“血必净”注射液生产过程近红外光谱分析技术的应用研究
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摘要
目前,不同批次间药品质量难以稳定均一,已成为中药产业亟待解决的重大技术难题,严重阻碍了中药现代化进程。缺乏全过程有效、快速的质量分析方法和技术手段是造成上述质控难题的主要原因之一。
近红外光谱技术(Near-infrared Spectroscopy,NIRS)作为一种在线监测技术,具有快速、无损的特点,已在众多领域得到广泛应用,但在中药制药过程监控中的应用研究刚刚起步。研究适合中药生产过程特点的近红外光谱分析技术,建立中药生产过程关键环节的质量控制技术体系,从而保障中药产品质量的稳定均一,已成为当前中药质控的重点研究方向。本文以中药大品种“血必净注射液”的生产过程为具体研究对象,针对注射液中不同药材(包括君药红花,臣药赤芍),不同工艺环节有序开展近红外光谱分析技术应用研究。主要内容包括:
1.针对赤芍提取过程中缺乏有效检测手段的问题,采用近红外(NIR)透射光谱法对芍药苷等有效成分含量进行实时跟踪预测,建立了一种快速测定赤芍水提过程有效成分含量的新方法。该方法以HPLC为对照分析法测定了芍药苷含量,运用偏最小二乘(PLS)法建立NIR光谱与芍药苷含量HPLC分析值之间的多元校正模型,并对未知样本进行含量预测。结果表明,所建方法操作简便、快速无损、准确可靠,可用于中药赤芍提取过程有效成分芍药苷含量的快速监测。
2.采用NIRS测定红花逆流提取过程中羟基红花黄色素A(HSYA)的含量变化,并对逆流提取不同阶段进行了HSYA浓度预测。所建的HSYA定量模型性能良好,相关系数达0.98,预测结果较为准确地反映了红花逆流提取过程的含量变化。研究结果表明,所建的定量模型能够应用于红花逆流提取过程HSYA的含量预测,实现不同阶段提取终点的快速判断。
3.将近红外光谱分析技术引入到中药生产的浓缩过程,以红花浓缩除醇过程为例,首次同时实现对红花醇沉液浓缩过程中HSYA浓度、乙醇浓度和密度值的实时监测。浓缩过程上述三个指标的同时检测尚未见文献报道。同时,在本研究中探讨了红花乙醇溶液密度与乙醇浓度之间的关系,有效地避免了气相色谱测定的繁琐操作,缩短了分析周期,实现了乙醇浓度的快速在线监测。该成果有望发展形成一种快速无损、高效便捷的浓缩过程关键指标的测定技术,为中药浓缩过程的在线监测、浓缩终点的快速判断提供可靠的方法,从而保证中药制剂产品的质量。
4.选用“血必净注射液”中君药红花大孔树脂纯化过程为对象,探讨采用近红外光谱分析技术快速检测树脂吸附和洗脱过程中HSYA浓度变化曲线,实现泄漏点的快速预测,同时采用移动块标准偏差法(moving block of standard deviation,MBSD)计算采集的吸附和洗脱过程的光谱偏差,以此作为判断吸附饱和点和洗脱终点的指标,实现过程终点的快速判断。
The modernization of Traditional Chinese Medicine(TCM) is blocked by its poor consistence and instability.One of the main reasons is the absence of fast and efficient analytical methods for manufacture process of TCM.As one of the techniques for on-line monitoring,fast and non-destructive analyzing,near infrared spectroscopy(NIRS) has already been widely used in many areas,but scarily in TCM pharmacy process.As a result,establishing the technology of quality control for the whole process,which is solidly based the study of NIRS suitable for the manufacture process of TCM,will ensure the consistence and stability of TCM products.The study of different raw materials and process links in the production of "xuebijing" injection by NIRS is carried out in this dissertation.The main researches are as followed:
1.The research set up a novel method for fast determination of active components in water extracting process of Paeonia lactiflora by near infrared spectroscopy(NIRS) targeted at the absence of on-line detection means in the process.HPLC was used as the reference method to determine the content of Paeoniflorin and a multivariate calibration model based on PLS algorithm was developed to correlate the spectra and the corresponding values determined by the reference method.The method mentioned above is proved to be convenient,rapid and nondestructive,accurate and reliable,and is applicable for fast determination and monitoring of active components in extraction process of traditional Chinese medicine.
