基于sHS-GC技术的高灵敏度药物有机溶剂残留分析研究
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摘要
药物有机残留溶剂是指在原料药或辅料的生产以及药品制备过程中使用，但很难完全除去的挥发性有机化合物（VOCs）。大部分残留有机溶剂对人体都呈现不同程度的毒性，因此必须对药物中残留有机溶剂的种类和含量进行控制。各国药典均对有机溶剂残留的控制进行了明确规定，提高药物有机溶剂残留的分析检测灵敏度是药物分析研究领域的重要课题。本论文基于静态顶空气相色谱分析（sHS-GC，Static Headspace Gas ChromatographyAnalysis）技术，就提高药物中有机残留溶剂的分析灵敏度进行了系统研究。针对欧洲药典关于残留溶剂检查的方法无法检出二甲基亚砜（DMSO）等低蒸汽压、高沸点、难挥发性有机溶剂残留，以及采用常规有机溶媒分析药物有机溶剂残留灵敏度过低的问题，建立了二甲基亚砜（DMSO）、N，N－二甲基甲酰胺（DMF）、N，N－二甲基乙酰胺（DMA）、苯甲醇（BA）等低蒸汽压、高沸点、难挥发性有机溶剂残留的分析检测方法，并以制药中常用的多种常规有机溶剂残留为研究对象，就提高其静态顶空气相色谱分析灵敏度进行了系统研究。论文主要研究内容及结论如下：
①基于静态顶空气相色谱分析的气液（固）相比理论，保持顶空瓶中待测分析物的量恒定，考察了顶空分析中液相体积对顶空灵敏度的影响。发现顶空瓶中液相体积对分析灵敏度有较大影响，顶空分析液相体积越小，待测分析物在液相中的分配系数越小，分析物的峰面积响应越大，分析灵敏度越高。在考察的液相体积范围内，液相体积为1mL时的分析灵敏度约为6mL时的4倍。
②基于待测分析物在液相和气相中的分配系数理论，采用欧洲药典的残留溶剂分析方法，对分析溶媒进行了筛选，分别研究了水、N，N－二甲基甲酰胺、N，N－二甲基乙酰胺、1，3－二甲基咪唑啉酮、苯甲醇、正辛醇等溶媒测定DMSO溶剂残留的分析结果，并引入液体石蜡作为溶媒对DMSO残留进行了分析。研究发现，只有液体石蜡作为溶媒成功检测到了ICH规定限度的DMSO溶剂残留，其他溶剂作为溶媒则无法检出。因此液体石蜡作为一种新型溶媒，对分析DMSO等低蒸汽压、高沸点、难挥发性有机溶剂残留提供了新思路。
③对sHS-GC相关参数对DMSO分析灵敏度的影响进行了研究，确定了最佳顶空平衡温度、平衡时间、加压时间以及进样时间分别为160°C、10min、1.0min、0.08min。对气相升温程序进行了研究，优化结果为初始温度140°C，初始温度持续时间为5min，升温幅度为6°C/min，中间温度为165°C，中间温度持续时间为10min。与欧洲药典规定的sHS-GC参数相比较，参数优化后的DMSO残留溶剂分析灵敏度提高了10倍，分析时间缩短为原来的1/6，提高了分析效率。
④对分析方法进行了验证，结果表明方法具有良好的专属性、线性（r>0.9996）和较高的精密度（RSD（%）<3.0），试验回收率在95－105％之间，具有较高的准确度，用信噪比和回归曲线法确定了DMSO的sHS-GC分析检测限和定量限分别为1.0ppm和3.0ppm左右。将该方法成功应用于新型药物包衣材料Kollicoat IR样品中DMSO残留的分析检测，分别使用外标法和标准添加法两种定量方法测定，分析结果十分接近，分别为4640ppm和4750ppm。采用该分析方法对多个不同批次的Kollicoat IR样品进行了测定，DMSO残留量均在ICH限度要求之内。采用液体石蜡作为溶媒对局部治疗用药RadoSalil样品中的挥发性成分进行了sHS-GC分析，有效检出了药物中的挥发性成分，印证了液体石蜡可作为溶媒分析部分药物中的挥发性有机化合物。
⑤将研究结果进一步应用于除DMSO外的其他低蒸汽压、高沸点、难挥发性有机溶剂残留的分析。采用该方法使用不同的sHS-GC仪器对DMF、DMA及BA三种有机溶剂残留进行了分析测定，结果显示该分析方法高灵敏度、高选择性地检出了三种有机溶剂残留。对该分析方法进行了验证，结果表明该分析具有良好的专属性、线性（r>0.9996）、精密度（溶剂峰保留时间和峰面积的RSD（%）值分别为0.5和小于4.0），DMF、DMA的分析检测限和定量限分别为0.3ppm和1.0ppm左右，BA的分析检测限和定量限分别为1.0ppm和3.0ppm左右。
⑥对制药中常用的18种常规有机溶剂残留的sHS-GC分析进行了研究，系统研究了有机溶媒DMF、DMA以及DMSO等与水形成的混合溶媒对顶空分析灵敏度的影响，研究了顶空分析中液相体积以及溶媒离子强度等因素对常规有机溶剂残留分析灵敏度的影响。研究发现有机溶媒与水以合适的比例混合后可显著提高分析灵敏度，增加溶媒的离子强度以及较低的液相体积也可显著提高分析灵敏度，并对18种常规有机溶剂残留分析的线性、范围及分析精密度进行了研究。研究结果可使待分析样品的使用量减少，也减少了有机溶剂的使用量，既对环境友好又节约分析成本。
综上，本论文针对药物有机溶剂残留分析的热点问题展开研究，以提高残留溶剂的sHS-GC分析检测灵敏度为研究目标，对低蒸汽压、高沸点、难挥发性、高极性的特定有机残留溶剂以及制药中常用的常规有机溶剂残留的sHS-GC分析进行了系统研究，论文研究结论对药物有机溶剂残留的分析检测具有重要理论意义和应用价值。
Residual solvents in pharmaceuticals are defined as organic volatile chemicals thatare used or produced in the manufacture of active substances or excipients, or in thepreparation of medicinal products. Generally, many of these volatile organic chemicalscan not be completely removed by standard manufacturing processes or techniques andare left behind, preferably at low levels. Residual solvent analysis of bulk drugsubstances and finished pharmaceutical products is necessary for