碳[~11C]乙酸钠注射液质量分析方法的建立
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摘要
目的:建立碳[~(11)C]乙酸钠注射液的质量分析方法。方法:用高效液相色谱法(HPLC)测定放射化学纯度;用气相色谱法(GC)测定残留溶剂;凝胶限度法测定细菌内毒素;直接接种法进行无菌检查。结果:建立了放射化学纯度的测定方法,该方法在进样量为0.039～0.963μCi的范围内线性关系良好(r=1.0),可有效分离~(11)C-乙酸钠和~(11)C-碳酸盐、~(11)C-丙酮等放射性杂质。建立了残留溶剂的测定方法,四氢呋喃、乙醇、乙醚分离度较好,线性关系良好(r≥0.993),回收率均在89%～108%之间;碳[~(11)C]乙酸钠注射液对细菌内毒素检查无干扰,可用凝胶限度法进行内毒素检查;抑菌实验结果表明,《中华人民共和国药典》(ChP)2015年版规定的6种实验菌株均可正常生长,本品可采用直接接种法进行无菌检查。结论:对于半衰期为20 min的短半衰期碳[~(11)C]乙酸钠注射液,本研究所建立的分析方法可操作性强、结果准确、对分析人员的辐射危害较小,可用于该注射液的质量分析和控制。
Objective:To establish a quality method for sodium acetate[~(11)C]injection.Methods:Measuring radiochemical purity by using HPLC;using Gas Chromatography to determine the residual solvents;measuring bacterial endotoxins by gel-clot limit test;using direct inoculation method to test sterility.Results:Built the method for determining the radiochemical purity.A good linear relationship was observed in the radioactivity of0.039～0.963μCi(r=1.0).~(11)C-carbonate,~(11)C-acetone and other radioactive impurities were separated from~(11)C-sodium acetate effectively.Built the method for determining the residual solvents.The separation degree of tetrahydrofuram,ethanol and aether was well.The linear relationship was good(r≥0.993).The average recoveries were between 89%and 108%.The test solution does not contain interfering factors,so the gel-clot limit test can be applied to the test for bacterial endotoxins of sodium acetate[~(11)C]injection.The results of bacteriostasis experiment showed that six test strains required for sterility test according to Chinese pharmacopoeia(2015 edition)exhibited good growth.The direct inoculation method was workable for sterile test of sodium acetate[~(11)C]injection.Conclusion:For sodium acetate[~(11)C]injection with short half-life of 20 minutes,the established analytical methods have strong operability,accurate results and less radiation hazard to analysts.The methods can be used for quality control of sodium acetate[~(11)C]injection.
Objective:To establish a quality method for sodium acetate[~(11)C]injection.Methods:Measuring radiochemical purity by using HPLC;using Gas Chromatography to determine the residual solvents;measuring bacterial endotoxins by gel-clot limit test;using direct inoculation method to test sterility.Results:Built the method for determining the radiochemical purity.A good linear relationship was observed in the radioactivity of0.039～0.963μCi(r=1.0).~(11)C-carbonate,~(11)C-acetone and other radioactive impurities were separated from~(11)C-sodium acetate effectively.Built the method for determining the residual solvents.The separation degree of tetrahydrofuram,ethanol and aether was well.The linear relationship was good(r≥0.993).The average recoveries were between 89%and 108%.The test solution does not contain interfering factors,so the gel-clot limit test can be applied to the test for bacterial endotoxins of sodium acetate[~(11)C]injection.The results of bacteriostasis experiment showed that six test strains required for sterility test according to Chinese pharmacopoeia(2015 edition)exhibited good growth.The direct inoculation method was workable for sterile test of sodium acetate[~(11)C]injection.Conclusion:For sodium acetate[~(11)C]injection with short half-life of 20 minutes,the established analytical methods have strong operability,accurate results and less radiation hazard to analysts.The methods can be used for quality control of sodium acetate[~(11)C]injection.
引文
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[12]何山震,王淑侠,王朋,等.肿瘤分子探针11C-乙酸钠的标记及其临床应用[J].医学分子生物学杂志,2013,10(5):264-267.
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[14]欧洲药典委员会.欧洲药典[S]. 9. 0版.欧洲药典成员国:欧洲药典委员会,2017:1166-1167.
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[2]霍力,党永红,付喆,等.碳-11乙酸盐正电子断层显像临床应用[J].中国医学影像学杂志,2010,18(4):293-300.
[3] MOERLEIN SM,GAEHLE GG,WELCH MJ. Robotic preparation of sodium acetate C 11 injection for use in clinical PET[J].Nucl Med Biol,2002,29(5):613-621.
[4] ROEDA D,DOLLE F,CROUZEL C. An improvement of11Cacetate synthesis-non-radioactive contaminants by irradiation-induced species emanating from the11Ccarbon dioxide production target[J]. Appl Radiat Isot,2002,57(6):857-860.
[5] MITTERHAUSER M,WADSAK W,KRCAL A,et al. New aspects on the preparation of[11C] acetate-a simple and fast approach via distillation[J]. Appl Radiat Isot,2004,61(6):1147-1150.
[6] SOLOVIEV D,TAMBURELLA C. captive solvent[11C] acetate synthesis in GMP conditions[J]. Appl Radiat Isot,2006,64(9):995-1000.
[7] CHEUNG MK,HO CL. A simple,versatile,low-cost and remotely operated apparatus for[11C]acetate,[11C]choline,[11C]methionine and[11C]PIB synthesis[J]. Appl Radiat Isot,2009,67(4):581-589.
[8] FELICINI C,NAGREN K,BERTON A,et al. Development of an automated modular system for the synthesis of11Cacetate[J]. Nucl Med Commun,2010,31(12):1033-1039.
[9]张锦明,田嘉禾,陈燕,等.11C-胆碱模块合成11C-乙酸钠的研究[J].中华核医学杂志,2008,28(5):319-322.
[10]霍力,周前,傅喆.11C-乙酸钠制备方法的改进及生物体内分布[J].国际放射医学核医学杂志,2008,32(4):193-196.
[11]甘满权,唐小兰,唐刚华,等.11C-乙酸钠自动化合成改进工艺及PET/CT显像[J].同位素,2013,26(2):73-78.
[12]何山震,王淑侠,王朋,等.肿瘤分子探针11C-乙酸钠的标记及其临床应用[J].医学分子生物学杂志,2013,10(5):264-267.
[13]李彦生.碳[11C]乙酸钠的全自动合成及临床前研究[D].天津:天津大学,2013.
[14]欧洲药典委员会.欧洲药典[S]. 9. 0版.欧洲药典成员国:欧洲药典委员会,2017:1166-1167.
[15]国家药典委员会.中华人民共和国药典[S]. 2015年版.第四部.北京:中国医药科技出版社,2015.