Thesis
Crystallization in multicomponent chiral systems : thermodynamic characterization and guidelines for chiral resolution of racemic compounds with cocrystallization
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2023
- Thesis identifier
- T16592
- Person Identifier (Local)
- 201958154
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Chiral molecules are asymmetrical objects, and from this geometric property emerge enantiomers, that are a pair of non-superimposable mirror-image compounds. More than 50% of marketed drugs are chiral, and enantiomeric separation is a major research area. Enantiomers possess the same physical properties, but they interact differently with chiral receptors in the human body, which induces a different biological response. While one enantiomer has a desired therapeutic effect, its opposite-enantiomer can be inactive or produce unwanted side effects. Moreover, an inactive opposite-enantiomer in a racemic drug can be considered as an impurity representing up to 50% of the formulation, which presents economic consequences. Consequently, the manufacture of chiral active pharmaceutical ingredients (API) is regulated to prefer enantiopure drugs. Because enantioselective synthesis is not always possible, robust separation methods are required to achieve enantiomeric purity from racemic mixtures. Crystallization-based resolution processes are preferred at industrial scale because of more interesting costs. When a racemic mixture crystallizes as a stable racemic compound, one resolution strategy relies on the cocrystal engineering with an additional coformer molecule to prompt new thermodynamic equilibria more favorable. The work outlined in this thesis focuses on the thermodynamic characterization and understanding of multicomponent chiral systems to apply chiral resolution strategies of racemic compounds with cocrystallization. In Chapter 3, the detection of new cocrystals is discussed through the investigation of results obtained during a campaign aiming to find cocrystals to resolve the racemic compound of praziquantel. A total of 30 coformers are screened with four cocrystal screening methods, which are compared thoroughly by defining quantified parameters that help to review their strengths and weaknesses. The objective of this chapter is to conclude on screening methods’ efficiencies and convenience, with the view to provide relevant advice on the optimization of cocrystal screening method selection. Chapter 4 addresses the issue of chiral quantification in multicomponent systems and presents a novel chiral quantification method using ultraviolet circular dichroism spectroscopy and multivariate partial least square models. The method is used to understand the solid-liquid equilibria in the complex quaternary system of levetiracetam enantiomers with a chiral coformer in a solvent, through the accurate determination of the full quaternary phase diagram. The aim of this chapter is to propose a new approach for multicomponent chiral quantification in order to characterize complex systems and identify the conditions permitting a chiral separation process with crystallization. By using the acquired quaternary phase diagram, an enantioselective cocrystallization process is designed in Chapter 5 to recover levetiracetam from its racemic compound through the isolation of its enantiospecific cocrystal. This process is combined with a solvent-mediated transformation step that permits the retrieval of pure levetiracetam from its cocrystal. The objective of Chapter 5 is to propose guidelines to build and optimize chiral resolution processes with chiral cocrystallization from the understanding of phase diagram information. While cocrystallization provides a relevant collection of strategies for the chiral resolution of stable racemic compounds, several parameters must be considered to identify the best scenario permitting the resolution of a target compound. Therefore, in Chapter 6, the key points leading to a quick and efficient identification of the optimal resolution strategy are discussed, such as the racemic compound stability, the coformer selection methods and its chirality, and the identification of the thermodynamic equilibria compatible with a resolution. The aim of this chapter is to propose relevant guidelines for chiral resolution strategy identification with cocrystallization. The work in this thesis deepens the knowledge about chiral resolution of racemic compounds with cocrystallization by providing relevant new tools to this research area. New approaches are introduced to screen more efficiently for new cocrystals, to quantify complex multicomponent chiral systems, to design chiral resolution processes, and to identify the parameters for choosing the optimal resolution strategies. It is hoped that these methodologies will contribute to solve the challenges of enantiomers separation.
- Advisor / supervisor
- Johnston, Karen
- Ter Horst, Joop H.
- Resource Type
- DOI
- Funder
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