a number of reasons.High levels of residual organic solvents represent a risk to human health because oftheir toxicity. RS analysis is described in all Pharmacopoeias, among which EuropeanPharmacopoeia has strictest rules, however, method from Ph. Eur. fails to detect lowevapor pressure and high boiling point RS. Sensitivity of RS determination is alsoreduced with pure organic solvents as media. So, the development of the new method todetect high boiling point RS has significant academic value and application prospective.A static headspace gas chromatography analysis method was used in the study toanalyze residual solvent in this study. However, the sensitivity of the analytical methoddescribed in the Ph. Eur. is not sufficient for those solvents with high boiling point, lowvapour pressures and non volatile like dimethylsulfoxide, N, N-Dimethylformamide, N,N-Dimethylacetamide and Benzyl alcohol. The research started from the shortcomingsof Eur. Ph. that fails to identify the high boiling point residual solvents. A new staticheadspace chromatography analysis method was developed based on sHS-GC analysis.The research also investigated the increase of sHS-GC analysis sensitivity fordetermination of residual solvents which are often used in pharmaceuticals. The mainconclusions and results are as following:
①Based on principles of headspace gas chromatography, the concentration ofvolatile compounds in the gas phase can be expressed as Cg=Cs0/(K+β). In order toyield higher concentrations of volatile analytes in the gas phase and better sensitivity,influence of phase ratio on sensitivity was investigated. The difference between ourstudy and traditional phase ratio was that the amout of analytes in the vial was constant.The liquid volume in the vial was set to be1mL to12mL with interval of1mL. It wasclear that the highest sensitivity was obtained using only1.0mL of liquid phase in thevial. The response with1.0mL total volume is almost5times higher than the responsewith6.0mL total volume. The result shows that the lower liquid volume the higher concentration of analytes.
②Concerning the partition of analyte in two phases and high boiling point ofdimethylsulfoxide of189°C, liquid paraffin was introduced as the new dilution solventto solve high boiling point residual solvents. With settings described in Ph. Eur., Water,N, N-dimethylformamide, N, N-dimethylacetamide, Benzyl alcohol,1-octnal and liquidparaffin were investigated as dilution. Only liquid paraffin as dilution successfullydetected solvent peak at the limit described in ICH. However, other dilutions were notable to detect the dimethylsulfoxide peak. Introduction of liquid paraffin provided a newway to determine the high boiling points residual solvents.
