CN110398555A - A kind of detection method of the capecitabine in relation to substance - Google Patents
A kind of detection method of the capecitabine in relation to substance Download PDFInfo
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- CN110398555A CN110398555A CN201810374775.3A CN201810374775A CN110398555A CN 110398555 A CN110398555 A CN 110398555A CN 201810374775 A CN201810374775 A CN 201810374775A CN 110398555 A CN110398555 A CN 110398555A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
Abstract
The present invention discloses a kind of detection method of the capecitabine in relation to substance: this method is detected using high performance liquid chromatography, include the following steps: step 1, configuration capecitabine sample solution, the capecitabine sample solution includes capecitabine test liquid and capecitabine comparison liquid；The resulting sample solution of step 1 is injected high performance liquid chromatograph by step 2, carries out gradient elution as mobile phase using mobile phase A and Mobile phase B, and record chromatogram.The detection method uses pentafluorophenyl group bonded silica gel chromatographic column.The detection method is easy to operate, capecitabine main peak retention time is suitable, it overcomes the deficiencies of existing technologies, impurity D and impurity E are efficiently separated, other known impurities can be detected effectively, and separating degree is high, and measuring method specificity is strong, testing result is accurately credible, provides a kind of reasonable detection method of simplicity for quality control, the impurity research of capecitabine.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, and in particular to separation of the antineoplastic medicine capecitabine in relation to substance, especially
It is related to a kind of detection method of the capecitabine in relation to substance.
Background technique
Capecitabine (Capecitabine) is a kind of fluoropyrimidine deoxyribonucleoside ammonia developed by Roche Holding Ag, Switzerland
Carbamate series antineoplastic medicament is listed through U.S.'s food and the approval of Drug Safety Management office in the U.S., for treating for 1998
Metastatic colorectal cancer treats metastatic breast cancer with docetaxel drug combination.The medicine 2001 is in Discussion on Chinese Listed, and 2008
Year August, Chinese food Drug Administration ratify its treatment for advanced gastric carcinoma.Capecitabine is more at home and abroad
A country is widely used, for treating above-mentioned several cancers.Capecitabine chemical name are as follows: 5'- deoxidation -5- fluoro- N- [(penta oxygen
Base) carbonyl] cytidine, chemical structure is as follows:
。
It is as follows currently used for the capecitabine synthetic route of productionization:
。
Such as the synthetic method of above-mentioned report, following impurity can be generated during preparing capecitabine:
Impurity A: 5 '-deoxidation -5- fluorine cytidines
Impurity B: 5 '-'-Deoxy-5-fluorouridines
The fluoro- N4-(pentyloxy carbonyl of impurity C:2 ', 3 '-oxygen-carbonyl -5 '-deoxidation -5-) cytidine
Impurity the D:5 '-fluoro- N4- of deoxidation-5- (2- methyl-1-tertbutyloxycarbonyl) cytidine
Impurity E: 5’The fluoro- N4- of deoxidation-5- (3- methyl-1-tertbutyloxycarbonyl) cytidine
Impurity F: 2 ', 3 '-two oxy-acetyls -5 '-deoxidation -5- fluorine cytidine
Impurity G:[1- [5- deoxidation -3-O-(5- deoxidation-β-d- ribose)-β-d- ribose] fluoro- 2- oxo -1,2- dihydro of -5- is phonetic
Pyridine]-amyl carbamate
Impurity H:[1- [5- deoxidation -2-O-(5- deoxidation-β-d- ribose)-β-d- ribose] fluoro- 2- oxo -1,2- dihydro of -5- is phonetic
Pyridine]-amyl carbamate
Impurity I:[1- [5- deoxidation -3-O-(5- deoxidation-α-d- ribose)-β-d- ribose] fluoro- 2- oxo -1,2- dihydro of -5- is phonetic
Pyridine]-amyl carbamate
United States Pharmacopeia, European Pharmacopoeia, domestic literature (Chinese Journal of New Drugs, 2015,24(16) at present, 1902-1910；Straits medicine
Learn 2013,25(1), 48-50) have and has detection method in relation to the detection proposition of substance to capecitabine, but for above-mentioned
Impurity D and impurity E in impurity not can be carried out and efficiently separate, the two impurity are difficult to effectively examine in the actual amount of bulk pharmaceutical chemicals
Out.
