CN1306210A - 用于拉莫三嗪的参比标识物 - Google Patents
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Abstract
本发明涉及一种检测拉莫三嗪或含有拉莫三嗪的药物剂型样品的纯度或降解稳定性的方法,该方法包括分析所述样品中所存在的选自3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮(化合物A)和N-[5-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-3-基]-2,3-二氯苯甲酰胺(化合物B)的化合物。本发明还公开了一种制备新化合物B的方法。
Description
本发明涉及用作分析拉莫三嗪及其药物制剂参比标识物的化合物。
为使新的药物产品能获准安全上市,药品制造商必须向有关管理机构提供详尽的证据以示该产品适合投放上市。有关管理机构需认可该活性剂的给药可为人体所接受,而且其特定的市售制剂在给药时应没有杂质并具有合适的搁置寿命。
因此,提交给管理机构的证据中一般包括分析数据,以证实(a)药物在生产期间不含有或仅含有可忽略不计水平的杂质,和(b)可接受的药物储存稳定性(即搁置寿命)。这些数据常常通过外标或参比标识物对药物的检测获得,所述外标或参比标识物是可能性杂质或可能性降解产物的适当纯样品。
在药物活性剂以及含有它们的制剂中,可能的杂质包括:残余量的活性剂合成前体、活性剂合成中产生的副产物、剩余溶剂、活性剂异构体、合成活性剂或制备药物制剂中存在于原料内的杂质以及未知的异物。储存时可能出现的其他杂质包括活性剂降解产物,例如氧化或水解的产物。
拉莫三嗪是如式(Ⅳ)所示的3,5-二氨基-6-(2,3-二氯苯基)-1,2,4-三嗪:它是一种适合治疗中枢神经系统(CNS)疾病,尤其是癫痫症的已知化合物,这已公开在EP-A-0021121中。拉莫三嗪本身及其药物制剂在生产中都较纯。特别是,在其药物制剂制备期间,拉莫三嗪能够保持稳定。
现已知道,有两种化合物可以在分析拉莫三嗪或含拉莫三嗪的药物剂型中用作参比标识物。化合物之一是拉莫三嗪可能的降解物,另一种是合成拉莫三嗪期间由副反应产生的可能性杂质。
因此,本发明提供一种用于检测拉莫三嗪或其药物制剂的样品的纯度或降解稳定性的方法,该方法包括,检测所述样品中所存在的选自3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮和N-[5-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-3-基]-2,3-二氯苯甲酰胺的化合物。在本发明的方法中,上述化合物充当参比标识物。
式A化合物(化合物A)是拉莫三嗪可能的降解产物,是在药物水解时生成的。所以,式A化合物通过拉莫三嗪在碱性条件下的水解产生。这种水解作用适合发生在拉莫三嗪和碱的水溶液加热回流时。优选的碱是强碱,例如碱金属氢氧化物。尤其优选氢氧化钠。这样的碱性水溶液可在回流条件下加热1至48小时,例如10小时至36小时,优选24小时。
通过在吡啶中用2,3-二氯苯甲酰氯处理拉莫三嗪可直接制得式B化合物(化合物B)。然而,由于它是由药物合成中的副反应所产生的可能性杂质,所以它也可用作拉莫三嗪的参比标识物。实际上,通过薄层色谱,这种杂质在拉莫三嗪粗品中的水平被控制在最高值为0.5%。进而重结晶这种品质的药物粗品,所得拉莫三嗪符合总杂质不超过2%的商业化生产的纯度水平。
参照例1描述了拉莫三嗪的合成。在合成中作为中间体1.4的2,3-二氯苯甲酰氰化物可以含有至多10%的2,3-二氯苯甲酸酐作为杂质。当用氨基胍碳酸氢盐在硫酸中的溶液处理2,3-二氯苯甲酰氰化物时(参照例1的步骤(d)),生成了加合物(Z)-2-(2,3-二氯苯基)-2-(胍基亚氨基)乙腈(中间体1.5)。随后,酸酐类杂质可以和后一种加合物反应生成(Z)-2-(2,3-二氯苯基)-2-[N’-(2,3-二氯苯甲酰基)胍基亚氨基]乙腈,该产物是化合物B的直接前体。该前体在1-丙醇中经回流环化成化合物B。
