CN109030653A - Detection method in relation to substance in a kind of l-leucovorin - Google Patents
Detection method in relation to substance in a kind of l-leucovorin Download PDFInfo
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The present invention relates to the detection methods in relation to substance in a kind of l-leucovorin, belong to chemicals detection method technical field.Detection method provided by the invention includes using high performance liquid chromatography, and chromatographic condition includes: chromatographic column using octadecylsilane chemically bonded silica；Mobile phase A is used mutually to carry out gradient elution with Mobile phase B for mixed flow；The mobile phase A uses the disodium hydrogen phosphate buffer comprising tetrabutylammonium hydroxide；The Mobile phase B uses methanol；The solvent of sample dissolution uses the mixed solvent comprising mobile phase A, Mobile phase B and dimethyl sulfoxide.The impurity that the present invention detects is more, and can efficiently separate, and can quickly, effectively, accurately monitor the related substance in l-leucovorin.High-specificity of the present invention, high sensitivity, the rate of recovery is high, carries out quantitative detection to impurity by using the mode that external standard method and Self-control method combine, and can increase the accuracy of the related substance detection of the present invention.
Description
Technical field
The invention belongs to chemicals detection method technical fields, and in particular to the inspection in relation to substance in a kind of l-leucovorin
Survey method.
Background technique
L-leucovorin (Levofolinic Acid), entitled (-)-N- of chemistry [4 [[[formoxyl -1 (6S) -2- amino -5-,
4,5,6,7,8- hexahydro -4- oxo -6- pteridyls] methyl] amino] benzoyl]-Pidolidone, molecular formula C20H23N7O7,
Molecular weight is 473.44, and No. CAS is 68538-85-2, and structural formula is as follows:
Adjuvant drug of the levo leucovorin as antitumor antidote and anti-megaloblastic anemia, dosage is folinic acid
1/2, levo leucovorin do not need by dihyrofolate reductase restore can participate in using folate as one carbon unit source
Reaction, and levo leucovorin can actively or passively pass through cell membrane；Levo leucovorin basic role is identical with folic acid, but
Effect is better than folic acid, while levo leucovorin also has the function of stimulating Leukocyte Growth mature, and it is poor to improve megaloblastic
Blood.
The product with the listing of its main component domestic at present has Sodium folinate injection, Calcium Folinate for injection and folinic acid
Calcium injection, the lercovorin calcium injection and Calcium Levofolinate injection that the product of foreign countries' listing has Wyeth of the U.S. to list,
German MEDAC lists a company sodium folinate injection and l-leucovorin sodium injection.
In order to guarantee the safe and effective of drug, need that the related substance in drug is studied, detected and monitored.It is related
Substance is mainly process byproducts and catabolite, and in placement process, impurity spectrum is changing drug, it is therefore desirable to according to
Different synthetic route and production technology, holding conditions establish suitable detection method, reach quasi- to the related substance of l-leucovorin
Really, it effectively detects and monitors.
Summary of the invention
The purpose of the present invention is on the basis of existing technology, provide the detection side in relation to substance in a kind of l-leucovorin
Method.
Technical scheme is as follows:
Detection method in relation to substance in a kind of l-leucovorin, the detection method include using high performance liquid chromatography,
Chromatographic condition includes: chromatographic column using octadecylsilane chemically bonded silica；Use mobile phase A and Mobile phase B for mixed flow phase
Carry out gradient elution；The mobile phase A uses the disodium hydrogen phosphate buffer comprising tetrabutylammonium hydroxide；The Mobile phase B
Using methanol；The solvent of sample dissolution uses the mixed solvent comprising mobile phase A, Mobile phase B and dimethyl sulfoxide.
Gradient elution of the invention the following steps are included: (1) in 0-20 minutes, with the volume of mobile phase A and Mobile phase B
Than carrying out isocratic elution for 86~80:14~20；(2) in 20-35 minutes, the volume ratio of mobile phase A and Mobile phase B from 86~
80:14~20 at the uniform velocity gradual change is to 70:30；(3) in 35-45 minutes, the volume ratio of mobile phase A and Mobile phase B keeps 70:30 not
Become.
The present invention using the mixed solvent comprising mobile phase A, Mobile phase B and dimethyl sulfoxide come sample dissolution, at other
Under part cooperation, the impurity detected is more, can related substance quick, effectively, in accurate monitoring l-leucovorin.The present invention is preferably mixed
The volume ratio of mobile phase A, Mobile phase B and dimethyl sulfoxide is 86~80:14~20:100 in bonding solvent, in embodiment specific stream
The volume ratio of dynamic phase A, Mobile phase B and dimethyl sulfoxide are 86:14:100.
