WO2019046997A1 - 一种高效液相色谱法测定安立生坦含量的方法 - Google Patents

一种高效液相色谱法测定安立生坦含量的方法 Download PDF

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WO2019046997A1
WO2019046997A1 PCT/CN2017/100460 CN2017100460W WO2019046997A1 WO 2019046997 A1 WO2019046997 A1 WO 2019046997A1 CN 2017100460 W CN2017100460 W CN 2017100460W WO 2019046997 A1 WO2019046997 A1 WO 2019046997A1
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ambrisentan
content
phase
high performance
liquid chromatography
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PCT/CN2017/100460
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French (fr)
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黄乐群
周磊
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江苏嘉逸医药有限公司
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Publication of WO2019046997A1 publication Critical patent/WO2019046997A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

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  • the invention relates to a quality control method for a national 3.1 class new drug Anlishengtan bulk drug
  • the invention relates to a method for determining the content of ambrisentan by high performance liquid chromatography.
  • Endothelin-1 ET-1) is a potent autocrine and paracrine peptide.
  • Two receptor subtypes (ETA and ETB) work together to regulate the role of ET-1 in vascular smooth muscle and endothelial cells.
  • the main role of ETA is vasoconstriction and cell proliferation, while the main role of ETB is vasodilation, inhibition of proliferation, and clearance of ET-1.
  • ET-1 may play an important role in the pathogenesis and progression of pulmonary hypertension.
  • Anriline is a receptor antagonist that binds highly to ETA. It has high selectivity for ETA compared with ETB, and the clinical impact on high selectivity of ETA is unknown.
  • GlaxoSmithKline obtained the market license for this product outside the US.
  • the trade name 'LETAIRIS®' was approved by the FDA on June 15, 2007.
  • the batch form is an oral tablet, and the preparation specifications are 5 mg and 10 mg tablets. It is clinically used to treat WHO heart function grade I-III PAH to improve activity and delay clinical deterioration.
  • the ampicillin dosage form currently marketed is a tablet with a specification of 5 mg.
  • the object of the present invention is to provide a high performance liquid color in view of the deficiencies of the prior art.
  • the technical proposal of the present invention is: a method for determining the content of ambrisentan by high performance liquid chromatography, and the innovation is as follows: the chromatographic conditions are: filling with octadecylsilane bonded silica gel Agent, column length 250mm, detection wavelength 220nm, column temperature 35 °C, flow rate 1.0ml/min; the detector used is a UV detector; eluted by a reverse phase high performance liquid chromatography with a gradient of a phosphate buffer solution and a polar organic solvent.
  • the phosphate buffer solution is phase A
  • the polar organic solvent is phase B
  • the organic solvent of phase B in the mobile phase is acetonitrile.
  • the phosphate in the A phase phosphate buffer solution The amount of addition is 10 to 60 mmol/L; the pH of the phosphate is 2 to 4.
  • the mixed volume ratio of the B phase to the A phase is 40 to 60: 40 to 60.
  • ambrisentan content was calculated from the peak area according to the external standard method.
  • the diluent is a mixture of water and acetonitrile, and the mixed volume ratio of the water to acetonitrile is 25:75.
  • the present invention adopts By reversed-phase high performance liquid chromatography, the test solution and the control solution were prepared, and 20 ⁇ l of the test solution and the control solution were respectively weighed, injected into the chromatograph, and the chromatogram was recorded, and the peak area was calculated and dried according to the external standard method, that is, The determination of the content of ambrisentan is completed, and the invention fills the gaps in the current test and analysis method of ambrisentan content.
  • the invention can meet the needs of research and development and production, and can effectively and effectively control the content of ambrisentan. control.
  • Figure 1 is an adaptation diagram of the ambrisentan system of the present invention
  • Figure 2 is a linear diagram of the ambrisentan bulk drug of the present invention.
  • a high performance liquid chromatography method for determining the content of ambrisentan the chromatographic conditions are: Using octadecylsilane bonded silica as a filler, column length 250mm, detection wavelength 220nm, column temperature 35 ° C, flow rate 1.0ml / min; detector used as UV detector; using reversed-phase high performance liquid chromatography Elution is carried out according to the gradient.
  • the mobile phase is a phosphate buffer solution and a polar organic solvent, the phosphate buffer solution is phase A, the polar organic solvent is phase B, and the organic solvent of phase B in the mobile phase is acetonitrile.
  • phase A phosphate buffer solution The amount of addition is 10 mmol/L; the pH of phosphate is 2, and the volume ratio of phase B to phase A is 40:60.
  • ambrisentan content was calculated from the peak area according to the external standard method.
  • Phosphate in phase A phosphate buffer solution The addition amount is 60 mmol/L; the pH of the phosphate is 4, and the volume ratio of the B phase to the A phase is 60:40.
  • ambrisentan content was calculated from the peak area according to the external standard method.
  • phase A phosphate buffer solution The amount of addition was 35 mmol/L; the pH of phosphate was 3, and the volume ratio of phase B to phase A was 45:55.
  • ambrisentan content was calculated from the peak area according to the external standard method.
  • the content of the product is determined to be linear in the concentration range of amphoteric acid concentration of 4.032-40.32 ⁇ g/ml.
  • test solution with the content of this product was injected at 0, 2, 4, 6 and 8 hours, and the solution stability of the liquid phase method was determined by examining the content of the product.
  • the high performance liquid chromatography solution for the determination of the content of the product is stable within 8 hours.
  • the reproducibility results are the intermediate precision data set 1, and the other experimental results are the intermediate precision data set 2 and the data set 3, and the intermediate precision of the high performance liquid chromatography method for determining the content of the product is examined.
  • the invention adopts By reversed-phase high performance liquid chromatography, the test solution and the control solution were prepared, and 20 ⁇ l of the test solution and the control solution were respectively weighed, injected into the chromatograph, and the chromatogram was recorded, and the peak area was calculated and dried according to the external standard method, that is, The determination of the content of ambrisentan is completed, and the invention fills the gaps in the current test and analysis method of ambrisentan content.
  • the invention can meet the needs of research and development and production, and can effectively and effectively control the content of ambrisentan. control.

