Pressure-dependent In-Situ Monitoring of Granular Materials

Lead Research Organisation: University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci

Abstract

The majority of medicines are marketed as oral solid dosage forms and tablets in particular. The building blocks of each tablet include the active ingredient (or drug) and other components (excipients) that when formulated together confer stability, ease of handling and administration, patient compliance and assure delivery of the correct dose of medicine to patients in every tablet. These ingredients are typically presented in granular or powdered form, whether as individual particles, aggregates or formulated intermediates. This proposal seeks to couple an experimental process simulator with advanced measurement to improve our understanding of the relationship between the structure and properties of granular raw materials, compaction processes and the structure and final product performance. This will lead to a range of advances including: predictive or digital formulation design; rapid process development; and digital manufacturing. Consequently, these advances will accelerate the speed with which new medicines can reach the market and reduce costs, which is necessary if we are to realise the supply chains to meet patients' future medicines needs.
New pharmaceutical products are far more complex than the standard immediate-release tablets that can be found in simple over-the-counter medicines. The development and manufacture of present-day drugs is much more demanding given the need to achieve target physicochemical and biopharmaceutical properties of the tablet which are themselves a function of more complex molecular and physical properties of the input materials. The advances in the chemistry of such new molecules are staggering, whilst the science that underpins the manufacturing methods used to formulate and produce them is still not very well understood for any given formulation. This necessitates new approaches and technologies to access chemical and physical performance-related material properties during manufacturing development.
We will push the limits of existing techniques by integrating state-of-the-art terahertz time-domain spectroscopy into a high-end compaction simulator. This fully integrated system will be capable of monitoring the physical and chemical changes of granular materials during compaction into tablets in situ using terahertz technology. The system will provide an innovative and powerful research platform to address key research challenges in pharmaceutical sciences and manufacturing: analysis of phase transformations in pharmaceutical materials during compression (Theme 1), in-situ monitoring of bulk properties in formulated systems under pressure (Theme 2), digital design of oral pharmaceutical drug products (Theme 3). The outcomes of these research themes are ranging from predicting drug stability (Theme 1) and enabling direct compression by rapid formulation design (Theme 2) to predicting drug performance based on digital process and product design (Theme 3).
The equipment will be housed within a well managed, state-of-the-art laboratory facility supported by a dedicated team of academic and support staff. This equipment will provide exciting opportunities for Strathclyde and other UK academics to collaborate and partner with other world-leading groups having complementary analytical facilities and manufacturing processes, thereby creating an international collaborative network of non-duplicated facilities for transnational access. Moreover, the equipment will generate new research opportunities in high value manufacturing, cutting-edge measurement technologies and advanced materials science in partnership with the National Physical Laboratory (NPL), Medicines Manufacturing Innovation Centre (MMIC), Centre for Process Analytics and Control Technology (CPACT), UK industry and academia.

Planned Impact

The research enabled by this project will impact the pharmaceutical industry, knowledge in pharmaceutical sciences, manufacturing research and quality control, academics, students/researchers, patients and the environment.
Both patients and manufacturers will benefit from a better understanding of the stability and variations of performance-related properties of a tablet that will lead to lower manufacturing costs, improve control over product quality and regulatory compliance enhance flexibility leading to greater responsiveness of supply to product life cycle and market demands. Critically the advances enabled by the equipment will contribute to major industry wide initiatives such as adoption of continuous manufacturing, Quality by Design (QbD) and Industry 4.0.
The enabled research will provide the fundamental understanding to link raw material properties to performance-related characteristics of a tablet. This will facilitate the production of more complex medications with predictable stability and performance in an increasingly challenging economic environment. Gaining more insights into the compaction process and its impact on the tablet quality will enable the development of models that are capable of predicting the dissolution behaviour. This will be transformational, displacing destructive quality tests that require days to be carried out with real-time release testing. Dissolution testing is one of the most widely used and expensive tools to assure the quality of pharmaceutical products and batch-to-batch reproducibility hence there is potential to impact here too. In addition to the technical and economic effects, the research enabled by this equipment will have a major impact in the area of Green Chemistry and affects positively and immediately the environment. At present the dissolution test requires the use and subsequent disposal of a range of solvents: diluted acids containing surfactants (> 2000 L/year per dissolution testing setup), acetonitrile (> 500 L/year per dissolution testing setup) and other solvents for liquid chromatography assays. Models will allow to predict dissolution performance without the environmental and health hazard associated with using toxic heavy metals.
The pharmaceutical industry will particularly benefit in the early development of a new product, where formulators have only access to a small amount of drug substance. Accessing performance-related information at an early stage and thereby eliminating unexpected manufacturing problems at an early stage of formulation will greatly accelerate timelines on the development cycle and minimise late stage failures, reworking and costly trouble shooting or reformulation. This will lead to an economic benefit for the company and a faster delivery of new medicines to patients. The instrument will also impact later development stages in identifying the impact of changes of raw material physical properties (e.g. surface area, mechanical properties) on the internal tablet structure controlling performance. This can arise due to change in upstream processes or suppliers. The equipment thus allows direct and rapid assessment of performance-related properties under commercially relevant conditions, which will reduce delays in getting new products to market. This reduction allows for potentially substantial savings in manufacturing development costs.
The THz-TDS/compactor system will also provide a platform to train people not only in compaction but also in in-line analytics, formulation design, quality control and data analysis as well as predictive modelling. PhD students and post-doctoral researchers will have skills in the areas of formulation and manufacture, where the pharmaceutical industry currently has a shortage of skilled expertise (see LoS from Pitt).

Publications

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