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Title: Understanding and predicting the physicochemical properties and crystallisation behaviour of carbamazepine co-crystals
Author: Abd Rahim, Syarifah
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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The crystallisation and associated phase composition of carbamazepine (CBZ) co-crystals is presented with respect to the chemical nature of the co-crystal formers. Through an analysis of 50 structures representing three packing motif types, using both experimental and computational modeling, the respective physical properties are reviewed. Using a graded selection approach of increasing complexity, 3 CBZ co-crystals with succinic acid (SCA), aspirin (ASP) and saccharin (SAC) representing each of the known packing motif types are selected and their crystallisation and particulate properties examined. The co-crystal screening using stoichiometry and non-stoichiometry methods revealed that successful co-crystal formation depends on the method used in the screening, i.e. CBZ-glutaric acid forms a co-crystal in the stoichiometry method but not via the non-stoichiometric method. Two polymorphs of CBZSAC are obtained without the use of additive and the structure of CBZ-fumaric acid is solved. The synthon analysis from computational chemistry calculations revealed that van der Weals interaction make a significant contribution to the lattice energy with the hydrogen bonding interactions comprising both homosynthon and heterosynthon interactions with their respective strengths being affected by the electronegativity of the atoms involved. Slip planes calculations demonstrated that translational stack and conformer pairing packing have only one slip plane whereas, the inversion cup packing tend to have more. The predicted morphology revealed translational stack packing to be fine and thin needle-like whilst for inversion cup and co-former pairing packing a mixture of prismatic and thick needle-like morphologies is found. Cooling crystallisation studies revealed that CBZ-SCA and CBZ-SAC are easier to nucleate compared to CBZ-ASP whilst variation in co-crystal former content revealed no clear trend with respect to their crystallisability. Van't Hoff analysis based on solubility showed all carbamazepine co-crystals to exhibit comparatively have strong interactions between the solute and solvent. Crash cooling crystallisation demonstrated an increase in the induction time as the saturation temperature was increased for all the CBZ co-crystals with homogeneous nucleation dominant at high supersaturation. Particulate properties studies showed that CBZ-SCA has the highest mean particle size and better flowability compared to CBZ-ASP and CBZ-SAC.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available