Powder Characterisation Techniques for Wet Granulation Applications
The challenge of developing wet granulation processes
High shear mixers are traditionally the preferred choice for wet granulation. After initial blending of the dry components, a binder solution is added, whilst mixing continues, to wet the blend and promote granulation to a desirable endpoint. Control parameters include the amount of binder added, the rate of addition, processing time and impeller speed.
Two major issues complicate process development. Firstly, wet granulation is often an intermediate step so determining an optimal endpoint frequently involves working-up a number of batches at small scale, through to a final end product, such as a tablet. This can be a lengthy process but is essential if the properties of this intermediate material cannot be used to predict attributes of the finished tablet.
Secondly, the process variables used to control wet granulation do not scale in a linear manner. For example, a large-scale unit may need a water addition of 27% instead of the 24% required by a pilot scale process, to reach the same endpoint.
Identifying a property that can be used to accurately detect granulation endpoint throughout the development cycle is advantageous.
The value of dynamic powder properties
Basic Flowability Energy (BFE), a dynamic powder property measured using a Powder Rheometer, has been successfully used to track wet granulation processes to an optimal endpoint. BFE remains approximately constant in the early stages of a granulation but increases sharply as the mass becomes wetter. Image analysis confirms that this sharp rise corresponds with the processes of nucleation and granule growth. The rapidity of the rise makes BFE extremely sensitive at this most crucial part of the process, providing an opportunity for precise endpoint definition.
For a new wet granulation process, BFE monitoring quickly identifies the operating region of interest. Working up a number of batches made under different conditions within this region precisely sets a target BFE that exactly defines an optimal granule. For example, in pharmaceutical applications the BFE of granules has been successfully correlated with certain critical quality attributes of tablets made from them, notably hardness. A BFE specification for granules can therefore be set to ensure the manufacture of tablets with a consistent, required hardness. Associating an optimum granule with a BFE value rather than a specific set of processing conditions defines a relationship that is independent of scale.
Once established such BFE specifications can be used for all subsequent development work. As the process moves towards commercialisation, optimised processing conditions can be determined relatively quickly, at each stage or scale, to meet the target BFE. Furthermore, over the longer term, operating the process to a BFE endpoint, rather than with preset parameters, introduces the potential for adaptive control, the timely manipulation of process variables to maintain a consistent output even when excipient properties unexpectedly vary.
Process control can be further improved using inline monitoring technology. The Drag Force Flow (DFF) sensor measures the flow force associated with the movement of granules, in real-time, producing data that have been shown to correlate with BFE measurements. Going forward there may therefore be potential to define a wet granulation endpoint in terms of BFE and then transfer that specification into the process environment as a set point for real-time control, on the basis of DFF data.
Wet granulation can undoubtedly be a challenging process to develop and operate but dynamic testing can help, to accelerate process optimisation and to achieve flexible and efficient manufacture across the lifetime of the product.
Watch the webinar on Uniaxial Powder Testing for Optimizing High Shear Wet Granulation on demand here.