The presence of impurity is directly related to the quality and safety of drug, and separation is carried out to it and identifies the matter final to product
Amount control has great significance, therefore those skilled in the art are dedicated to developing a kind of effective related substance detecting method,
Make the related substance of capecitabine especially impurity D and impurity E is available efficiently separates.
Summary of the invention
In view of the above drawbacks of the prior art, the technical problems to be solved by the present invention are: providing a kind of effective inspection
Survey method, can efficiently separate impurity D, impurity E and other in relation to substance.
To achieve the above object, the present invention provides a kind of detection method of the capecitabine in relation to substance, wherein the card is trained
The related substance in his shore includes: 5 '-deoxidation -5- fluorine cytidines (impurity A), 5 '-'-Deoxy-5-fluorouridines (impurity B), 2 ', 3 '-oxygen-carbonyl
The fluoro- N4-(pentyloxy carbonyl of base -5 '-deoxidation -5-) cytidine (impurity C), the 5 '-fluoro- N4- of deoxidation -5- (2- methyl-1s-tertiary butyloxycarbonyl
Base) cytidine (impurity D), the 5 '-fluoro- N4- of deoxidation-5- (3- methyl-1-tertbutyloxycarbonyl) cytidine (impurity E), 2 ', 3 '-dioxies-second
Acyl group -5 '-deoxidation -5- fluorine cytidine (impurity F), [1- [5- deoxidation -3-O-(5- deoxidation-β-d- ribose)-β-d- ribose] -5- are fluoro-
2- oxo -1,2- dihydro-pyrimidin]-amyl carbamate (impurity G), [1- [5- deoxidation -2-O-(5- deoxidation-β-d- ribose)-β -
D- ribose] the fluoro- 2- oxo -1,2- dihydro-pyrimidin of -5-]-amyl carbamate (impurity H), [1- [5- deoxidation -3-O-(5- deoxidation -
α-d- ribose)-β-d- ribose] the fluoro- 2- oxo -1,2- dihydro-pyrimidin of -5-] one of-amyl carbamate (impurity I) or more
Kind, this method is carried out using high performance liquid chromatography, is included the following steps:
Step 1, configuration capecitabine sample solution, the capecitabine sample solution include capecitabine test solution and
Capecitabine reference substance solution；
The resulting sample solution of step 1 is injected high performance liquid chromatograph by step 2, using mobile phase A and Mobile phase B as stream
It is dynamic mutually to carry out gradient elution, and record chromatogram；
Wherein it is appropriate to include the following steps: that precision weighs capecitabine for the preparation method of the test solution, molten with dilution
It solves and is diluted to sample of every 1mL containing 0.3mg, as test solution；
The preparation method of the reference substance solution includes the following steps: separately to take capecitabine reference substance appropriate, molten with dilution
It solves and is diluted to solution of every 1mL containing 0.15 μ g as reference substance solution；
The chromatographic column fixed phase filler of the high performance liquid chromatography is pentafluorophenyl group hybridisation silica gel；
Wherein the eluting order of the high performance liquid chromatography is as follows:
Mobile phase when 0min are as follows: 90 ~ 100% mobile phase As and 10 ~ 0% Mobile phase B；
Mobile phase when 5min are as follows: 90 ~ 100% mobile phase As and 10 ~ 0% Mobile phase B；
Mobile phase when 60min are as follows: 50 ~ 55% mobile phase As and 50 ~ 45% Mobile phase B；
Mobile phase when 61min are as follows: 90 ~ 100% mobile phase As and 10 ~ 0% Mobile phase B；
Preferably, the gradient elution sequence of the high performance liquid chromatography is as follows:
Mobile phase when 0min are as follows: 98% mobile phase A and 2% Mobile phase B；
Mobile phase when 5min are as follows: 98% mobile phase A and 2% Mobile phase B；
Mobile phase when 60min are as follows: 52% mobile phase A and 48% Mobile phase B；
Mobile phase when 61min are as follows: 98% mobile phase A and 2% Mobile phase B；
The mobile phase A is methanol: acetonitrile: 0.1% acid solution 4:1:15；The Mobile phase B is methanol: acetonitrile: 0.1% acid solution
18:1:1.
