School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China.
Shenyang Sinochem Agrochemicals R&D Co., Ltd., Shenyang, Liaoning 110021, PR China.
Eur J Pharm Sci. 2022 Feb 1;169:106091. doi: 10.1016/j.ejps.2021.106091. Epub 2021 Dec 5.
2-Hydroxybenzylamine (2-HOBA) is a drug used to effectively treat oxidative stress. To improve its aqueous solubility and thermal stability, salt screening and synthesis was carried out. The conductor-like screening model for the real solvents model (COSMO-RS) was applied to virtual screening of coformers among 200 commonly used candidates for salification of 2-HOBA. As a result, 40 hit compounds were subjected to experimental liquid-assisted grinding (LAG) with 2-HOBA, then 21 systems were characterized as new solid phases by PXRD. Nine multicomponent single crystals of 2-HOBA with succinic acid, p-aminobenzoic acid, p-nitrobenzoic acid, o-nitrobenzoic acid, p-toluic acid, 2,3-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, p-nitrophenol, and 5-hydroxyisophthalic acid were obtained and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. All of them were salts and exhibited higher decomposition temperatures compared with pure 2-HOBA. The apparent aqueous solubility of three new salts, i.e., those with succinic acid, p-aminobenzoic acid, and p-nitrophenol were higher than the equilibrium solubility of 2-HOBA. The accelerated stability test indicated that all salts show excellent stability under conditions (40 °C and 75% RH) for 4 weeks. Overall, this work introduced a protocol that combined the virtual screening tool based on the COSMO-RS model and the experimental LAG method to screen new salts for a target compound. The feasibility of this protocol was confirmed in the case of 2-HOBA whose new salts were successfully obtained and represented an improvement for aqueous solubility and thermal stability.
2-羟基苄胺（2-HOBA）是一种用于有效治疗氧化应激的药物。为提高其水溶解度和热稳定性，进行了盐筛选和合成。应用预测真实溶剂模型的电化学相似筛选模型（COSMO-RS）对 200 种常用候选共晶剂进行了 2-HOBA 成盐的虚拟筛选。结果，40 个命中化合物与 2-HOBA 进行了实验性液辅助研磨（LAG），然后通过 PXRD 对 21 个系统进行了新固相的特征描述。获得并通过单晶 X 射线衍射、粉末 X 射线衍射、差示扫描量热法和热重分析对 2-HOBA 与琥珀酸、对氨基苯甲酸、对硝基苯甲酸、邻硝基苯甲酸、对甲苯酸、2,3-二羟基苯甲酸、3,4-二羟基苯甲酸、对硝基苯酚和 5-羟基间苯二甲酸的 9 个多组分单晶进行了特征描述。它们都是盐，与纯 2-HOBA 相比，它们的分解温度更高。三种新盐，即琥珀酸、对氨基苯甲酸和对硝基苯酚的表观水溶解度均高于 2-HOBA 的平衡溶解度。加速稳定性试验表明，所有盐在 4 周的（40°C 和 75% RH）条件下均表现出良好的稳定性。总的来说，这项工作结合了基于 COSMO-RS 模型的虚拟筛选工具和实验性 LAG 方法，为目标化合物筛选了新的盐。在 2-HOBA 的情况下，该方案的可行性得到了验证，成功获得了新盐，并提高了水溶解度和热稳定性。
