Critical quality attribute assessment of big brand traditional Chinese medicine: visualization of blending process for rare medicines in Tongren Niuhuang Qingxin Pills based on spatial distribution uniformity / 中国中药杂志

The spatial distribution uniformity of valuable medicines is the critical quality attribute in the process control of Tongren Niuhuang Qingxin Pills. With the real world sample of the mixed end-point powder of Tongren Niuhuang Qingxin Pills as the research object, hyperspectral imaging technology was used to collect a total of 32 400 data points with a size of 180 pix×180 pix. Spectral angle matching(SAM), classical least squares and mixed tuned matched filtering(MTMF) were used to identify the spatial distribution of rare medicines. MTMF model showed higher identification accuracy, therefore the spatial distribution of the blended intermediates was identified based on the MTMF model. The histogram method was also used to evaluate the spatial distribution uniformity of rare medicines. The results showed that the standard deviation was 4.78, 6.5, 3.48, 1.96, and 3.00 respectively for artificial bezoar, artificial musk, Borneol, Antelope horn and Buffalo horn; the variance was 22.8, 42.3, 12.1, 3.82, and 9.00, and the skewness was 1.26, 1.71, 0.06,-0.86, and 1.04, respectively. The final results showed that the most even blending was achieved in concentrated powder of Borneol, Antelope horn and Buffalo horn, followed by artificial bezoar, and last artificial musk. A visualization method was established for quality attributes of distribution uniformity in blending process of Tongren Niuhuang Qingxin Pills. It could provide evidences of quality control methods in the mixing process of big brand traditional Chinese medicine.

Critical quality attribute assessment of big brand traditional Chinese medicine: quality control of Tongren Niuhuang Qingxin Pills in texture and sensory attributes / 中国中药杂志

Texture sensory attributes are the key items in quality control of Chinese medicinal honeyed pills. The purpose of this study is to develop a quality control method for assessing the texture sensory attributes of Chinese medicinal honeyed pills based on real-world Tongren Niuhuang Qingxin pilular masses and finished products. First, parameters of texture profile analysis(TPA) were optimized through single factor and central composite design(CCD) experiments to establish a detection method for texture sensory attri-butes of Tongren Niuhuang Qingxin Pills. The results showed that the established detection method was stable and reliable, with the optimal parameters set up as follows: deformation percentage of 70%, detection speed at 30 mm·min~(-1), and interval time of 15 s. Furthermore, 540 data points yielded form six texture sensory attributes of pills from 30 batches were subjected to multivariate statistical process control(MSPC) with Hotelling T~2 and squared prediction error(SPE) control charts to establish the quality control method of Tongren Niuhuang Qingxin Pills. This study is expected to provide a reference for improving the quality control system of Chinese medicinal honeyed pills.

Critical quality attribute assessment of big brand traditional Chinese medicine: modular identification of Tongren Niuhuang Qingxin Pills based on efficacy with chemical properties / 中国中药杂志

Identification of critical quality attribute(CQA) is crucial in quality control of Tongren Niuhuang Qingxin Pills(TRNHQXP). In this study, 661 active components in TRNHQXP were selected by liquid chromatography-mass spectrometry(LC-MS) and network pharmacology based on reported data and TCMSP, BATMAN-TCM, and TCMID databases, as well as mass spectrometry data, and 1 413 targets of the active components were obtained through SwissTargetPrediction. The 152 potential targets obtained from the intersection of predicted targets with 456 stroke targets underwent functional enrichment analysis by Metascape. The 27 Chinese medicinals in TRNHQXP were divided into four sets according to efficacies. Thirty-seven key targets in the blood-activating and stasis-resolving set and 41 in the tonifying set were screened out. On the basis of these potential key targets, 137 potential key CQA of TRNHQXP for stroke were reversely predicted. This study revealed the possible mechanism of TRNHQXP in treating stroke and established a modular identification method for the potential CQA of big brand traditional Chinese medicine(TCM) based on efficacies and chemical properties. Consequently, the CQA of TRNHQXP were identified by this method, which has provided a reference for the following experimental studies of CQA.

