Title:
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Understanding and predicting the physicochemical properties and crystallisation behaviour of carbamazepine co-crystals
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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.
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