In-Line, Real-Time Measurement for Process Improvement

When processing powders, a number of challenges may be faced. For instance, they may flow differently in the process; certain blends may be prone to agglomeration or segregation; they may react differently to process inputs such as added water content, affecting the bulk material’s properties.

In the pharmaceutical industry, High Shear Wet Granulation (HSWG) is often used to combine multiple components of a blend into a more free-flowing, homogeneous intermediate product for downstream processing.

Typically, the effect of changes caused by formulation, equipment scale, or process design is assessed on the attributes of end-products or dried granules. However, it is essential to understand both process parameters and material properties in a Quality by Design (QbD) approach.

An accurate in-line method to quantify the evolution of granule properties during a granulation process is a key step toward understanding the process, and offers the potential to develop enhanced process control strategies.

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Drag Force Flow as an In-Line Measurement

An in-line drag force flow (DFF) sensor, such as the one made by Lenterra Inc. (Figure 1), provides highly sensitive and robust in-line measurement of flow forces within the granulator. The thin DFF sensor is mounted on a stationary base and is equipped with two fiber-optic gauges, which are connected to a controller through a fiber-optic cable.

The DFF sensor bends under the force of the flow when immersed in a powder, and measures the drag force. The amount of bending is measured in-line and in real-time. This allows the user to immediately determine the attributes of the in process material and whether any adjustments are required. It also eliminates the need to stop the process so that an offline measurement is avoided.

Drag Force Flow Sensor (Lenterra Inc.)

Figure 1. Drag Force Flow Sensor (Lenterra Inc.)

The force pulse magnitude (FPM) – the difference between the force at each maximum and the preceding minimum – is recorded by the DFF sensor. In the granulator, the wet mass densifies into granules and the force with which the material passes across the sensor increases, as shown in Figure 2.

Drag force flow, as measured by FPM, is a dynamic property of the bulk assembly of granules that is related to properties such as density, size, and shear viscosity of the material. It can be compared with downstream product attributes in the same way as those of the dried granules, or those of the wet granules obtained by at-line measurements.

Principle of DFF Operation

Figure 2. Principle of DFF Operation

Correlating DFF with Granule Properties

Three mixtures of anhydrous lactose (Sheffield Bioscience), MCC (PH102, FMC Biopolymer), hydroxypropyl cellulose (HPC, Klucel EXF, Ashland Speciality Ingredients), and sodium croscarmellose (AcDiSol, FMC Biopolymer) were wet granulated with 40% wt/wt water in a GEA PharmaConnect™ high shear wet granulator.

 FT4 Powder Rheometer® (Freeman Technology)

Figure 3. FT4 Powder Rheometer® (Freeman Technology)

% wt/wt
Mixture 1 Mixture 2 Mixture 3
MCC 61 59 57
Lactose Anhydrous 37 37 37
Sodium Croscarmellose 1 1 1
HPC 1 3 5

To investigate the degree of correlation between changes in drag force flow signal and changes in Basic Flowability Energy as a function of the granulation process, changes in drag force flow during the granulation step were directly monitored in-line using a Lenterra in-line DFF sensor, and at-line using a Freeman Technology FT4 Powder Rheometer® (Figure 3), by withdrawing aliquots from the granulator and measuring their BFE. This was done for each formulation.

Test Results

The change in FPM as a function of time for the three formulations can be seen in Figure 4. FPM is relatively consistent in each case until the point when water is added. FPM increases at the point of water addition as the granules develop and begin to grow.

Soon after the end of the water addition period, a maximum FPM value occurs. This is consistent with the conventional understanding that wet granulation end point is obtained shortly after the end of water addition. It also suggests the higher binder content increases the time taken to achieve granulation end point, but results in the growth of stronger granules.

Change in FPM (from DFF Sensor) as a Function of Time

Figure 4. Change in FPM (from DFF Sensor) as a Function of Time

The evolution of BFE for the wet mass as a function of time for all three formulations can be seen in Figure 5. Observations made based on the results of the DFF sensor, include:

  • Higher levels of binder lead to higher BFE values, indicating denser, stronger, larger granules
  • After the start of water addition, there is an increase and a subsequent decrease in BFE as a function of time
  • After the completion of water addition, granules with the higher binder content appear more robust, maintaining a relatively high BFE, where the granules with lower binder contents show a significant reduction in BFE during the same period, probably due to granulate degeneration.

Change in BFE (from FT4) as a Function of Time

Figure 5. Change in BFE (from FT4) as a Function of Time


Wet mass consistency measured in-line and in real-time using the DFF sensor is a good indicator of powder rheology. It correlates well with BFE measurements from the FT4 Powder Rheometer.

The data rich process fingerprinting provided by the DFF sensor makes it a useful tool for wet granulation formulation and process development, as well as for regular monitoring and control during manufacturing.

The results obtained from both the FT4 and DFF sensor can be correlated to granulation end point, and can be useful in experimental studies of the effect of process parameters on drug product CQAs.

In order to fully understand the relationship between material properties, process parameters, and product CQAs, process relevant characterisation methodologies are required, the results from which can be correlated with CQAs. To produce a design space of parameters that correspond to optimal process configuration, the results from those process-relevant characterization methodologies can be correlated with CQAs.

Instead of relying on classical techniques that produce one value to describe behavior across all processes, the DFF and FT4’s approach measures granule properties in conditions relevant to the wet granulation operation, or directly within it. This enables the direct investigation of a powder’s response to various process and environmental conditions within this process.

This information has been sourced, reviewed and adapted from materials provided by Freeman Technology.

For more information on this source, please visit Freeman Technology.

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