WO2022151841A1 - 法维拉韦中有关物质的测定方法 - Google Patents

法维拉韦中有关物质的测定方法 Download PDF

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WO2022151841A1
WO2022151841A1 PCT/CN2021/133028 CN2021133028W WO2022151841A1 WO 2022151841 A1 WO2022151841 A1 WO 2022151841A1 CN 2021133028 W CN2021133028 W CN 2021133028W WO 2022151841 A1 WO2022151841 A1 WO 2022151841A1
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favipiravir
solution
related substances
mobile phase
diluent
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PCT/CN2021/133028
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English (en)
French (fr)
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李宏杰
陈小艳
谭奕
高华
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浙江海正药业股份有限公司
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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
    • 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
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • 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
    • G01N30/62—Detectors specially adapted therefor
    • G01N30/74—Optical detectors

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  • the invention relates to a method for detecting related substances of favipiravir and a tablet containing favipiravir, and belongs to the field of drug analysis.
  • Favipiravir chemical name 6-fluoro-3-hydroxypyrazine-2-carboxamide
  • RdRp RNA-dependent RNA polymerase
  • the present invention adopts liquid chromatography to rapidly detect related substances of favipiravir preparations, To ensure that the quality of its preparations can be controlled.
  • the currently retrieved HPLC method for the determination of related substances of favipiravir has the characteristics of long determination time and the use of a diode array detector, which has the characteristics of low sensitivity. Therefore, it is necessary to develop low detection cost, short detection time and high sensitivity. Determination method of favipiravir related substances with high specificity and good accuracy.
  • the object of the present invention is to provide a simple HPLC detection method for favipiravir related substances, the method adopts an ultraviolet detector, has low inspection cost, short detection time, high sensitivity, and adopts the main component of favipiravir that is easy to obtain.
  • the method of adding correction factor to calculate the content of related substances has high specificity and good accuracy.
  • the invention provides an HPLC detection method for related substances in favipiravir, which comprises:
  • Chromatographic column AQ-C18 chromatographic column and ghost-Buster chromatographic column are used; the ghost-Buster chromatographic column is a ghost peak-removing column to ensure a stable baseline of the chromatographic system.
  • Mobile phase potassium dihydrogen phosphate solution (mobile phase A)-acetonitrile (mobile phase B) is mobile phase; wherein the concentration range of mobile phase A potassium dihydrogen phosphate solution is 0.5mmol/L-1.5mmol/L, preferably 1mol/ L, the pH range is 1.0-3.0, preferably 2.5.
  • the column temperature of the chromatographic column is 33-37°C, preferably 35°C, the flow rate of the mobile phase is 0.9-1.1ml/min, preferably 1.0ml/min, and the gradient elution procedure is as follows:
  • the detector is a UV detector, detection wavelength: 225nm;
  • the diluent is 10mM sodium carbonate solution
  • Preparation of reference substance solution take an appropriate amount of favipiravir reference substance, add diluent to prepare a reference substance solution containing favipiravir with a concentration of about 2.5 ⁇ g/mL.
  • Preparation of sample solution take an appropriate amount of favipiravir or related preparations containing favipiravir, and add diluent to prepare a sample solution containing about 0.5 mg/mL of favipiravir.
  • the HPLC determination method for related substances of the present invention is suitable for favipiravir and related preparations containing favipiravir that need to be detected for related substances, and the preparations are preferably tablets, capsules, injections and compound preparations.
  • the pharmacopoeia of various countries do not contain the determination methods for related substances of favipiravir, the source of impurity reference substances cannot be determined, and the raw materials and preparations of favipiravir have problems such as harsh storage conditions and easy degradation.
  • the invention establishes the favipiravir main component-external standard method with correction factor, which can accurately determine the content of known impurity A and other impurities in favipiravir raw materials and preparations, and realizes the detection of favipiravir related substances.
  • Quality inspection that is, the reference substance of favipiravir, establishes the correction factor of this component and the known impurity A, calculates the content of the impurity, and realizes the quality control of favipiravir.
  • the method realizes the quantitative detection of impurity A and other single impurities in favipiravir raw materials and preparations, and has the advantages of simple operation, short detection time, strong specificity, accurate and reliable measurement results, and provides detection of impurities, product quality control and guarantee. A whole new choice.
  • Chromatography system high performance liquid chromatography (ultraviolet absorption detector); chromatographic column (AQ-C18 and ghost-Buster column); mobile phase: potassium dihydrogen phosphate solution (mobile phase A)-acetonitrile (mobile phase B), wherein The concentration of potassium dihydrogen phosphate solution is 1.0mmol/L, pH is 2.5; diluent: 10mM sodium carbonate solution; column temperature: 35°C; flow rate: 1.0ml/min; detection wavelength: 225nm; total running time: 45min; gradient Elution procedure:
  • the Favipiravir reference substance Precisely weigh an appropriate amount of the Favipiravir reference substance and the known impurity A reference substance solution, and use the diluent to prepare the favipiravir containing 0.15 ⁇ g/ml, 1.27 ⁇ g/ml, 2.02 ⁇ g/ml, 2.53 ⁇ g/ml and 5.06 ⁇ g/ml solution, containing impurity A concentration of 0.23 ⁇ g/ml, 0.39 ⁇ g/ml, 0.62 ⁇ g/ml, 0.78 ⁇ g/ml and 1.56 ⁇ g/ml solution, injection analysis, injection volume 20 ⁇ l.
  • the concentration range of favipiravir reference solution is 0.15 ⁇ g/ml-5.06 ⁇ g/ml, the peak area and concentration have a good linear relationship, the slope of the linear equation is 49.42878, and the linear correlation coefficient is 0.99998; the known impurity A reference solution concentration
  • the correction factor for Impurity A is known to be 1.26.
  • the linearity of favipiravir is shown in Figure 1, the linearity of impurity A is shown in Figure 2, and the chromatogram of the known impurity A solution with a concentration of 0.78 ⁇ g/ml is shown in Figure 3.
  • favipiravir tablets (batch number: 17FR05069, provided by Zhejiang Hisun Pharmaceutical Co., Ltd.) with a specification of 0.2 g, weigh them, grind them into fine powder, and accurately weigh the tablets containing 50 mg of favipiravir
  • the powder into a 100ml volumetric flask, add about 50ml of diluent, sonicate and shake for 15 minutes from time to time, let it cool down and add diluent to dilute to the mark, mix well, filter with a 0.45 ⁇ m nylon (NL) membrane filter, discard After removing 3ml of the initial filtrate, collect the subsequent filtrate (favipiravir is about 0.5mg/ml).
  • Chromatography system high performance liquid chromatography (ultraviolet absorption detector); chromatographic column (AQ-C18 and ghost-Buster column); mobile phase: potassium dihydrogen phosphate solution (mobile phase A)-acetonitrile (mobile phase B), wherein The concentration of potassium dihydrogen phosphate solution is 1.0mmol/L, pH is 2.5; diluent: 10mM sodium carbonate solution; column temperature: 35°C; flow rate: 1.0ml/min; detection wavelength: 225nm; total running time: 45min; gradient Elution procedure:
  • the detection method for favipiravir related substances in the present invention can quickly and accurately detect the impurities and degradation products of favipiravir.
  • the operation is simple, the accuracy is good, the sensitivity is high, and the product quality can be better controlled.

