Advanced Imaging and modelling of pharmaceutical materials

Continuous manufacturing is efficient, flexible and has time and cost saving features. There is currently a high level of interest in continuous manufacturing in the pharmaceutical industry with this process gradually replacing the traditional step-by-step manufacturing process in the majority of modern industries. Despite these advances, there are gaps and challenges that must be addressed to enable continuous manufacturing to be a viable approach in the pharmaceutical industry. This project will use advanced imaging techniques such as X-ray micro-tomography and a Focus Variation (FV) optical surface metrology instrument from AliconaTM as a tool for validation, qualification and PAT testing in generating a mathematical predictive models.

To date there has been a lot of work done using advanced imaging techniques to investigate the quality of the products produced from the continuous manufacturing process. For example, many tablet formulations need to be coated in order for the desired final product characteristics to be achieved after the compression process. Filaments produced from Holt-melt extrusion process are often pelletized or ground into fine powders for use in final dosage forms. This however is traditionally investigated using a scanning electron microscope. The X-ray micro-tomography technique can show how tooling geometry can affect the internal structure of the tablet (final product) and give added information on the porosity of various formulation based on density differences. In cases where internal cracks have been evident in potential formulations, potentially failure can be averted.
A Focus Variation (FV) optical surface metrology instrument from AliconaTM allows the determination of surface texture as a function of: grade of material, compression pressure and formulations used. This study will lead to the development of an appropriate method of measurement and testing using X-ray micro-tomography as a used as a tool for validation, qualification and PAT testing in determining blend uniformity and the quality of hot-melt extruded systems in the continuous manufacturing process rather than through post-production, batch-based testing thereby enhancing the processes reliability through modelling. The FV instrument will give information on how the various processing parameters can affect the surface metrology of the filaments and their impact on dissolution for example will be investigated.

The proposed outcome is to use X-ray micro-tomography and AliconaTM as a validation and PAT testing system as part of the continuous manufacturing system is developing a mathematical model that allows the prediction of various parameters to be determined.
1. Firstly, a model poorly soluble drug will be investigated. Various polymers that have the ability to allow drugs to be molecularly dispersed within them to improve their solubility will be investigated also. These will be investigated using the continuous manufacturing process (the hot-melt extrusion system).
2. An extensive study will be conducted on continuous manufacturing process in areas of scale-up, on-line and in-line processes, feed rates, screw designs and so forth to determine how full amorphorisation can be obtained.
3. The optimization of the continuous manufacturing process will be conducted and the various filaments obtained characterized using several techniques including the FV instrument. This will be used to determine how the various processing parameters impact the surface metrology properties
4. Pelletization and fine powders would be obtained from the grinding process and X-ray micro-tomography will be used to determine porosity differences as a result of the processing parameters and correlations drawn out.
5. Sessile drop analysis (contact angle testing) would be conducted to draw correlations between the physiologically relevant dissolution media and the formulation and predictions on how they impact dissolutions made.