Discrete element simulation study of mixing process of Guizhi Fuling Capsules: parameter calibration / 中国中药杂志

The mixing process is a critical link in the formation of oral solid preparations of traditional Chinese medicine. This paper took the extract powder of Guizhi Fuling Capsules and Paeonol powder as research objects. The angle of repose, loose packing density, and particle size of the two powders were measured to calibrate discrete element simulation parameters for the mixing process. The discrete element method was used to calibrate the simulated solid density of Paeonol powder and extract powder of Guizhi Fuling Capsules based on the Hertz-Mindlin with JKR V2 contact model and particle scaling. The Plackett-Burman experimental design was used to screen out the critical contact parameters that had a significant effect on the simulation of the angle of repose. The regression model between the critical contact parameters and the simulated angle of repose was established by the Box-Behnken experimental design, and the critical contact parameters of each powder were optimized based on the regression model. The best combination of critical contact parameters of the extract powder of Guizhi Fuling Capsules was found to be 0.51 for particle-particle static friction coefficient, 0.31 for particle-particle rolling friction coefficient, and 0.64 for particle-stainless steel static friction coefficient. For Paeonol powder, the best combination of critical contact parameters was 0.4 for particle-particle static friction coefficient and 0.19 for particle-particle rolling friction coefficient. The best combination of contact parameters between Paeonol powder and extract powder of Guizhi Fuling Capsules was 0.27 for collision recovery coefficient, 0.49 for static friction coefficient, and 0.38 for rolling friction coefficient. The verification results show that the relative error between the simulated value and the measured value of the angle of repose of the two single powders is less than 1%, while the relative error between the simulated value and the measured value of the angle of repose of the mixed powder with a mass ratio of 1∶1 is less than 4%. These research results provide reliable physical property simulation data for the mixed simulation experiment of extract powder of Guizhi Fuling Capsules and Paeonol powder.

Manufacturing classification system for oral solid dosage forms of traditional Chinese medicines(Ⅳ): classification of hygroscopicity behaviors of capsules / 中国中药杂志

Hard capsules of traditional Chinese medicine(TCM) have different degrees of hygroscopicity, which affects the stability and efficacy of drugs. In this paper, 30 kinds of commercially available TCM capsules were used as the research object. The hygroscopicity curves of capsule contents, capsule shells, and capsules were tested respectively, and the first-order kinetic equation was used for fitting. The results show that during the 24 h hygroscopicity process, the capsule shell can reduce the weight gain caused by the hygroscopicity of the contents by 0.80%-53.0% and the hygroscopicity rate of the capsule contents by 1.74%-91.3%, indicating that the capsule shell has a strong delay effect on the hygroscopicity of the contents of the TCM capsules. Seven physical parameters of the contents of 30 kinds of TCM capsules were determined, and 14 prescription process-related parameters were sorted out. A partial least squares model for predicting the hygroscopicity rate of the contents of TCM capsules(with shell) for 24 h was established. It is found that the hygroscopicity rate of the capsule shell is positively correlated with the hygroscopicity of the contents of TCM capsules(with shell), suggesting that the capsule shell with a low hygroscopicity rate is helpful for moisture prevention. In addition, the pre-treatment process route of the preparation and the type of molding raw materials affect the hygroscopicity. A larger proportion of the extract in the capsule content and a smaller proportion of the fine powder of the decoction pieces indicate stronger hygroscopicity of the capsule content. The 24 h hygroscopicity rate of 15% was used as the classification node of hygroscopicity strength, and the hygroscopicity rate constant of 0.58 was used as the classification node of hygroscopicity speed. The classification system of hygroscopicity behaviors of TCM capsules was established: the varieties with strong and fast hygroscopicity accounted for about 6.67%, while those with strong and slow hygroscopicity accounted for about 33.3%; the varieties with weak and fast hygroscopicity accounted for about 26.7%, while those with weak and slow hygroscopicity accounted for about 33.3%. The classification system is helpful to quantify and compare the hygroscopicity behavior of different TCM capsules and provides a reference for the quality improvement, moisture prevention technologies, and material research of TCM capsules.