Abstract

涉及分析化学领域，一种法维拉韦的有关物质检测方法，以磷酸盐溶液（流动相A）-乙腈（流动相B）为流动相，碳酸钠溶液为稀释剂。取法维拉韦及含法维拉韦的片剂适量，加稀释剂配制成含法维拉韦0.5mg/mL的样品溶液，并取法维拉韦加稀释剂稀释成2.5ug/mL的对照品溶液。采用主成分加校正因子法定量测定法维拉韦及制剂中有关物质的含量。法维拉韦有关物质的检测方法，可快速准确的检测出法维拉韦的杂质及降解产物情况。操作简便，准确度好，灵敏度高，可较好控制产品质量。

Description

法维拉韦中有关物质的测定方法 技术领域
本发明涉及一种法维拉韦及含法维拉韦的片剂的有关物质检测方法，属于药物分析领域。
背景技术
法维拉韦，化学名为6-氟-3-羟基吡嗪-2-甲酰胺，是一种新型RNA依赖的RNA聚合酶(RdRp)抑制剂，属光谱抗流感病毒药物，用于治疗成人新型或复发流感。由于法维拉韦在合成过程中有可能产生副产物及其他有关物质，在储藏过程中还有可能产生降解产物，本发明采用液相色谱法，对法维拉韦制剂的有关物质快速检测，保证其制剂的质量可控。目前检索到的法维拉韦有关物质的HPLC测定方法，其测定时间较长且需采用二极管阵列检测器，存在灵敏度低等特点；因此有必要开发检测成本低且检测时间较短，灵敏度高，专属性高、准确度好的法维拉韦有关物质的测定方法。
发明内容
本发明的目的在于提供一种简便的法维拉韦有关物质的HPLC检测方法，该方法采用紫外检测器，检验成本低且检测时间较短，灵敏度高，采用易于得到的法维拉韦主成分加校正因子方法计算有关物质含量，专属性高、准确度好。
本发明提供了一种法维拉韦中有关物质的HPLC检测方法，所述测定方法包括：
色谱条件：
色谱柱：采用AQ-C18色谱柱和Ghost-Buster色谱柱；其中Ghost-Buster色谱柱为去鬼峰柱可保证色谱系统基线平稳。
流动相：磷酸二氢钾溶液(流动相A)-乙腈(流动相B)为流动相；其中流动相A磷酸二氢钾溶液的浓度范围0.5mmol/L-1.5mmol/L，优选为1mol/L，pH范围为1.0-3.0，优选为2.5。色谱柱柱温为33-37℃，优选为35℃，流动相流速为0.9-1.1ml/min，优选为1.0ml/min，梯度洗脱程序如下表：
时间(分钟) 流动相A(％) 流动相B(％)
0 100 0
3 100 0
25 80 20
35 80 20
35.01 100 0
45 100 0
检测器为紫外检测器，检测波长：225nm；
稀释剂为10mM碳酸钠溶液；
对照品溶液的配制：取法维拉韦对照品适量，加稀释剂配制成含法维拉韦浓度约为2.5μg/mL的对照品溶液。
样品溶液的配制：取法维拉韦或含法维拉韦的相关制剂适量，加稀释剂配制成含法维拉韦约为0.5mg/mL的样品溶液。
测定方法
按高效液相色谱法(中国药典2020年版四部通则0512)测定，照上表进行梯度洗脱；进样20μl对照品溶液，查看信噪比，应不小于100，查看法维拉韦典型保留时间，约为13min；再精密量取对照品溶液与样品溶液各20μl，注入液相色谱仪，记录色谱图。
计算
每针样品溶液采用色谱峰峰面积计算有关物质的量；采用主成分加校正因子法计算杂质含量；已知杂质A(相对保留时间约0.6)的校正因子为1.26，其他单个杂质的校正因子为1.0；总杂质％＝已知杂质A+其他单个杂质1+其他单个杂质2…+其他单个杂质N。
已知杂质A的分子式：C 5H 3O 3N 2F；分子量：158.1；结构式如下：
Figure PCTCN2021133028-appb-000001
