Feng Yumiao, Meng Yuanyuan, Tan Fangyun, Lv Lin, Li Zhiping, Wang Yuli, Yang Yang, Gong Wei, Yang Meiyan
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Department of Pharmacy, Pharmaceutical College, Henan University, Kaifeng 475001, China.
Pharmaceutics. 2021 Oct 22;13(11):1772. doi: 10.3390/pharmaceutics13111772.
(1) Background: Pharmaceutical cocrystals have attracted remarkable interest and have been successfully used to enhance the absorption of poorly water-soluble drugs. However, supersaturable cocrystals are sometimes thermodynamically unstable, and the solubility advantages present a risk of precipitation because of the solution-mediated phase transformation (SMPT). Additives such as surfactants and polymers could sustain the supersaturation state successfully, but the effect needs insightful understanding. The aim of the present study was to investigate the roles of surfactants and polymers in the dissolution-supersaturation-precipitation (DSP) behavior of cocrystals. (2) Methods: Five surfactants (SDS, Poloxamer 188, Poloxamer 407, Cremophor RH 40, polysorbate 80) and five polymers (PVP K30, PVPVA 64, HPC, HPMC E5, CMC-Na) were selected as additives. Tecovirimat-4-hydroxybenzoic (TEC-HBA) cocrystals were chosen as a model cocrystal. The TEC-HBA cocrystals were first designed and verified by PXRD, DSC, SEM, and FTIR. The effects of surfactants and polymers on the solubility and dissolution of TEC-HBA cocrystals under sink and nonsink conditions were then investigated. (3) Results: Both the surfactants and polymers showed significant dissolution enhancement effects, and most of the polymers were more effective than the surfactants, according to the longer T and higher C. These results demonstrate that the dissolution behavior of cocrystals might be achieved by the maintained supersaturation effect of the additives. Interestingly, we found a linear relationship between the solubility and C of the dissolution curve for surfactants, while no similar phenomena were found in solutions with polymer. (4) Conclusions: The present study provides a basis for additive selection and a framework for understanding the behavior of supersaturable cocrystals in solution.
(1) 背景：药物共晶体已引起了极大关注，并已成功用于提高难溶性药物的吸收。然而，过饱和共晶体有时在热力学上不稳定，由于溶液介导的相变（SMPT），其溶解度优势存在沉淀风险。表面活性剂和聚合物等添加剂可以成功维持过饱和状态，但这种效果需要深入理解。本研究的目的是研究表面活性剂和聚合物在共晶体溶解 - 过饱和 - 沉淀（DSP）行为中的作用。(2) 方法：选择五种表面活性剂（十二烷基硫酸钠、泊洛沙姆188、泊洛沙姆407、聚氧乙烯蓖麻油RH 40、聚山梨酯80）和五种聚合物（聚乙烯吡咯烷酮K30、聚乙烯吡咯烷酮VA 64、羟丙基纤维素、羟丙甲纤维素E5、羧甲基纤维素钠）作为添加剂。选择替考韦酯 - 4 - 羟基苯甲酸（TEC - HBA）共晶体作为模型共晶体。首先通过粉末X射线衍射（PXRD）、差示扫描量热法（DSC）、扫描电子显微镜（SEM）和傅里叶变换红外光谱（FTIR）对TEC - HBA共晶体进行设计和验证。然后研究表面活性剂和聚合物在漏槽和非漏槽条件下对TEC - HBA共晶体溶解度和溶出度的影响。(3) 结果：表面活性剂和聚合物均显示出显著的溶出增强作用，根据较长的T和较高的C，大多数聚合物比表面活性剂更有效。这些结果表明，共晶体的溶出行为可能是通过添加剂维持的过饱和效应实现的。有趣的是，我们发现表面活性剂的溶解度与溶出曲线的C之间存在线性关系，而在含有聚合物的溶液中未发现类似现象。(4) 结论：本研究为添加剂的选择提供了依据，并为理解过饱和共晶体在溶液中的行为提供了框架。
