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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.
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Alcohols , Big Data , Drugs, Chinese Herbal/chemistry , Solvents , Technology, PharmaceuticalABSTRACT
To explore the relationship between the variations of the physiochemical properties of traditional Chinese medicine(TCM) decoction before or after precipitation in alcohol and the wall stickiness in spray drying. In this study, widely used TCMs in clinic were selected to determine the physiochemical properties of TCM decoction before or after precipitation in alcohol separately.Afterwards, the principle component analysis(PCA),Hierarchical cluster analysis(HCA),and orthogonal partial least squares-discriminate analysis(OPLS-DA) were used to evaluate the relationship between the variations of those liquid before or after precipitation in alcohol and hot-melt stickiness in spray drying.Three types of statistical analysis methods all indicated that ethanol precipitation affected physiochemical properties of TCM decoction, and the variations of physical properties showed significant association with hot-melt stickiness in spray drying.The results of PCA-X and HCA suggested that the dynamic surface tension(DST) was impacted most by the alcohol deposition treatment,at the same time,the other 5 physiochemical properties were also affected.OPLS-DA verified that PCA-X and HCA results, and revealed that DST,equilibrium surface tension(EST) and pH were significantly affected by alcohol deposition treatment,and the order of the affecting factors from high to low was DST,EST and pH.Therefore,the downward trend of DST and pH were the important factors that directly affected the hot-melt stickiness of TCM after precipitation in alcohol,which would be probably caused by losing macromolecules alcoholic insoluble components and increasing relative proportions of organic acid and small molecule sugar.
Subject(s)
Cluster Analysis , Desiccation/methods , Drugs, Chinese Herbal/chemistry , Ethanol/chemistry , Hot Temperature , Least-Squares Analysis , Medicine, Chinese Traditional , Principal Component AnalysisABSTRACT
Objective To optimize the extraction and alcohol precipitation process of Qizhi Yifei Granules by multi index orthogonal experiment. Methods With extraction rate of astragaloside in Astragali Radix, quercetin-3-O-β-D-glucose-7-O-β-D-gentian diglucoside in Descurainiae Semen Lepidii Semen and yield rate of dry extract as indexes, the extraction process of Qizhi Yifei Granules was optimized. Taking the retention rate of astragaloside and quercetin-3-O-β-D-glucose-7-O-β-D-gentian diglucoside as indexes, the alcohol precipitation process was optimized. Results The best water extraction process was as follows: adding 10 times amount of water, extracting for 1.5 h, 3 times. The optimum alcohol precipitation process was: concentrated to the relative density of 1.05–1.10 (60 ℃), adding ethanol to 60％ and alcohol precipitation. Conclusion The optimized extraction and alcohol precipitation process is stable and feasible, which can provide the basis for the preparation.
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Objective: The calibration models were developed in the concentration of alcohol precipitation proee for Artemisiae Annuae Herba (AAH) and Lonicerae Flos (LF) in Reduning Injection (RI) to realize the on-line monitoring of production process. Methods: Based on the near infrared reflectance spectroscopy (NIRS), partial least regression (PLS) models were developed to fast measure the contents of neochlorogenic acid, chlorogenic acid, and 4-O-caffeoylquinic acid in the concentration of the alcohol precipitation proee for AAH and LF. Results: In the quantitative models of neochlorogenic acid, chlorogenic acid, and 4-O-caffeoylquinic acid, the coefficient of determination (R2) of cross validation sets were 0.954 5, 0.975 2, and 0.969 1; The root mean square errors of calibration (RMSEC) were 0.213, 0.676, and 0.225; The root mean square errors of cross-validation (RMSECV) were 0.233, 0.692, and 0.258. When the established models were applied to on-line monitoring, the coefficient of determination of neochlorogenic acid, chlorogenic acid, and 4-O-caffeoylquinic acid were 0.984 2, 0.983 7, and 0.987 0, the residual predictive deviation (RPD) were 4.77, 5.29, and 4.37; The relative standard errors of prediction (RSEP) were 3.519%, 3.778%, and 3.895%. Conclusion: The models above are proved to fast measure the contents of neochlorogenic acid, chlorogenic acid, and 4-O-caffeoylquinic acid in the concentration of alcohol precipitation proee for AAH and LF in RI.
