Distinct Disordered Forms of Promethazine Hydrochloride: A Case of Intergrowth of Polymorphic Domains?

Determination of the first crystalline structures of the antihistaminic drug promethazine hydrochloride (PTZ) by single crystal X-ray diffraction revealed a possible case of intergrowth of polymorphic domains that requires further experimentation for confirmation. The two crystal structures of PTZ are characterized by high similarity of both molecular conformation and crystal packing and slight variations of the unit cell parameters induced by two distinct disorder levels in the PTZ aliphatic chain. These unit cell variations lead to small displacements of the molecules in the crystal structures and, consequently, to slight energy, density, and melting point differences between the forms. Although highly similar, the two crystalline forms of PTZ are clearly distinct disordered forms: they were repeatedly and reproducibly obtained, no intermediate disorder levels were found so far, and solvent-mediated transformation between them was evidenced by slurry experiments. In addition, the two distinct disorder levels were confirmed by solid-state nuclear magnetic resonance. Our study emphasizes the benefit of single-crystal structure data for the judgment of the phase purity and of solid forms exhibiting subtle structural differences. The newly discovered effect of disorder on the unit cell dimensions contributes to understanding the similarity limits between distinct disordered forms and, consequently, may provide important clues for crystal structure prediction.