Crystallization of Chiral Molecules from Emulsions: DL-Threonine, R,S-2-Chloromandelic Acid and R,S-Clopidogrel Hydrogen Sulphate

  • Sara Gilks

Student thesis: Phd


The objective of this project is to explore the potential for enantiomer separation by preferential crystallization using tailor-made emulsions. Preferential crystallization is widely used as a means of separating pure enantiomers from racemic solutions. This is usually assisted by the addition of seed crystals of one enantiomer for which crystallization yields a conglomerate rather than a racemic compound. Three racemic materials, DL-threonine (stable conglomerate), R,S-2-chloromandelic acid (racemic compound with the occurrence of a metastable conglomerate) and R,S-clopidogrel hydrogen sulphate (stable racemic compound) were chosen based on their different racemic properties to both develop and test the limitations of an emulsion crystallization process. Since threonine is reported to form only a stable conglomerate it seemed an ideal material to use for the development of an emulsion crystallization process. Indeed this was successful with enantiomer enrichments of up to 88 % of the D-enantiomer being achievable. 2-Chloromandelic acid is reported to crystallize as a stable racemic compound but with both metastable (polymorphic) compound and conglomerate known. An investigation into solution crystallization was performed as a means of preparing the metastable conglomerate and also to explore the possibility of developing an emulsion crystallization process in this system. Crystallization of 2-chloromandelic acid yielded both stable and metastable racemic compounds and the metastable conglomerate. Solubility data of the pure enantiomer, stable racemic compound and metastable conglomerate have been determined in acetonitrile and a robust drown-out method developed for consistent preparation of the conglomerate in diethyl ether. In situ UV-Vis spectroscopy studies revealed that in a stirred slurry, the metastable conglomerate converts to the stable racemic compound in approximately 10 minutes at 15 °C. This time scale defined the subsequent process of preferential crystallization from a seeded, tailor-made, non-aqueous emulsion which was successful in providing a route to a product with significant chiral enrichment of the R-enantiomer. R,S-Clopidogrel hydrogen sulphate is a stable compound forming system, which has been reported in patents to form six different polymorphs. The possibility of conglomerate formation is not known. During the course of this work, attempts were made to preferentially crystallize one enantiomer from an already enriched racemic solution. This was unsuccessful, largely due to the fact that the pure enantiomer was found to be more soluble that the enriched starting material. No evidence of a conglomerate was found, but an amorphous form and four crystalline forms of S-clopidogrel hydrogen sulphate (S-I, S-II, S-III and S-IV) have been crystallized from various solvents via different crystallization conditions. Forms III and IV are believed to be present as hydrates which are not currently reported in the literature. The amorphous form and crystalline polymorphs have been characterized using DSC, pXRD and FTIR, of which data for the latter technique is lacking in the literature. Overall this thesis demonstrates the development of both aqueous and non-aqueous emulsion crystallisation processes for enantiomer separations, highlighting the importance of the phase behaviour of the solute as a major determinant for success.
Date of Award31 Dec 2014
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorRoger Davey (Supervisor)


  • Crystallization, Chiral, Eanantiomer, Emulsion, Threonine, 2-Chloromandelic Acid, Clopidogrel

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