Disorder and additive control of solid form and morphology in continuous crystallisation

Abstract

Crystallisation is an important unit operation in the processing of pharmaceuticals and other fine chemicals. This thesis presents research in the area of crystallisation and solid-state chemistry and investigates methods towards optimising the physical and particle properties of organic solid forms. The work was carried out in the context of the EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC). CMAC aims to accelerate the adoption of continuous manufacturing processes for the production of higher quality chemical products at lower cost and more sustainably. Chapters 1-3 present an introduction to the research area in crystallisation tackled, along with background theory and experimental methods employed.Crystal morphology is important for the ease of downstream processing in the production of pharmaceuticals and fine chemicals due to its impact on the bulk properties of a substance. Impurities can play a significant role in the final crystal morphology produced from crystallisation and can therefore be added intentionally (known as additives) to tune the morphology of a substance to a more desirable shape. Chapter 4 presents the discovery of a polymer-additive mediated effect on the crystal morphology of succinic acid; the effect of the additive is dependent on both the concentration of succinic acid and the polymer additive and a thorough investigation of these parameters at different scales is presented. A possible mechanism for the interaction of the polymer with the crystal surface is also described. Chapter 5 reports the transfer of the crystallisation of succinic acid carried out in Chapter 4 into the continuous environment using two different platforms. The system is used to characterise the design of a mesoscale segmented flow crystalliser as well as transferred to a well-established oscillatory flow platform. In the latter platform the additive effect of the polymer on the crystal morphology of succinic acid is successfully reproduced in the continuous environment. Chapter 6 explores the effect of a range of structurally similar additive candidates on the crystallisation of the Active Pharmaceutical Ingredient (API), isoniazid. As employed in Chapter 4, face indexing and analysis of the crystal structure are used to rationalise the effect of the additives.Chapter 7 and 8 detail small-scale molecular crystallisation studies in attempts to induce disordered or layered solid forms and understand orientational disorder. In Chapter 7 the production of a range of multi-component molecular complexes of the API piroxicam are reported. This includes a solvated system which shows interesting structural and thermal properties which have been studied in detail. Chapter 8 is concerned with studies of orientational disorder in 5-chlorouracil.

Date of Award	27 Jun 2017
Original language	English
Awarding Institution	University of Bath
Supervisor	Chick Wilson (Supervisor)