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马来酸噻吗洛尔滴眼液中有关物质的测定及杂质定性研究
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| 篇名： | 马来酸噻吗洛尔滴眼液中有关物质的测定及杂质定性研究 |
| TITLE： | |
| 摘要： | 目的：建立测定马来酸噻吗洛尔滴眼液中有关物质的方法，并对其杂质进行定性。方法：采用高效液相色谱法测定有关物质的含量，色谱柱为ACES C18，流动相为甲醇与4.32 g/L辛烷磺酸钠溶液（冰醋酸调pH至3.0）的混合溶液（50 ∶ 50，V/V）-甲醇（梯度洗脱），流速为1.0 mL/min，检测波长为295 nm，柱温为30 ℃，进样量为20 μL。采用制备液相色谱法制备杂质纯品，色谱柱为YMC-PACK ODS-A，流动相为甲醇-0.01％三氟乙酸（40 ∶ 60，V/V）和甲醇-0.01％三氟乙酸（20 ∶ 80，V/V），流速为8 mL/min，检测波长为295 nm，柱温为20 ℃，进样量为0.8 mL。采用液相色谱串联质谱法进行结构推测，色谱柱为Waters ACQUITY UPLC BEH C18，流动相为甲醇-5 mmol/L甲酸铵溶液（含0.05％甲酸）（梯度洗脱），流速为0.2 mL/min，柱温为20 ℃，进样量为2 μL；采用电喷雾离子源，以质谱全扫描模式检测母离子，以子离子扫描模式检测碎片离子。采用氢谱、碳谱进行结构确证和推测。结果：马来酸噻吗洛尔检测质量浓度线性范围为0.501～10.02 μg/mL（r＝0.999 9）；定量限为3.012 ng，检出限为1.004 ng；精密度试验的RSD为0.2％，稳定性和重复性试验的RSD均小于5％。确证了杂质Ⅰ、Ⅱ、Ⅲ的结构，并推测了杂质Ⅳ和Ⅴ的结构。结论：该方法快速、准确、专属性好，可用于马来酸噻吗洛尔滴眼液的质量控制。 |
| ABSTRACT： | OBJECTIVE： To establish a method for the determination of related substances in Timolol maleate eye drops， and to conduct qualitative analysis of its degradation impurities. METHODS： HPLC method was adopted for determination of related substance. The determination was performed on ACES C18 column with mobile phase consisted of the mixed solution of methanol and 4.32 g/L sodium octane sulfonate （pH adjusted to 3.0 with glacial acetic acid）（50 ∶ 50，V/V）-methanol （gradient elution） at flow rate of 1.0 mL/min. The detection wavelength was set at 295 nm， and column temperature was 30 ℃. The sample size was 20 μL. Preparative LC method was used to prepare pure impurities. The determination was performed on YMC-PACK ODS-A column with mobile phase consisted of methanol-0.01％ trifluoroacetic acid （40 ∶ 60，V/V） and methanol-0.01％ trifluoroacetic acid （20 ∶ 80，V/V） at flow rate of 8 mL/min. The detection wavelength was set at 295 nm， and column temperature was 20 ℃. The sample size was 0.8 mL. LC-MS/MS method was adopted. The determination was performed on Waters ACQUITY UPLC BEH C18 column with mobile phase consisted of methanol-5 mmol/L ammonium formate （0.05％ formic acid） （gradient elution） at flow rate of 0.2 mL/min. The column temperature was 20 ℃. The sample size was 2 μL. The electrospray ionization source was conducted， detecting patient ion by MS full scan and fragment ion by daughter ion scan. The structure was confirmed and speculated by 1H-NMR and 13C-NMR. RESULTS： The linear range of timolol maleate was 0.501-10.02 μg/mL （r＝0.999 9）. The limit of quantitation was 3.012 ng， and the limit of detection was 1.004 ng. RSD of precision test was 0.2％. RSDs of stability and reproducibility tests were all lower than 5％. The structures of impurityⅠ， Ⅱ and Ⅲ were confirmed， and those of impurity Ⅳ and Ⅴ were speculated. CONCLUSIONS： The method is rapid， accurate and specific. It can be used for the determination of related substance in Timolol maleate eye drops. |
| 期刊： | 2018年第29卷第16期 |
| 作者： | 刘荷英，程奇珍，周敏，易巧 |
| AUTHORS： | LIU Heying，CHENG Qizhen，ZHOU Min，YI Qiao |
| 关键字： | 马来酸噻吗洛尔；有关物质；降解杂质；高效液相色谱法；制备液相色谱；液相色谱串联质谱法；氢谱；碳谱；测定；结构推测 |
| KEYWORDS： | Timolol maleate； Related substance； Degradation impurity； HPLC； Preparative LC； LC-MS/MS； 1H-NMR； 13C-NMR； Determination； Structure speculation |
| 阅读数： | 541 次 |
| 本月下载数： | 16 次 |
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