本发明的有关物质的HPLC测定方法适用于需要进行有关物质检测的法维拉韦及含法维拉韦的相关制剂，所述制剂优选为片剂、胶囊剂、注射剂和复方制剂。
各国药典包括日本药典均未收载法维拉韦有关物质的测定方法，杂质对照品无法定来源，并且法维拉韦原料和制剂存在储存条件苛刻易发生降解等问题。本发明 建立了加校正因子的法维拉韦主成分-外标法，可以精准测定法维拉韦原料和制剂中已知杂质A及其他杂质的含量，实现了对法维拉韦有关物质的质量检测，即用法维拉韦对照品，建立该成分与已知杂质A的校正因子，计算杂质的含量，实现对法维拉韦的质量控制。本发明实现了对法维拉韦原料和制剂中杂质A和其他单个杂质的定量检测，操作简便，检测时间短，专属性强，测定结果准确可靠，为杂质的检测、产品质量控制与保障提供了全新的选择。
附图说明：
图1：实施例1中法维拉韦线性图
图2：实施例1中已知杂质A线性图
图3：实施例1中浓度为0.78μg/ml的已知杂质A溶液色谱图
图4：实施例1中法维拉韦对照品溶液色谱图
图5：实施例1中法维拉韦片样品溶液色谱图
图6：实施例2中法维拉韦样品溶液色谱图
具体实施方式
实施例1
方法描述
色谱系统：高效液相色谱仪(紫外吸收检测器)；色谱柱(AQ-C18和Ghost-Buster柱)；流动相：磷酸二氢钾溶液(流动相A)-乙腈(流动相B)，其中磷酸二氢钾溶液的浓度为1.0mmol/L，pH为2.5；稀释剂：10mM碳酸钠溶液；柱温：35℃；流速：1.0ml/分钟；检测波长：225nm；总运行时间：45min；梯度洗脱程序：
时间(分钟) 流动相A(％) 流动相B(％)
0 100 0
3 100 0
25 80 20
35 80 20
35.01 100 0
45 100 0
线性
精密称取法维拉韦对照品及已知杂质A对照品溶液适量，用稀释剂制成含法维拉韦为0.15μg/ml，1.27μg/ml，2.02μg/ml，2.53μg/ml和5.06μg/ml的溶液，含杂质A浓度各为0.23μg/ml，0.39μg/ml，0.62μg/ml，0.78μg/ml和1.56μg/ml的溶液，进样分析，进样量20μl。法维拉韦对照品溶液浓度范围在0.15μg/ml-5.06μg/ml，峰面积与浓度呈良好的线性关系，线性方程斜率为49.42878，线性相关系数为0.99998；已知杂质A对照品溶液浓度范围在0.23μg/ml-1.56μg/ml，峰面积与浓度呈良好的线性关系，线性方程斜率为39.1833，线性相关系数为0.9997；2个线性方程的斜率之比(49.42878/39.1833＝1.26)即已知杂质A的校正因子为1.26。法维拉韦线性见图1，杂质A线性见图2，浓度为0.78μg/ml的已知杂质A溶液色谱图见图3。
灵敏度测定
测定线性试验项下样品稀释后检测，取基线噪声2-5倍值为检测限；取基线噪音10-15倍值为定量限。法维拉韦的检测限(S/N＝2-5)为0.038μg/ml，定量限(S/N＝10-15)为0.152μg/ml；已知杂质A的检测限(S/N＝2-5)为0.058μg/ml，定量限(S/N＝10-15)为0.233μg/ml。结果表明，该方法灵敏度高，同时也说明进样20μL可充分满足有关物质检测要求。
对照品溶液配制
精密称取约25mg法维拉韦对照品置50ml量瓶中，加适量稀释剂超声溶解并稀释至刻度，混匀得储备液1；精密移取2.0ml储备液1置100ml量瓶中，用稀释剂稀释至刻度，混匀得储备液2；精密移取5.0ml储备液2置20ml容量瓶中，用稀释剂稀释至刻度，混匀得到含法维拉韦浓度约为2.5μg/ml的对照品溶液。
