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

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.