③Keep liquid paraffin as dilution and1ml of liquid volume in the vial,parameters of static headspace combine gas chromatography analysis were optimized.The experimental parameters such as headspace vial equilibration temperature,headspace vial equilibration time, autosampler injection time, headspace vial pressurizetime were optimized to be160°C,10min,0.08min and1.0min respectively. GC oventemperature programs were optimized, maintaining the temperature at140°C for5min,then raising the temperature at a rate of6°C/min to165°C and maintaining it for10min. New developed method was used to analyze DMSO of250ppm in liquid paraffin,the peak area of DMSO is10times higher than initial parameters in Ph. Eur.. Analysistime was shortened to1/6of initial one; sensitivity and efficiency were improvedsignificantly.
④A new developed method must be validated before use in pharmaceuticalanalysis to ensure that the obtained result is reliable. Results show that the linearity isgood with r of0.9996. The repeatability was checked by calculating the relativestandard deviation (RSD) values at each concentration point, RSD (n=4) of sixconcentrations are less than10%. Acurracy was determined by recovery ratio to bebetween95％and105％. The limits of detection (LOD) and quantitation (LOQ) of thestandard solutions were determined to be around1.0ppm and3.0ppm respectively.Linear range from25ppm to300ppm was obtained with a correlation coefficient of0.9996. New method gives higher sensitivity for the determination of DMSO comparingPh. Eur. The application of this new method was demonstrated successfully bydetermining residual DMSO in drug coating materials Kollicoat IR samples. Theamounts of DMSO in samples were determined to be4640ppm and4750ppm withexternal calibration and standard addition respectively.
⑤The method was applied using another s HS-GC instrument to determine the DMF, DMA and BA as RS, the specificity and selectivity was good. The linearity wasgood with r higher than0.996, RSD (%) cvalues of RT and peak area precision andaccuracy were found to be0.5and4.0respectively which shows good precision.Recovery values were between95-105%presents good accuracy. LOD and LOQ ofDMF and DMA were determined to be0.3and1.0ppm, LOD and LOQ of BA was1.0and3.0ppm respectively.
⑥Analysis of18residual solvents often used in pharmaceuticals wereinvestigated. Influences of organic media DMF, DMA and BA mixed with water asdilution media on analysis sensitivity were studied. Influences of liquid phase volumeand ionic strength of the dilution media on analysis sensitivity were also investigated. Itwas concluded that mixed media, high ionic strength and lower liquid volume increasedanalysis significantly. The determination of18residual solvents was evaluated on termsof linearity, range and precision. Conclusions could save drugs samples and organicsolvents, which is good for environment and saving analysis cost.
This work focused on the determination of RS in pharmaceuticals, aimed toincrease the sHS-GC analysis sensitivity. sHS-GC analysis of high boiling point, lowvapour pressures and non volatile residual solvents and regular organic solvent oftenused in pharmaceuticals were investigated. Research conculsions have high theoreticalsignificance and application value on analysis of RS in pharmaceuticals.
①基于静态顶空气相色谱分析的气液（固）相比理论，保持顶空瓶中待测分析物的量恒定，考察了顶空分析中液相体积对顶空灵敏度的影响。发现顶空瓶中液相体积对分析灵敏度有较大影响，顶空分析液相体积越小，待测分析物在液相中的分配系数越小，分析物的峰面积响应越大，分析灵敏度越高。在考察的液相体积范围内，液相体积为1mL时的分析灵敏度约为6mL时的4倍。
②基于待测分析物在液相和气相中的分配系数理论，采用欧洲药典的残留溶剂分析方法，对分析溶媒进行了筛选，分别研究了水、N，N－二甲基甲酰胺、N，N－二甲基乙酰胺、1，3－二甲基咪唑啉酮、苯甲醇、正辛醇等溶媒测定DMSO溶剂残留的分析结果，并引入液体石蜡作为溶媒对DMSO残留进行了分析。研究发现，只有液体石蜡作为溶媒成功检测到了ICH规定限度的DMSO溶剂残留，其他溶剂作为溶媒则无法检出。因此液体石蜡作为一种新型溶媒，对分析DMSO等低蒸汽压、高沸点、难挥发性有机溶剂残留提供了新思路。
