CN116148361A - Separation and purification method of methylprednisolone impurity B - Google Patents
Separation and purification method of methylprednisolone impurity B Download PDFInfo
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Abstract
The invention provides a separation and purification method of methylprednisolone impurity B, and relates to the technical field of analytical chemistry. The separation and purification method adopts high performance liquid chromatography, and the chromatographic conditions include: octadecyl bonded silica gel is used as a filler, a water-acetonitrile-acid reagent is used as a mobile phase A, acetonitrile is used as a mobile phase B, and gradient elution is carried out. According to the separation and purification method for the methylprednisolone impurity B, through the optimization design of a mobile phase, a chromatographic column and the like, the chromatographic column is easy to obtain, the mobile phase system is simple, the methylprednisolone Long Zazhi B and the methylprednisolone 21-aldehyde impurity can be accurately and effectively separated, and the method can be used for separating and purifying the commercially available methylprednisolone impurity B to obtain the high-purity methylprednisolone impurity B, and fills the gap of no high-purity impurity B in the market.
Description
Technical Field
The invention relates to the technical field of analytical chemistry, in particular to a method for separating and purifying methylprednisolone impurity B.
Background
Methylprednisolone (CAS: 83-43-2) is an artificially synthesized halogen-free glucocorticoid drug with anti-inflammatory, immunosuppressive, antiallergic, antishock and other pharmacological effects. The medicine has strong anti-inflammatory effect, which is equivalent to 5 times of hydrocortisone and 1.4 times of prednisone. Among the numerous glucocorticoids, methylprednisolone has the strongest affinity for the glucocorticoid receptor, 12 times that of hydrocortisone and 23 times that of prednisone. While mineralocorticoid-like action (such as water and sodium retention) is weak, about 1/200 of that of deoxycorticosterone, and is remarkably smaller than that of prednisone, so that the inhibition effect on hypothalamus-pituitary gland-adrenal gland axis is weak, and the medicine itself exists in the form of active ingredient, and has quick effect.
Methylprednisone is generally subjected to iodine adding, replacement, hydrolysis and other steps to obtain a finished product. Along with the increase of drug evaluation in recent years, the research and detection requirements on impurities of starting materials, intermediates and finished products in the synthesis process of raw materials are higher and higher, so that the development of a separation preparation method for single impurities is also important. Methylprednisolone Long Zazhi B (abbreviated as "21-dihydroxyl compound") is an impurity in the finished product of methylprednisolone, and although the impurity is named as a single impurity, the commercially available methylprednisolone impurity B is actually a mixture of the 21-dihydroxyl compound and 21-aldehyde, and pure methylprednisolone impurity B cannot be obtained commercially. Methylprednisolone Long Zazhi B and Methylprednisolone 21-aldehyde impurities have the following structural formulas:
at present, related substances of methylprednisolone are measured by USP40, EP10 and BP2021, but the methods have large differences, and methylprednisolone Long Zazhi B and methylprednisolone 21-aldehyde impurities cannot be effectively separated by the methods. No method has been found by literature search to effectively separate the two.
In view of this, the present invention has been made.
Disclosure of Invention
The invention mainly aims to provide a separation and purification method of methylprednisolone impurity B.
The invention provides a method for separating and purifying methylprednisolone impurity B, which adopts high performance liquid chromatography, and chromatographic conditions comprise: octadecyl bonded silica gel is used as a filler, a water-acetonitrile-acid reagent is used as a mobile phase A, acetonitrile is used as a mobile phase B, and gradient elution is carried out.
Further, the gradient was set as follows, based on 100% mobile phase volume:
further, the gradient was set as follows, based on 100% mobile phase volume:
further, the volume ratio of water, acetonitrile and acid reagent in mobile phase A is selected from (92-98): (2-8): (0.5-1.5).
Further, the volume ratio of water, acetonitrile and acid reagent in mobile phase A is selected from (95-98): (2-5): (0.5-1).
Further, the acid reagent is selected from acetic acid, formic acid or phosphoric acid.
Further, the detector used is selected from ultraviolet detectors.
Further, the wavelength used is selected from 250-260nm.
Further, the wavelength used is selected from 252-258nm.
