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.
Keywords: IR; cocrystal; crystal structure; hydrogen bonding; promethazine.