Studies On The End-point Determination Methods Of Pharmaceutical Technics Of Traditional Chinese Medicine Based On Near Infrared Spectroscopy

In the production process of traditional Chinese medicine(TCM),the quality of the final products is influenced by many factors.Among them,the quality difference of raw materials and the change of process parameters are the decisive factors affecting the quality consistency of products.However,TCM is an extremely complex multi-component system.Although relevant departments have successively formulated and promulgated a number of quality standards for Chinese herbal medicines,it is not easy to obtain the raw materials with zero fluctuation in quality.It is difficult to get the high quality products with the changing materials quality and the fixed end-point.Therefore,in the pharmaceutical process,for different batches of the raw materials it is particularly important to realize the real-time monitoring of processes end-points.At present,the traditional chromatographic analysis technologies can not realize the effective monitoring of pharmaceutical process due to the long analytical cycle and high cost of human and material resources.To solve the problem,the blending process of Qingyan tablets and Dahuang Soda tablets,the column chromatographic process of Phellodendri Chinensis Cortex,and the extraction process of Gegenqinlian decoction were taken as case studies.Near infrared(NIR)spectroscopy combined with chemometrics algorithms were used for developing the both methods of the end-points determination and the on-line monitoring of pharmaceutical processes.The main contents are as follows:1.Determination of the blending end-point of Qingyan tablets during the simplified blending process based on NIR spectroscopy.The raw materials with different particle sizes were prepared,and eight different batches of the mixture were obtained by experimental design.Partial least squares(PLS)regression algorithm was used to establish the contents calibration models of Platycodonis Radix,Fructus Chebulae and other five raw and auxiliary materials were developed,and the other three batches were used to verify the models.Moreover,the moving block of standard deviation(MBSD)algorithm was used as a qualitative method for determination of the blending end-points,so as to realize developing the method of blending end-point determination of Qingyan tablets during the simplified simulation blending process,and to explore the potential impact of particle size difference on the end-point of the blending process.2.A NIR spectroscopy-based end-point determination method for the blending process of Dahuang soda tablets.In this study,the end-point of blending process of Dahuang soda tablets was monitored using NIR spectroscopy.Different levels of Dahuang extracts were mixed with different composition ratio of the four excipients,and then,18 different batches of mixture were obtained.The NIR spectra including pressure variables were collected after the first 15 batches of samples arriving to a homogenous state.Meanwhile,the contents of active components(emodin and emodin methyl ether)were determined.PLS regression algorithm was used to establish the pressure sensitive model and the pressure insensitive model of each component,respectively,and the differences of their robustness were compared.Moreover,the principal component analysis-moving block standard deviation(PCA-MBSD)method was used for the end-point determination of the blending with the process spectra.In the research,a more robust pressure insensitive model has been developed,and this robust modeling strategy has a certain application prospect.3.End-point determination of the column chromatographic process of Phellodendri Chinensis Cortex based near infrared spectroscopy combined with machine learning algorithms.By changing the concentration of sample solution,an experiments plan including10 batches of elution experiments were obtained.During the elution process,the NIR spectra were collected,and the contents of active components(berberine hydrochloride and hydrochloride phellodendrine)in the eluent at corresponding sampling points were determined.PLS regression,Gaussian process(GP)regression and extreme learning machine(ELM),were utilized to establish quantitative calibration models of the active ingredients.Comparing the performance of the three calibration models,the results showed that the model established using GP regression algorithm showed the best robustness and the highest prediction accuracy.This research has successfully achieved the accurate monitoring of the end-point in the column chromatographic process of Phellodendri Chinensis Cortex.And the method developed from the research will make up for some shortcomings of the traditional methods,and has high application value.4.An on-line monitoring method for the column chromatographic process of Phellodendri Chinensis Cortex based on NIR spectroscopy.A total of 17 batches of elution experiments were designed by changing the process parameters of column chromatography,including 10 normal operation batches and 7 abnormal operation batches.The NIR spectra of the eluent of each batch of samples were collected on-line by adding a flow cell at the liquid outlet,and the on-line monitoring model of elution process was further established.According to the control charts of principal component scores,Hotelling T~2 and DMod X,the accurate identification of abnormal elution process was realized.The study has provided a simple and feasible method for on-line monitoring of column chromatography process.5.End-point determination of the extraction process of Gegenqinlian decoction.The extraction process of Gegenqinlian decoction was selected as the research object.A total of 16batches of extraction experiments were designed by setting different levels of the herbal pieces,the extraction solvent volume,the particle size of the materials and the heating power.The in-line NIR spectra of the extract were collected according to the optical fiber probe installed in the extraction tank.And the quantitative calibration models of the active components(puerarin,berberine hydrochloride,baicalin,glycyrrhizic acid)were established using chemometrics algorithms.The in-line monitoring method of the end-point determination for the extraction process of Gegenqinlian decoction was realized successfully.6.An in-line monitoring method for the extraction process of Gegenqinlian decoction based on NIR spectroscopy.On the basis of the fifth section,an in-line monitoring model of extraction process of Gegenqinlian decoction was established using multivariate statistical process control(MSPC).The real-time monitoring of the extraction process was carried out by the control charts of principal component scores,Hotelling T~2 and DMod X.This method achieved the goal of identifying the abnormal extraction process,and provided a new strategy for in-line monitoring of the extraction process.