CN102692462B - Danhong injection quality control method - Google Patents
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- CN102692462B CN102692462B CN201210184920.4A CN201210184920A CN102692462B CN 102692462 B CN102692462 B CN 102692462B CN 201210184920 A CN201210184920 A CN 201210184920A CN 102692462 B CN102692462 B CN 102692462B
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- 239000008522 danhong Substances 0.000 title claims abstract description 81
- 238000002347 injection Methods 0.000 title abstract description 16
- 239000007924 injection Substances 0.000 title abstract description 16
- 238000003908 quality control method Methods 0.000 title abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 47
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- ZMMKVDBZTXUHFO-DDWIOCJRSA-M sodium;(2r)-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate Chemical compound [Na+].[O-]C(=O)[C@H](O)CC1=CC=C(O)C(O)=C1 ZMMKVDBZTXUHFO-DDWIOCJRSA-M 0.000 claims abstract description 22
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Abstract
The invention relates to a Danhong injection quality control method. According to the method, an efficient liquid chromatography is used for measuring fingerprint spectrums of Danhong injection products to be measured, and in addition, three kinds of algorithms including the included angle cosine algorithm, the relative coefficient algorithm and the ratio qualitative algorithm are adopted for calculating the qualitative similarity of fingerprint spectrums of the Danhong injection; and the P value and the M value are calculated, and the qualitative similarity of the fingerprint spectrums of the Danhong injection is obtained. Meanwhile, a content measuring method of eight effective ingredients of the Danhong injection is built. Finally, a high performance liquid chromatography (HPLC) is used for measuring, the conditions that the sodium danshensu and protocatechualdehyde content is greater than 350mug/mL, the qualitative similarity is greater than 0.95, the quantitative similarity P is between 0.80 and 1.20, and the M is between 0.90 and 1.10 are used as quality control standards for controlling the Danhong injection quality. The fingerprint spectrum qualitative and quantitative discrimination is combined with the multi-index quantitative analysis, and the reliability and the safety of the Danhong injection quality are further ensured.
Description
Technical field
The present invention relates to a kind of compound Chinese medicinal preparation DANHONG ZHUSHEYE method of quality control, specifically use finger-print to control the quality of DANHONG ZHUSHEYE in conjunction with the method for high performance liquid chromatography (HPLC) multi-target ingredient assay.
Background technology
DANHONG ZHUSHEYE system by the red sage root, safflower two flavor medicinal materials through extracting, the traditional Chinese medicine made of the techniques such as concentrated, alcohol precipitation, depositing in water, preparation, be mainly used in treating the cardiovascular and cerebrovascular diseases such as angina pectoris, miocardial infarction, atherosclerotic.It has the effects such as rapid-action, good effect, has been widely used at present clinical.But due to factors such as crude drug quality inequality, fluctuation of operating conditions, often cause difference between product batches, be difficult to realize DANHONG ZHUSHEYE steady quality, the controlled target of homogeneous.Therefore, how to set up a kind of comprehensive, comprehensive DANHONG ZHUSHEYE quality evaluating method, thereby guarantee the further upgrading of product quality, seem very important.
Existing " promulgated by the ministries or commissions of the Central Government " standard is to the DANHONG ZHUSHEYE quality assessment except the conventional formulation inspection item, and the assay item is only required several index components such as Sodium Danshensu and protocatechualdehyde in general flavone and injection.Determination of total flavonoids adopts sodium nitrite---aluminium nitrate development process, and phenolic acid compound in parenteral solution, as Sodium Danshensu, protocatechualdehyde, tanshin polyphenolic acid B etc. all have response to this coloration method, the method specificity is not strong, can't truly reflect main pharmacodynamics population size in parenteral solution.In addition, the DANHONG ZHUSHEYE liquid content is only measured also for one or two chemical composition such as Sodium Danshensu, protocatechualdehyde wherein and is characterized and control.Yet, the complex material system that Chinese medicine is comprised of numerous chemical compositions often, the method for traditional one or several chemical composition content of mensuration can't be made holistic approach to traditional Chinese medicine quality.
