The Study On Quality Analysis Of Key Production Processes Of QiLong Capsule By Using Near Infrared Spectroscopy

There are many reasons which hamper the development of the process of modern Chinese medicine industrialization,for example,the qualities of medicinal herbs are not uniformly,critical productive technologies lack of process control,and quality indexes and control range of pharmaceutical intermediates were too small.Safe,effective,stable and controllable are the foundational attributions of drugs,which are also the necessities to the modernization of traditional Chinese medicines(TCM).Along with the development of TCM becoming the national development strategy,future production of TCM will direct to process controllable,functional components clearly and quality strictly.Study on quality analysis of key production processes of TCM can protect the material foundation and guarantee the stability of the absorption and utilization of drugs,so as to ensure the quality uniformity of TCM products.In this study,Qilong capsule derived from classic Chinese medicine prescription"Buyang huanwu decoction",which was used for cardiovascular and cerebtovascular disease,was as the research object.Near infrared spectroscopy technology(NIRS)was introduced in the procedure of TCM as a process analytical technology(PAT).To establish the methods of rapid quality analysis of key production processes of QiLong Capsule by using near infrared spectroscopy from three aspects including critical material attributes(CMA),water extraction processes and the important pharmaceutical intermediate,which were used to providing a reference method to ensure the consistency of TCM quality.The contributions of this dissertation include the following three aspects.(1)Rapid quality analysis of CMAs of raw materials of QiLong CapsuleThis study selected principal medicinal herbs "Astragali Radix" and "Pheretima"as critical raw materials and determined the moisture,Calycosin-7-O-β-D-glucopyranoside,(CCG)content in Astragali Radix as well as the moisture,Hypoxanthine(HT)content in Pheretima were critical CMAs,according to the Qilong capsule prescription composition an clinical efficacy.Finally,we established the NIRS quantitative models to evaluate the qualities of "Astragali Radix" and"Pheretima" rapidly.In this study,a quantitative NIR spectroscopy method was explored and established for the simultaneous determination of moisture and CCG of the Astragali Radix.Determination coefficients(R2c and R2p),root mean squares error of calibration(RMSEC),root mean squares error of prediction(RMSEP)were applied to verify the performance of the models,and the corresponding values were 0.9864,0.9626,0.0751%and 0.1755%for moisture;0.9836,0.9747,0.0007596%and 0.001061%for CCG.Besides,a quantitative NIR spectroscopy method was explored and established for the simultaneous determination of moisture and CCG of the Pheretima.R2c,R2p,RMSEC and RMSEP were applied to verify the performance of the models,and the corresponding values were 0.9925,0.9608,0.04973%and 0.1325%for moisture;0.9978,0.9595,0.00598 mg/g and 0.03502 mg/g for HT.(2)Rapid quality analysis of the water extraction processes of QiLong CapsuleThis study selected the water extraction process of Astragali Radix and Pheretima as key production processes,besides determined the concentration of CCG and the concentration of HT as key process parameters according to the characteristic of manufacture techniques of QiLong Capsule.The quantitative analysis models of key process parameters were established to strengthen the process control in drug productionIn this study,quantitative NIR spectroscopy methods was explored and established for the determination of CCG in the first step and the second step of Astragali Radix extract during the water extraction process of Astragali Radix.R2c R2p,RMSEC and RMSEP were applied to verify the performance of the models,and the corresponding values were 0.9873,0.9742,2.0611μg/mL and 3.1235μg/mL for the first step of water extraction process of Astragali Radix;0.9729,0.9640,1.0684μg/mL and 1.3446μg/mL for the second step of water extraction process of Astragali Radix.By means of PLSR,quantitative NIR models for the determination of HT in the Pheretima extract during the water extraction process of Pheretima were successfully built between the spectra and the corresponding reference values obtained by HPLC-UV.R2c,R2p,RMSEC and RMSEP were applied to verify the performance of the models,and the corresponding values were 0.9655,0.9531,4.8057μg/mL and 4.6978μg/mL.In this study,a new batch of samples of water extraction process of Astragali Radix and Pheretima was collected as an external independent predictive set respectively.The corresponding concentration of CCG or HT was obtained by these new quantitative NIR models.The trend of key process parameters changed over time is similar to that of modeling,which proved the NIR models established in this study meted the requirements.(3)Evaluation of quality analysis of pharmaceutical intermediate,and the application research of variables selection based on combination algorithms.The titer of Lumbrokinase(LK)in intermediate of the water extraction process of Pheretima of QiLong Capsule(IMQL)was regard as the critical material attributes(CQA).In this study,a quantitative NIR spectroscopy method was explored and established for the determination of titer the LK in IMQL.By means of PLSR,quantitative NIR models were successfully built between the spectra and the corresponding reference values obtained by fiber plate method whose methodological evaluation showed that the linearity is good.R2c,R2p,RMSEC and RMSEP were applied to verify the performance of the models,and the corresponding values were 0.9398,0.9340,489.62 U.538.31 U.Compared with the fiber plate method,the NIR spectroscopy method can significantly save manpower and time。In this study,5 kinds of variables selection algorithms including SPA、UVE、CARS、GA、CC were combined.It was found that all variable selected by the 5 algorithms are results of modeling variable and the model performances has improved significantly.