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The traditional Chinese medicine(TCM) enterprises have accumulated a large amount of product quality review(PQR) data. Mining these data can reveal the hidden knowledge in production and helps improve pharmaceutical manufacturing technology. However, there are few studies involving the mining of PQR data and thus enterprises lack the guidance to analyze the data. This study proposed a method to mine the PQR data, which consisted of 4 functional modules: data collection and preprocessing, risk classification of variables, risk evaluation by batches, and the regression analysis of quality. Further, we carried out a case study of the formulation process of a TCM product to illustrate the method. In the case study, the data of 398 batches of products during 2019-2021 were collected, which contained 65 process variables. The risks of variables were classified according to the process performance index. The risk of each batch was analyzed through short-term and long-term evaluation, and the critical variables with the strongest impact on the product quality were identified by partial least square regression. The results showed that 1 variable and 13 batches were of high risk, and the critical process variable was the quality of the intermediates. The proposed method enables enterprises to comprehensively mine the PQR data and helps to enhance the process understanding and improve the quality control.
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Medicina Tradicional China , Medicamentos Herbarios Chinos , Minería de Datos/métodos , Control de Calidad , Tecnología FarmacéuticaRESUMEN
A simulating method for dripping process of Ginkgo biloba leaf dripping pills based on computational fluid dynamics was constructed. Ginkgo biloba leaf dripping pills was explored as the experimental subject to simulate the dripping process based on FLOW-3D software. The dripping process was simulated through the derivation of the governing equations, the selection of the models, and simulation parameters. Firstly, the droplet morphologies and drop speeds under different liquid viscosity were simulated. It was found that with the increase of the liquid viscosity, the drop speed decreased and the difficulty of droplet preparation gradually increased. The simulation results were consistent with the experiment results. Secondly, the droplet morphologies at different drop speeds were investigated and verified by experiments. It was found that the simulation results had a good correlation with the experiment results. The results shown that the viscosity of the liquid was the critical material attribute, and the drop speed was the critical process parameter, according to the droplet morphology. The establishment of the simulation method can deepen the understanding of the dripping process and provide a reference for the selection of raw materials and process parameters.
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At present, the digitalization and intelligence level of dripping pills production process is low, and there is a lack of process monitoring methods, which makes it difficult to effectively control the quality of dripping pills. Therefore, this paper proposed an online monitoring method for the dripping process of dripping pills based on laser detection technology and multivariate data analysis (MVDA) technology. Firstly, the width data of the falling droplets during the dripping process of the dripping pills were collected by the laser detector at a high frequency. Secondly, based on the width data, the nodes were selected for each droplet and the features were extracted. Then, the principal component analysis (PCA) model was established based on the feature dataset under normal process conditions, and Hotelling's T2 or DModX statistic was selected to determine whether the droplets in the dripping process were abnormal, and the abnormalities were classified and diagnosed by the principal component score map combined with K-nearest neighbor (KNN) algorithm. In this study, the feasibility of this method was investigated by taking the dripping process of Ginkgo biloba leaf dripping pills as an example. The results showed that the obtained model has good detection and diagnosis ability for abnormal valve opening, abnormal liquid temperature, and abnormal liquid volume. This method can provide some reference for the industrial production of dripping pills.
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Chinese medicinal injection, made of active components extracted from Chinese medicine or Chinese medicinal compound, is a novel dosage form of Chinese patent medicine in China and is pivotal in the traditional Chinese medicine(TCM) industry. The quality control standard of Chinese medicinal injection determines its safety and efficacy. The quantitative nuclear magnetic resonance(qNMR) spectroscopy is a non-targeted, non-invasive, and non-destructive technique with high reproducibility, short measurement time, convenient sample preparation, a broad range of linearity, and no requirement on the reference substance of tested components, which is advantageous as compared with traditional chromatographic methods, and it can provide information about the molecular composition of the tested samples. Therefore, in light of multiple challenges in the quality control of Chinese medicinal injection, such as complex composition, difficulties in quantitative analysis, and the shortage of reference substances, the application of qNMR spectroscopy combined with chemometrics techniques was proposed for the quality evaluation of Chinese medicine reference substances, Chinese medicinal injection, and intermediates in the production process, as well as for the stability analysis of Chinese medicinal injection. This study is expected to provide references for the application of qNMR spectroscopy in the quality control of Chinese medicinal injection.