Using finger-print as the method for quality control of Chinese medical extract and preparation thereof, become a consensus of the international community at present.FDA (Food and Drug Adminstration) (FDA) allows to provide chromatographic fingerprinting in herbal health care product declaration material; The World Health Organization (WHO) also stipulates in herbal medicine in 1996 is estimated governing principle, if the active component of herbal medicine is indefinite, can provide chromatographic fingerprinting consistent with the proof product quality; The European Community (EU) also claims in the herbal medicine quality guideline, and depending merely on certain effective constituent, to investigate the stability of quality be inadequate, because herbal medicine and preparation thereof are to take integral body as active substance.Calendar year 2001, National Drug Administration promulgates that " technical requirement of traditional Chinese medicine injection and finger-print research " (provisional) requires finger-print is detected to index and the technical requirement single-row project as quality standard, thereby the Chinese medicine method of quality control has been carried out to useful supplementing.The foundation of traditional Chinese medicine fingerprint can not only reflect kind and the quantity of contained chemical composition in Chinese medicine and preparation thereof comparatively all sidedly, and then drug quality is carried out to integral body and describe and estimate, simultaneously, for improving traditional Chinese medicine quality, promote that the modernization of Chinese medicine is significant.
At present, the method for traditional Chinese medicine fingerprint research and comparison main flow is that chromatography comprises thin-layered chromatography, liquid phase chromatography, vapor-phase chromatography etc.Thin-layer chromatography due to reappearance and precision poor, be mainly used in the discriminating of Chinese medicine; Gas chromatography is mainly used in analyzing effumability chemical composition Chinese medicine; And liquid chromatography is because the characteristics such as its analysis usefulness is high, favorable reproducibility, sensitivity height obtain applying the most widely in traditional Chinese medicine fingerprint.Particularly in recent years, the coupling of multiple technologies, make the analysis means of finger-print move towards multidimensional from one-dimensional especially.The fingerprint map analyzing technology of multidimensional mainly contains HPLC/MS/MS and HPLC/DAD, and HPLC/MS/MS, because of expensive, promote and remains at certain difficulty in traditional Chinese medicine quality is controlled; And HPLC/DAD is not only simple, be easy to popularize, can as much as possiblely provide Chinese medicine chromatogram and spectral information simultaneously, extremely be suitable for fingerprint map analyzing.
In practical application area, finger-print is as the existing Patents of a kind of comprehensive, comprehensive Quality Control Technology, as (CN102323345.2, CN201110073973.4, CN201110072539.4, CN201010108838.4).At present, the Qualitative fingerprint similarity mainly adopts the included angle cosine algorithm, and this ratio juris is to regard each sample finger-print as a vector
calculate test sample fingerprint vector and contrast fingerprint vector
between the included angle cosine value, but this method does not have quantitative property, exists large peak simultaneously and covers the small peak problem; (2002,60 (17): 2018) propose to adopt correlation coefficient process, its formula is Cheng Yiyu etc. for Cheng Yiyu etc., chemical journal
correlation coefficient process can judge the similarity of finger-print on the whole, but the frequent existence of this method is insensitive to sample, the problem that the result of calculation similarity is higher; Sun Guoxiang (Sun Guoxiang etc., Acta Pharmaceutica Sinica, 2007,42 (1): 75) proposed on this basis a kind of more outstanding evaluation method, to reference fingerprint
do
sample
do
calculate
with
between the included angle cosine value, the advantage of the method is to eliminate the impact at large peak, and each peak is had etc. to power property.Quantitatively the auspicious grade of similarity aspect ，Sun state has also proposed a kind of calculation in quantity similarity P (P=S
fr, wherein R is the ratio between the total fingerprint peaks total mark area of sample and reference fingerprint; S
ffor the included angle cosine value) method.This method is when estimating the quantitative similarity of finger-print, although considered the ratio of different component, only at S
fwhen low, impact obviously.Quantitative similarity
wherein
for the ratio between the integration face area of i characteristic peak in sample and reference fingerprint) regard each total peak as relatively independent integral body, all having peak and reference fingerprint characteristic peak degree of closeness by calculation sample, is a kind of more outstanding comparative approach.