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Objective:To optimize the alcohol precipitation technology of Dingtongning granule and investigate the rationality of al-cohol precipitation technology by pharmacodynamics. Methods:With the yield of extract and the transfer rates of paeoniflorin and feru-lic acid as the comprehensive evaluation indices,L9(34) orthogonal test was used to optimize the alcohol precipitation technology by taking the concentration of alcohol precipitation,relative density of extract and alcohol precipitation time as the influencing factors,and the efficacy of water extract before and after the alcohol precipitation was compared through the biochemical indices of mice. Results:The optimum alcohol precipitation process was as follows:the extracting liquid was concentrated to the relative density of 1.10 g·ml-1 (25 ℃),and then 90% ethanol was added till the concentration of ethanol up to 70%,and last,the extract was stored in cold for 18 h. The efficacy had no obvious changes before and after the alcohol precipitation. Conclusion:The optimal alcohol precipitation tech-nology is stable and feasible,which can maintain the efficacy and shows good purification. The optimal alcohol precipitation technology provides experimental basis for the scientific production of Dingtongning granule.
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Objective Ganglouyuchuang lotion was used to dress the wound for Anal fistula in Crohn's disease, control inflammation and promote wound healing.This paper studied the extraction techonology of ganglouyuchuang lotion.Methods Four factors of ganglouyuchuang lotion, including volume of water, extraction time, extraction times and liquid ratio, were studied by the orthogonal test, and three levels were selected for each factor.The content of sodium danshensu, the active component contained in Chinese herbal medicine, was regarded as evaluating indicator, and the content of Danshensu Sodium was determined by HPLC.The water extraction and alcohol precipitation technology of ganglouyuchuang lotion was optimized according to the results of measurement.Results The optimum extraction technology of ganglouyuchuang lotion was as follows: four herbs, including Salvia miltiorrhiza, Radix Astragali, Radix sanguisorbae and Senecio were added with8 times amount of water overnight and decocted 3 times with 2 h, 1.5 h, and 1.5 h respectively, and then the extraction was concentrated to the ratio of herbs and concentrate of 1∶1.5.The results showed that the contents of Danshensu Sodium from the three examples were 0.520, 0.498, and 0.521 mg/mL, and the RSD were 0.34%, 0.41%, and 0.29%.Conclusion The optimum extraction technology is feasible and applicable for the preparation of ganglouyuchuang lotion.
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To develop a method for the rapid monitoring of five components during the alcohol precipitation process of Shenzhiling oral solution using near infrared spectroscopy(NIRS).The contents of five components detemined by high performance liquid chromatography(HPLC) were used as the reference values, and the NIRS based partial least square regression(PLSR) models were used to monitor the concentrations of paeoniflorin, albiflorin, liquiritin, cinnamic acid and glycyrrhizic acid during the alcohol precipitation process of Shenzhiling oral solution, which were optimized and verified through comparing of different spectral pre-processing and variables selection methods. Determination coefficients(Rcal2 and Rpred2), root mean squares error of prediction (RMSEP), root mean squares error of calibration(RMSEC) and ratiao of performance to deviation(RPD) were applied to evaluate the performance of the models, and the corresponding values were 0.993 3 and 0.997 6, 0.084 9 g•L⁻¹, 0.073 3 g•L⁻¹ and 14.7 for paeoniforin; 0.991 4, 0.992 7, 0.028 1 g•L⁻¹, 0.030 5 g•L⁻¹ and 10.2 for albiforin; 0.955 3, 0.976 1, 0.012 0 g•L⁻¹, 0.012 3 g•L⁻¹ and 5.1 for liquiritin; 0.958 8, 0.990 3, 0.003 89 g•L⁻¹, 0.002 89 g•L⁻¹ and 7.1 for cinnamic acid; 0.982 0, 0.986 3, 0.053 8 g•L⁻¹, 0.059 0 g•L⁻¹, 7.2 for glycyrrhizic acid, respectively. The results indicated that the presented approach was effectively for the quantitative monitoring of the alcohol precipitation process of Shenzhiling oral solution.
