Multi-component Crystallisation in the Continuous Flow Environment

  • Kate Wittering

Student thesis: Doctoral ThesisPhD


The research described in this thesis was carried out as part of the EPSRC National Centre in Continuous Manufacturing and Crystallisation (CMAC), whose vision is to accelerate the adoption of continuous manufacturing processes for the production of high-value chemical products. Results focus upon the crystallisation of multi-component molecular complexes (MMCs), in particular co-crystals, an important class of potential functional molecular materials. MMCs are commonly discovered through small scale batch solvent evaporation, a method that provides little control over the crystallisation process, often yields only small quantities of crystalline material which may not be phase pure and is not generally scalable. Methods have been developed to help translate traditional small scale batch co-crystallisation of MMCs to selective continuous co-crystallisation processes. The co-crystal system urea-barbituric acid (UBA) has three polymorphs, previously identified in the literature and was selected as a candidate for transfer to continuous crystallisation as its polymorphism offers a development challenge in being able to achieve selectivity of solid products through by various crystallisation processes. Chapter 4 describes small scale crystallisation studies of UBA using evaporation, cooling and mechano-crystallisation techniques, demonstrating that UBAI is the more prevalent polymorph. Solid state and solubility analysis of the isolated UBA polymorphs are detailed; these data provide information on the energetic relationship between the polymorphs highlighting the similarity in energy of UBAI and UBAIII, and the metastable nature of elusive UBAII. In addition the polymorphic nature of the barbituric acid starting material has been investigated with samples from different suppliers proving to consist of different polymorphs. As well as being important in designing subsequent crystallisation processes, results from these studies corroborate work previously reported in the literature Chapter 5 describes how these results have been used in development of continuous crystallisation experiments using Mixed-Suspension Mixed-Product Removal (MSMPR) with a cascade of three stirred tank reactors, while Chapter 6 investigates flow crystallisation of UBA using the Continuous Oscillatory Baffled Crystalliser (COBC) and the Kinetically Regulated Automated Input tubular flow Crystalliser (KRAIC). The KRAIC was designed and constructed as part of this research. The continuous crystallisation experiments presented in Chapters 5 and 6 demonstrate the selective continuous co-crystallisation of UBAI across all three continuous crystallisation platforms. In Chapter 7 a range of novel co-crystalline MMCs is presented, with structural determinations, using single crystal X-ray diffraction, coupled with characterisation of properties and crystallisation characteristics; these studies emphasise the physical property advantages of MMCs and in some cases their potential for future translation to continuous crystallisation.
Date of Award9 Feb 2016
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorChick Wilson (Supervisor)

Cite this