In addition, to the quantitative measurement of many indexs active component in parenteral solution, avoided the limitation of traditional independent one or two effective constituent of mensuration, to a greater degree other plurality of active ingredients information in response sample; Simultaneously, quantitative to Multiple components, further formulate its content limit standard, the requirement of quality control is also more gone a step further, the further quality upgrading of the product contributed to undoubtedly.
Therefore, for guaranteeing the total quality of DANHONG ZHUSHEYE product, that the present invention adopts is qualitative, the quantitative finger print atlas technology combines with many indexs active constituent content measuring, set up the comprehensive method of quality control of a kind of DANHONG ZHUSHEYE, set up quality control standard and the Quality Control parameter of system simultaneously, reach the operating of finger-print, controlled, stable and can quantize, make Quality Control more accurately rationally, thereby realize the quality of DANHONG ZHUSHEYE finished product is strictly controlled.
Summary of the invention
The purpose of this invention is to provide a kind of DANHONG ZHUSHEYE method of quality control, by this assay method, can control better the product quality of DANHONG ZHUSHEYE.
The present invention realizes through the following steps:
(1) foundation of DANHONG ZHUSHEYE HPLC finger-print and mensuration
1. the preparation of DANHONG ZHUSHEYE control sample solution:
Get DANHONG ZHUSHEYE 2mL, be placed in the 10mL measuring bottle, with acetonitrile-0.5% formic acid solution (50:50, v/v), be settled to scale, shake up, the miillpore filter filtration through 0.45 μ m, obtain.
2. the mensuration of DANHONG ZHUSHEYE reference fingerprint:
The accurate need testing solution of drawing injects high performance liquid chromatograph, measures, and obtain the DANHONG ZHUSHEYE reference fingerprint, chromatographic condition: octadecylsilane key and silica gel are filler, gradient elution, flow velocity 0.5-1.5mL/min; Mobile phase: A is 0.5% aqueous formic acid, and B is acetonitrile; The scanning of employing program variable wavelength; Column temperature 20-40 ℃.
Preferred finger-print chromatographic condition is: Agilent Zorbax C
18(5 μ m, 10mm * 4.6mm); Mobile phase A is 0.5% aqueous formic acid; Mobile phase B is acetonitrile; 35 ℃ of column temperatures; The gradient elution program is: 0-15min, 98%-90%A; 15-20min, 90%-83%A; 20-45min, 83%-72%A; 45-48min, 72%-40%A; The program variable wavelength condition of scanning is: 0-18min, 280nm; 19-48min, 326nm.
(2) foundation and the mensuration of many indexs of DANHONG ZHUSHEYE HPLC content assaying method
1. the preparation of DANHONG ZHUSHEYE control sample solution:
Take Sodium Danshensu, protocatechualdehyde, caffeic acid, forulic acid, Rosmarinic acid, alkannic acid, tanshin polyphenolic acid B, salviandic acid A, be placed in measuring bottle, with acetonitrile-0.5% formic acid solution (50:50, v/v), be settled to scale, shake up, filter, join to obtain reference substance solution;
2. the preparation of DANHONG ZHUSHEYE need testing solution:
Get DANHONG ZHUSHEYE 2mL, be placed in the 10mL measuring bottle, with acetonitrile-0.5% formic acid solution (50:50, v/v), be settled to scale, shake up, the miillpore filter filtration through 0.45 μ m, obtain.
3. the mensuration of DANHONG ZHUSHEYE need testing solution:
The accurate need testing solution of drawing injects high performance liquid chromatograph, measures, and obtains Sodium Danshensu in DANHONG ZHUSHEYE, protocatechualdehyde, caffeic acid, Rosmarinic acid, alkannic acid, tanshin polyphenolic acid B, salviandic acid A content.Chromatographic condition: octadecylsilane key and silica gel are filler, gradient elution, flow velocity 0.5-1.5mL/min; Mobile phase: A is 0.5% aqueous formic acid, and B is acetonitrile; The scanning of employing program variable wavelength; Column temperature 20-40 ℃.
