离子液体与传统顶空溶剂在HS-GC中的顶空富集效率及药物残留溶剂检测方法的研究
摘要
药物有机溶剂残留量的检测主要采用直接进样气相色谱法和顶空进样气相色谱法(HS-GC),其中顶空进样法集分离、富集于一体,是目前使用较多的方法,然而对于某些热不稳定的药物或不溶于常用的顶空溶剂(如水、二甲基乙酰胺DMA或二甲基亚砜DMSO等)药物,仅限于直接进样法检测,而直接进样不仅灵敏度较低,且严重污染色谱系统,很难达到痕量残留溶剂的检测要求。此外,传统顶空溶剂具有挥发性,顶空平衡时不但会与残留溶剂同时争夺上层顶空空间,影响残留溶剂的富集,且高沸点的顶空溶剂进入色谱系统后,其宽大的色谱峰会干扰有机溶剂的检出甚至污染检测器,造成检测器“中毒”。不仅如此,传统顶空溶剂DMSO等本身并不稳定,长时间放置或加热可生成多种挥发性杂质,因此当使用这些溶剂时,往往需要扣除“溶剂空白”。上述这些因素在很大程度上影响了痕量溶剂残留分析的检测灵敏度,因此寻找溶解性强及对残留溶剂顶空分配行为好的顶空溶剂,对药物中残留溶剂检测灵敏度的提高具有重要的意义。
离子液体(Ionic liquids,ILs)溶解性强、无蒸汽压、几乎不挥发、热稳定性好,液程宽、在常温甚至高温三百度以上均以液态存在;其可设计性强,可根据特定的目的设计所需的离子液体体系。ILs的这些天然特性,使其在一定程度上可作为优良的顶空溶剂应用于药物溶剂残留量的检测。相关文献已报道了ILs可作为顶空溶剂应用于药物残留溶剂的检测,其对某些高沸点的残留溶剂具有良好的顶空分配行为。然而,对于某些低沸点的或烷烃类、醇类及芳烃类等有机溶剂残留在ILs及传统顶空溶剂中的顶空分配行为的系统研究未见报道。
因此,本文的目的是通过研究不同顶空溶剂(如水、DMSO、DMA、ILs等)对药物的溶解性及其有机残留溶剂的顶空分配行为,筛选出更为合适的顶空溶剂用于马来酸氯苯那敏、薁磺酸钠、伊班膦酸钠及一些难溶性药物例如紫杉醇、萘替芬、布洛芬等原料药的溶剂残留量检测,进一步解决残留溶剂检测灵敏度低的问题。结果表明:在一些水溶性溶剂(如丙酮、四氢呋喃、吡啶等)及某些醇类(如甲醇、乙醇及异丙醇等)残留溶剂分析中,ILs比水、DMSO等表现出更高的顶空富集能力;对于某些低沸点的残留溶剂(如乙酸乙酯)及某些正烷烃类(如正己烷、正庚烷等)ILs对其的顶空富集效率高于DMSO、DMA等传统顶空溶剂;ILs具有不挥发,不会被引入色谱系统而造成污染,其空白色谱图中基线平稳,几乎不存在杂质,也避免了传统顶空溶剂因挥发而产生的宽大色谱峰干扰测定的问题;但ILs对芳烃类残留溶剂(如甲苯、氯苯等)的顶空富集能力不及水,水是这些残留溶剂的理想顶空溶剂。此外,ILs对药物溶解性与结构有关,疏水性ILs对萘替芬药物的溶解能力强于亲水性ILs,烷基链长的ILs对布洛芬的溶解能力强于烷基链短的ILs,然而ILs对盐类药物(如薁磺酸钠、伊班膦酸钠)的溶解性能较传统溶剂差,因而针对这些原料药检测,本研究选择了传统顶空溶剂进行了检测,灵敏度得到了改善。
综上研究,ILs可作为新型顶空溶剂,有效的提高检测灵敏度,为药物原料药的有机溶剂残留分析提供了新途径、新方法,对药品质量控制具有重要意义。针对某些在ILs中难溶的药物,可采用传统的顶空溶剂来分析残留量。
第一部分新型顶空溶剂离子液体在药物有机溶剂残留检测中的应用
(一)室温离子液体为溶剂对马来酸氯苯那敏中多种有机溶剂残留的同时顶空分析
目的:研究ILs与水、DMSO对残留溶剂的理想行为,来提高水溶性的有机残留溶剂丙酮、四氢呋喃、吡啶等溶剂的富集效率,并建立灵敏、准确、专属性强的马来酸氯苯那敏原料药中丙酮、四氢呋喃、二氧六环、吡啶及甲苯五种溶剂残留量的检测方法。
方法:采用顶空气相色谱法,以峰面积大小为比较指标,考察[Emim][BF_4]及水、DMSO对五种有机溶剂残留的顶空富集能力。顶空富集方法:精密量取2mL待测溶液于10mL顶空瓶中,在平衡温度100℃下,平衡20min进样1.0mL。色谱分析条件:以[Emim][BF_4]为顶空溶剂的HS-GC法检测马来酸氯苯那敏中五种溶剂残留量,采用ZB-1毛细管柱,进样口温度180℃,检测器(FID)温度200℃,柱温采用程序升温方式:初始60℃维持4min,以4℃/min升温至130℃,维持10min。
结果:[Emim][BF_4]对所研究的有机残留溶剂的顶空富集能力明显比DMSO及水强,且其不干扰检测,对于在水中易溶解的丙酮、四氢呋喃及吡啶,ILs对这些残留溶剂的顶空富集能力比水要高出近3倍。方法学验证结果:丙酮、四氢呋喃、二氧六环、吡啶及甲苯分别在3.13~100、2.25~72.0、1.13~36.0、0.625~20.0及2.78~89.0μg·mL~(-1)范围内线性关系良好,回收率为86.0% ~96.9%,RSD均小于5.0%。
结论:离子液体为顶空溶剂,能够解决丙酮、四氢呋喃及吡啶等水溶性残留溶剂检测灵敏度低的问题,而且其无蒸汽压,能够避免传统顶空溶剂对色谱系统的污染。以[Emim][BF_4]为顶空溶剂的顶空气相色谱法新颖、灵敏、准确、专属性强,适合于马来酸氯苯那敏原料药中有机溶剂残留的检测分析。
(二) [Emim][BF_4]与DMSO、DMA分别作为顶空溶剂的HS-GC法检测紫杉醇药物中痕量有机残留溶剂的研究
目的:研究[Emim][BF_4]与DMSO、DMA对待测残留溶剂的检测灵敏度的影响,来解决多种低沸点的及烷烃类有机残留溶剂的同时检测时检测灵敏度低的问题,并建立难溶性药物紫杉醇中丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷等五种溶剂残留量的灵敏、准确、专属性强的色谱检测方法。
方法:以顶空峰面积大小为比较指标,采用顶空气相色谱法来研究[Emim][BF_4]与DMSO、DMA对丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷等五种溶剂检测灵敏度的影响。顶空富集方法:精密量取待测溶液2mL置10mL顶空瓶中,加盖密封,于110℃顶空温度下平衡20min,抽取上层顶空空间气体1mL,进样测定。色谱分析方法:采用DB-624毛细管柱,FID温度200℃,进口温度180℃,柱温采用程序升温:初温50℃维持5min,以20℃/min的速率升温至120℃维持10min;顶空分析条件:样品在110℃顶空温度下平衡20min后,进样1.0mL检测。
结果:[Emim][BF_4]对丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷等残留溶剂的顶空富集能力(用峰面积表示)分别约是DMSO作为顶空溶剂时的2.10倍、2.50倍、2.80倍、3.40倍及1.30倍,约是DMA作为顶空溶剂时的2.04倍、4.50倍、3.00倍、3.00倍及6.0倍,且待测残留溶剂在[Emim][BF_4]中的检测限明显比DMSO及DMA的低,离子液体空白基线平稳,不干扰测定。方法学验证结果:丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷分别在31.3~500、1.82~29.0、31.3~500、4.50~72.0及31.3~500μg·mL~(-1)范围内线性关系良好,回收率为90.8%~97.8%,RSD均小于5.0%。
结论:[Emim][BF_4]作为顶空溶剂对丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷的顶空富集效率较传统顶空溶剂DMSO、DMA高出2~6倍,而且可避免传统顶空溶剂的干扰。采用[Emim][BF_4]作为顶空溶剂的气相色谱法检测难溶性药物紫杉醇中的多种溶剂残留量,方法灵敏,准确可靠,专属性强,为药物溶剂残留检测提供了新途径。
(三)离子液体与水、DMSO分别作为顶空溶剂的HS-GC法检测难溶性药物萘替芬中残留溶剂的研究
目的:选择对难溶性药物萘替芬溶解性好及对一些短链醇类及甲苯顶空富集能力强的顶空溶剂,并建立难溶性药物萘替芬原料药中甲醇、乙醇、异丙醇及甲苯残留量的灵敏、准确、专属性强的色谱检测方法。
方法:采用静态平衡法,考察不同温度下[Bmim][BF_4]和[Bmim][PF_6]对萘替芬的溶解特性,并以顶空气相色谱法比较研究上述两种离子液体、二甲基亚砜(DMSO)及水分别作为顶空溶剂对残留有机溶剂的顶空分配行为。顶空富集方法:取待测溶液2mL置10mL顶空瓶中,加盖,密封,在100℃顶空温度下平衡20min后,抽取顶空气体0.5mL,进样测定。对萘替芬中甲醇、乙醇、异丙醇及甲苯等残留溶剂进行方法学考察,色谱分析条件为:DB-624毛细管柱,FID温度200℃,进样口温度180℃,柱温采用程序升温:初温45℃维持3min,以25℃/min的速率升温至120℃维持5min;
结果:[Bmim][PF_6]在90℃时对药物的溶解量达到120mg·mL~(-1)以上,而同温度下[Bmim][BF_4]对药物的溶解量不到90mg·mL~(-1),同时两种离子液体对甲醇、乙醇及异丙醇的顶空富集能力较水、DMSO强,且其中[Bmim][BF_4]顶空富集能力最强,而水对甲苯的顶空富集能力最好。方法学验证结果:甲醇、乙醇、异丙醇及甲苯分别在3.00×10~(-1)~1.50×10~2、5.00×10~(-1)~2.50×10~2、5.00×10~(-1)~2.5×10~2及1.40×10~(-1)~89.0μg·mL~(-1)范围内线性关系良好,回收率为92.0%~95.9%,RSD均小于4.0%。
结论:亲水性ILs对药物的溶解能力相对于疏水性ILs稍弱,但通过提高顶空温度,其对药物的溶解量能够满足检测要求,并且其对三种醇类有机溶剂的顶空富集能力比[Bmim][PF_6]强,尤其明显比传统顶空溶剂水、DMSO强。因此本文选择了无蒸汽压的[Bmim][BF_4]作为顶空溶剂进行了残留溶剂分析,方法新颖独特,准确可靠,方法的检测灵敏度得到了改善。
(四)混合离子液体为顶空溶剂测定布洛芬原料药中残留有机溶剂
目的:以混合离子液体为顶空溶剂,解决难溶性药物布洛芬的溶解问题及其残留溶剂检测灵敏度低的问题。
方法:采用顶空气相色谱法,考察阴离子相同的两种不同烷基链的离子液体[Bmim][BF_4]、[Hmim][BF_4]及其不同配比的混合溶剂对三氯甲烷、异丙醇及甲苯的顶空能力,并考察其对布洛芬原料药的溶解情况。顶空富集方法:取待测溶液2mL置10mL顶空瓶中,加盖密封,在110℃顶空温度下平衡30min后,抽取顶空气体0.5ml,进样测定。色谱分析条件为:采用HP-1毛细管色谱柱,FID温度200℃,进样口温度180℃,柱温采用程序升温:初温50℃维持5min,以10℃/min的速率升温至130℃维持5min。样品在110℃顶空温度下平衡30min后,抽取顶空气体0.5mL进样测定。
结果:[Bmim][BF_4]和[Hmim][BF_4]按以2:1配比混合作顶空溶剂,既改善了药物的溶解量,使其达到100mg·mL~(-1)以上,又提高了检测灵敏度。方法学验证结果:三氯甲烷、异丙醇及甲苯分别在5.00~400μg·mL~(-1)、6.00×10-2 ~6.00μg·mL~(-1)及0.890~71.2μg·mL~(-1)浓度范围内线性关系良好,其平均回收率分别为97.1%、93.8%及96.9%,RSD均小于4.0%。
结论:采用混合的离子液体作为顶空溶剂,解决了单个离子液体使用时对药物的溶解性差而对残留溶剂顶空富集效率高或对药物溶解性好而对残留溶剂顶空富集效率低的问题。以[Bmim][BF_4]和[Hmim][BF_4]按2:1配比混合作顶空溶剂的气相色谱法检测难溶性药物布洛芬的有机溶剂残留量,方法灵敏独特,准确可靠,为药物有机溶剂残留检测提供了新途径。
第二部分传统顶空溶剂在药物有机溶剂残留检测中的应用
(一) DMSO为顶空溶剂的毛细管气相色谱法测定薁磺酸钠原料药中有机溶剂的残留量
目的:解决薁磺酸钠的溶解问题,并建立该原料药中二氯乙烷和二氧六环有机溶剂残留量的检测方法。
方法:考察该药在水、DMSO及咪唑基离子液体中的溶解情况,并采用顶空气相色谱法检测该药中两种有机溶剂残留量。以DMSO为顶空溶剂检测药物残留溶剂的HS-GC法的色谱分析方法为:采用DB-624毛细管柱,FID温度200℃,进样口温度180℃,柱温采用程序升温:初温60℃,维持6min后,以30℃·min-1的速率升温至130℃,维持5min。顶空平衡温度为80℃,平衡时间为30min;进样量为1.0mL。
结果:薁磺酸钠在水中溶解量大,但加热会发生水解反应,产生的物质影响待测溶剂的富集;咪唑基离子液体[Emim][BF_4]对该药在80℃恒温水浴条件下仅有约20mg·mL~(-1)溶解,而DMSO对该药极易溶解,且该药溶解其中不发生水解反应。所建的DMSO为顶空溶剂的HS-GC法检测药物残留量的方法学验证结果:二氯乙烷和二氧六环分别在3.13×10-2~5.00×10~(-1)μg·mL~(-1)、2.38~38.0μg·mL~(-1)的浓度范围内线性关系良好,平均回收率分别为95.6%、97.2%,RSD(n=5)分别为2.0%、1.5%。
