Liquid Distribution and Mixing in Continuous Granulation

The global pharmaceutical industry is gearing up to escape the constraints of narrow validated processes through implementation of Process Analytical Technology (PAT): a combination of process understanding and process instrumentation that will allow manufacturers to control processes to maintain quality within a defined operating space. This is expected to give more flexibility and less waste than the traditional narrow operating windows that result from empirical scale up from the bench to batch.
Continuous processing and, in the case of this project, continuous granulation, is widely seen as route to implementation of PAT. The advantages of steady state operation and straightforward implementation of feedback and feedforward control (with appropriate measurement technology and process models), has seen continuous processing dominate most of chemical manufacture apart from pharma. The specific challenge for this project is to further develop our understanding of granulation mechanisms and hence mixing processes in continuous granulation; this is fundamentally important since granulation is the stage in the process that determines whether the drug is uniformly and accurately distributed among the final dose forms (e.g. tablets).
The techniques we have used for this include: Particle Size Distribution; use of tracers to quantify distribution of liquid binder among particles; use of Positron Emission Particle Tracking to characterise flow, mixing, fill level and RTD within the granulator in real; torque and power measurement; x-ray micro-tomography to characterise particle structure to a resolution of better than 5 micron; mechanical properties of granules.

This project aims to explore granulation mechanisms and their outcome in order build a full understanding of Critical Product Qualities and Critical Process Parameters and to present this in the form of a regime map. Key to this is will be development of methodologies for measurement of the distribution of liquid binders and solid drugs and excipients within the granulated product. This knowledge is expected to contribute fundamental understanding of granulation mechanisms and how these impact granule and tablet properties.