Further, the chromatographic column of the high performance liquid chromatography is preferably Boltimate EXT-PFP, and 2.7 μm 4.6
×250mm。
Further, the acid of the acid solution is perchloric acid, acetic acid or trifluoroacetic acid.
Further, the chromatogram column temperature of the high performance liquid chromatography is 35 ~ 45 DEG C, preferably 40 DEG C.
Further, the Detection wavelength of the high performance liquid chromatography is 220 ~ 280nm, preferably 250nm.
Further, the flow velocity of the high performance liquid chromatography is 0.5 ~ 1.5mL/min.
Further, the capecitabine sample solution further includes impurity sample-adding solution；The preparation of the impurity solubilization liquid
Method includes the following steps: to take 5 '-deoxidation -5- fluorine cytidines (impurity A), 5 '-'-Deoxy-5-fluorouridines (impurity B), 2 ', 3 '-respectively
The fluoro- N4-(pentyloxy carbonyl of oxygen-carbonyl -5 '-deoxidation -5-) cytidine (impurity C), the 5 '-fluoro- N4- of deoxidation -5- (2- methyl-1s-uncle
Butoxy carbonyl) cytidine (impurity D), the 5 '-fluoro- N4- of deoxidation-5- (3- methyl-1-tertbutyloxycarbonyl) cytidine (impurity E), 2 ', 3 '-
Two oxy-acetyls -5 '-deoxidation -5- fluorine cytidine (impurity F), [1- [5- deoxidation -3-O-(5- deoxidation-β-d- ribose)-β-d- core
Sugar] the fluoro- 2- oxo -1,2- dihydro-pyrimidin of -5-]-amyl carbamate (impurity G), [1- [5- deoxidation -2-O-(5- deoxidation-β-d-
Ribose)-β-d- ribose] the fluoro- 2- oxo -1,2- dihydro-pyrimidin of -5-]-amyl carbamate (impurity H), [1- [5- deoxidation -3-O-
(5- deoxidation-α-d- ribose)-β-d- ribose] the fluoro- 2- oxo -1,2- dihydro-pyrimidin of -5-] control of-amyl carbamate (impurity I)
Product, it is accurately weighed, 0.10 ~ 0.30 μ g/mL is dissolved and be diluted to dilution respectively, obtains each impurity reference substance solution；It takes suitable
The capecitabine comparison liquid and impurity comparison liquid of amount mix, and obtain impurity sample-adding solution.
Further, the dilution is methanol: acetonitrile: water 4:1:15.
Further, the step 2 specifically includes following sub-step:
Step 2.1, by the impurity sample-adding solution injection liquid chromatograph in, record chromatogram, confirm separating degree, impurity A with
For the separating degree of impurity B not less than 1.5, the separating degree of impurity E and capecitabine is not less than 2.0；
In step 2.2, the accurate measurement reference substance solution and test solution injection liquid chromatograph, chromatography is recorded
Figure, the calculated by peak area impurity content after being corrected by principal component external standard method.
Detection method of the invention measures the related substance of capecitabine, the detection method operation under same liquid-phase condition
Simplicity, capecitabine main peak retention time is more appropriate, overcomes the deficiencies of existing technologies, and impurity D and impurity E is carried out effective
Separation, other known impurities can be detected effectively, and separating degree is high, and measuring method specificity is strong, and testing result is accurately credible,
A kind of reasonable detection method of simplicity is provided for quality control, the impurity research of capecitabine.The method of the present invention is suitable for card
Train measurement and sample survey in relation to substance in his shore bulk pharmaceutical chemicals and preparation.
Detailed description of the invention
Fig. 1 is that the impurity of a preferred embodiment of the invention is loaded solution sample introduction map.
Specific embodiment
The preferred embodiment of the present invention is introduced below with reference to Figure of description, keeps its technology contents more clear and convenient for reason
Solution.The present invention can be emerged from by many various forms of embodiments, and protection scope of the present invention is not limited only to text
In the embodiment mentioned.