结论:DMSO对该药物具有较好的溶解量,并且避免了该药的水解,因而适合作为顶空溶剂测定该药物中有机溶剂残留量。
(二)水为顶空溶剂的气相色谱法检测伊班膦酸钠中甲苯和氯苯的残留量目的:建立伊班膦酸钠原料药中甲苯和氯苯残留量检测的高灵敏方法。
方法:以峰面积大小为比较指标,考察水、DMA及ILs对甲苯和氯苯的顶空富集效率,并以水为溶剂采用顶空气相色谱法对该药残留量进行检测。其色谱分析条件为:采用DB-624毛细管柱,FID温度200℃;进样口温度180℃,柱温采用程序升温:初温50℃维持3min,并以20℃/min的速率升温至130℃维持20min;顶空瓶平衡温度60℃,平衡时间30min,进样0.5mL。
结果:水对两种有机溶剂的顶空富集能力比DMA、咪唑基ILs强。以水为顶空溶剂的HS-GC法检测药物溶剂残留量的方法学验证结果表明:甲苯、氯苯分别在5.56~89.0μg·mL~(-1)、2.2~36.0μg·mL~(-1)的浓度范围内线性关系良好,平均回收率分别为91.1%、93.7%,RSD (n=5)分别为1.6%、1.4%。
结论:水对芳烃类溶剂的顶空富集效率最理想,适合作为水溶性药物中芳烃类溶剂残留量检测的顶空溶剂。
Residues in pharmaceuticals are commonly detected by gas chromatography, which includes direct injection and headspace sampling. HS injection is more frequently used than drect injection for its good seperation and sensitivity. However, for some thermal unstable drugs or ones having poor dissolubility in headspace diluents such as water, DMA, DMSO et al, direct injection is still adopted to determine residues in these drugs, and which has the low sensitivity and the GC system contaminated seriously. In determinating organic residual solvent by HS-GC, the reasonable choice of matrix medium is directly related to sensitivity and accuracy of detective methods. On account of volatility, conventional solvents not only affect the enrichment efficiency of residual solvents, but wide chromatographic peak produced in the process of analysis also interfere with analytes, even result in detector’s intoxication. Furthermore, some headspace matrix medium such as DMSO in themselves may produce many varieties of volatile impurities,when stored for a long time or heat. In that case, the result of the analysis of organic residual solvents should be correct by the blank matrix medium. In a word, the sensitivity of analysis of trace residues is influenced by the above factors to a large extent. Accordingly, looking for the ideal headspace matrix medium plays an important role in improving the sensitivity of the analysis of residues in pharmaceuticals.
Ionic liquids (ILs) as novel solvents show many unique properties, such as extraordinary dissolution, negligible vapor pressure, chemical stability, good thermal and wide liquid range. In addition, compared with traditional solvents, ILs can be better worked out, and it is possible to design ILs for practical application by varying structures of cation and anion. Therefore, ILs as fine headspace matrix medium may be applied for the detection of organic residual solvents in pharmaceuticals. It was reported that ILs had more sensitive enriching ability than DMSO for analytes with high boiling point or some water-insoluble drugs. However, the analysis of these residues, such as alkanes, spirits, aromatichydrocarbon or residues with low boiling point, is not reported recently.
The purpose of our research is to choose the suitable headspace matrix medium to analyze residues in Chlorphenamine Maleate, Sodium Azulenesulfonate, Ibandronate Sodium and some water-insoluble sample such as Paclitaxel, Naftifine, Ibuprofen , et al. By studying solubility of ILs and comparing ILs with traditional solvents, further to improve detective sensitivity. The results showed: Ionic liquids possed better behavior than water and DMSO for enriching some water-solution organic solvents and some spirits. The enrichment efficiency of some alkane or ones with low boiling point in ILs was much higher than that in DMSO and DMA. Furthermore, there was no contamination from matrix medium for its property of negligible vapor pressure, and a steady baseline could be attained. But ILs had lower enriching ability than water at the same temperature in the analysis of Aromatic hydrocarbon residuals, even though the temperature was gradually elevated. In addition, ILs with [PF6]- possed better dissolving ability for some water-insoluble sample matrix such as Naftifine than ones with [BF_4]-. Ibuprofen dissolved better in [Hmim][BF_4] than that in [Bmim][BF_4]. However, some salts such as Sodium Azulenesulfonate and Ibandronate Sodium dissolved worse in ILs than that in water, so traditional solvents were selected for testing in the end on the basis of conditions in laboratory.
According to the results studied above, ILs could be suitable as novel matrix medium for improving detection sensetivity, and this will be a new analytical mean to determine residues in the raw materials, which contribute to quality control in pharmaceutical studies. But to aim directly at some special water- insoluble pharmaceuticals, which have worse dissolubility in ILs, the conventional matrix medium could be still selected.
PART 1 The application of ionic liquids as novel headspace matrix medium for residuals analysis in pharmaceuticals.
(Ⅰ) Room temperature ionic liquid as matrix medium for the simultaneous determination of residual solvents by static headspace gas chromatography.
Objective: To study ideal behaviors of ILs, water and DMSO to improve the detective sensitivity of water-soluble organic residual solvents and establish a sensitive, accurate and specific method for the determination of acetone, tetrahydrofuran, dioxane, pyridine and toluene in Chlorphenamine Maleate.
Methods: By HS-GC, the ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in [Emim][BF_4], water and DMSO. The analytes were equilibrated with oven temperature 100℃for 10 min and the volume injected was 1.0 mL. The chromatographic analysis was carried out on ZB-1 capillary column. The injector and detector temperature was set at 180℃and 150℃, respectively. The GC temperature program was 60℃isothermal for 4 min, and then increased at 4℃·min- 1 to 130℃and held for 10 min.
