国产罗红霉素杂质谱及与合成工艺相关性评价

Evaluation of relativity between impurity profile and synthesis technology of domestic roxithromycin

目的：考察国产罗红霉素的杂质谱情况,并与合成工艺相关性进行初步评价。方法：采用欧洲药典7.0版罗红霉素有关物质方法对国产样品进行分析,使用Waters Symmetry ShieldTMC18色谱柱（150 mm×3.9 mm,5μm）,以0.52 mol·L^-1磷酸二氢铵溶液[用氢氧化钠溶液（8.5→100）调节p H至4.3]-乙腈（74∶26）为流动相A,以水-乙腈（30∶70）为流动相B,梯度洗脱（0～50 min,100%A;50～51 min,100%A→90%A;51～80 min,90%A;80～81 min,90%A→100%A;81～100 min,100%A）,色谱柱温15℃,自动进样器温度8℃,检测波长205 nm。以系统适用性对照品对11种已知杂质进行定位,以罗红霉素为外标计算杂质含量。结果：国产罗红霉素中检出的主要杂质为杂质H、杂质F和杂质C。杂质H是影响国产罗红霉素质量的主要杂质。结论：国产罗红霉素的主要杂质H和杂质F与合成工艺中起始反应物硫氰酸红霉素中红霉素B和去甲基红霉素的含量相关;杂质C为反应中间体红霉素（E）肟的残留,通过优化纯化工艺可降低杂质C的含量。国产罗红霉素的合成工艺可有效的去除侧链合成中引入的杂质G、杂质J和杂质K。

Objective： To investigate the impurity profile of domestic roxithromycin and evaluate the correlation between the impurity profile andthe synthesis technology. Methods： Using the EP 7. 0 roxithromycin related substances method in the European Pharmacopoeia（ version 7. 0）,the domestic samples were analyzed. A Waters Symmetry ShieldTMC18column（ 150 mm × 3. 9 mm,5 μm） was used; the mobile phase A was the mixture of 0. 52 mol·L^-1ammonium dihydrogen phosphate solution [adjusted to p H 4. 3 with sodium hydroxide solution（ 8. 5→100） ]-acetonitrile（ 74∶ 26）,the mobile phase B was the mixture of water-acetonitrile（ 70 ∶ 30）,eluting with a gradient program（ 0-50 min,100% A; 50-51 min,100% A →90% A; 51-80 min,90% A; 80-81 min,90% A →100% A;81-100 min,100% A）. The column temperature was maintained at 15 ℃ and the injector temperature was maintained at 8 ℃,the detection wavelength was set at 205 nm. The 11 known impurities were located by injecting the roxithromycin system suitability standard. The contents of impurities were calculated using roxithromycin as an external standard. Results： The major impurities of domestic roxithromycin were impurities H,F and C. Impurity H was the main impurity influencing the quality of domestic roxithromycin. Conclusion： The contents of impurities H and F are related to the contents of erythromycin B and demethylerythromycin present in the initial reactant thiocyanate erythromycin. Impurity C is the residue of reaction intermediate erythromycin-9-（ E）-oxime,the content of which can be reduced by optimizing the purification process. The synthesis technology of the domestic roxithromycin can effectively remove the impurities G,J and K induced in side-chain synthesis of roxithromycin.