Embodiment 1
1, testing conditions
It is measured according to high performance liquid chromatography (Chinese Pharmacopoeia version general rule 0512 in 2015), using Boltimate EXT-PFP,
2.7 μm of 4.6 × 250mm are chromatographic column, with -0.1% trifluoroacetic acid solution of methanol-acetonitrile (4:1:15) for mobile phase A；Methanol-
- 0.1% trifluoroacetic acid solution of acetonitrile (18:1:1) is Mobile phase B, by as follows:
Gradient elution is carried out, flow velocity is 1.0mL per minute, and column temperature is 40 DEG C, Detection wavelength 250nm.
2, sample solution is prepared
It takes capecitabine appropriate, dissolved with diluent (methanol: acetonitrile: water 4:1:15) and dilutes sample of every 1ml containing 0.3mg is made
Product, as test solution.
Separately take capecitabine reference substance appropriate, dissolved with diluent and dilute be made every 1mL contain 0.15 μ g solution, as
Reference substance solution.
5 '-deoxidation -5- fluorine cytidines (impurity A), 5 '-'-Deoxy-5-fluorouridines (impurity B), 2 ', 3 '-oxygen-carbonyl-are taken respectively
The fluoro- N4-(pentyloxy carbonyl of 5 '-deoxidation -5-) cytidine (impurity C), the 5 '-fluoro- N4- of deoxidation -5- (2- methyl-1s-tertiary butyloxycarbonyl
Base) cytidine (impurity D), the 5 '-fluoro- N4- of deoxidation-5- (3- methyl-1-tertbutyloxycarbonyl) cytidine (impurity E), 2 ', 3 '-dioxies-second
Acyl group -5 '-deoxidation -5- fluorine cytidine (impurity F), [1- [5- deoxidation -3-O-(5- deoxidation-β-d- ribose)-β-d- ribose] -5- are fluoro-
2- oxo -1,2- dihydro-pyrimidin]-amyl carbamate (impurity G), [1- [5- deoxidation -2-O-(5- deoxidation-β-d- ribose)-β -
D- ribose] the fluoro- 2- oxo -1,2- dihydro-pyrimidin of -5-]-amyl carbamate (impurity H), [[5- deoxidation -3-O-(5- is de- by 1-
Oxygen-α-d- ribose)-β-d- ribose] fluoro- 2- oxo -1, the 2- dihydro-pyrimidin of -5-]-amyl carbamate (impurity I) reference substance, essence
It is close weighed, 0.10 ~ 0.30 μ g/mL is dissolved and be diluted to dilution respectively, obtains each impurity reference substance solution；Take suitable card
His shore comparison liquid and the mixing of impurity comparison liquid are trained, impurity sample-adding solution is obtained.
3, measuring method
Impurity sample-adding 20 μ L of solution injection liquid chromatograph is taken, and records chromatogram, confirms separating degree, point of impurity A and impurity B
From degree not less than 1.5, the separating degree of impurity E and capecitabine is not less than 2.0.As shown in Fig. 1, it is respectively by the sequence of appearance
Impurity A, impurity B, impurity F, impurity D, impurity E, capecitabine, impurity C, impurity G, impurity H, impurity I.It is accurate again to measure control
Product solution and each 20 μ L of test solution are injected separately into liquid chromatograph, record chromatogram, by main composition external standard method to correct after
Calculated by peak area impurity content, impurity A and impurity B must not cross 0.3%, and impurity D and impurity E must not cross 0.1%, known to remaining
Impurity must not cross 0.05%, and unknown single impurity must not cross 0.05%, and total impurities must not cross 0.5%.
The preferred embodiment of the present invention has been described in detail above.It should be appreciated that the ordinary skill of this field is without wound
The property made labour, which according to the present invention can conceive, makes many modifications and variations.Therefore, all technician in the art
Pass through the available technology of logical analysis, reasoning, or a limited experiment on the basis of existing technology under this invention's idea
Scheme, all should be within the scope of protection determined by the claims.
