【摘要】：摘要：本文按照新藥研發(fā)的技術(shù)要求,對(duì)兩種在研的1.1類新藥CBS原料藥和DXQ片劑進(jìn)行了質(zhì)量標(biāo)準(zhǔn)研究,制定了CBS原料藥及DXQ片劑的質(zhì)量標(biāo)準(zhǔn)(草案),同時(shí)通過影響因素試驗(yàn)、加速試驗(yàn)、長(zhǎng)期試驗(yàn)對(duì)新藥CBS及DXQ片劑穩(wěn)定性進(jìn)行了考察。第一部分：CBS原料藥質(zhì)量標(biāo)準(zhǔn)及穩(wěn)定性研究 1)建立了兩種CBS原料藥的含量測(cè)定方法：容量分析方法是化學(xué)原料藥含量測(cè)定的首選方法,容量分析方法測(cè)定法如下：精密加入過量0.1mol/L鹽酸滴定液,待反應(yīng)完全,過濾并洗滌濾渣,合并濾液,以酚酞為指示劑,用0.1mol/L氫氧化鈉滴定,至溶液變粉紅色,記錄氫氧化鈉消耗量,計(jì)算CBS原料藥含量。高效液相色譜法色譜條件如下：色譜柱：Phenomenex LUNAC18250×4.6mm5μm;流動(dòng)相：乙腈-0.1%三氟乙酸(45：55)；檢測(cè)波長(zhǎng)：279nm；流速：1ml/min;進(jìn)樣體積：20μ.1；柱溫：40℃。但由于CBS具有同分異構(gòu)體,影響容量分析方法專屬性,準(zhǔn)確度,難以準(zhǔn)確測(cè)定其含量；而高效液相色譜法專屬性強(qiáng),準(zhǔn)確度高,且可用于有關(guān)物質(zhì)的檢測(cè),故含量測(cè)定方法選擇高效液相色譜法。同時(shí),對(duì)建立的HPLC方法進(jìn)行了靈敏度、線性、精密度、重復(fù)性等方法學(xué)考察；結(jié)果顯示：本方法精密度高,重復(fù)性好,并且在10-100μg/ml范圍內(nèi)線性關(guān)系良好,可用于CBS原料藥的含量測(cè)定。本品按干燥品計(jì)算,CBS含量應(yīng)不低于98%。 2)建立了CBS有關(guān)物質(zhì)分析方法：采用高效液相色譜法對(duì)CBS原料藥進(jìn)行了有關(guān)物質(zhì)的分析,并用液質(zhì)聯(lián)用儀對(duì)強(qiáng)光照條件下含量明顯增多的有關(guān)物質(zhì)進(jìn)行了初步結(jié)構(gòu)確證。通過強(qiáng)酸、強(qiáng)堿及氧化試驗(yàn)考察了方法的耐用性。試驗(yàn)結(jié)果表明：CBS在強(qiáng)酸條件下穩(wěn)定,在強(qiáng)堿、雙氧水氧化條件下用HPLC檢測(cè)有降解產(chǎn)物產(chǎn)生,純度降至90%左右。所建立的高效液相色譜法作為有關(guān)物質(zhì)檢查的方法專屬性強(qiáng),分離度好(分離度大于1.5)。有關(guān)物質(zhì)的測(cè)定選擇不加校正因子的主成分自身對(duì)照法。 3)建立了頂空-毛細(xì)管氣相色譜法(GC)測(cè)定CBS原料藥中有機(jī)溶劑的殘留量。氣相色譜條件：DB-WAX(30m×0.45mm,0.85μm)毛細(xì)管色譜柱,FID檢測(cè)器,載氣為高純氮,分流比為10：1,進(jìn)樣口溫度為200℃,FID檢測(cè)器溫度為250℃,程序升溫：起始溫度為50℃,保持6min,以40℃/min速率升至200℃,保持5min。頂空條件：爐溫：80℃定量環(huán)溫度：90℃?zhèn)鬏敼芫�溫度：100℃,頂空瓶平衡時(shí)間：30.0min。結(jié)果顯示,2種殘留溶劑甲醇、乙醇分離良好,在所考察的濃度范圍內(nèi)有較好的線性關(guān)系,平均回收率為95%-105%,且本品甲醇、乙醇均未檢出。 4)無機(jī)檢查：對(duì)CBS按照藥典規(guī)定進(jìn)行無機(jī)檢查,結(jié)果顯示：氯化物小于0.025%、硫酸鹽小于0.05%、重金屬小于20ppm、砷鹽小于2ppm、干燥失重小于0.5%；本品由于為有機(jī)鈉鹽,熾灼殘?jiān)鼤憾ㄐ∮?0%,各項(xiàng)均符合藥典規(guī)定。 5)CBS穩(wěn)定性研究：穩(wěn)定性研究主要包括影響因素試驗(yàn)、加速試驗(yàn)及長(zhǎng)期試驗(yàn)。影響因素試驗(yàn)進(jìn)行了高溫、高濕、強(qiáng)光照試驗(yàn)。于第0、5、10天取樣檢測(cè),結(jié)果表明CBS原料藥在高溫、高濕條件下比較穩(wěn)定,強(qiáng)光照條件下有降解產(chǎn)物產(chǎn)生；加速試驗(yàn)在40℃、相對(duì)濕度75%條件下,于第0、1、2、3、6、9個(gè)月末取樣檢測(cè),結(jié)果表明,在此條件下,CBS原料藥較穩(wěn)定；長(zhǎng)期試驗(yàn)在25℃、相對(duì)濕度60%條件下,于第0、3、6、9個(gè)月末取樣檢測(cè),結(jié)果表明,在此條件下CBS原料藥穩(wěn)定；進(jìn)一步試驗(yàn)仍在進(jìn)行。第二部分：DXQ原料藥晶型及片劑質(zhì)量標(biāo)準(zhǔn)及穩(wěn)定性研究 1)DXQ原料藥晶型制備與表征：采用溶劑緩慢揮發(fā)法對(duì)DXQ進(jìn)行了晶型制備,并采用單晶X-射線衍射(SCXIm)、粉末X-射線衍射(PXRD)以及差示掃描量熱(DSC)分析技術(shù)對(duì)制備得到的晶型進(jìn)行了表征。結(jié)果表明：?jiǎn)尉-射線衍射分析表明DXQ晶體屬于單斜晶系,空間群為P21/n,晶胞參數(shù)a=6.8746(5)A,b:4.9454(4)A,c=24.798(2)A, α=90°,β=92.117(7)°,γ=90°；DXQ晶型粉末X-射線衍射特征峰位于13.37°、14.14°、16.94°、21.70°、24.74°、26.60°、28.36°、36.50°;差示掃描量熱儀測(cè)試顯示DXQ在109-112℃左右僅出現(xiàn)一個(gè)吸熱峰。本文對(duì)DXQ晶型進(jìn)行了制備和表征。 2)DXQ片劑及質(zhì)量標(biāo)準(zhǔn)及穩(wěn)定性研究：主要從外觀、性狀、鑒別、檢查、含量測(cè)定及穩(wěn)定性研究等方面進(jìn)行。溶出度試驗(yàn)中,考察了不同溶出介質(zhì)、不同轉(zhuǎn)速條件下的溶出現(xiàn)象；最終確定采用槳法,以900ml水為溶出介質(zhì),每分鐘50轉(zhuǎn)的轉(zhuǎn)速,45分鐘取樣的溶出條件,溶出量大于90%。穩(wěn)定性研究中采用已建立的高效液相色譜法,通過影響因素試驗(yàn),加速和長(zhǎng)期試驗(yàn),考察DXQ片劑在高溫、高濕、光照條件下的變化,結(jié)果表明DXQ片劑在高溫、高濕及光照條件下比較穩(wěn)定；目前已經(jīng)完成的加速及長(zhǎng)期試驗(yàn)表明DXQ片劑穩(wěn)定性良好,長(zhǎng)期試驗(yàn)仍在進(jìn)行中。