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Espectroscopía de Resonancia Magnética , Medicina Tradicional China , Control de Calidad , Reproducibilidad de los ResultadosRESUMEN
The present study established a quality evaluation method for ginsenoside reference substances based on quantitative nuclear magnetic resonance(qNMR) spectroscopy. ~1H-NMR spectra were collected on Bruker Avance Ⅲ 500 MHz NMR spectrometer equipped with a 5 mm BBO probe. The acquire parameters were set up as follows: pulse sequence of 30°, D_1=20 s, probe temperature= 303 K, and the scan number = 32. Dimethyl terephthalate, a high-quality ~1H-qNMR standard, was used as the internal standard and measured by the absolute quantitative method. Methyl peaks of comparatively good sensitivity were selected for quantification, and linear fitting deconvolution was adopted to improve the accuracy of integration results. The qNMR spectroscopy-based method was established and validated, which was then used for the quality evaluation of ginsenoside Rg_1, ginsenoside Re, ginsenoside Rb_1, ginsenoside Rd, and notoginsenoside R_1. The results suggested that the content of these ginsenoside reference standards obtained from the qNMR spectroscopy-based method was lower than that detected by the normalization method in HPLC provided by the manufacturers. In conclusion, the qNMR spectroscopy-based method can ensure the quality of ginsenoside reference substances and provide powerful support for the accurate quality evaluation of Chinese medicine and its preparations. The qNMR spectroscopy-based method is simple, rapid, and accurate, which can be developed for the quantitative assay of Chinese medicine standard references.
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Cromatografía Líquida de Alta Presión/métodos , Ginsenósidos/análisis , Espectroscopía de Resonancia Magnética/métodos , Espectroscopía de Protones por Resonancia Magnética , Estándares de ReferenciaRESUMEN
Shenmai Injection is a Chinese medicinal injection prepared from Ginseng Radix et Rhizoma Rubra and Ophiopogonis Radix, which is widely used in clinical practice for the treatment and adjuvant therapy of cardiovascular diseases with significant pharmacological effects. Proton nuclear magnetic resonance spectroscopy(~1H-NMR) has the advantages of simple and nondestructive sample pretreatment, fast analysis, abundant chemical information, quantification and no need to follow the standard curve. It is widely used in the analysis and research of complex mixtures of traditional Chinese medicine, clinical blood and urine samples. In this study, the ~1H-NMR fingerprint of Shenmai Injection was established. Thirty-two chemical components were identified, including seven amino acids, eight small molecular organic acids, one alkaloid, four sugars, two nucleosides, seven saponins, and three other components. Pearson's correlation coefficient and multivariate analysis of variance(principal component analysis combined with hierarchical cluster analysis) were applied based on the ~1H-NMR fingerprint to evaluate the quality consistency. The results showed high-quality consistency of 82 batches of Shenmai Injection. This study confirms that the ~1H-NMR fingerprint has great potential in the application of quality control of Chinese medicinal injection.
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Cromatografía Líquida de Alta Presión , Combinación de Medicamentos , Medicamentos Herbarios Chinos/química , Espectroscopía de Protones por Resonancia Magnética , Rizoma/químicaRESUMEN
A content determination method based on ~1H-qNMR was developed for the determination of total ginsenosides in Shenmai Injection. The parameters were optimized with CD_3OD as the solvent, dimethyl terephthalate as the internal standard, the peak at δ 8.11 as the internal standard peak, and the peaks at δ 1.68 and δ 0.79 as quantitative peaks of total ginsenosides. The developed ~1H-qNMR-based method was validated methodologically. The results showed that the method could achieve accurate measurement of total ginsenosides in Shenmai Injection in the range of 0.167 6-3.091 1 mmol·L~(-1). The developed ~1H-qNMR-based method for total ginsenosides is simple in operation, short in analysis time, strong in specificity, independent of accompanying standard curve, and small in sample volume, which can serve as a reliable mean for the quality control of Shenmai Injection. This study is expected to provide new ideas for the development of quantification methods of total ginsenosides.
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Combinación de Medicamentos , Medicamentos Herbarios Chinos , Ginsenósidos/análisis , Control de CalidadRESUMEN
In this study, Fick's first law and partition equilibrium were used to represent the internal and external mass transfer processes of Salviae Miltiorrhizae Radix et Rhizoma at the macroscopic level, and a mass transfer model was established. The specific surface area was integrated into the mass transfer resistance, which effectively avoided the irregular shape of medicinal materials and expanded the application scope of the model. Meanwhile, the mass transfer model was further combined with the kinetic model of salvia-nolic acid degradation to establish the extraction kinetic models of salvianolic acid B, lithospermic acid and Danshensu. The model was applied to study the extraction process of Salviae Miltiorrhizae Radix et Rhizoma. According to the sensitivity analysis results, the relative error of the model prediction was within 5% near the maximum extraction rate(320 min), and the prediction performance of the model was good. According to the investigation results of different process parameters, stirring could significantly accelerate the mass transfer rate of salvianolic acid B, while the mass transfer resistance and degradation rate constant were not affected by solvent-to-solid ratio. The linear relationship between the reciprocal of temperature and the logarithm of mass transfer resistance was good(R~2=0.996), indicating that the temperature and mass transfer resistance conformed to Arrhenius formula. In addition, we also found that the concentration changes of lithospermic acid and Danshensu were weakly affected by mass transferwhen the extraction temperature was higher than 358 K. This study has provided the basis for the process optimization and quality control of traditional Chinese medicine extraction.