Claims (10)
1. a kind of detection method of capecitabine in relation to substance, which is characterized in that the related substance of the capecitabine includes 5 '-de-
Oxygen -5- fluorine cytidine (impurity A), 5 '-'-Deoxy-5-fluorouridines (impurity B), the fluoro- N4-(penta of 2 ', 3 '-oxygen-carbonyl -5 '-deoxidation -5-
Epoxide carbonyl) it is cytidine (impurity C), the 5 '-fluoro- N4- of deoxidation-5- (2- methyl-1-tertbutyloxycarbonyl) cytidine (impurity D), 5 '-de-
The fluoro- N4- of oxygen-5- (3- methyl-1-tertbutyloxycarbonyl) cytidine (impurity E), 2 ', 3 '-two oxy-acetyls-5 '-deoxidation-5- fluorine born of the same parents
Glycosides (impurity F), [1- [5- deoxidation -3-O-(5- deoxidation-β-d- ribose)-β-d- ribose] fluoro- 2- oxo -1,2- dihydro of -5- are phonetic
Pyridine]-amyl carbamate (impurity G), [1- [5- deoxidation -2-O-(5- deoxidation-β-d- ribose)-β-d- ribose] the fluoro- 2- oxygen of -5-
Generation -1,2- dihydro-pyrimidin]-amyl carbamate (impurity H), [1- [5- deoxidation -3-O-(5- deoxidation-α-d- ribose)-β-d- core
Sugar] fluoro- 2- oxo -1, the 2- dihydro-pyrimidin of -5-] one of-amyl carbamate (impurity I) or a variety of, the detection party
Method is carried out using high performance liquid chromatography, comprising the following steps:
Step 1, configuration capecitabine sample solution, the capecitabine sample solution include capecitabine test solution and
Capecitabine reference substance solution；
The resulting sample solution of step 1 is injected high performance liquid chromatograph by step 2, using mobile phase A and Mobile phase B as stream
It is dynamic mutually to carry out gradient elution, and record chromatogram；
Wherein it is appropriate to include the following steps: that precision weighs capecitabine for the preparation method of the test solution, molten with dilution
It solves and is diluted to sample of every 1mL containing 0.3mg, as test solution；
The preparation method of the reference substance solution includes the following steps: separately to take capecitabine reference substance appropriate, molten with dilution
It solves and is diluted to solution of every 1mL containing 0.15ug as reference substance solution；
The chromatographic column fixed phase filler of the high performance liquid chromatography is pentafluorophenyl group hybridisation silica gel；
Wherein the eluting order of the high performance liquid chromatography is as follows:
Mobile phase when 0min are as follows: 90 ~ 100% mobile phase As and 10 ~ 0% Mobile phase B；
Mobile phase when 5min are as follows: 90 ~ 100% mobile phase As and 10 ~ 0% Mobile phase B；
Mobile phase when 60min are as follows: 50 ~ 55% mobile phase As and 50 ~ 45% Mobile phase B；
Mobile phase when 61min are as follows: 90 ~ 100% mobile phase As and 10 ~ 0% Mobile phase B；
The mobile phase A is methanol: acetonitrile: 0.1% acid solution 4:1:15；The Mobile phase B is methanol: acetonitrile: 0.1% acid solution
18:1:1.
2. detection method as described in claim 1, which is characterized in that the chromatographic column of the high performance liquid chromatography is
Boltimate EXT-PFP, 2.7 μm of 4.6 × 250mm.
3. detection method as described in claim 1, which is characterized in that the gradient elution sequence of the high performance liquid chromatography is such as
Under:
Mobile phase when 0min are as follows: 98% mobile phase A and 2% Mobile phase B；
Mobile phase when 5min are as follows: 98% mobile phase A and 2% Mobile phase B；
Mobile phase when 60min are as follows: 52% mobile phase A and 48% Mobile phase B；
Mobile phase when 61min are as follows: 98% mobile phase A and 2% Mobile phase B.
4. the detection method as described in claim 1, which is characterized in that the acid of the acid solution is perchloric acid, acetic acid or trifluoro
Acetic acid.
