CN113820432A - Hplc-dad-cad联用定量筛查清热解毒口服液中14个添加剂成分的方法 - Google Patents
Hplc-dad-cad联用定量筛查清热解毒口服液中14个添加剂成分的方法 Download PDFInfo
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Abstract
本发明公开了HPLC‑DAD‑CAD联用定量筛查清热解毒口服液中14个添加剂成分的方法,14个添加剂成分为山梨酸、羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯异丙酯、羟苯丁酯、羟苯异丁酯、糖精钠、安赛蜜、苯甲酸、阿斯巴甜、纽甜、阿力甜和甜蜜素,HPLC色谱参数包括:规格为4.6×250mm、5μm的C18色谱柱,甲醇‑20mM乙酸铵水梯度洗脱,DAD检测器和CAD电喷雾检测器联用。本发明提供的方法操作简便,灵敏度高,实用性好,可以同时对清热解毒口服液中14个有限量的成分进行筛查,克服了现有技术中大批量样品多类成分同时测定的困难。
Description
技术领域
本发明属于药物分析领域,具体涉及一种HPLC-DAD-CAD联用定量筛查清热解毒口服液中14个添加剂成分的方法。
背景技术
药用辅料系指生产药品和调配处方时使用的赋形剂和附加剂,包括了防腐剂、矫味剂及甜味剂等。口服液中所用的辅料,主要为矫味剂、甜味剂和防腐剂。目前我国药用辅料标准不足,导致药品生产企业所用的辅料标准存在多样性,既有国家法定标准,如药典标准、局颁标准,又有地方药品标准,还有其他标准,如食品标准、化工标准、企业标准等。非药典标准的材料作为药用辅料的现象较为常见。同时生产企业的辅料管理水平参差不齐,非药用级别的辅料直接使用,存在一定的风险。
在调研中我们发现清热解毒口服液生产企业所使用的添加剂类型众多(矫味剂有蛋白糖、甜菊糖苷、蔗糖、糖精钠、薄荷脑、甜蜜素、香蕉或桔子香精等,防腐剂有苯甲酸、山梨酸等),且添加剂量不明。为了能批量快速地考察清热解毒口服液中添加剂的情况,我们需要建立一种能同时测定多种添加剂的分析方法。目前的分析方法多为单个检测器检测,无法满足大批量样品多类成分的同时测定。
为了克服现有技术的不足,特提出本发明。
发明内容
本发明的目的在于克服现有技术的不足,提供一种HPLC-DAD-CAD联用定量筛查清热解毒口服液中14个添加剂成分的方法。
本发明上述目的通过如下技术方案实现:
一种HPLC-DAD-CAD联用定量筛查清热解毒口服液中14个添加剂成分的方法,所述14个添加剂成分为山梨酸、羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯异丙酯、羟苯丁酯、羟苯异丁酯、糖精钠、安赛蜜、苯甲酸、阿斯巴甜、纽甜、阿力甜和甜蜜素,该方法包括如下HPLC色谱参数:
色谱柱:C18色谱柱,规格为4.6×250mm、5μm;
流动相:甲醇-20mM乙酸铵水,梯度洗脱程序如下:
检测器:DAD检测器和CAD电喷雾检测器。
进一步地,C18色谱柱为Waters XBridge Shield RP18。
进一步地,流速为0.8mL·min-1。
进一步地,柱温为35℃。
进一步地,所述DAD检测器的检测波长为230nm和255nm,同时开启全波长检测。
进一步地,所述CAD电喷雾检测器的采集频率为10Hz,滤光片为1s,雾化器温度为35℃。
有益效果:
本发明提供的方法操作简便,灵敏度高,实用性好,可以同时对清热解毒口服液中14个有限量的成分进行筛查,克服了现有技术中大批量样品多类成分同时测定的困难。
附图说明
图1为防腐剂混合对照品溶液的色谱图;
图2为甜味剂混合对照品溶液的色谱图;
图3为自制标准制剂溶液(空白)的色谱图;
图4为口服液中添加剂F1苯甲酸的筛查液相色谱图;
图5为口服液中添加剂T1糖精钠的筛查液相色谱图;
图6为口服液中添加剂T5安赛蜜的筛查液相色谱图。
具体实施方式
下面结合实施例具体介绍本发明实质性内容,但并不以此限定本发明的保护范围。
一、仪器与试药
1、仪器
Dionex Ultimate 3000型高效液相色谱仪配DAD检测器及Corona Veo电喷雾检测器(Thermo FisherScientific,USA)。AG245电子天平(METTLER,Swiss)。
2、试药
纯水(Millpore,USA);色谱级甲醇(Honeywell,USA)。对照品来源、批号及纯度见表1。空白制剂为参照标准处方未加任何添加剂的自制制剂。样品来源为2021年清热解毒口服液国家药品抽验。
表1对照品信息表
二、方法与结果
1、色谱条件
采用Waters XBridge Shield RP18色谱柱(4.6×250mm,5μm),流动相为甲醇-20mM乙酸铵水,梯度洗脱见表2液相梯度洗脱程序。流速为0.8mL·min-1,柱温为35℃。DAD检测器:检测波长230nm及255nm,同时开启全波长检测。CAD电喷雾检测器:采集频率10Hz,滤光片1s,雾化器温度35℃(混合对照品溶液及空白色谱图见图1~3)。
