CBS原料药及DXQ片质量标准及稳定性研究

发布时间：2019-06-08 11:31

【摘要】：摘要：本文按照新药研发的技术要求,对两种在研的1.1类新药CBS原料药和DXQ片剂进行了质量标准研究,制定了CBS原料药及DXQ片剂的质量标准(草案),同时通过影响因素试验、加速试验、长期试验对新药CBS及DXQ片剂稳定性进行了考察。第一部分：CBS原料药质量标准及稳定性研究 1)建立了两种CBS原料药的含量测定方法：容量分析方法是化学原料药含量测定的首选方法,容量分析方法测定法如下：精密加入过量0.1mol/L盐酸滴定液,待反应完全,过滤并洗涤滤渣,合并滤液,以酚酞为指示剂,用0.1mol/L氢氧化钠滴定,至溶液变粉红色,记录氢氧化钠消耗量,计算CBS原料药含量。高效液相色谱法色谱条件如下：色谱柱：Phenomenex LUNAC18250×4.6mm5μm;流动相：乙腈-0.1%三氟乙酸(45：55)；检测波长：279nm；流速：1ml/min;进样体积：20μ.1；柱温：40℃。但由于CBS具有同分异构体,影响容量分析方法专属性,准确度,难以准确测定其含量；而高效液相色谱法专属性强,准确度高,且可用于有关物质的检测,故含量测定方法选择高效液相色谱法。同时,对建立的HPLC方法进行了灵敏度、线性、精密度、重复性等方法学考察；结果显示：本方法精密度高,重复性好,并且在10-100μg/ml范围内线性关系良好,可用于CBS原料药的含量测定。本品按干燥品计算,CBS含量应不低于98%。 2)建立了CBS有关物质分析方法：采用高效液相色谱法对CBS原料药进行了有关物质的分析,并用液质联用仪对强光照条件下含量明显增多的有关物质进行了初步结构确证。通过强酸、强碱及氧化试验考察了方法的耐用性。试验结果表明：CBS在强酸条件下稳定,在强碱、双氧水氧化条件下用HPLC检测有降解产物产生,纯度降至90%左右。所建立的高效液相色谱法作为有关物质检查的方法专属性强,分离度好(分离度大于1.5)。有关物质的测定选择不加校正因子的主成分自身对照法。 3)建立了顶空-毛细管气相色谱法(GC)测定CBS原料药中有机溶剂的残留量。气相色谱条件：DB-WAX(30m×0.45mm,0.85μm)毛细管色谱柱,FID检测器,载气为高纯氮,分流比为10：1,进样口温度为200℃,FID检测器温度为250℃,程序升温：起始温度为50℃,保持6min,以40℃/min速率升至200℃,保持5min。顶空条件：炉温：80℃定量环温度：90℃传输管线温度：100℃,顶空瓶平衡时间：30.0min。结果显示,2种残留溶剂甲醇、乙醇分离良好,在所考察的浓度范围内有较好的线性关系,平均回收率为95%-105%,且本品甲醇、乙醇均未检出。 4)无机检查：对CBS按照药典规定进行无机检查,结果显示：氯化物小于0.025%、硫酸盐小于0.05%、重金属小于20ppm、砷盐小于2ppm、干燥失重小于0.5%；本品由于为有机钠盐,炽灼残渣暂定小于20%,各项均符合药典规定。 5)CBS稳定性研究：稳定性研究主要包括影响因素试验、加速试验及长期试验。影响因素试验进行了高温、高湿、强光照试验。于第0、5、10天取样检测,结果表明CBS原料药在高温、高湿条件下比较稳定,强光照条件下有降解产物产生；加速试验在40℃、相对湿度75%条件下,于第0、1、2、3、6、9个月末取样检测,结果表明,在此条件下,CBS原料药较稳定；长期试验在25℃、相对湿度60%条件下,于第0、3、6、9个月末取样检测,结果表明,在此条件下CBS原料药稳定；进一步试验仍在进行。第二部分：DXQ原料药晶型及片剂质量标准及稳定性研究 1)DXQ原料药晶型制备与表征：采用溶剂缓慢挥发法对DXQ进行了晶型制备,并采用单晶X-射线衍射(SCXIm)、粉末X-射线衍射(PXRD)以及差示扫描量热(DSC)分析技术对制备得到的晶型进行了表征。结果表明：单晶X-射线衍射分析表明DXQ晶体属于单斜晶系,空间群为P21/n,晶胞参数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-射线衍射特征峰位于13.37°、14.14°、16.94°、21.70°、24.74°、26.60°、28.36°、36.50°;差示扫描量热仪测试显示DXQ在109-112℃左右仅出现一个吸热峰。本文对DXQ晶型进行了制备和表征。 2)DXQ片剂及质量标准及稳定性研究：主要从外观、性状、鉴别、检查、含量测定及稳定性研究等方面进行。溶出度试验中,考察了不同溶出介质、不同转速条件下的溶出现象；最终确定采用桨法,以900ml水为溶出介质,每分钟50转的转速,45分钟取样的溶出条件,溶出量大于90%。稳定性研究中采用已建立的高效液相色谱法,通过影响因素试验,加速和长期试验,考察DXQ片剂在高温、高湿、光照条件下的变化,结果表明DXQ片剂在高温、高湿及光照条件下比较稳定；目前已经完成的加速及长期试验表明DXQ片剂稳定性良好,长期试验仍在进行中。
[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，

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