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Medicamentos Herbarios Chinos , Cinética , Medicina Tradicional China , Rizoma , Salvia miltiorrhizaRESUMEN
A rapid analysis method based on ultraviolet-visual(UV-Vis) spectroscopy, near infrared(NIR) spectroscopy and multivariable data analysis was established for quality evaluation of Shengxuebao Mixture. The contents of eight active ingredients of Shengxuebao Mixture including albiflorin, paeoniflorin, 2, 3, 5, 4'-tetra-hydroxy-stilbene-2-O-β-D-glucopyranoside, specnuezhenide,ecliptasaponin D, emodin, calycosin-7-glucoside and astragaloside Ⅳ were simultaneously detected by using this method. HPLC-UV-MS was used as a reference method for determining the contents of these ingredients. Partial least squares(PLS) analysis was implemented as a linear method for multivariate models calibrated between UV spectrum/NIR spectrum and contents of 8 ingredients. Finally, the performance of the model was evaluated by 24 batches of test samples. The results showed that both UV-Vis and NIR models gave a good calibration ability with an R~2 value above 0.9, and the prediction ability was also satisfactory, with an R~2 value higher than 0.83 for UV-Vis model and higher than 0.79 for NIR model. The overall results demonstrate that the established method is accurate, robust and fast, therefore, it can be used for rapid quality evaluation of Shengxuebao Mixture.
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Calibración , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos , Análisis de los Mínimos Cuadrados , Espectrometría de Masas , Espectroscopía Infrarroja CortaRESUMEN
Percolation extraction is a conventional extraction method used in the processing of traditional Chinese medicines. After medicinal material powder is placed in a percolation tank, the extraction solvent is continuously added, and percolation extract is collected simultaneously. The percolation equipment is simple. The percolation operation is easy. It is applicable to a wide range of medicinal materials. Components that are unstable under thermal conditions can be effectively extracted. However, there are also disadvantages, such as high solvent consumption, long extraction time, and high energy consumption in subsequent concentration processes. This article mainly reviews the research progress on the common equipment types, affecting factors, parameter optimization methods, and process monitoring. According to analysis on literatures, solvent composition, impregnation time, percolation speed, and solvent consumption are considered as the important factors of percolation processes. At present, near-infrared spectroscopy is widely used in the monitoring of percolation process, and partial least square is a commonly used quantitative modeling method. According to the concept of "Quality by Design", in-depth investigation of the percolation process mechanism and development of process control methods are future development trends. Therefore, process modeling, process optimization and process monitoring shall be improved. The mechanism models and the empirical models of column chromatography can be used as references to construct the percolation process models. The effect of the quality changes of medicinal materials shall be taken into account when optimizing the percolation process parameters. More simple and easy methods shall be developed to monitor the percolation process status and key properties of percolation extracts.
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Química Farmacéutica , Medicamentos Herbarios Chinos/química , Análisis de los Mínimos Cuadrados , Medicina Tradicional China , Polvos , Espectroscopía Infrarroja CortaRESUMEN
This study aims to develop the quality standards of Fructus Corni piece standard decoction. Morroniside and loganin were considered as index components. The content determination method of morroniside and loganin were developed. The fingerprint analysis method was also established. The standard decoctions of 15 batches of Fructus Corni pieces from Henan, Zhejiang, and Shaanxi were analyzed. The similarity values of fingerprint were all above 0.99. The transfer rates of morroniside were all higher than 100%. The quality evaluation indices of standard decoction were discussed. The transfer rate of an index component was not easy to be measured accurately and its concept was not rigorous. Therefore, index component yield was suggested as an evaluation index of standard decoction. Two methods for setting quality standards of standard decoctions, which were the ■ method and the ■ method, were compared. It was found that the standard range of ■ method was wider and more suitable for smaller sample size of standard decoction. The quality standards of Fructus Corni standard decoction were as follows, dry matter extraction ratio 37.48%-69.60%; morroniside yield 8.719-16.19 mg·g~(-1) piece; loganin yield 4.342-8.064 mg·g~(-1) piece.