The preparation of mobile phase A mentioned in the present invention can comprise the following steps that by concentration be 5-15% tetrabutylammonium hydroxide
Ammonium salt solution, disodium hydrogen phosphate and water are configured to solution, then with phosphorus acid for adjusting pH value to 7.6-7.9 to get.
In a preferred embodiment, the preparation of mobile phase A mentioned in the present invention is the following steps are included: be 10% by concentration
Tetrabutylammonium hydroxide solution 8.0ml, disodium hydrogen phosphate 2.2g and water prepare 780ml solution, then extremely with phosphorus acid for adjusting pH value
7.8 to get.
The condition for the high performance liquid chromatography that the present invention mentions further include: the length of chromatographic column is 250mm, and diameter is
4.6mm, packing material size are 5 μm；Preferably, the Detection wavelength of detector is 280nm.
The sample volume of detection method provided by the invention is 5-50 μ l.
Detection method in relation to substance in a kind of l-leucovorin provided by the invention, wherein related substance includes following object
Matter:
The specific steps of detection method provided by the invention are as follows: prepare impurity respectively and principal component positions solution, test sample
Solution and sample introduction, calculate the content of impurity.
Wherein, impurity and l-leucovorin position solution are as follows: and take impurity 1,2,3,4,6,7,8 and l-leucovorin sample appropriate,
It is dissolved and is diluted with solvent (mobile phase A-Mobile phase B-dimethyl sulfoxide=86:14:100) and be made in every 1ml containing about each 4 μ g of impurity
With the solution of l-leucovorin 0.5mg, solution is positioned as impurity and l-leucovorin.
Test solution are as follows: take l-leucovorin test sample about 25mg, after accurately weighed, set in 50ml measuring bottle, solubilizer (stream
Dynamic phase A- Mobile phase B-dimethyl sulfoxide=86:14:100) simultaneously constant volume is dissolved, it shakes up, as test solution.
The present invention passes through screening proper flow phase and optimizes each component ratio in mobile phase, and screens its suitable allochromatic colour
Spectral condition carries out chromatography detection to l-leucovorin and 7 impurity, it is determined that detection method, by each miscellaneous
The Degrading experiment of the peak location test of matter and l-leucovorin, interference test and l-leucovorin carries out specificity to the present invention and tests
Card.
Using technical solution of the present invention, advantage is as follows:
In relation to the detection method of substance in l-leucovorin provided by the invention, each research impurity can be efficiently separated, examined
The impurity measured is more, can quickly, effectively, accurately monitor the related substance in l-leucovorin.
Detailed description of the invention
Fig. 1 is impurity 1,2,3,4,6,7,8 and l-leucovorin positioning high-efficient liquid phase chromatogram；
Fig. 2 is the related substance high-efficient liquid phase chromatogram of l-leucovorin of embodiment 1；
Fig. 3 is the related substance high-efficient liquid phase chromatogram of l-leucovorin of embodiment 2；
Fig. 4 is the related substance high-efficient liquid phase chromatogram of l-leucovorin of comparative example 1；
Fig. 5 is the related substance high-efficient liquid phase chromatogram of l-leucovorin of comparative example 2；
Fig. 6 is the related substance high-efficient liquid phase chromatogram of l-leucovorin of comparative example 3.
Specific embodiment
Detection method of the invention is further described by following embodiment and in conjunction with attached drawing, but these embodiments
It does not form any restrictions to the present invention.
Embodiment 1
High-efficient liquid phase chromatogram condition:
Chromatographic column is octadecylsilane chemically bonded silica chromatographic column (4.6 × 250mm, 5 μm), to contain tetrabutylammonium hydroxide
Disodium hydrogen phosphate buffer (take 10% tetrabutylammonium hydroxide solution 8.0ml and disodium hydrogen phosphate 2.2g, being dissolved in water makes into
780ml, and using methanol as Mobile phase B, gradient elution is carried out, Detection wavelength is to being 7.8) mobile phase A with phosphorus acid for adjusting pH value
280nm。
Gradient elution process are as follows: in 0-20 minutes, the volume ratio of mobile phase A and Mobile phase B is from 86:14 isocratic elution；20-
In 35 minutes, the volume ratio of mobile phase A and Mobile phase B is from 86:14 at the uniform velocity gradual change to 70:30；In 35-45 minutes, mobile phase A and
The volume ratio of Mobile phase B keeps 70:30 constant.
