Ren Shuzhen, Liu Mingyu, Hong Chao, Li Guowen, Sun Jiabin, Wang Jianying, Zhang Lei, Xie Yan
Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Acta Pharm Sin B. 2019 Jan;9(1):59-73. doi: 10.1016/j.apsb.2018.09.008. Epub 2018 Sep 19.
Pharmaceutical cocrystals are a promising technology that can be used to improve the solubility of poor aqueous compounds. The objective of this study was to systematically investigate the solubility of myricetin (MYR) cocrystals, including their kinetic solubility, thermodynamic solubility, and intrinsic dissolution rate (IDR). The effects of pH, surfactant, ion concentration, and coformers on the cocrystal solubility were evaluated. Furthermore, single crystal structures of MYR, myricetin-isonicotinamide (MYR-INM) and myricetin-caffeine (MYR-CAF) cocrystals were analyzed to discuss the possible reasons for the enhancement of cocrystal solubility from the perspective of the spatial structure. The results indicated that the kinetic solubility of MYR cocrystals was modulated by pH and cocrystal coformer (CCF) ionization in buffer solution, while it primarily depended on the CCF solubility in pure water. In addition, the solubility of MYR cocrystals was increased in a concentration dependent fashion by the surfactant or ion concentration. The thermodynamic solubility of MYR-INM (1:3) cocrystals decreased with the increases of the pH value of the dissolution media. The IDR of MYR cocrystals was faster than that of MYR in the same medium and extremely fast in pH 4.5 buffer. The improved solubility of MYR cocrystals was probably related to the alternate arrangements of MYR and INM/CAF molecules and increased intermolecular distance. The present study provides some references to investigate the solubility behavior of pharmaceutical cocrystals.
药物共晶体是一种很有前景的技术，可用于提高难溶性化合物在水中的溶解度。本研究的目的是系统地研究杨梅素（MYR）共晶体的溶解度，包括其动力学溶解度、热力学溶解度和固有溶解速率（IDR）。评估了pH值、表面活性剂、离子浓度和共形成物对共晶体溶解度的影响。此外，对MYR、杨梅素-异烟酰胺（MYR-INM）和杨梅素-咖啡因（MYR-CAF）共晶体的单晶结构进行了分析，以便从空间结构的角度探讨共晶体溶解度提高的可能原因。结果表明，在缓冲溶液中，MYR共晶体的动力学溶解度受pH值和共晶体共形成物（CCF）电离的调节，而在纯水中则主要取决于CCF的溶解度。此外，表面活性剂或离子浓度会以浓度依赖的方式提高MYR共晶体的溶解度。MYR-INM（1:3）共晶体的热力学溶解度随溶解介质pH值的升高而降低。在相同介质中，MYR共晶体的IDR比MYR快，在pH 4.5缓冲液中极快。MYR共晶体溶解度的提高可能与MYR和INM/CAF分子的交替排列以及分子间距离的增加有关。本研究为研究药物共晶体的溶解度行为提供了一些参考。
