The manufacture of many pharmaceutical products relies on high shear wet granulation (HSWG), a process that transforms fine powder materials into more easily compressed, more uniform, free-flowing granules. Granulation helps optimize operations such as tableting but can present challenges, particularly with respect to scale-up.
This article introduces the fundamental principles of measuring drag force flow (DFF) and explores the application of this technique for monitoring and control of a HSWG operation. DFF is recorded in-line by needle-like sensors that provide high frequency and high resolution measurements. The resulting data can be used to ensure conformity with a Design Space, perhaps previously defined using laboratory scale information, which in turn can be used to support a Quality by Design (QbD) approach of managing critical process parameters (CPP) to control critical quality attributes (CQAs) of the final product.
Why High Shear Wet Granulation Is Important
High shear wet granulation uses a liquid (often water) to help combine a formulation of active ingredient and excipients into homogeneous granules that also improve throughput and aid processes such as tableting. Granulation typically improves a material’s ability to flow freely through the manufacturing system.
Granule properties can be manipulated by varying CPPs, such as the quantity and rate of water addition, operational speeds (e.g. impeller rotation and/or chopper speed), and the granulation time. Understanding how changes in each of these CPPs affects the properties of the resulting granulate often involves empirical studies to investigate the relationships between CPPs and final product CQAs. These links can, however, become difficult to assess and maintain when manufacturing processes are scaled-up.
The Fundamentals Of Drag Force Flow Measurements
A DFF sensor is a thin, hollow, cylindrical needle, approximately 1-4 mm in diameter, which is mounted inside processing equipment such as granulators, mixers or feeders. Two optical strain gauges, made up of Fiber Bragg Gratings (FBGs) and fixed to opposite walls inside the needle, continuously measure the deflection experienced by the needle as material flows against it. As the material being processed interacts with the needle, the FBGs compress or stretch, leading to a shift in their relative spectra. This spectral shift is proportional to the deflection of the needle and is transferred via optical fibers to an interrogator which assesses the response. The device is sensitive to both force and temperature which enables any temperature-related drift to be automatically corrected. The force associated with the deflection of the needle is then reported as a Force Pulse Magnitude (FPM). Variation in FPM correlates directly with properties of the wet mass as granules are formed and the material becomes denser.
Sensor sensitivity is defined by the length, diameter, and material of construction of the needle, with tip deflection as low as one micrometer being detectable. The sensors employ no moving parts, have no material traps and are relatively insensitive to material build-up on the surface. The small diameter of the sensor offers minimal intrusion to the flow of material and high frequency measurement rates are achievable.
Figure 1: In-line sensor installation within a granulator.
Case Study: Monitoring HSWG
A study was carried out to investigate whether in-line drag force flow (DFF) measurements can be used to track a granulation process by comparing the DFF data with off-line dynamic measurements of basic flowability energy (BFE), an established parameter for assessing granule development.
Six batches of three pharmaceutical formulations with different levels of Hydroxypropyl Cellulose were produced (1% w/w HPC, 3% w/w HPC and 5% w/w HPC). Two kilogram batches of dry powder were made up according to pre-determined compositions and granulated with 800g of water in a 10 L high shear wet granulator (Pharma-Connect, GEA). Processing conditions were set in accordance with previous optimization studies. In-line data was gathered during the granulation step using a DFF sensor (measurement range +/- 3N, Lenterra Inc., USA) mounted in the granulator lid, 2.5 cm above the blade and 8.2 cm off the blade rotation axis. Samples of the granulate were taken after fixed time periods and BFE was measured using an FT4 Powder Rheometer (Freeman Technology, UK). A comparison was then made between the in-line FPM data and the BFE measured using the powder rheometer (figure 2).
Figure 2: Comparing in-line with at-line data for three formulations.
In-line DFF measurements showed excellent repeatability with the derived FPM reflecting the change in consistency of the granulating mass throughout the process.
The three formulations generate similar profiles. The initial work (shear) to mix the dry powders does not result in significant changes in FPM, however, FPM rises rapidly as water is added, indicating the development of larger, denser, less compressible and more adhesive granules. A peak FPM is observed shortly after the end of water addition, after which FPM declines as the continued mixing generates smaller granules. It was also observed that FPM increases with respect to HPC percentage, suggesting that higher binder concentration results in stronger, denser and larger granules. The BFE profiles support the FPM data, showing a rising profile during water addition and subsequent decay as water addition ends, as well as the increase with respect to binder content.
The sensitivity of DFF measurement is illustrated by the magnitude of the increase in signal associated with water addition compared to the corresponding increase in BFE. For these formulations, FPM values peak shortly after water addition is complete, while the BFE values peak towards the end of the water addition phase. However, the data demonstrate how both techniques can be used to track granule development.
Combining Drag Force Flow and Powder Rheology
The data presented here demonstrate that in-line DFF measurements can be used to monitor the variation in granule properties during a HSWG process. The resulting FPM correlates with parameters delivered by at-line powder rheology techniques that have previously been shown to provide valuable data for optimizing HSWG processes in order to generate granules suitable for downstream processing.
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About the Author
Katrina Brockbank, Powder Technologist at Freeman Technology Ltd, undertook her Ph.D. in Powder Flow Characterization at the University of Bradford. While completing her thesis she also undertook several projects for the Institute of Pharmaceutical Innovation, including pharmaceutical formulation. In addition to her field of study she is also familiar with solid state characterization methods including DSC, TGA, and DVS. Brockbank has worked as a Powder Technologist at Freeman Technology since 2012.
