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Title: Experimental and theoretical investigation of chiral separation by crystallisation
Author: Ardid Candel, M.
ISNI:       0000 0004 5362 5389
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Chiral molecules often show different pharmacological and toxicological properties, making their separation crucial for pharmaceutical companies. The resolution of racemic mixtures is often achieved via crystallisation methods. The lack of experimental data has been a major constraint in validating proposed computational methods for aiding the design of crystallisation processes for chiral resolution. This thesis provides both structural and thermodynamic data, and uses it to assess the limitations of current computer modelling methods. Progress in computational methods might eventually result in the design of resolving agents and hence reduce production costs of drugs and fine chemicals. Previous studies of naproxen have concentrated on the marketed enantiopure form of this anti-inflammatory drug. A crystallisation screen was conducted to identify all possible crystal phases of racemic and enantiopure naproxen. No polymorphs were detected and the crystal structure of the racemic compound was solved from powder X-ray diffraction data. The nature of the racemic species was confirmed with thermal methods, and differential scanning calorimetric and solubility measurements were used to estimate the enthalpy difference between the crystals at 156 °C and in the range of 10 to 40 °C. These data were used to test the different approximations involved in determining the energy differences between the racemic and enantiopure crystals. An extensive crystallisation screen was also performed for (1R,2S)-ephedrine 2-phenylpropionate salts. The crystal structure of the least soluble salt and three polymorphs of the most soluble salt were determined by low temperature single crystal X-ray diffraction or powder X-ray diffraction. Solubility measurements and differential scanning calorimetry were used to determine the relative stability of the salt pairs and polymorphs. These results showed the inadequacies of lattice energy calculations of the diastereomeric salt pair and their polymorphs. Experimental work on related diastereomeric salt pairs emphasised the difficulty in fully structurally and thermodynamically characterising these systems.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available