WO2022142152A1 - 一种克林霉素磷酸酯阴道片的含量测定方法 - Google Patents

一种克林霉素磷酸酯阴道片的含量测定方法 Download PDF

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WO2022142152A1
WO2022142152A1 PCT/CN2021/099456 CN2021099456W WO2022142152A1 WO 2022142152 A1 WO2022142152 A1 WO 2022142152A1 CN 2021099456 W CN2021099456 W CN 2021099456W WO 2022142152 A1 WO2022142152 A1 WO 2022142152A1
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mobile phase
clindamycin phosphate
acid
content
volume ratio
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PCT/CN2021/099456
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韦家华
刘玉
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海南海神同洲制药有限公司
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02Column chromatography
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02Column chromatography
    • G01N30/26Conditioning of the fluid carrier; Flow patterns
    • G01N30/28Control of physical parameters of the fluid carrier
    • G01N30/34Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient

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  • the application relates to the field of drug analysis, in particular to a method for determining the content of clindamycin phosphate vaginal tablets.
  • Clindamycin phosphate (clindamycin phosphate) is a semi-synthetic derivative of clindamycin, widely used in severe infections caused by Gram-positive cocci and anaerobic bacteria. Clindamycin phosphate is ineffective in vitro and can be rapidly converted into the antibacterial and effective clindamycin in vivo.
  • Patent document CN103487518B discloses using octadecyl silane-bonded silica gel as filler; potassium dihydrogen phosphate solution-methanol is the high performance liquid chromatography method of mobile phase, but the main peak separation in the obtained HPLC spectrum is not obvious, The content of the main peak decreased greatly, and the retention time of the main peak was too long.
  • the present application proposes a method for determining the content of clindamycin phosphate vaginal tablets, so as to achieve rapid and accurate detection of the content of clindamycin phosphate in clindamycin phosphate tablets.
  • the application provides a method for determining the content of clindamycin phosphate vaginal tablets:
  • step S2 Measure 0.3-1.5ml of the supernatant filtered in step S1 into a measuring bottle, dilute with mobile phase, and use it as the test solution,
  • Mobile phase A potassium dihydrogen phosphate-acetonitrile-water-fluorinated organic acid-ferric chloride
  • the elution conditions are:
  • the volume ratio of mobile phase A to mobile phase B is 40 to 45:55 to 60;
  • the volume ratio of mobile phase A to mobile phase B is 55 to 60:40 to 45 in 5.01 to 9 minutes;
  • the mobile phase B can be an aqueous formic acid solution with a mass fraction of 0.1-1.3%.
  • the volume ratio of potassium dihydrogen phosphate-acetonitrile-water-fluorinated organic acid-ferric chloride in the mobile phase may be (10 ⁇ 15):(3 ⁇ 8):(11 ⁇ 15):(2 ⁇ 4 ): (1 to 3).
  • the fluorinated organic acid can be selected from any one of trifluoroacetic acid, pentafluoropropionic acid, heptafluorobutyric acid, nonafluorovaleric acid, undecafluorohexanoic acid, tridecafluoroheptanoic acid and pentafluorooctanoic acid kind.
  • the flow rate in the detection conditions may be 1.4 ml/min.
  • the column temperature in the detection conditions may be 60°C.
  • the supernatant is diluted with a mobile phase to contain 3.2-5.2 mg of clindamycin per milliliter.
  • the content determination method of clindamycin phosphate vaginal tablets adopts high performance liquid chromatography to detect, and the chromatographic conditions include using octanylsilane bonded silica gel as the stationary phase, potassium dihydrogen phosphate-acetonitrile-water-fluorine Substitute organic acid-ferric chloride as mobile phase A, formic acid aqueous solution as mobile phase B, select gradient elution.
