CN113848279A - 一种药物中残留试剂硫酸二甲酯的检测方法 - Google Patents
一种药物中残留试剂硫酸二甲酯的检测方法 Download PDFInfo
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Abstract
本发明属于药物杂质分析检测领域,针对硫酸二甲酯易水解难检测问题,建立了一个准确测定药物中残留硫酸二甲酯的离子色谱检测方法。在室温下硫酸二甲酯在水中易水解为硫酸单甲酯,故通过离子色谱法检测硫酸单甲酯含量,即可达到控制硫酸二甲酯含量的目的。精密称取待测药物250mg,置50ml量瓶中,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀即可。将上述溶液经固相萃取小柱过滤后,直接用离子色谱测定硫酸单甲酯的含量。该方法成本低、简便快速、灵敏度高、精密度好,检测定量限可达15ng/ml。该法适用于药物中硫酸二甲酯的准确测定,同时为制定相关的药物检测质量标准提供了参考。
Description
技术领域
本发明属于药物检测技术领域,具体涉及一种药物中残留杂质硫酸二甲酯的检测方法。
技术背景
硫酸二甲酯英文名称Dimethyl sulfate,别名硫酸甲酯,化学式C2H6O4S,为无色或微黄色、略有葱头气味的油状可燃性液体,分子量126.14,相对密度1.3322(20℃/4℃),熔点31.8℃。沸点188℃/开环。溶于乙醇和乙醚,在水中溶解度2.8g/100ml。在室温下极易水解为硫酸单甲酯和甲醇,在50℃或者碱水易迅速水解成硫酸和甲醇。遇热、明火或氧化剂可燃。
硫酸二甲酯是潜在的致癌物质和可引起染色体畸变的诱变剂,属高毒类物质,作用与芥子气相似,急性毒性类似光气,比氯气大15倍。对眼、上呼吸道有强烈刺激作用,对皮肤有强腐蚀作用。可引起结膜充血、水肿、角膜上皮脱落,气管、支气管上皮细胞部分坏死,穿破导致纵膈或皮下气肿。此外,还可损害肝、肾及心肌等。
硫酸二甲酯是重要的化工原料,常作为甲基化试剂用于有机合成领域。硫酸二甲酯在药物合成中常做为甲基化试剂,因其含有遗传毒性致癌性杂质的警示结构,人用药物注册技术要求国际协调会指南ICH M7分类为3类基因毒性杂质,可能成为引发癌症的诱因,因此,能够检测药物中残留的硫酸二甲酯对于控制临床用药的安全性具有非常重要的意义。
目前,报道的硫酸二甲酯的相关检测方法主要有气相色谱法、气质联用法、液相色谱法和液质联用法,检测领域包括空气、土壤、药物及表面活性剂等,还未见用离子色谱法对硫酸二甲酯进行检测的报道。气相色谱法和液相色谱法均需要进行衍生化反应,操作步骤繁琐。而气质和液质联用法检测的灵敏度低,无法达到药物对遗传毒性杂质的限度控制要求。
硫酸二甲酯和硫酸单甲酯的化学结构式如下:
硫酸二甲酯常温下在水中不稳定,易水解为硫酸单甲酯。用离子色谱对硫酸单甲酯进行检测,即可达到准确测定硫酸二甲酯的目的。该方法前处理简单,定量准确,灵敏度、精密度和回收率良好。
发明内容
本发明所要解决的技术问题是提供一种能够准确测定药物中残留硫酸二甲酯的检测方法,检测对象为硫酸单甲酯。用氢氧化钠水溶液将硫酸二甲酯水解为硫酸单甲酯后,直接用离子色谱法进行检测。该检测方法灵敏度高,专属性良好,可以准确评价药物的质量,对临床用药安全性具有非常重要的意义。
为此,本发明公开了一种药物中硫酸二甲酯的检测方法,包括以下步骤:
1.样品前处理:精密称取待测药物250mg,置50ml量瓶中,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀即可。将上述溶液经固相萃取小柱过滤后,直接用离子色谱测定硫酸单甲酯的含量。其水解方程式如下:
2.离子色谱仪器条件
色谱柱:Dinex IonPac7M AS11-HC RFIC7M 4*250mm Analytical
保护住:Dinex IonPac7M AG11-HC RFIC7M 4*250mm Guard
淋洗液:30mmol/L氢氧化钾
检测器:电导检测器
抑制器:阴离子抑制器