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Cornus , Química , Medicamentos Herbarios Chinos , Estándares de Referencia , Frutas , Química , Control de CalidadRESUMEN
Traditional Chinese medicine( TCM) glues,including leather glues,horn glues,nail glues and bone glues,have a long application history and unique characteristics. In recent years,their market demand has increased year by year because of their remarkable curative efficacy and nourishing effects,which leads to insufficient supply of raw material resources,and widespread use of fake and inferior products,seriously affecting the reputation of TCM glues and drug safety. In this context,the establishment of a more specific quality detection method for the TCM glues according to their specific characteristics can effectively improve the quality control level,promote rational use,and have a far-reaching impact on the industrial development of TCM glues. In this paper,the classification of TCM glues,as well as the production and application status of their representative( Ejiao) were briefly introduced; the papers on quality control technologies of TCM glues,including traditional identification experience,authenticity identification,physical property determination,protein,peptide and amino acid contents determination,element analysis,biological evaluation,and brand protection technology of TCM glues,were reviewed,and their advantages and disadvantages were summarized and analyzed comprehensively.Based on the specific characteristics of TCM glues,such as complex material basis,unclear pharmacodynamic components and different production processes,it was proposed in this paper to research and develop information-rich,convenient,fast,and non-destructive analytical techniques for the quality control of TCM glues and brand protection of famous products,thus promoting the healthy development of TCM glues industry.
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Adhesivos , Medicina Tradicional China , Control de Calidad , InvestigaciónRESUMEN
In this work,a high performance liquid chromatography-ultraviolet( HPLC-UV) detection technology was used to establish fingerprint analysis method for Sanye Tangzhiqing Decoction following an analytical quality by design( AQb D) approach. Firstly,column temperature,flow rate,and gradient elution conditions were determined as the method parameters needing to be optimized. Then according to the results of definitive screening design,three critical method attributes( CMAs) were identified,including peak number,the percentage of common peak area to total peak area,and retention time of the last peak. A stepwise regression method was used then to build quantitative models between CMAs and method parameters. Probability-based design space was calculated and successfully verified using the experimental error simulation method. After the analysis conditions were optimized,the contents of six components,namely chlorogenic acid,paeoniflorin,rutin,hyperoside,quercetin-3-O-β-D-glucuronide,and salvianolic acid B were simultaneously determined. There were 19 common peaks in the fingerprint and their common peak area accounted for 96% of the total peak area. Both fingerprint and quantitative analysis methods were validated applicable in methodology study,and they can be applied to determine new samples.
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Ácido Clorogénico , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios ChinosRESUMEN
In this work, we obtained the quality information of Panax notoginseng with near infrared spectroscopy in an efficient way. By combining the quality information of raw materials with process parameters in experimental design, quantitative relationship models were established between material quality information, process parameters and product quality of P. notoginseng, thus realizing the feedforward control of the alcohol extraction process. The quantitative models established have high robustness and satisfactory forecasting ability. With new batches of P. notoginseng introduced for the alcohol extraction process, the quality information of raw materials was rapidly obtained. Based on the established models, the process parameters were optimized according to the expected critical quality attributes (CQA), thereby reducing the fluctuation of product quality caused by raw material variation.
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In this work, two algorithms (overlapping method and the probability-based method) for design space calculation were compared by using the data collected from extraction process of Codonopsis Radix as an example. In the probability-based method, experimental error was simulated to calculate the probability of reaching the standard. The effects of several parameters on the calculated design space were studied, including simulation number, step length, and the acceptable probability threshold. For the extraction process of Codonopsis Radix, 10 000 times of simulation and 0.02 for the calculation step length can lead to a satisfactory design space. In general, the overlapping method is easy to understand, and can be realized by several kinds of commercial software without coding programs, but the reliability of the process evaluation indexes when operating in the design space is not indicated. Probability-based method is complex in calculation, but can provide the reliability to ensure that the process indexes can reach the standard within the acceptable probability threshold. In addition, there is no probability mutation in the edge of design space by probability-based method. Therefore, probability-based method is recommended for design space calculation.
