【作者】 雷健；

【导师】 范琦； 张小松；

【作者基本信息】 重庆医科大学 ， 药物分析， 2007， 硕士

【摘要】 复方坎地沙坦酯片由血管紧张素II受体抑制剂坎地沙坦酯( Candesartan Cilexetil, CAN )与噻嗪类利尿剂氢氯噻嗪(Hydrochlorothiazide, HYD)组成,用于治疗单一药物不能控制的高血压患者,在临床试验中已被证明安全有效。目前国外已有复方坎地沙坦酯制剂和药理的相关研究报道,但国内的相关研究报道较少。国外文献报道采用一阶导数紫外分光光度法和HPLC-DAD法测定坎地沙坦酯和氢氯噻嗪的复方制剂或人血浆中坎地沙坦酯和氢氯噻嗪的含量。但这些方法操作繁琐,或在我国未广泛应用。某复方坎地沙坦酯片临床药品用标准(草案)中,采用双波长紫外分光光度法分别测定坎地沙坦酯和氢氯噻嗪的含量。以上方法均存在一定的局限性。不确定度信息是一个完整的定量分析结果的重要组成部分,可用于评估定量分析方法的可靠性和测量结果的准确性,并可提供分析过程的主要误差来源,以拟定解决方案。测量不确定度在药物分析领域的应用日益增多。本课题旨在建立专属性强、精密度好、准确度高、简便快捷的HPLC-UV法以同时测定复方坎地沙坦酯片中坎地沙坦酯和氢氯噻嗪的含量,并对该方法进行不确定度分析,以利于准确测定复方坎地沙坦酯片的含量。目的:1)建立HPLC-UV法同时测定复方坎地沙坦酯片中坎地沙坦酯和氢氯噻嗪的含量:为有效控制复方坎地沙坦酯片的质量,制订药品质量标准提供依据。2)建立HPLC-UV法测定复方坎地沙坦酯片含量的不确定度分析方法:用于评估分析方法的可靠性和测量结果的准确性,并提供分析过程的主要误差来源以拟定解决方案。方法:1)复方坎地沙坦酯片中坎地沙坦酯和氢氯噻嗪的HPLC-UV同时测定方法:采用Phenomenex C18(250 mm×4.6 mm,5μm)色谱柱,流动相为乙腈-0.1 mol·L-1磷酸二氢钠溶液(1 L溶液中加入0.1%三乙胺,磷酸调pH 5.0)(65:35),流速1.0 mL·min-1,检测波长262 nm,柱温35℃,进样量20μL。2)HPLC-UV法测定复方坎地沙坦酯片含量的不确定度分析方法:建立HPLC含量测定的不确定度分析数学模型,找出影响不确定度的因素并对各个不确定度分量进行评估。结果:1)复方坎地沙坦酯片中坎地沙坦酯和氢氯噻嗪的HPLC-UV同时测定方法:坎地沙坦酯和氢氯噻嗪分别在1.6~32.0μg·mL-1(r = 0.9998)和1.2~25.0μg·mL-1(r = 0.9999)浓度范围内线性关系良好;平均回收率(n = 9)分别为101.3%和100.7%;精密度试验的RSD(n = 9)分别为1.5%和1.7%;供试品溶液在8 h内稳定。2)HPLC-UV法测定复方坎地沙坦酯片含量的不确定度分析方法:坎地沙坦酯和氢氯噻嗪含量测定扩展不确定度分别为2.08%和1.88%,含量测定结果可分别表示为98.7%±2.08%(k = 2)和97.9%±1.88%(k = 2)。更多还原

【Abstract】 Compound tablets of Candesartan Cilexetil (CAN) plus Hydrochlorothiazide (HYD) have been used in clinic. The assay methods reported for CAN and HYD in compound preparation and human plasma mainly were First Derivative UV-Spectrophotometry and HPLC-DAD. However, these methods were complex or unusual in China. Therefore, it is necessary to establish an HPLC-UV method for simultaneous determinations of CAN and HYD in compound tablets.Uncertainty plays an important role in quantitative analysis. It can be used to evaluate reliability of quantitative analysis method and veracity of result. On the other hand, uncertainty can provide the information of resources for analytical error.OBJIEVTIVES1) To establish an HPLC-UV method for simultaneous determinations of CAN and HYD in compound tablets. 2) To establish a method for valuate uncertainties in the assay with HPLC-UV.METHODS1) HPLC-UV method for simultaneous determinations of CAN and HYD in compound tablets:A Phenomenex C18 column(250 mm×4.6 mm,5μm) was used with the mobile phase of acetonitrile-0.1 mol·L-1 sodium dihydrogen phosphate solution (added 0.1% triethylamine to 1L solution, adjusted to pH 5.0 with phosphoric acid) (65:35) at the detection wavelength of 262nm,the flow rate was 1.0 mL·min-1 and the column temperature was 35℃,injection volume is 5μL.2) An evaluative method for uncertainties of simultaneous determinations of CAN and HYD in compound tablets by HPLC-UV:The calculation formulas for the uncertainties of the assay were deduced.RESULTS1) HPLC-UV method for simultaneous determinations of CAN and HYD in compound tablets:The calibration curves of CAN and HYD were linear in the ranges of 1.6-32.0μg·mL-1 (r=0.9998) and 1.2-25.0μg·mL-1 (r=0.9999), respectively, the average recoveries (n=9) were 101.3% and 100.7%, respectively, the RSD (n=9) of precision are 1.5% and 1.7% respectively, the sample solutions were stable in 8h. 2) An evaluate method for uncertainties of simultaneous determinations of CAN and HYD in compound tablets by HPLC-UV:The determination Expanded Uncertainty of CAN and HYD are 2.08% and 1.88% respectively, the determination results of CAN and HYD are 98.7%±2.08%(k = 2) and 97.9%±1.88%(k = 2) respectively.更多还原