表2液相梯度洗脱程序
2、对照品储备液的制备
精密称取各对照品10mg,甜味剂加水定容于10mL容量瓶中,防腐剂加50%乙醇定容于10mL容量瓶中,即得。甜味剂对照品溶液需临用新制。
3、供试品溶液的制备
精密量取清热解毒口服液1mL,加水稀释并定容至5mL,0.22μm滤膜滤过,即得供试品溶液。
4、标准曲线的制备及线性考察
将对照品储备液对半稀释,配成系列浓度的对照品溶液。按“1、色谱条件”分别进样进行测定,CAD检测器数据以各对照品的峰面积(Y)对其质量浓度(X,mg)分别取对数绘制标准曲线,DAD检测器数据以各对照品的峰面积(Y)对其质量浓度(X,mg)绘制标准曲线,计算回归方程、线性范围及相关系数。14个成分在线性范围内均有良好的线性关系。对照品溶液逐级稀释后进样,以信噪比(S/N)为3:1为检测限,10:1为定量限。结果见表3。
表3 14个化学成分线性关系及LOD、LOQ
5、精密度
分别取质量浓度约为250、100、50μg·mL-1混合对照品溶液,按“1、色谱条件”分别进样6次进行测定,结果14个成分的RSD均小于3.0%,表明仪器精密度良好(表4精密度)。
表4精密度
6、重复性
取以苯甲酸为防腐剂的口服液供试品溶液(YP0020),按“1、色谱条件”分别进样6次进行测定,口服液中苯甲酸的RSD为0.04%。取以糖精钠为甜味剂的口服液供试品溶液(YP0122),按“1、色谱条件”分别进样6次进行测定,口服液中糖精钠的RSD为0.09%。
7、稳定性
取质量浓度约为250μg·mL-1混合对照品溶液,分别放置2,4,8,12及24h后,按“1、色谱条件”分别进样进行测定,计算各组分的RSD,结果14个成分的RSD均小于4.0%,表明在24h内稳定性良好(表5稳定性)。
表5稳定性
8、加样回收率
取阴性口服液样品,分别加入高、中、低3个水平(0.5、0.25、0.025μg·mL-1)的混合对照品溶液,每个浓度溶液按下表方法平行制备6份供试品溶液,按“1、色谱条件”进样测定,计算各成分的加样回收率及RSD。14个成分的平均回收率为91.2-101.9%,RSD均小于5.0%(表6加样回收率)。
表6加样回收率
9、样品测定
对44家企业200批次口服液样品进行液相测定,结果防腐剂检出苯甲酸、山梨酸共计2种,甜味剂检出糖精钠、安赛蜜共计2种(色谱图见图4~6)。根据《中国药典》2020年版四部制剂通则0181合剂项下规定苯甲酸用量不得超过0.3%。参照GB2760饮料类国标,糖精钠最大使用量以糖精计最大使用量为0.15g/kg(mg/g),安赛蜜为0.3g/kg(mg/g)。涉及超出限度的添加剂有苯甲酸、糖精钠和安赛蜜。苯甲酸涉及1家生产企业2批次样品,糖精钠涉及5家生产企业15批次样品,安赛蜜涉及2家企业4批次样品,具体数据见表7口服液样品中超出限度添加剂含量。涉及22家生产企业92批次样品使用苯甲酸为防腐剂,含量为0.01~0.53%,均值为0.20%。
表7口服液样品中超出限度添加剂含量
口服液现行标准中处方内容为“加矫味剂适量”及“滤过,灌封,灭菌,即得”,根据标准处方内容应不需添加防腐剂,而矫味剂种类不限。根据食品药品监管总局2016年8月9日发布《关于药包材药用辅料与药品关联审评审批有关事项的公告》(2016年第134号)有关内容解读:(一)矫味剂(甜味剂):如蔗糖、单糖浆、甘露醇、山梨醇、糖精钠、阿司帕坦、三氯蔗糖、甜菊糖苷、葡萄糖、木糖醇、麦芽糖醇等。该类品种仅限于在制剂中作为矫味剂(甜味剂)使用。(二)香精、香料:如桔子香精、香蕉香精、香兰素等。执行食品标准的,应符合现行版GB2760《食品安全国家标准食品添加剂使用标准》、GB30616《食品安全国家标准食品用香精》及GB29938《食品安全国家标准食品用香料通则》等相关要求。根据GB2760《食品安全国家标准食品添加剂使用标准》中要求部分矫味剂具有明确的使用范围和最大使用量,本次研究口服液检出的甜味剂中涉及甜糖精钠及安赛蜜有最大使用量的要求。200批次清热解毒口服液中共21批次涉及8家企业超出拟定限度,但超出含量有限,根据风险研判,安全性风险较低。
综上可见,本发明提供的方法操作简便,灵敏度高,实用性好,可以同时对清热解毒口服液中14个有限量的成分进行筛查。
上述实施例的作用在于具体介绍本发明的实质性内容,但本领域技术人员应当知道,不应将本发明的保护范围局限于该具体实施例。
Claims (6)
2.根据权利要求1所述的方法,其特征在于:C18色谱柱为Waters XBridgeShieldRP18。
3.根据权利要求1所述的方法,其特征在于:流速为0.8mL·min-1。
4.根据权利要求1所述的方法,其特征在于:柱温为35℃。
5.根据权利要求1所述的方法,其特征在于:所述DAD检测器的检测波长为230nm和255nm,同时开启全波长检测。
6.根据权利要求1所述的方法,其特征在于:所述CAD电喷雾检测器的采集频率为10Hz,滤光片为1s,雾化器温度为35℃。
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