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)

Abstract

一种高效液相色谱法测定安立生坦含量的方法，色谱条件为：选用以十八烷基硅烷键合硅胶为填充剂，柱长250mm，检测波长220nm，柱温35℃，流速1.0ml/min；采用反相高效液相色谱法按梯度进行洗脱，流动相为磷酸盐缓冲溶液与极性有机溶剂，磷酸盐缓冲溶液为A相，极性有机溶剂为B相，流动相中B相的有机溶剂为乙腈。采用了反相高效液相色谱法，通过制备供试液和对照液，并且分别量取供试液及对照溶液20μl，注入色谱仪，记录色谱图，按外标法以峰面积计算并折干，即完成了安立生坦含量的测定，填补了目前安立生坦含量测试分析方法尚无的空缺，可以满足研发和生产的需求，能够有效的对安立生坦含量进行更为严格有效的控制。

Description

一种高效液相色谱法测定安立生坦含量的方法 一种高效液相色谱法测定安立生坦含量的方法
技术领域
本发明涉及国家3.1类新药安立生坦原料药的质量控制方法，具
体涉及一种高效液相色谱法测定安立生坦含量的方法。
背景技术
内皮素-1 ( ET-1)是一种有效的自分泌和旁分泌肽。两种受体亚型（ETA和ETB)共同调节ET-1在血管平滑肌和内皮细胞中的作用。ETA的主要作用是血管收缩和细胞增殖，而ETB的主要作用是血管舒张、抑制增殖、以及清除ET-1。
在患有肺动脉高压的患者中，血浆ET-1的浓度增高了10倍，并且与右心房平均压力的增加和疾病的严重程度相关。肺动脉高压患者肺组织中ET-1和ET-1mRNA浓度增加9倍，主要集中在肺动脉内皮细胞。这些发现提示了ET-1可能在肺动脉高压的发病和进展中起了重要的作用。
安立生坦是一种与ETA高度结合的受体拮抗剂，与ETB相比对ETA有高选择性，有关对ETA高选择性的临床影响还是未知。
安立生坦由Myogen公司研制，后期由吉利德公司开发，葛兰素史克公司获得本品在美国以外的市场许可权，商品名'LETAIRIS®'，于2007年6月15日获FDA批准，获批剂型为口服片剂，制剂规格有5mg和10mg片剂。临床上用于治疗WHO心功能I-III级PAH，以提高活动能力和延缓临床恶化。
该原料药的含量分析方法尚无文献报道，目前上市的安立生坦剂型为片剂，规格5mg。为了保证安立生坦制剂研发和生产的质量，需要对原料药的含量进行控制。因此我们通过大量实验，摸索了一套检测方法，并严格进行方法验证，保证方法的科学严谨，满足了研发和生产的需求。
发明内容
本发明的目的在于 针对现有技术的不足，现提供一种高效液相色
谱法测定安立生坦含量的方法。
为实现上述目的，本发明的技术方案是：一种高效液相色谱法测定安立生坦含量的方法，其创新点在于：所述色谱条件为：选用以十八烷基硅烷键合硅胶为填充剂，柱长250mm，检测波长220nm，柱温35 ℃ ，流速1.0ml/min；采用的检测器为紫外检测器；采用反相高效液相色谱法按梯度进行洗脱，所述流动相为 磷酸盐缓冲溶液 与极性有机溶剂，所述 磷酸盐缓冲溶液 为A相，所述极性有机溶剂为B相，所述流动相中Ｂ相的有机溶剂为乙腈。
进一步的，所述A相 磷酸盐缓冲溶液 中的 磷酸盐 的加入量为10～60mmol/L；所述磷酸盐的PH值为2～4。
进一步的，所述B相与A相混合体积比例为40～60：40～60。
进一步的，所述测定安立生坦含量的具体操作步骤为：
（1）取20-150mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为供试品溶液；
（2）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
（3）取20-150mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为对照品溶液；
（4）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
（5）按照外标法以峰面积计算得到安立生坦含量。
进一步的，所述稀释液为水和乙腈的混合液，所述水和乙腈的混合体积比为25:75。
本发明的有益效果如下：本发明采用了 反相高效液相色谱法，通过制备供试液和对照液，并且分别量取供试液及对照溶液20μl，注入色谱仪，记录色谱图，按外标法以峰面积计算并折干，即完成了安立生坦含量的测定，本发明填补了目前安立生坦含量测试分析方法尚无的空缺，本发明可以满足研发和生产的需求，能够有效的对安立生坦含量进行更为严格有效的控制。
附图说明
图1为本发明的安立生坦系统适应性图；
图2为本发明的安立生坦原料药线性图。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式，熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效。