Real time release testing of disintegration time of uncoated Tianshu Tablets / 中国中药杂志

In this paper, a real time release testing(RTRT) model for predicting the disintegration time of Tianshu tablets was established on the basis of the concept of quality by design(QbD), in order to improve the quality controllability of the production process. First, 49 batches of raw materials and intermediates were collected. Afterwards, the physical quality attributes of all materials were comprehensively characterized. The partial least square(PLS) regression model was established with the 72 physical quality attributes of raw materials and intermediates as input and the disintegration time(DT) of uncoated tablets as output. Then, the variable screening was carried out based on the variable importance in the projection(VIP) indexes. Moisture content of raw materials(%HR), tapped density of wet masses(D_c), hygroscopicity of dry granules(%H), moisture content of milling granules(%HR) and Carr's index of mixed granules(IC) were determined as the potential critical material attributes(pCMAs). According to the effects of interactions of pCMAs on the performance of the prediction model, it was finally determined that the wet masses' D_c and the dry granules'%H were critical material attributes(CMAs). A RTRT model of the disintegration time prediction was established as DT=34.09+2×D_c+3.59×%H-5.29×%H×D_c,with R~2 equaling to 0.901 7 and the adjusted R~2 equaling to 0.893 3. The average relative prediction error of validation set for the RTRT model was 3.69%. The control limits of the CMAs were determined as 0.55 g·cm~(-3)<D_c<0.63 g·cm~(-3) and 4.77<%H<7.59 according to the design space. The RTRT model of the disintegration time reflects the understanding of the process system, and lays a foundation for the implementation of intelligent control strategy of the key process of Tianshu Tablets.

Predictive model for hygroscopicity of contents in Guizhi Fuling Capsules / 中国中药杂志

To control the risks of powder caking and capsule shell embrittlement of Guizhi Fuling Capsules, a predictive model for hygroscopicity of contents in Guizhi Fuling Capsules was built. A total of 90 batches of samples, including raw materials, intermediate powders and capsules, were collected during the manufacturing of Guizhi Fuling Capsules. According to the production sequence, 47 batches were used as the calibration set, and the properties of raw materials and the four intermediate powders were comprehensively characterized by the physical fingerprint. Then, the partial least squares(PLS) model was developed with the content hygroscopicity as the response variable. The variable importance in projection(VIP), variance inflation factor(VIF) and regression coefficients were used to screen out potential critical material attributes(pCMAs). As a result, five pCMAs from 54 physical parameters were screened out. Furthermore, different models were built by different combinations of pCMAs, and their predictive robustness of 43 batches was evaluated on the basis of the validation set. Finally, the tap density(D_c) of wet granules obtained from wet granulation and the angle of repose(α) of raw materials were identified as the critical material attributes(CMAs) affecting the hygroscopicity of the contents of Guizhi Fuling Capsules. The prediction model established with the two CMAs as independent variables had an average relative prediction error of 2.68% for samples in the validation set, indicating a good accuracy of prediction. This paper proved the feasibility of predictive modeling toward the control of critical quality attributes of Chinese medicine oral solid dosage(OSD). The combination of the continuous quality improvement, the industrial big data and the process modeling technique paved the way for the intelligent manufacturing of Chinese medicine oral solid preparations.

