Towards continuous crystallization-based separation, chiral resolution and deracemization of chiral compounds

Student thesis: Doctoral Thesis


A large number of modern active pharmaceutical ingredients (API) are chiral molecules. In most cases only one enantiomer has the desired effect in the human body, while the other enantiomer can have no effect or be harmful. Therefore the pharmaceutical industry aims for the direct production of the only the target enantiomer through asymmetric catalyzed chiral synthesis. However the asymmetric syntheses route is not always available and the racemate is produced instead, therefore chiral separation techniques are needed. Crystallization based chiral separation techniques have shown to be a selective and efficient tool for the separation, resolution and deracemization of chiral racemates. As there is a drive in the pharmaceutical industry towards continuous processes, the aim of this thesis is to demonstrate a number of new resolution and deracemization process configurations easily adaptable to continuous operation. In chapter 3, a batch and continuous antisolvent deracemization process is introduced, to investigate if and to which extend control over secondary nucleation can be preserved during an antisolvent crystallization. As antisolvent crystallization causes a fast drop in solubility and causes high local supersaturations, often thought to trigger chrially unselective primary nucleation, it is usually not selected for chiral separation. In this chapter the objective is to extend the scope of existing deracemization processes with antisolvent crystallization. Preferential crystallization has been used to successfully separate chiral conglomerate forming systems. However conglomerate systems are rather rare with racemic compound forming systems being the majority. While direct separation through preferential crystallization is not possible at racemic composition for compound forming systems, at the eutectic the pure enantiomer and racemic compound can be separated. This can be used in a hybrid process, where a primary method is used to enrich a racemic solution to eutectic composition, followed by a preferential crystallization. The objective of chapter 4 is to investigate and compare a semi-batch parallel and serial process configuration for the separation of racemic compound and pure enantiomer at eutectic solution composition, with regards to feasibility and process operating conditions. While crystallization based chiral separation processes provide a selective and efficient method for separation, there are a large number of process configurations for different compound types. The objective of chapter 5 is to develop and validate a general process design configuration which allows for the crystallization based separation, resolution and deracemization for racemic compound, as well as conglomerate forming systems with and without racemization. The findings in this thesis, together with work found in literature are used in chapter 6 to construct industrially relevant guidelines and criteria, based on process specifications such as productivity, yield and enantiomeric excess, to choose continuous crystallization-based chiral separation processes.
Date of Award4 Jun 2021
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SupervisorJoop Ter Horst (Supervisor) & William Kerr (Supervisor)

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