CN111007168B - 超高效液相色谱分析阿德福韦酯n3-异构体的方法 - Google Patents
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Abstract
本发明涉及超高效液相色谱分析阿德福韦酯中N3‑异构体的方法,包括:分析方法的色谱条件:色谱柱:十八烷基硅烷键合硅胶色谱柱;流动相:乙腈(A)‑0.1%甲酸溶液(氨水调节pH值)(B),梯度洗脱18%B(0min)~18%B(1min)~25%B(5min)~35%B(13min)~79%B(18min);流速:0.5ml/min;检测波长272~276nm;柱温28~32℃。本发明提供一种检测阿德福韦酯中N3‑异构体的超高效液相色谱含量测定的方法。根据本发明所建立的检测阿德福韦酯中N3‑异构体的超高效液相色谱含量测定方法灵敏度高,分离度和重现性好;所获得的含量测定方法能完全的区分阿德福韦酯及其N3‑异构体并准确测定阿德福韦酯N3‑异构体的含量,且该色谱体系亦可直接用于LC‑MS的分析,可同步对N3‑阿德福韦酯异构体进行分子量的监测。
Description
技术领域
本发明涉及药物分析领域,具体涉及一种检测阿德福韦酯中N3-异构体超高效液相色谱分析方法。
背景技术
乙肝病毒性肝炎是由乙型肝炎病毒引起的传染性疾病,严重威胁我国人民肝脏健康,目前我国慢性乙肝患者约2000~3000万,临床有效抗乙肝病毒药物主要为干扰素和核苷(酸)类似物(NAs)。目前我国主要应用的核苷(酸)类似物(NAs)有拉米夫定、恩替卡韦、替比夫定、阿德福韦酯等。
阿德福韦酯为阿德福韦的前体,在体内水解为阿德福韦转运进入细胞,并在细胞激酶的作用下,二次磷酸化转化为活性代谢物二磷酸阿德福韦,抑制病毒DNA聚合酶和逆转录酶起到抗病毒的作用。阿德福韦酯耐药发生率低、发生耐药时间晚、长期用药安全,不与拉米夫定发生交叉耐药,故适合于需长期用药或已发生拉米夫定耐药的慢性乙型肝炎患者。
阿德福韦酯分子结构中腺嘌呤环的9位仲氨基氢可发生共振位移,得到同分异构体杂质,其中N3-异构体是其中最可能存在的异构体杂质。阿德福韦酯的同分异构体杂质理化性质可能与主成分比较接近,后续工艺步骤对其清除能力相对其他杂质可能比较有限,在阿德福韦酯成品中残留的可能性也较大。因此控制该异构体杂质的含量非常重要。
超高效液相色谱(Ultra Performance Liquid Chromatography,UPLC)的理论及原理与高效液相色谱(HPLC)相同,但比HPLC更能实现小颗粒填料、更低系统体积及更快速检测,增加了分析的灵敏度及色谱峰容量。
目前暂无阿德福韦酯中N3-异构体专项检测技术,《中国药典》项下阿德福韦酯质量标准仅收载了反相色谱法的有关物质检项,并不能准确控制N3-阿德福韦酯异构体,且目前检测同分异构体的方法一般都是无机缓冲盐,普通HPLC体系,分离效果不佳,且相对于UPLC耗时更长。因此,建立可靠快捷的测定阿德福韦酯中N3-异构体的方法,为进一步控制阿德福韦酯的质量以确保其制剂的临床使用安全非常有必要。
发明内容
本发明提出一种超高效液相色谱分析阿德福韦酯中N3-异构体的方法,包括以下步骤:
1)将样品溶液注入超高效液相色谱仪中,获得色谱图,采用如下色谱条件:
色谱柱:十八烷基硅烷键合硅胶色谱柱;
流动相:乙腈(A)-0.1%甲酸溶液(氨水调节pH值)(B),梯度洗脱18%B(0min)~18%B(1min)~25%B(5min)~35%B(13min)~79%B(18min);流速:0.5ml/min;
检测波长272~276nm;柱温28~32℃。
5.作为优选,色谱柱采用规格为1.7μm,2.1×50mm的Waters Acquity UPLC色谱柱。
更优选地,流速为0.5ml/min;检测波长274nm;柱温30℃。
2)利用对照品溶液的浓度和峰面积的确定标准曲线,用上述相同的方式获得一个待评价样品的峰面积;
3)用标准曲线计算所述待评价样品的阿德福韦酯中N3-异构体的含量,含量小于0.10%即判定所述待评价样品符合质量要求。
根据本发明的供试品溶液制作方法操作,具有较高的精密度、稳定性、和重现性,系统适用性强,可适用于该类化合物的制作。所建立的阿德福韦酯N3异构体的超高效液相色谱分析方法灵敏度高,能准确的测定阿德福韦酯中N3异构体的含量,进而为阿德福韦酯药物的纯度和安全性提供一个更有效的方法。本发明建立的阿德福韦酯N3异构体的超高效液相色谱分析方法,弥补了现今检测阿德福韦酯中N3异构体尚属空白的质量控制方法,使其质量控制技术更加全面。
附图说明
图1是根据本发明的方法获得的阿德福韦酯及其N3异构体图谱。
图2是根据本发明的方法获得的阿德福韦酯N3异构体检测限。