Results: Enrichment efficiency of the most residual solvents is higher in [Emim][BF_4] than in DMSO and water, and [Emim][BF_4] as matrix midium do not interfere detection. Good linear relationships of acetone, tetrahydrofuran, dioxane, pyridine and toluene were abtained in the range of 3.13~100, 2.25~72.0, 1.13~36.0, 0.625~20.0 and 2.78~89.0μg·mL~(-1), respectively. The recoveries of five analytes were during 86.0%~96.9%, and RSD were less than 5.0 %.
Conclusion: Ionic liquid as a headspace solvent can improve the sensitivity of water-soluble residues such as acetone, tetrahydrofuran and pyridine, and because of its property of negligible vapor pressure, can avoid contamination of chromatographic system with conventional headspace solvents.The method is novel, sensitive, accurate and specific, and could be used to detect residuals in Chlorphenamine Maleate.
(Ⅱ) Study of [Emim][BF_4] and DMSO, DMA as Matrix Medium in Determining Trace Residual Solvents in Paclitaxel by HS-GC.
Objective: To research the peak intensity and detection limit of five residues for making better of the sensitivity of residues with low-boiling point and alkanes, also to establish a sensitive, accurate and specific method for determining extraction solvent such as acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane in water-insoluble Paclitaxel.
Methods: The peak intensity and detection limit of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane residues in [Emim][BF_4], DMSO and DMA were systematically compared by HS-GC, respectively. The sample was equilibrated at temperature 110℃for 20 min, and the volume injected was 1.0ml. The condition of chromatograph showed: the injector was maintained at 180℃with a splitless injection, and temperature of the FID was set to 200℃. The column oven temperaure program involved an initial temperature of 50℃for 5min, then this was increased at 40℃/min to 120℃and held for 10min.
Results: The experimental results showed that the peak areas of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane in [Emim][BF_4] were as about 2.10, 2.50, 2.80, 3.40, 1.30 times as those in DMSO, and were as about 2.04, 4.50, 3.00, 3.00, 6.00 times as those in DMA, respectively. The detection limits of several organic residuals in [Emim][BF_4] was also higher than that in DMSO and DMA, and the baseline of ILs blank matrix medium was steady. Five solvents detected had good linearity in the ranges of 31.3~500, 1.82~29.0, 31.3~500, 4.50~72.0 and 31.3~500μg·mL~(-1), respectively. The recoveries of five analytes were during 90.8%~97.8% and RSD were less than 4.0%.
Conclusion: The enrichment efficiency of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane residues in [Emim][BF_4] is two or six times higher than those in conventional solvents, and ILs can minimized the contamination of chromatographic system. The method is novel, sensitive, accurate and specific, and could be adopted to detect residuals in Paclitaxel, and It provides a new way for determining residues in Pharmaceutical.
(Ⅲ) Study of ionic liquids and DMSO, water as Matrix Medium in Determining Trace Residual Solvents in water-insoluble Niftifine by HS-GC.
Objective: To choose a headspace solvent with good dissolubility and high enrichment efficiency, and establish a sensitive, accurate and specific method for determining methanol, ethanol isopropyl alcohol and toluene in water-insoluble Niftifine.
Methods: The static equilibrium method was first used to determine solubilities of the drug in [Bmim][BF_4] and [Bmim][PF6], and the comparison of [Bmim][BF_4], [Bmim][PF6], DMSO and water as matrix medium respectively were carried out in this study, based on the partition coefficients between liquid and gas phases. The chromatographic analysis was performed by using DB-624capillary column. The injector temperature at 180℃and the FID detector with the temperature of 200℃. The column oven temperaure program involved an initial temperature of 45℃for 3min, then this was increased at 25℃/min to 120℃and held for 5min. The headspace sampler vials was equilibrated at 100℃for 20min.
Results: The dissolubility of the drug in [Bmim][PF6] could get by 120 mg·mL~(-1) at 90℃, while in [Bmim][BF_4] it had less than 90 mg·mL~(-1)at the same temperature. Enrichment efficiency of methanol, ethanol and isopropyl alcohol in two kinds of ionic liquid is higher than that in DMSO and water, futhermore, [Bmim][BF_4] was the best headspace matrix medium of all. However, enrichment efficiency of toluene in water was highest. Because Naftifine is a water-insoluble drug, [Bmim][BF_4] was the final selection as solvent. Good linear relationships of four residuals were abtained in the range of 3.00×10~(-1)~1.50×10~2, 5.00×10~(-1)~2.50×10~2, 5.00×10~(-1)~2.50×10~2and 0.140~89.0μg·mL~(-1), respectively. The average recoveries were 95.6%, 95.1%, 92.0% and 94.9% respectively. RSD was less than 4.0%.
Conclusion: The dissolubility of the drug in [Bmim][BF_4] is lower than that in [Bmim][PF_6], but the enrichment efficiency of methanol, ethanol and isopropyl alcohol in [Bmim][BF_4] is higher than that in [Bmim][PF_6], especially in water and DMSO. According to the above studies, [Bmim][BF_4] was selected as matrix medium in the end, and deployed to the futher analysis. The method is novel and accurate, and the sensitivity was improved finally.
(Ⅳ) The mixed Ionic liquid as matrix medium for the determination of residual solvents in Ibuprofen by HS-GC.
Objective: To use the mixed ionic liquid as matrix medium to solve the drug’s bad dissolubility and low sensitivity of some residues.
Methods: The enrichment efficiency of residual solvents and dissolubility of Ibuprofen in [Bmim][BF_4] and [Hmim][BF_4] were investigated by HS-GC. Sample equilibrated at temperature 110℃for 30min. The condition of chromatograph showed: HP-1 capillary column with temperature programmed was used with an initial temperature of 50℃for 5min, then increased at 10℃/min to130℃and held for 5min. The injector and FID were maintained at 180℃and 200℃, respectively.
Results: The mixed [Bmim][BF_4] and [Hmim][BF_4] as matrix medium (the ratio is 2:1) can increase the dissolubility, which could get by 100mg·mL~(-1) also can improve sensitivity. Good linear relations of isopropyl alcohol, trichlormethane and toluene were abtained in the ranges of 5.00~400μg·mL~(-1), 6.00×10-2~6.00μg·mL~(-1) and 0.890~71.2μg·mL~(-1), respectively. The average recoveries were 97.1%, 93.8% and 96.9%, respectively. RSD were less than 4.0%.
Conclusion: The mixed ionic liquids as matrix medium could be used to solve the problem that the single ionic liquid has bad dissolubility of the drug while has good enrichment efficiency of residual solvents or which has good dissolubility of the drug while has bad enrichment efficiency. The method is novel, sensitivity and accurate with the mixed ionic liquids; It provides a new means for determining residues in Pharmaceutical.
PART 2 The application of traditional headspace matrix medium for residuals analysis in pharmaceuticals.
(Ⅰ) DMSO as headspace diluent for determining residual organic solvents in Sodium Azulenesulfonate by Headspace Capillary GC.
Objective: To select a agreeable headspace solvent, which has good dissolubility of the drug, and estabilish a method for determining 1,2-dichloroethane and 1,4-dioxane residuals in sodium azulenesulfonate.
Methods: The dissolubility of sodium azulenesulfonate and the enrichment efficiency of residual solvents in water, DMSO and ILs with good dissolubility were investigated, respectively. The headspace sampler vials was equilibrated at 80℃for 30min. DMSO was matrix medium. The chromatographic analysis was performed by using DB-624capillary column. The injector temperature at 180℃and the FID detector with the temperature of 200℃. The column oven temperaure program involved an initial temperature of 60℃for 6min, then this was increased at 30℃/min to 130℃and held for 5min.
Results: Sodium Azulenesulfonate dissolved better in water, whereas the lytic response happened when it was heated, and the enrichment efficiency of ananlytes could be effected. the dissolubility of the drug in ILs with limidazolium reached to only 20mg·mL~(-1). there was no water in DMSO, and the hydrolysis to the drug did not happen, futhermore, Sodium Azulenesulfonate dissolved better in DMSO. Therefore the headspace diluent DMSO was eventually selected. Good linear relationships of 1,2-dichloroethane and 1,4-dioxane were 3.13×10~(-)2~5.00×10~(-1), 2.38~38.0μg·mL~(-1), respectively. The average recoveries were 95.6% and 97.2% with RSD of 2.0 % and 1.5 %, respectively.
Conclusion: The dissolubility of the drug was better in DMSO, which could meet the requirement of detection and avoid the drug hydrolysis. DMSO is used as the headspace matrix medium and fit to determine residual organic solvent.
(Ⅱ) Water as headspace matrix medium for determining methylbenzene and chlorobenzene residuals in Ibandronate Sodium by Capillary GC.
Objective: To choose a suitable solvent to improve the sensitivity of methylbenzene and chlorobenzene, and establish a HS-GC method for quantification of residual organic solvents in Ibandronate Sodium with water as matrix medium.
Methods: The enrichment efficiency of methylbenzene and chlorobenzene in water, DMA and ILs were investigated, The column oven temperaure program involved an initial temperature of 50℃for 3min, then this was increased at 20℃·min-1to 130℃and held for 20min. The sample was equilibrated at temperature 60℃for 30min, and the volume injected was 0.5mL.
Results: The dissolubility of the drug and the enrichment efficiency of residual solvents is higher in water than these in ILs. So water is selected as the headspace matrix medium. Good linear relationships of toluene and chlorobenzene were 5.56~89.0μg·mL~(-1), 2.25~36.0μg·mL~(-1), respectively. The average recoveries were 91.1% and 93.7% with RSD of 1.6% and 1.4%, respectively. The detection limits were 0.35 and 1.13μg·mL~(-1), respectively.
Conclusion: Water is the ideal dillute for aromatic hydrocarbon residuals, and used to detect residuals in water-solubility drugs.
