文献类型：期刊文献

英文题名：Insight into the Relationship of Aqueous Solubility and Single-Crystal Structure of Harmine's New Organic Salt Forms

作者：Hong, Minghuang[1];Wu, Nan[1];Wang, Qinglin[1];Zhou, Rong[1];Zhu, Bin[1];Qi, Ming-Hui[1];Ren, Guo-Bin[1]

机构：[1]East China Univ Sci & Technol, Engn Res Ctr Pharmaceut Proc Chem, Lab Pharmaceut Crystal Engn & Technol, State Key Lab Bioreactor Engn,Shanghai Frontiers S, Shanghai 200237, Peoples R China

年份：2024

卷号：24

期号：8

起止页码：3114

外文期刊名：CRYSTAL GROWTH & DESIGN

收录：;EI(收录号：20241515862818);WOS:【SCI-EXPANDED(收录号:WOS:001196513000001)】；

基金：This work was financially supported by the National Natural Science Foundation of China (Nos. 21706064, 21776073, and 22108073) and the Natural Science Foundation of Shanghai (No. 20ZR1413600).

语种：英文

外文关键词：Crystal structure - Hardness - Hydration - Hydrogen bonds - Ions - Meats - Molecules - Single crystals - Solubility

摘要：Harmine (HAM) is a natural product with neuroprotective and antitumor activity. Its poor aqueous solubility is the major factor limiting its clinical application. In this work, seven new organic acid salts of HAM were prepared and systematically characterized. Their single crystals were obtained, and the structures were identified by a single-crystal X-ray diffractometer. The corresponding solubilities in water were determined in the temperature range of 20-35 degrees C by the HPLC method. All HAM salts showed significantly improved powder solubility profiles compared with the free base. The relationship between the aqueous solubility and the single-crystal structures of HAM organic salts was explored from several perspectives, including the basic properties of acidic counterions, the intermolecular force in crystals (type of lattice force, cohesive energy density, and lattice energy), the factors affecting the dissolution process (hydration energy and sublimation energy), and the external environmental factors (chemical hardness). The aqueous solubility of different HAM salts was dependent on the type of charge assistant hydrogen bonds; that is, the salts with N+-HO and O-HO- hydrogen bonds exhibited better solubility than the other salts with N+-HO- hydrogen bonds. In addition, the results revealed that HAM salts with higher acidic counterion intrinsic solubility (S-ACID) showed smaller cohesive energy density of the crystal; the larger the absolute value of hydration energy (Delta G(hyd)(0)), the greater the chemical hardness (eta) of acidic anions in the crystal and ultimately the better the equilibrium solubility in water. The rank order of the linear fitting accuracy of these four parameters regarding solubility was as follows: Delta eta > CED > Delta G(hyd)(0). The solubility of HAM organic acidic salts is associated with several factors, even though the chemical hardness seems to play a central role.