Engineering Defects and Disorder for Enhanced Pharmaceutical Properties

Abstract

This thesis focuses on the research areas of crystallisation and solid-state chemistry and studies the relationship between crystallisation parameters and the resultant formation of a solid form (e.g. crystal nucleation, growth and morphology) and its associated attributes (e.g. disorder, solubility and stability), focusing on Active Pharmaceutical Ingredients (APIs). The work falls into the Healthcare theme of the Centre for Sustainable and Circular Technologies (CSCT) and focuses on approaches that have the potential to extract the maximum value out of pharmaceutical drugs by establishing methods to enhance a solid form under development.

In Chapter 1, an introduction into the research areas tackled in this work are discussed including context of research, background theory and the scope of research conducted. In Chapters 2 and 3, accounts of the experimental methods implemented in this work are reported and the theory behind the analytical methods utilised discussed.

Chapter 4 focuses on the development of a new crystallisation method, electrospraying, and investigates the influence of several crystallisation parameters on the electrosprayed product. This chapter focuses on gaining a higher level of control over the resulting solid form, including polymorphic control of paracetamol (PCM) via a templating approach and the formation of a novel multi-component complex of PCM and metacetamol (MCM). In addition, Chapter 4 explores the resultant physical properties and particle attributes of the electrosprayed product. The successful transfer of the material produced by electrospraying into a cooling crystallisation platform via crystal seeding is demonstrated, also showing that deploying electrosprayed seeds is to date the only established conventional route to access the PCM-MCM co-crystal.

Chapter 5 explores the co-crystallisation and characterisation of a series of molecular complexes of the API salbutamol (SA). Dicarboxylic acids of increasing chain length are used to facilitate the study of the effect of small changes in the molecular nature of the co-former on crystallographic disorder in the resulting co-crystal structure. Different crystallisation methods and conditions are studied and the presence of crystallographic disorder is identified in each multi-component complex of interest. A structural informatics assessment is conducted alongside a number of physical property studies that compare and contrast each form.

In Chapter 6, single crystals from a series of small scale crystallisations containing salbutamol sulfate (SAS) and the structurally similar salbutamol oxalate are analysed by X-ray crystallography to obtain a portfolio of crystallographic data. A systematic approach is used to characterise the presence of solid-state disorder in individual single crystals in a batch, quantifying variations in disorder between these single crystals. The crystallographic data collected is paired with a bulk analysis technique (solid-state NMR spectroscopy) to promote further understanding of the nature of disorder. The influence of different crystallisation and process parameters is investigated to study if the crystallisation conditions utilised can be used to control variations of disorder seen in a batch of crystals.

The research discussed in Chapter 7 looks to establish a simple empirical method of quantifying the extent of diffuse scattering in a material. A portfolio of crystallographic data is collected for a solid form known to show signs of stacking disorder, phloroglucinol dihydrate (PhG dihydrate), from single crystals prepared by evaporative, cooling and vapour diffusion methods. An investigation into the degree of disorder seen in a batch as a function of crystallisation method is presented alongside the establishment of a new empirical methodology for quantifying the amount of diffuse scattering seen in single crystals, the counting spots method.

The final chapter, Chapter 8, presents concluding remarks from the results presented in Chapters 4 to 7, pulling the findings together. The potential of future work in this area of research is discussed.

Date of Award	17 Jan 2022
Original language	English
Awarding Institution	University of Bath
Supervisor	Chick Wilson (Supervisor), Matthew Davidson (Supervisor) & Bernardo Castro Dominguez (Supervisor)