End -point determination in wet granulation

Most challenging task while performing wet granulation in high-shear

mixers, is the detection of end point and reproducibility of same end point
by controlling various process variables. End-point can be defined by the
formulator as a target particle size mean or distribution. It has been shown
that once you have reached the desired end-point, the granule properties and
the subsequent tablet properties are very similar regardless of the granulation
processing factors, such as impeller or chopper speed or binder addition rate.
This is called “the principle of equifinality”. The ultimate goal of any
measurement in a granulation process is to estimate viscosity and density of
the granules, and, perhaps, to obtain an indication of the particle size mean
and distribution. These factors may be monitored and controlled by use of
suitable measuring devices to achieve reproducibility in the process. Various
primary independent factors in different granulation processes which can
affect the granulation end point are presented in (Table 1).

 TABLE 1 Factors affecting high-shear wet granulation process

PROCESS
PRODUCT APPARATUS
VARIABLES VARIABLES
VARIABLES

·         Impeller Speed ·         Amount of liquid binder ·         Size and shape of
·         Chopper Speed ·         Type of binder mixing chamber
·         Size and shape of
·         Liquid Flow rate ·         Surface tension impeller

·         Impeller Load ·         Viscosity ·         Size and shape of

chopper
·         Liquid addition ·         Adhesiveness

method ·         Particle size distribution

 ·         Solubility
·         Mixing time
·         Wettability

While performing wet granulation in a high-shear mixer, formulation

scientist is in regular concern with few variables which plays leading role in
determining the end product properties, brief description of these variables
are given below:

Power Consumption

Measurements of Power Consumption of the mixer motor have been widely

used for end point determination because measurement is economical and
well co-related with the growth of granules . Power consumption can also be
co-related with mean particle size of the granules although it is not linear in
the entire range . Intra granular porosity also shows some co-relation with
power consumption . Pharmaceutical high-shear mixers are generally
equipped with one or more device for such measurements. Significant
drawback of the power consumption measurement is that it reflects load on
the motor rather than load on the impeller where actual action is being
performed and can vary with time regardless of the load. Lindberg [30] co-
relate the power consumption and the saturation level S of the granules as
shown in eq.-1 below.

S = H (1– ε) / ε * P                 (eq-1)

The saturation level S of an agglomerate is defined as the ratio of pore

volume occupied by liquid to the total volume of pores available in the
agglomerate. Where H is the mass ratio of liquid to solid, ε is the intra-
granular porosity and P is the density of the particle relative to the density of
the liquid

Impeller Load
Load on the main impeller can be estimated by measuring current in DC
motor because torque generated by the impeller is proportional to the current
applied. Current meter (ammeter can be used for small scale DC motors. In
case of AC motor impeller load does not vary linearly with the current
applied therefore current is completely in-effective as a measurement of
impeller load in AC motor

Power ~ Torque * Speed

Impeller power consumption can be calculated as a product of the direct

torque, rotational impeller speed, and a coefficient (usually equal to 2Πtimes
a unit conversion factor, if required). Impeller torque, on the other hand, is
directly related to the load on the impeller. It was observed that when the
end-point region of a granulation is reached, the frequency distribution of a
power consumption signal reaches a steady state .

Impeller Torque

In wet granulation process change in impeller torque and power

consumption of the impeller occurs as a result of change in the cohesive
force or the tensile strength of the granules in the powder bed. Therefore
impeller torque is an excellent in-line measurement of the load on the main
impeller. Torque rheometer has been extensively used for the off- line
measurement of torque required to rotate the blade of the device and this
torque has been used to access rheological properties of the granules and the
end point of the granulation process. The torque value thus obtained was
termed as “measurement of wet mass consistency” which describes the
rheological properties of the wet mass.

Liquid/ Binder solution Addition

Both moisture content and rate of addition of binding solvent is important in

successful attainment of granulation end point. Mean granule size is strongly
dependent on the specific surface area of the excipients, as well as the
moisture content and liquid saturation of the agglomerate. During the wet
massing stage, granules may increase in size to a certain degree while the
intragranular porosity goes down. Binder addition rate controls granule
density, while impeller and chopper speed control granule size and
granulation rate. There are conflicting reports on preferred method addition
to the granulating mixture. Some recommend not to add dry binder to the
blend because homogeneous binder distribution cannot be assured, other
recommend dry binder addition. However, slow addition of solvent or binder
solution to the blend is a preferred method of choice to avoid local over
wetting.

Mixing Time

An increase in wet-mixing time resulted in a decrease in intragranular

porosity, as measured with mercury intrusion, an increase in mean granular
size, and an increase in bulk density. The strength of granules was also
inversely related to the intragranular porosity.

Impeller or Motor Shaft Speed

Rate of impeller rotation could be used as some indication of the work being
done on the material. Since the motor or impeller power consumption is
proportional to the product of torque and speed, the latter is an important
factor in evaluating the corresponding load. Other factors that may affect the
granules quality includes spray position, spray nozzle type and the product
composition. Variables such as mixing time and bowl or product
temperature are not independent factors in the process but rather are
responses of the primary factors listed above. Various articles have been
published regarding end point detection in high shear wet granulation using
sound and vibration signals and using Infra-red (IR) sensors. Emerging
technologies for the detection of end point in wet granulation process are –

1. Acoustic Emission Sensors Technology

2. Near Infra-Red (NIR)
3. Focused Beam Reflectance Measurement (FBRM)

End Point in a wet granulation process is characterized by rheological

properties of the wet mass such as density, viscosity etc which are in turn a
function of particle size, shape and other physical properties. End Point can
be quantified with the help of dimensionless numbers such as Newton Power
Number (Np), Froud Number (Fr), and Reynolds Number (Re) that will
assume a certain numeric value for every state (condition) of granulate. For
eg under fixed processing conditions Np will be proportional to the Net
Power Consumption ∆P for any end point. Thus, in order to reproduce an
end-point, it is sometimes sufficient to monitor power of the impeller (or the
motor) and stop when a predefined net level of the signal is reached.

Np = ∆P / (ƥ n d) (Power Number)

Fr = n d / g (Froude Number)

Re = d n ƥ / ἡ (Reynolds Number)

P = Power required by the impeller or motor

ƥ = Specific density of particles (kg / m3)

n = Impeller speed (revolutions / s)

d = Impeller (blade) diameter or radius (m)]

g = Gravitational constant (m / s2)

ἡ = Dynamic viscosity

Newton (power) number Np, which relates the drag force acting on a unit
area of the impeller and the inertial stress, represents a measure of power
requirement to overcome friction in fluid flow in a stirred reactor. In mixer-
granulation applications, this number can be calculated from the power
consumption of the impeller or estimated from the power consumption of the
motor. Froude Number has been described for powder blending and was
suggested as a criterion for dynamic similarity and a scale-up parameter in
wet granulation. The mechanics of the phenomenon was described as
interplay of the centrifugal force (pushing the particles against the mixer
wall) and the centripetal force produced by the wall, creating a “compaction
zone”. Reynolds numbers relate the inertial force to the viscous force. They
are frequently used to describe mixing processes and viscous flow,
especially in chemical engineering