离子液体(Ionic liquids,ILs)溶解性强、无蒸汽压、几乎不挥发、热稳定性好,液程宽、在常温甚至高温三百度以上均以液态存在;其可设计性强,可根据特定的目的设计所需的离子液体体系。ILs的这些天然特性,使其在一定程度上可作为优良的顶空溶剂应用于药物溶剂残留量的检测。相关文献已报道了ILs可作为顶空溶剂应用于药物残留溶剂的检测,其对某些高沸点的残留溶剂具有良好的顶空分配行为。然而,对于某些低沸点的或烷烃类、醇类及芳烃类等有机溶剂残留在ILs及传统顶空溶剂中的顶空分配行为的系统研究未见报道。
因此,本文的目的是通过研究不同顶空溶剂(如水、DMSO、DMA、ILs等)对药物的溶解性及其有机残留溶剂的顶空分配行为,筛选出更为合适的顶空溶剂用于马来酸氯苯那敏、薁磺酸钠、伊班膦酸钠及一些难溶性药物例如紫杉醇、萘替芬、布洛芬等原料药的溶剂残留量检测,进一步解决残留溶剂检测灵敏度低的问题。结果表明:在一些水溶性溶剂(如丙酮、四氢呋喃、吡啶等)及某些醇类(如甲醇、乙醇及异丙醇等)残留溶剂分析中,ILs比水、DMSO等表现出更高的顶空富集能力;对于某些低沸点的残留溶剂(如乙酸乙酯)及某些正烷烃类(如正己烷、正庚烷等)ILs对其的顶空富集效率高于DMSO、DMA等传统顶空溶剂;ILs具有不挥发,不会被引入色谱系统而造成污染,其空白色谱图中基线平稳,几乎不存在杂质,也避免了传统顶空溶剂因挥发而产生的宽大色谱峰干扰测定的问题;但ILs对芳烃类残留溶剂(如甲苯、氯苯等)的顶空富集能力不及水,水是这些残留溶剂的理想顶空溶剂。此外,ILs对药物溶解性与结构有关,疏水性ILs对萘替芬药物的溶解能力强于亲水性ILs,烷基链长的ILs对布洛芬的溶解能力强于烷基链短的ILs,然而ILs对盐类药物(如薁磺酸钠、伊班膦酸钠)的溶解性能较传统溶剂差,因而针对这些原料药检测,本研究选择了传统顶空溶剂进行了检测,灵敏度得到了改善。
综上研究,ILs可作为新型顶空溶剂,有效的提高检测灵敏度,为药物原料药的有机溶剂残留分析提供了新途径、新方法,对药品质量控制具有重要意义。针对某些在ILs中难溶的药物,可采用传统的顶空溶剂来分析残留量。
第一部分新型顶空溶剂离子液体在药物有机溶剂残留检测中的应用
(一)室温离子液体为溶剂对马来酸氯苯那敏中多种有机溶剂残留的同时顶空分析
目的:研究ILs与水、DMSO对残留溶剂的理想行为,来提高水溶性的有机残留溶剂丙酮、四氢呋喃、吡啶等溶剂的富集效率,并建立灵敏、准确、专属性强的马来酸氯苯那敏原料药中丙酮、四氢呋喃、二氧六环、吡啶及甲苯五种溶剂残留量的检测方法。
方法:采用顶空气相色谱法,以峰面积大小为比较指标,考察[Emim][BF_4]及水、DMSO对五种有机溶剂残留的顶空富集能力。顶空富集方法:精密量取2mL待测溶液于10mL顶空瓶中,在平衡温度100℃下,平衡20min进样1.0mL。色谱分析条件:以[Emim][BF_4]为顶空溶剂的HS-GC法检测马来酸氯苯那敏中五种溶剂残留量,采用ZB-1毛细管柱,进样口温度180℃,检测器(FID)温度200℃,柱温采用程序升温方式:初始60℃维持4min,以4℃/min升温至130℃,维持10min。
结果:[Emim][BF_4]对所研究的有机残留溶剂的顶空富集能力明显比DMSO及水强,且其不干扰检测,对于在水中易溶解的丙酮、四氢呋喃及吡啶,ILs对这些残留溶剂的顶空富集能力比水要高出近3倍。方法学验证结果:丙酮、四氢呋喃、二氧六环、吡啶及甲苯分别在3.13~100、2.25~72.0、1.13~36.0、0.625~20.0及2.78~89.0μg·mL~(-1)范围内线性关系良好,回收率为86.0% ~96.9%,RSD均小于5.0%。
结论:离子液体为顶空溶剂,能够解决丙酮、四氢呋喃及吡啶等水溶性残留溶剂检测灵敏度低的问题,而且其无蒸汽压,能够避免传统顶空溶剂对色谱系统的污染。以[Emim][BF_4]为顶空溶剂的顶空气相色谱法新颖、灵敏、准确、专属性强,适合于马来酸氯苯那敏原料药中有机溶剂残留的检测分析。
(二) [Emim][BF_4]与DMSO、DMA分别作为顶空溶剂的HS-GC法检测紫杉醇药物中痕量有机残留溶剂的研究
目的:研究[Emim][BF_4]与DMSO、DMA对待测残留溶剂的检测灵敏度的影响,来解决多种低沸点的及烷烃类有机残留溶剂的同时检测时检测灵敏度低的问题,并建立难溶性药物紫杉醇中丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷等五种溶剂残留量的灵敏、准确、专属性强的色谱检测方法。
方法:以顶空峰面积大小为比较指标,采用顶空气相色谱法来研究[Emim][BF_4]与DMSO、DMA对丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷等五种溶剂检测灵敏度的影响。顶空富集方法:精密量取待测溶液2mL置10mL顶空瓶中,加盖密封,于110℃顶空温度下平衡20min,抽取上层顶空空间气体1mL,进样测定。色谱分析方法:采用DB-624毛细管柱,FID温度200℃,进口温度180℃,柱温采用程序升温:初温50℃维持5min,以20℃/min的速率升温至120℃维持10min;顶空分析条件:样品在110℃顶空温度下平衡20min后,进样1.0mL检测。
结果:[Emim][BF_4]对丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷等残留溶剂的顶空富集能力(用峰面积表示)分别约是DMSO作为顶空溶剂时的2.10倍、2.50倍、2.80倍、3.40倍及1.30倍,约是DMA作为顶空溶剂时的2.04倍、4.50倍、3.00倍、3.00倍及6.0倍,且待测残留溶剂在[Emim][BF_4]中的检测限明显比DMSO及DMA的低,离子液体空白基线平稳,不干扰测定。方法学验证结果:丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷分别在31.3~500、1.82~29.0、31.3~500、4.50~72.0及31.3~500μg·mL~(-1)范围内线性关系良好,回收率为90.8%~97.8%,RSD均小于5.0%。
结论:[Emim][BF_4]作为顶空溶剂对丙酮、正己烷、乙酸乙酯、四氢呋喃及正庚烷的顶空富集效率较传统顶空溶剂DMSO、DMA高出2~6倍,而且可避免传统顶空溶剂的干扰。采用[Emim][BF_4]作为顶空溶剂的气相色谱法检测难溶性药物紫杉醇中的多种溶剂残留量,方法灵敏,准确可靠,专属性强,为药物溶剂残留检测提供了新途径。
(三)离子液体与水、DMSO分别作为顶空溶剂的HS-GC法检测难溶性药物萘替芬中残留溶剂的研究
目的:选择对难溶性药物萘替芬溶解性好及对一些短链醇类及甲苯顶空富集能力强的顶空溶剂,并建立难溶性药物萘替芬原料药中甲醇、乙醇、异丙醇及甲苯残留量的灵敏、准确、专属性强的色谱检测方法。
方法:采用静态平衡法,考察不同温度下[Bmim][BF_4]和[Bmim][PF_6]对萘替芬的溶解特性,并以顶空气相色谱法比较研究上述两种离子液体、二甲基亚砜(DMSO)及水分别作为顶空溶剂对残留有机溶剂的顶空分配行为。顶空富集方法:取待测溶液2mL置10mL顶空瓶中,加盖,密封,在100℃顶空温度下平衡20min后,抽取顶空气体0.5mL,进样测定。对萘替芬中甲醇、乙醇、异丙醇及甲苯等残留溶剂进行方法学考察,色谱分析条件为:DB-624毛细管柱,FID温度200℃,进样口温度180℃,柱温采用程序升温:初温45℃维持3min,以25℃/min的速率升温至120℃维持5min;
结果:[Bmim][PF_6]在90℃时对药物的溶解量达到120mg·mL~(-1)以上,而同温度下[Bmim][BF_4]对药物的溶解量不到90mg·mL~(-1),同时两种离子液体对甲醇、乙醇及异丙醇的顶空富集能力较水、DMSO强,且其中[Bmim][BF_4]顶空富集能力最强,而水对甲苯的顶空富集能力最好。方法学验证结果:甲醇、乙醇、异丙醇及甲苯分别在3.00×10~(-1)~1.50×10~2、5.00×10~(-1)~2.50×10~2、5.00×10~(-1)~2.5×10~2及1.40×10~(-1)~89.0μg·mL~(-1)范围内线性关系良好,回收率为92.0%~95.9%,RSD均小于4.0%。
结论:亲水性ILs对药物的溶解能力相对于疏水性ILs稍弱,但通过提高顶空温度,其对药物的溶解量能够满足检测要求,并且其对三种醇类有机溶剂的顶空富集能力比[Bmim][PF_6]强,尤其明显比传统顶空溶剂水、DMSO强。因此本文选择了无蒸汽压的[Bmim][BF_4]作为顶空溶剂进行了残留溶剂分析,方法新颖独特,准确可靠,方法的检测灵敏度得到了改善。
(四)混合离子液体为顶空溶剂测定布洛芬原料药中残留有机溶剂
目的:以混合离子液体为顶空溶剂,解决难溶性药物布洛芬的溶解问题及其残留溶剂检测灵敏度低的问题。
方法:采用顶空气相色谱法,考察阴离子相同的两种不同烷基链的离子液体[Bmim][BF_4]、[Hmim][BF_4]及其不同配比的混合溶剂对三氯甲烷、异丙醇及甲苯的顶空能力,并考察其对布洛芬原料药的溶解情况。顶空富集方法:取待测溶液2mL置10mL顶空瓶中,加盖密封,在110℃顶空温度下平衡30min后,抽取顶空气体0.5ml,进样测定。色谱分析条件为:采用HP-1毛细管色谱柱,FID温度200℃,进样口温度180℃,柱温采用程序升温:初温50℃维持5min,以10℃/min的速率升温至130℃维持5min。样品在110℃顶空温度下平衡30min后,抽取顶空气体0.5mL进样测定。
结果:[Bmim][BF_4]和[Hmim][BF_4]按以2:1配比混合作顶空溶剂,既改善了药物的溶解量,使其达到100mg·mL~(-1)以上,又提高了检测灵敏度。方法学验证结果:三氯甲烷、异丙醇及甲苯分别在5.00~400μg·mL~(-1)、6.00×10-2 ~6.00μg·mL~(-1)及0.890~71.2μg·mL~(-1)浓度范围内线性关系良好,其平均回收率分别为97.1%、93.8%及96.9%,RSD均小于4.0%。
结论:采用混合的离子液体作为顶空溶剂,解决了单个离子液体使用时对药物的溶解性差而对残留溶剂顶空富集效率高或对药物溶解性好而对残留溶剂顶空富集效率低的问题。以[Bmim][BF_4]和[Hmim][BF_4]按2:1配比混合作顶空溶剂的气相色谱法检测难溶性药物布洛芬的有机溶剂残留量,方法灵敏独特,准确可靠,为药物有机溶剂残留检测提供了新途径。
第二部分传统顶空溶剂在药物有机溶剂残留检测中的应用
(一) DMSO为顶空溶剂的毛细管气相色谱法测定薁磺酸钠原料药中有机溶剂的残留量
目的:解决薁磺酸钠的溶解问题,并建立该原料药中二氯乙烷和二氧六环有机溶剂残留量的检测方法。
方法:考察该药在水、DMSO及咪唑基离子液体中的溶解情况,并采用顶空气相色谱法检测该药中两种有机溶剂残留量。以DMSO为顶空溶剂检测药物残留溶剂的HS-GC法的色谱分析方法为:采用DB-624毛细管柱,FID温度200℃,进样口温度180℃,柱温采用程序升温:初温60℃,维持6min后,以30℃·min-1的速率升温至130℃,维持5min。顶空平衡温度为80℃,平衡时间为30min;进样量为1.0mL。
结果:薁磺酸钠在水中溶解量大,但加热会发生水解反应,产生的物质影响待测溶剂的富集;咪唑基离子液体[Emim][BF_4]对该药在80℃恒温水浴条件下仅有约20mg·mL~(-1)溶解,而DMSO对该药极易溶解,且该药溶解其中不发生水解反应。所建的DMSO为顶空溶剂的HS-GC法检测药物残留量的方法学验证结果:二氯乙烷和二氧六环分别在3.13×10-2~5.00×10~(-1)μg·mL~(-1)、2.38~38.0μg·mL~(-1)的浓度范围内线性关系良好,平均回收率分别为95.6%、97.2%,RSD(n=5)分别为2.0%、1.5%。
结论:DMSO对该药物具有较好的溶解量,并且避免了该药的水解,因而适合作为顶空溶剂测定该药物中有机溶剂残留量。
(二)水为顶空溶剂的气相色谱法检测伊班膦酸钠中甲苯和氯苯的残留量目的:建立伊班膦酸钠原料药中甲苯和氯苯残留量检测的高灵敏方法。
方法:以峰面积大小为比较指标,考察水、DMA及ILs对甲苯和氯苯的顶空富集效率,并以水为溶剂采用顶空气相色谱法对该药残留量进行检测。其色谱分析条件为:采用DB-624毛细管柱,FID温度200℃;进样口温度180℃,柱温采用程序升温:初温50℃维持3min,并以20℃/min的速率升温至130℃维持20min;顶空瓶平衡温度60℃,平衡时间30min,进样0.5mL。
结果:水对两种有机溶剂的顶空富集能力比DMA、咪唑基ILs强。以水为顶空溶剂的HS-GC法检测药物溶剂残留量的方法学验证结果表明:甲苯、氯苯分别在5.56~89.0μg·mL~(-1)、2.2~36.0μg·mL~(-1)的浓度范围内线性关系良好,平均回收率分别为91.1%、93.7%,RSD (n=5)分别为1.6%、1.4%。
结论:水对芳烃类溶剂的顶空富集效率最理想,适合作为水溶性药物中芳烃类溶剂残留量检测的顶空溶剂。
Residues in pharmaceuticals are commonly detected by gas chromatography, which includes direct injection and headspace sampling. HS injection is more frequently used than drect injection for its good seperation and sensitivity. However, for some thermal unstable drugs or ones having poor dissolubility in headspace diluents such as water, DMA, DMSO et al, direct injection is still adopted to determine residues in these drugs, and which has the low sensitivity and the GC system contaminated seriously. In determinating organic residual solvent by HS-GC, the reasonable choice of matrix medium is directly related to sensitivity and accuracy of detective methods. On account of volatility, conventional solvents not only affect the enrichment efficiency of residual solvents, but wide chromatographic peak produced in the process of analysis also interfere with analytes, even result in detector’s intoxication. Furthermore, some headspace matrix medium such as DMSO in themselves may produce many varieties of volatile impurities,when stored for a long time or heat. In that case, the result of the analysis of organic residual solvents should be correct by the blank matrix medium. In a word, the sensitivity of analysis of trace residues is influenced by the above factors to a large extent. Accordingly, looking for the ideal headspace matrix medium plays an important role in improving the sensitivity of the analysis of residues in pharmaceuticals.