样品溶液配制
取20片规格为0.2g法维拉韦片(批号：17FR05069，由浙江海正药业股份有限公司提供)，称重，研磨成细粉，精密称取相当于含法维拉韦50mg的片粉末置100ml量瓶中，加入约50ml稀释剂，超声并不时振摇15分钟，静置冷却后再加稀释剂稀释至刻度，混匀，用0.45μm尼龙(NL)滤膜过滤器过滤，弃去3ml初滤液后收集续滤液即得(法维拉韦约为0.5mg/ml)。
测定方法
按高效液相色谱法(中国药典2020年版四部通则0512)测定，照上表进行梯度洗脱；进样20μl对照品溶液，查看信噪比，应不小于100，查看法维拉韦典型保留时间，约为13min；对照品溶液色谱图见图4；再精密量取对照品溶液与样品溶液各20μl，注入液相色谱仪，记录色谱图，样品溶液色谱图见图5。
计算
每针样品溶液采用色谱峰峰面积计算有关物质的量；采用主成分加校正因子法计算杂质含量；已知杂质A(相对保留时间约0.6)的校正因子为1.26，其他单个杂质的校正因子为1.0；总杂质(％)＝已知杂质A+其他单个杂质1+其他单个杂质2…+其他单个杂质N。
检测结果
法维拉韦片 已知杂质A 其他单个杂质1 总杂质
结果 0.13％ 0.05％ 0.18％
实施例2
方法描述
色谱系统：高效液相色谱仪(紫外吸收检测器)；色谱柱(AQ-C18和Ghost-Buster柱)；流动相：磷酸二氢钾溶液(流动相A)-乙腈(流动相B)，其中磷酸二氢钾溶液的浓度为1.0mmol/L，pH为2.5；稀释剂：10mM碳酸钠溶液；柱温：35℃；流速：1.0ml/分钟；检测波长：225nm；总运行时间：45min；梯度洗脱程序：
时间(分钟) 流动相A(％) 流动相B(％)
0 100 0
3 100 0
25 80 20
35 80 20
35.01 100 0
45 100 0
对照品溶液配制
精密称取约25mg法维拉韦对照品置50ml量瓶中，加适量稀释剂超声溶解并稀释至刻度，混匀得储备液1；精密移取2.0ml储备液1置100ml量瓶中，用稀释剂稀释至刻度，混匀得储备液2；精密移取5.0ml储备液2置20ml容量瓶中，用稀释剂稀释至刻度，混匀得到含法维拉韦浓度约为2.5μg/ml的对照品溶液。
样品溶液配制
称取法维拉韦(批号：S141101，由浙江海正药业股份有限公司提供)适量，加稀释剂溶解后并配制成含法维拉韦约为0.5mg/ml的溶液)。
测定方法
按高效液相色谱法(中国药典2020年版四部通则0512)测定，照上表进行梯度洗脱；进样20μl对照品溶液，查看信噪比，应不小于100，查看法维拉韦典型保留时间，约为13min；再精密量取对照品溶液与样品溶液各20μl，注入液相色谱仪，记录色谱图，样品溶液色谱图见图6。
计算
每针样品溶液采用色谱峰峰面积计算有关物质的量；采用主成分加校正因子法计算杂质含量；已知杂质A(相对保留时间约0.6)的校正因子为1.26，其他单个杂质的校正因子为1.0；总杂质(％)＝已知杂质A+其他单个杂质1+其他单个杂质2…+其他单个杂质N。
检测结果
法维拉韦 已知杂质A 其他单个杂质1 总杂质
结果 0.00％ 0.05％ 0.05％
已知杂质A的分子式：C 5H 3O 3N 2F；分子量：158.1；结构式如下：
Figure PCTCN2021133028-appb-000002
本发明中法维拉韦有关物质的检测方法，可快速准确的检测出法维拉韦的杂质及降解产物情况。操作简便，准确度好，灵敏度高，可较好控制产品质量。