电流:75mA
流速:1.0ml/min
进样量:25μl
上控柱温箱:25℃
柱温:40℃
池温:35℃
样品前处理溶剂:30mmol/L氢氧化钠
有益效果
目前,未见用离子色谱法检测药物中硫酸二甲酯的有关报道,本发明提供的一种药物中残留硫酸二甲酯的检测方法,该方法有利于实现对药物的质量控制,具备操作简单、准确度高、专属性良好和灵敏度高的优点。
附图说明
图1为硫酸单甲酯的标准曲线。
具体实施方法
以下结合具体实施例,进一步阐述本发明。这些实施例仅用于说明本发明,而不用于
限制本发明的使用范围。
实施例1
泮托拉唑钠中残留硫酸二甲酯的检测:
泮托拉唑钠,化学名为:5-二氟甲氧基-2-[[(3,4-二甲氧基-2-吡啶基)-甲基]亚磺酰基]-1H-苯并咪唑钠一水合物,化合物结构式为:
注射用泮托拉唑钠,用于治疗消化性溃疡出血、非甾体类抗炎药引起的急性胃黏膜损伤和应激状态下溃疡大出血的发生、全身麻醉或大手术后以及衰弱昏迷患者防止胃酸反流合并吸入性肺炎。本品为胃壁细胞质子泵抑制剂,在中性和弱酸性条件下相对稳定,在强酸性条件下迅速活化,其pH依赖的活化特性,使其对H+、K+-ATP酶的作用具有更好的选择性。本品能特异性地抑制壁细胞顶端膜构成的分泌性微管和胞浆内的管状泡上的H+、K+-ATP酶,引起该酶不可逆性的抑制,从而有效地抑制胃酸的分泌。硫酸二甲酯是制备泮托拉唑钠的甲基化试剂,含有遗传毒性致癌性杂质的警示结构,ICH M7分类为3类基因毒性杂质,可能成为引发癌症的诱因。因此,能够建立泮托拉唑钠中残留硫酸二甲酯的检测方法,对于控制临床用药的安全性具有非常重要的意义。
检测的操作过程如下:
1.样品前处理:精密称取待测药物250mg,置50ml量瓶中,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀即可。将上述溶液经固相萃取小柱过滤后,直接用离子色谱测定硫酸单甲酯的含量。
2.仪器与试剂:
热电公司ICS-6000离子色谱仪
标准物质:硫酸单甲酯
氢氧化钠:优级纯
氢氧化钾:优级纯
3.仪器分析条件:
色谱柱:Dinex IonPac7M AS11-HC RFIC7M 4*250mm Analytical
保护住:Dinex IonPac7M AG11-HC RFIC7M 4*250mm Guard
淋洗液:30mmol/L氢氧化钾
检测器:电导检测器
抑制器:阴离子抑制器
电流:75mA
流速:1.0ml/min
进样量:25μl
上控柱温箱:25℃
柱温:40℃
池温:35℃
样品前处理溶液:30mmol/L氢氧化钠
4.实验过程
(1)灵敏度:
硫酸单甲酯储备液(100μg/ml):精密称取硫酸单甲酯2.5mg,置25ml量瓶中,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀。
硫酸单甲酯定位溶液(10μg/ml):精密量取硫酸单甲酯储备液2.5ml,置25ml量瓶中,用30mmol/L氢氧化钠溶液定容至刻度,摇匀。
定量限溶液:精密量取硫酸单甲酯定位溶液(10μg/ml)0.15ml,置100ml量瓶中,用30mmol/L氢氧化钠溶液定容至刻度,摇匀。
检测限溶液:精密量取定量限溶液12.5ml,置25ml量瓶中,用30mmol/L氢氧化钠溶液定容至刻度,摇匀。
检测结果如下:
表1灵敏度实验结果
(2)线性:
标准溶液1(定量限):定量限溶液0.015μg/ml。
标准溶液2(0.06μg/ml):精密量取硫酸单甲酯定位溶液(10μg/ml)0.6ml,置100ml量瓶中,用30mmol/L氢氧化钠溶液定容至刻度,摇匀。
标准溶液3(0.2μg/ml):精密量取硫酸单甲酯定位溶液(10μg/ml)1ml,置50ml量瓶中,用30mmol/L氢氧化钠溶液定容至刻度,摇匀。
标准溶液4(1μg/ml):精密量取硫酸单甲酯定位溶液(10μg/ml)2.5ml,置25ml量瓶中,用30mmol/L氢氧化钠溶液定容至刻度,摇匀。
标准溶液5(5μg/ml):精密量取硫酸单甲酯储备液(100μg/ml))5.0ml,置100ml量瓶中,用30mmol/L氢氧化钠溶液定容至刻度,摇匀。
