Bridging the Gap in Sustainable Continuous Chemicals Manufacture: Integrating Upstream Synthesis and Downstream Crystallisation

  • C. Daniel Scott

Student thesis: Doctoral ThesisPhD


Continuous manufacturing (CM) is effective for sustainable chemical manufacture, but production of pharmaceuticals and fine chemicals requires complex, multi-step procedures often carried out in batch. Gaps in the CM supply chain, such as between upstream flow synthesis and downstream continuous crystallisation form a major bottleneck in the take-up of CM. The
motivation for the research presented in this thesis was to demonstrate integrated CM of pharmaceuticals and multi-component complexes.

The oximation of 4-hydroxyacetophenone (4HAP) to 4-hydroxyacetophenone oxime (4- HAPO) and subsequent Beckmann rearrangement of 4HAPO to paracetamol (PCM) was investigated. A one-pot method was transferred to flow using a packed bed column, but leaching into the feed limited downstream
integration. A two-step approach was transferred into flow to give 4HAPO and PCM respectively. Synthesis of 4HAPO was integrated with a compact flow crystalliser with partial success, while a semi-batch approach showed 4HAPO could be directly crystallised from the flow synthesis effluent.

The catalytic flow hydration of pyrazinecarbonitrile (PyCN) to the drug pyrazinamide (PZA) was integrated with the segmented flow kinetically regulated automated input crystalliser (KRAIC). A cooling step introduced controlled nucleation and resulted in a five-fold reduction in crystal
size. The crystallisation technique selectively formed the γ-PZA polymorph from the aqueous solution without the need for additives.

Production of multi-component complexes, 4-bromo-2-methylaniline (4Br2MA):3,5-dinitrobenzoic acid (35DNBA) and 4-iodo-2-methylaniline (4I2MA):35DNBA, was investigated using antisolvent crystallisation. Crystallisation of 4Br2MA:35DNBA was transferred into a segmented flow
crystalliser and off-line isolation of the precipitate allowed characterisation of 4Br2MA:35DNBA crystals. A novel form of 4I2MA:35DNBA was isolated and characterised from batch crystallisation experiments. Thermal analysis of the thermochromic behaviour of the cocrystals showed that the single-crystal-to- single-crystal (SCSC) phase transition may be enabled by water in the bulk

Two flow crystallisers (a tubular mixer reactor and a periodic withdrawal, continuous stirred tank reactor (CSTR) system) were evaluated for production of a commercial active pharmaceutical ingredient (API) salt. Crystallisation in the tubular mixer reactor was effective only for short periods at high velocity flow rates. Crystallisation in the CSTRs successfully operated for twelve residence times (RTs); with a 70 % yield of the API salt. The API salt formed spherical
agglomerates in flow which showed higher uniformity and lower cake resistance compared to the batch sample.
Date of Award1 May 2020
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorChick Wilson (Supervisor) & Matthew Davidson (Supervisor)


  • Continuous flow reactor
  • Crystallisation
  • Continuous crystallisation
  • Process development
  • Flow Synthesis

Cite this