Identification of critical process parameters of Jinqing alcohol precipitation of Reduning Injection by big data / 中国中药杂志

Lonicerae Japonicae Flos and Artemisiae Annuae Herba(LA or Jinqing) alcohol precipitation has various process parameters and complex process mechanism, and is one of the key units for manufacturing Reduning Injection. In order to identify the critical process parameters(CPPs) affecting the weight of the extract produced from the alcohol precipitation process, 259 batches of historical production data from 2017 to 2018 were collected, with a total of 829 318 data points. These data showed characteristics of large data, such as a large data volume, a low value density, and diverse sources. The data cleaning and feature extraction were first performed, and 48 feature variables were selected. The original data points were reduced to 9 936. Then, a combination of Pearson correlation analysis and grey correlation analysis were used to screen out 15 potential critical process parameters(pCPPs). After that, the partial least squares(PLS) was used in prediction of the weight of the extract, proving that the performance of predictive model based on 15 pCMAs is equivalent to that of predictive model based on 48 feature variables. The variable importance in projection(VIP) index was used to identify 9 CPPs, including 2 alcohol precipitation supernatant volume parameters, 4 initial extract weight parameters and 3 added alcohol volume parameters. As a result, the number of data points was 1 863, accounting for 0.28% of the original data. The big data analysis approach from a holistic point of view can effectively increase the value density of the original data. The critical process parameters obtained can help to accurately describe the quality transfer mechanism of the Jinqing alcohol precipitation process.

Rapid Determination of Coating Film Thickness of Tianshu Tablets by Near Infrared Spectroscopy / 中国实验方剂学杂志

<b>Objective::To investigate the feasibility of near-infrared spectroscopy for detecting the coating film thickness of Tianshu tablets. <b>Method::Nine batches of Tianshu tablets were taken during the coating process. Then, their near-infrared diffuse reflection spectra were collected. The sample set was divided into calibration set and validation set by Kennard-Stone algorithm. The preprocessing method was selected. The synergy interval partial least squares (siPLS) and moving window partial least squares (mwPLS) were employed to screen the optimal spectral interval. And the corresponding quantitative calibration model of partial least squares (PLS) were established. Some evaluation parameters were adopted to assess the performance of the model. <b>Result::The method of first derivative and Norris Derivative smoothing combined with standard normal variate transformation was suitable for processing the spectra. The optimal PLS model was established in the preferred band interval of siPLS. The correlation coefficient between the predicted value and the measured value of calibration set was 0.966, and the correlation coefficient between the predicted value and the measured value of validation set was 0.991.Both root mean square error of calibration (RMSEC) and root mean square error of prediction (RMSEP) values were small, which showed the fitness and predictive performance of the model were favorable. <b>Conclusion::The near-infrared spectroscopy technique can be used to determine coating film thickness of Tianshu tablets with high accuracy, which provides technical supports for the in-line determination of coating thickness in the production process of traditional Chinese medicine tablets.

Simultaneous Determination of Four Alkaloid Components in Xiangbin Decoction by UPLC-QqQ-MS/MS / 中国实验方剂学杂志

Objective: To establish a quantitative method for the simultaneous determination of arecaine,arecoline,norisoboldine and boldine in Xiangbin decoction by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-QqQ-MS/MS), and compare the variation of their contents between single and mixed decoctions. Method: The separation was carried on a Waters ACQUITY UPLC BEH Shield RP18(2.1 mm×150 mm,1.7 μm)column, with 0.1%formic acid solution-acetonitrile as mobile phase for gradient elution. The flow rate was 0.2 mL·min-1, and the column temperature was 30℃. The quantitative MRM transitions of the four components were m/z 142.10/44.11 for arecaine,m/z 156.20/44.07 for arecoline,m/z 314.29/265.12 for norisoboldine and m/z 328.13/265.10 for boldine. The determination was performed in multiple reaction monitoring (MRM) mode by mass spectrometry with electrospray ionization (ESI) source under positive mode. Result: The linear ranges of arecaine,arecoline,norisoboldine and boldine were 0.479 0-57.48,0.976 0-78.08,0.812 0-64.96, 0.091 2-18.24 μg·L-1,respectively. The average recoveries of the above compounds ranged from 93.73%to 104.34%, with RSD (n=6) of less than 5%. The contents of arecoline,arecoline,norbibeldine and boltinine in Xiangbin decoction were (90.07±1.26),(445.27±12.39),(742.35±38.39),(38.50±3.33) μg·g-1,which were significantly lower than the contents in Linderae Radix and Arecae Semen. Conclusion: The method is rapid,sensitive,accurate and reproducible,and suitable for the simultaneous determination of multiple components in Xiangbin decoction,so as to provide a basis for the quality control of Xiangbin decoction. The compatibility of Xiangbin decoction has a significant effect on the dissolution contents of arecaine,arecoline,norisoboldine and boldine.

