盐酸曲唑酮杂质对照品核磁共振定量方法的建立

目的：建立盐酸曲唑酮杂质对照品的核磁共振定量方法。方法：采用Bruker 500 MHz核磁共振谱仪，采集一维核磁共振氢谱，以对苯二甲酸二甲酯为内标物，扫描次数设为32次，采样时间为3.28 s，弛豫延迟时间（D1）的设置如下：盐酸曲唑酮杂质A和杂质F为20 s[以氘代二甲亚砜（DMSO-d₆）为溶剂]，曲唑酮杂质B、杂质C、杂质D的D1为30 s（以氘代丙酮为溶剂），分别进行定量研究。结果：5个盐酸曲唑酮杂质对照品的qNMR结果与质量平衡法结果基本一致。结论：本文建立的qNMR方法简单快捷，准确度高，为盐酸曲唑酮的质量控制及其杂质对照品的定值提供了新的方法，同时，可作为质量平衡法定值结果的有力佐证。

Objective:To establish a quantitative ¹H-NMR method (qNMR) for reference standards of trazodone hydrochloride impurity. Methods:The 1D quantitative ¹H-NMR spectra were collected at Bruker 500 MHz NMR spectrometer. Dimethyl terephthalate was used as the internal standard with the number for scan set at 32 and the acquisition time set at 3.28 s. The relaxation time delay (D1) was set at 20 s for impurities A and F of trazodone hydrochloride (DMSO-d₆ used as the solvent) while 30 s for impurities B, C, D of trazodone hydrochloride (acetone-d₆ used as the solvent) to carry out quantitative study. Results:The results of quantitative ¹H-NMR method were basically consistent with those of mass balance method. Conclusion:The qNMR method is simple, rapid and accurate for the quality control of trazodone hydrochloride and quantitative determination of reference standards of trazodone hydrochloride impurity. Meanwhile, it provides a supportive evidence for the results of mass balance method.

[1] HARA M,FITTON A,MCTAVISH D.Trazodone:a review of its pharmacology,therapeutic use in depression and therapeutic potential in other disorders[J].Drugs Aging,1994,4(4):331
[2] FAGIOLINI A, COMANDINI A, KASPER S,et al.Rediscovering trazodone for the treatment of major depressive disorder[J].CNS Drugs,2012,26(12):1033
[3] 陈桂良,徐新元,王依婷.新药开发研究过程中药品标准物质的标定[J].上海计量测试,2002,29(2):18 CHEN GL,XU XY,WANG YT.The determination of pharmaceutical reference materials during new drug development and research[J].Shanghai Meas Test,2002,29(2):18
[4] 冯艳春,刘书妤,胡昌勤.比阿培南标准物质的研制[J].中国抗生素杂志,2010,35(9):679 FENG YC,LIU SY,HU CQ.Establishment of national reference standard of biapenem[J].J Chin Antibiot,2010,35(9):679
[5] BHARTI SK,ROY R.Quantitative ¹H NMR spectroscopy[J].Trends Anal Chem,2012,35:5
[6] 张芬芬,蒋孟虹,沈文斌.定量核磁共振(qNMR)技术及其在药学领域的应用进展[J].南京师范大学学报(工程技术版),2014,14(2):8 ZHANG FF,JIANG MH,SHEN WB.Progress in quantitative nuclear magnetic resonance technology in pharmaceutical applications[J].J Nanjing Norm Univ(Eng Technol Ed),2014,14(2):8
[7] SIMMLER C,NAPOLITANO JG,MCALPINE JB,et al.Universal quantitative NMR analysis of complex natural samples[J].Curr Opin Biotechnol,2014,25:51
[8] HOLZGRABE U.Quantitative NMR spectroscopy in pharmaceutical applications[J].Prog Nucl Magn Reson Spectrosc,2010,57(2):229
[9] SHEN S,YAO J,SHI Y.Quantitative proton nuclear magnetic resonance for the structural and quantitative analysis of atropine sulfate[J]. J Pharm Biomed Anal,2014,89:118
[10] 张琪,朱洪波,杨化新,等.核磁共振法定量影响因素探析.[J].中国药品标准,2014,15(6):405 ZHANG Q,ZHU HB,YANG HX,et al.Discussion on the factors influencing quantitative nuclear magnetic resonance determination[J].Drug Stand China,2014,15(6):405
[11] MALZ F,JANCKE H.Validation of quantitative NMR[J].J Pharm Biomed Anal,2005,38(5):806
[12] RIZZO V,PINCIROLI V.Quantitative NMR in synthetic and combinatorial chemistry[J].J Pharm Biomed Anal,2005,38(5):851
[13] SOININEN P.Quantitative ¹H NMR Spectroscopy Chemical and Biological Applications[EB/OL].(2008-10-10)[2015-10-28]. http://epublications.uef.fi/pub/urn_isbn_978-951-27-1093-5/urn_isbn_978-951-27-1093-5.pdf.Kuopio,Kuopio University Publications.2008:1
[14] HOLZGRABE U,DEUBNER R,SCHOOLLMAYER C,et al.Quantitative NMR spectroscopy-Application in drug analysis[J].J Pharm Biomed Anal,2005(38):806