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Ganmaoling granule is the first brand of domestic cold medicine sales, but its preparation method and process control parameters are relatively rough. Therefore it is urgent to upgrade the technologies of large varieties of traditional Chinese medicine (TCM). This paper focused on the balance between the remove of impurity and the retention of linarin during the process of alcohol precipitation of Ganmaoling granules. The effects of four factors on the process were investigated via single factor experiments. The results showed that the precipitating period, the initial ethanol concentration and the final ethanol concentration had a great effect on retention of linarin while the initial density of the extract has not. Similarly, the initial ethanol concentration, the final ethanol concentration and the initial extract density have a great effect on the yield of dry extract while the time of alcohol precipitation has not. The parameters of alcohol precipitation of Ganmaoling granules were optimized as 16 h of precipitating period, 95% ethanol as the initial reagent, 70% of the final ethanol concentration, and 1.10 of the initial extract density.
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To evaluate the rationality of alcohol precipitation technology of Biqiu granule by investigating its effect on serum histamine, IgE, IL-4, IFN and TNF-α. The contents of cafferic acid and rosmarinic acid were used as the evaluation indexes, and some factors affecting index were firstly evaluated by Plackett-Burman design; then alcohol precipitation technology was further optimized by Box-Behnken design to determine the optimal alcohol precipitation conditions. The best alcohol precipitation conditions were as follows: the relative density of herb liquor was 1.15 (65 ℃); the concentration of alcohol was 70%, and standing time was 12 hours. Optimal alcohol precipitation technology of Biqiu granules determined by pharmacodynamic screening, Plackett-Burman and Box-Behnken design tests, was stable and feasible with good predictability, providing reliable basis for the industrialization production of Biqiu granules.
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Objective:To study the application of statistical process control technology to establish the real-time release criteria of alcohol precipitation process of ArtemisiaeAnnuae Herba and Lonicerae Flos. Methods: Twenty-ninebatches of samples came from alcohol precipitation process of ArtemisiaeAnnuae Herba and Lonicerae Flos were collected as the calibration set. The contents of neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, and solid content were determined to establish the quantitative real-timerelease criteria based on statistical process control technology. Thirteenbatches of alcohol precipitation process of ArtemisiaeAnnuae Herba and Lonicerae Flos were prepared under the different process conditions by the central composite design. They were regarded as the validation set to test the dependability of the real-time release criteria. Results: The established quantitative release ranges were neochlorogenic acid 0.279-0.541 mg/g, chlorogenic acid 1.941-2.610 mg/g, cryptochlorogenic acid 0.453-0.570 mg/g, and solid content3.565%-4.925%. The four index component contentsof the samples 1, 4, 8, 9, and 10 from the validation set werewithin the range of the real-time release criteria. Conclusion: Univariate statistical process control could be well monitored and understood of production process for Chinses materiamedica.They are used to achieve the purpose of real-time release.
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OBJECTIVE: To select the optimum extracting procedure for Kangdu Mixture by the application of L9 (34). METHODS: Orthogonal design was used to observe and study the effects of the factors of water volume, extracting times and extracting time on kangdu Mixture, the chlorogenic Acid and yield of dry extract was determined by high performance liquid chromatography, the synthetic weighted mark method was used to evaluate the extraction process. RESULTS: The optimum water extraction is as follows; 10 times of water, extracting twice by relux, 2 hours for each time. CONCLUSION: The process choosed in this experiment is practicable and can be applied for preparation of Kangdu Mixture, the optimal process is simple and high precision.