Sample preparation:
Take l-leucovorin test sample appropriate, solubilizer (mobile phase A-Mobile phase B-dimethyl sulfoxide=86:14:100) makes molten
Solution is made containing about the solution of 0.5mg l-leucovorin in every 1ml, as test solution.
Test operation: taking 20 μ l sample introduction of test solution, records chromatogram.
Typical chromatogram is shown in Fig. 2.
L-leucovorin is taken to prepare test solution, sample introduction simultaneously records map, calculates impurity 4 by impurity reference substance external standard method
Content is calculated the content of other impurities in test sample with principal component Self-control method, the results are shown in Table 1 and Fig. 2.
The assay result of each impurity in 1 l-leucovorin of table
Impurity 2,5 is not detected in l-leucovorin test sample it can be seen from table 1 and Fig. 2, largest single impurity 0.44%,
Always miscellaneous is 0.65%.
The present invention passes through screening proper flow phase and optimizes each component ratio in mobile phase, and the suitable solvent of screening,
Chromatography detection is carried out to l-leucovorin and 7 impurity, it is determined that the detection method of the embodiment of the present invention 1.
By the peak location test to each impurity and l-leucovorin, the Degrading experiment of interference test and l-leucovorin is to this
Invention carries out specificity verifying.
The preparation of impurity and l-leucovorin positioning solution: it takes impurity 1,2,3,4,6,7,8 and l-leucovorin sample appropriate, uses
Solvent (mobile phase A-Mobile phase B-dimethyl sulfoxide=86:14:100) dissolve and dilute be made in every 1ml containing about each 4 μ g of impurity and
The solution of l-leucovorin 0.5mg positions solution as impurity and l-leucovorin.
It takes impurity and l-leucovorin to position solution, is detected by the high-efficient liquid phase chromatogram condition and method of this example, as a result
It is shown in Table 1 and Fig. 1.
2 specificity verification result of table
Separation between each impurity peaks it can be seen from table 2 and Fig. 1, between l-leucovorin main peak and its other impurities peak
Degree is all larger than 1.5, and peak purity is preferable, and specificity of the invention is good.
The detection limit of 3 l-leucovorin of table and each impurity, quantitative limit, linear test result
As can be seen from Table 3, l-leucovorin of the present invention and each defects inspecting sensitivity are higher, detection limit and quantitative limit
It is smaller, and each impurity linear relationship within the scope of low concentration is good.
The present inventor prepares test solution, 0H, 1H, 2H and 4H sample detection after preparation, impurity 3,4,6,
7,8 have detection, and at room temperature, in 1H, 6 peak area of impurity significantly increases l-leucovorin sample, and 8 peak area of impurity reduces,
Illustrate that sample solution is unstable, need to face with now matching.
The rate of recovery verification result of each impurity of table 4
| Test | Rate of recovery 90-108% | Rate of recovery RSD≤5.0% |
| Impurity 1 | 94.3-102.1% | 3.08 |
| Impurity 2 | 101.1-103.6% | 0.80 |
| Impurity 3 | 98.7-103.6% | 1.29 |
| Impurity 4 | 95.7-103.7% | 2.24 |
| Impurity 6 | 97.2-105.9% | 3.07 |
| Impurity 7 | 94.6-103.8% | 3.37 |
As can be seen from Table 4, recovery test result of the invention meets the requirements, and the rate of recovery of the present invention is high.
Embodiment 2
High-efficient liquid phase chromatogram condition:
Chromatographic column is octadecylsilane chemically bonded silica chromatographic column (4.6 × 250mm, 5 μm), to contain tetrabutylammonium hydroxide
Disodium hydrogen phosphate buffer (take 10% tetrabutylammonium hydroxide solution 8.0ml and disodium hydrogen phosphate 2.2g, being dissolved in water makes into
780ml, and using methanol as Mobile phase B, gradient elution is carried out, Detection wavelength is to being 7.8) mobile phase A with phosphorus acid for adjusting pH value
280nm。
Gradient elution process are as follows: in 0-20 minutes, the volume ratio of mobile phase A and Mobile phase B is from 84:16 isocratic elution；20-
In 35 minutes, the volume ratio of mobile phase A and Mobile phase B is from 84:16 at the uniform velocity gradual change to 70:30；In 35-45 minutes, mobile phase A and
The volume ratio of Mobile phase B keeps 70:30 constant.