本发明还提供制备化合物B的方法,该方法包括:
(ⅰ)在低于35℃的温度下,将2当量的2,3-二氯苯甲酰氯与1当量溶解在吡啶中的拉莫三嗪反应;或
通过2,3-二氯苯甲酰基氰化物与氨基胍碳酸氢盐的硫酸溶液间的反应,可以制得式(Ⅱ)化合物。
在用作参比标识物时,化合物A和B必须是其适当的纯净体。若需要,如上所得的化合物A和B可以被纯化至所需的纯度级别。所以,本发明上述制备化合物B的方法中包括附加的提纯所得化合物的步骤。
提纯是利用常见于有机合成的惯用方法来完成。例如,可将该化合物在有机溶剂例如C1-C6链烷醇中加热,过滤并真空干燥化合物。通常,加热是在溶剂的回流温度下进行。优选的C1-C6链烷醇是丙醇。而且,化合物也可以从热的C1-C6链烷醇,优选在热丙醇中重结晶。
可取的是,最终回收的化合物A和B是基本上纯净的形式。两种化合物最终的样品纯度一般至少为80%,例如至少85%,更优选至少90%。纯度水平高于90%是期望的,但不是必需的。所述纯度可以是,例如至少92%、至少95%或至少98%。99%或99.5%的纯度水平是更希望的。
人们要检测出拉莫三嗪本身(也称作药用物质)或含有拉莫三嗪的药物剂型(还称作药品)的纯度或降解稳定性。例如,需保证生产后的拉莫三嗪是纯净的。因此,一般要对药用物质进行降解产物(化合物A)和加工过程中的杂质(化合物B)的检测。还需要分析拉莫三嗪的药物制剂,从而检定出在药品生产期间和储存若干年后活性剂对降解所保持的稳定性。所以,通常仅需检测出包括常规口服片剂和可分散片剂在内的药物剂型中的化合物A。
可通过一种或多种常规分析技术来检测药用物质或药品的被测样品。所述分析技术包括高效液相色谱法(HPLC)和薄层色谱(TLC)。所得结果与由化合物A或B基本纯净的参比样品获取的结果进行比较。进而测定出两种化合物或各化合物在被测样品中的含量。
一方面,本发明所述方法可以用来测定拉莫三嗪样品的纯度,包括步骤:
(ⅰ)将拉莫三嗪样品溶于溶剂中以制得样品溶液;
(ⅱ)将3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮或N-[5-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-3-基]-2,3-二氯苯甲酰胺的样品溶解在溶剂中,以制备参比标识物的标准溶液;
(ⅲ)将所述样品溶液和所述标准溶液上样到薄层色谱上,得到各自的TLC色谱;和
(ⅳ)估算出得自样品溶液的色谱图中相对于标准溶液色谱图中的标准标识物点、相当于参比标识物Rf值的任何次要点的强度。
本发明所述方法另一方面是,检测含有拉莫三嗪的药物剂型对降解的稳定性,包括步骤:
(ⅰ)将剂型样品溶于溶剂中以制得样品溶液;
(ⅱ)将3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮的样品溶解在溶剂中,以制备参比标识物的标准溶液;
(ⅲ)将所述样品溶液和所述标准溶液上样到薄层色谱上,得到各自的TLC色谱;和
(ⅳ)估算出得自样品溶液的色谱图中相对于标准溶液色谱图中的标准标识物点、相当于参比标识物Rf值的任何次要点的强度。
本发明所述方法的又一个方面是,检测含有拉莫三嗪的药物剂型对降解的稳定性,包括步骤:
(ⅰ)将剂型的样品溶解在溶剂中以生成一种或多种样品溶液;
(ⅱ)将拉莫三嗪参比标准物样品溶解在溶剂中以生成标准溶液;
(ⅲ)将样品溶液和标准溶液注射到HPLC柱内,和
(ⅳ)测出各溶液的主峰的面积,并由此计算出参比标识物3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮在各样品溶液中的含量。
此时,可能需要在步骤(ⅲ)之前用系统适应性溶液(system suitability solution)通过HPLC柱,目的在于测出药物剂型中拉莫三嗪与任意制剂赋形剂间的分辨率。这种情况下,所述方法包括附加步骤:
