本文選題：瑞舒伐他汀鈣　切入點(diǎn)：有關(guān)物質(zhì)　出處：《成都學(xué)院》2017年碩士論文

【摘要】：瑞舒伐他汀鈣是一種新一代的選擇性HMG-CoA還原酶抑制劑,該藥由阿斯利康公司開發(fā)研制,于2003年8月經(jīng)美國FDA批準(zhǔn)上市,主要用于高膽固醇血癥、單純高甘油三酯血癥以及血脂代謝紊亂癥的治療[1]。經(jīng)查閱文獻(xiàn)后發(fā)現(xiàn)有印度藥典(2010版)、歐洲藥典(8.8版)和英國藥典(2016版)收載該品種。本論文對一種利用綠色工藝合成的瑞舒伐他汀鈣產(chǎn)品進(jìn)行了全面的質(zhì)量控制和雜質(zhì)研究,建立適宜的質(zhì)量標(biāo)準(zhǔn)及其起始原料和關(guān)鍵中間體的內(nèi)控標(biāo)準(zhǔn),為終產(chǎn)品的質(zhì)量可控提供了保障。首先本文針對瑞舒伐他汀鈣進(jìn)行了全面、深入的質(zhì)量控制研究。結(jié)合本品的合成工藝路線,對本品理化常數(shù)進(jìn)行了檢測,根據(jù)相關(guān)標(biāo)準(zhǔn)建立適宜的鑒別方法,并對含鈣量、水分、重金屬、氯化物等一般雜質(zhì)進(jìn)行了檢查,研究建立了有關(guān)物質(zhì)、殘留溶劑、殘留氧化物(起始原料)的檢查方法,建立了光學(xué)異構(gòu)體及含量測定的檢查方法,并對上述方法進(jìn)行了方法學(xué)驗證。有關(guān)物質(zhì)檢查方法采用C18色譜柱,以水-乙腈-1%三氟乙酸水溶液(64:35:1)為流動相A,水-乙腈-1%三氟乙酸水溶液(24:75:1)為流動相B進(jìn)行梯度洗脫;波長242nm,流速1m L/min,柱溫40℃。異構(gòu)體檢查采用CHIRALPAK AD-H色譜柱,流動相為正己烷-乙醇-三氟乙酸(85:15:0.1),檢測波長244nm,流速0.5 m L/min,柱溫30℃。以兩種氣相色譜方法測定本品的殘留溶劑和起始原料,采用頂空進(jìn)樣法測定乙醇、乙腈、乙酸乙酯、四氫呋喃的含量,采用直接進(jìn)樣法測定DMSO及殘留氧化物的含量。含量測定方法為HPLC外標(biāo)法,采用C18色譜柱,以水-乙腈-1%三氟乙酸溶液(62:37:1)為流動相,檢測波長為242nm,流速為0.8m L/min,柱溫40℃。上述方法均經(jīng)過方法學(xué)驗證,可用于瑞舒伐他汀鈣的檢查與含量測定。本文根據(jù)樣品有關(guān)物質(zhì)檢查的雜質(zhì)情況,結(jié)合合成工藝路線和降解試驗結(jié)果,對樣品中的雜質(zhì)進(jìn)行了歸屬研究。結(jié)果表明,樣品中最大的雜質(zhì)為瑞舒伐他汀鈣的非對映異構(gòu)體(雜質(zhì)B),樣品中除各已知雜質(zhì)外,還含有微量未知雜質(zhì)。為保證藥品使用安全性,本文通過MS、NMR等技術(shù)對未知雜質(zhì)進(jìn)行了研究,推測了雜質(zhì)K結(jié)構(gòu)為:雙[4-(4-氟苯基)-6-異丙基-2-(N-甲基-N-甲基磺�；�-氨基)-嘧啶-5-基]-(3R,5S)-2,2-二甲基-1-二氧己環(huán)-4-乙酸]鈣鹽(2:1),推斷雜質(zhì)L為瑞舒伐他汀鈣異構(gòu)體。最后對合成工藝中的起始原料(母核、氧化物)及關(guān)鍵中間體(骨架)進(jìn)行了系統(tǒng)的質(zhì)量控制研究,分別進(jìn)行了理化常數(shù)測定及一般檢查項的檢查,建立了有關(guān)物質(zhì)檢查方法及含量測定方法,并進(jìn)行了相關(guān)方法學(xué)驗證。結(jié)合合成工藝與終產(chǎn)品的質(zhì)量制訂相應(yīng)的內(nèi)控標(biāo)準(zhǔn)對其質(zhì)量進(jìn)行控制,為工藝穩(wěn)定性和終產(chǎn)品的質(zhì)量可控性提供有效保障。
[Abstract]:Risuvastatin calcium is a new generation of selective HMG-CoA reductase inhibitors developed by AstraZeneca, which was approved for sale by FDA in the United States in August 2003 and is mainly used for hypercholesterolemia.Treatment of hypertriglyceridemia and dyslipidemia [1].It is found that there are Indian Pharmacopoeia (2010), European Pharmacopoeia (8.8) and British Pharmacopoeia (2016).In this paper, the quality control and impurity of a kind of rosuvastatin calcium product synthesized by green process were studied, and the suitable quality standard and the internal control standard of the starting material and the key intermediate were established.For the final product quality control provides a guarantee.Firstly, the quality control of rosuvastatin calcium was studied in detail.The physical and chemical constants of the product were determined, the suitable identification method was established according to the relevant standards, and the general impurities, such as calcium content, water content, heavy metal, chloride and so on, were examined.A method for the detection of related substances, residual solvents and residual oxides (starting raw materials) was established. The method for the determination of optical isomers and their contents was established, and the above methods were validated.The related substances were detected on C18 column with water acetonitrile-1% trifluoroacetic acid aqueous solution (64: 35: 1) as mobile phase A and water acetonitrile-1% trifluoroacetic acid aqueous solution as mobile phase B for gradient elution at a wavelength of 242 nm at a flow rate of 1m L / min and column temperature at 40 鈩，

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