Ionic liquids (ILs) as novel solvents show many unique properties, such as extraordinary dissolution, negligible vapor pressure, chemical stability, good thermal and wide liquid range. In addition, compared with traditional solvents, ILs can be better worked out, and it is possible to design ILs for practical application by varying structures of cation and anion. Therefore, ILs as fine headspace matrix medium may be applied for the detection of organic residual solvents in pharmaceuticals. It was reported that ILs had more sensitive enriching ability than DMSO for analytes with high boiling point or some water-insoluble drugs. However, the analysis of these residues, such as alkanes, spirits, aromatichydrocarbon or residues with low boiling point, is not reported recently.
The purpose of our research is to choose the suitable headspace matrix medium to analyze residues in Chlorphenamine Maleate, Sodium Azulenesulfonate, Ibandronate Sodium and some water-insoluble sample such as Paclitaxel, Naftifine, Ibuprofen , et al. By studying solubility of ILs and comparing ILs with traditional solvents, further to improve detective sensitivity. The results showed: Ionic liquids possed better behavior than water and DMSO for enriching some water-solution organic solvents and some spirits. The enrichment efficiency of some alkane or ones with low boiling point in ILs was much higher than that in DMSO and DMA. Furthermore, there was no contamination from matrix medium for its property of negligible vapor pressure, and a steady baseline could be attained. But ILs had lower enriching ability than water at the same temperature in the analysis of Aromatic hydrocarbon residuals, even though the temperature was gradually elevated. In addition, ILs with [PF6]- possed better dissolving ability for some water-insoluble sample matrix such as Naftifine than ones with [BF_4]-. Ibuprofen dissolved better in [Hmim][BF_4] than that in [Bmim][BF_4]. However, some salts such as Sodium Azulenesulfonate and Ibandronate Sodium dissolved worse in ILs than that in water, so traditional solvents were selected for testing in the end on the basis of conditions in laboratory.
According to the results studied above, ILs could be suitable as novel matrix medium for improving detection sensetivity, and this will be a new analytical mean to determine residues in the raw materials, which contribute to quality control in pharmaceutical studies. But to aim directly at some special water- insoluble pharmaceuticals, which have worse dissolubility in ILs, the conventional matrix medium could be still selected.
PART 1 The application of ionic liquids as novel headspace matrix medium for residuals analysis in pharmaceuticals.
(Ⅰ) Room temperature ionic liquid as matrix medium for the simultaneous determination of residual solvents by static headspace gas chromatography.
Objective: To study ideal behaviors of ILs, water and DMSO to improve the detective sensitivity of water-soluble organic residual solvents and establish a sensitive, accurate and specific method for the determination of acetone, tetrahydrofuran, dioxane, pyridine and toluene in Chlorphenamine Maleate.
Methods: By HS-GC, the ideal headspace diluent was selected by comparing enrichment efficiency of residual solvens in [Emim][BF_4], water and DMSO. The analytes were equilibrated with oven temperature 100℃for 10 min and the volume injected was 1.0 mL. The chromatographic analysis was carried out on ZB-1 capillary column. The injector and detector temperature was set at 180℃and 150℃, respectively. The GC temperature program was 60℃isothermal for 4 min, and then increased at 4℃·min- 1 to 130℃and held for 10 min.
Results: Enrichment efficiency of the most residual solvents is higher in [Emim][BF_4] than in DMSO and water, and [Emim][BF_4] as matrix midium do not interfere detection. Good linear relationships of acetone, tetrahydrofuran, dioxane, pyridine and toluene were abtained in the range of 3.13~100, 2.25~72.0, 1.13~36.0, 0.625~20.0 and 2.78~89.0μg·mL~(-1), respectively. The recoveries of five analytes were during 86.0%~96.9%, and RSD were less than 5.0 %.
Conclusion: Ionic liquid as a headspace solvent can improve the sensitivity of water-soluble residues such as acetone, tetrahydrofuran and pyridine, and because of its property of negligible vapor pressure, can avoid contamination of chromatographic system with conventional headspace solvents.The method is novel, sensitive, accurate and specific, and could be used to detect residuals in Chlorphenamine Maleate.
(Ⅱ) Study of [Emim][BF_4] and DMSO, DMA as Matrix Medium in Determining Trace Residual Solvents in Paclitaxel by HS-GC.
Objective: To research the peak intensity and detection limit of five residues for making better of the sensitivity of residues with low-boiling point and alkanes, also to establish a sensitive, accurate and specific method for determining extraction solvent such as acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane in water-insoluble Paclitaxel.
Methods: The peak intensity and detection limit of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane residues in [Emim][BF_4], DMSO and DMA were systematically compared by HS-GC, respectively. The sample was equilibrated at temperature 110℃for 20 min, and the volume injected was 1.0ml. The condition of chromatograph showed: the injector was maintained at 180℃with a splitless injection, and temperature of the FID was set to 200℃. The column oven temperaure program involved an initial temperature of 50℃for 5min, then this was increased at 40℃/min to 120℃and held for 10min.
Results: The experimental results showed that the peak areas of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane in [Emim][BF_4] were as about 2.10, 2.50, 2.80, 3.40, 1.30 times as those in DMSO, and were as about 2.04, 4.50, 3.00, 3.00, 6.00 times as those in DMA, respectively. The detection limits of several organic residuals in [Emim][BF_4] was also higher than that in DMSO and DMA, and the baseline of ILs blank matrix medium was steady. Five solvents detected had good linearity in the ranges of 31.3~500, 1.82~29.0, 31.3~500, 4.50~72.0 and 31.3~500μg·mL~(-1), respectively. The recoveries of five analytes were during 90.8%~97.8% and RSD were less than 4.0%.
