Solid-State Investigation of a Novel (1:2) Venlafaxine-Catechol Cocrystal: Structural, Thermal, Spectroscopic, and Solubility Studies

Abstract This work reports the third cocrystal of venlafaxine (VLF), expanding the limited database of multicomponent solid forms of this clinically important antidepressant. A systematic cocrystal screening is conducted using a mechanochemical method and catechol (CAT) as coformer. The structure of the novel cocrystal is successfully solved from powder X-ray diffraction data, providing detailed insights into its crystal lattice and revealing a venlafaxine-catechol cocrystal in 1:2 stoichiometry. Hirshfeld surface analysis is employed to characterize the distribution and nature of intermolecular interactions within the cocrystal. A binary phase diagram of the system shows the formation of one cocrystal and two eutectic mixtures at different stoichiometric ratios (7:3 and 1:4 (n/n)). All solid forms are further characterized by DSC, PXRD, and FTIR spectroscopy, confirming their distinct structural and chemical features. Solubility studies show that the cocrystal exhibits the highest solubility in comparison to the eutectic mixtures and pure VLF, while the eutectics also enhance solubility relative to the VLF. These results indicate that the enhanced solubilization of the eutectic systems results from the combined effects of CAT-mediated solubilization and solid-state transformations, including in situ formation of the (1:2) VLF-CAT cocrystal, with the extent of these processes depending on the initial solid-state composition. The identification of a novel (1:2) VLF-CAT cocrystal, alongside the characterization of eutectic mixtures, highlights the relevance of cocrystallization strategies for improving the bioavailability, physical stability, and potential therapeutic performance of poorly water-soluble drugs. These findings provide a framework for the rational design of multicomponent solid forms, with implications for future pharmaceutical development and optimization of drug formulations.