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.