Multicomponent templating approaches to solid form control in the continuous crystallisation environment

Abstract

The work presented in this thesis looks at using multi-component crystallisation techniques to impart solid form control to pharmaceutically relevant systems. In this thesis solid form encompasses both different polymorphic forms of the same material as well as the chemical and physical stability of a non-polymorphic single component compound. The work emerges as part as the EPSRC Future Manufacturing Hub in Continuous Manufacturing and Advanced Crystallisation (CMAC); an academic-industrial collaboration set up to aid the adoption of continuous manufacturing processes into an industrial setting.

Chapters 3-5 explore the use of incorporating a second molecular component into the crystallisation process, termed a template in this work, in order to direct the formation of metastable polymorphic forms. Chapter 3 investigates this templating effect on the formation of the metastable form (II) of paracetamol (PCM) in a small scale batch crystallisation environment; PCM-II displays enhanced compressibility and solubility in comparison to the stable PCM-I. A number of structurally similar and size-matched template molecules are investigated for their templating effects, with the most success observed with the structurally similar metacetamol (MCM). Possible mechanistic insights into the action of the template molecules are also investigated. In Chapter 4, the conditions for the templated production of PCM-II with MCM at the 100 ml scale are optimised through use of a Design of Experiments analysis. Identification of optimal conditions for the production of PCM-II are then used in further batch scale-up experiments at the 800 ml scale, monitored with process analytical technologies.

Chapter 4 also describes initial transfer to continuous crystallisation platforms, investigating production in a periodic mixed suspension mixed product removal (PMSMPR) crystalliser, with Chapter 5 describing flow crystallisation experiments in the continuous oscillatory baffled crystalliser (COBC) and the kinetically regulated automated input crystalliser (KRAIC). The use of the COBC resulted in the successful continuous crystallisation of PCM-II; however elimination of an impurity proved problematic. The use of the PMSMPR platform resulted in the first ever successful continuous crystallisation of phase pure samples of PCM-II.

Chapter 6 describes obtaining solid form control of reactive pharmaceuticals through incorporation inside benign host molecules. Investigations focussed on two hosting systems whereby the APIs thiamphenicol and α-lipoic acid were hosted within γ- and β- cyclodextrin, respectively. Full NMR analysis to elucidate host-guest stoichiometry was performed, with the transfer to cooling crystallisation environments targeted, with preliminary investigations carried out.

Date of Award	1 Sept 2017
Original language	English
Awarding Institution	University of Bath
Sponsors	Engineering and Physical Sciences Research Council
Supervisor	Charles Wilson (Supervisor)