Thesis
Deracemization of less reactive conglomerates through enabling technologies
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2025
- Thesis identifier
- T17450
- Person Identifier (Local)
- 201769612
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Crystallization enhanced deracemization (CED) techniques represent robust and scalable processes that can be embedded into the synthetic routes for the production of active pharmaceutical ingredients (APIs). Just like all the other strategies to obtain one single enantiomer, CED techniques are not universally applicable, since only roughly 10% of the enantiomers known in the literature are conglomerates in the solid state. In a conglomerate the enantiomeric molecules crystallize as separate phases. This is a requirement for crystallization induced deracemization. However, it is possible to find conglomerate derivatives along the synthetic route, for instance through reversible covalent functionalization or through salts and co-crystals formation. In addition, solution racemization of such molecules, necessary for deracemization, requires reaction conditions that often turn out to be inconvenient when combined with a crystallization process. The aim of this thesis is to find new pharmaceutically interesting conglomerates together with the development of new racemization methods that can be embedded in CED techniques. This thesis is constituted of three parts where three different pharmaceutically interesting conglomerates are used as targets to achieve one single enantiomer out of the racemic mixture. One part focuses on the characterization of 2-chlorophenylglycinamide, a conglomerate intermediate in the synthesis of Clopidogrel (Chapter 2), the discovery of racemization in the melt without the use of external bases and thus the potential of melt crystallization as a deracemization technique. This easily racemizable compound was then used in preliminary experiments where solution racemization and crystallization were conducted simultaneously in two different units allowing the selective recirculation of the mother liquor. The second part focuses on the identification of a new conglomerate along the synthetic route to the API Praziquantel (Chapter 3) by using a set of analytical methods on a library of derivatives, reversibly functionalized through covalent bonds. The racemization of the novel conglomerate was studied in flow, in the recycle of the mother liquor and eventually successfully applied to two CED techniques, namely crystallization induced asymmetric transformation (CIAT) and temperature cycling induced deracemization (TCID). The third part focuses on the application of the base- and bio-catalyzed racemization of two Flurbiprofen salts (Chapter 4) known to be conglomerate from patent literature after a thorough characterization of the solid state of such salts
- Advisor / supervisor
- Oswald, Iain
- Resource Type
- DOI
Beziehungen
Objekte
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PDF of Thesis T17450 | 2025-09-18 | Öffentlich | Herunterladen |