Investigating the factors leading to crystallisation in drug melts and glasses

Objectives: 1) we will elucidate the structural connections between the melt and the resulting crystal form of drug compounds to explain why some crystal forms can only be obtained from the glass or melt, and 2) we will generate fundamental data on the glass or melt as a model for the solvent-free dense phase in solution crystallisation.

The crystal form of drug compounds is of utmost importance in the formulation and manufacture of medicines, as it influences not only the hardness, compressability and physical/chemical stability of the drug material, but also its solubility and dissolution rate and thus its bioavailability to the patient. Even though a huge research effort has been made over the last ~60 years to predict crystal forms and crystallisation outcomes, this goal has still not been achieved, and pharmaceutical industry is investing a large part of its R&D budget (£5b/annum in the UK) into solid-state research of novel drug compounds. While most crystallisation processes in industry are performed from solution, crystals can be obtained from the pure liquid or the gas phase with sometimes surprising results.

Crystallisation from the neat drug compound in its liquid or solid amorphous phase, the melt or glass, respectively, can yield crystal forms that are not available through classical solution crystallisation. This long-known phenomenon has gained renewed interest in recent years, where it could be shown that well-examined compounds can be crystallised in novel crystal forms even after decades of study.1, 2 The reasons for this ability are not yet clear and many studies concentrate on the nucleation and growth step of the melt crystallisation with few considering molecular interactions, density, and local ordering. In addition, the amorphous phase has important applications, such as in drug delivery by increasing bioavailability of poorly soluble drugs. Here, crystallisation has to be avoided at any cost, but despite recent exciting studies,3 why and when a material crystallises is poorly understood. In this project we will fill the following knowledge gap: What are the molecular interactions in the neat liquid that drive specific crystal forms to crystallise? We anticipate our results to be an essential part in the development of robust prediction methods - either computational or based on experiment - for crystallisation outcome.

We will follow the intermolecular interactions in melt or glass phases using Fourier Transform Infrared Spectroscopy (FTIR), solid-state magic-angle-spinning NMR spectroscopy in collaboration with the group of Dr Daniel Lee at Manchester University, and neutron total scattering at the ISIS neutron and muon science facility at Harwell in Oxfordshire. The two spectroscopic methods will allow us to gauge the energy of interactions present in the melt/glass phases as well as the lifetime of the assemblies, while the scattering enables us to construct a structural model of this highly disordered systems.

Many compounds have been described to show different crystallisation behaviour from the melt, including the pharmaceuticals aspirin, paracetamol, nicotinamide and isonicotinamide, ROY, indomethacin, celecoxib, and hexamidine diisethionate, some of which have been model compounds for solid-state investigation for decades. We will start our investigations from these systems already spanning a wide variety of chemical structures, physicochemical characteristics, and solid-state landscape, and will expand the sample group to further include compounds that have been reported to crystallise differently from the melt.

This position is supporting a recently awarded ERC Consolidator grant.