Applying risk management to analytical methods for the desorbing process of ginkgo diterpene lactone meglumine injection / 中国天然药物

Analysis errors can occur in the desorbing process of ginkgo diterpene lactone meglumine injection (GDMI) by a conventional analysis method, due to several factors, such as easily crystallized samples, solvent volatility, time-consuming sample pre-processing, fixed method, and offline analysis. Based on risk management, near-infrared (NIR) and mid-infrared (MIR) spectroscopy techniques were introduced to solve the above problems with the advantage of timely analysis and non-destructive nature towards samples. The objective of the present study was to identify the feasibility of using NIR or MIR spectroscopy techniques to increase the analysis accuracy of samples from the desorbing process of GDMI. Quantitative models of NIR and MIR were established based on partial least square method and the performances were calculated. Compared to NIR model, MIR model showed greater accuracy and applicability for the analysis of the GDMI desorbing solutions. The relative errors of the concentrations of Ginkgolide A (GA) and Ginkgolide B (GB) were 2.40% and 2.89%, respectively, which were less than 5.00%. The research demonstrated the potential of the MIR spectroscopy technique for the rapid and non-destructive quantitative analysis of the concentrations of GA and GB.

Applying risk management to analytical methods for the desorbing process of ginkgo diterpene lactone meglumine injection / 中国天然药物

Analysis errors can occur in the desorbing process of ginkgo diterpene lactone meglumine injection (GDMI) by a conventional analysis method, due to several factors, such as easily crystallized samples, solvent volatility, time-consuming sample pre-processing, fixed method, and offline analysis. Based on risk management, near-infrared (NIR) and mid-infrared (MIR) spectroscopy techniques were introduced to solve the above problems with the advantage of timely analysis and non-destructive nature towards samples. The objective of the present study was to identify the feasibility of using NIR or MIR spectroscopy techniques to increase the analysis accuracy of samples from the desorbing process of GDMI. Quantitative models of NIR and MIR were established based on partial least square method and the performances were calculated. Compared to NIR model, MIR model showed greater accuracy and applicability for the analysis of the GDMI desorbing solutions. The relative errors of the concentrations of Ginkgolide A (GA) and Ginkgolide B (GB) were 2.40% and 2.89%, respectively, which were less than 5.00%. The research demonstrated the potential of the MIR spectroscopy technique for the rapid and non-destructive quantitative analysis of the concentrations of GA and GB.

Effective connectivity within the default mode network modulated by methylphenidate using dynamic causal modeling on resting-state functional magnetic resonance imaging / 生理学报

The effective connectivity of default mode network (DMN) and its change after taking methylphenidate (MPH) were investigated in this study based on resting-state functional magnetic resonance imaging. Dynamic causal modeling (DCM) was applied to compare the effective connectivity between the conditions of taking MPH and placebo for 18 healthy male volunteers. Started with the network structural basis provided by a recent literature, endogenous low frequency fluctuation signals (0.01-0.08 Hz) of each node of DMN were taken as the driving input, and thirty-two possible models were designed according to the modulation effect of MPH on different connections between nodes. Model fitting and Bayesian model selection were performed to find the winning model and corresponding parameters. Our results indicated that the effective connectivity from medial prefrontal cortex (MPFC) to posterior cingulated cortex (PCC), from left/right inferior parietal lobule (L/RIPL) to MPFC, and from RIPL to PCC were excitatory, whereas the connectivity from LIPL to PCC was inhibitory. Further t-test statistics on connectivity parameters found that MPH significantly reduced the link from RIPL to MPFC in DMN (t = 2.724, P = 0.016) and changed the weak excitatory state to inhibitory state. However, it had no significant effect on other connections. In all, our results demonstrated that MPH modulates the effective connectivity within DMN in resting state.

