Novel multi-component systems of propyphenazone and lonidamine: characterisation, physicochemical properties and quantum crystallography studies

Abstract

This thesis reports novel multi-component systems of two APIs, PROPY and LON. Design and prediction strategies, tailored for each API, have been used to select appropriate co-former molecules used for subsequent screening and synthesis. Comprehensive characterisation of the products was followed by single crystal X-ray diffraction structural analysis and physicochemical property measurements. These include thermal properties, stability, dissolution and solubility which were characterised by DSC, TGA, PXRD and HPLC.

A subset of PROPY systems were selected to probe the nature of the API···co-former interactions. The experimental electron density distribution, based on very high resolution single crystal diffraction, was modelled and a topological analysis undertaken using Bader’s Atoms in Molecules (AIM) approach. Atomic charges, intermolecular interactions and their energies have been subsequently derived and compared between systems. Complementary theoretical calculations using the PIXEL and Crystal Explorer interaction energy approaches were undertaken and used to investigate the intermolecular interactions beyond atom···atom contacts. These permitted the decomposition of the intermolecular interactions into their constituent energy components for a comprehensive analysis. This novel approach provided new insight into the driving forces behind the formation of the solid state. Furthermore, this quantum crystallography approach enabled an analysis of the effect of the co-former on structure and the range of influencing factors that determine the physicochemical properties of these multi-component systems.

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Identifiers

ORCID for Simon J. Coles: orcid.org/0000-0001-8414-9272

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