Enhancing the Stability, Solubility, and Antioxidant Activity of Cinchonine through Pharmaceutical Cocrystallization

• Published in: Pharmaceutical research 2024-06, Vol.41 (6), p.1257-1270
• Main Authors: Zhou, Yi, Tu, Yan, Yang, Jie, Qian, Kun, Liu, Xueyang, Fu, Qingxia, Xu, Xianghong, Chen, Shiyu
• Format: Article
• Language: English
• Subjects: Analysis; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Chemistry, Pharmaceutical - methods; Crystallization; Dissolution; Drug Stability; Fumaric acid; High temperature; Humidity; Malic acid; Medical Law; Original Research Article; Pharmacology/Toxicology; Pharmacy; Phosphates; Salts; Salts - chemistry; Solubility; Spectrophotometry; Wettability
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-024-03712-3

Purpose 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. Method 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. Result 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). Conclusion Cocrystallization technology is a viable option for improving cinchonine's poor physicochemical qualities. Graphical Abstract