③对sHS-GC相关参数对DMSO分析灵敏度的影响进行了研究，确定了最佳顶空平衡温度、平衡时间、加压时间以及进样时间分别为160°C、10min、1.0min、0.08min。对气相升温程序进行了研究，优化结果为初始温度140°C，初始温度持续时间为5min，升温幅度为6°C/min，中间温度为165°C，中间温度持续时间为10min。与欧洲药典规定的sHS-GC参数相比较，参数优化后的DMSO残留溶剂分析灵敏度提高了10倍，分析时间缩短为原来的1/6，提高了分析效率。
④对分析方法进行了验证，结果表明方法具有良好的专属性、线性（r>0.9996）和较高的精密度（RSD（%）<3.0），试验回收率在95－105％之间，具有较高的准确度，用信噪比和回归曲线法确定了DMSO的sHS-GC分析检测限和定量限分别为1.0ppm和3.0ppm左右。将该方法成功应用于新型药物包衣材料Kollicoat IR样品中DMSO残留的分析检测，分别使用外标法和标准添加法两种定量方法测定，分析结果十分接近，分别为4640ppm和4750ppm。采用该分析方法对多个不同批次的Kollicoat IR样品进行了测定，DMSO残留量均在ICH限度要求之内。采用液体石蜡作为溶媒对局部治疗用药RadoSalil样品中的挥发性成分进行了sHS-GC分析，有效检出了药物中的挥发性成分，印证了液体石蜡可作为溶媒分析部分药物中的挥发性有机化合物。
⑤将研究结果进一步应用于除DMSO外的其他低蒸汽压、高沸点、难挥发性有机溶剂残留的分析。采用该方法使用不同的sHS-GC仪器对DMF、DMA及BA三种有机溶剂残留进行了分析测定，结果显示该分析方法高灵敏度、高选择性地检出了三种有机溶剂残留。对该分析方法进行了验证，结果表明该分析具有良好的专属性、线性（r>0.9996）、精密度（溶剂峰保留时间和峰面积的RSD（%）值分别为0.5和小于4.0），DMF、DMA的分析检测限和定量限分别为0.3ppm和1.0ppm左右，BA的分析检测限和定量限分别为1.0ppm和3.0ppm左右。
⑥对制药中常用的18种常规有机溶剂残留的sHS-GC分析进行了研究，系统研究了有机溶媒DMF、DMA以及DMSO等与水形成的混合溶媒对顶空分析灵敏度的影响，研究了顶空分析中液相体积以及溶媒离子强度等因素对常规有机溶剂残留分析灵敏度的影响。研究发现有机溶媒与水以合适的比例混合后可显著提高分析灵敏度，增加溶媒的离子强度以及较低的液相体积也可显著提高分析灵敏度，并对18种常规有机溶剂残留分析的线性、范围及分析精密度进行了研究。研究结果可使待分析样品的使用量减少，也减少了有机溶剂的使用量，既对环境友好又节约分析成本。
综上，本论文针对药物有机溶剂残留分析的热点问题展开研究，以提高残留溶剂的sHS-GC分析检测灵敏度为研究目标，对低蒸汽压、高沸点、难挥发性、高极性的特定有机残留溶剂以及制药中常用的常规有机溶剂残留的sHS-GC分析进行了系统研究，论文研究结论对药物有机溶剂残留的分析检测具有重要理论意义和应用价值。
Residual solvents in pharmaceuticals are defined as organic volatile chemicals thatare used or produced in the manufacture of active substances or excipients, or in thepreparation of medicinal products. Generally, many of these volatile organic chemicalscan not be completely removed by standard manufacturing processes or techniques andare left behind, preferably at low levels. Residual solvent analysis of bulk drugsubstances and finished pharmaceutical products is necessary for a number of reasons.High levels of residual organic solvents represent a risk to human health because oftheir toxicity. RS analysis is described in all Pharmacopoeias, among which EuropeanPharmacopoeia has strictest rules, however, method from Ph. Eur. fails to detect lowevapor pressure and high boiling point RS. Sensitivity of RS determination is alsoreduced with pure organic solvents as media. So, the development of the new method todetect high boiling point RS has significant academic value and application prospective.A static headspace gas chromatography analysis method was used in the study toanalyze residual solvent in this study. However, the sensitivity of the analytical methoddescribed in the Ph. Eur. is not sufficient for those solvents with high boiling point, lowvapour pressures and non volatile like dimethylsulfoxide, N, N-Dimethylformamide, N,N-Dimethylacetamide and Benzyl alcohol. The research started from the shortcomingsof Eur. Ph. that fails to identify the high boiling point residual solvents. A new staticheadspace chromatography analysis method was developed based on sHS-GC analysis.The research also investigated the increase of sHS-GC analysis sensitivity fordetermination of residual solvents which are often used in pharmaceuticals. The mainconclusions and results are as following:
①Based on principles of headspace gas chromatography, the concentration ofvolatile compounds in the gas phase can be expressed as Cg=Cs0/(K+β). In order toyield higher concentrations of volatile analytes in the gas phase and better sensitivity,influence of phase ratio on sensitivity was investigated. The difference between ourstudy and traditional phase ratio was that the amout of analytes in the vial was constant.The liquid volume in the vial was set to be1mL to12mL with interval of1mL. It wasclear that the highest sensitivity was obtained using only1.0mL of liquid phase in thevial. The response with1.0mL total volume is almost5times higher than the responsewith6.0mL total volume. The result shows that the lower liquid volume the higher concentration of analytes.