线性实验结果如下:R2=0.9996
表2线性实验结果
名称 | 浓度(μg/ml) | 峰面积 |
定量限 | 0.015 | 0.0008 |
2 | 0.06 | 0.0028 |
3 | 0.2 | 0.006 |
4 | 1 | 0.0534 |
5 | 5 | 0.2891 |
(3)进样精密度:
取定量限溶液连续进样六次,检测结果如下:
表3进样精密度实验结果
名称 | 1 | 2 | 3 | 4 | 5 | 6 | RSD(%) |
峰面积 | 0.0009 | 0.0008 | 0.0009 | 0.0008 | 0.0009 | 0.0008 | 6.44 |
保留时间 | 5.370 | 5.360 | 5.360 | 5.360 | 5.360 | 5.360 | 0.08 |
(4)加标回收率:
溶液配制:
硫酸单甲酯储备液(0.8μg/ml):精密称取硫酸单甲酯2mg,置50ml量瓶中,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀。取1ml上述溶液,置50ml量瓶中,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀,同法配制三份。
硫酸单甲酯对照品溶液(0.08μg/ml):精密量取硫酸单甲酯储备液5ml置50ml量瓶中,用30mmol/L氢氧化钠溶液定容至刻度,摇匀,同法配制两份。
50%加标回收率溶液:精密称取自制品200420批次泮托拉唑钠样品250mg,置50ml量瓶中,加入批检验项下硫酸单甲酯储备液(0.8μg/ml)2.5ml,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀,同法配制三份。
100%回收率溶液:精密称取自制品200420批次泮托拉唑钠样品250mg,置50ml量瓶中,加入批检验项下硫酸单甲酯储备液(0.8μg/ml)5ml,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀,同法配制三份。
150%回收率溶液:精密称取自制品200420批次泮托拉唑钠样品250mg,置50ml量瓶中,加入批检验项下硫酸单甲酯储备液(0.8μg/ml)7.5ml,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀,同法配制三份。
取上述溶液各25μl进样,用离子色谱仪进行检测。实验结果如下:
表4加标回收率实验结果
可接受标准为:回收率在80-115%之间,RSD值小于20%。
(5)泮托拉唑钠中硫酸二甲酯的检测:
精密称取自制品200420批次泮托拉唑钠样品250mg,置50ml量瓶中,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀,同法配制三份。直接上级检测,泮托拉唑钠中未检出硫酸二甲酯。
Claims (1)
1.一种药物中残留硫酸二甲酯的检测方法,其特征在于:所述检测对象为硫酸单甲酯;包括下列步骤:精密称取待测药物250mg,置50ml量瓶中,用30mmol/L氢氧化钠溶液溶解并定容至刻度,摇匀即可;将上述溶液经固相萃取小柱过滤后,直接用离子色谱测定硫酸单甲酯的含量;其水解方程式如下:
检测的仪器条件为:
离子色谱仪
色谱柱:Dinex IonPac7M AS11-HC RFIC7M 4*250mm Analytical
保护住:Dinex IonPac7M AG11-HC RFIC7M 4*250mm Guard
淋洗液:30mmol/L氢氧化钾
检测器:电导检测器
抑制器:阴离子抑制器
电流:75mA
流速:1.0ml/min
进样量:25μl
上控柱温箱:25℃
柱温:40℃
池温:35℃
样品前处理溶剂:30mmol/L氢氧化钠。
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