一种高效液相色谱法测定安立生坦含量的方法，色谱条件为：选 用以十八烷基硅烷键合硅胶为填充剂，柱长250mm，检测波长220nm，柱温35℃，流速1.0ml/min；采用的检测器为紫外检测器；采用反相高效液相色谱法按梯度进行洗脱，流动相为磷酸盐缓冲溶液与极性有机溶剂，磷酸盐缓冲溶液为A相，极性有机溶剂为B相，流动相中Ｂ相的有机溶剂为乙腈。
实施例1
A 相 磷酸盐缓冲溶液 中的 磷酸盐 的加入量为10mmol/L；磷酸盐的PH值为2，B相与A相混合体积比例为40：60。
测定安立生坦含量的具体操作步骤为：
（1）取20mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为供试品溶液，稀释液为水和乙腈的混合液，水和乙腈的混合体积比为25:75；
（2）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
（3）取20mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为对照品溶液，稀释液为水和乙腈的混合液，水和乙腈的混合体积比为25:75；
（4）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
（5）按照外标法以峰面积计算得到安立生坦含量。
实施例2
A 相 磷酸盐缓冲溶液 中的 磷酸盐 的加入量为60mmol/L；磷酸盐的PH值为4，B相与A相混合体积比例为60：40。
测定安立生坦含量的具体操作步骤为：
（1）取150mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为供试品溶液，稀释液为水和乙腈的混合液，水和乙腈的混合体积比为25:75；
（2）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
（3）取150mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为对照品溶液，稀释液为水和乙腈的混合液，水和乙腈的混合体积比为25:75；
（4）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
（5）按照外标法以峰面积计算得到安立生坦含量。
实施例3
A 相 磷酸盐缓冲溶液 中的 磷酸盐 的加入量为35mmol/L；磷酸盐的PH值为3，B相与A相混合体积比例为45：55。
测定安立生坦含量的具体操作步骤为：
（1）取85mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为供试品溶液，稀释液为水和乙腈的混合液，水和乙腈的混合体积比为25:75；
（2）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
（3）取85mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为对照品溶液，稀释液为水和乙腈的混合液，水和乙腈的混合体积比为25:75；
（4）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
（5）按照外标法以峰面积计算得到安立生坦含量。
对安立生坦含量测定方法的以下项目进行了验证：
1 、系统适应性
用安立生坦来分析此色谱条件是否符合要求。由图1可见此条件下各个杂质与主峰以及杂质之间分离度符合要求，峰纯度和单点阈值均符合要求。
2 、标准曲线
配制各浓度梯度的供试液，分别精密量取20μl，注入色谱仪，记录色谱图，以浓度（μg/ml）为横坐标，峰面积（A）为纵坐标，绘制回归曲线，计算回归系数。
No. 1 2 3 4 5
测定浓度百分比 50% 75% 100% 125% 150%
浓度(µg/ml) 25.63 38.44 51.25 64.06 76.88
平均峰面积A 1411775 2119065 2798463 3492528 4223715
响应因子 1.815E-05 1.814E-05 1.831E-05 1.834E-05 1.820E-05
平均响应因子(RSD%) 1.823E-05(0.50%) 1.823E-05(0.50%) 1.823E-05(0.50%) 1.823E-05(0.50%) 1.823E-05(0.50%)
线性回归方程 Y=51788X+6039.1(R=0.9999) Y=51788X+6039.1(R=0.9999) Y=51788X+6039.1(R=0.9999) Y=51788X+6039.1(R=0.9999) Y=51788X+6039.1(R=0.9999)