2.The content of HSYA in the process of countercurrent extracting of Carthamus tinctorius L.was determined by Near-infrared Spectroscopy(NIRS),which was used to predict the concentration variation of HSYA in the different stages of countercurrent extracting.The performance of calibration model established was good,the correlation coefficient of which achieved 0.98.Meanwhile,the model gave a good prediction which exactly reflected the trend of HSYA content.It was concluded that the proposed method provides a novel efficient and environmental friendly approach for the fast determination of the active components in traditional Chinese medicine for countercurrent extracting process analysis and the rapid on-line endpoint determination during the process.
3.NIRS was adopted in the concentrating process of Carthamus tinctorius L.to realize the real-time monitoring on HSYA content,alcohol content and density value,which hadn't been reported in literature.At the same time,the fitting curve of the density and alcohol concentration were developed, avoiding effectively tedious operations by GC,shortening analytical time and eventually realizing fast determination of alcohol content.It is concluded that NIRS can be used as a rapid method to determinate three key quality control indexes(the density,concentration of HSYA and ethanol) at one time in the process of concentrating process of Carthamus tinctorius L.alcohol sedimentation solution, which provided a reliable vector for on-line detection and rapid endpoint determination on the process of concentration of Chinese herb,eventually ensured the quality of Chinese medicine preparations.
4.To realize fast judgment on the leak point,NIRS was used for rapid determination on change curve of HSYA content based on the purification of Carthamus tinctorius L.by macroporous resin. Meanwhile,spectral variance in absorption and elution was calculated by moving block of standard deviation(MBSD) and worked as evaluation index of endpoint judgment to realize the rapid fast determination of endpoint.
近红外光谱技术(Near-infrared Spectroscopy,NIRS)作为一种在线监测技术,具有快速、无损的特点,已在众多领域得到广泛应用,但在中药制药过程监控中的应用研究刚刚起步。研究适合中药生产过程特点的近红外光谱分析技术,建立中药生产过程关键环节的质量控制技术体系,从而保障中药产品质量的稳定均一,已成为当前中药质控的重点研究方向。本文以中药大品种“血必净注射液”的生产过程为具体研究对象,针对注射液中不同药材(包括君药红花,臣药赤芍),不同工艺环节有序开展近红外光谱分析技术应用研究。主要内容包括:
1.针对赤芍提取过程中缺乏有效检测手段的问题,采用近红外(NIR)透射光谱法对芍药苷等有效成分含量进行实时跟踪预测,建立了一种快速测定赤芍水提过程有效成分含量的新方法。该方法以HPLC为对照分析法测定了芍药苷含量,运用偏最小二乘(PLS)法建立NIR光谱与芍药苷含量HPLC分析值之间的多元校正模型,并对未知样本进行含量预测。结果表明,所建方法操作简便、快速无损、准确可靠,可用于中药赤芍提取过程有效成分芍药苷含量的快速监测。
2.采用NIRS测定红花逆流提取过程中羟基红花黄色素A(HSYA)的含量变化,并对逆流提取不同阶段进行了HSYA浓度预测。所建的HSYA定量模型性能良好,相关系数达0.98,预测结果较为准确地反映了红花逆流提取过程的含量变化。研究结果表明,所建的定量模型能够应用于红花逆流提取过程HSYA的含量预测,实现不同阶段提取终点的快速判断。
3.将近红外光谱分析技术引入到中药生产的浓缩过程,以红花浓缩除醇过程为例,首次同时实现对红花醇沉液浓缩过程中HSYA浓度、乙醇浓度和密度值的实时监测。浓缩过程上述三个指标的同时检测尚未见文献报道。同时,在本研究中探讨了红花乙醇溶液密度与乙醇浓度之间的关系,有效地避免了气相色谱测定的繁琐操作,缩短了分析周期,实现了乙醇浓度的快速在线监测。该成果有望发展形成一种快速无损、高效便捷的浓缩过程关键指标的测定技术,为中药浓缩过程的在线监测、浓缩终点的快速判断提供可靠的方法,从而保证中药制剂产品的质量。
4.选用“血必净注射液”中君药红花大孔树脂纯化过程为对象,探讨采用近红外光谱分析技术快速检测树脂吸附和洗脱过程中HSYA浓度变化曲线,实现泄漏点的快速预测,同时采用移动块标准偏差法(moving block of standard deviation,MBSD)计算采集的吸附和洗脱过程的光谱偏差,以此作为判断吸附饱和点和洗脱终点的指标,实现过程终点的快速判断。