②Concerning the partition of analyte in two phases and high boiling point ofdimethylsulfoxide of189°C, liquid paraffin was introduced as the new dilution solventto solve high boiling point residual solvents. With settings described in Ph. Eur., Water,N, N-dimethylformamide, N, N-dimethylacetamide, Benzyl alcohol,1-octnal and liquidparaffin were investigated as dilution. Only liquid paraffin as dilution successfullydetected solvent peak at the limit described in ICH. However, other dilutions were notable to detect the dimethylsulfoxide peak. Introduction of liquid paraffin provided a newway to determine the high boiling points residual solvents.
③Keep liquid paraffin as dilution and1ml of liquid volume in the vial,parameters of static headspace combine gas chromatography analysis were optimized.The experimental parameters such as headspace vial equilibration temperature,headspace vial equilibration time, autosampler injection time, headspace vial pressurizetime were optimized to be160°C,10min,0.08min and1.0min respectively. GC oventemperature programs were optimized, maintaining the temperature at140°C for5min,then raising the temperature at a rate of6°C/min to165°C and maintaining it for10min. New developed method was used to analyze DMSO of250ppm in liquid paraffin,the peak area of DMSO is10times higher than initial parameters in Ph. Eur.. Analysistime was shortened to1/6of initial one; sensitivity and efficiency were improvedsignificantly.
④A new developed method must be validated before use in pharmaceuticalanalysis to ensure that the obtained result is reliable. Results show that the linearity isgood with r of0.9996. The repeatability was checked by calculating the relativestandard deviation (RSD) values at each concentration point, RSD (n=4) of sixconcentrations are less than10%. Acurracy was determined by recovery ratio to bebetween95％and105％. The limits of detection (LOD) and quantitation (LOQ) of thestandard solutions were determined to be around1.0ppm and3.0ppm respectively.Linear range from25ppm to300ppm was obtained with a correlation coefficient of0.9996. New method gives higher sensitivity for the determination of DMSO comparingPh. Eur. The application of this new method was demonstrated successfully bydetermining residual DMSO in drug coating materials Kollicoat IR samples. Theamounts of DMSO in samples were determined to be4640ppm and4750ppm withexternal calibration and standard addition respectively.
⑤The method was applied using another s HS-GC instrument to determine the DMF, DMA and BA as RS, the specificity and selectivity was good. The linearity wasgood with r higher than0.996, RSD (%) cvalues of RT and peak area precision andaccuracy were found to be0.5and4.0respectively which shows good precision.Recovery values were between95-105%presents good accuracy. LOD and LOQ ofDMF and DMA were determined to be0.3and1.0ppm, LOD and LOQ of BA was1.0and3.0ppm respectively.
⑥Analysis of18residual solvents often used in pharmaceuticals wereinvestigated. Influences of organic media DMF, DMA and BA mixed with water asdilution media on analysis sensitivity were studied. Influences of liquid phase volumeand ionic strength of the dilution media on analysis sensitivity were also investigated. Itwas concluded that mixed media, high ionic strength and lower liquid volume increasedanalysis significantly. The determination of18residual solvents was evaluated on termsof linearity, range and precision. Conclusions could save drugs samples and organicsolvents, which is good for environment and saving analysis cost.
This work focused on the determination of RS in pharmaceuticals, aimed toincrease the sHS-GC analysis sensitivity. sHS-GC analysis of high boiling point, lowvapour pressures and non volatile residual solvents and regular organic solvent oftenused in pharmaceuticals were investigated. Research conculsions have high theoreticalsignificance and application value on analysis of RS in pharmaceuticals.
引文
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