Preferred finger-print chromatographic condition is: Agilent Zorbax C
18(5 μ m, 10mm * 4.6mm); Mobile phase A is 0.5% aqueous formic acid; Mobile phase B is acetonitrile; 35 ℃ of column temperatures; The gradient elution program is: 0-15min, 98%-90%A; 15-20min, 90%-83%A; 20-45min, 83%-72%A; 45-48min, 72%-40%A; The program variable wavelength condition of scanning is: 0-18min, 280nm; 19-48min, 326nm.
(3) finger-print of described product to be measured is combined with HPLC assay result, comprehensive evaluation injection products quality.
Adopt matlab7.11.0 to be processed the finger-print data that obtain.Calculate the qualitative similarity of included angle cosine, related coefficient and ratio and quantitative similarity between different batches sample finger-print and reference fingerprint, measure simultaneously and take danshensu as 8 kinds of main active constituent contents, according to result, the parenteral solution quality is made to evaluation.
Wherein, quantitatively similarity calculating P value and M value are as evaluation index, and the computing formula of described P value is P=S
fr, wherein S
ffor the included angle cosine value, the ratio of the total fingerprint peaks total mark area that R is the total fingerprint peaks total mark area of sample finger-print and reference fingerprint; Quantitatively the computing formula of similarity M value is
wherein n is total peak number amount,
for the ratio between the integration face area of i characteristic peak in sample and reference fingerprint.
In the present invention, finger-print is finally chosen 19 common characteristic peaks in the parenteral solution finished product, and peak area accounts for a peak area more than 90%, and wherein No. 2 peaks (Sodium Danshensu) are with reference to peak.
Finally, the standard of quality assessment is greater than 0.35mg/mL with the content summation of HPLC assay Sodium Danshensu, protocatechualdehyde, included angle cosine, related coefficient, the qualitative similarity of ratio all are greater than 0.95, quantitatively similarity P is in 0.80～1.20 scope, thinks the up-to-standard of described DANHONG ZHUSHEYE product to be measured.
In HPLC assay result, the content summation of Sodium Danshensu, protocatechualdehyde is greater than 1.2mg/mL, included angle cosine, related coefficient, the qualitative similarity of ratio all are greater than 0.97, quantitatively similarity P is between 0.90～1.10, M is between 0.90～1.10, think that described DANHONG ZHUSHEYE is batch comparatively stable, the best in quality.
The content summation that HPLC assay result meets (1) Sodium Danshensu, protocatechualdehyde is less than 0.35mg/mL; (2) qualitative fingerprint similarity is lower than 0.95; (3) P value > 1.20 or<0.80; (4) M value > 1.10 or<0.90, two of arbitrary samples met and more than, judge that described DANHONG ZHUSHEYE product quality is defective.
Usefulness of the present invention:
(1) adopt the HPLC-DAD coupling technique of multidimensional to set up the DANHONG ZHUSHEYE finger-print, this invention has that method is easy, stable, the characteristics such as precision is high, favorable reproducibility.
(2) adopt the scanning of program variable wavelength to set up the DANHONG ZHUSHEYE finger-print, can in a collection of illustrative plates, obtain the more effective constituent information of horn of plenty.
(3) adopt Qualitative fingerprint and quantitative analysis method.Qualitative finger-print Comprehensive has been considered DANHONG ZHUSHEYE product total quality, the one-sidedness of the parenteral solution quality of having avoided one or two chemical index component content of simple mensuration to bring; The quantitative similarity evaluation adopted can reflect the quantity relative ratio relationship of effective constituent in parenteral solution to a certain extent.The Quality Control process adopts the quantitative and qualitative analysis dual indexes to differentiate, and the quality of product is had higher requirement.
