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How To Determine An Accurate Endpoint of High-Shear Mixer Granulation
How To Determine An Accurate Endpoint of High-Shear Mixer Granulation
Accounting for more than 70% of the global industry’s granulation1, wet granulation is
indisputably the most preferred method for preparing high-quality granules. Among different
methods for wet granulation, granulation using an HSM remains the method of choice and
has been used for several decades. However, formulation scientists are still attempting to
establish an accurate endpoint determination method for the HSM granulation process.
What is the granulation endpoint? It is the time when granules with desirable properties are
formed. This is required to be determined to ensure smooth tablet compression and
obtain desired tablet properties. These pre-compression granule properties include
strength, bulk density, particle size distribution, and flowability. Researchers have devised
various means to predict the results of the HSM granulation process. Simultaneously,
granulation equipment manufacturers have upgraded their machines to provide more reliable
results. Despite these efforts, the HSM granulation process relies heavily on empirical
methods to determine a precise endpoint. As a result, in most cases, the material remains
either under-granulated or over-granulated, leading to a range of problems during
downstream processes. Even today, operators conduct a traditional manual checking of
granules which is a highly subjective method and can lead to extreme inaccuracies. Hence,
the FDA is also insisting on pharma companies to establish a precise method for granulation
endpoint.
More difficult than detecting the endpoint of granulation is achieving reproducible endpoints
by controlling a range of process variables. For a given set of processing parameter values,
the granulation endpoint is determined by measuring the strength, rheological properties such
as density, and physical properties, such as mean particle size distribution of the granules. An
endpoint measurement technique that can provide accurate and reproducible
results, considering changes in processing parameters of granulation (mixer geometry, blade
speed, batch size, amount, and method of binder addition), is therefore desirable.
One common approach used by formulation scientists when predicting the endpoint is
identifying the amount of resistance an impeller encounters during the wet mixing phase and
then measuring the current drawn by the motor in amperes (A). Manufacturers record these
endpoint results by specifying a certain range during the wet granulation process, which can
help obtain the desired quality attributes of granules in many cases. Alternatively, fluid bed
process granulation, the outcomes of which are more predictable during development and
production processes, is gaining increasing popularity as a substitute to HSM wet
granulation. In a fluid bed processor, controlled granulation takes place, and
hence, the particle size distribution of granules is narrow. In contrast, HSM is the more
abrupt granulation method and provides a wide range of particle size distribution. Hence, it is
becoming increasingly essential to ensure the accurate endpoint determination of HSM wet
granulation.
This method measures the impeller torque in Newton-meters (Nm) in real-time using a direct
torque measurement device mounted onto the impeller drive shaft. In comparison to standard
torque measurement techniques, where a theoretical impeller torque value is calculated from
the impeller drive’s current consumption, the this-state-of-the-art technique can eliminate all
factors influencing the current consumption, including wear and tear of bearings and
gearings, oil viscosity, and temperature fluctuations; it provides the most accurate process
control available. Figure 1 shows the arrangement of a direct torque measurement device on
an impeller hub.
Torque sensors use strain gauges that are applied to rotating parts. This process can be
accomplished using rings, wireless telemetry, or rotary transformers. The underlying
principle of direct torque measurement is based on measuring the force used to turn the
impeller shaft. When a force or torque is applied to the shaft, it twists by a very small
amount. This twisting causes a “stretch” in the material of the shaft, in a direction 45° to the
axis. Torque transducers measure the change in the shaft bending to calculate the torque. This
measurement is conducted using strain gauges bonded to the shaft, which measure the strain
induced in the shaft by the applied torque or force.