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.

Study on fast prediction of film coating terminal point of Tianshu Tablets by near- infrared spectroscopy / 中草药

Objective: To investigate how to rapidly predict coating terminal point in the thin film coating of Tianshu Tablets by near-infrared spectroscopy (NIRS). Methods: Firstly, synergy interval partial least square (siPLS) was used to optimize the modeling intervals and the pretreatment methods were screened. Secondly, according to the optimal modeling parameters, the conformity test and similarity matching were used to establish calibration models based on the established reference spectra library. Subsequently, by comparing the similarities between the test spectra and the reference spectra, the threshold value was set. The relation among the similarities, threshold value and the coating end point was obtained. Finally, the performance of the calibration model was verified by the validation set. Results: During the coating process, the similarities between the test spectra and the reference spectra were gradually increasing until the similarities of continuous test spectra exceeded the threshold, thus, indicating the end point. Conclusion: Conformity test and similarity matching can sensitively monitor the change of similarities among spectra and the corresponding trend. Both models have high performance, which can accurately predict the coating terminal point. It’s of great significance to reduce batch-to-batch variation in film coating and the loss of coating materials, and improve the coating efficiency and the quality uniformity of solid preparation.

Markers of hepatic ischemia reperfusion injury: A recent progress / 第二军医大学学报

Hepatic ischemia reperfusion injury (IRI) is a critical problem of liver surgery, especially when comes to liver transplantation. Presently, there are no effective measures for diagnosis, prevention and therapy of IRI, as the mechanisms of IRI still remain unclear. This review summarizes several new hepatic ischemia-reperfusion markers related to cell signal transduction pathway, including transcription factor STAT, HIF-1 and PPARs, transmission factor MAPK, membrane receptor TLR4 and PARs, and iNOS. Animal studies have indicated that IRI was ameliorated by activating or blockading these markers, which might serve as targets for diagnosis, prevention and therapy of IRI.

Expression of angiotensin-converting enzyme 2 is increased during preservation injury of liver transplantation in rats / 第二军医大学学报

Objective: To observe the expression of local angiotensin-converting enzyme 2 (ACE-2) in rat liver and its relationship with preservation injury (PI) after transplantation, so as to determine the possible role of local renin-angiotensin system (RAS) in PI caused by the cold-preservation in liver transplantation. Methods: The donor liver grafts were divided into cold preservation (CP) and non-cold preservation (NCP) groups; we also included a sham operation group without transplantation. The mRNA and protein levels of ACE-2 in the transplanted livers were detected by quantitative real-time PCR and Western blotting assay, respectively. The location of ACE-2 protein and pimonidazole in liver was detected by immunohistochemistry. Furthermore, histological evaluation was applied to verify the extent of liver damage. Results: Histological injuries of different degrees existed after liver transplantation; the injury was more obvious in the CP group. Compared with the sham operation group, the mRNA and protein expression of ACE-2 was significantly increased after liver transplantation (P<0.05 or P<0.01), and the expression of the CP group was significantly higher than that of the NCP group (P<0.05). Pimonidazole staining was positive around the hepatic veins in the transplantation groups, and the intensity of staining was positively correlated with the expression of ACE-2 mRNA (r=0. 78, P<0.001). Conclusion: It is indicated that ACE-2 expression is closely associated with tissue hypoxia during cold preservation-induced PI, and local RAS may play an important role in PI during liver transplantation.

Markers of hepatic ischemia-reperfusion injury:a recent progress / 第二军医大学学报

Hepatic ischemia-reperfusion injury(IRI)is a critical problem of liver surgery,especially when comes to liver transplantation.Presently.there are no effective measures for diagnosis,prevention and therapy of IRI,as the mechanisms of IRI still remain unclear.This review summarizes several new hepatic ischemia-reperfusion markers related to cell signal transduetion pathway.including transcription factor STAT,HIF-1 and PPARs,transmission factor MAPK,membrane receptor TLR4 and PARs.and iNOS.Animal studies have indicated that IRI was ameliorated by activating or blockading these markers,which might serve as targets for diagnosis,prevention and therapy of IRI.