[Abstract]:Abstract: According to the technical requirements of new drug R & D, the quality standard of two kinds of new drug CBS drug substance and DXQ tablet were studied, and the quality standard (draft) of CBS drug substance and DXQ tablet was established. At the same time, the influence factor test and the acceleration test were carried out. The stability of new drug CBS and DXQ tablets was investigated for a long time. Part 1: Study on Quality Standard and Stability of CBS Drug Substance 1) The method for determining the content of two CBS drug substances is established: the capacity analysis method is the preferred method for the determination of the content of the chemical drug substance, and the capacity analysis method is as follows: the excess of 0.1 mol/ L hydrochloric acid titration is accurately added After the reaction is complete, the filter residue is filtered and washed, the filtrate is combined, the phenolphthalein is used as an indicator, and is titrated with 0.1mol/ L sodium hydroxide until the solution is pink, and the consumption of sodium hydroxide is recorded, and the CBS drug substance is calculated. The HPLC conditions for high performance liquid chromatography are as follows: chromatographic column: Phenomenex LUNAC18250-4.6 mm5. m; mobile phase: acetonitrile-0.1% trifluoroacetic acid (45:55); detection wavelength:279 nm; flow rate:1 ml/ min; injection volume:20. m.1; column temperature:40 The method is high in specificity and high in accuracy, and can be used for the detection of related substances, and the high-performance liquid chromatography is selected according to the content determination method. The results show that the method has high precision and good repeatability, and the linear relationship is good in the range of 10-100 & mu; g/ ml, and can be used for measuring the content of CBS drug substance. The content of CBS shall not be less than 98 as calculated according to the dried product. %.2) The analysis of the related substances of CBS was established by HPLC. The related substances were analyzed by high performance liquid chromatography (HPLC). The method is investigated by strong acid, strong base and oxidation test. The test results show that the CBS is stable under strong acid conditions, and the degradation products are detected by HPLC under the conditions of strong alkali and hydrogen peroxide, and the purity is reduced to 90. The established high-performance liquid chromatography is specific and has good separation degree (the degree of separation is greater than 1). .5) Determination of related substances and selection of main components without correction factor themselves Control method.3) The headspace-capillary gas chromatography (GC) was established to determine the organic solubility in the CBS drug substance. The gas chromatography conditions: DB-WAX (30 m, 0.45 mm, 0.85. mu.m) capillary column, FID detector, carrier gas as high-purity nitrogen, split ratio of 10:1, injection port temperature of 200 & deg; C, FID detector temperature of 250 & deg; C, temperature rise of the program: starting temperature of 50 & deg; C, holding for 6 min, and rising at 40 & deg; C/ min to 200 & deg; C, protected 5 min. Headspace condition: furnace temperature:80 鈩，

本文編號(hào)：2495252