(ⅱa)将拉莫三嗪和制剂赋形剂的参比标准物溶解在溶剂中,以生成HPLC系统适应性溶液,并将该系统适应性溶液注射到HPLC柱上,以便测定拉莫三嗪和制剂赋形剂之间的分辨率。所述制剂赋形剂可以是例如糖精钠。
本发明还提供了化合物在分析拉莫三嗪或含拉莫三嗪的药物剂型的纯度或对降解的稳定性中作为参比标识物的用途,所述化合物选自3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮和N-[5-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-3-基]-2,3-二氯苯甲酰胺。
实际上,拉莫三嗪较纯并且储存时也相当稳定。因此,对药用物质本身或含有拉莫三嗪的药物制剂进行分析试验主要是为了证实化合物A和/或B并不存在,或仅以低于所用分析技术检测限的水平(TLC为约0.3%w/w,HPLC为0.06%w/w)存在。
作为每次都分别测试参比标识物样品的替代方法,人们希望使用从药用物质或药品的分析中获得确定的数据,即用一种称作响应因子(R)的参数来代替。响应因子是一个预先测定的比值,该比值是化合物A或B样品通过用已知分析技术测定的数值结果对于等浓度纯拉莫三嗪试验数据结果的比值。所测数值结果可以是例如HPLC峰面积响应值。因此,已知纯净的拉莫三嗪和拉莫三嗪药物制剂被测样品的合适分析结果后,可以用化合物A或B的响应因子计算出被测样品中具体参比标识物的含量。
对于HPLC分析的结果,可根据下式计算:被测样品中化合物A或B相对于拉莫三嗪的
其中Ar=HPLC试验溶液中化合物主峰的面积As=HPLC标准溶液中单独的拉莫三嗪主峰面积R=化合物的响应因子Ws=标准物的重量(mg)
本发明化合物A的HPLC响应因子是0.79。
本发明将在下列实施例中作进一步的描述。参考例1:拉莫三嗪的制备
P9-反应路线步骤a:制备化合物1.2
搅拌化合物1.1(1mol)、叔丁醇、水和氢氧化钠(2mol)的溶液,并在50至60℃下在3小时内加入过氧化氢溶液(35%w/w,4mol)。在55至60℃下搅拌30分钟后,蒸除叔丁醇,用甲苯洗涤该水溶液。水溶液的pH被酸化至1-2,过滤产物,用水洗涤。湿固体或者直接用于下步反应,或者在80至90℃下干燥以75%的收率得到白色固体。步骤(b)和(c):制备化合物1.4
搅拌化合物1.2(1mol)的甲苯溶液并蒸干。随后冷却,加入吡啶(0.005mol),进而缓慢加入亚硫酰氯(1.1mol)。该溶液加热回流1小时,再真空浓缩,得到化合物1.3粗品。依次加入碘化钾(1.2mol)、氰化亚铜(1.2mol),并且将所有残余溶剂蒸馏除去,直至内温达到140至144℃为止。在该温度下保持18至24小时,随后冷却反应混合物,用甲苯稀释,滤出无机盐。在60至70℃下真空蒸干该溶液,残余的油状物从石油醚中重结晶,得到化合物1.4的黄色固体,收率77%。步骤d:制备化合物1.5
将氨基胍碳酸氢盐(1.75mol)溶解在9.3至10.0M的硫酸溶液中。加入2,3-二氯苯甲酰基氰化物(1mol)的乙腈溶液,在20至30℃下搅拌该悬浮液42至48小时。滤出粗产物,用水洗涤。将该固体加入到35℃以下的氢氧化钠溶液中,进而过滤产物,用水洗涤,在80至90℃下干燥,得到化合物1.5的黄色固体,收率66%。步骤(e):拉莫三嗪粗品的制备
化合物1.5的1-丙醇溶液在搅拌下回流90至120分钟,冷却至15至25℃,过滤拉莫三嗪的粗产物,得到浅棕色固体,收率90%(基于干重)。通过在1-丙醇中重结晶来纯化拉莫三嗪,用活性炭处理并将溶液冷却至15至25℃。过滤固体,用1-丙醇洗涤,在80至90℃下干燥,得到纯的拉莫三嗪。实施例1:3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5(4H)-酮(化合物A)的制备
将拉莫三嗪(614.4g,2.4mol)和固体氢氧化钠(242.4g)混合与水(60l)混合,搅拌下回流24小时。所得溶液冷却至15至20℃,用盐酸将pH调至5.5至6.0。过滤所得固体,再依次以40℃,50℃并且最终70℃的温度干燥24小时。通过HPLC测出的产物纯度为82%。HPLC条件如下:
