Polymorph control of pharmaceuticals within a continuous oscillatory baffled crystalliser

  • Naomi Briggs

Student thesis: Doctoral Thesis


Continuous processing is a widely used application that provides a number of benefits to manufacturing including improved process control and high quality products. The continuous oscillatory baffled crystalliser (COBC) is a type of continuous platform that enables crystallisation and growth of pharmaceutical systems, moving crystallising solutions and suspensions through a series of baffled tubes. Application of oscillatory flow results in the formation of eddy currents enabling an efficient mixing and near-plug net flow experience of the bulk solution. The enhanced turbulence provides the possibility of linear scale up and uniformity in bulk solution environment (distributions of shear rates and temperature gradients are reduced) alongside the decoupling of mixing and net flow resulting in long residence times. Considering this, COBC systems offer promise to the enable effective operation and scaling of pharmaceutical crystallisation to industrial-sized processes. Residence time distributions (RTD) in a DN15 COBC have been studied for the first time as a function of flow and oscillatory conditions, illustrating operation with a near-plug profile. A novel moving fluid (MF) batch oscillatory baffled crystalliser has been developed as an improved model of the hydrodynamic conditions in a DN15 COBC and thus eliminates many of the assumptions made during the tradition approach for moving to continuous oscillatory flow. This batch system was combined with imaging technology to investigate nucleation and fouling. Experiments illustrated variations in nucleation kinetics for L-glutamic acid polymorphs when comparted to the tradition batch platforms, thus highlighting the importance to use representative systems for crystallisation scale-up. Polymorph control during continuous oscillatory crystallisation was investigated using two pharmaceutically relevant systems: L-Glutamic Acid and Carbamazepine. Due to excessive fouling in the COBC during spontaneous nucleation, continuous processes were designed and operated to decouple the two step crystallisation process. Through the use of seeding, fouling could be eliminated, and a focus on the control over particle growth could be made. In addition, a basic methodology from batch to continuous oscillatory baffled crystallisation is presented to achieve polymorphic control. This work has advanced the practical and scientific understanding towards a methodology for successful oscillatory flow operation in addition to the possibilities of a control approach, through implementation of process analytical technologies, thus facilitating the rapid development and understanding of COBC processes in future studies.
Date of Award17 Jun 2015
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsScottish Funding Council SFC & EPSRC (Engineering and Physical Sciences Research Council)

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