發(fā)布時(shí)間：2018-05-27 17:02

  本文選題：曲格列汀琥珀酸鹽 + 有關(guān)物質(zhì)��； 參考：《成都學(xué)院》2017年碩士論文

【摘要】：曲格列汀琥珀酸鹽(Trelagliptin succinate)是日本制藥巨頭武田(Takeda)公司開發(fā)研制的II型糖尿病治療的新型藥物,于2015年3月26日由日本衛(wèi)生勞動福利部(MHLW)批準(zhǔn)上市,其商品名為Zafatek,為口服片劑。迄今為止,本品的質(zhì)量標(biāo)準(zhǔn)仍未被載入各國藥典及藥品標(biāo)準(zhǔn),其質(zhì)量控制方法仍處于新藥研究階段。本課題依據(jù)國家食品藥品監(jiān)督管理局相關(guān)指導(dǎo)原則、2015版《中國藥典》及ICH指導(dǎo)原則的要求,對曲格列汀琥珀酸鹽原料藥進(jìn)行系統(tǒng)、深入的質(zhì)量研究,包括結(jié)構(gòu)研究、理化性質(zhì)、有關(guān)物質(zhì)檢查、含量測定及原料藥穩(wěn)定性考察。按照2015版中國藥典第四部,對曲格列汀琥珀酸鹽的外觀、溶解度、引濕性、吸光系數(shù)、熔點(diǎn)及比旋度等理化常數(shù)進(jìn)行檢測,根據(jù)本品結(jié)構(gòu)特點(diǎn)建立適合的鑒別方法,并對其進(jìn)行氯化物、熾灼殘?jiān)�、重金屬等一般雜質(zhì)檢查和有機(jī)殘留溶劑檢查。建立適合曲格列汀琥珀酸鹽有關(guān)物質(zhì)檢查及含量測定的方法,并進(jìn)行方法學(xué)驗(yàn)證。根據(jù)2015《中國藥典》穩(wěn)定性試驗(yàn)指導(dǎo)原則對曲格列汀琥珀酸鹽進(jìn)行原料藥穩(wěn)定性研究。最后,采用UV、LC-MS、NMR等波譜技術(shù)、熱分析技術(shù)及X射線粉末衍射技術(shù)對本品進(jìn)行結(jié)構(gòu)及晶型研究,并結(jié)合合成工藝對其主要雜質(zhì)進(jìn)行結(jié)構(gòu)研究。結(jié)果表明,曲格列汀琥珀酸鹽為白色粉末,無引濕性,比旋度為+16.5°~+17.1°,在二甲基亞砜及水中易溶、在甲醇中略溶,熔點(diǎn)為186~189℃,水溶液中吸收系數(shù)為286.1;確立了紅外吸收光譜、紫外吸收光譜、氟離子特征反應(yīng)及琥珀酸鹽特性反應(yīng)的鑒別方法;其一般雜質(zhì)及有機(jī)殘留溶劑檢查結(jié)果均符合2015年中國藥典的限度要求。建立了曲格列汀琥珀酸鹽有關(guān)物質(zhì)檢查及含量測定的反相高效液相色譜方法,色譜條件為:采用Phenomenex Gemini C18 110A(250×460nm,5μm),以醋酸鹽緩沖液(醋酸銨3.9g,三乙胺3ml,水980ml,冰醋酸調(diào)pH值至4.00)-乙腈(90:10)為流動相A,以醋酸鹽緩沖液-乙腈(45:55)為流動相B,梯度洗脫,流速為1.0ml/min,柱溫30℃,檢測波長為278nm,進(jìn)樣體積20μl;方法學(xué)驗(yàn)證結(jié)果顯示,該方法準(zhǔn)確、簡便、專屬性強(qiáng)、靈敏度高。穩(wěn)定性試驗(yàn)結(jié)果表明本品含量穩(wěn)定,無降解現(xiàn)象。經(jīng)結(jié)構(gòu)研究,確定本品為目標(biāo)化合物曲格列汀琥珀酸鹽的A晶型,主要雜質(zhì)為曲格列汀的去氰基化合物及氰基水解產(chǎn)物,其主要堿降解雜質(zhì)之一為2-氨基甲基-4-氟-芐腈。本課題開發(fā)的鑒定及檢測方法適用于曲格列汀琥珀酸鹽的質(zhì)量控制,為曲格列汀琥珀酸鹽原料藥質(zhì)量標(biāo)準(zhǔn)的制定及工藝優(yōu)化提供了依據(jù)。
[Abstract]:Trelagliptin succinateis a new type of drug for the treatment of type II diabetes developed by Japanese pharmaceutical giant Takeda. It was approved by MHLW, Japan's Ministry of Health, Labor and Welfare, on March 26, 2015. It is called Zafatek. it is an oral tablet. Up to now, the quality standard of this product has not been included in the national pharmacopoeia and drug standard, and its quality control method is still in the new drug research stage. According to the requirements of the relevant guidelines of the State Food and Drug Administration (SFDA), the Chinese Pharmacopoeia and the ICH guidelines, a systematic and in-depth study on the quality of triglutin succinate raw materials, including structural studies, physicochemical properties, was carried out. Examination of related substances, determination of content and stability of raw materials. According to the fourth part of Chinese Pharmacopoeia 2015, the physical and chemical parameters of triglutin succinate, such as appearance, solubility, hygroscopicity, absorptivity, melting point and specific curl, were determined, and a suitable identification method was established according to the structural characteristics of the product. General impurities such as chloride, incandescent residue, heavy metal and organic residual solvents were examined. To establish a suitable method for the determination and determination of the related substances of traglutin succinate, and to verify the methodology. The stability of traglutin succinate was studied on the basis of the 2015 Chinese Pharmacopoeia stability test. Finally, the structure and crystal structure of the product were studied by means of UVX LC-MS NMR spectroscopy, thermal analysis and X-ray powder diffraction, and the structure of the main impurity was studied in combination with the synthesis process. The results show that triglutin succinate is a white powder with no moisture, and its specific curl is 16.5 擄~ 17.1 擄. It is easy to dissolve in dimethyl sulfoxide and water, dissolves slightly in methanol, and the melting point is 186 ~ 189 鈩，

本文編號：1943017