色谱柱:Spherisorb 50 DS
洗脱剂:水(600)∶乙腈(400)∶0.5M硫酸(15)
流速:2.0ml/min
样品:100ml中含50mg
进样:5或10μl
检测:270nm
纯度82%的产物样品(583g)和丙醇(15L)混合并回流0.5小时。提取和干燥后,得到化合物A,其通过HPLC测定的纯度为96.2%,所用HPLC的条件同上。
将纯度96.2%的产物样品在丙醇(5L)中搅拌回流1小时,以便进一步的纯化。过滤固体,在40℃下真空干燥,得到标题化合物(460.7g,收率74.7%)。终产物通过HPLC测定的纯度为99.1%。
产物的物理特性如下:分子式:C9H6Cl2N4O 分子量:257.08元素分析
C H N
理论值 42.06% 2.35% 21.80%
计算值 42.02% 2.25% 21.23%TLC:(硅胶,氯仿∶甲醇∶冰醋酸∶1-丁醇=80∶10∶10∶5)
-主要点,Rf=0.38
-痕量点,Rf=0.82
红外(KBr):νmax(cm-1):3301,3127,1655
1556,1484,1413,
1290,1200,1056
812,785,748
737,7191Hnmr:δ/ppm,溶剂d6-DMSO(22mg/ml-1)/300MHz12.43(1H,bs);7.71,7.68(1H,m);7.40(2H,m);6.99(2H,bs);3.3(bs(水));2.5(q(DMSO-d5));0(s,TMS)质谱:m/z:256(M+),258和260(缔合的同位素离子),221,186,171,85(如下所示的离子碎片)
P12-结构式实施例2:N-[5-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-3-基]-2,3-二氯苯甲酰胺(化合物B)的制备
将拉莫三嗪(512.00g,2.00mol)溶解在吡啶(31)中,在低于35℃和无水的条件下,搅拌的同时加入2,3-二氯苯甲酰氯(873.00g,纯度96%,相当于838.10g,4.00mol)。所述酰氯分成两等份加入。第二份酰氯是在反应开始后30分钟时加料,并且在35℃以下进一步搅拌30分钟。
所得混合物被浓缩至近干,搅拌下用氯仿(1300ml)研制10分钟。过滤所得固体,氯仿(3×50ml)洗涤,室温干燥至重量为308g,36%(基于化合物B)。搅拌中的粗产物样品(50.0g)与甲醇(500ml)一起在回流温度下加热1小时,热过滤所得的混合物,得到极纯的化合物B(37.0g)。
该产物具有下列物理特性:分子式:C16H9Cl4N5O 分子量:429.09红外(KCl):νmax(cm-1):3468,3300,3202,
3385,3277,1687,
1625,1 559,1414,
1387,1538,1459,
1253,1157,1136,
1116,790,775,
741,7241Hnmr:δ/ppm,溶剂d6-DMSO(39mg/ml)/300MHz10.85(1H,bs);7.8(1H,bs);7.1(1H,bs);7.77(1H,d,J=7Hz);7.73(1H,d,J=7Hz);7.5(4H,m);4.80(bs);3.32(bs,水);3.18(s);2.50(五重峰,DMSO-d5);2.31(s,磺酸甲酯);0.00(s,TMS)质谱:化学电离(CI):m/z:428(M+1+);430,432和434(相关的同位素离子)。电子碰撞(EI):m/z:428(M+1)+;392,199,185,173,145(如下所示的离子碎片)
P13-结构式实施例3:通过HPLC分析药品(可分散片剂)中的拉莫三嗪和化合物A制备标准物和系统适应性溶液
标准溶液的制备是通过:将拉莫三嗪参比标准物(接近100mg,精确称重)转移到500ml容量瓶中,加入甲醇(200ml)以溶解固体,进而加入盐酸(100ml,0.5M)并混合;所得溶液冷却至室温,用水稀释到刻度体积。
