Salts of 2-hydroxybenzylamine with improvements on solubility and stability: Virtual and experimental screening

被引：5

作者：

Li, Jiulong ^{[1
]}

Wu, Di ^{[1
]}

Xiao, Yuntian ^{[1
]}

Li, Chang ^{[1
]}

Ji, Xu ^{[1
]}

Sun, Qin ^{[2
]}

Chang, Dewu ^{[3
]}

Zhou, Lina ^{[1
,4
]}

Jing, Dingding ^{[5
]}

Gong, Junbo ^{[1
,4
]}

Chen, Wei ^{[1
,4
]}

机构：

[1] Tianjin Univ, Sch Chem Engn & Technol, Tianjin 300072, Peoples R China

[2] Shenyang Sinochem Agrochem R&D Co Ltd, Shenyang 110021, Liaoning, Peoples R China

[3] Shandong Lukang Pharmaceut Co Ltd, Jining 272104, Shandong, Peoples R China

[4] Natl Collaborat Innovat Ctr Chem Sci & Engn Tianj, Tianjin 300072, Peoples R China

[5] Asymchem Life Sci Tianjin Co Ltd, Tianjin 300457, Peoples R China

来源：

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES | 2022年 / 169卷

基金：

中国国家自然科学基金;

关键词：

2-Hydroxybenzylamine; Aqueous solubility; Thermal stability; Salt; Virtual screening; COSMO-RS; WAVE-FUNCTION; COSMO-RS; COCRYSTALLIZATION; APPROXIMATION; PREDICTION; SOLVATION; DESIGN; TOOLS;

D O I：

10.1016/j.ejps.2021.106091

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 degrees 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.

引用

页数：12