Novel approach to control pharmaceutical crystallisation using heterogeneous nucleation

Crystallisation is widely used for purification of commodity and speciality chemicals and pharmaceuticals and for making advanced materials for catalysis, separations and sensing applications. One of the main challenges in developing robust and efficient crystallisation processes is to control the nucleation rate. In addition, many systems tend to crystallise in multiple structural forms of the same composition called polymorphs, and controlling polymorphism is extremely important in the development of pharmaceutical products as polymorphs have different properties, such as solubility, dissolution rate and thus bioavailability in resulting dosage forms.
Nucleation mainly occurs via heterogeneous mechanisms, with the nucleus forming on a surface or interface, rather than in bulk solution. In large-scale industrial processes, heterogeneous nucleation is often undesirable in industry as it leads to fouling of vessels and a lower product yield, however, nucleants are often added to induce nucleation and/or produce a particular polymorph via heterogeneous nucleation. Numerous strategies have been proposed for the design of nucleant surfaces under three broad areas: epitaxy and surface topology, and surface chemistry. However, the role of dispersion and dipole-dipole interactions at crystal/nucleant interfaces is generally overlooked.
This project will take a combined experimental and simulation approach to understand how to manipulate surface dipole layers and dispersion interactions to control nucleation rate and the direct formation of a particular polymorph. In the experimental part, we will systematically investigate the effect of tunable monolayers on heterogeneous nucleation of representative organic compounds relevant to the pharmaceutical industry in order to explore the design space of novel heterogeneous nucleants. Characterisation of functionalised surfaces and crystals grown on them will be performed with a suite of advanced characterisation techniques available in the CMAC National Facility housed in TIC, including AFM, SEM, Raman microscopy and GI-SAXS. In the simulation part, we will gain a molecular level insight using a combination of quantum mechanical calculations and classical molecular dynamics simulations, which will enable calculation of relative energetics of competing polymorphs on various interfaces corresponding to systems investigated experimentally.