There are four possible mechanisms of ball growth,
which are illustrated in Figure 1 [3]:
Coalescence. Two or more granules join to
form a larger granule.
Breakage. Granules break into fragments
which adhere to other granules, forming a layer of
material over the surviving granule.
Layering. When a second batch of powder mix
is added to a bed of granules, the powder will adhere
to the granules, forming a layer over the surface and
increasing the granule size.
Abrasion Transfer. Agitation of the granule
bed leads to the attrition of material from granules.
This abraded material adheres to other granules.
Granulation Methods [4]
Dry Granulation. This requires two pieces of equipment, a machine for compressing the dry
powders into compacts or flakes, and a mill for breaking up these intermediate products into
granules. The dry method may be used for drugs that do not compress well after wet
granulation, or those which are sensitive to moisture.
Wet Granulation. In this method, the wet mass is forced through a sieve to produce wet
granules which are then dried. A subsequent screening stage breaks agglomerates of granules.
Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry
granulation, or when a rapid drying time is required. Because direct compressing is not the best
technology for many active substances, wet granulation is still a preferred method. Even if the
active substance is sensitive to hydrolysis, modern equipment (e.g., a fluidized bed) eliminates
all problems in wet granulation [2].
Factors Affecting Granulation Methods
Liquid Requirement. High-shear mixers may exhibit a narrow margin between the liquid
required to obtain granule growth and the amount that results in an over-wetted mass.
Because of the intensive wet massing and densification of the granules, less liquid is normally
required with high- than with low-shear mixers [5]. In addition, impeller rotation speed
influences the liquid requirements, as does evaporation of the solvent, usually water, in the
binder solution. Especially with high-shear mixers, intense agitation results in a temperature
rise and loss of solvent by evaporation.
Effects of Raw Material Properties. The following properties influence granule formation and
growth:
Contact angle of the binder liquid to the solids
Solubility of the particles in the binder liquid
Mean particle size and size distribution of the solids
Particle shape and surface morphology
Packing properties of the solids
Raw materials must have good wetting properties if there is to be uniform liquid distribution
and, hence, controlled granule growth. The smaller the particle size of the raw material, the
more binder liquid required.
Binder Properties
Binder Concentration. The binder forms an internal matrix; consequently, the granule strength
and tablet strength increase as binder concentration increases.
Mechanical Properties of Binder. The mechanical properties of the binder determine binder
strength and deformation behavior of the binder matrix.
Properties of Drug and Other Excipients in the Formulation
Wet granulation depends upon wetting of powder by the binder solution, surface tension of
lenticular bridge films formed and solution viscosity. Binder Distribution. The distribution
influences the binder’s ability to produce strong and non-friable granules. The processing
method used to distribute the binder influences binder efficiency.
Endpoint Determination
Endpoint can be defined as a target particle size mean or distribution.
Traditional Methods
a) Power Consumption. Power consumption of the mixer motor for end-point determination
and scale-up is widely used because the measurement is economical, does not require
extensive mixer modifications and is well correlated with granule growth [14]. Intragranular
porosity also shows some correlation with power consumption. Normalized work of granulation
(power profile integrated over time) can accurately determine endpoints and is correlated well
with properties of granulates.
b) Impeller Torque. Direct torque measurement requires installation of strain gauges on the
impeller shaft or on the coupling between the motor and impeller shaft. Since the shaft is
rotating, a device called a slip ring is used to transmit the signal to the stationary data
acquisition system.
c) Torque Rheometer. A torque rheometer provides an off-line measurement of torque
required to rotate the blades of the device and can be used to assess rheological properties of
the granulation. It has been extensively used for endpoint determination. The torque values
obtained have been termed a “measure of wet mass consistency” [15].
d) Reaction Torque. As the impeller shaft rotates, the motor tries to rotate in the opposite
direction, but does not because it is bolted in place. The tensions in the stationary motor base
can be measured by a reaction torque transducer.
e) Other Possibilities. When agglomeration is progressing very rapidly, neither power
consumption nor torque on the impeller may be sensitive enough to adequately reflect
material changes. Some investigators feel that other measurements, such as torque or force on
the impeller blades, may be better suited to monitor such events. There are other ideas floating
around—for example, use of neural networks to describe and predict the behavior of the wet
granulation [16] or control of the endpoint by a rapid image processing system [17]. A
technique for measuring tensile strength of granules, in addition to power consumption
measurement, to facilitate optimal endpoint determination, has been described by Betz, Bürgin
and Leuenberger. Powder flow patterns in wet granulation can be studied using positron
emission particle tracking [18].
Emerging Technologies
a) Acoustic. Applicability of piezo-electric acoustic emission sensors to endpoint determination
has been studied since the beginning of this century [19]. The technique is very promising,
especially since it is non-invasive, sensitive and relatively inexpensive. Granulation process
signatures obtained with an acoustic transducer can be used to monitor changes in particle size,
flow and compression properties.
b) Near-Infrared (NIR). Use of a refractive NIR moisture sensor for endpoint determination of
wet granulation has been described by several authors [20]. There are technological challenges
associated with this approach, as the sensor can only measure the amount of water at the
powder surface.
c) FBRM. Focused beam reflectance measurement (FBRM) is a particle-size determination
technique based on a laser beam focusing in the vicinity of a sapphire window of a probe [21].
The beam follows a circular path at speeds of up to 6 m/s. When it intersects with the edge of a
particle passing by the window surface, an optical collector records a backscatter signal. The
time interval of the signal multiplied by the beam speed represents a chord length between
two points on the edge of a particle. The chord length distribution (CLD) can be recalculated to
represent either a number or volume-weighted particle size distribution. In many cases, CLD
measurements are adequate to monitor dynamic changes in process parameters related to
particle size and shape, concentration and rheology of fluid suspensions.