Claims (6)

  1. 一种法维拉韦中有关物质的HPLC测定方法，其特征在于：所述测定方法包括：
    色谱条件：
    色谱柱：AQ-C18色谱柱和Ghost-Buster色谱柱；
    流动相：流动相A磷酸二氢钾溶液-流动相B乙腈，其中磷酸二氢钾溶液的浓度为0.5-1.5mmol/L，pH范围为1.0-3.0；
    梯度洗脱程序如下表：
    时间(分钟) 流动相A(％) 流动相B(％) 0 100 0 3 100 0 25 80 20 35 80 20 35.01 100 0 45 100 0
    检测器为紫外检测器，检测波长：225nm
    测定方法
    按高效液相色谱法测定，照上表进行梯度洗脱；进样20μl对照品溶液，查看信噪比，应不小于100，查看法维拉韦典型保留时间，约为13min；再精密量取对照品溶液与样品溶液各20μl，注入液相色谱仪，记录色谱图；
    计算
    每针样品溶液采用色谱峰峰面积计算有关物质的量；采用主成分加校正因子法计算杂质含量；已知杂质A(相对保留时间约0.6)的校正因子为1.26，其他单个杂质的校正因子为1.0；总杂质(％)＝已知杂质A+其他单个杂质1+其他单个杂质2…+其他单个杂质N。
  2. 根据权利要求1所述的法维拉韦中有关物质的HPLC测定方法，其特征在于：流动相A磷酸二氢钾溶液的浓度为1.0mmol/L，pH值为2.5。
  3. 根据权利要求1-2任一项所述的法维拉韦中有关物质的HPLC测定方法，其特征在于：其中所述的高效液相色谱条件中，色谱柱柱温为33-37℃，优选为35℃。
  4. 根据权利要求1-3任一项所述的法维拉韦中有关物质的HPLC测定方法，其 特征在于：其中所述的高效液相色谱条件中，流动相流速为0.9-1.1ml/min，优选为1.0ml/min。
  5. 根据权利要求1-4任一项所述的法维拉韦中有关物质的HPLC测定方法，其特征在于：
    所述对照品溶液的配制：取法维拉韦对照品适量，加稀释剂配制成含法维拉韦浓度约为2.5μg/mL的对照品溶液；
    所述样品溶液的配制：取法维拉韦或含法维拉韦的相关制剂适量，加稀释剂配制成含法维拉韦约为0.5mg/mL的样品溶液；
    其中所述的稀释剂为10mM碳酸钠溶液。
  6. 根据权利要求1-5中任一项所述的法维拉韦中有关物质的HPLC测定方法，其特征在于：该方法适用于需要进行有关物质检测的法维拉韦及含法维拉韦的相关制剂，所述制剂优选为片剂、胶囊剂、注射剂和复方制剂。
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