罗沙司他共晶的合成、表征与理化性质研究

doi:10.11949/0438-1157.20191198

摘要/Abstract

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。

关键词: 罗沙司他, 结晶, 共晶, 合成, 溶解性, 稳定性

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.

Key words: roxadustat, crystallization, co-crystals, synthesis, solubility, stability

中图分类号:

TQ 460.6

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.

Jinchao XU, Yong CHEN, Huiqing YE, Jie ZHANG, Ji ZHANG, Zhonghua LUO. Synthesis, characterization and physicochemical properties study ofroxadustat co-crystals[J]. CIESC Journal, 2020, 71(4): 1851-1858.

图/表 8

图2 罗沙司他四种共晶的XRD谱图

Fig.2 XRD patterns of RDXT co-crystals

图1 罗沙司他以及CCF的化学结构式

Fig.1 Chemical structures of roxadustat (RDXT) and CCF

图3 罗沙司他四种共晶的DSC谱图

Fig.3 DSC curves of RDXT co-crystals

图4 罗沙司他四种共晶的IR谱图

Fig.4 Infrared spectra (IR) of RDXT co-crystals

图5 罗沙司他四种共晶的1H NMR谱图

Fig.5 1H NMR spectrum of RDXT co-crystals

图6 罗沙司他四种共晶和晶型A在pH 4.5缓冲液中的固有溶出曲线

Fig.6 Intrinsic dissolution rate of RDXT co-crystals and form A in pH 4.5 buffer

图7 罗沙司他四种共晶和晶型A在pH 6.8缓冲液中的固有溶出曲线

Fig.7 Intrinsic dissolution rate of RDXT co-crystals and form A in pH 6.8 buffer

图8 罗沙司他四种共晶和晶型A在纯水中的平衡溶解度(37℃)

Fig.8 Solubility of RDXT co-crystals and form A in water at 37℃

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