(4) adopt above-mentioned identical analytical approach to set up 8 kinds of effective constituent quantitative analysis methods in DANHONG ZHUSHEYE, for the final mass of DANHONG ZHUSHEYE provides more reliable technical guarantee.
The accompanying drawing explanation
Fig. 1 is the HPLC figure of 8 kinds of active constituent content measurings in DANHONG ZHUSHEYE.
Fig. 2 is 19 total peak chromatograms in the DANHONG ZHUSHEYE finger-print.
Fig. 3 is 15 crowdes of DANHONG ZHUSHEYE finger-print HPLC figure.
Fig. 4 is that 15 batches of DANHONG ZHUSHEYEs adopt included angle cosine to calculate similarity result.
Fig. 5 is the qualitative similarity evaluation comparison diagram of DANHONG ZHUSHEYE included angle cosine, related coefficient and ratio.
Fig. 6 is DANHONG ZHUSHEYE included angle cosine value and quantitative similarity P value and M value evaluation result comparison diagram.
Fig. 7 is the quantitative similarity P value of DANHONG ZHUSHEYE and qualitative similarity (included angle cosine) comparison diagram as a result.
Embodiment
The present invention is further described in conjunction with the accompanying drawings and embodiments.
Embodiment 1: the DANHONG ZHUSHEYE finger-print is formulated
1.1 instrument and reagent
Agilent1200RRLC(is contained in the line vacuum degasser, high pressure binary gradient pump, automatic sampler, column oven, diode array detector (DAD), chemstaion chromatographic work station); Acetonitrile and formic acid are chromatographically pure; Ultrapure water; 15 batches of DANHONG ZHUSHEYEs (Heze City, Shandong Province step-length pharmaceutical Co. Ltd, lot numbers (10mL): 101149,101150,110931,110932,110933,110934,110935,110936,101171,101170,101165,101167,101145,101147,101157).
1.2 the preparation of DANHONG ZHUSHEYE control sample solution
Precision pipettes DANHONG ZHUSHEYE 2mL, is placed in the 10mL measuring bottle, with acetonitrile-0.5% formic acid solution (50:50, v/v), is settled to scale, shakes up, and the miillpore filter filtration through 0.45 μ m, obtain.
1.3 liquid phase chromatogram condition
Chromatographic condition: Agilent Zorbax C
18(5 μ m, 10mm * 4.6mm), gradient elution, flow velocity 1mL/min; Mobile phase: A is 0.5% aqueous formic acid, and B is acetonitrile; The scanning of employing program variable wavelength; 35 ℃ of column temperatures.The gradient elution program is: 0-15min, 98%-90%A; 15-20min, 90%-83%A; 20-45min, 83%-72%A; 45-48min, 72%-40%A; The program variable wavelength condition of scanning is: 0-18min, 280nm; 19-48min, 326nm.
1.4 choosing of characteristic peak
1.5 methodological study
Instrument precision test: appoint and get a collection of sample preparation need testing solution, under above-mentioned chromatographic condition, continuous sample introduction 5 times, take Sodium Danshensu as reference calculating retention time and peak area ratio, obtain 19 total peak-to-peak area ratio RSD values 0.04～2.57%, retention time ratio, 0.04～0.22%, shows that the method precision is good.
Replica test: get arbitrary batch of DANHONG ZHUSHEYE, by 1.2 methods, 5 parts of need testing solutions of parallel preparation, sample introduction analysis under above-mentioned chromatographic condition.Take Sodium Danshensu as reference calculates each retention time and peak area ratio, obtain 19 total peak-to-peak area ratio RSD 0.17～1.67%, SD is 0.01～0.13% for the retention time ratio R, and result shows that the method repeatability is good.Result is referring to table 1.
Stability test: to a DANHONG ZHUSHEYE need testing solution, by above-mentioned chromatographic condition respectively at 0,2,4,8,12h measures once, take Sodium Danshensu as reference calculating retention time and peak area ratio, obtain 19 total peak-to-peak area ratio RSD values 0.15～7.09%, retention time ratio is 0.08～1.24%, illustrate that DANHONG ZHUSHEYE is comparatively stable in 12h, meet and measure needs.Result is referring to table 1.
