A Study On The Dissolution Behavior Modeling Method Of TCM Solid Preparations

Solid preparation has become the most widely used dosage form of Traditional Chinese medicine(TCM).The consistency of its quality is the prerequisite for safety and effectiveness,and in vitro dissolution test can not only guide development of new formulations,optimize the production process,but also can effectively evaluate the consistency of drug quality.Once the design space of the drug is comprehensively and thoroughly explored by in vitro dissolution test,it can be used as the basis of the control strategy and also help to realize Real-time Release Test(RTRT).However,the conventional in vitro dissolution test not only wastes materials and manpower time,but more importantly,it is destructive and cannot trace the critical factors affecting its dissolution behavior through experimental results.In order to solve this problem and provide new ideas for the study of dissolution behavior of TCM Solid preparation,this thesis is carried out research direction on the dissolution behavior modeling of TCM Solid preparation.The main research contents are as follows:1.Comparative study on dissolution behavior of Fufang Danshen Pian from different sourcesMultiple dissolution curves were used to compare the dissolution behavior of 7 index components in Fufang Danshen tablets from different manufacturers and batches in 4 dissolution mediums to evaluate the quality of tablets.The dissolution test was carried out based on the paddle method with the dissolution mediums as pH=1.2 hydrochloride buffer,pH=4.0 acetate buffer solution,purified water and pH=6.8 phosphate buffer solution,the rotation speed was 75 rpm.The content of 7 index components at each sampling point was measured by ultra-performance liquid chromatography(UPLC).The accumulative dissolution rate was calculated,the cumulative dissolution curve was plotted,and the dissolution curve was fitted by the model.The dissolution behaviors and dissolution curve fitting equations of Fufang Danshen tablets from different batches and different manufacturers in different dissolution mediums were quite different.The dissolution of the same preparation from different manufactures was different in the same dissolution medium,and the dissolution of different index components from the same manufacturer was not synchronized in the same dissolution medium;the dissolution behaviors of different batches and different manufacturers tablets in the same dissolution medium were different,and greatly affected by pH value.It indicated that the quality of the Fufang Danshen tablets from different batches and different manufacturers was different,which provided a scientific basis for the improvement of preparation process and the evaluation of batch consistency.2.Dissolution prediction of sinomenine hydrochloride sustained-release tablets based on NIR spectroscopyTaking self-made sinomenine hydrochloride sustained-release tablets as the research object,fourier-transform near infrared(FT-NIR)spectroscopy and chemometric methods were used to predict the dissolution behavior of self-made sinomenine hydrochloride sustained-release tablets.Sinomenine hydrochloride sustained-release tablets were prepared according to the experimental design,and the NIR spectroscopy of the tables was collected and modeled.Spectral preprocessing methods used multiplicative scatter correction(MSC),Savitzky-Golay smoothing(S-G),standard normal variate(SNV),first derivative(1D),etc.;The modeling method uses back-propagation artificial neural network(BP-ANN)and partial least squares(PLS)method.The "MSC-PLSR" model of the tablet samples had the best performance.The difference factor f1 and similarity factor f2 of the measured dissolution curve and the predicted dissolution curve of the prediction group samples basically met the corresponding requirements.The fitting parameters of dissolution curves of the two groups were subjected to pair t test,the P values were all greater than 0.05,indicating that the results of the two groups were not significantly different.It showed that NIR spectroscopy technology could provide a rapid and effective method for predicting the dissolution curve of self-made sinomenine hydrochloride sustained-release tablets.3.Dissolution prediction of sinomenine hydrochloride sustained-release tablets based on multi-source data fusion technologyNIR spectroscopy and micro-raman spectroscopy were used to collect the mixed powder of 180 batches of sinomenine hydrochloride sustained-release tablets before compression.Based on the results of different preprocessing method and characteristic variable screening,the optimal main number of principal component was determined and combined with formulation parameters and process parameters for multi-source data fusion.BP-ANN and PLS method were selected as modeling methods.The results of NIR spectroscopy modeling determined that the optimal number of principal components was 11,and the micro-raman spectroscopy was 13.Multi-source data fusion modeling results showed that the performance of "NIR+Formulation+CPPs " was similar to that of "NIR+Raman+Formulation+CPPs ",and the variable projection importance analysis value(VIP)showed that the amount of hydroxypropyl methylcellulose was main factor affecting the dissolution behavior of self-made sinomenine hydrochloride sustained-release tablets.The difference factor f1 and similarity factor f2 between the measured and predicted dissolution curve of the prediction group sample,and the paired t-test of the fitting equation parameters showed that the results were not significantly different.The results proved that the multi-source data fusion technology could effectively move the quality control of the product forward to the mixed powder,providing a new idea for the quality control of the TCM Solid preparation.In summary,this thesis was based on spectroscopy technology,multi-source data fusion technology and related chemometric analysis technology,from the compound solid preparation to find the problem,starting with the TCM solid preparation containing a single active pharmaceutical ingredient(API),moving the quality control process from tablet to powder,to predict the dissolution behavior of TCM solid preparations.An effective and rapid prediction method was established for the dissolution curve of TCM solid preparations,and the modeled study of its dissolution behaviors was realized.It provided new ideas and guiding significance for the development of modeled dissolution behaviors of TCM solid preparations.