Process Analytical Technology for High Shear Wet Granulation

Process Analytical Technology for High Shear Wet Granulation

Overview

  • Post By : Kumar Jeetendra
  • Source: Freeman Technology a Micromeritics company
  • Date: 09 September, 2018

High shear wet granulation (HSWG) transforms fine powder blends into free-flowing granules with improved compression properties during the tabletting process. Granulation also enhances the uniformity of a blend, increases density and reduces dust levels, an important health and safety benefit. The pharmaceutical industry is one of several which rely heavily on HSWG processes, most especially in the manufacture of oral solid dosage forms.

A Quality-by-Design (QbD) approach in drug development and manufacture relies on data collection at relevant points in the process to control the critical quality attributes (CQAs) of the product.

Granules are typically an intermediate, rather than the end product, making it more difficult to identify the critical process parameters (CPPs) that impact the CQAs of the finished product. Research has shown that HSWG processes can be successfully optimised using at-line techniques such as dynamic powder testing, but continuous, real-time analysis has the ability to provide further information by measuring the wet granulated mass, in-process, without interrupting the granulation operation.

The Lenterra Flow Sensor (LFS) System (Lenterra Inc. USA) is a Process Analytical Technology (PAT) that provides high frequency, high resolution in-line flow force measurement. In this article we look at how it work and examine its potential application in HSWG monitoring and control. Research using an FT4 Powder Rheometer® (Freeman Technology, UK) suggests that both can be used at different stages of development and manufacturing to optimise HSWG processes.

Figure 1: FT4 Powder Rheometer (left), Lenterra Drag Force Flow Sensor (right)


The challenge of HSWG

During HSWG a blend of active ingredients and excipients are energetically combined with liquid, often water, to form relatively large, homogeneous granules. These undergo further processing to produce an optimal feed for downstream tablet manufacture. A typical objective for tableting would be to produce homogeneous granules that enable high throughput on the press and result in tablets with target CQAs.

The properties of granules are controlled through manipulation of a number of processing parameters, including:

  1. Quantity of water added
  2. Water addition rate
  3. Impeller/hopper speed
  4. Granulation time

Altering these variables enables the optimisation of granule properties and is usually a lengthy empirical process that relies on the implementation of statistical design-of-experiment (DoE) studies to correlate CPPs with the critical quality attributes of the manufactured granules. The resulting correlations tend to be scale-dependent, and process scale-up is a widely recognised challenge.

Producing granules with properties that are well-matched to the requirements of subsequent processes relies on being able to measure relevant properties during the course of the granulation. Dynamic powder testing, an at-line technique that measures bulk powder/granule flowability, has been shown to be valuable [1]. Its application enables characterisation of the developing granules, wet or dry, in terms of parameters that directly correlate with, for example, the CQAs of finished tablets [2]. The development of equally successful techniques for in-line measurement has the potential to deliver more responsive HSWG control and process scale-up.

In-line HSWG monitoring

A number of the PAT options proposed for granulation monitoring are based on the measurement of specific properties of the developing granules, for example, particle size. However, rather than focusing on individual particle parameters, which may or may not be relevant, measuring bulk properties, such as flowability, can have potential benefits.

The LFS system incorporates a drag force flow (DFF) sensor for in-line measurement of flow and an optical sensor interrogator for data processing and analysis. The sensor is a thin hollow cylindrical needle, in the order of 1-4 mm diameter, that can be mounted inside processing equipment such as a mixer, granulator or feeder, to provide real-time local measurement of the flow forces within the in- process material. Material flow causes a deflection of the pin, the magnitude of which is measured using two optical strain gauges, fixed to the inner surfaces of the sensor. The resulting measurements correlate directly with fundamental parameters of the material, such as density and shear viscosity, and can therefore be used to track the progression of a process, such as HSWG, that changes these attributes. Complementary temperature measurements enable the automatic correction of any temperature-related drift in measurement baseline.


Figure 2: Drag Force Flow Sensor in a High Shear Wet Granulator


Key advantages of this type of sensor are minimal intrusion into the flow, and relative insensitivity to the adherence of material on the sensor surface; an important attribute for robust continuous operation within a granulator. Furthermore, the probe has no moving parts, enhancing its inherent reliability, and measures at a sufficiently high frequency, up to 500 samples per second, to provide a high-resolution data-stream t at is able to successfully detect the evolving properties of the in-process materials. In a mixer or granulator it is typically installed through a standard port in the lid of the vessel, above the impeller and, like all in-line technologies, offers the opportunity to monitor the process without stopping and sampling. This is an important gain for process optimisation studies, and process control.

A DFF sensor reports data in the form of the Force Pulse Magnitude (FPM) which characterises the flow force associated with the passing of in-process material, and associated deflection of the pin. Changes in FPM therefore correlate directly with bulk properties of the process material - wet mass consistency and/or densification in the case of an HSWG process. FPM is a differential measurement and monitoring.therefore not subject to baseline drift - an important additional benefit for process


Case study – monitoring HSWG

A study was carried out to investigate whether in-line drag force flow 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 evelopment.

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 condi ions were set in accordance with previous optimization studies. In-line data was gathered during the granulation step using a DFF sensor (measurement range +/- 3N) 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. A comparison was then made between the in-line FPM data and the BFE measured using the powder rheometer (Figure 3).


Figure 3: 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, can be used to track granule development.The data demonstrate how both techniques can be used to track granule development.

Looking ahead

Wet granulation is a much-valued process in the pharmaceutical industry, but is notoriously difficult to control and scale-up. There is considerable value in developing analytical techniques that can reliably monitor HSWG processes. It is increasingly recognised that the quality of granules is not easily defined in terms of a single granule property but rather is a function of a number of parameters including density, porosity, surface adhesion, and size. Techniques that focus on bulk properties, as a function of water content, formulation or process changes, therefore have considerable potential.

Research has provided evidence of the value of dynamic powder testing and in-line flow force measurement for monitoring HSWG processes. While dynamic powder testing is an at-line technique, flow force measurement has been successfully implemented as an in-line sensor, via the LFS system. This PAT tool for real-time continuous measurement offers robust technology for routine HSWG monitoring and control during scale-up and into manufacture.

References

  1. Freeman, T. (2014) Choosing a Powder Tester. Freeman Technology.
  2. Freeman, T. (2014) In Pursuit of Wet Granulation Optimization. Pharmaceutical Manufacturing.
  3. Narang, AS. (2016) Process Analytical Technology for High Shear Wet Granulation: Wet Mass Consistency Reported by In-Line Drag Flow Force Sensor Is Consistent With Powder Rheology Measured by At-Line FT4 Powder Rheometer®. Journal of Pharmaceutical Sciences. 105:185-187

About Author

Tim Freeman, Managing Director, Freeman Technology Ltd

Tim Freeman, Managing Director, Freeman Technology Ltd