Increasing the symmetry of drug crystals: a monoclinic conformational polymorph of the platelet antiaggregating agent ticlopidine hydrochloride

Abstract

Ticlopidine hydrochloride (TICLID®) is a platelet antiaggregating agent whose use as a potent antithrombotic pharmaceutical ingredient is widespread, even though this drug has not been well characterized in the solid state. Only the crystal phase used for drug product manufacturing is known. Here, a new polymorph of ticlopidine hydrochloride was discovered and its structure was determined. While the antecedent polymorph crystallizes in the triclinic space groupP , the new crystal phase was solved in the monoclinic space groupP2₁/c. Both polymorphs crystallize as racemic mixtures of enantiomeric (ticlopidine)⁺ cations. Detailed geometrical and packing comparisons between the crystal structures of the two polymorphs have allowed us to understand how different supramolecular architectures are assembled. It was feasible to conclude that the main difference between the two polymorphs is a rotation of about 120° on the bridging bond between the thienopyridine and o-chlorobenzyl moieties. The differential o-chlorobenzyl conformation is related to changeable patterns of weak intermolecular contacts involving this moiety, such as edge-to-face Cl⋯π and C–H⋯π interactions in the new polymorph and face-to-face π⋯π contacts in the triclinic crystal phase, leading to a symmetry increase in the ticlopidine hydrochloride solid state form described for the first time in this study. Other conformational features are slightly different between the two polymorphs, such as the thienopyridine puckerings and the o-chlorophenyl orientations. These conformational characteristics were also correlated to the crystal packing patterns.