College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, People's Republic of China.
Pharm Res. 2024 Jun;41(6):1257-1270. doi: 10.1007/s11095-024-03712-3. Epub 2024 Jun 6.
Cinchoninze hydrochloride solves the problem of the low solubility of cinchonine, but it is unstable and susceptible to deliquescence. In this study, we designed and prepared cinchonine cocrystal salts or cinchonine salts with better stability, solubility and antioxidant activity than cinchonine.
We successfully synthesized and characterized three cinchonine salts, namely, cinchonine-fumaric acid, cinchonine-isoferulic acid, and cinchonine-malic acid. The high humidity (92.5% RH) and high temperature (60°C) tests were conducted to determine the physical stability and hygroscopicity of cinchonine hydrochloride, cinchonine and three cinchonine salts. And the ultraviolet spectrophotometry was conducted to determine the equilibrium solubility and intrinsic dissolution rate of cinchonine and salts. Moreover, the DPPH, ABTS, and FRAP assays determined the antioxidant activity of cinchonine and salts.
Compared with cinchonine hydrochloride and cinchonine, all three cinchonine salts exhibited good physical stability over 15 days under high humidity (92.5% RH) and high temperature (60°C) conditions. While cinchonine and cinchonine hydrochloride are categorized as hygroscopic and deliquescent, respectively, three cinchonine salts are classified as slightly hygroscopic, meaning that they have a lower hygroscopicity than cinchonine and cinchonine hydrochloride. And three cinchonine salts had higher equilibrium solubility, faster intrinsic dissolution rates, and higher antioxidant activity in comparison to cinchonine. Moreover, they showed a "spring and parachute" pattern in the phosphate buffer (pH = 6.8).
Cocrystallization technology is a viable option for improving cinchonine's poor physicochemical qualities.
盐酸辛可宁解决了辛可宁溶解度低的问题，但它不稳定，容易潮解。本研究设计并制备了辛可宁共晶盐或辛可宁盐，其稳定性、溶解度和抗氧化活性均优于辛可宁。
我们成功合成并表征了三种辛可宁盐，即辛可宁富马酸盐、辛可宁异阿魏酸盐和辛可宁苹果酸盐。通过高湿度（92.5%RH）和高温（60°C）测试，确定盐酸辛可宁、辛可宁和三种辛可宁盐的物理稳定性和吸湿性。采用紫外分光光度法测定辛可宁及其盐的平衡溶解度和内在溶出速率。此外，DPPH、ABTS 和 FRAP 测定法测定了辛可宁及其盐的抗氧化活性。
与盐酸辛可宁和辛可宁相比，在高湿度（92.5%RH）和高温（60°C）条件下，三种辛可宁盐在 15 天内均表现出良好的物理稳定性。而辛可宁和盐酸辛可宁分别为吸湿性和潮解性，三种辛可宁盐则为稍吸湿性，即比辛可宁和盐酸辛可宁的吸湿性低。与辛可宁相比，三种辛可宁盐具有更高的平衡溶解度、更快的内在溶解速率和更高的抗氧化活性。此外，它们在磷酸盐缓冲液（pH=6.8）中呈现“弹簧和降落伞”模式。
共晶技术是改善辛可宁较差物理化学性质的可行方法。
