Abstract
Investigation on the solid-state pharmaceutical chemistry has been known as an intriguing strategy to not only modify the physicochemical properties of drugs but also expand the solid form landscape. Vortioxetine (VOT) is an effective but poorly soluble antidepressant. To improve the solubility of vortioxetine and expand possible solid forms, in this paper, four novel solid forms of vortioxetine with dihydroxybenzoic acids (VOT-23BA, VOT-24BA-TOL, VOT-25BA, and VOT-26BA, 23BA = 2,3-dihydroxybenzoic acid, 24BA = 2,4-dihydroxybenzoic acid, 25BA = 2,5-dihydroxybenzoic acid, 26BA = 2,6-dihydroxybenzoic acid, and TOL = toluene) were synthesized first by a solvent evaporation method and then characterized by single-crystal X-ray diffraction (SCXRD), thermal, and XRD techniques. VOT-24BA-TOL, VOT-25BA, and VOT-26BA, showed similar [2+2] tetrameric R 4 4 (12) hydrogen bonds by acid-piperazine heterosynthon. In the VOT-23BA-H2O salt, the VOT cation and 23BA anion interacted through protonated piperazine-hydroxyl N-H···O hydrogen bonds, not protonated piperazine-deprotonated carboxylic acid N-H···O hydrogen bonds. Solubility studies were carried out in purified water and it was found that the VOT-23BA-H2O, VOT-25BA, and VOT-26BA salts exhibited an increase in water compared to pure VOT. The solubility of the stabilized salt formations followed the order of VOT-25BA > VOT-26BA > VOT-23BA-H2O in purified water.
Highlights
In recent years, the study of solid-state pharmaceutical chemistry, including cocrystals, salts, polymorphs, and solvates, has been extensively applied in the area of pharmaceutical technology [1,2,3,4,5]
Four dihydroxybenzoic acid salts of the antidepressant drug vortioxetine were synthesized by slow solvent evaporation crystallization
Showed similar [2+2] tetrameric R44 (12) hydrogen bonds by acid-piperazine heterosynthon, whereas in the VOT-23BA-H2 O salt, the VOT cation and 23BA anion interacted through protonated piperazine-hydroxyl N-H···O hydrogen bonds, not protonated piperazine-deprotonated carboxylic acid N-H···O hydrogen bonds
Summary
The study of solid-state pharmaceutical chemistry, including cocrystals, salts, polymorphs, and solvates, has been extensively applied in the area of pharmaceutical technology [1,2,3,4,5]. Salt formations, in particular, usually improve the physicochemical properties, solubility, and dissolution rate of drugs [7,8,9,10,11]. These advantages are useful for judging whether salt formations can be new API candidates. Dihydroxybenzoic acids contain two hydroxyl groups and one carboxyl group and have the ability to form complex and robust hydrogen-bond networks [11,12,13,14,15,16,17,18,19,20], which are often used as the preferred candidate. These molecules are considered GRAS (generally recognised as safe) compounds, except for 2, 4-dihydroxybenzoic acid (24BA)
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