One of the most risky and time-consuming steps of the manufacture of medicines is the scale-up, especially to generate powders and particles that further can be processed into formulations such as tablets. It is particularly difficult to control particle properties such as shape, size, size distribution, powder flow and compactability. The effort needed to control these particle properties and the risk management around it significantly contribute to the time-to-launch of a new medicine (both small molecular and new modality), not least because there are currently very limited tools available to predict particle property control during scale up showing low success rate.

In this project, we will use the thermodynamic microscale structuring of specific binary solvent systems to tailor particle properties, with the focus on shape in the first instance. Solvent mixtures such as acetonitrile/water have been described to show microheterogeneity, which is the demixing on the microscale while macroscopically the mixture behaves like a single phase. Due to the microheterogeneity, the solvent mixture contains droplets of one solvent in a continuous matrix of the other solvent, comparable with an emulsion but without the need to add surfactants for stabilisation. Our hypothesis is that the confinement of these droplets will enable us to control the particle shape of any compound showing a higher solubility in the droplet-forming solvent. Since the microheterogeneity forms spontaneously due to its thermodynamic nature, our proposed method will be scale- and equipment independent and thus can be tested on the small scale and robustly translated into batch scale up as well as continuous manufacture.

The proposed methodology will not only reduce the carbon footprint of the manufacturing process of any active pharmaceutical ingredient through reduction of additives and excipients needed but also provide a valuable tool to reduce the risk of scale-up and the time-to-launch for new drug compounds, which will have a direct benefit to the patient community and healthcare providers.

The main objectives are:

Generate proof-of-concept for the use of microheterogeneous binary solvent mixtures to control particle shape as pain point particle property. We will start with the well-understood mixture of acetonitrile/water as a model solvent and at least 20 model small-molecule drug compounds. Through controlled cooling crystallisation, we will then investigate the influence of droplet size and geometry - as a function of the solvent ratio - on the particle shape of the crystallisation product. This will allow us to map the influence of MH on particle shape over the phase diagram of the binary solvent mixture and control the particle shape. We will then widen the study to other binary and ternary solvent systems described to form microstructured mixtures.

Translate the developed lab-based method into batch scale up. We will then take the method developed in 1 to increase from a laboratory scale of ~10 ml to 20 L batch manufacture. It is the aim to prove that the thermodynamic nature of the microheterogeneity will allow for an equipment-independent scale up and hence minimise the risk accompanying traditional scale up.

Translate the developed lab-based method into continuous processes. We will use the particle shape control method in continuous crystallisation as part of continuous processing and manufacture. We will use continuous crystallisers to scale up the manufacture with controlled particle shape. The aim is to prove that the method is equipment-independent and could be used as part of continuous manufacture, such as for oral solid dosage forms.

The project work will be guided by our partner AstraZeneca, who will have frequent input and ensure that the research follows industry-relevant lines.