由上表可见，本品的含量测定于安立生坦浓度4.032-40.32μg/ml的浓度范围内有良好线性。
3 、重复性
取样品6份，分别精密称定，按高效液相色谱法含量测定方法进行测定，考察测定方法的重复性，具体如下表：
№ 1 2 3 4 5 6 AVE RSD(%)
含量 99.27 99.93 98.88 99.89 99.09 99.46 99.42 0.43
由上表可知，本品含量测定高效液相色谱法的重复性良好。
4 、回收率
取本品10mg共九份于50ml容量瓶中，标示为低、中、高三个浓度梯度，分别加入8mg、10mg、12mg的对照品各三份，精密量取1mL至20mL容量瓶，照含量测定的高效液相色谱法测定，计算测得量和回收率，结果如下表所示：
样品
浓度		 № 加入量
(mg)		 实测量
(mg)		 回收率
(%)		 ` X RSD
(%)
50% 1 11.12 11.05 99.48 99.28% 0.80
50% 2 11.42 11.36 99.57 99.28% 0.80
50% 3 11.05 11.02 99.76 99.28% 0.80
100% 1 29.51 29.08 98.56 99.28% 0.80
100% 2 32.02 31.20 97.45 99.28% 0.80
100% 3 30.81 30.67 99.59 99.28% 0.80
150% 1 48.01 47.72 99.40 99.28% 0.80
150% 2 47.86 47.88 100.1 99.28% 0.80
150% 3 47.75 47.58 99.66 99.28% 0.80
由上表可见，本高效液相色谱法含量测定的回收率良好。
  1. 5、 溶液稳定性
取本品含量测定的供试液，分别于0、2、4、6、8小时进样，考察本品含量测定液相法的溶液稳定性。
时间(h) 含量% 平均值（%） 含量平均值% RSD( ％)
0 99.45 99.46 99.42 0.19
0 99.48 99.46 99.42 0.19
2 99.54 99.55 99.42 0.19
2 99.56 99.55 99.42 0.19
4 99.44 99.48 99.42 0.19
4 99.52 99.48 99.42 0.19
8 99.58 99.61 99.42 0.19
8 99.65 99.61 99.42 0.19
12 99.44 99.51 99.42 0.19
12 99.59 99.51 99.42 0.19
24 99.04 99.49 99.42 0.19
24 99.95 99.49 99.42 0.19
由上表可见，本品含量测定的高效液相色谱法溶液于8小时内稳定。
  1. 6、 中间精密度
以重复性结果为中间精密度数据组1，另行实验结果为中间精密度数据组2和数据组3，考察本品含量测定高效液相色谱法的中间精密度。
仪器及分析人员 百分含量% 平均含量%(RSD%) 平均含量(RSD%)
仪器A
( 分析人员甲)		 99.27 99.42(0.43) 99.41(0.42)
仪器A
( 分析人员甲)		 99.93 99.42(0.43) 99.41(0.42)
仪器A
( 分析人员甲)		 98.88 99.42(0.43) 99.41(0.42)
仪器A
( 分析人员甲)		 99.89 99.42(0.43) 99.41(0.42)
仪器A
( 分析人员甲)		 99.09 99.42(0.43) 99.41(0.42)
仪器A
( 分析人员甲)		 99.46 99.42(0.43) 99.41(0.42)
仪器B
( 分析人员乙)		 99.24 99.41(0.46) 99.41(0.42)
仪器B
( 分析人员乙)		 99.87 99.41(0.46) 99.41(0.42)
仪器B
( 分析人员乙)		 99.69 99.41(0.46) 99.41(0.42)
仪器B
( 分析人员乙)		 99.84 99.41(0.46) 99.41(0.42)
仪器B
( 分析人员乙)		 99.03 99.41(0.46) 99.41(0.42)
仪器B
( 分析人员乙)		 98.79 99.41(0.46) 99.41(0.42)
由上表可知，本品含量测定高效液相色谱法的中间精密度良好。
本发明采用了 反相高效液相色谱法，通过制备供试液和对照液，并且分别量取供试液及对照溶液20μl，注入色谱仪，记录色谱图，按外标法以峰面积计算并折干，即完成了安立生坦含量的测定，本发明填补了目前安立生坦含量测试分析方法尚无的空缺，本发明可以满足研发和生产的需求，能够有效的对安立生坦含量进行更为严格有效的控制。
上述实施例只是本发明的较佳实施例，并不是对本发明技术方案的限制，只要是不经过创造性劳动即可在上述实施例的基础上实现的技术方案，均应视为落入本发明专利的权利保护范围内 。