Critical quality attribute assessment of big brand traditional Chinese medicine: quality control method of ginkgo leaves extract material based on powder physical properties / 中国中药杂志

The physical properties of ginkgo leaves extract(GLE) are the critical quality attributes for the control of the manufacturing process of ginkgo leaves preparations. In this study, 53 batches of GLE with different sources from the real world were used as the objects to carry out the research from 3 levels. First, based on micromeritics evaluation method, a total of 29 physical attribute quality parameters in five dimensions were comprehensively characterized, with a total of 1 537 data points. Further, with use of physical fingerprinting technology combined with similarity evaluation, the powder physical properties of 53 batches of GLE showed obvious differences from an overall perspective, and the similarity of the physical fingerprints was 0.876 to 1.000. Secondly, hierarchical clustering analysis(HCA) and principal component analysis(PCA) models were constructed to realize the reliable identification and differentiation of real-world materials produced by GLE from different sources. Multivariate statistical process control(MSPC) model was used to create GLE material Hotelling T~2 and squared prediction error(SPE) control charts. It was found that the SPE score of B_(21) powder exceeded the 99% confidence control limit by 22.495 9, and the SPE scores of A_1 and C_(10) powder exceeded the 95% confidence control limit by 16.099 2, realizing the determination of abnormal samples in the materials of GLE from the production in real world. Finally, the physical quality control method of GLE in the production process of ginkgo leaves preparations was established in this study, providing a reference for the quality control methods of ginkgo leaves preparations in their manufacturing process.

Critical quality attribute assessment of big brand traditional Chinese medicine: quality control method of Huangjing Zanyu Capsules based on chemical properties of characteristic components / 中国中药杂志

The chemical properties of characteristic components are significant to the manufacturing quality control of big brand traditional Chinese medicine. In this study, the Huangjing Zanyu Capsules were used as the research carrier to determine the content of five characteristic components including icraiin, emodin, schisandrin A, 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside, and osthole simultaneously by high-performance liquid chromatography(HPLC). The results showed that the chemical properties of five cha-racteristic components had a good linear relationship(r>0.999 9) within the quantitative range; the relative standard deviations(RSD) was 0.11%-2.0% and 0.25%-2.8% respectively for intra-day and inter-day precision; the RSD of repeatability was 1.8%-2.6%; the RSD of stability within 48 hours was 0.19%-2.8%, and the average recovery rate was 95.52%-100.1%, all meeting the requirements of pharmaceutical quantitative analysis. Additionally, the interval estimation method was used to directly reflect the distribution of samples with abnormal chemical properties of characteristic components, and the results showed ten samples were detected beyound the 95% control line of confidence level. Multivariate statistical process control(MSPC) method was used to monitor the abnormal samples of Huangjing Zanyu Capsules collectively, and the results showed that two samples were beyond the 95% control line of Hotelling's T~2 and three samples beyond the 95% control line of squared prediction error(SPE), indicating consistent quality control of Huangjing Zanyu Capsules. In conclusion, the proposed method is not only accurate and efficient but also a compensation for the traditional single-component quality control method, providing a scientific basis for the quality control in manufacturing process of Huangjing Zanyu Capsules. Furthermore, it could also serve as a reference method for the quality control in manufacturing big brand traditional Chinese medicine.

