Improving Processes with In-Line, Real-Time Measurement

Many challenges may be faced when processing powders. For example, they might flow differently in the process; particular blends may be prone to segregation or agglomeration; or they may respond in different ways to process inputs like added water content which may influence the properties of the bulk material.

High Shear Wet Granulation (HSWG) is frequently utilized in the pharmaceutical industry to mix several components of a blend into a more homogeneous, free-flowing intermediate product for downstream processing.

The influence of changes as a result of process design, formulation, or equipment scale is normally evaluated on the characteristics of dried granules or end-products.

It is critical to establish both material properties and process parameters in a Quality by Design (QbD) approach.

A precise in-line technique to quantify the transformation of granule features within a granulation process is a major advancement in understanding the process, and provides the possibility to produce optimized process control strategies.

Drag Force Flow as an In-Line Measurement

An in-line drag force flow (DFF) sensor, for example the one created by Lenterra Inc. (Figure 1), offers a robust and highly sensitive in-line measurement of flow forces inside of the granulator.

The thin DFF sensor is secured onto a stationary base and is equipped with two fiber-optic gauges, which are fixed to a controller by a fiber-optic cable.

The DFF sensor measures the drag force as it bends when subjected to the force of the flow when submerged in a powder. The extent of the bending is analyzed in-line and in real-time.

This enables the user to instantly establish the attributes of the in-process material and discover whether any changes are needed. It also takes away the requirement to halt the process as a means to avoid an offline measurement.

Drag Force Flow Sensor.

Figure 1. Drag Force Flow Sensor. Image Credit: Lenterra Inc.

The difference between the force at each maximum and the preceding minimum is called the force pulse magnitude (FPM) and is tracked by the DFF sensor.

Within the granulator, the wet mass densifies into granules and the force with which the material travels along the sensor increases, as displayed in Figure 2.

As measured by FPM, drag force flow is a dynamic characteristic of the bulk granule assembly that corresponds to the material’s features, for example size, density, and shear viscosity.

It can be used in comparison with downstream product characteristics in an equivalent way to those of the dried granules, or those of the wet granules acquired by at-line measurements.

Principle of DFF Operation

Figure 2. Principle of DFF Operation. Image Credit: Freeman Technology

Correlating DFF with Granule Properties

In a GEA PharmaConnect™ high shear wet granulator, three combinations 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.

FT4 Powder Rheometer®

Figure 3. FT4 Powder Rheometer® Image Credit: 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

 

Changes in drag force flow throughout the granulation stage were directly observed in-line utilizing a Lenterra in-line DFF sensor, and at-line employing a Freeman Technology FT4 Powder Rheometer® (Figure 3).

This was performed in order to evaluate the extent of correlation between changes in drag force flow signal and changes in Basic Flowability Energy as a function of the granulation process. It was achieved by retrieving aliquots from the granulator and calculating their BFE. This was performed for every formulation.

Test Results

Figure 4 demonstrates the change in FPM as a function of time for the three formulations. FPM is comparatively stable in every case until the moment that water is added. FPM enhances when water is introduced as the granules evolve and start to grow.

A maximum FPM value happens soon after the end of the water addition stage. This is in line with the traditional understanding that the wet granulation end point is acquired soon after the water addition ends.

It additionally indicates that the higher binder content expands the time taken to attain granulation end point, but produces 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. Image Credit: Freeman Technology

Figure 5 demonstrates the transformation of BFE for the wet mass as a function of time for all three formulations. The following are observations made that are established on the results of the DFF sensor:

  • Greater levels of binder result in higher BFE values, suggesting granules are more dense, stronger, and larger.
  • After the beginning of water addition, there is an increase and a consequent decline in BFE as a function of time
  • Once water addition has been completed, granules with the greater binder content seem to be more robust, keeping a relatively high BFE, where the granules with lower binder contents display a strong decrease in BFE in the same period, likely a result of granulate degeneration.

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

Figure 5. Change in BFE (from FT4) as a Function of Time. Image Credit: Freeman Technology

Conclusion

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

The data-intensive process fingerprinting offered by the DFF sensor makes it a helpful tool for wet granulation formulation and process development, as well as for standard monitoring and control throughout manufacturing.

The results acquired from both the DFF and FT4 can be matched to the granulation end point, and can be helpful in experimental investigations of the influence of process parameters on drug product CQAs.

Process parameters, product CQAs, and process relevant characterization techniques are necessary in order to understand the relationship between material properties. The results from this can correspond with CQAs.

The results from those process-relevant characterization techniques can be correlated with CQAs in order to create a design space of parameters that are in line with optimal process configuration.

Rather than depending on traditional methods that create one value to outline behavior throughout all processes, the FT4 and DFF’s approach quantifies granule features in conditions suited to the wet granulation operation, or directly inside of it.

This allows the direct study of a powder’s reaction to a range of environmental and process conditions inside of this process.

About Freeman Technology

Freeman Technology specialises in systems for measuring the flow properties of powders and has over 15 years’ experience in powder flow and powder characterisation. The company invests significantly in R&D and applications development, and provides detailed know-how to support its range of products. Expert teams guide and support users around the world in addressing their individual powder challenges, focusing on delivering the most relevant information for the process. The result is world-leading solutions for understanding powder behaviour - in development, formulation, scale-up, processing, quality control, or anywhere that powders have a role.

Freeman Technology’s solutions include the FT4 Powder Rheometer®, a uniquely universal powder tester, and the Uniaxial Powder Tester, a complementary tool for quick and robust powder assessment. Systems are installed around the world in the chemical, pharmaceutical, toners, foods, powder coatings, metals, ceramics, cosmetics, and many other industries. They deliver data that maximise process and product understanding, accelerating R&D and formulation towards successful commercialisation, and supporting the long term optimisation of powder processes.

Freeman Technology is also the global distributor for Lenterra sensor instrumentation which provides in-line, real-time flow measurement solutions to enhance process understanding, and improve manufacturing efficiency and quality.

Founded in 1989 as a developer of automated testing systems for materials characterisation, the company has focused exclusively on powders since the late 1990s and in 2018 became part of Micromeritics Instrument Corporation The company’s R&D, manufacturing and commercial headquarters are in Gloucestershire, UK, with operations and distribution partners in key global territories.

In 2007 the company received the Queen’s Award for Enterprise in Innovation and in 2012 the Queen’s Award for Enterprise in International Trade.


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Last updated: Nov 28, 2019 at 5:15 AM

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