Construction of NIRS in-line rapid detection model of concentration process of Artemisiae Annuae Herba / 中草药

Objective: In this study, an in-line near infrared spectroscopy (NIRS) rapid detection model of single-effect concentration process of ArtemisiaeAnnuae Herba(AAH) was established and the impact of absorbance to model was discussed. Methods: Nine batches of concentration process samples were collected inline and partial least square (PLS) method was applied to build its quantitative model which was used to predict an unknown batch of samples. Results: The parameters of PLS model of total acid and soluble solid content were as follows: coefficient of determination (R2) of 0.9623 and 0.9679, root mean square errors of calibration (RMSEC) of 0.7835 and 0.9488, and root mean square errors of cross-validation (RMSECV) of 0.8258 and 0.9780, respectively. Conclusion: Absorbance of concentration process samples of AAH was between 0 and 2.0 and RSEP values of total acid and soluble solid content was less than 10%. It can meet the quality requirements of production process of AAH and indicate that the effect of high absorbance (namely low tansmittance) on NIRS model of AAH can be eliminated by adding samples and using chemometrics when the absorbance is between 0.0 and 2.0.

Review on process analytical technology application in production process of Chinese medicine injection / 中草药

Based on "Quality by Design" concept, this study summarized that quality control of Chinese materia medica (CMM) injection should introduce the process analytical technology during the processes of herbs cultivation, processing, casting herbs, extraction, concentration, macroporous resin purification, column chromatography, extraction, alcohol precipitation, crystallization, and final examination of product. The control proposal of how to control the production of CMM injection by process analytical technology was also suggested, aimed at a thorough understanding and control of the production process of injection, thereby ensuring uniformity of inter-batch quality and stability of process of CMM injections.

Preparation of hydrophilic matrix sustained release tablets of total lactones from Andrographis paniculata and study on its in vitro release mechanism / 中国中药杂志

In this study, hydrophilic matrix sustained release tablets of total lactones from Andrographis paniculata were prepared and the in vitro release behavior were also evaluated. The optimal prescription was achieved by studying the main factor of the type and amount of hydroxypropyl methylcellulose (HPMC) using single factor test and evaluating through cumulative release of three lactones. No burst drug release from the obtained matrix tablets was observed. Drug release sustained to 14 h. The release mechanism of three lactones from A. paniculata was accessed by zero-order, first-order, Higuchi and Peppas equation. The release behavior of total lactones from A. paniculata was better agreed with Higuchi model and the drug release from the tablets was controlled by degradation of the matrix. The preparation of hydrophilic matrix sustained release tablets of total lactones from A. paniculata with good performance of drug release was simple.

Effects of intervene on occupational health knowledge, attitude and practice of people with occupational disease risk in private enterprises / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To evaluate the effects of health promotion on occupational health based on the changes in knowledge, attitude and practice (KAP) before and after intervention of people with occupational disease risk in private enterprises.</p><p><b>METHODS</b>202 people with occupational disease risk in private leather enterprises of Wenzhou were surveyed, who were rechecked with the same questionnaire after three months intervention.</p><p><b>RESULTS</b>The knowledge, attitude and practice scores (9.34 ± 2.57, 7.79 ± 2.58 and 7.24 ± 2.50, respectively) of post-intervention group were significantly increased more than those of pre-intervention (8.06 ± 2.71, 7.63 ± 2.67, 7.11 ± 2.60, respectively) (P < 0.01, P < 0.05). The net increases of knowledge, attitude and practice scores were significantly different with different length of service, educational level, registered residence and training experience (P < 0.05, P < 0.01).</p><p><b>CONCLUSIONS</b>Health promotion could increase knowledge, attitude and practice levels; The effect of intervention on people with short length of service, low educational level, coming from country and had not attended training is significant.</p>