| 罗沙司他共晶的合成、表征与理化性质研究 |
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| 引用本文： | 徐巾超,陈勇,叶辉青,张杰,张霁,罗忠华.罗沙司他共晶的合成、表征与理化性质研究[J].化工学报,2020,71(4):1851-1858. |
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| 作者姓名： | 徐巾超 陈勇 叶辉青 张杰 张霁 罗忠华 |
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| 作者单位： | 1.广东东阳光药业有限公司，广东 东莞 523871;2.抗感染新药研发国家重点实验室，广东 东莞 523871 |
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| 摘 要： | 肾性贫血药物罗沙司他是在中国本土孵化、率先在中国获批的新药。利用溶液结晶法制备了罗沙司他-烟酰胺共晶(RDXT-N)、罗沙司他-肉桂酰胺共晶(RDXT-C)、罗沙司他-苯甲酰胺共晶(RDXT-B)以及罗沙司他-脯氨酸共晶(RDXT-P)四种共晶，并通过X射线粉末衍射(XRD)、差示扫描量热仪(DSC)、热重分析(TGA)、傅里叶变换红外光谱仪(FTIR)和核磁共振氢谱分析法(1H NMR)来表征四种共晶。对罗沙司他四个共晶的固有溶出速率、溶解度和稳定性等性质进行了研究。固有溶出速率实验表明，在pH 4.5缓冲介质中这四个共晶的溶出速率均快于罗沙司他晶型A，其中罗沙司他-肉桂酰胺共晶的溶出速率最快，接近罗沙司他晶型A的10倍。平衡溶解度实验表明，在纯水中37℃条件下溶解度最大是罗沙司他-脯氨酸共晶，是晶型A的5.3倍。影响因素稳定性实验证明，罗沙司他-肉桂酰胺共晶和罗沙司他-烟酰胺共晶有着良好的湿热稳定性和光稳定性。因此，这些罗沙司他共晶可以为新剂型设计提供选择方案。
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| 关 键 词： | 罗沙司他 结晶 共晶 合成 溶解性 稳定性 |
| 收稿时间： | 2019-10-12 |
| 修稿时间： | 2019-12-26 |
Synthesis,characterization and physicochemical properties study ofroxadustat co-crystals |
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| XU Jinchao,CHEN Yong,YE Huiqing,ZHANG Jie,ZHANG Ji,LUO Zhonghua.Synthesis,characterization and physicochemical properties study ofroxadustat co-crystals[J].Journal of Chemical Industry and Engineering(China),2020,71(4):1851-1858. |
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| Authors: | XU Jinchao CHEN Yong YE Huiqing ZHANG Jie ZHANG Ji LUO Zhonghua |
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| Affiliation: | 1.Sunshine Lake Pharma Co. , Ltd. , Dongguan 523871, Guangdong, China;2.State Key Laboratory of Anti-Infective Drug Development, Dongguan 523871, Guangdong, China |
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| Abstract: | A kidney anemia drug roxadustat is a new drug to be hatched in China and to be approved in China. Roxadustat has a poor solubility with 1.71 mg/L in water. In order to improve the solubility of roxadustat, we carried out co-crystal investigation of roxadustat. Hundreds of experiments were carried out using a serial of CCF. Four roxadustat co-crystals, synthesized with cinnamamide, niacinamide, benzamide and proline, were prepared by solution crystallization. Their structures were characterized by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectra (FTIR) and 1H nuclear magnetic resonance (1H NMR) respectively. These results show that the new crystalline phase of roxadustat was formed and there was no electronic transfer between roxadustat and CCF indicating the formation of roxadustat co-crystals. Intrinsic dissolution rate, solubility and stability of roxadustat co-crystals were investigated. The results show that the intrinsic dissolution rate of the four roxadustat co-crystals are faster than that of roxadustat form A in pH 4.5 buffer and roxadustat-cinnamamide is the fastest, nearly 10 times as large as that of roxadustat form A．The equilibrium solubility of the four roxadustat co-crystals are higher than that of roxadustat form A in water at 37℃ and the solubility of roxadustat-proline co-crystal is the highest, nearly 5.3 times as large as that of roxadustat form A．The stability results show that roxadustat-cinnamamide co-crystal and roxadustat-niacinamide co-crystal had good light-stability and thermostability. Therefore, these rosalastam co-crystals can provide options for new formulation design and circumvention of patents for rosalastam generics. |
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| Keywords: | roxadustat crystallization co-crystals synthesis solubility stability |
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