Studies On The Quality Control Of Alcohol Precipitation Process Of Shenqi Fuzheng Injection Using Near Infrared Spectroscopy

With the concept of Quality by Design(QbD)gradually applied to the pharmaceutical industry,the quality control of raw materials and pharmaceutical processes become more important compared with the quality tests of drugs for Traditional Chinese Medicines(TCMs).To improve quality control of pharmaceutical processes and assure the batch-to-batch consistency of the end products,effective process monitoring methods should be established for critical unit operations,using process analytical technologies.In this thesis,a series of near infrared(NIR)spectroscopy methods in conjunction with multivariate data analysis technology were developed for the alcohol precipitation processes in the manufacture of Shenqi Fuzheng Injection.The main contents and achievements are summarized as follows:1.A real-time monitoring model was built for the first alcohol precipitation process of Astragali Radix using NIR spectroscopy in conjunction with multivariate statistical process control(MSPC).The principal scores,Hotelling T2 and DModX statistics of each time point were calculated to monitor the process.The process trajectories being in control limits reflected that the batch was running normally.The results suggested that the process trajectories reflected the process characteristics of each batch effectively.The established model could identify process abnormities in time.2.An NIR spectroscopy approach was established for the quality control of the alcohol precipitation supernatants of Codonopsis Radix.Design of experiments and a concentrating-diluting method were used to obtain a sample set with sufficient representativeness.Quantitative models were established by a step-wise optimization.Rapid multi-components quantification of lobetyolin,total flavonoids,pigments,and total solid contents in alcohol precipitation supernatants of Codonopsis Radix was realized.3.Development of an in-line monitoring method for the second alcohol precipitation process of Astragali Radix.An HPLC-UV-ELSD method was firstly built for the determination of calycosin-7-O-?-D-glucoside,formononetin-7-O-?-D-glucoside,9,10-dimethoxypterocarpan-3-O-?-D-glucopyranoside,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-?-D-glucopyranoside,astragloside ?,and astragloside ?.A calibration set,which included raw material variations,critical process parameters variations,temperature variations,and spectral acquisition variations,was obtained according to experimental design.An independent external validation set was used for the model evaluation.Furthermore,the optimizing direction of pretreatment strategy was found out using design of experiments,and the best parameters of the algorithms was choosen.Therefore,the number of calculations of trial-and-error approach was reduced,and the predictive performance of the target process was improved.The simultaneous quantification of total solid contents and the 6 chemical indices were realized with the established models,which were robust with low complexity.4.Validation of an in-line monitoring method for the second alcohol precipitation process of Astragali Radix based on accuracy profile.To generally evaluate the predictive capacity of the established models,model performance indices were firstly calculated for independent external validation set.Model performances of trueness,precision,accuracy,linearity,range,specificity,robustness,and measurement uncertainty were further evaluated.Accuracy profile was taken as a decision tool to assess the method validity.?-Expectation tolerance limits of predictive bias at different content levels were calculated.The effective contents ranges were obtained within the 15%accepted error limits:8.44%-39.8%0.541-2.26 mg/mL,0.118-0.502 mg/mL,0.220-0.940 mg/mL,0.106-0.167 mg/mL,0.137-0.320 mg/mL,and 0.484-0.879 mg/mL for total solid contents,calycosin-7-O-?-D-glucoside,formononetin-7-O-?-D-glucoside,9,10-dimethoxypterocarpan-3-O-?-D-glucopyranoside,2'-dihydroxy-3',4'-dimethoxyisoflavan-7-O-?-D-glucopyranoside,astragloside ?,and astragloside ?,respectively.Hence,accurate and robust quantification of the 7 indices in the effective content ranges can be achieved using the in line NIR spectroscopy method.The accurate monitoring of the second alcohol precipitation process of Astragali Radix was realized.