Venlafaxine Caffeic Acid Salt: Synthesis, Structural Characterization, and Hypoglycemic Effect Analysis

[Image: see text] Depression is a recurrent and chronic mental disorder requiring long-term treatment. Major depressive disorder is present in 15–20% of patients with type 1 or type 2 diabetes. Large-scale evidence revealed that depression and depressive symptoms are independent risk factors for the development of type 2 diabetes, and they may contribute to hyperglycemia and even accelerate the premature onset of diabetes complications. Venlafaxine is a clinical first-line antidepressant used for more than 30 years. Recently, clinical reports showed that venlafaxine overdose might cause hypoglycemia. Venlafaxine is insoluble and salt formation technology is the most appropriate method to improve the physicochemical properties and the pharmacokinetic profile of the drug. In the present work, the use of the solvent evaporation method, slurry, and the liquid-assisted grinding method resulted in the crystalline salt venlafaxine–caffeic acid (1:1). The compounds were characterized using a series of solid-state techniques, viz., powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, and solid-state nuclear magnetic resonance, and the crystal structure was determined by single-crystal X-ray diffraction. Besides, a comparative study of solubility, dissolution, and hypoglycemic activity of the parent drug and the new salt has been carried out. The tested venlafaxine–caffeic acid salt showed about 16-fold higher solubility than the pure drug. Moreover, the glucose consumption assay results showed that the novel salt possesses potent hypoglycemic activity in vitro, suggesting that it is a promising candidate effective for major depressive disorder patients with type 2 diabetes.