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The paper-based analytical device (PAD) was applied in this study to analyze the antioxidant activity of Danhong injection and its intermediates. First polycaprolactone was printed on the surface of a filter paper with a 3D printing device. The modified filter paper was then prepared using polycaprolactone and solid paraffin as the modifiers. The PAD was prepared after adding DPPH ethanol solution to the modified filter paper. Ascorbic acid solutions with different concentrations were used as the positive drug on PAD. After the occurrence of color reactions, the PAD was dried, and the data of color were collected by a cell phone. The color component G and grayscale were selected as the potential indices for measurement according to the values of determination coefficients, detection limits, and effective number of digits. Qualitative and quantitative analysis of Danhong injection and the concentrate of aqueous extract were realized with the PAD. Because no significant differences were observed between the results obtained using the two potential indices, the average values of these two were used for analysis, and the antioxidant activity of Danhong injection and the concentrate of aqueous extract was equivalent to ascorbic acid solutions of 3.7, 46 g·L⁻¹, respectively. The PAD method presented in this work can be a simple method to determine biological activities of Chinese medicines and their intermediates.
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In this study, the HPLC-UV-MS method for the simultaneous determination of eight active ingredients of Shengxuebao Mixture were developed based on the concept of quality by design(QbD)with a stepwise optimization approach. After the analytical target profile(ATP)had been defined, albiflorin, paeoniflorin, 2, 3, 5, 4'-tetra-hydroxy-stilbene-2-O-β-D-glucopyranoside, specnuezhenide, ecliptasaponin D, emodin, calycosin-7-glucoside, and astragaloside Ⅳ were identified as the indicator components. The resolution and the signal-to-noise ratio of indicator components were then selected as critical method attributes (CMA) for the first step optimization. According to the results collected from fractional factorial design, critical method parameters (CMP) were determined with a multiple linear regression method, which included the amount of acid addition in the mobile phase, temperature, gradient, and wavelength. After that, the amount of acid addition and the wavelength were optimized to improve the resolution and the signal-to-noise ratio of the indicator components. The peak symmetry factors of specnuezhenide and emodin were then set as CMA for the second step optimization. The Box-Behnken designed experiments were conducted. The temperature and gradient were optimized after modelling. The design space were calculated and verified. The optimized analytical method was validated, and the results showed a good precision, accuracy and stability, which means that it can be used for the quantification of the indicator components in Shengxuebao Mixture.
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Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos , Espectrometría de Masas , Fitoquímicos , Reproducibilidad de los ResultadosRESUMEN
Design space approach was applied in this study to optimize the lime milk precipitation process of Lonicera Japonica (Jinyinhua) aqueous extract. The evaluation indices for this process were total organic acid purity and amounts of 6 organic acids obtained from per unit mass of medicinal materials. Four critical process parameters (CPPs) including drop speed of lime milk, pH value after adding lime milk, settling time and settling temperature were identified by using the weighted standardized partial regression coefficient method. Quantitative models between process evaluation indices and CPPs were established by a stepwise regression analysis. A design space was calculated by a Monte-Carlo simulation method, and then verified. The verification test results showed that the operation within the design space can guarantee the stability of the lime milk precipitation process. The recommended normal operation space is as follows: drop speed of lime milk of 1.00-1.25 mL•min⁻¹, pH value of 11.5-11.7, settling time of 1.0-1.2 h, and settling temperature of 10-20 ℃..
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Quality by design principle was used as a guideline in this study to optimize ethanol reflux extraction of red ginseng. Firstly, hazard and operability analysis(HAZOP) was used as a risk assessment tool to evaluate the hazard degree of process parameters.Ethanol concentration, the ratio of alcohol and herbal material (A/M ratio), and extraction time were identified as the critical process parameters(CPPs) according to HAZOP method.Secondly, Box-Behnken experimental design was applied to establish theregression models between CPPs and the process indices. Finally, the design space was calculated. The recommended operation space of parametersis as follows:alcohol concentration of 90.3%-90.7%, A/M ratio of 2.5-3.1 mL•g ⁻¹ and extraction time of 124-130 min. The study shows that the design space approach combined with the risk assessment using HAZOP has the potential to reduce the risk of red ginseng extraction process, which might ultimately improve the process control..
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To recognize the key influential factors during the liquid preparation process of Tanreqing injection, the near infrared(NIR) spectra of the raw materials and the operating parameters of 24 batches of physical manufacturing were recorded as independent variables, and the total soluble solids contents and the light inspection acceptance rate of the final products were collected as dependent variables. The calibration models were developed using the partial least-square regression (PLSR) method, and the correlation coefficients between the independent variables and the dependent variables were calculated. For the quantitative models, the correlation coefficients for the calibration and inner cross validation of total soluble solids contents and the light inspection acceptance rate reached 0.911 9, 0.724 2 and 0.873 8, 0.795 9, respectively. Using the correlation coefficients diagrams, several key influence factors were preliminarily determined, and the physical significance were analyzed combined with production experience. This work demonstrated that NIR spectroscopy with PLSR algorithm could be used for the key influential factors recognization during the liquid preparation process of Tanreqing injection and can be popularized to solve similar problems..