Measuring powder behaviour in relation to quality by design

21st February 2013

Characterising and understanding a powder's flowability is critical, particularly in relation to the pharmaceutical industry's Quality by Design (QbD) and PAT initiatives. Tim Freeman explains.

The advent of quality by design (QbD) and the process analytical technology (PAT) initiative invites the process industry to transform process operation and efficiency.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline Q8: Pharmaceutical Development, describes the principles of QbD. It suggests changing from an approach that checks for quality by testing, to one that designs quality into the product and manufacturing process. PAT is a US Food and Drug Administration initiative designed to aid the uptake of new analytical technologies.

It must be borne in mind that powder behaviour is complex and has little mathematical understanding underpinning it. No 'unit of flowability' exists. To answer the question 'What should be measured?' it is necessary to consider the factors that influence powder flowability, encompassing both the physical properties of the particles and the environmental variables within the process.

Flowability is a measure of the ease with which a material moves relative to itself and its containing environment. The long list of physical property variables that have an affect on it ranges from particle size, shape and surface texture through to cohesivity, adhesivity and amorphous content. At the same time, a number of mechanisms influence powder flow: friction between the particles and container wall is important, as is mechanical interlocking of particles; liquid bridges, whether water or a binder, increase particle-particle and particle-wall adhesion; and cohesive forces and gravity play significant roles. Environmental variables such as consolidation, aeration, flow rate, moisture, electrostatic charge and storage time, all have an impact on powder flow.

The impossibility of building a small-scale rig of each process makes it necessary to use instead a tool that simulates process conditions and measures a material's response. It is in this context that the modern powder rheometer is proving so effective (Fig.1). A system such as the FT4 from Freeman Technology provides comprehensive powder flowability data, delivering automated shear testing, dynamic flowability and bulk properties measurements.

QbD relies on being able to describe how a powder will behave in a process and direct measurement of flow behaviour is the only way to achieve this. However it is essential to measure the properties relevant to process conditions. While these may be estimated, it can be difficult to know exactly what they are, raising the question of how to proceed without knowing, say, the exact level of consolidation, flow rates or degree of aeration that will be encountered. Fortunately, because the pharmaceutical industry has been manufacturing powders for many years, there is extensive qualitative knowledge as to which formulations work well through certain equipment and which are problematic.

If all materials are characterised and their flow properties recorded in a database, then a correlation can be established between flowability and process performance, enabling quantification of the extensive know-how that already exists in the industry. When this information is fed into the development environment, formulators are provided with a design space for a given process step. This is the essence of QbD and can be illustrated using tablet compression as an example.

Tablet compression is a widely used process. Intermittent flow from the hopper, variation in tablet hardness/weight, and content uniformity/segregation are all typical problems. In the following example (Fig.2), using the same equipment to process different formulations leads to different results.

Formulation A always has problems with flow from the hopper, but not with tablet hardness or content uniformity. Formulation B invariably flows well from the hopper but often results in problems with tablet hardness. Formulation C exhibits no problems with either flow from the hopper or tablet hardness but content uniformity is often compromised. So which flow properties are important?

Flow from the hopper is influenced by shear properties, wall friction, compressibility and permeability. For tablet hardness, basic flow energy, consolidation index, de-aeration and conditioned bulk density are all important. Content uniformity is affected by the cohesive properties of the blend, so aeration, specific flow energy, flow rate sensitivity and permeability are important. These characteristics, measurable using a powder rheometer, must be examined to understand specific process behaviour.

How does this relate to QbD? Take the issue of intermittent flow from the hopper. By selecting the key variables - shear properties, wall friction, compressibility, permeability - it is possible to describe the three formulations in relation to their flow from the hopper, and to give each one a processability ranking. Formulation A is always problematic, with blockages or bridging, warranting a processability ranking of just 2 out of 10. Formulation B is excellent and flows freely every time, elevating it to 9 out of 10. Formulation C is somewhere in between, displaying moderate performance with occasional bridging but generally few problems, giving it 6 out of 10.

Having assigned processability rankings, the next step is to measure shear and wall friction in order to characterise each formulation's sensitivity to the environment. Here Formulation A has high sensitivity, or high shear and high wall friction; Formulation B quite the opposite; and Formulation C is in between. The same exercise can be undertaken for compressibility and permeability.

Correlating processability ranking with measured flow properties enables the identification of acceptable process behaviour for each of these parameters, thus defining the design space (Fig.3). This correlation must be achieved for every step of the process.

Tim Freeman is Director of Operations, Freeman Technology, Welland, UK.

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