利用³¹P NMR谱快速测定依替膦酸二钠片中依替膦酸钠及其杂质的含量

目的：建立核磁共振磷谱分析方法同时测定依替膦酸二钠片中依替膦酸钠及其杂质亚磷酸根、磷酸根的含量。方法：以重水为溶剂，草铵膦为内标，采用5 mmBBO探头测定，温度为296.5 K，扫描64次，对3批依替膦酸二钠片样品进行测定，并与非水电位滴定法测定结果进行比较。结果：依替膦酸钠、亚磷酸根、磷酸根摩尔浓度分别在1.25～400.00、1.25～400.00、1.00～400.00 mmol·L^-1的范围内呈良好的线性关系（R²=1.000），检测下限分别为1.25、1.25、1.00 mmol·L^-1，精密度RSD为0.10%～0.43%（n=6），片剂的平均回收率为99.2%～101.8%，RSD为0.028%～0.42%（n=5），3批样品主成分含量分别为95.65%、97.53%、96.47%。结论：实验结果表明，该方法可为依替膦酸二钠片质量控制提供新的分析依据。

Objective: To establish a ³¹P NMR method for the simultaneous determination of etidronate disodium and its inpurities in etidronate disodium tablets,including etidronate disodium,phosphite and phosphate. Methods: Glyphosate was used as an internal standard,D2O was used as a solvent,and three batches of etidronate disodium tablets were determined by 5 mmBBO probe at 296.5 K and 64 times of scanning. The results were compared to those obtained with non-aqueous potentiometric titration. Results: Good linearity (R²=1.000) was achieved for etidronate disodium,phosphite and phosphate in the range of 1.25-400.00,1.25-400.00 and 1.00-400.00 mmol·L^-1. The limits of detection were 1.25,1.25,1.00 mmol·L^-1 for etidronate disodium,phosphite and phosphate,respectively. The RSD of precision was 0.10%~0.43% (n=6),and the average recoveies were 99.2%-101.8% with RSD of 0.028%-0.42% (n=5). The contents of main component in three batches of samples were 95.65%,97.53% and 96.47%,respectively. Conclusion: This method provided a new reliable analytical method for the quality control of etidronate disodium tablets.

[1] TSAI EW,IP DP,BROOKS MA.Determination of etidronate disodium tablets by ion chromatography with indirect UV detection[J].J Pharm Biomed Anal,1993,11(6):513
[2] 王嘉琪,罗轶凡,姜明燕,等.双膦酸盐类药物的药动学及药物相互作用研究进展[J].药物评价研究,2019,42(3):223 WANG JQ,LUO YF,JIANG MY,et al.Research progress in pharmacokinetics and drug interactions of bisphosphonates[J].Eval Res Drugs,2019,42(3):223
[3] 张晓青,蒋晔,徐智儒.依替膦酸钠及其有关物质的反相离子对色谱分析[J].分析测试学报,2005,24(4):105 ZHANG XQ,JIANG Y,XU ZR.An assay of etidronate and its related metabolites by ion-pair RP-HPLC inversion of etidronate and related substances ion pair chromatography[J].J Instrum Anal,2005,24(4):105
[4] 熊婧,吴建敏,岳志华,等.离子色谱法测定依替膦酸二钠及其片剂的含量及有关物质[J].药物分析杂志,2012,32(2):128 XIONG J,WU JM,YUE ZH,et al.Determination of etidronate disodium and its related substances in its tablets by ion chromatography[J].Chin J Pharm Anal,2012,32(2):128
[5] FERNANDES C,LEITE RS,FERNANDO ML.Rapid determination of bisphosphonates by ion chromatography with indirect UV detection[J].J Chromatogr Sci,2007,45(5):236
[6] 邢玉仁,刘金荣.EHDP含量测定的研究[J].齐鲁医药工业,1997,16(2):17 XING YR,LIU JR.Study on determination of EHDP[J].Qilu Pharm Aff,1997,16(2):17
[7] 徐继红,陈卫民.Th-EDTA络合滴定法测定羟乙膦酸二钠片含量[J].解放军药学学报,1999,15(4):56 XU JH,CHEN WM.Determination of etidronate disodium tablets by Th-EDTA complexometric titration[J].Pharm J Chin PLA,1999,15(4):56
[8] 王秀文,张红梅,刘素艳,等.羟乙膦酸二钠的电位滴定法测定[J].中国医药工业杂志,2002,33(3):140 WANG XW,ZHANG HM,LIU SY,et al.Determination of etidronate disodium by potentiometric titration[J].Chin J Pharm,2002,33(3):140
[9] 邵青,李士敏,郑琦,等.血浆中羟乙膦酸钠含量测定方法研究[J].中国药科大学学报,1997,28(4):222 SHAO Q,LI SM,ZHENG Q,et al.Study on determination of disodium etidronate in plasma[J].J China Pharm Univ,1997,28(4):222
[10] 邵青,李士敏,曾苏,等.健康人口服羟乙膦酸钠胶囊剂的相对生物利用度试验[J].中国药学杂志,2000,35(3):177 SHAO Q,LI SM,ZENG S,et al.Relative bioavailability of disodium etidronate capsules in healthy volunteers[J].Chin Pharm J,2000,35(3):177
[11] 楼永军,李煜,李会林.衍生化紫外分光光度法测定依替膦酸二钠片的溶出度[J].中国现代应用药学,2010,27(4):350 LOU YJ,LI Y,LI HL.Determination of dissolution in etidronate disodium tablets by derivatization with UV spectrophotometry[J].Chin J Mod Appl Pharm,2010,27(4):350
[12] WALASH MI,METWALLY ES,EID MI,et al.Spectrophotometric determination of risedronate and etidronate in pharmaceutical formulation via the molybdovanadate method[J].Anal Lett,2009,42(11):1571
[13] 安普丽,蒋晔,李海霞.依替膦酸钠片的毛细管电泳-间接UV法测定[J].中国医药工业杂志,2009,40(6):57 AN PL,JIANG Y,LI HX.Determination of etidronate disodium tablets by capillary electrophoresis indirect UV[J].Chin J Pharm,2009,40(6):57
[14] 方洪壮,孙长海.依替膦酸钠的电位滴定[J].中国医药工业杂志,1998,29(4):174 FANG HZ,SUN CH.Potentiometry of etidronate disodium[J].Chin J Pharm,1998,29(4):174.
[15] 雷毅,钟新林.离子色谱法测定氯膦酸二钠及其制剂的含量和有关物质[J].分析化学,2009,37(7):1065 LEI Y,ZHONG XL.Determination of clodronate disodium and its related substances in its preparations by ion chromatography[J].Chin J Anal Chem,2009,37(7):1065
[16] 中华人民共和国药典2015年版.二部[S].2015:675 ChP 2015.Vol Ⅱ[S].2015:675