Sample preparation:
Take l-leucovorin test sample appropriate, solubilizer (mobile phase A-Mobile phase B-dimethyl sulfoxide=86:14:100) makes molten
Solution is made containing about the solution of 0.5mg l-leucovorin in every 1ml, as test solution.
Test operation: taking 20 μ l sample introduction of test solution, records chromatogram.
Typical chromatogram is shown in Fig. 3.
Comparative example 1
High-efficient liquid phase chromatogram condition:
Chromatographic column is octadecylsilane chemically bonded silica chromatographic column (4.6 × 250mm, 5 μm), to contain tetrabutylammonium hydroxide
Disodium hydrogen phosphate buffer (take 10% tetrabutylammonium hydroxide solution 8.0ml and disodium hydrogen phosphate 2.2g, being dissolved in water makes into
780ml, and with phosphorus acid for adjusting pH value to 7.8): methanol (78:22) is mobile phase, and map retains to 3 times of retention times.Detect wave
A length of 280nm, column temperature: 40 DEG C, flow velocity: 1.0ml/min, sample volume: 20 μ l.
Sample preparation:
It takes l-leucovorin test sample appropriate, adds mobile phase that dissolution is made molten containing about 0.5mg l-leucovorin in every 1ml
Liquid, as test solution.
Test operation: taking 20 μ l sample introduction of mixed solution, records chromatogram.
Typical chromatogram is shown in Fig. 4.
The detection method of comparative example 1 there are the problem of: impurity 7 is not completely separated with main peak, and 3 appearance time of impurity compared with
Evening.
Comparative example 2
High-efficient liquid phase chromatogram condition:
Chromatographic column is octadecylsilane chemically bonded silica chromatographic column (4.6 × 250mm, 5 μm), to contain tetrabutylammonium hydroxide
Disodium hydrogen phosphate buffer (take 10% tetrabutylammonium hydroxide solution 8.0ml and disodium hydrogen phosphate 2.2g, being dissolved in water makes into
780ml, and using methanol as Mobile phase B, gradient elution is carried out, Detection wavelength is to being 7.8) mobile phase A with phosphorus acid for adjusting pH value
280nm。
Gradient elution process are as follows: in 0-25 minutes, the volume ratio of mobile phase A and Mobile phase B is from 80:20 isocratic elution；25-
In 35 minutes, the volume ratio of mobile phase A and Mobile phase B is from 80:20 at the uniform velocity gradual change to 70:30；In 35-45 minutes, mobile phase A and
The volume ratio of Mobile phase B keeps 70:30 constant.
Sample preparation:
Take l-leucovorin test sample appropriate, dissolution is made in every 1ml in solubilizer [mobile phase A-Mobile phase B (80:20)]
Containing about the solution of 0.5mg l-leucovorin, as test solution.
Test operation: taking 20 μ l sample introduction of test solution, records chromatogram.
Typical chromatogram is shown in Fig. 5.
The detection method of comparative example 2 there are the problem of: baseline separation, baseline drift are unable to reach between impurity.
Comparative example 3
High-efficient liquid phase chromatogram condition:
Chromatographic column is octadecylsilane chemically bonded silica chromatographic column (4.6 × 250mm, 5 μm), to contain tetrabutylammonium hydroxide
Disodium hydrogen phosphate buffer (take 10% tetrabutylammonium hydroxide solution 8.0ml and disodium hydrogen phosphate 2.2g, being dissolved in water makes into
780ml, and using methanol as Mobile phase B, gradient elution is carried out, Detection wavelength is to being 7.8) mobile phase A with phosphorus acid for adjusting pH value
280nm。
Gradient elution process are as follows: in 0-20 minutes, the volume ratio of mobile phase A and Mobile phase B is from 84:16 isocratic elution；20-
In 35 minutes, the volume ratio of mobile phase A and Mobile phase B is from 84:16 at the uniform velocity gradual change to 70:30；In 35-45 minutes, mobile phase A and
The volume ratio of Mobile phase B keeps 70:30 constant.
Sample preparation:
Take l-leucovorin test sample appropriate, dissolution is made in every 1ml in solubilizer [mobile phase A-Mobile phase B (84:16)]
Containing about the solution of 0.5mg l-leucovorin, as test solution.
Test operation: taking 20 μ l sample introduction of test solution, records chromatogram.
Typical chromatogram is shown in Fig. 6.
