Department of Hygiene Inspection & Quarantine Science, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong 510515, China.
Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China.
Int J Pharm. 2021 May 15;601:120537. doi: 10.1016/j.ijpharm.2021.120537. Epub 2021 Mar 27.
Herein, we reported a new bergenin: 4-aminobenzamide (BGN-4AM) cocrystal with significantly enhanced solubility and low hygroscopicity probed from two aspects such as phase solubility diagrams and theoretical calculations. Compared with anhydrous BGN, BGN-4AM solubilities in water and different buffer solutions (pH = 1.2, 4.5, 6.8) increase significantly. It is noted that BGN-4AM solubility in pH = 6.8 buffer solution presents 32.7 times higher than anhydrous BGN. Interestingly, BGN-4AM (0.31 ± 0.07%) showcases lower hygroscopicity than anhydrous BGN (9.31 ± 0.16%). The predicted and experimental solubilities agree with each other when considering solubility product (K) and solution binding constant (K) in phase solubility diagrams, indicating the solution complexes formation occurs. Further crystal surface-water interactions and Bravais, Friedel, Donnay-Harker (BFDH) analyses based on Density Functional Theory with dispersion correction (DFT-d) methods support the enhanced solubility. The water probe demonstrates an average interaction energy of -6.48 kcal/mol on the 002 plane of BGN-4AM, and only -5.47 kcal/mol on the 011 plane of BGN monohydrate. The lower lattice energy of BGN-4AM guarantees its lower hygroscopicity than BGN monohydrate. BGN-4AM with enhanced solubility and low hygroscopicity can be a potential candidate for further formulation development.
4-氨基苯甲酰胺（BGN-4AM）共晶，其溶解度显著提高，吸湿性降低，这是从相溶解度图和理论计算两个方面探测到的。与无水 BGN 相比，BGN-4AM 在水中和不同缓冲液（pH = 1.2、4.5、6.8）中的溶解度显著增加。值得注意的是，BGN-4AM 在 pH = 6.8 缓冲液中的溶解度比无水 BGN 高 32.7 倍。有趣的是，BGN-4AM（0.31 ± 0.07%）的吸湿性比无水 BGN（9.31 ± 0.16%）低。考虑到相溶解度图中的溶解度积（K）和溶液结合常数（K），预测和实验溶解度是一致的，表明溶液配合物的形成。进一步的晶体表面-水相互作用和基于密度泛函理论与色散校正（DFT-d）方法的布拉维、弗里德尔、唐纳-哈克（BFDH）分析支持了溶解度的提高。水探针在 BGN-4AM 的 002 面上的平均相互作用能为-6.48 kcal/mol，而在 BGN 一水合物的 011 面上仅为-5.47 kcal/mol。BGN-4AM 的晶格能较低，保证了其吸湿性比 BGN 一水合物低。具有高溶解度和低吸湿性的 BGN-4AM 可能是进一步制剂开发的潜在候选药物。
