课题名称 Validation of stability indicating HPLC method for morphine sulfate andSodium benzonatein morphine sulfate oral solution课题性质 基础研究应用课题 设计型 调研综述 理论研究开题报告内容：（包括拟研究或解决的问题、采用的研究手段及文献综述，不少于2000字）1.Project introduction1.1Drug introductionChemically,Morphine Sulfate is, Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl-,(5alpha;,6alpha;)-, sulfate(2:1)(salt), pentahydrate, which can be represented by the following structural formula:Morphine sulfate(（C17H19NO3）2H2SO4) oral solution is indicated for the relief of moderate to severe acute and chronic pain where use of an opioid analgesic is appropriate,which also is an anesthetic drug specially managed by the country. Morphine sulfate is reductive and it can be oxidized by air under light conditions. It can produce pseudo-morphine and N-oxidized morphine, and its aqueous solution is easily oxidized under neutral or alkaline conditions. So there exists sodium benzoate which is a preservative used for oral administration of liquid medicines for the effect of preventing deterioration and acidity and extending shelf life.1.2 Background introductionThe warns of overdose risk With morphine sulfate is very important,so we should have a quality control to test the dose of this medicine before it enter the market. And the preparation of morphine sulfate oral solution have been studied and discussed. Based on this study, the quality and stability of selected prescriptions should be further examined. According to the Chinese Pharmacopoeia requirements and related methods,this method uses high performance liquid chromatography to determine the content of morphine sulfate in morphine sulfate oral solution when we need to explore its stability .Now we have established a HPLC stability- indicating method to determine the assay of Morphine sulfate and sodium benzoate in Morphine Sulfate Oral solution .The intention of this study is to validate this method to ensure it meet proper standards of accuracy and reliability for its intended purpose according to ICH Harmonised tripartite guideline. 2.The project research method2.1 Experimental MaterialsWaters e2695 High Performance Liquid Chromatography2487 Dual-Wavelength UV Detector (US Waters Corporation)2.2 Establish a stability-indicating HPLC methodThe purpose is to establish a HPLC method through documented evidence ,which is used to test the content of Morphine sulfate and sodium benzoate in Morphine Sulfate Oral solution and to see the stability of the Morphine sulfate at 100% standard solution rested for different hours.Assay procedures are intended to measure the analyte present in a given sample. In the context of this document, the assay represents a quantitative measurement of the major component(s) in the Morphine sulfate and sodium benzoate . Procedure is as followed:Read reference, find suitable parameters according to the Chinese Pharmacopoeia.Prepare standard solution for stability-indicating method.The test of system suitability. Have an experiment and analysis the related data.2.3 To validate this stability-indicating methodThe purpose is to establish through documented evidence ,a high degree of assurance that the HPLC method for direct determination of content of Morphine sulfate and sodium benzoate in Morphine Sulfate Oral solution. For example,We can use two methods for determining accuracy , one is application of the analytical procedure to synthetic mixtures of the drug productcomponents to which known quantities of the drug substance to be analyzed have been added;Another is in cases where it is impossible to obtain samples of all drug product components ,it may be acceptable either to add known quantities of the analyte to the drug product or to compare the results obtained from a second, well characterized procedure, the accuracy of which is stated and/or defined. Typical validation characteristics which should be considered are listed below: 2.3.1 System suitability System suitability tests are an integral part of liquid chromatographic method.this is to ensure that the chromatographic system is adequate for the intended analysis. It involves preparation of standard before proceeding with the actual validation according to the test method and performs 6 replicate injections and the standard solution . Then evaluate the following parameters : relative standard deviation (RSD) of the retention time and response ,theoretical plate count ,tailing factor and resolution if applicable.2.3.2 Specificity and selectivityThe specificity is the degree of bias (or lack thereof) caused by expected sample components,common interference , impurities and degradation products determined by measuring the analyte with and without anticipated interference.As appropriate, this should include samples stored under relevant stress conditions: light, heat, humidity, acid/base