¹⁹F_qNMR在含氟制剂含量测定中的应用

目的：建立¹⁹F核磁共振定量（qNMR）测定片剂中含氟药物含量的方法。方法：以4，4'-二氟二苯甲酮为内标，氘代DMSO为溶剂，采用反门控去耦的zgfhigqn.2脉冲序列，利用¹⁹F qNMR测定卡格列净片中卡格列净含量。试验参数如下：谱宽SW=40×10^-6，射频中心频率O1P=-110×10^-6，采样点数TD=128 k，采样时间AQ=3.5 s，弛豫延迟时间D1=20 s，扫描次数32次。结果：通过简单的过滤或离心处理后，使用¹⁹FqNMR测得6片卡格列净片中卡格列净含量分别为98.2%、98.9%、101.0%、99.7%、99.2%，与HPLC外标法测定结果相近。结论：¹⁹F qNMR可以用于含氟药物制剂中药品含量测定，这种技术前处理简单，检测速度快，不受辅料等干扰，可以用于含氟药物制剂含量的高通量测定。

Objective: To establish a ¹⁹F quantitative nuclear magnetic resonance (qNMR) method to determine the content of active pharmaceutical ingredient (API) in fluorine-containing preparation. Methods: In ¹⁹F qNMR experiments, 4, 4-difluorobenzophenone was used as an internal standard. DMSO-d₆ was used as solvent and zgfhigqn.2 pulse sequence with inverse gated decoupling was applied. Other parameters were as follows:SW=40×10^-6, O1P=-110×10^-6, TD=128 k, AQ=3.5 s, D1=20 s and NS=32. Results: After simple pre-treatment of filtration or centrifuge, the content of canagliflozin in 5 tablets were measured using ¹⁹F-qNMR. The results were 98.2%, 98.9%, 101.0%, 99.7% and 99.2%, respectively. The results were similar to those from HPLC method. Conclusion: ¹⁹F qNMR can be used in determining the contents of fluorine-containing APIs in tablets. This method only requires minimal pre-treatment and its testing speed is rapid. Meanwhile, the excipients have no interference with the determination. This technology is suitable for high-throughput measuring the API content in fluorine-containing preparation.

[1] 中华人民共和国药典2015年版.四部[S].2015:441 ChP 2015.Vol Ⅳ[S].2015:441
[2] USP 40-NF 35[S].2017:761
[3] BP 2017[S].2017:Appendix Ⅱ C
[4] EP 9.0[S].2017:2.2.33
[5] HOLZGRABE U.Quantitative NMR spectroscopy in pharmaceutical applications[J].Prog Nucl Magn Reson Spectrosc,2010,57(2):229
[6] 张芬芬,蒋孟虹,沈文斌,等.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,2014,14(2):8 ZHANG FF,JIANG MH,SHEN WB,et al.Progress in quantitative nuclear magnetic resonance technology in pharmaceutical applications[J].J Nanjing Norm Univ,2014,14(2):8
[7] 张才煜,吴建敏,李憬,等.核磁共振法定量测定氢溴酸东莨菪碱的绝对含量[J].药物分析杂志,2012,32(2):327 ZHANG CY,WU JM,LI J,et al.,Quantitative nuclear magnetic resonance determination of the absolute content of scopolamine hydrobromide[J].Chin J Pharm Anal,2012,32(2):327
[8] LIU Y,LIU ZX,LIN L,et al.Direct comparison of ¹⁹F qNMR and 1H qNMR by characterizing atorvastatin calcium content[J/OL].J Anal Methods Chem,2016,7627823/1-5[2016-08-09].https://www.hindawi.com/journals/jamc/2016/7627823/
[9] 刘阳,魏宁漪,岳瑞齐,等.新型¹⁹F核磁共振定量技术测定氟哌利多含量[J].中国新药杂志,2014,23(16):1960 LIU Y,WEI NY,YUE RQ,et al.Application of novel ¹⁹F quantitative NMR(¹⁹F-qNMR)in assay of droperidol[J].Chin J New Drugs,2014,23(16):1960
[10] 刘阳,魏宁漪,张琪,等.¹⁹F核磁共振定量技术测定酒石酸吉米格列汀倍半水合物含量[J].药物分析杂志,2014,34(7):1197 LIU Y,WEI NY,ZHANG Q,et al.Quantitative analysis of gemigliptin tartrate sesquihydrate by ¹⁹F quantitative NMR(¹⁹F-qNMR)[J].Chin J Pharm Anal,2014,34(7):1197
[11] PAULI GF,GODECKE T,dc JAKI BU,et al.,Quantitative ¹H-NMR development and potential of an analytical method:an update[J].J Nat Prod,2012,75(4):834
[12] 于小波,沈文斌,相秉仁.定量核磁共振技术及其在药学领域中的应用进展[J].药学进展,2010,34(1):17 YU XB,SHEN WB,XIANG BR.Advances in application of quantitative nuclear magnetic resonance technique in pharmaceutical field[J].Prog Pharma Sci,2010,34(1):17
[13] 刘英,胡昌勤,核磁共振在抗生素药物定量分析中的应用[J].药物分析杂志,2001,21(6):447 LIU Y,HU CQ.Application of NMR in quantitative analysis of antibiotics[J].Chin J Pharm Anal,2001,21(6):447
[14] DIXON AM,LARIVE CK. Modified pulsed-field gradient NMR experiments for improved selectivity in the measurement of diffusion coefficients in complex mixtures:application to the analysis of the Suwannee River fulvic acid[J].Anal Chem,1997,69(11):2122
[15] PAULI GF,JAKI BU,LANKIN DC.Quantitative ¹H NMR:development and potential of a method for natural products analysis[J].J Nat Prod,2005,68(1):133