系统适应性溶液的制备通过:将拉莫三嗪参比标准物(100mg)和糖精钠参比标准物(20mg)转移到500ml容量瓶内并用水稀释至刻度体积。样品溶液的制备溶液S1
按照表1的配方,溶液S1的制备是通过:将特定数量的片剂转移到特定的容量瓶内。加入一定体积的盐酸(0.5M),旋转溶液直至片剂崩解和泡腾停止。
加入特定体积的甲醇,将这种溶液在超声浴中放置10分钟。随后使溶液平衡至室温,用水稀释至刻度体积。
表1
溶液S2a)5mg片剂
片剂的含量 | 片剂数量 | 容量瓶的体积(ml) | 0.5M盐酸的体积(ml) | 甲醇体积(ml) |
5mg | 10 | 250 | 50 | 100 |
25mg | 8 | 200 | 40 | 80 |
50mg | 5 | 250 | 50 | 100 |
100mg | 5 | 500 | 100 | 200 |
200mg | 5 | 1000 | 200 | 400 |
按上述方法制备的溶液S1用Whatman No.1滤纸过滤。弃去最先的10ml滤液。以澄清滤液作为样品溶液。b)25mg,50mg,100mg和200mg片剂
用Whatman No.1滤纸过滤溶液S1。将最初的10ml滤液弃去。将滤液(10.0ml)转移到50ml容量瓶内,用盐酸(0.5M)∶水∶甲醇(20∶20∶40v/v)的混合液稀释至刻度体积。色谱方法
所用条件如下:色谱柱:125×4.6mm(内径),不锈钢,装有Spherisorb 5μm ODS 1或有效等同物。流动相:水/甲醇/乙腈/冰醋酸/正辛胺(700/100/100/20/0.5v.v)温度:常温流速:2.0ml/min波长:275nm进样体积:20μl注意:(a)色谱柱在使用前以低流速泵入30分钟甲醇来进行调整(b)色谱特性受到水对甲醇∶乙腈的配比的影响。(c)减少流动相中的甲醇∶乙腈含量可提高拉莫三嗪和糖精钠的分辨率;所有组分的保留时间也增加。(d)酸浓缩物甲醇对于乙腈的比例和乙酰胺浓度的较小变化不会对色谱特性造成显著影响(e)色谱柱使用后应依次用甲醇∶水(1∶9)和甲醇洗脱。进样过程
当基线稳定后,取系统适应性溶液进样,计算出拉莫三嗪和糖精钠间的分辨率。利用欧洲药典计算系统适应性参数的通用方法算出拉莫三嗪的对称因素和理论塔板数。
数值如下:分辨率:10对称因素:1.2理论塔板数:1400
随后,取标准溶液和样品溶液S2进样。计算
从标准溶液主峰的面积,按照下式计算拉莫三嗪的响应因子(R):R=Ws×PAs×100其中:Ws=所取拉莫三嗪标准物的重量(mg)P=拉莫三嗪参比标准物的纯度百分比As=标准溶液中的拉莫三嗪峰面积。
用平均响应因子(MR)根据下式计算出样品的拉莫三嗪含量, 其中:Au=进样样品溶液S2中拉莫三嗪的峰面积N=被测片剂的数量DFs=标准溶液的稀释因子(500)DFu=样品溶液的稀释因子(5mg片剂的是250,25mg片剂的是1000,50mg片剂的是1250,100mg片剂的是2500,200mg片剂的是5000)L=标签上含量
根据下式计算出在化合物A的保留时间洗脱出的次要分相对于拉莫三嗪标准物的含量:其中Ai=进样的样品溶液S2中的化合物A峰面积Ws=所取拉莫三嗪参比标准物的重量(mg)As=进样标准溶液中的拉莫三嗪峰面积0.79-对化合物A的相对响应因子
同样,与拉莫三嗪的有关其它第二组分的含量以%w/w的基值来计算,并假设该基值的相对响应因子为1.0。所得结果如表2所列:
表2
实施例4:通过HPLC测定药用物质(拉莫三嗪,粒度为125um)中的化合物A和B试验1-化合物B
组分 | 保留时间(分钟) | 相对保留时间 | 相对响应因子(RRf) |
化合物A | 5.5 | 3.9 | 0.79 |
拉莫三嗪 | 1.4 | 1.0 | 1.0 |
黑醋栗矫味剂 | 2.5 | 1.8 | - |
糖精钠 | 3.2 | 2.3 | - |
在甲醇和2-甲氧基乙醇的等体积混合物中制备下列标准溶液和被测溶液。
溶液1:5.0%w/v的样品溶液
溶液2:5.0%w/v的拉莫三嗪参比样品的溶液
溶液3:0.02%w/v的化合物B溶液
溶液4:溶液2从1.0ml稀释至250ml