图3是根据本发明的方法获得的标准曲线。
图4是4批检测样品叠加图。
具体实施方式
供试品与对照品溶液的制备
该环节中,精密称取样品,加适量流动相,溶解,摇匀,过0.45μm微孔滤膜,即得;精密称取对照品适量,配置一定浓度的对照品溶液,并按一定比例稀释为不同浓度,分别过0.45μm微孔滤膜,即得。
色谱条件
本发明中使用的色谱条件优选为:色谱柱:十八烷基硅烷键合硅胶色谱柱;
流动相:乙腈(A)-0.1%甲酸溶液(氨水调节pH值)(B),梯度洗脱18%B(0min)~18%B(1min)~25%B(5min)~35%B(13min)~79%B(18min);流速:0.5ml/min;检测波长272~276nm;柱温28~32℃;进样量1μl;
在本发明的最佳实施例中,确定阿德福韦酯超高效液相分析的最优色谱条件为:色谱柱:1.7μm,2.1×50mm的Waters Acquity UPLC色谱柱;流动相:乙腈(A)-0.1%甲酸溶液(氨水调节pH值为5.5)(B),梯度洗脱18%B(0min)~18%B(1min)~25%B(5min)~35%B(13min)~79%B(18min);流速:0.5ml/min;检测波长274nm;柱温30℃。
分析方法的建立
采用上述色谱条件,测定阿德福韦酯N3异构体检测限、建立标准曲线,方法学考察,包括精密度、稳定性、重复性和加样回收率,之后将需要检测的4批样品按上述建立方法进行分析,测定其阿德福韦酯N3异构体含量,确定4批药品是否合格。
采用前述最优选的各项参数和色谱条件,确定N3-异构体相对于阿德福韦酯的RRT为0.81,见表1。
表1相对保留时间
检测限确定
取4.4673μg/ml的阿德福韦酯N3异构体溶液,多次稀释确定检测限,最终确定检测限为0.0009μg,见图1。
标准曲线制作
取不同浓度的阿德福韦酯N3异构体溶液按上述方法进样,依据浓度和峰面积做线性图,测得校正因子子为0.9,回归系数R为0.9998,确立其标准曲线见图3。
方法学考察
精密度试验
取同一样品分别按照确立的色谱条件进样6次,确定仪器精密度,峰面积RSD为1.70%,仪器精密度良好。
稳定性试验
取同一样品分别按照确立的色谱条件在0h,8h,16h和32h,进样,测定样品稳定性,得到其峰面积RSD为1.46%,样品在32h内稳定。
重复性试验
取6份同一批次样品同时按照上述样品制备方法制备,并按照确立的色谱条件分析,计算阿德福韦酯N3异构体含量,含量RSD为5.21%,重复性较好。
加样回收率试验
以相对供试品浓度0.05%、0.1%、0.2%做加样回收率试验,回收率结果显示在97.32%~102.88%之间。
表2加样回收率
注1:原有量为中间精密度项下的均值计算所得。
样品含量检测
在本发明的实施例中,测定如下来源的4批阿德福韦酯样品中N3异构体含量,见表3和图4。
表3. 4批样品N3异构体含量
以上方法学考察表明:目前建立的超高效液相分析的操作方法可行,可用于阿德福韦酯样品中N3异构体含量测定。利用上述建立的条件获得待评价样品的峰面积,结合标准曲线得出4批样品中,160501、160502和160503批样品均未检测到N3-异构体,170201批检测到0.010%的N3-异构体杂质,结果均小于0.1%,符合标准。
Claims (5)
1.超高效液相色谱分析阿德福韦酯N3-异构体的方法,包括以下步骤:
a)分别将各供试品溶液和对照品溶液注入超高效液相色谱仪中,分别获得色谱图,色谱条件为:色谱柱:十八烷基硅烷键合硅胶色谱柱;流动相:乙腈A-氨水调节的0.1%甲酸溶液B,梯度洗脱18%B,0min~18%B,1min~25%B,5min~35%B,13min~79%B,18min;流速:0.5ml/min;检测波长272~276nm;柱温28~32℃;b)利用对照品溶液的浓度和峰面积的确定标准曲线;用上述相同的方式获得一个待评价样品的峰面积;c)用标准曲线计算所述待评价样品的阿德福韦酯中N3-异构体的含量,阿德福韦酯样品中N3-异构体含量小于0.10%即判定所述待评价样品符合质量要求。
2.如权利要求1所述的方法,其中,色谱柱采用规格为1.7μm,2.1×50mm的WatersAcquity UPLC色谱柱。
3.如权利要求1所述的方法,其中,0.1%甲酸溶液用氨水调节pH值为5.5。
4.如权利要求1所述的方法,其中,流速为0.5ml/min;检测波长274nm;柱温30℃。
5.如权利要求1所述的方法,其中,所述阿德福韦酯中N3-异构体以阿德福韦酯为参照峰,其相对保留时间为0.81。
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