Conclusion: The enrichment efficiency of acetone, N-hexane, acetic ether, tetrahydrofuran and N-hepane residues in [Emim][BF_4] is two or six times higher than those in conventional solvents, and ILs can minimized the contamination of chromatographic system. The method is novel, sensitive, accurate and specific, and could be adopted to detect residuals in Paclitaxel, and It provides a new way for determining residues in Pharmaceutical.
(Ⅲ) Study of ionic liquids and DMSO, water as Matrix Medium in Determining Trace Residual Solvents in water-insoluble Niftifine by HS-GC.
Objective: To choose a headspace solvent with good dissolubility and high enrichment efficiency, and establish a sensitive, accurate and specific method for determining methanol, ethanol isopropyl alcohol and toluene in water-insoluble Niftifine.
Methods: The static equilibrium method was first used to determine solubilities of the drug in [Bmim][BF_4] and [Bmim][PF6], and the comparison of [Bmim][BF_4], [Bmim][PF6], DMSO and water as matrix medium respectively were carried out in this study, based on the partition coefficients between liquid and gas phases. The chromatographic analysis was performed by using DB-624capillary column. The injector temperature at 180℃and the FID detector with the temperature of 200℃. The column oven temperaure program involved an initial temperature of 45℃for 3min, then this was increased at 25℃/min to 120℃and held for 5min. The headspace sampler vials was equilibrated at 100℃for 20min.
Results: The dissolubility of the drug in [Bmim][PF6] could get by 120 mg·mL~(-1) at 90℃, while in [Bmim][BF_4] it had less than 90 mg·mL~(-1)at the same temperature. Enrichment efficiency of methanol, ethanol and isopropyl alcohol in two kinds of ionic liquid is higher than that in DMSO and water, futhermore, [Bmim][BF_4] was the best headspace matrix medium of all. However, enrichment efficiency of toluene in water was highest. Because Naftifine is a water-insoluble drug, [Bmim][BF_4] was the final selection as solvent. Good linear relationships of four residuals were abtained in the range of 3.00×10~(-1)~1.50×10~2, 5.00×10~(-1)~2.50×10~2, 5.00×10~(-1)~2.50×10~2and 0.140~89.0μg·mL~(-1), respectively. The average recoveries were 95.6%, 95.1%, 92.0% and 94.9% respectively. RSD was less than 4.0%.
Conclusion: The dissolubility of the drug in [Bmim][BF_4] is lower than that in [Bmim][PF_6], but the enrichment efficiency of methanol, ethanol and isopropyl alcohol in [Bmim][BF_4] is higher than that in [Bmim][PF_6], especially in water and DMSO. According to the above studies, [Bmim][BF_4] was selected as matrix medium in the end, and deployed to the futher analysis. The method is novel and accurate, and the sensitivity was improved finally.
(Ⅳ) The mixed Ionic liquid as matrix medium for the determination of residual solvents in Ibuprofen by HS-GC.
Objective: To use the mixed ionic liquid as matrix medium to solve the drug’s bad dissolubility and low sensitivity of some residues.
Methods: The enrichment efficiency of residual solvents and dissolubility of Ibuprofen in [Bmim][BF_4] and [Hmim][BF_4] were investigated by HS-GC. Sample equilibrated at temperature 110℃for 30min. The condition of chromatograph showed: HP-1 capillary column with temperature programmed was used with an initial temperature of 50℃for 5min, then increased at 10℃/min to130℃and held for 5min. The injector and FID were maintained at 180℃and 200℃, respectively.
Results: The mixed [Bmim][BF_4] and [Hmim][BF_4] as matrix medium (the ratio is 2:1) can increase the dissolubility, which could get by 100mg·mL~(-1) also can improve sensitivity. Good linear relations of isopropyl alcohol, trichlormethane and toluene were abtained in the ranges of 5.00~400μg·mL~(-1), 6.00×10-2~6.00μg·mL~(-1) and 0.890~71.2μg·mL~(-1), respectively. The average recoveries were 97.1%, 93.8% and 96.9%, respectively. RSD were less than 4.0%.
Conclusion: The mixed ionic liquids as matrix medium could be used to solve the problem that the single ionic liquid has bad dissolubility of the drug while has good enrichment efficiency of residual solvents or which has good dissolubility of the drug while has bad enrichment efficiency. The method is novel, sensitivity and accurate with the mixed ionic liquids; It provides a new means for determining residues in Pharmaceutical.
PART 2 The application of traditional headspace matrix medium for residuals analysis in pharmaceuticals.
(Ⅰ) DMSO as headspace diluent for determining residual organic solvents in Sodium Azulenesulfonate by Headspace Capillary GC.
Objective: To select a agreeable headspace solvent, which has good dissolubility of the drug, and estabilish a method for determining 1,2-dichloroethane and 1,4-dioxane residuals in sodium azulenesulfonate.
Methods: The dissolubility of sodium azulenesulfonate and the enrichment efficiency of residual solvents in water, DMSO and ILs with good dissolubility were investigated, respectively. The headspace sampler vials was equilibrated at 80℃for 30min. DMSO was matrix medium. The chromatographic analysis was performed by using DB-624capillary column. The injector temperature at 180℃and the FID detector with the temperature of 200℃. The column oven temperaure program involved an initial temperature of 60℃for 6min, then this was increased at 30℃/min to 130℃and held for 5min.
Results: Sodium Azulenesulfonate dissolved better in water, whereas the lytic response happened when it was heated, and the enrichment efficiency of ananlytes could be effected. the dissolubility of the drug in ILs with limidazolium reached to only 20mg·mL~(-1). there was no water in DMSO, and the hydrolysis to the drug did not happen, futhermore, Sodium Azulenesulfonate dissolved better in DMSO. Therefore the headspace diluent DMSO was eventually selected. Good linear relationships of 1,2-dichloroethane and 1,4-dioxane were 3.13×10~(-)2~5.00×10~(-1), 2.38~38.0μg·mL~(-1), respectively. The average recoveries were 95.6% and 97.2% with RSD of 2.0 % and 1.5 %, respectively.
Conclusion: The dissolubility of the drug was better in DMSO, which could meet the requirement of detection and avoid the drug hydrolysis. DMSO is used as the headspace matrix medium and fit to determine residual organic solvent.
(Ⅱ) Water as headspace matrix medium for determining methylbenzene and chlorobenzene residuals in Ibandronate Sodium by Capillary GC.
Objective: To choose a suitable solvent to improve the sensitivity of methylbenzene and chlorobenzene, and establish a HS-GC method for quantification of residual organic solvents in Ibandronate Sodium with water as matrix medium.
Methods: The enrichment efficiency of methylbenzene and chlorobenzene in water, DMA and ILs were investigated, The column oven temperaure program involved an initial temperature of 50℃for 3min, then this was increased at 20℃·min-1to 130℃and held for 20min. The sample was equilibrated at temperature 60℃for 30min, and the volume injected was 0.5mL.
Results: The dissolubility of the drug and the enrichment efficiency of residual solvents is higher in water than these in ILs. So water is selected as the headspace matrix medium. Good linear relationships of toluene and chlorobenzene were 5.56~89.0μg·mL~(-1), 2.25~36.0μg·mL~(-1), respectively. The average recoveries were 91.1% and 93.7% with RSD of 1.6% and 1.4%, respectively. The detection limits were 0.35 and 1.13μg·mL~(-1), respectively.
Conclusion: Water is the ideal dillute for aromatic hydrocarbon residuals, and used to detect residuals in water-solubility drugs.