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Objective: To investigate the preparation procedure of Zhenjing Xiehuo granules. Methods: Using the dry extract yielding rate and the contents of liquiritin and salvianolic acid B as the indices, an orthogonal test was adopted to choose the best ex-traction and purification technology. Using the qualified ratio of granules as the index, an orthogonal test was adopted to choose the best preparation process of the granules. Results:The optimized preparation conditions were as follows:Pulvis ferri was decocted first for 60 min. The other medicines were dipped in 8-fold amount of water for 90 min, and then added into pulvis ferri extracts and decocted for 3 times with 90 min for each time. The extracts were collected and concentrated till the relative density was 1. 3 (measured at 60℃), water was added with the dilution ratio of 1:2, ethanol was added till the percentage of ethanol was 50%, and then the mixed liquid was filtered after 24 hours. After ethanol was recycled from the filtrate, the filtrate was concentrated till the relative density was 1. 3 (measured at 60℃), and then dried at 60℃. Starch as the diluent, the ratio of extract to excipient was 1:0. 8, and the wet granules were prepared with 90% ethanol as the wetting agent, dried 3 hours at 60℃ followed by size stabilization to obtain the products. Con-clusion:The optimized preparation procedure of Zhenjing Xiehuo granules is stable and feasible.
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To optimize the alcohol precipitation process for Lonicerae Flos and Artemisiae Annuae Herba (LA) in Reduning Injection and obtain the relationship equation of the key process parameters and quality attributes, which could provided a theoretical basis of the control automization in the alcohol precipitation process. With the transfer rates of neochlorogenic acid, chlorogenic acid, cryptochlorogenin acid, caffeic acid, secoxyloganin and solid content in precipitation liquid as evaluation indexes, the effect of the seven factors, such as relative density and the temperature of LA in liquid phase before alcohol precipitation, alcohol concentration in the end of alcohol precipitation, stirring speed in alcohol precipitation, adding alcohol speed, standing temperature, and standing time, on the alcohol precipitation process was investigated by the single factor experiment. By analysis of variance, the key factors that could influence the alcohol precipitation process were determined. Then the range of parameters of key factors was further studied and explored by Box-Behnken response surface methodology. The optimum preparation conditions of the alcohol precipitation process of LA were as follows: stirring speed was 550 r/min, adding alcohol speed was 4.0 mL/s, standing temperature was 30℃, standing time was 24 h, alcohol concentration was 75%, the relative density of LA was 1.10, and the temperature of LA was 25℃. Under these conditions, the transfer rates of neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, caffeic acid, and secoxyloganin were 94.8%, 97.6%, 97.4%, 97.2%, and 96.1%, and the solid content was 4.2%. The alcohol precipitation process of LA have been optimized by the response surface method, which could help to enhance the stability of the process.
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Objective: Through studying the rationalization of alcohol precipitation process of Liuwei Dihuang Prescription to obtain the stability alcohol precipitation process which could be used to promote industrialization. Methods: It screens the most reasonable alcohol precipitation process taking the contents, the relative molecular weight distribution, and the extract of loganin, peoniflorin, morroniside, manninotriose, and polysaccharide as the evaluation index to investigate the way of adding ethanol, centrifugation,, and whether to carry out the ethanol washing process. Results: The alcohol precipitation process is reasonable by calculating the alcohol volume method. The polysaccharides and alcohol precipitation supernatant could be efficiently separated by ethanol washing method. The polysaccharide extract and the contents of glycosides and manninotriose were up to the standard after the process improved. Conclusion: The optimized alcohol precipitation process is easy operation with good controllability and repeatability. It is worthy of popularization and application of industrialization.
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Objective: Near-infrared (NIR) spectroscopy was used to rapidly determine the concentration of chlorogenic acid (CA) and soluble solid content in alcohol precipitation of Lonicerae Japonicae Flos and Artemisiae Annuae Herba (LA) in Reduning Injection, so as to increase the level of quality control of alcohol precipitation process. Methods: The LA samples of alcohol precipitation were collected. The PLS algorithm was used to establish NIR models between spectra and concentration of CA and total solid content, and the concentration of CA and soluble solid content in unknown batch were predicted. Results: The correlation coefficients (R) of NIR models were above 0.980 in calibration sets. The R of verification model was above 0.980, the root mean square error of prediction (RMSEP) for CA and soluble solid content were 0.541 and 0.218, respectively, and the relative standard errors (RSEP) for CA and soluble solid content were no more than 8%. Conclusion: The results demonstrate that NIR could determine the concentration of CA and soluble solid content in alcohol precipitation of Reduning Injection rapidly and accurately.