Critical quality attribute assessment of big brand traditional Chinese medicine: process quality control method of Suhuang Zhike Capsules intermediate based on physical properties of powder and granules / 中国中药杂志

The physical properties of powder and granules are the critical quality attributes for the process control of Suhuang Zhike Capsules, a big brand traditional Chinese medicine. This paper took the production of 25 batches of real-world Suhuang Zhike Capsules dry extract powder and granules intermediates as the research object. Firstly, a method for testing the physical properties of Suhuang Zhike Capsules powder and granules with 19 physical indicators was established. The results showed that the granules of dry extract powder after granulation had a smaller particle size, wider particle size distribution range and poor fluidity, which easily caused the problem of over-limit capsule loading. Secondly, correlation analysis, principal component analysis and cluster analysis were used for mathematical statistics. The correlation analysis showed that the density of dry extract powder could affect the chroma and fluidity. At the same time, the particle size in the granules had a stronger effect on the chroma and fluidity than the density. The study also found that the particle size and hygroscopicity of dry extract powder were potentially key physical properties that affected the physical properties of granules. Furthermore, the results of principal component analysis and cluster analysis showed that the consistency of the physical properties between the dry extract powder and intermediate granules was relatively poor. To this end, similarity analysis was carried out, and the quality control method of powder and granules based on physical fingerprint was established. The results showed that the physical fingerprint similarity of 25 batches of dry extract powder was 0.639-0.976, and the physical fingerprint similarity of the gra-nules was 0.716-0.983. With the similarity of 0.85 as the threshold, the batches with abnormal physical properties could be identified. In this study, the process quality control method of Suhuang Zhike Capsules based on the physical properties of powder and granules was established finally, which realized the identification of abnormal batches, and provided a reference for the process quality control of Suhuang Zhike Capsules.

Critical quality attribute assessment of big brand traditional Chinese medicine: online NIR quality control research on boiling time during extraction process / 中国中药杂志

Assessment of the status property(boiling time) is a challenge for the quality control of extraction process in pharmaceutical enterprises. In this study, the pilot extraction process of Phellodendron chinense was used as the research carrier to develop an online near-infrared(NIR) quality control method based on the status property(boiling time). First, the NIR spectra of P. chinense were collected during the two pilot-scale extraction processes, and the status property(boiling time) was assessed by observing the state of bubbles in the extraction tank using a transparent window during the extraction process, which was then used as a reference standard. Based on the moving block standard deviation(MBSD) algorithm, the assessment model using online NIR spectra for boiling time during extraction process was established. In addition, the model was optimized as follows: standard normal variable(SNV) for spectral pretreatment, modeling band of 800-2 200 nm, and window size of 4. The results showed that, with 0.002 0 as the MBSD model threshold, the boiling time can be accurately assessed using online NIR spectra during extraction process. Furthermore, the principal component analysis-moving block standard deviation(PCA-MBSD) model was developed by our group to reduce the influence of online NIR spectral noise and background signal on the model, and the number of principal components was optimized into 2 in the PCA-MBSD model. The results showed that, with 0.000 075 as the PCA-MBSD model threshold, the boiling time can be accurately assessed using online NIR spectra during extraction process, with improved reliability. This study can provide a assessment method for boiling time during extraction process using online NIR spectra, which can replace the empirical judgment in manual observation, and realize the digitalization of the extraction process for big brand traditional Chinese medicine.

Critical quality attribute assessment of big brand traditional Chinese medicine: study on NIR field detection method of chemical properties of moisture in Tongren Niuhuang Qingxin Pills / 中国中药杂志

For the field detection problems of critical quality attribute(CQA) of moisture content in traditional Chinese medicine(TCM) manufacturing process, big brand TCM Tongren Niuhuang Qingxin Pills were used as the carrier, to establish a moisture content NIR field detection model with or without cellophane in real world production with use of near infrared(NIR) spectroscopy combined with stoichiometry. With the moisture content determined by drying method as reference value, the partial least square method(PLS) was used to analyze the correlation between the spectrum and the moisture reference value. Then the spectral pretreatment methods were screened and optimized to further improve the accuracy and stability of the model. The results showed that the best quantitative model was developed by the spectral data pretreatment of standard normal variate(SNV) with the latent variable factor number of 2 and 7 of Tongren Niuhuang Qingxin Pills with or without cellophane samples. The prediction coefficient of determination(R_(pre)~2) and standard deviation of prediction(RMSEP) of the model with cellophane samples were 0.765 7 and 0.157 2%; R_(pre)~2 and RMSEP of the model without cellophane samples were 0.772 2 and 0.207 8%. The NIR quantitative models of moisture content of Tongren Niuhuang Qingxin Pills with and without cellophane both showed good predictive performance to realize the rapid, accurate and non-destructive quantitative analysis of moisture content in such pills, and provide a method for the field quality control of the critical chemical attributes of moisture in the manufacturing of big brand TCM.

