Chiral resolution control in batch and continuous crystallization processes for a conglomerate forming compound

  • Andrew Steven Dunn

Student thesis: Doctoral Thesis


Chiral molecules are molecules that have a non-superimposable mirror image. Each of these mirror image forms is known as an enantiomer. Such molecules exist throughout nature, from amino acid and sugar molecules, to the complex helical structure of our own DNA. However, the separation of enantiomers (resolution) is extremely important in the pharmaceutical industry due to the potentially different physiochemical response that each enantiomer can induce. Where one enantiomer binds to the target receptor in the body causing the desired therapeutic response, the other enantiomer may bind to a different receptor site causing a potentially hazardous response. One of the most common resolution methods in the pharmaceutical industry is preferential crystallization. In a preferential crystallization process, supersaturated racemic (equal mixture of both enantiomers) solution is seeded with pure crystals of the preferred enantiomer. Over time these crystals grow, removing the preferred enantiomer from solution whilst the unwanted enantiomer remains in solution. Given enough time, however, nucleation of the unwanted enantiomer in the supersaturated solution is inevitable in any preferential crystallization process, batch or continuous.The work outlined in this thesis focuses on the control in both batch and continuous preferential crystallization processes by improving product enantiopurity and increasing the overall process yield and productivity compared to a conventional batch-wise preferential crystallization process. Chapter 3 addresses the issue of inevitable unwanted counter enantiomer nucleation in a batch preferential crystallization process and demonstrates a novel seeding method in which this can be avoided. A controlled concomitant preferential crystallization of both enantiomers in a single vessel is demonstrated, where a bias in the crystal size distributions of each enantiomer is exploited in order to mechanically separate pure enantiomer crystals after the crystallization process. Using this strategy any unwanted primary nucleation is avoided in the process. In Chapter 4, the simultaneous crystallization of both enantiomers in a single oscillatory baffled crystallizer is achieved whilst localizing the crystallization of each enantiomer in different sections of the crystallizer. This internally coupled system adopts the principles of a coupled batch preferential crystallization and applies it to a single reactor. The system allows the movement of solution between sections of the setup but keeps enantiomer crystals separated. The internal setup negates the need for additional tanks, pump and heating to the system.The start-up period of a continuous process before it reaches steady state generates a lot of unusable off-spec product. The aim of Chapter 5 is to identify the initial process parameters that influence the start-up time and also the robustness of the steady state that is achieved. A design of experiments approach is used to determine which initial process parameters are important such that they can be further optimized. This leads to shorter start-up times to steady state and less waste of valuable material by developing a robust steady state for the continuous process. Even in continuous operation, preferential crystallization processes are inherently unstable since nucleation of the counter enantiomer will occur in time. Therefore, in Chapter 6, a novel control strategy is demonstrated that takes back control of the continuous preferential crystallization process and allows the process to continue after nucleation of the counter enantiomer has occurred. This avoids the need to stop and restarted the process whenever the counter enantiomer crystallizes. The work in this thesis has achieved its aim in demonstrating control of preferential crystallization process in both batch and continuous platforms. The scientifi
Date of Award20 Mar 2020
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council)
SupervisorJoop Ter Horst (Supervisor) & Alastair Florence (Supervisor)

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