5. detection method as described in claim 1, which is characterized in that the Detection wavelength of the high performance liquid chromatography be 220 ~
280nm。
6. detection method as described in claim 1, which is characterized in that the chromatographic column column temperature of the high performance liquid chromatography is
35~45℃。
7. detection method as described in claim 1, which is characterized in that the flow velocity of the high performance liquid chromatography be 0.5 ~
1.5mL/min 。
8. the detection method as described in claim 1, which is characterized in that the capecitabine sample solution further includes that impurity adds
Sample solution；
The preparation method of the impurity sample-adding solution includes the following steps: to take 5 '-deoxidation -5- fluorine cytidines (impurity A), 5 '-respectively
The fluoro- N4-(pentyloxy carbonyl of '-Deoxy-5-fluorouridine (impurity B), 2 ', 3 '-oxygen-carbonyl -5 '-deoxidation -5-) cytidine (impurity C),
The 5 '-fluoro- N4- of deoxidation-5- (2- methyl-1-tertbutyloxycarbonyl) cytidine (impurity D), the 5 '-fluoro- N4- of deoxidation-5- (3- methyl-1s-uncle
Butoxy carbonyl) cytidine (impurity E), 2 ', 3 '-two oxy-acetyls -5 '-deoxidation -5- fluorine cytidine (impurity H), [1- [5- deoxidation -3-
O-(5- deoxidation-β-d- ribose)-β-d- ribose] the fluoro- 2- oxo -1,2- dihydro-pyrimidin of -5-]-amyl carbamate (impurity G),
[1- [5- deoxidation -2-O-(5- deoxidation-β-d- ribose)-β-d- ribose] the fluoro- 2- oxo -1,2- dihydro-pyrimidin of -5-]-carbamic acid
Pentyl ester (impurity H), [1- [5- deoxidation -3-O-(5- deoxidation-α-d- ribose)-β-d- ribose] the fluoro- 2- oxo -1,2- dihydro of -5-
Pyrimidine]-amyl carbamate (impurity I) reference substance, it is accurately weighed, it is dissolved respectively with dilution and is diluted to 0.10 ~ 0.30 μ g/
ML obtains each impurity reference substance solution；It takes suitable capecitabine comparison liquid and impurity comparison liquid to mix, it is molten to obtain impurity sample-adding
Liquid.
9. detection method as claimed in claim 8, which is characterized in that the dilution is methanol: acetonitrile: water 4:1:15.
10. detection method as claimed in claim 8, which is characterized in that the step 2 specifically includes following sub-step:
Step 2.1, by the impurity sample-adding solution injection liquid chromatograph in, record chromatogram, confirm separating degree, impurity A with
For the separating degree of impurity B not less than 1.5, the separating degree of impurity E and capecitabine is not less than 2.0；
In step 2.2, the accurate measurement reference substance solution and test solution injection liquid chromatograph, chromatography is recorded
Figure, the calculated by peak area impurity content after being corrected by principal component external standard method.
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| CN111521714A (en) * | 2020-06-08 | 2020-08-11 | 重庆三圣实业股份有限公司 | Method for separating and measuring capecitabine and impurities thereof |
| CN113009014A (en) * | 2021-02-24 | 2021-06-22 | 上海旭东海普药业有限公司 | High performance liquid detection method for 2-methoxy-5-fluorouracil impurity |
| CN114034805A (en) * | 2021-11-12 | 2022-02-11 | 大连润生康泰医学检验实验室有限公司 | Metabolic kinetic analysis method of pentafluorouracil drugs |
| CN114236008A (en) * | 2021-12-17 | 2022-03-25 | 山东铂源药业有限公司 | Method for detecting contents of D-ribose and 5-deoxy-D-ribofuranose in capecitabine intermediate |
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| CN113009014A (en) * | 2021-02-24 | 2021-06-22 | 上海旭东海普药业有限公司 | High performance liquid detection method for 2-methoxy-5-fluorouracil impurity |
| CN113009014B (en) * | 2021-02-24 | 2023-04-07 | 上海旭东海普药业有限公司 | High performance liquid detection method for 2-methoxy-5-fluorouracil impurities |
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| CN114236008B (en) * | 2021-12-17 | 2023-11-28 | 山东铂源药业股份有限公司 | Method for detecting content of D-ribose and 5-deoxy-D-ribofuranose in capecitabine intermediate |
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