Claims (5)

  1. 一种高效液相色谱法测定安立生坦含量的方法，其特征在于：所述色谱条件为：选用以十八烷基硅烷键合硅胶为填充剂，柱长250mm，检测波长220nm，柱温35℃，流速1.0ml/min；采用的检测器为紫外检测器；采用反相高效液相色谱法按梯度进行洗脱，所述流动相为磷酸盐缓冲溶液与极性有机溶剂，所述磷酸盐缓冲溶液为A相，所述极性有机溶剂为B相，所述流动相中Ｂ相的有机溶剂为乙腈。
  2. 根据权利要求1所述的一种高效液相色谱法测定安立生坦含量的方法，其特征在于：所述A相磷酸盐缓冲溶液中的磷酸盐的加入量为10～60mmol/L；所述磷酸盐的PH值为2～4。
  3. 根据权利要求1所述的一种高效液相色谱法测定安立生坦含量的方法，其特征在于：所述B相与A相混合体积比例为40～60：40～60。
  4. 根据权利要求1所述的一种高效液相色谱法测定安立生坦含量的方法，其特征在于：所述测定安立生坦含量的具体操作步骤为：
    （1）取20-150mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为供试品溶液；
    （2）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
    （3）取20-150mg安立生坦片剂，精密称重，放置于量瓶中，加入稀释液进行溶解并稀释成每1mL中含有0.05mg安立生坦的溶液，作为对照品溶液；
    （4）精密量取供试品溶液20μl，注入液相色谱仪，记录色谱图；
    （5）按照外标法以峰面积计算得到安立生坦含量。
  5. 根据权利要求4所述的一种高效液相色谱法测定安立生坦含量的方法，其特征在于：所述稀释液为水和乙腈的混合液，所述水和乙腈的混合体积比为25:75。
PCT/CN2017/100460 2017-09-05 2017-09-05 一种高效液相色谱法测定安立生坦含量的方法 WO2019046997A1 (zh)

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