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The data of the alcohol concentration in alcohol precipitation process of 22 Chinese materia medica (CMM) were investigated and analyzed. The result showed that the real alcohol concentration in the alcohol precipitation process was higher than the expected generally, and the real alcohol concentration in the alcohol precipitation process in the same product was different in different batches. The gap between the real alcohol concentration in the alcohol precipitation process and the expected maybe related to the product and the method to determine how much alcohol to be added and the way of operation. The data above were analyzed, and some suggestions were presented as follows: (1) Meaning of the expected alcohol concentration in the alcohol precipitation process described in the drug quality specification should be explained clearly; (2) The method used to determine how much alcohol should be added and the indicator of on-line control should be studied and determined; (3) During the process validation, the real alcohol concentration in the alcohol precipitation process should be detected according to the procedure in China Pharmacopeia (2010 edition) and make sure whether the real alcohol concentration in the alcohol precipitation process was the same as the expected; (4) The alcohol precipitation process of new CMM should be systematically studied, and the method used to determine how much alcohol should be added must be on record in `Production Process for Oon-site Inspection'.
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This study was aimed to optimize the alcohol precipitation techniques for honeysuckle extract in order to standardize the production of honeysuckle extract of Qingkailing Injection and reduce the differences among batches. The orthogonal test was applied in this study. The content of chlorogenic acid and galuteolin were taken as compre-hensive indicators. Multi-index comprehensive scoring method was used in the data analysis. Three influencing fac-tors, which were the fluid temperature, the stirring speed and the speed of adding alcohol, were optimized in the al-cohol precipitation techniques. The results showed that the optimal alcohol precipitation techniques were when the fluid temperature was 20℃, the stirring speed was 240 rpm and the speed of adding alcohol was one time of the ma-terial per minute. It was concluded that the optimized alcohol precipitation process was stable and feasible.
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Objective:To optimize the alcohol precipitation technology of Qingmai granules. Methods:The relative density of liq-uor,the concentration and time of alcohol precipitation were chosen as the factors,the yield of dry extract and content of diosgenin as the indices,the alcohol precipitation technology was optimized by orthogonal test. Results:The optimal alcohol precipitation technology was as follows:the extraction liquid was concentrated till the relative density was 1. 13-1. 18 g·ml-1 ,ethanol was added until the concen-tration was up to 60% with the alcohol precipitation time of 24h. Conclusion:The optimized technology is stable,reasonable and feasi-ble,which can provide experimental basis for the clinical application of Qingmai granules.
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OBJECTIVE:To study the extracting and purifying process of Achyranthes bidentata polysaccharides(ABP). METHODS:Crude polysaccharide was obtained by extracting ABP raw material by water decocting method.The Crude polysaccharide was purified(deproteinization,desalination and alcohol precipitation) to obtain ABP.The content of total polysaccharide was taken as an evaluation index to optimize the optimum conditions of extracting and purifying.RESULTS: The optimum water decoction conditions were as follows:ABP raw material was extracted three times (2 h/time) by adding 10 times amount of water.As for the deproteinization process,TCA(trichloracetic acid) method was superior to Sevage method and tannic acid method;Desalination by molecular sieve was superior to that by dialysis method; and alcohol precipitation was performed with 80% alcohol.CONCLUSION:ABP can be prepared by water decoction,deproteinization,desalination and alcohol precipitation of its raw material.
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OBJECTIVE:To optimize the extraction technique for Sidiming capsules.METHODS:The technical conditions for the water decoction and the alcohol precipitation were optimized respectively by the orthogonal experiment design L9(34)with hydrosoluble extract used as the index for the water decoction and the catalpol extract for alcohol precipitation.The content of Catalpol was determined by HPLC.RESULTS:The optimum conditions were as follows:decocting the crude drugs twice with 8-fold water,1 h each time.The physic liquor extracted by water was filtered,mixed and concentrated to 1.0 g?mL-1(crude drug),and then precipitated by 75% concentration of alcohol for 24 h.Then the physic liquor was filtered,concentrated and dried by microwave vacuum concentration dryer to obtain the dry ointment.CONCLUSION:The optimum extraction procedure is stable and reliable,and it can be used as the optimal extraction procedure of Sidiming capsules.