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The crystal growth kinetics of a proprietary active pharmaceutical ingredient (API) was investigated by isothermal seeded batch de-supersaturation experiments in solvent mixtures using the "true" thermodynamic representation of the supersaturation driving force, which considers the activities of the saturated and supersaturated states. Three approaches to approximate the experimentally inaccessible activity coefficients of the supersaturated state were assessed, as well as the most common approximation, which omits the activity coefficients altogether. Subsequently, the supersaturation data from the different expressions were fed into a population balance model to estimate kinetic parameters for the empirical, Burton− Cabrera−Frank, and birth-and-spread growth models. The results demonstrate that the approach used to compute the supersaturation alters the estimated kinetic parameters significantly, having potentially serious implications for their physical interpretation and for extracting the physical properties they represent in lumped form. Moreover, including the chemical activities in the supersaturation leads to kinetic parameters with a tighter joint confidence interval and weaker parameter correlation that can better explain the experimental observation of the API growing appreciably only under higher antisolvent amounts. Finally, the simultaneous occurrence of multiple crystal growth mechanisms is investigated, concluding that the additive contribution of B+S and BCF best explains the supersaturation decay observed in the experiments for this API.

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Four new methoxy-substituted derivatives of E,E-2,5-bis(2-phenylethenyl)pyrazine have been synthesized. The supramolecular structures of the resulting set of five polymorphs have been studied using single-crystal X-ray diffraction to gauge the influence of the position of the methoxy groups on the organization of the molecules in the solid state, as part of an attempt to dispense with the particular polymorphism of the parent compound. The crystal packing patterns were analyzed in terms of the two pyrazine-based synthons found in the parent compound's crystal structure, the π pyrazine 3 3 3 π phenyl stacking synthon, and the pyrazine hydrogen-bonded synthon, as well as in terms of weak intermolecular interactions such as CH 3 3 3 O, CH 3 3 3 N, and CH 3 3 3 π. The analysis shows that the introduction of methoxy groups in positions other than only the para position of the peripheral benzene rings successfully switches off the two synthons seen in the parent compound and that the new compounds adopt other packing strategies, based on methoxy 3 3 3 methoxy and -OCH 3 3 3 3 π contacts. Polymorphism, however, remains.

(E,E)-1-[2-(4-Nitrophenyl)ethenyl]-4-[2-(2,4-dimethoxyphenyl)ethenyl]benzene was characterised by X-ray diffraction and shown to be dynamically disordered at room temperature. The structure was re-determined over a range of temperatures to infer the thermodynamic parameters related to this disorder. A phase transition of third order according to the Ehrenfest classification scheme was discovered. To the best of our knowledge, this is the first experimentally observed phase transition of formal third order. It can be explained by the involvement of long-range lattice vibrations.