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.
Novel cocrystals of promethazine hydrochloride [PTZ‐Cl; systematic name: N,N‐dimethyl‐1‐(10H‐phenothiazin‐10‐yl)propan‐2‐aminium chloride] with succinic acid (PTZ‐Cl‐succinic, C17H21N2S+·Cl−·0.5C4H6O4), fumaric acid (PTZ‐Cl‐fumaric, C17H21N2S+·Cl−·0.5C4H4O4) and adipic acid (PTZ‐Cl‐adipic, C17H21N2S+·Cl−·0.5C6H10O4) were prepared by solvent drop grinding and slow evaporation from acetonitrile solution, along with two oxalic acid cocrystals which were prepared in tetrahydrofuran (the oxalic acid hemisolvate, PTZ‐Cl‐oxalic, C17H21N2S+·Cl−·0.5C2H2O4) and nitromethane (the hydrogen oxalate salt, PTZ‐oxalic, C17H21N2S+·C2HO4−). The crystal structures obtained by crystallization from tetrahydrofuran and acetonitrile include the Cl− ion in the lattice structures, while the Cl− ion is missing from the crystal structure obtained by crystallization from nitromethane (PTZ‐oxalic). In order to explain the formation of the two types of supramolecular configurations with oxalic acid, the intermolecular interaction energies were calculated in the presence of the two solvents and the equilibrium configurations were determined using density functional theory (DFT). The cocrystals were studied by X‐ray diffraction, IR spectroscopy and differential scanning calorimetry. Additionally, a stability test under special conditions and water solubility were also investigated. PTZ‐Cl‐succinic, PTZ‐Cl‐fumaric and PTZ‐Cl‐adipic crystallized having similar lattice parameter values, and showed a 2:1 PTZ‐Cl to dicarboxylic acid stoichiometry. PTZ‐Cl‐oxalic crystallized in a 2:1 stoichiometric ratio, while the structure lacking the Cl atom belongs has a 1:1 stoichiometry. All the obtained crystals exhibit hydrogen bonds of the type PTZ…Cl…(dicarboxylic acid)…Cl…PTZ, except for PTZ‐oxalic, which forms bifurcated bonds between the hydrogen oxalate and promethazinium ions, along with an infinite hydrogen‐bonded chain between the hydrogen oxalate anions.
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