Table 1
1.6 the formulation of DANHONG ZHUSHEYE finger-print
The accurate need testing solution 5 μ L that draw inject high performance liquid chromatograph, measure, and record chromatogram.
The standard finger-print of 15 batches of DANHONG ZHUSHEYE product fingerprint collection of illustrative plates to be measured and formulation is compared, calculate the total peak number amount that both have of identifying, adopt the included angle cosine algorithm to calculate qualitative similarity, similarity is greater than 0.95, think that injection is qualified, similarity is greater than 0.97, thinks that parenteral solution batch is stable, better quality.DANHONG ZHUSHEYE finished product fingerprint similarity is basicly stable more than 0.98 as seen from Figure 4, illustrates that the parenteral solution quality is comparatively reliable and stable.Result is referring to table 2.
Table 2
Embodiment 2:
According to the method for embodiment 1, the difference part is to calculate related coefficient for estimating fingerprint similarity.
The standard finger-print of 15 batches of DANHONG ZHUSHEYE product fingerprint collection of illustrative plates to be measured and formulation is compared, calculate and identify the total peak number amount that both have, similarity is greater than 0.95, think that injection is qualified, similarity is greater than 0.97, thinks that parenteral solution batch is stable, better quality.Found that, for similarity, more than 0.990, the similarity that the related coefficient algorithm obtains and included angle cosine value be very approaching, yet the similarity value difference calculated in lower sample in similarity is different obviously.Referring to table 3.
Table 3
Embodiment 3:
According to the method for embodiment 1, the difference part is the qualitative similarity of calculating ratio, to reference fingerprint
do
sample
do
calculate
with
between the included angle cosine value.Similarity is greater than 0.95, thinks that injection is qualified, and similarity is greater than 0.97, thinks that parenteral solution batch is stable, better quality.Result is referring to table 4.
Table 4
Embodiment 4:
According to the method for embodiment 1, the difference part is to calculate content similarity P (P=S
fr, the ratio of the total fingerprint peaks total mark area that wherein R is the total fingerprint peaks total mark area of sample finger-print and reference fingerprint; S
ffor the included angle cosine value).Similarity, between 0.80～1.20, thinks that injection is qualified; Similarity is between 0.90～1.10, thinks that parenteral solution is batch stable, better quality; Similarity > 1.20 or<0.80 sample, need be whether qualified with the common evaluation quality of other indexs, quantitatively similarity evaluation the results are shown in Figure 5.
Embodiment 5:
According to the method for embodiment 1, the difference part is to calculate the content similarity
wherein
for the ratio between the integration face area of i characteristic peak in sample and reference fingerprint; N is total peak number order).Similarity, between 0.90～1.10, thinks that injection is qualified; Similarity > 1.10 or<0.90 sample, need whether qualifiedly estimate in conjunction with other indexs are common, quantitatively similarity evaluation the results are shown in Figure 5.
Embodiment 5:HPLC-DAD measures 8 kinds of active component contents of DANHONG ZHUSHEYE
According to the method for embodiment 1, the difference part is preparation and the methodological study of reference substance solution.
1.1 the preparation of reference substance solution
Accurately weighed Sodium Danshensu 3.95mg, Rosmarinic acid 5.98mg, put in the 5mL volumetric flask, protocatechualdehyde 5.12mg, tanshin polyphenolic acid B 7.20mg, salviandic acid A 7.28mg, put in the 10mL volumetric flask, caffeic acid 4.08mg, forulic acid 6.87mg, alkannic acid 5.38mg put in the 50mL volumetric flask, be settled to scale with 0.5% formic acid-acetonitrile (50:50, v/v), shake up and get final product.
1.2 methodological study
Instrument precision test: get same sample and prepare need testing solution, under above-mentioned chromatographic condition, continuous sample introduction 6 times, with calculated by peak area, the RSD of Sodium Danshensu, protocatechualdehyde, caffeic acid, forulic acid, Rosmarinic acid, alkannic acid, tanshin polyphenolic acid B, salviandic acid A is respectively 0.28%, 0.34%, 1.78%, 0.57%, 0.27%, 0.23%, 0.15%, 0.31%, shows that the method precision is good.