hydrolysis and oxidation.And then we shoulddo the Peak purity tests and record the retention time and resolution of the analyte peak with its nearest neighboring peak in different stress condition.2.3.3 LinearityThe test method was calibrated by analysis of a series of 5 known concentration of the API freshly prepared from a standard stock solution .The analytical procedure for the assay of Morphine sulfate and sodium benzoate was found to be linear over the range of 50%,75%,100%,125% and 150% of the test concentration of the analyte. The response of the analyte was used to calculate the calibration curve.2.3.4 RangeThe range is the interval between the upper and lower concentration of analyte in Morphine Sulfate Oral solution. It is established by confirming that the analytical procedure provides an acceptable degree of linearity, accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of the specified range of the analytical procedure.2.3.5 AccuracyThe accuracy of analytical method is the closeness of the test results obtained to the true value . It is by percent recoveries by the assay of known spiked quantities of analyte in the placebo.the mean percent recoveries and relative standard deviations were calculated by the analysis of 3 different concentration spiked to placebo (80%,100%,120%) to determine the exactness of the method.2.3.6 Repeatability precision and intermediate precisionThe precision of an analytical method is the degree of agreement among individual test results when the procedure is applied repeatedly to multiple sampling of homogeneous sample.and The extent to which intermediate precision should be established depends on the circumstances under which the procedure is intended to be used. The applicant should establish the effects of random events on the precision of the analytical procedure. The analytical procedure for the assay of Morphine sulfate and sodium benzoate was found to be precise at 80%,100% and 120% of the test concentration.2.3.7 Robustness The robustness of an analytical procedure is a measure of its capacity to remainunaffected by small, but deliberate variations in method parameters and provides anindication of its reliability during normal usage.In this experiment, the effects of varying the mobile phase composition,flow rate and wavelength were studied.2.3.8 StabilityBefore HPLC test for assay determination, we should validatethe sample solution is stable or not. So we test the sample solution afteritResting for 0 ,2,4,6,12,24 hoursand then we observe the results.2.4 Results and discussingIn the experiment of validation,all of the data and Analytical chromatography should suit to the recommended acceptance criteria ,if not, this stability indicating HPLC method maybe not be suitable for assay of Morphine sulfate and sodium benzoate in Morphine Sulfate Oral solution .3.References :[1] ICH Harmonised Tripartite Guideline[2] The Pharmacopoeia of the Peoples Republic of China (PPRC) 2015[3] Singh S, Singh B, Bahuguna R, et al. Stress degradation studies on ezetimibe and development of a validated stability-indicating HPLC assay[J]. Journal of Pharmaceutical amp; Biomedical Analysis, 2006, 41(3):1037-1040.[4] Datar P A, Waghmare R U. Development and validation of an analytical method for the stability of duloxetine hydrochloride[J]. Journal of Taibah University for Science, 2014, 8(4):357-363.[5] Hertzog D L, Mccafferty J F, Fang X, et al. Development and validation of a stability-indicating HPLC method for the simultaneous determination of losartan potassium, hydrochlorothiazide, and their degradation products.[J]. Journal of Pharmaceutical amp; Biomedical Analysis, 2002, 30(3):747-760.[6] Strong M L, Schaaf L J, Pankaskie M C, et al. Shelf-lives and factors affecting the stability of morphine sulphate and meperidine (pethidine) hydrochloride in plastic syringes for use in patient-controlled analgesic devices[J]. Journal of Clinical Pharmacy amp; Therapeutics, 1994, 19(6):361-369.[7] Ho C, Chen G L. Stability-indicating High-Performance Liquid Chromatographic assay methods for drugs in pharmaceutical dosage forms: Part II[J]. Journal of Food amp; Drug Analysis, 1996, 4(4):271-292.[8] 胡蕾, 戴青, 刘芳,等. 硫酸吗啡口腔崩解片的稳定性研究[J]. 中国药房, 2015(4):515-518.[9] 胡蕾, 刘芳, 戴青,等. 硫酸吗啡口腔崩解片的制备及处方工艺研究[J]. 中国药房, 2014(37):3493-3496.[10] 张洁, 王录逊, 陈海刚. 注射用赖氨匹林中赖氨酸含量测定HPLC方法学验证[J]. 医药, 2016(4):00175-00176.[11] 张祥, 刘伟芬. 注射用三磷酸胞苷二钠含量测定的方法学验证[J]. 硅谷, 2010(13):165-167.叶勤建, 庞艺洁, 汤浩. 匹多莫德口服液中匹多莫德含量测定方法学验证[J]. 医药, 2016(5):00171-00173.[12] 李丹, 周本宏. 高效液相色谱法测定硫酸吗啡缓释栓含量[J]. 中国药师, 2016, 19(2):372-374.[13] 王宏枫. 高效液相色谱法检测头孢替唑残留的检验方法验证[J]. 科技创业家, 2012(24):198-198.学生签名：年月日指导教师意见：指导教师签名：年月日所在教研室审查意见： 负责人签名：年 月日填写说明1.指导教师意见填写对文献综述的评语，对本课题的深度、广度及工作量的意见和对论文结果的预测；2.所在教研室审查意见包括对指导教师意见的认定和是否同意开题等。
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