  • the detection results show that the retention time is 11 min, the number of theoretical plates is mostly above 2000, the tailing factor is in the range of 0.8 to 1.1, and the resolution is 0.1 to 7.2, indicating that the method of the application detects quickly, the retention time of the main peak is moderate, and the peak shape is relatively stable. , the tailing phenomenon and the separation degree are better, the chromatographic separation effect and measurement accuracy are higher, the detection accuracy is improved, and the quality control of clindamycin phosphate tablets is provided.
  • Fig. 1 is the HPLC chromatogram of Example 3 of the application.
  • Embodiment 1 Determination of the content of clindamycin phosphate vaginal tablets
  • the assay method includes:
  • step S2 measure 0.3 ml of the filtered supernatant in step S1 and place it in a measuring bottle, dilute it with a mobile phase to a solution containing 3.2 mg of clindamycin per milliliter, shake it up, and use it as the test solution,
  • HPLC chromatographic conditions are as follows:
  • Mobile phase A potassium dihydrogen phosphate-acetonitrile-water-heptafluorobutyric acid-ferric chloride, the volume ratio is 10:3:11:2:1;
  • Mobile phase B formic acid aqueous solution with a mass fraction of 0.1%
  • the elution conditions are:
  • the volume ratio of mobile phase A to mobile phase B is 40:60;
  • Embodiment 2 Determination of the content of clindamycin phosphate vaginal tablets
  • the assay method includes:
  • step S2 Measure 1.5 ml of the filtered supernatant in step S1 and place it in a measuring bottle, dilute it with a mobile phase to a solution containing 5.2 mg of clindamycin per milliliter, shake it up, and use it as the test solution,
  • HPLC chromatographic conditions are as follows.
  • Mobile phase A potassium dihydrogen phosphate-acetonitrile-water-pentafluoropropionic acid-ferric chloride, the volume ratio is 15:8:15:4:3;
  • Mobile phase B formic acid aqueous solution with a mass fraction of 1.3%
  • the elution conditions are:
  • Embodiment 3 Determination of Content of Clindamycin Phosphate Vaginal Tablets
  • the assay method includes:
  • step S2 measure 0.8 ml of the filtered supernatant in step S1 and place it in a measuring bottle, dilute the mobile phase to a solution containing 4.0 mg of clindamycin per milliliter, shake up, and use it as the test solution,
  • HPLC chromatographic conditions are as follows:
  • Mobile phase A potassium dihydrogen phosphate-acetonitrile-water-trifluoroacetic acid-ferric chloride, the volume ratio is 13:5:12:3:2;
  • Mobile phase B formic acid aqueous solution with a mass fraction of 1.0%;
  • the elution conditions are:
  • Example 3 The difference between this example and Example 3 is that the volume ratio of potassium dihydrogen phosphate-acetonitrile-water-trifluoroacetic acid-ferric chloride in the mobile phase is 18:2:16:5:5.
  • Example 3 The difference between this comparative example and Example 3 is that the elution condition is isocratic elution, and the volume ratio of mobile phase A to mobile phase B in 0-25 min is 57:43.
  • Example 3 The difference between this comparative example and Example 3 is that the mobile phase is potassium dihydrogen phosphate-acetonitrile.
  • the application adopts potassium dihydrogen phosphate-acetonitrile-water-fluorinated organic acid-ferric chloride as mobile phase A, and aqueous formic acid solution as mobile phase B, adjust the elution conditions and improve the separation effect; gradient washing Clindamycin phosphate tailing can be significantly improved.
  • the tailing factor is in the range of 0.8 to 1.1, indicating that the chromatographic separation effect and measurement accuracy are high. It can be accurately measured in 11 minutes and shorten the running time. Under this detection, the target components are correspondingly good, and the resolution meets the requirements.

