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A molecular mechanism for nucleation for the solid-state polymorph transformation of terephthalic acid is presented. New methods recently developed in our group, aimless shooting and likelihood maximization, are employed to construct a model for the reaction coordinate for the two system sizes studied. The reaction coordinate approximation is validated using the committor probability analysis. The transformation proceeds via a localized, elongated nucleus along the crystal edge formed by fluctuations in the supramolecular synthons, suggesting a nucleation and growth mechanism in the macroscopic system.

Evidence for a series of nonstoichiometric, isostructural, cocrystalline complexes of L-883555, a phosphodiesterase-IV inhibitor, and L-tartaric acid with stoichiometries ranging from 0.3:1 to 0.9:1 is reported here. The free base form of this compound had insufficient bioavailability and, hence, could not be developed as a candidate for safety assessment studies. Several L-tartaric acid complexes were produced during an attempted salt-formation process, with the objective of increasing the bioavailability. It was found that the amount of L-tartaric acid incorporated in the cocrystalline complexes could be controlled by adjusting the acid: base ratio in the reaction mixture without accompanying proton transfer between acid and base. Spectroscopic techniques were employed to locate the site of intermolecular interaction between the acid and base as the N-oxide group in the base and the carboxylic acid of L-tartaric acid. Thermal and spectroscopic analysis of the degradation behavior for the various complexes showed the existence of at least two types of binding between the acid and base in those complexes with stoichiometries >0.5:1. The canonical hemitartrate complex was found to be more thermally stable than the other complexes, with acid:base stoichiometries lesser than or greater than 0.5:1 and was found to have much higher bioavailability than the free base in rhesus monkeys. This work shows the potential of designing suitable cocrystalline complexes driven by favorable interactions between an acid and base in cases where conventional proton transfer does not occur to form a true salt, offering a route toward increased bioavailability in poorly absorbed compounds.