引文
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1肖颖,赵玉斌.红豆杉中紫杉醇抗癌研究进展.现代中西医结合杂志, 2008, 17(35): 5557
2 ChP (中国药典), VolⅡ(二部), Appendix(附录), 2005: 54
3戴维,周玲洁,梁建英.毛细管气相色谱法测定紫杉醇原料药中的有机溶剂残留量.复旦学报(医学版), 2007, 34: 608-610
4翁水旺.紫杉醇中有机溶剂残留量的毛细管GC测定.中国医药工业杂志, 2005, 36: 420-421
5 Liu FH, Jiang Y. Room temperature ionic liquid as matrix medium for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography. Journal of Chromatography A, 2007, 1167: 114-119
6江海亮,沈昊宇,乐长高,等.室温离子液体作溶剂顶空气-质联用测定药物中溶剂残留[J].分析化学, 2006, 34(7): 1027-1029
1左淑芳,杨凤艳.抗真菌药萘替芬的合成.中国医药工业杂志, 1998, 28(1): 8-9
2肖小华,刘淑娟,刘霞,等.离子液体及其在分离分析中的应用进展.分析化学评述与进展, 2005, 33(4): 569-574
3孔继华,王利生,毋俊生.苯基膦酸在有机溶剂中溶解度的测定及关联.广东化工, 2006, 33(5): 90-92
4 Grant VW, David A, Hernan C, et al. Background vapor from six ionic liquids and the partition coefficients and limits of detection for 10 different analytes in those ionic liquids measured using headspace gas chromatography. Journal of Chromatography A, 2008, 1201: 15-20
5张晨,崔铁兵,王钰,等.邻苯二甲酸酐、顺丁烯二甲酸酐在水中溶解度的测定及关联.河南化工, 2008, 25(1): 31-34
1 Kamondetdecha R, Tannirandorn Y. Ibuprofen versus acetaminophen for the relief of perineal pain after childbirth: A randomized controlled trial. Acute Pain, 2008, 10: 100
2韩学静,宋更申,房桂珍.顶空气相色谱法测定恩曲他滨中多种有机溶剂残留量.中国药事, 2006, 20(6): 353-355
3江海亮,沈昊宇,乐长高,等.室温离子液体作溶剂顶空气-质联用测定药物中溶剂残留.分析化学, 2006, 34(7): 1027-1029
4 Paulechka YU, Zaitsau DH, Kabo GJ,et al. Vapor pressure and thermal stability of ionic liquid1-butyl-3-methylimidazolium Bis(trifluoromethylsulfonyl)amide. Thermochimica Acta, 2005, 439: 158-160
5 Liu FH, Jiang Y. Room temperature ionic liquid as matrix medium for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography. Journal of Chromatography A, 2007, 1167:116-119
6罗爱庭,刘海峰,汪学楷,等.顶空气相色谱法测定普卢利沙星中的有机残留溶剂.现代仪器, 2006, 6: 31-33
7吴羽岚,钟春华,王磊.多潘立酮有机溶剂残留量的检测方法.江苏药学与临床研究, 2005, 13(5): 33-35
1刘绍华,杨大成,唐维高,等.新药薁磺酸钠的核磁共振谱分析.中国药物化学杂志, 2001, 11(40): 89-90
2陈桧平,徐彰,金抒清.麦滋林-S颗粒治疗儿童慢性胃炎疗效观察.临床医学, 2005, 25(12): 80-81
3刘庆彬,张占辉,薄海静,等.麦滋林-S中薁磺酸钠的高效液相色谱法测定.分析化学, 2000, 28(10): 1319
4 Swatloski RP, Spear SK, Holbrey JD. Dissolution of cellulose with ionic liquids. J. Am. Chem. Soc., 2002, 124: 4974-4975
5江海亮,沈昊宇,乐长高,等.室温离子液体作溶剂顶空气-质联用测定药物中溶剂残留.分析化学, 2006, 34(7): 1027-1029
6蔡太梅,蒋晔,田书霞.顶空气相色谱法测定阿立哌唑中有机溶剂N,N-二甲基甲酰胺残留量.中国新药杂志, 2005, 14(3): 327-329
1刘文超,张燕军,任军,等.伊班膦酸钠治疗恶性肿瘤骨转移性骨痛的临床研究.第四军医大学学报, 2004, 25(14): 1320-1322
2傅淑霞,张丽萍,杨林,等.伊班膦酸钠可防治肾小球疾病患者糖皮质激素引起的骨密度减低.中国骨质疏松杂志, 2005, 11(1): 88-90
3中国药典2005年版.二部. Appendix (附录): 55-57
4 ICH指导委员会,周海钧.残留溶剂的测定原则,药品注册的国际技术要求,人民卫生出版社, 2000: 70-100
1 Seddon KR. Ionic liquids for clean technology. J Chem Biotechnol, 1997, 68: 351-356
2 Di W,Ari I. Applications of ionic liquids in electrochemical sensors. Analytica Chimica Acta, 2008, 607: 126-135
3 Mizuuchi H, Jaitely V, Murdan S, et al. Room temperature ionic liquids and their mixtures: potential pharmaceutical solvents. Pharmaceutical Sciences, 2008, 33: 326-331
4 Earle1 MJ, Esperanca JM, Gilea MA, et al. The distillation and volatility of ionic liquids. Nature, 2006, 439: 831-834
5孙学文,赵锁奇.超临界条件下离子液体催化苯与丙烯烷基化的反应机理研究.化学学报, 2008, 66(4): 471-475
6党清雅,陈凤香,韩会景.离子液体负载钌络合物的合成及其催化环烯烃开环易位聚合.高分子学报, 2008, 4: 343-349
7 Aguilera-Herrador E, Lucena R, Cárdenas S, et al. Determination oftrihalomethanes in waters by ionic liquid-based single drop microextraction/gas chromatographic/mass spectrometry. Journal of Chromatography A, 2008, 1209: 76-82
8 Aguilera-Herrador E, Lucena R, Cárdenas S, et al. Ionic liquid-based single-drop microextraction/gas chromatographic/mass spectrometric determination of benzene, toluene, ethylbenzene and xylene isomers in waters. Journal of Chromatography A, 2008, 1201: 106-111
9 Zhao FQ, Li J, Zeng BZ. Coupling of ionic liquid-based headspace single-drop microextraction with GC for sensitive detection of phenols. J Sep Sci., 2008, 31: 3045-3049
10江海亮,沈昊宇,乐长高,等.室温离子液体作溶剂顶空气-质联用测定药物中溶剂残留.分析化学, 2006, 34(7): 1027-1029
11 Liu FH, Jiang Y. Room temperature ionic liquid as matrix medium for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography.Journal of Chromatography A, 2007, 1167: 116-119
12 Grant VW, David A, Hernan C,et al. Background vapor from six ionic liquids and the partition coefficients and limits of detection for 10 different analytes in those ionic liquids measured using headspace gas chromatography. Journal of Chromatography A, 2008, 1201: 15-20
13 Berthod A, Ruiz-ángel MJ, Carda-Broch S. Ionic liquids in separation techniques. Journal of Chromatography A, 2008, 1184: 6-18
14邹巧莉,陈志瑶,郑京京,等.离子液体改性的气相色谱固定相色研究.高等学校化学学报, 2007, 28(7): 1260-1262
15任朝兴,艾萍,袁黎明.离子液体和碳纳米管作为混合色谱固定相色研究和应用.分析试验室, 2008, 27(7): 23-25
16 Baltazar QQ, Leininger SK, Anderson JL. Binary ionic liquid mixtures as gas chromatography stationary phases for improving the separationselectivity of alcohols and aromatic compounds. Journal of Chromatography A, 2008, 1182: 119-127
17 Huang KP, Misra TK, Wang GR, et al. Novel stationary phase forcomplexation gas chromatography originating from ionic liquid and metallomesogen. Journal of Chromatography A, 2008, 1215: 177-184
18周岩,字敏,韩熠,等.新型离子液体气相色谱固定相色研究.化学试剂, 2006, 28(1): 8-10
19任朝兴,艾萍,李莉,等.手性离子液体和纤维素三(3,5-二甲基苯基氨基甲酸酯)混合气相色谱手性固定相研究.分析化学, 2006, 34(11): 1637-1640
20 Lorena V, Alberto C, Antonio C,et al. Sensitive determination of free benzophenone-3 in human urine samples based on an ionic liquid as extractant phase in single-drop microextraction prior to liquid chromatography analysis. Journal of Chromatography A, 2007, 1174: 95-103
21 Cruz-Vera M,Lucena R,Cárdenas S,et al. Determination of phenothiazine derivatives in human urine by using ionic liquid-based dynamic liquid-phase microextraction coupled with liquid chromatography. Journal of Chromatography B, 2009, 877: 37-42
22 Ye CL, Zhou QX, Wang XM. Headspace liquid-phase microextraction using ionic liquid as extractant for the preconcentration of dichlorodiphenyltrichloroethane and its metabolites at trace levels in water samples. Analytica Chimica Acta, 2006, 572: 165-171
23 Du FY, Xiao XH, Li GK. Application of ionic liquids in the microwave-assisted extraction of trans-resveratrol from Rhizma Polygoni Cuspidati. Journal of Chromatography A, 2007, 1140: 56-62
24杜甫佑,肖小华,李攻科.离子液体微波辅助萃取石蒜中生物碱的研究.分析化学, 2007, 35(11): 1570-1574
25 Zhou QX, Bai HH, Xie GH, et al. Trace determination of organophosphorus pesticides in environmental samples by temperature-controlled ionic liquid dispersive liquid-phase microextraction. Journal of Chromatography A, 2008, 1188: 148-153
26应丽艳,江海亮,沈昊宇,等.室温离子液体超声辅助萃取-高效液相色谱法测定水中的菲、荧蒽、芘的研究.分析试验室, 2008, 27: 323-623
27 Liu SJ, Zhou F, Zhao L, et al. Surface Confined Ionic Liquid-A New Stationary Phase for the Separation of Ephedrines in High-performance Liquid Chromatography.Chin. Chem. Lett., 2004, 15: 1060-1062
28 Van Meter DS, Stuart OD, Carle AB, et al. Characterization of a novel pyridinium bromide surface confined ionic liquid stationary phase for high-performance liquid chromatography under normal phase conditions via linear solvation energy relationships. Journal of Chromatography A, 2008, 1191: 67-71
29 Auler LM,Silva CR,Collins KE et al. New stationary phase for anion -exchange chromatography. Journal of Chromatography A, 2005, 1073(1-2): 147-153
30 Qiu H, Jiang Q, Wei Z, et al. Preparation and evaluation of a silica-based 1-alkyl-3-(propyl-3-sulfonate) imidazolium zwitterionic stationary phase for high-performance liquid chromatography. Journal of Chromatography A, 2007, 1163: 63-69
31 Berthod A, Carda-Borch S. Use of the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate in countercurrent chromatography. Anal Bioanal Chem, 2004, 380(1): 168-177
32 Ruiz-Angel MJ, Carda-Borch S, Berthod A. Ionic liquids versus triethylamine as mobile phase additives in the analysis ofβ-blockers. Journal of Chromatography A, 2006, 1119: 202-208