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  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
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Abstract

一种克林霉素磷酸酯阴道片的含量测定方法,采用高效液相色谱法检测,选择流动相组分,采用适当配比,并利用梯度洗脱,设定洗脱条件,能快速、精确检测克林霉素磷酸酯阴道片中克林霉素磷酸酯的含量。

Description

一种克林霉素磷酸酯阴道片的含量测定方法 技术领域
本申请涉及药物分析领域,特别涉及一种克林霉素磷酸酯阴道片的含量测定方法。
背景技术
克林霉素磷酸酯(clindamycin phosphate)为半合成的克林霉素衍生物,广泛应用于革兰阳性球菌及厌氧菌所致严重感染。克林霉素磷酸酯在体外无效,在体内可以迅速转化成抗菌有效的克林霉素。专利文献CN103487518B中公开了以十八烷基硅烷键合硅胶为填充剂;磷酸二氢钾溶液-甲醇为流动相的高效液相色谱法,但在所获得的HPLC谱图中主峰分离不明显,主峰含量下降较大,主峰保留时间偏长。
发明内容
鉴以此,本申请提出一种克林霉素磷酸酯阴道片的含量测定方法,以实现快速、精确检测克林霉素磷酸酯片剂中克林霉素磷酸酯的含量。
本申请提供了一种克林霉素磷酸酯阴道片的含量测定方法:
包括以下步骤:
S1、取克林霉素磷酸酯阴道片,研磨后溶解于乙醇中,过滤,
S2、量取步骤S1过滤后的上清液0.3~1.5ml置量瓶中,用流动相稀释,作为供试品溶液,
S3、将供试品溶液注入到高效液相色谱仪中进行检测,确定克林霉素磷酸酯阴道片剂中克林霉素磷酸酯的含量,其中,高效液相色谱法的色谱条件如下:
固定相:辛烷基硅烷键合硅胶
流动相A:磷酸二氢钾-乙腈-水-氟代有机酸-氯化铁
流动相B:甲酸水溶液
流速:1.3~1.5ml/min
柱温:50~70℃
检测波长:200~400nm;
洗脱条件为:
(1)第0~5.0min,流动相A与流动相B的体积比为40~45:55~60;
(2)第5.01~9min,流动相A与流动相B的体积比为55~60:40~45;
(3)第9.01~25min,流动相A与流动相B的体积比为75~80:20~25。
优选地,流动相B可为质量分数0.1~1.3%的甲酸水溶液。
优选地,流动相中磷酸二氢钾-乙腈-水-氟代有机酸-氯化铁的体积比可为(10~15):(3~8):(11~15):(2~4):(1~3)。
优选地,的氟代有机酸可选自三氟乙酸、五氟丙酸、七氟丁酸、九氟戊酸、十一氟己酸、十三氟庚酸、十五氟辛酸中的任一种。
优选地,检测条件中流速可为1.4ml/min。
优选地,检测条件中柱温可为60℃。
优选地,步骤S2中用流动相稀释上清液至每毫升含克林霉素3.2~5.2mg。
与现有技术相比,本申请的有益效果如下。
本申请提供的克林霉素磷酸酯阴道片的含量测定方法,采用高效液相色谱法检测,色谱条件包括以辛烷基硅烷键合硅胶为固定相,磷酸二氢钾-乙腈-水-氟代有机酸-氯化铁为流动相A,甲酸水溶液为流动相B,选择梯度洗脱。检测结果显示保留时间为11min,理论塔板数大部分在2000以上,拖尾因子在0.8~1.1范围内,分离度0.1~7.2,说明本申请方法检测迅速,主峰保留时间适中,峰形较稳定,拖尾现象和分离度较好,色谱分离效果和测量精度较高,提高了检测的准确率,为克林霉素磷酸酯片的质量控制提供了可参考依据。
其中,改进流动相A,限定磷酸二氢钾-乙腈-水-氟代有机酸-氯化铁的体积比,协同洗脱条件,有效改善拖尾现象,拖尾因子和分离度较好,理论塔板数更高,缩短主峰保留时间。
附图说明
图1为本申请实施例3的HPLC图谱。
具体实施方式
为了更好理解本申请技术内容,下面提供具体实施例,对本申请做进一步的说明。
本申请实施例所用的实验方法如无特殊说明,均为常规方法。
本申请实施例所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1 克林霉素磷酸酯阴道片的含量测定
该测定方法包括:
S1、取克林霉素磷酸酯阴道片8片(32mg),研磨后溶解于乙醇中,过滤,
S2、量取步骤S1过滤后的上清液0.3ml置于量瓶中,用流动相稀释至每毫升含克林霉素3.2mg的溶液,摇匀,作为供试品溶液,
S3、将供试品溶液注入到高效液相色谱仪中进行检测,确定克林霉素磷酸酯阴道片剂中克林霉素磷酸酯的含量。
HPLC色谱条件如下:
固定相:辛烷基硅烷键合硅胶;
流动相A:磷酸二氢钾-乙腈-水-七氟丁酸-氯化铁,体积比为10:3:11:2:1;
流动相B:质量分数为0.1%的甲酸水溶液;
流速:1.3ml/min;
柱温:50℃;
检测波长:200nm;
洗脱条件为:
(1)第0~5.0min,流动相A与流动相B的体积比为40:60;
(2)第5.01~9min,流动相A与流动相B的体积比为55:45;
(3)第9.01~25min,流动相A与流动相B的体积比为75:25。
实施例2 克林霉素磷酸酯阴道片的含量测定
该测定方法包括:
S1、取克林霉素磷酸酯阴道片13片(52mg),研磨后溶解于乙醇中,摇匀,过滤,
S2、量取步骤S1过滤后的上清液1.5ml置于量瓶中,用流动相稀释至每毫升含克林霉素5.2mg的溶液,摇匀,作为供试品溶液,
S3、将供试品溶液注入到高效液相色谱仪中进行检测,确定克林霉素磷酸酯阴道片剂中克林霉素磷酸酯的含量。
HPLC色谱条件如下。
固定相:辛烷基硅烷键合硅胶;
流动相A:磷酸二氢钾-乙腈-水-五氟丙酸-氯化铁,体积比为15:8:15:4:3;