Study on famous prescription of prestigious traditional Chinese medicine based on QbD concept: optimization of extraction process and granule forming process of Tuomin Dingchuan Prescription / 中国中药杂志

The quality of compound traditional Chinese medicine is the prerequisite and foundation for its stable efficacy. Based on the quality by design( QbD) concept,the controllable extraction times,extraction time and the ratio of water were the critical process parameters( CPPs) in the Tuomin Dingchuan Prescription extraction process. The CQAs corresponding to CPPs were screened from the four potential critical quality attributes( p CQAs),namely the extraction amount of solid matter,the content of amygdalin,the content of cimicifugoside and the content of 5-O-methylvisammioside by orthogonal experiment. The extraction amount of solid matter and the content of amygdalin were determined as CQAs in the extraction process by the variance analysis of Box-Behnken experimental. The optimal extraction process based on the linear model between CQAs and CPPs of the extraction process was immersion in water for 30 minutes,extraction for three times,extraction for 100 minutes each time and 10 times of water volume. The control space was established for the extraction amount of solid matter and the content of amygdalin,and both of them could be controlled simultaneously to achieve the optimization objective. The molding ratio of Tuomin Dingchuan granules was regarded as CQA in forming process. On the basis of the single factor investigation,the ratio of dry extract powder to excipient and the ratio of ethanol were determined as CPPs. The central composite design( CCD) was used to optimize the forming process of Tuomin Dingchuan granules. The results showed that the dextrin was used as the filler; the ratio of dry paste to dextrin was 1 ∶1; and 0. 3 m L·g-1 of 70% ethanol was added as binder. The soft material and granules conformed to the actual production requirements.

Research of hospital preparations based on QbD concept: whole process optimization strategy of gynecological antipruritic lotion / 中国中药杂志

The stable quality of hospital preparations is the basis for their clinical efficacy. Gynecological antipruritic prescription is widely used in gynecology clinics of Chinese medicine hospitals. Therefore,in this study,the production process of gynecological antipruritic lotion was optimized based on the concept of quality by design( QbD). The production process of the gynecological antipruritic lotion was developed to ensure its process stability and reliable quality,and enhance its clinical applicability. With total amount of matrine and oxymatrine used as the critical quality attribute( CQA) of the production process,parameter levels were designed based on production practice of hospital preparations,and Plackett-Burman and Box-Behnken experiments were used to optimize the water extraction and alcohol precipitation process of antipruritic lotion based on CQA of intermediates and final product. The soaking time,the first extraction time,and the second extraction time were determined as the critical process parameters( CPPs) of the production process. The optimal preparation process was as follows: water volume of 8 times,soaking for 0. 5 h,extraction for 2 times,the first extraction for 30 min,the second extraction for 56 min,alcohol concentration of 50%,and alcohol precipitation for 3 h. Furthermore,the design space was established based on the binomial regress model between CPPs and CQA,so as to set the optimization target and risk range; and the control space was displayed by overlay plot. The results of three repeated experiments in the control space showed that the relative standard deviation( RSD) of CQA was 4. 70%,and the similarity of chromatogram for gynecological antipruritic lotion was 0. 978,0. 974,and 0. 998,respectively. The above results indicated that the operation in the control space can guarantee the quality and stability of gynecological antipruritic lotion,suitable for practical application.