Structures and physicochemical properties of vortioxetine salts

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• 作者：Xinbo Zhou ; Xiurong Hu ; Suxiang Wu ; Jiali Ye ; Mengying Sun ; Jianming Gu ; Jianrong Zhu and Zhongliang Zhang
• 关键词：vortioxetine ; antidepressant ; salt ; solubility
• 刊名：Acta Crystallographica Section B
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：72
• 期：5
• 页码：723-732
• 全文大小：1319K
• ISSN：2052-5206

文摘

In the present work, novel salts of the multimodal antidepressant drug vortioxetine (VT) were crystallized with pharmaceutically acceptable acids, aiming to improve the solubility of VT. The acids for VT were selected based on ΔpK_a being greater than 2 or 3. Salts of hydrobromic acid (HBr), hydrochloric acid (HCl), p-hydroxybenzoic acid (PHBA), saccharin (SAC) and l-aspartic acid (ASP) were reported. All salts were characterized by single-crystal X-ray diffraction, FT–IR, powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The acidic proton is transferred to the secondary N atom on the piperazine ring of VT, forming the charge-assisted hydrogen bond N⁺—H…X⁻ (X = Cl, Br, O). Solubility and intrinsic dissolution rate (IDR) experiments were carried out in distilled water (pH = 7.0) to compare the solubilities of the salts with that of VT. The VT–ASP–H₂O (1:1:2) salt showed 414 times higher solubility and 1722 times faster IDR compared with VT. VT–ASP–H₂O (1:1:2) is a high solubility salt that is stable in a slurry experiment at 298 K in 95% ethanol. The experimental data for the VT–ASP–H₂O (1:1:2) salt identify it as a promising drug candidate.