流动相B:质量分数为1.3%的甲酸水溶液;
流速:1.5ml/min;
柱温:70℃;
检测波长:400nm;
洗脱条件为:
(1)第0~5.0min,流动相A与流动相B的体积比为45:55;
(2)第5.01~9min,流动相A与流动相B的体积比为60:40;
(3)第9.01~25min,流动相A与流动相B的体积比为80:20。
实施例3 克林霉素磷酸酯阴道片的含量测定
该测定方法包括:
S1、取克林霉素磷酸酯阴道片10片(40mg),研磨后溶解于乙醇中,过滤,
S2、量取步骤S1过滤后的上清液0.8ml置量瓶中,流动相稀释至每毫升含克林霉素4.0mg的溶液,摇匀,作为供试品溶液,
S3、将供试品溶液注入到高效液相色谱仪中进行检测,确定克林霉素磷酸酯阴道片剂中克林霉素磷酸酯的含量。
HPLC色谱条件如下:
固定相:辛烷基硅烷键合硅胶
流动相A:磷酸二氢钾-乙腈-水-三氟乙酸-氯化铁,体积比为13:5:12:3:2;
流动相B:质量分数为1.0%的甲酸水溶液;
流速:1.4ml/min;
柱温:60℃;
检测波长:210nm。
洗脱条件为:
(1)第0~5.0min,流动相A与流动相B的体积比为42:58;
(2)第5.01~9min,流动相A与流动相B的体积比为57:43;
(3)第9.01~25min,流动相A与流动相B的体积比为78:22。
采用实施例3的方法测定克林霉素磷酸酯阴道片后,进行方法学考察,具体分析如下:
峰号 保留时间 面积 高度 理论塔板数(USP) 拖尾因子 分离度(USP)
1 2.425 2052 357 54 - -
2 2.518 4667 516 1029 - 0.114
3 2.813 11837 1845 4035 - 1.200
4 2.967 2203 393 93 - 0.219
5 3.189 15802 1452 2945 - 0.303
6 3.694 11895 1814 8382 0.801 2.552
7 5.025 9681 1267 9410 1.027 7.221
8 6.154 2140 215 7988 1.047 4.676
9 7.612 6928 669 11703 1.041 5.238
10 8.262 1952 108 4403 - 1.667
11 8.977 1895610 162873 13299 0.980 1.767
12 9.367 1014 142 40890 1.095 1.568
13 11.329 1241 96 8787 - 5.868
14 11.663 4061 261 11625 - 0.730
总计   1971084 171709      
实施例4
本实施例与实施例3的区别在于流动相中磷酸二氢钾-乙腈-水-三氟乙酸-氯化铁的体积比为18:2:16:5:5。
采用实施例4的方法测定克林霉素磷酸酯阴道片后,进行方法学考察,具体分析如下:
峰号 保留时间 面积 高度 理论塔板数(USP) 拖尾因子 分离度(USP)
1 2.513 2652 397 68 - -
5 3.618 3617 516 1030 1.218 1.234
10 8.833 6937 1345 4054 1.236 8.364
15 12.367 2903 323 193 1.978 7.210
结果显示拖尾因子在12min时为1.978,拖尾现象较实施例3明显,分离度较实施例3高。
对比例1
本对比例与实施例3的区别在于洗脱条件为等度洗脱,在0~25min中流动相A与流动相B的体积比为57:43。
采用对比例1的方法测定克林霉素磷酸酯阴道片后,进行方法学考察,具体分析如下:
峰号 保留时间 面积 高度 理论塔板数(USP) 拖尾因子 分离度(USP)
1 4.313 2052 347 54 - -
5 6.528 3667 586 1029 1.907 5.114
10 10.813 6837 1945 4035 1.995 4.200
15 19.967 2603 333 93 1.998 9.219
20 23.189 4802 1952 2945 - 8.303
结果显示保留时间过长,达到23min,拖尾现象和分离度较实施例3更明显,含量检测不够精准。
对比例2
本对比例与实施例3的区别在于流动相为磷酸二氢钾-乙腈。
采用对比例2的方法测定克林霉素磷酸酯阴道片后,进行方法学考察,具体分析如下:
峰号 保留时间 面积 高度 理论塔板数(USP) 拖尾因子 分离度(USP)
1 4.065 2052 357 54 1.969 -
5 6.218 4967 516 1029 1.993 0.114
10 11.603 10137 1755 4035 1.990 1.200
15 18.997 2903 3931 93 - 0.219
20 22.149 15402 1402 2945 - 0.303
结果显示,保留时间过长,达到22min,拖尾现象和分离度较实施例3更明显,含量检测不够精准。
由上述测定结果可知,本申请采用了磷酸二氢钾-乙腈-水-氟代有机酸-氯化铁为流动相A,甲酸水溶液为流动相B,调整洗脱条件,改善分离效果;梯度洗脱显著改善克林霉素磷酸酯的拖尾现象,拖尾因子在0.8~1.1的范围内,说明色谱分离效果和测量精度较高,在11min能精准测出,缩短运行时间,结果证明,在此检测下,目标成分相应良好,分离度符合要求。
以上所述仅为本申请的较佳实施例而已,并不用以限制本申请,凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。

