Xia Yanming, Wei Yuanfeng, Chen Hui, Qian Shuai, Zhang Jianjun, Gao Yuan
School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
IUCrJ. 2021 Jan 21;8(Pt 2):195-207. doi: 10.1107/S2052252520015997. eCollection 2021 Mar 1.
Recently, cocrystallization has been widely employed to tailor physicochemical properties of drugs in the pharmaceutical field. In this study, cocrystallization was applied to separate natural compounds with similar structures. Three flavonoids [baicalein (BAI), quercetin (QUE) and myricetin (MYR)] were used as model compounds. The coformer caffeine (CAF) could form cocrystals with all three flavonoids, namely BAI-CAF (cocrystal 1), QUE-CAF (cocrystal 2) and MYR-CAF (cocrystal 3). After adding CAF to methanol solution containing MYR and QUE (or QUE and BAI), cocrystal 3 (or cocrystal 2) preferentially formed rather than cocrystal 2 (or cocrystal 1), indicating that flavonoid separation could be achieved by competitive cocrystallization. After co-mixing the slurry of two flavonoids with CAF followed by centrifugation, the resolution ratio that could be achieved was 70-80% with purity >90%. Among the three cocrystals, cocrystal 3 showed the lowest formation constant with a negative Gibbs free energy of nucleation and the highest energy gap. Hirshfeld surface analysis and density of states analysis found that cocrystal 3 had the highest strong interaction contribution and the closest electronic density, respectively, followed by cocrystal 2 and cocrystal 1, suggesting CAF could competitively form a cocrystal with MYR much more easily than QUE and BAI. Cocrystallization is a promising approach for green and effective separation of natural products with similar chemical structures.
近年来，共结晶在制药领域被广泛用于调整药物的物理化学性质。在本研究中，共结晶被应用于分离结构相似的天然化合物。三种黄酮类化合物[黄芩素（BAI）、槲皮素（QUE）和杨梅素（MYR）]被用作模型化合物。共形成剂咖啡因（CAF）能与所有三种黄酮类化合物形成共晶体，即BAI-CAF（共晶体1）、QUE-CAF（共晶体2）和MYR-CAF（共晶体3）。在向含有MYR和QUE（或QUE和BAI）的甲醇溶液中加入CAF后，优先形成的是共晶体3（或共晶体2）而非共晶体2（或共晶体1），这表明通过竞争性共结晶可以实现黄酮类化合物的分离。将两种黄酮类化合物的浆液与CAF共混后离心，可实现的拆分率为70-80%，纯度>90%。在三种共晶体中，共晶体3的形成常数最低，成核吉布斯自由能为负，能隙最高。 Hirshfeld表面分析和态密度分析发现，共晶体3分别具有最高的强相互作用贡献和最接近的电子密度，其次是共晶体2和共晶体1，这表明CAF与MYR竞争性形成共晶体比与QUE和BAI更容易得多。共结晶是一种用于绿色、有效分离化学结构相似的天然产物的有前景的方法。