溶液5:用10.0ml溶液3稀释10.0ml溶液4
溶液6:溶液5从7.5ml稀释至10.0ml
溶液7:溶液5从5.0ml稀释至10.0ml
溶液8:溶液5从2.5ml稀释至10.0ml
TLC的操作条件是:
平板:20×20cm,0.25mm厚的硅胶60F254涂层的平板,
流动相:乙酸乙酯/冰醋酸/甲醇(85∶10∶5v/v)
载样点:每种溶液10μl
展开长度:10cm
所述TLC平板风干后在254nm的紫外光下观测。只有当溶液5的色谱图出现两个明显分开的点,并且溶液8的色谱图也相应测出两个点时,试验才算有效。
估计出溶液1色谱图中Rf值相当于化合物B的次要点相对于溶液5、6、7和8色谱图中相当于化合物B(分别等于0.2、0.15、0.1和0.05%)的点的强度。
估计出溶液1色谱图中的次要点相对于溶液5、6、7和8色谱图中相当于拉莫三嗪(分别等于0.2、0.15、0.1和0.05%)的点的强度。
所得Rf值是:拉莫三嗪:0.20
化合物B:0.60
试验2-化合物A
在甲醇和2-甲氧基乙醇的等体积混合物中制备下列被测溶液和标准溶液。
溶液1:试验1中的溶液1
溶液2:0.05%w/v的化合物A溶液
TLC的操作条件是:
平板:20×20cm,0.25mm厚的硅胶60F254涂层的平板,
流动相:氯仿/甲醇/冰醋酸/1-丁醇(80∶10∶10∶5v/v)
载样点:溶液1为10μl,溶液2为1μl和2μl
展开长度:15cm
所述平板风干后在254nm的紫外光下观测。估计出溶液1色谱图中Rf值相当的次要点对于溶液2色谱图中相当于化合物A(分别等于0.1和0.2%w/w)的点的强度。
所得Rf值是:拉莫三嗪:0.25
化合物B:0.37实施例5:通过TLC测定药品(100mg拉莫三嗪片剂)中的化合物A标准溶液和样品溶液的制备
标准溶液的制备是通过:在100ml容量瓶内精确称重约10mg的化合物A,用甲醇溶解该化合物并稀释至刻度体积。
样品溶液的制备是通过:将一定量的粉化片剂(等于500mg拉莫三嗪)置于50ml容量瓶中。将粉末分散在15ml盐酸(0.1M)中,并加入甲醇∶2-甲氧基乙醇(15/15v/v,30ml)的混合物。将溶液置于超声浴中10分钟。该溶液随后被冷却至常温,用甲醇∶2-甲氧基乙醇溶剂混合物稀释至刻度体积。充分混合该溶液,经滤纸(WhatmanNo.1)过滤。澄清的滤液作为被测溶液。试验方法
TLC的操作条件是:
平板:20×20cm,0.25mm厚的硅胶60F254涂层的平板,
流动相:氯仿/甲醇/冰醋酸/1-丁醇(80∶10∶10∶5v/v)
载样点:被测溶液为10μl,标准溶液为3μl和5μl
展开长度:15cm
所述平板经风干后在254nm的紫外光下观测。
估计出样品溶液色谱图中除主要点以外其它所有点对于3μl标准溶液色谱图中(杂质率等于0.3%w/w)的点的强度。全部次要点的强度和不高于5μl上样的标准溶液(杂质率等于0.3%w/w)。
所得Rf值是:拉莫三嗪:0.20
化合物B:0.34
通过本说明书和所附的权利要求书,人们可以理解,词语“含有”和“包括”以及它们的变形(例如“它含有”、“含有着”、“它包括”“包括着”)是包含的解释,除非文中另有定义。也就是说,这些词语的使用可以暗示包括了没有特别引述的一种或多种成员。
本发明只是通过实施例进行说明,人们可以意识到,它们的改变形式同样属于本权利要求书的范围和实质中和本发明的范围内,对于所属领域专业人员来说基于上述公开的变化是显而易见的。
Claims (11)
1.一种检测拉莫三嗪或含有拉莫三嗪的药物剂型样品的纯度或降解稳定性的方法,该方法包括:检测所述样品中所存在的选自3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮和N-[5-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪3-基]-2,3-二氯苯甲酰胺的化合物。
2.根据权利要求1的检测拉莫三嗪样品纯度的方法,其中包括步骤:
(ⅰ)将拉莫三嗪样品溶于溶剂中以制得样品溶液;
(ⅱ)将3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮或N-[5-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-3-基]-2,3-二氯苯甲酰胺的样品溶解在溶剂中,以制备参比标识物的标准溶液;
(ⅲ)将所述样品溶液和所述标准溶液进行薄层色谱,得到各自的TLC色谱;和
(ⅳ)估算出得自样品溶液的色谱图中相对于标准溶液色谱图中的参比标识物点、相当于参比标识物Rf值的任何次要点的强度。
3.根据权利要求1的检测含有拉莫三嗪的药物剂型降解稳定性的方法,该方法包括步骤:
(ⅰ)将剂型样品溶于溶剂中以制得样品溶液;
(ⅱ)将3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮的样品溶解在溶剂中,以制备参比标识物的标准溶液;
(ⅲ)将所述样品溶液和所述标准溶液进行薄层色谱,得到各自的TLC色谱;和
(ⅳ)估算出得自样品溶液的色谱图中相对于标准溶液色谱图中的参比标识物点相当于参比标识物Rf值的任何次要点的强度。
4.根据权利要求1所述的检测含有拉莫三嗪的药物剂型降解稳定性的方法,该方法包括步骤:
(ⅰ)将剂型的样品溶解在溶剂中以生成一种或多种样品溶液;
(ⅱ)将拉莫三嗪参比标准物样品溶解在溶剂中以生成标准溶液;
(ⅲ)将样品溶液和标准溶液注射到HPLC柱内,和
(ⅳ)测出各溶液的主峰的面积,并由此计算出参比标识物3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮在各样品溶液中的含量。
6.权利要求6所述化合物的样品,该样品基本上纯净。
7.根据权利要求6所述的样品,该样品的纯度等于或高于90%。
9.根据权利要求8所述的一种方法,其中,步骤(ⅱ)中,化合物(Ⅰ)是通过将式(Ⅱ)和(Ⅲ)的化合物在无机酸的存在下进行反应而制成。
10.根据权利要求9的方法,其中式(Ⅱ)化合物是通过用氨基胍碳酸氢盐的硫酸溶液处理2,3-二氯苯甲酰基氰化物而制得。
11.选自3-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-5-(4H)-酮和N-[5-氨基-6-(2,3-二氯苯基)-1,2,4-三嗪-3-基]-2,3-二氯苯甲酰胺的化合物在检测拉莫三嗪或含有拉莫三嗪的药物剂型样品的纯度或降解稳定性中作为参比标识物的用途。
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GR68380B (zh) | 1979-06-01 | 1981-12-28 | Wellcome Found | |
EP0021120B1 (en) | 1979-06-01 | 1983-04-06 | The Wellcome Foundation Limited | 3,5-diamino-1,2,4-triazine derivatives, process for preparing such compounds and pharmaceutical compositions containing them |
GB8613183D0 (en) | 1986-05-30 | 1986-07-02 | Wellcome Found | Triazine salt |
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GB9426448D0 (en) * | 1994-12-30 | 1995-03-01 | Wellcome Found | Process |
GB9512854D0 (en) * | 1995-06-23 | 1995-08-23 | Wellcome Found | Novel formulation |
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