Replica test: get same batch of DANHONG ZHUSHEYE, press 2 methods in embodiment 1,6 parts of need testing solutions of parallel preparation, sample introduction analysis under above-mentioned chromatographic condition.With calculated by peak area, the RSD of Sodium Danshensu, protocatechualdehyde, caffeic acid, forulic acid, Rosmarinic acid, alkannic acid, tanshin polyphenolic acid B, salviandic acid A is respectively 0.73%, 0.53%, 2.84%, 0.68%, 0.53%, 0.56%, 0.63%, 0.54%, and result shows that the method repeatability is good.
Average recovery: add basic, normal, high concentration (being respectively 50%, 100%, 150%) Sodium Danshensu, protocatechualdehyde, caffeic acid, forulic acid, Rosmarinic acid, alkannic acid, tanshin polyphenolic acid B, salviandic acid A reference substance respectively in need testing solution, each concentration level three duplicate samples, and measure its content, obtain the recovery of 8 kinds of effective constituents referring to table 5.
Table 5
The range of linearity: accurate Sodium Danshensu, protocatechualdehyde, caffeic acid, forulic acid, Rosmarinic acid, alkannic acid, tanshin polyphenolic acid B, the salviandic acid A reference substance solution drawn, dilute respectively 2,4,8,16,32,64 times, sample introduction analysis under above-mentioned chromatographic condition.Take peak area as ordinate, reference substance concentration are horizontal ordinate, obtain regression equation referring to table 6.
Table 6
Stability test: to a DANHONG ZHUSHEYE need testing solution, by above-mentioned chromatographic condition respectively at 0,2,4,8,12h measures once, it is comparatively stable in 12h that acquired results RSD is respectively 0.81%, 0.69%, 1.34%, 0.77%, 0.38%, 0.62%, 0.37%, 0.43% explanation DANHONG ZHUSHEYE, meets and measure needs.
1.3 measurement result
Get 15 batches of DANHONG ZHUSHEYEs, measure as stated above, the 8 kinds of active component contents of measuring in Table 7.Wherein the content sum of Sodium Danshensu and protocatechualdehyde must not be lower than 0.35mg/mL.
Table 7
Claims (5)
1. 8 kinds of active constituent content measuring methods in a DANHONG ZHUSHEYE, is characterized in that comprising the steps:
(1) foundation of DANHONG ZHUSHEYE HPLC finger-print and mensuration
1. the preparation of DANHONG ZHUSHEYE control sample solution:
Precision pipettes DANHONG ZHUSHEYE 2 mL, is placed in 10 mL measuring bottles, and the acetonitrile that is 50:50 by volume ratio-0.5% formic acid solution is settled to scale, shakes up, and the miillpore filter filtration through 0.45 μ m, obtain;
2. the mensuration of DANHONG ZHUSHEYE finished product finger-print:
The accurate need testing solution of drawing injects high performance liquid chromatograph, measures, and obtain the DANHONG ZHUSHEYE reference fingerprint, chromatographic condition: octadecylsilane key and silica gel are filler, gradient elution, flow velocity 0.5 ~ 1.5 mL/min; Mobile phase: A is 0.5% aqueous formic acid, and B is acetonitrile; The scanning of employing program variable wavelength; 20 ~ 40 ℃ of column temperatures;
(2) foundation and the mensuration of many indexs of DANHONG ZHUSHEYE HPLC content assaying method
1. the preparation of DANHONG ZHUSHEYE control sample solution:
It is appropriate that precision takes Sodium Danshensu, protocatechualdehyde, caffeic acid, forulic acid, Rosmarinic acid, alkannic acid, tanshin polyphenolic acid B, salviandic acid A, be placed in measuring bottle, the acetonitrile that is 50:50 by volume ratio-0.5% formic acid solution is settled to scale, shakes up, filter, obtain reference substance solution;
2. the preparation of DANHONG ZHUSHEYE need testing solution:
Precision pipettes DANHONG ZHUSHEYE 2 mL, is placed in 10 mL measuring bottles, and the acetonitrile that is 50:50 by volume ratio-0.5% formic acid solution is settled to scale, shakes up, and the miillpore filter filtration through 0.45 μ m, obtain;
3. the mensuration of DANHONG ZHUSHEYE need testing solution:
The accurate need testing solution of drawing injects high performance liquid chromatograph, measure, obtain Sodium Danshensu in DANHONG ZHUSHEYE, protocatechualdehyde, caffeic acid, forulic acid, Rosmarinic acid, alkannic acid, tanshin polyphenolic acid B, salviandic acid A content, chromatographic condition: octadecylsilane key and silica gel are filler, gradient elution, flow velocity 0.5 ~ 1.5 mL/min; Mobile phase: A is 0.5% aqueous formic acid, and B is acetonitrile; The scanning of employing program variable wavelength; 20 ~ 40 ℃ of column temperatures;
(3) finger-print of described product to be measured is combined with HPLC assay result, measures 8 kinds of active constituent contents
Adopt matlab7.11.0 to be processed the finger-print data that obtain, calculate the qualitative similarity of included angle cosine, related coefficient, ratio and quantitative similarity between different batches sample finger-print and reference fingerprint, simultaneously, measure in DANHONG ZHUSHEYE and take danshensu as 8 kinds of main active constituent contents;
Chromatographic condition described in step (1), (2) is: Agilent Zorbax C
18, 5 μ m, 10 mm
4.6 mm; Mobile phase A is 0.5% aqueous formic acid, and Mobile phase B is acetonitrile, 35 ℃ of column temperatures, and the gradient elution program is: 0-15 min, 98%-90% A; 15-20 min, 90%-83% A; 20-45 min, 83%-72% A; 45-48 min, 72%-40% A; The program variable wavelength condition of scanning is: 0-18 min, 280 nm; 19-48 min, 326 nm.
2. 8 kinds of active constituent content measuring methods in a kind of DANHONG ZHUSHEYE according to claim 1, it is characterized in that: in described step (1), fingerprint spectrum method is applied to 19 common characteristic peaks in the qualitative similarity mensuration of DANHONG ZHUSHEYE finished product, its peak area sum accounts for total peak area more than 90%, and wherein No. 2 peak Sodium Danshensus are with reference to peak.
3. 8 kinds of active constituent content measuring methods in a kind of DANHONG ZHUSHEYE according to claim 1, is characterized in that: the described Qualitative fingerprint similarity calculating of step (3) employing included angle cosine S
f, the qualitative similarity of ratio and related coefficient comprehensive evaluation, calculate
p, Mvalue obtains quantitative similarity.
4. 8 kinds of active constituent content measuring methods in a kind of DANHONG ZHUSHEYE according to claim 3, is characterized in that: described quantitative similarity
pthe computing formula of value is
, wherein
s f for the included angle cosine value,
rratio for the total fingerprint peaks total mark area of the total fingerprint peaks total mark area of sample finger-print and reference fingerprint; Quantitatively the computing formula of similarity M value is
, wherein n is total peak number amount,
for in sample and reference fingerprint
iratio between the integration face area of individual characteristic peak.
5. 8 kinds of active constituent content measuring methods in a kind of DANHONG ZHUSHEYE according to claim 3 is characterized in that: described fingerprint similarity calculates and adopts Matlab7.11.0 to carry out the data processing.
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Address after: 310027 Hangzhou, Zhejiang Province, Xihu District, Zhejiang Road, No. 38, No. Patentee after: Zhejiang University Patentee after: SHANDONG DANHONG PHARMACEUTICAL CO., LTD. Address before: 310027 Hangzhou, Zhejiang Province, Xihu District, Zhejiang Road, No. 38, No. Patentee before: Zhejiang University Patentee before: Heze Buchang Pharmaceutical Co.,Ltd. |