The detection method of comparative example 3 there are the problem of: impurity 1 and impurity 8 can reach baseline separation (R > 1.5), but miscellaneous
8 peak symmetry of matter is poor.
The impurity that the present invention detects is more, can quickly, effectively, accurately monitor the related substance in l-leucovorin；The present invention
1.5 are all larger than with the separating degree between good specificity, each impurity, between l-leucovorin and its other impurities peak, impurity
It can be efficiently separated with main peak；The lesser impurity of polarity of the present invention improves detection limit, determines by using gradient elution program
Amount limit, high sensitivity of the invention；The rate of recovery is high, can accurately measure the related substance in l-leucovorin；The present invention can be quasi-
Really accumulation data observe the conversion trend of each impurity in study on the stability.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should all cover within that scope of the present invention.
Claims (10)
1. in relation to the detection method of substance in a kind of l-leucovorin, which is characterized in that the detection method uses high performance liquid chromatography
Method, chromatographic condition include: chromatographic column using octadecylsilane chemically bonded silica；Use mobile phase A and Mobile phase B for mixed flow
It is dynamic mutually to carry out gradient elution；The mobile phase A uses the disodium hydrogen phosphate buffer comprising tetrabutylammonium hydroxide；The flowing
Phase B uses methanol；The solvent of sample dissolution uses the mixed solvent comprising mobile phase A, Mobile phase B and dimethyl sulfoxide.
2. in relation to the detection method of substance in l-leucovorin according to claim 1, which is characterized in that the gradient elution
It is that 86~80:14~20 carry out etc. with the volume ratio of mobile phase A and Mobile phase B the following steps are included: (1) in 0-20 minutes
Degree elution；(2) in 20-35 minutes, the volume ratio of mobile phase A and Mobile phase B is from 86~80:14~20 at the uniform velocity gradual change to 70:
30；(3) in 35-45 minutes, the volume ratio of mobile phase A and Mobile phase B keeps 70:30 constant.
3. in relation to the detection method of substance in l-leucovorin according to claim 1, which is characterized in that the mixed solvent
The volume ratio of middle mobile phase A, Mobile phase B and dimethyl sulfoxide is 86~80:14~20:100.
4. in relation to the detection method of substance in l-leucovorin according to claim 3, which is characterized in that the mixed solvent
The volume ratio of middle mobile phase A, Mobile phase B and dimethyl sulfoxide is 86:14:100.
5. in relation to the detection method of substance in l-leucovorin according to claim 1, which is characterized in that the mobile phase A
Preparation the following steps are included: by concentration be 5-15% tetrabutylammonium hydroxide solution, disodium hydrogen phosphate and water be configured to solution,
Again with phosphorus acid for adjusting pH value to 7.6-7.9 to get.
6. in relation to the detection method of substance in l-leucovorin according to claim 5, which is characterized in that the mobile phase A
Preparation the following steps are included: being that 10% tetrabutylammonium hydroxide solution 8.0ml, disodium hydrogen phosphate 2.2g and water are prepared by concentration
780ml solution, then with phosphorus acid for adjusting pH value to 7.8 to get.
7. in relation to the detection method of substance in l-leucovorin described according to claim 1~any one of 6, which is characterized in that
The chromatographic condition includes: that the length of the chromatographic column is 250mm, and diameter 4.6mm, packing material size is 5 μm.
8. in relation to the detection method of substance in l-leucovorin described according to claim 1~any one of 6, which is characterized in that
The chromatographic condition includes: that the Detection wavelength of the detector is 280nm.
9. in relation to the detection method of substance in l-leucovorin described according to claim 1~any one of 6, which is characterized in that
The chromatographic condition includes: that sample volume is 5-50 μ l.
10. in relation to the detection method of substance in l-leucovorin according to claim 1, which is characterized in that the related object
Matter includes following substance:
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| CN115078609A (en) * | 2022-07-13 | 2022-09-20 | 山东省药学科学院 | Method for determining dissolution curve in strong acid medium of folic acid tablets by ultra-high performance liquid chromatography |
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| CN113295787A (en) * | 2021-05-08 | 2021-08-24 | 南京海纳医药科技股份有限公司 | Detection method of related substances in levofolinic acid raw material medicine |
| CN115078609A (en) * | 2022-07-13 | 2022-09-20 | 山东省药学科学院 | Method for determining dissolution curve in strong acid medium of folic acid tablets by ultra-high performance liquid chromatography |
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| CN109030653B (en) | 2021-05-07 |
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