Control of solid form and particle morphology using additives and crystallisation conditions

Abstract

The research presented in this thesis concerns the improvement of the particle morphology of pharmaceutically relevant materials, focussing largely on the use of additives in crystallisations. The work fits into the wider context of the research carried out at the Future Manufacturing Hub in Continuous Manufacturing and Advanced Crystallisation (CMAC), funded by the EPSRC.
Opening chapters provide an introduction to the general research area, including the background of the project. A general overview of the analysis techniques used and methodology employed are also detailed in chapters 2-3.
Chapter 4-5 pertain to the experiments carried out to improve the morphology of the primary Active Pharmaceutical Ingredient (API) being investigated, isoniazid (IZN). Chapter 4 focuses on the use of different solvents and intentionally added impurities (additives). Additives chosen include both size- matched molecules and polymers. The effect of the additives is related to the crystallisation method and dependent on the concentration added. This chapter also reports the successful transfer of solvent effects into a continuous crystallisation platform, the Kinetically Regulated Automated Input Crystalliser (KRAIC). Face indexing and analysis of the crystal structure were used to rationalise the effects of the additives. In chapter 5, additives are used as co-formers with the aim of producing new multi-component crystals with favourable morphologies. The properties of each new co-crystal were determined and the improvements to morphology discussed with respect to experimental face indexing.
Chapter 6 applies the methodology used in the IZN research to a second API, pyridoxine (PYR). The effects of solvent, additives and formation of multi-component materials are discussed in terms of their influence on the crystal morphology achieved. Face indexing analysis was carried out to aid the comparison of crystal shapes produced.
Chapter 7 details the benchmarking of a workflow, produced by Dr. Lauren Hatcher, using CMAC target molecules fenamic acid (FA) and mefenamic acid (MFA).

Date of Award	16 Jun 2021
Original language	English
Awarding Institution	University of Bath
Supervisor	Chick Wilson (Supervisor)