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

Abstract

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.

Sinapic Acid Co-Amorphous Systems with Amino Acids for Improved Solubility and Antioxidant Activity

“…Changes in the C=O groups could be attributed to the restriction with the –NH group of LYS. Analogous changes in the FT-IR spectra of the salt were observed by Yu et al for caffeic acid with venlafaxine [ 27 ]. Losing a proton indicates ionization, which can lead to the creation of salt [ 28 , 29 , 30 ].…”

Levofloxacin Cocrystal/Salt with Phthalimide and Caffeic Acid as Promising Solid-State Approach to Improve Antimicrobial Efficiency

“…The diffraction peaks of CFA observed at 2-theta (deg) and PDA peaks were noted. The diffraction peaks of starting material LEV [ 13 , 15 ], PTH [ 27 ] and CFA [ 51 , 76 ] show good consistency with previously compiled values. New diffraction peaks appeared at 11.50°, 20°, 29.699° and 44.2° while LEV peaks (6.29° and 26.36°) and some of the PTH peaks disappeared in the diffractogram of LEV-PTH cocrystal.…”

“…Therefore, the active interaction sites of PTH and CFA have also the possibility to interact with N of methylpiprizine ring to form supramolecular synthons. Furthermore, in lamotrigine-PTH cocrystals the amide part of PTH interacts with the aminopyridine of lamotrigine [ 27 ] while transfers of protons from the carboxylic group of CFA to the tertiary amino group of venlafaxine have taken place in venlafaxine-CFA salt [ 51 ].…”

“…In LEV-PTH cocrystal spectrum the N-H and two C=O bands shifted to lower wavelength 3180, 1770 and 1711 cm −1 , respectively. In LEV-CFA salt the CFA COOH group bands disappeared due to deprotonation whereas the OH peak disappeared due to its involvement in hydrogen bonding, these bands disappeared in the reported FTIR spectrum of venlafaxine-CFA salt [ 51 ]. Additionally, the COO − bands appeared at 1524, 1375 and 702 cm −1 which suggests a deprotonated form of CFA [ 64 ] in LEV-CFA.…”

Enhancing Solubility and Dissolution Rate of Antifungal Drug Ketoconazole through Crystal Engineering

“…The molecular/ionization states of the four complexes could not be fully disclosed from the ∆pK a values, since the four values fell in the range of −1 to 4, but the most positive value of KTZ−GTA indicates a higher probability of salt formation. Secondly, the residual density map provided by the SXRD data (Figure S3) could be used to distinguish the location of the H atom and, thus, the cocrystal, salt, and salt-cocrystal continuum could be distinguished [43]. In the KTZ−GTA, KTZ−PCA-II, and KTZ−35DNB, the H atom was close to the oxygen atom on the carboxylic hydroxyl group, which could be regarded as cocrystals, while in the KTZ−26DHB, the H atom was close to the imidazole-N atom of the KTZ molecule, suggesting the salt nature of KTZ−26DHB.…”