Discovery of Binary and Ternary Colored Crystalline Phases in Atovaquone: From Stoichiomorphs to Solvates

Liquid-assisted mechanochemical grinding (LAG) was explored as a method to synthesize multicomponent forms of the active pharmaceutical ingredient (API), which includes salt, cocrystal, and solvates. Trans-atovaquone (AT), the API used in this research, was subjected to LAG with different coformers, of which new phases were obtained with three coformers: piperazine, 3,4-diaminopyridine, and 4-dimethylaminopyridine. Interestingly, the yellow-colored AT after dry grinding gave a red colored powder, which in turn changed into a deep red color by the addition of solvent. Powder X-ray diffraction confirmed the formation of new phases in the obtained product. Crystallization experiments performed on this powder by the slow evaporation method at low temperature yielded seven novel multicomponent forms of the API, namely, a salt, salt solvate, and salt cocrystal solvate. These multicomponent forms were characterized using single-crystal and powder X-ray diffraction and infrared and ultraviolet–visible spectroscopy, along with thermal methods like differential scanning calorimetry, thermogravimetric analysis, and hot stage microscopy. The crystal packing analysis revealed charge-assisted N+–H···O– short hydrogen bonds, formed by the proton transfer interaction between the AT and the coformer. Infrared spectroscopy analysis also revealed deprotonation of the AT. The origin behind the drastic color change due to LAG was explored by the band gap calculations from the ultraviolet–visible spectrum using the Tauc plot, as well as density functional theory calculations, and such studies support the observed color change. A significant decrease in the band gap energy for the multicomponent forms in comparison to that of the parent drug was observed. Further study explored the presence of C–H···O/N/Cl, N–H···O, O–H···O/N, C–H···π, and π···π interactions that contributed toward the stability of the various crystalline forms. The crucial discovery involves direct evidence of change of color and reduction of the band gap by the cocrystallization method, which to the best of our knowledge is unprecedented in the field of pharmaceutical cocrystals. These results can open up new avenues of research toward the use of drug molecules for more efficient drug delivery, biomedical, and optoelectronic applications in the years to come.