33 Tang F, Tao L, Luo XB, et al. Determination of octopamine, synephrine and tyramine in Citrus herbs by ionic liquid improved‘green’chromatographyJournal of Chromatography A, 2006, 1125: 182-188
34 Xiao XH, Zhao L, Liu X, et al. Ionic liquids as additives in high performance liquid chromatography Analysis of amines and the interaction mechanism of ionic liquids. Analytica Chimica Acta, 2004, 519: 207-211
35江海亮,应丽艳,王强,等.离子液体作添加剂对高效液相色谱分离植物激素的影响.分析化学, 2007, 35(9): 1327-1330
36 Gao Y, Xiang Q, Xu Y, et al. The use of CE-electrochemiluminescence with ionic liquid for the determination of bioactive constituents in Chinese traditional medition. Electrophoresis., 2006, 27: 4842-4848
37 Qi SD, Li YQ, Deng YR, et al. Simultaneous determination of bioactive flavone derivatives in Chinese herb extraction by capillary electrophoresis used different electrolyte systems-Borate and ionic liquids. Journal of Chromatography A, 2006, 1109: 300-306
38 Li T, Li B, Dong S, Wang E. Ionic liquid as selectors for the enhanced detection proteins. Chemistry, 2007, 13: 8516-8521
39 Li JY, Wei DQ, Sam Fong YL. Ionic liquids as additives for separation of benzoic acid and chlorophenoxy acid herbicides by capillary electrophoresis. Analytica Chimica Acta, 2005, 547: 165-171
40 Kan T, Sheng DQ, Yu QC, et al. Separation and determination of lignans from seeds of Schisandra species by micellar electrokinetic capillary chromatography using ionic liquid as modifier. Journal of Chromatography A, 2005, 1078: 181-187
41 Xu YH, Li J, Wang EK. Microchip Micellar Electrokinetic Chromatography Based on One Functionalized Ionic liquid and Its Excellent Performance on Proteins Separation. Journal of Chromatography A, 2008, 1207: 175
42 Zhang HG, Tian K, Tang JH, et al. Analysis of baicalein,baicalin and wogonin in Scutellariae radix and its preparation by microemulsion electrokinetic chromatography with 1-butyl-3-methylimizolium tetrafluoborate ionic liquid as additive. Journal of Chromatography A, 2006, 1129: 304-307
43 Chieu D. Tran,Irena Mejac. Chiral ionic liquids for enantioseparation of pharmaceutical products by capillary electrophoresis. Journal of Chromatography A, 2008, 1204: 204-209
44侯经国,杜红英,高锦章.羟乙基-β-环糊精作为手性选择剂对手性药物的毛细管电泳拆分.分析测试学报, 2006, 25(2): 84-86
45吴俊森,林秀丽.手性药物山莨菪碱的毛细管电泳拆分研究.分析科学学报, 2005, 21(3): 277-279
46 Qin WD, Li YSF. Determination of ammonium and metal ions by capillary electrophoresis-potential gradient detection using ionic liquid as background electrolyte and covalent coating reagent. Journal of Chromatography A, 2004, 1048: 253-256
47 Wu X, Wei W, Su Q, et al. Simultaneous separation of basic and acidic proteins using 1-butyl-3-methylimidazolium-based ion liquid as dynamic coating and background electrolyte in capillary electrophoresis. Electrophoresis, 2008, 29: 2356-2362
48 Borissova M, Vaher M, Koel M, et al . Capillary zone electrophoresis on chemically bonded imidazolium based salts . Journal of Chromatography A, 2007, 1160: 320-325
49吕芳,何丽君,伍艳,等.离子液体作薄层色谱添加剂对麻黄碱分离的影响.化学试剂, 2006, 28(9): 551-552
2 ChP (中国药典), VolⅡ(二部), Appendix(附录), 2005: 54
3陆小芬,茅海琼.毛细管柱气相色谱法测定马来酸氯苯那敏中残留溶剂.中国药学杂志, 2008, 43(20): 1599-1600
4凌飒,周祖坤,程天贵.马来酸氯苯那敏中有机溶剂残留量的GC测定.中国医药工业杂志, 2004, 35: 234-235
5陈日南.药物中有机溶剂残留量测定评述法.中国医药工业杂志, 1997, 28(6): 275-278
6肖小华,刘淑娟,刘霞,等.离子液体及其在分离分析中的应用进展.分析化学, 2005, 33(4): 569-574
7 Berthod A, Ruiz-ángel MJ, Carda-Broch S. Ionic liquids in separation techniques. Journal of Chromatography A, 2008, 1184: 6-18
8 Liu FH, Jiang Y. Room temperature ionic liquid as matrix medium for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography. Journal of Chromatography A, 2007, 1167: 116-119
9梁振益,杨作德,贺杨洋,等.毛细管气相色谱法同时测定马来酸氯苯那敏中5种有机溶剂的残留量.海南大学学报自然科学版, 2008, 26(3):278-280
10李心泓,茅纯,愈慧丽.顶空进样法测定头孢克肟中有机溶剂残留量.中国抗生素杂志, 2009, 34(2): 89
11柯正芳,裴秋菊.顶空气相色谱法测定米非司酮中5种残留溶剂.中国现代应用药学杂志, 2009, 26(5): 398-400
12江海亮,沈昊宇,乐长高,等.室温离子液体作溶剂顶空气-质联用测定药物中溶剂残留.分析化学, 2006, 34(7): 1027-1029
13中国药典2005年版,附录ⅧP,药物残留溶剂测定
1肖颖,赵玉斌.红豆杉中紫杉醇抗癌研究进展.现代中西医结合杂志, 2008, 17(35): 5557
2 ChP (中国药典), VolⅡ(二部), Appendix(附录), 2005: 54
3戴维,周玲洁,梁建英.毛细管气相色谱法测定紫杉醇原料药中的有机溶剂残留量.复旦学报(医学版), 2007, 34: 608-610
4翁水旺.紫杉醇中有机溶剂残留量的毛细管GC测定.中国医药工业杂志, 2005, 36: 420-421
5 Liu FH, Jiang Y. Room temperature ionic liquid as matrix medium for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography. Journal of Chromatography A, 2007, 1167: 114-119
6江海亮,沈昊宇,乐长高,等.室温离子液体作溶剂顶空气-质联用测定药物中溶剂残留[J].分析化学, 2006, 34(7): 1027-1029
1左淑芳,杨凤艳.抗真菌药萘替芬的合成.中国医药工业杂志, 1998, 28(1): 8-9
2肖小华,刘淑娟,刘霞,等.离子液体及其在分离分析中的应用进展.分析化学评述与进展, 2005, 33(4): 569-574
3孔继华,王利生,毋俊生.苯基膦酸在有机溶剂中溶解度的测定及关联.广东化工, 2006, 33(5): 90-92
4 Grant VW, David A, Hernan C, et al. Background vapor from six ionic liquids and the partition coefficients and limits of detection for 10 different analytes in those ionic liquids measured using headspace gas chromatography. Journal of Chromatography A, 2008, 1201: 15-20
5张晨,崔铁兵,王钰,等.邻苯二甲酸酐、顺丁烯二甲酸酐在水中溶解度的测定及关联.河南化工, 2008, 25(1): 31-34
1 Kamondetdecha R, Tannirandorn Y. Ibuprofen versus acetaminophen for the relief of perineal pain after childbirth: A randomized controlled trial. Acute Pain, 2008, 10: 100
2韩学静,宋更申,房桂珍.顶空气相色谱法测定恩曲他滨中多种有机溶剂残留量.中国药事, 2006, 20(6): 353-355
3江海亮,沈昊宇,乐长高,等.室温离子液体作溶剂顶空气-质联用测定药物中溶剂残留.分析化学, 2006, 34(7): 1027-1029
4 Paulechka YU, Zaitsau DH, Kabo GJ,et al. Vapor pressure and thermal stability of ionic liquid1-butyl-3-methylimidazolium Bis(trifluoromethylsulfonyl)amide. Thermochimica Acta, 2005, 439: 158-160
5 Liu FH, Jiang Y. Room temperature ionic liquid as matrix medium for the determination of residual solvents in pharmaceuticals by static headspace gas chromatography. Journal of Chromatography A, 2007, 1167:116-119
6罗爱庭,刘海峰,汪学楷,等.顶空气相色谱法测定普卢利沙星中的有机残留溶剂.现代仪器, 2006, 6: 31-33
7吴羽岚,钟春华,王磊.多潘立酮有机溶剂残留量的检测方法.江苏药学与临床研究, 2005, 13(5): 33-35
1刘绍华,杨大成,唐维高,等.新药薁磺酸钠的核磁共振谱分析.中国药物化学杂志, 2001, 11(40): 89-90
2陈桧平,徐彰,金抒清.麦滋林-S颗粒治疗儿童慢性胃炎疗效观察.临床医学, 2005, 25(12): 80-81
3刘庆彬,张占辉,薄海静,等.麦滋林-S中薁磺酸钠的高效液相色谱法测定.分析化学, 2000, 28(10): 1319
4 Swatloski RP, Spear SK, Holbrey JD. Dissolution of cellulose with ionic liquids. J. Am. Chem. Soc., 2002, 124: 4974-4975
5江海亮,沈昊宇,乐长高,等.室温离子液体作溶剂顶空气-质联用测定药物中溶剂残留.分析化学, 2006, 34(7): 1027-1029
6蔡太梅,蒋晔,田书霞.顶空气相色谱法测定阿立哌唑中有机溶剂N,N-二甲基甲酰胺残留量.中国新药杂志, 2005, 14(3): 327-329
1刘文超,张燕军,任军,等.伊班膦酸钠治疗恶性肿瘤骨转移性骨痛的临床研究.第四军医大学学报, 2004, 25(14): 1320-1322
2傅淑霞,张丽萍,杨林,等.伊班膦酸钠可防治肾小球疾病患者糖皮质激素引起的骨密度减低.中国骨质疏松杂志, 2005, 11(1): 88-90
3中国药典2005年版.二部. Appendix (附录): 55-57
4 ICH指导委员会,周海钧.残留溶剂的测定原则,药品注册的国际技术要求,人民卫生出版社, 2000: 70-100
1 Seddon KR. Ionic liquids for clean technology. J Chem Biotechnol, 1997, 68: 351-356
2 Di W,Ari I. Applications of ionic liquids in electrochemical sensors. Analytica Chimica Acta, 2008, 607: 126-135
3 Mizuuchi H, Jaitely V, Murdan S, et al. Room temperature ionic liquids and their mixtures: potential pharmaceutical solvents. Pharmaceutical Sciences, 2008, 33: 326-331
4 Earle1 MJ, Esperanca JM, Gilea MA, et al. The distillation and volatility of ionic liquids. Nature, 2006, 439: 831-834
5孙学文,赵锁奇.超临界条件下离子液体催化苯与丙烯烷基化的反应机理研究.化学学报, 2008, 66(4): 471-475
6党清雅,陈凤香,韩会景.离子液体负载钌络合物的合成及其催化环烯烃开环易位聚合.高分子学报, 2008, 4: 343-349
7 Aguilera-Herrador E, Lucena R, Cárdenas S, et al. Determination oftrihalomethanes in waters by ionic liquid-based single drop microextraction/gas chromatographic/mass spectrometry. Journal of Chromatography A, 2008, 1209: 76-82
8 Aguilera-Herrador E, Lucena R, Cárdenas S, et al. Ionic liquid-based single-drop microextraction/gas chromatographic/mass spectrometric determination of benzene, toluene, ethylbenzene and xylene isomers in waters. Journal of Chromatography A, 2008, 1201: 106-111
9 Zhao FQ, Li J, Zeng BZ. Coupling of ionic liquid-based headspace single-drop microextraction with GC for sensitive detection of phenols. J Sep Sci., 2008, 31: 3045-3049
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