【摘要】：目的:對(duì)國(guó)內(nèi)不同廠家生產(chǎn)的氯氮平片進(jìn)行法定標(biāo)準(zhǔn)檢驗(yàn)及探索性研究,對(duì)該品種的質(zhì)量狀況作出總體分析和評(píng)價(jià)。方法:法定標(biāo)準(zhǔn)檢驗(yàn)依據(jù)《中國(guó)藥典》2010年版二部,進(jìn)行了全項(xiàng)檢驗(yàn)。探索性研究參照美國(guó)藥典USP35版氯氮平原料藥項(xiàng)下有關(guān)物質(zhì)檢測(cè)方法,采用HPLC法檢測(cè),結(jié)合UPLC-MS,對(duì)不同企業(yè)提供的氯氮平原料藥及國(guó)內(nèi)制劑進(jìn)行雜質(zhì)研究,與進(jìn)口原料藥及制劑進(jìn)行雜質(zhì)譜比對(duì);采用HPLC法測(cè)定了18個(gè)企業(yè)的46批樣品在4種不同p H值介質(zhì)中的溶出曲線,并采用f2因子與參比制劑TEVA公司生產(chǎn)的氯氮平片溶出曲線進(jìn)行比較;對(duì)25 mg規(guī)格的氯氮平片測(cè)定了含量均勻度;用光散射的濕法測(cè)定進(jìn)行粒度分析;采用DSC、X衍射進(jìn)行原料晶型研究;進(jìn)行溶劑殘留、重金屬及有害元素的檢測(cè),以及制劑與包材穩(wěn)定性考察;建立氯氮平片近紅外光譜快速檢驗(yàn)?zāi)Ｐ?建立了快速液相定量方法。結(jié)果:法定標(biāo)準(zhǔn)檢驗(yàn):在199批樣品中,全檢合格198批,有1批樣品重量差異項(xiàng)目不合格,不合格率為0.5%。探索性研究:有關(guān)物質(zhì)研究表明,氯氮平原料藥的國(guó)內(nèi)外雜質(zhì)譜基本一致,《中國(guó)藥典》2010年版有關(guān)物質(zhì)檢查方法不能有效分離并控制單個(gè)特殊雜質(zhì)。溶出曲線考察,僅有少數(shù)的樣品在4種介質(zhì)中溶出行為與參比制劑相似,多數(shù)樣品溶出行為與參比制劑存在差異。粒度研究表明國(guó)產(chǎn)原料藥平均粒徑遠(yuǎn)遠(yuǎn)大于進(jìn)口原料藥。晶型研究未見不同晶型及結(jié)晶水情況。未檢出溶劑殘留;原料藥及制劑的重金屬和有害元素含量遠(yuǎn)遠(yuǎn)低于藥典規(guī)定;產(chǎn)品在高溫高濕條件下比較穩(wěn)定;現(xiàn)有外包材能夠滿足藥品儲(chǔ)存運(yùn)輸?shù)囊蟆９步?8個(gè)氯氮平片近紅外光譜快速檢驗(yàn)?zāi)Ｐ�。建立了氯氮平片的快速液相定量分析方法。結(jié)論:氯氮平片質(zhì)量總體較好,未發(fā)現(xiàn)違規(guī)違法生產(chǎn)問(wèn)題。現(xiàn)行質(zhì)量標(biāo)準(zhǔn)基本可行,個(gè)別項(xiàng)目檢查方法需要改進(jìn)。
[Abstract]:Aim: to analyze and evaluate the quality of clozapine tablets produced by different manufacturers in China. Methods: according to part two of Chinese Pharmacopoeia (2010 edition), the legal standard test was carried out. According to the related substances detection methods of clozapine in USP35 version of US Pharmacopoeia, the HPLC method and UPLC-MS, were used to study the impurities of clozapine raw materials and domestic preparations provided by different enterprises. The impurity spectra were compared with imported raw materials and preparations. The dissolution curves of 46 batches of samples from 18 enterprises in four media with different pH values were determined by HPLC, and the dissolution curves of clozapine tablets produced by reference agent TEVA were compared with f2 factor. The content uniformity of 25 mg clozapine tablets was determined, the particle size analysis was carried out by wet method of light scattering, the crystal structure of raw materials was studied by DSC,X diffraction, and the content uniformity of clozapine tablets was determined by DSC,X diffraction. The determination of solvent residues, heavy metals and harmful elements, as well as the stability of preparation and coating, the rapid detection model of near infrared spectrum of clozapine tablets and the quantitative method of rapid liquid phase were established. Results: in 199 batches of samples, 198 batches of total samples were qualified, one batch of sample weight difference items were not qualified, and the unqualified rate was 0.5%. Exploratory research shows that the impurity spectra of chloro-nitrogen plain drugs are basically the same at home and abroad, and the methods for the determination of related substances in the 2010 edition of Chinese Pharmacopoeia cannot effectively separate and control individual special impurities. The dissolution curve showed that only a few of the samples were similar to the reference formulation in four media, and the dissolution behavior of most samples was different from that of the reference preparation. Particle size studies show that the average particle size of domestic raw materials is much larger than that of imported raw materials. There are no different crystal forms and crystal water in the study of crystal form. Solvent residues were not detected; the contents of heavy metals and harmful elements in raw drugs and preparations were far lower than those prescribed in pharmacopoeia; the products were stable under high temperature and humidity; and the existing outsourcing materials could meet the requirements of drug storage and transportation. A total of 28 fast detection models of clozapine tablets by near infrared spectroscopy (NIR) were established. A rapid liquid phase quantitative analysis method for clozapine tablets was established. Conclusion: clozapine tablets were of good quality and no illegal production was found. The current quality standards are basically feasible, and individual inspection methods need to be improved.
【作者單位】： 云南省食品藥品檢驗(yàn)所;
【基金】：2013年國(guó)家藥品計(jì)劃抽驗(yàn)品種、中央補(bǔ)助地方經(jīng)費(fèi)項(xiàng)目(編號(hào)110)
【分類號(hào)】：R917

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本文編號(hào)：2460397