醋酸奥曲肽原料及其制剂的杂质分析

目的：探讨醋酸奥曲肽原料及其制剂的杂质情况。方法：采用高效液相色谱法，色谱柱为HypersilC₁₈（4.6 mm×250 mm，5 μm），流动相A 为四甲基氢氧化铵溶液（取10% 四甲基氢氧化铵溶液20 mL，加水880 mL，用10% 磷酸溶液调节pH 至5.4）-乙腈（900：100），流动相B 为四甲基氢氧化铵溶液（取10% 四甲基氢氧化铵溶液20 mL，加水380 mL，用10% 磷酸溶液调节pH 至5.4）-乙腈（400：600），流速1.0 mL·min^-1，紫外检测波长为210 nm，分析醋酸奥曲肽原料及制剂的杂质谱，并比较了原料间、制剂间的杂质情况。再结合影响因素试验、加速试验、配伍稳定性试验，分析影响杂质产生的因素及杂质的变化情况，并确证未知杂质的结构。结果：醋酸奥曲肽杂质谱显示其主要杂质共21 个，不同企业间的原料、制剂杂质谱均有差异，同一企业不同剂型的制剂杂质谱也有差异；影响因素试验及加速试验表明温度、湿度、光及贮藏均可增加醋酸奥曲肽的杂质；确定了5 个未知杂质的结构，分别为杂质6（D-Thr⁶-OCTR）、杂质7（［des-Thr-ol⁸］-OCTR）、杂质9（Des-Thr⁶-OCTR）、杂质12（D-Cys⁷-OCTR）、杂质13（Des-Lys⁵-OCTR）及杂质15（［AC-D-phe¹］-OCTR）。结论：醋酸奥曲肽的杂质主要来源于制剂的生产及贮藏过程，应进一步提高制剂的生产工艺及严格控制贮藏条件，以提高产品的质量。

Objective: To study the impurity profiles of octreotide acetate and its injection. Methods: The HPLC method was used to analyze the impurity profiles of octreotide acetate and its injection. A Hypersil C₁₈ (4.6 mm×250 mm,5 μm)column was adopted,the mobile phase A was tetramethylammonium hydroxide solution (20 mL of 10% tetramethylammonium hydroxide solution and 880 mL water were added,pH was adjusted to 5.4 with 10% phosphoric acid)-acetonitrile(900:100),the mobile phase B was tetramethylammonium hydroxide solution (20 mL of 10% tetramethylammonium hydroxide solution and water 380 mL were added,pH was adjusted to 5.4 with 10% phosphoric acid)-acetonitrile(400:600),and the flow rate was 1.0 mL·min^-1,the UV detective wavelength was 210 nm. The impurity profiles of octreotide acetate and its injection were analyzed,the impurities in raw materials and preparations from different manufacturers were compared respectively. In addition,the source and influence factor of impurities of octreotide acetate and its injection were analyzed by stress testing,accelerating testing and compatibility testing,and the structures of impurities were determined. Results: The impurity profiles showed that there were 21 major impurities in octreotide acetate. The impurity profiles of raw materials from different manufacturers were different,so was the preparations from different manufacturers. The impurity profile of different formulations of the preparations from the same manufacturer were different. The temperature,humidity, light and storage could increase the impurities of octreotide acetate. The structures of five unknown impurities were identified,namely impurity 6(D-Thr⁶-OCTR),impurity 7(［des-Thr-ol⁸］-OCTR),impurity 9(Des-Thr⁶-OCTR),impurity 12(D-Cys⁷-OCTR),impurity 13(Des-Lys⁵-OCTR)and impurity 15(［AC-D-phe¹］-OCTR). Conclusion: The impurities of octreotide acetate mainly come from producing process and storage of the preparation. In order to improve the quality of the products. it is important to improve the manufacturing procedures and control the storage conditions.

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