The modernization of Traditional Chinese Medicine(TCM) is blocked by its poor consistence and instability.One of the main reasons is the absence of fast and efficient analytical methods for manufacture process of TCM.As one of the techniques for on-line monitoring,fast and non-destructive analyzing,near infrared spectroscopy(NIRS) has already been widely used in many areas,but scarily in TCM pharmacy process.As a result,establishing the technology of quality control for the whole process,which is solidly based the study of NIRS suitable for the manufacture process of TCM,will ensure the consistence and stability of TCM products.The study of different raw materials and process links in the production of "xuebijing" injection by NIRS is carried out in this dissertation.The main researches are as followed:
1.The research set up a novel method for fast determination of active components in water extracting process of Paeonia lactiflora by near infrared spectroscopy(NIRS) targeted at the absence of on-line detection means in the process.HPLC was used as the reference method to determine the content of Paeoniflorin and a multivariate calibration model based on PLS algorithm was developed to correlate the spectra and the corresponding values determined by the reference method.The method mentioned above is proved to be convenient,rapid and nondestructive,accurate and reliable,and is applicable for fast determination and monitoring of active components in extraction process of traditional Chinese medicine.
2.The content of HSYA in the process of countercurrent extracting of Carthamus tinctorius L.was determined by Near-infrared Spectroscopy(NIRS),which was used to predict the concentration variation of HSYA in the different stages of countercurrent extracting.The performance of calibration model established was good,the correlation coefficient of which achieved 0.98.Meanwhile,the model gave a good prediction which exactly reflected the trend of HSYA content.It was concluded that the proposed method provides a novel efficient and environmental friendly approach for the fast determination of the active components in traditional Chinese medicine for countercurrent extracting process analysis and the rapid on-line endpoint determination during the process.
3.NIRS was adopted in the concentrating process of Carthamus tinctorius L.to realize the real-time monitoring on HSYA content,alcohol content and density value,which hadn't been reported in literature.At the same time,the fitting curve of the density and alcohol concentration were developed, avoiding effectively tedious operations by GC,shortening analytical time and eventually realizing fast determination of alcohol content.It is concluded that NIRS can be used as a rapid method to determinate three key quality control indexes(the density,concentration of HSYA and ethanol) at one time in the process of concentrating process of Carthamus tinctorius L.alcohol sedimentation solution, which provided a reliable vector for on-line detection and rapid endpoint determination on the process of concentration of Chinese herb,eventually ensured the quality of Chinese medicine preparations.
4.To realize fast judgment on the leak point,NIRS was used for rapid determination on change curve of HSYA content based on the purification of Carthamus tinctorius L.by macroporous resin. Meanwhile,spectral variance in absorption and elution was calculated by moving block of standard deviation(MBSD) and worked as evaluation index of endpoint judgment to realize the rapid fast determination of endpoint.
引文
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