Chinese Medicine Powder Mixing Process Analysis And Research Pilot Amplification Effect

Powder blending is an essential process in solid dosage production of traditional Chinese medicine (TCM). Blending homogeneity is a critical quality attribute to ensure the quality of final product. A fully understanding of the characteristics and disciplines and precise control of blending process is of great significant for the quality of TCM solid dosages. This article is aimed on both quantitative and qualitative characteristics of powder blending process of small scale and pilot scale using NIR (Near infrared) and PAT (Process analytical technology) as technical means.And discussed the amplifying effect of the blending process of traditional Chinese medicine, main contents are as follows:Firstly, NIR quantitative analysis of TCM powder blending. PLS quantitative models were built based on Liuyisan powder and salvia extract powder after comparing pretreat methods including first derivative, S-G smoothing, MSC (multiplicative scatter correction) and SNV(standard regular variation) and iPLS (interval partial least squares) is used to select the best infrared band. The results show in the study of glycyrrhizin quantitative analysis, the optimal pretreatment method is S-G smoothing plus first derivative, quantitative band of the model is10000cm-1~4000cm-1.The quantitative method has a good prediction performances with RMSEC and RMSEP values are0.0440mg-g-1and0.124mg-g-1; in the study of dextrin quantitative analysis, the optimal pretreatment method is first derivative, quantitative band of the model is10000cm-1~4000cm-1.The quantitative method has a good prediction performances with RMSEC and RMSEP values are0.998%and1.085%.The study used accuracy profile as a decision tool to validate the NIR quantitative madels. The result shows that the accuracy, precision, linearity, risk and other indicators comply with the requrements in the default concentration range. Based on the validation of the method,(B, y)-Tolerance interval was used to evaluate the uncertainty of the method. The uncertainty evaluation result shows that the expanded uncertainty of the glycyrrhizin NIR quantitative model at concentration levels of1.56mg-g-1,2.34mg-g-1,3.12mg-g-1and3.89mg-g-1were11.35%,8.30%,6.46%and8.95%, indicating that the method is accurate and reliable at [1.56mg-g-1,3.89mg-g-1]; the expanded uncertainty of the dextrin NIR quantitative model at at concentration levels of10%~20%were12.05%and6.94%, indicating that the method is accurate and reliable at [10%,20%].Secondly, sdudy of the determination of TCM blending end point. The determination of end point is an important part of blending process analysis. This study is based on Liuyisan powder blending process, compared the result of classical end-point determination methods and a new approach based on PAT. Using multi-point sampling strategy in classical method and calculating the RSD of the concentrations of active ingredient between different sampling positions detected with HPLC. The powder is considered uniform when the RSD is less than3%. The result shows that the blending end point of Liuyisan powder is17min. Collected NIR spectra, using MBSD and PCA-MBSD calculates the MBSD value during the blending process. The powder is considered uniform when the MBSD is below3%o. The result shows that the trend of MBSD value is not obvious, and the trend of MBSD value is obvious and the end point is consistent with the HPLC method.Thirdly, study of amplification effect in the scaling-up of TCM powder blending. In regard of the blending process, models established based on small scale is probably not suitable in pilot or manufacturer scale. In order to investigate the amplification effect, the filling factor (A) and the number of spindle rotation (B) is considered as critical process parameters and the RSD of glycyrrhizin concentrations is considered as critical quality attributes. Central composite design and uniform design were applied in the experiments of small scale (10L) and pilot scale (100L). Using linear regression models to reflect the relationship between the critical process parameters X and critical quality attributes Y. Design space of both two production scale were established based on the process models. The process model of small-scale experiment is Y=-3.63719+0.16491XA-0.016227XB (r=0.8176), and the process model of pilot-scale experiment Y=-12.49348+0.36267X A-0.020696XB (1=0.9543). The result of anova shows that, filling factor has a bigger affect to the production (P5<0.0001, Pp=0.0034) and the small scale process is more sensitive to the changes of process parameters.By the analyzing of the impact of critical process parameters on the process model can be found that The comparing the design space of the small scale with the pilot scale shows that, the design space of pilot scale is significantly smaller than the small one. Amplification effect is serious during the scaling procedure. Process parameters should be changed to adjust the actual productin and to avoid the impact on final product.This paper is focus on the establishment and validation of NIR quantitation methods based on both active ingredients and excipients, the determination of the end-point of Liuyisan blending process as well as the scaling-up of the circuit. Established rapid NIR quantitative method of TCM powder and study on the end-point determination strategy and try to use the concept of QbD to accomplish powder blending scale-up processs. This study can provide references for other aspects of quantitative analysis methods and scale-up processes.