Claims (7)

  1. 一种克林霉素磷酸酯阴道片的含量测定方法,包括以下步骤:
    S1、取克林霉素磷酸酯阴道片,研磨后溶解于乙醇中,过滤,
    S2、量取步骤S1过滤后的上清液0.3~1.5ml置于量瓶中,用流动相稀释,作为供试品溶液,
    S3、将供试品溶液注入到高效液相色谱仪中进行检测,确定克林霉素磷酸酯阴道片剂中克林霉素磷酸酯的含量,
    其中,高效液相色谱法的色谱条件如下:
    固定相:辛烷基硅烷键合硅胶,
    流动相A:磷酸二氢钾-乙腈-水-氟代有机酸-氯化铁,
    流动相B:甲酸水溶液,
    流速:1.3~1.5ml/min,
    柱温:50~70℃,
    检测波长:200~400nm;
    洗脱条件为:
    (1)第0~5.0min,流动相A与流动相B的体积比为40~45:55~60;
    (2)第5.01~9min,流动相A与流动相B的体积比为55~60:40~45;
    (3)第9.01~25min,流动相A与流动相B的体积比为75~80:20~25。
  2. 如权利要求1所述的克林霉素磷酸酯阴道片的含量测定方法,其特征在于:所述流动相B为质量分数0.1~1.3%的甲酸水溶液。
  3. 如权利要求1所述的克林霉素磷酸酯阴道片的含量测定方法,其特征在于:所述流动相中磷酸二氢钾-乙腈-水-氟代有机酸-氯化铁的体积比为(10~15):(3~8):(11~15):(2~4):(1~3)。
  4. 如权利要求1所述的克林霉素磷酸酯阴道片的含量测定方法,其特征在于:所述的氟代有机酸选自三氟乙酸、五氟丙酸、七氟丁酸、九氟戊酸、十一氟己酸、十三氟庚酸、十五氟辛酸中的任一种。
  5. 如权利要求1所述的克林霉素磷酸酯阴道片的含量测定方法,其特征在于:所述色谱条件中流速为1.4ml/min。
  6. 如权利要求1所述的一种克林霉素磷酸酯阴道片的含量测定方法,其特征在于:所述色谱条件中柱温为60℃。
  7. 如权利要求1所述的一种克林霉素磷酸酯阴道片的含量测定方法,其特征在于:所述步骤S2中用流动相稀释所述上清液至每毫升含克林霉素3.2~5.2mg。
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