Further, the flow rate used is selected from 2.5-3.5mL/min.
Further, the flow rate used is selected from 2.8-3.2mL/min.
Further, high performance liquid chromatography is adopted, and chromatographic conditions include: octadecyl bonded silica gel is used as a filler, a water-acetonitrile-acid reagent is used as a mobile phase A, acetonitrile is used as a mobile phase B, and the volume ratio of water, acetonitrile and acid reagent in the mobile phase A is selected from (95-98): (2-5): (0.5-1), performing gradient elution; the detector is selected from ultraviolet detector, and wavelength is selected from 252-258nm; the flow rate is selected from 2.8-3.2mL/min; the gradient was set as follows, based on 100% mobile phase volume:
further, the volume ratio of water, acetonitrile and acetic acid in the mobile phase A is selected from 95:5:1.
further, the flow rate used is selected from 3mL/min.
Further, the wavelength used is selected from 254nm.
Further, the acid reagent is selected from acetic acid.
Further, the gradient was set as follows, based on 100% mobile phase volume:
further, high performance liquid chromatography is adopted, and chromatographic conditions include: octadecyl bonded silica gel is used as a filler, water-acetonitrile-acetic acid is used as a mobile phase A, acetonitrile is used as a mobile phase B, and the volume ratio of water, acetonitrile and acetic acid in the mobile phase A is selected from 95:5:1, performing gradient elution; the detector is selected from ultraviolet detector, and wavelength is 254nm; the flow rate is selected from 3.0mL/min; the gradient was set as follows, based on 100% mobile phase volume:
further, the method also comprises the following steps: and dissolving methylprednisolone Long Zazhi B in the solution to obtain a sample solution, and purifying and separating the sample solution.
Further, the solution is selected from dimethyl sulfoxide.
Further, the amount of sample introduced was 300. Mu.L.
The separation and purification in the invention are carried out under the room temperature condition, and the room temperature condition can be 20-30 ℃.
Compared with the prior art, the invention has the following beneficial effects:
according to the separation and purification method for the methylprednisolone impurity B, through the optimization design of a mobile phase, a chromatographic column and the like, the chromatographic column is easy to obtain, the mobile phase system is simple, the methylprednisolone Long Zazhi B and the methylprednisolone 21-aldehyde impurity can be accurately and effectively separated, and the method can be used for separating and purifying the commercially available methylprednisolone impurity B to obtain the high-purity methylprednisolone impurity B, and fills the gap of no high-purity impurity B in the market.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is an HPLC spectrum of a test sample of methylprednisolone impurity B in example 1-1;
FIG. 2 is a mass spectrum of methylprednisolone impurity B of example 1-1;
FIG. 3 is a mass spectrum of methylprednisolone 21-aldehyde impurity of example 1-1;
FIG. 4 is an HPLC profile of a test sample of methylprednisolone impurity B in comparative example 1;
fig. 5 is an HPLC profile of a test sample of methylprednisolone impurity B of comparative example 2.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The examples were conducted under conventional conditions, except that the specific conditions were not specified. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The methylprednisolone impurity B test sample is a self-made sample, and the HPLC purity is 67.35%. In the embodiment of the invention, the test samples of the methylprednisolone impurity B are all from the same batch.
Example 1
Preparing a solution:
methylprednisolone impurity B test solution: about 50mg of methylprednisolone Long Zazhi B is taken, 2.0mL of dimethyl sulfoxide is added for dissolution, and filtration is carried out for later use.
Example 1-1
Chromatographic conditions:
chromatographic column: ai Jieer Venusil MP C18 (250×10.0mm,5 μm);
wavelength: 254nm, ultraviolet detector;
flow rate: 3.0mL/min;
sample injection amount: 300. Mu.L;
gradient elution was performed as follows, based on 100% mobile phase volume:
the separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
the HPLC spectrum of the methylprednisolone impurity B test solution is shown in figure 1.
As can be seen from FIG. 1, the methylprednisolone impurity B has 2 peaks in the sample, the retention time is 51.86min and 55.90min respectively, the 2.25,2 peaks can be completely separated, and no interference exists between the peaks. The impurity in the methylprednisolone impurity B test sample is shown, and the methylprednisolone impurity B test sample can be completely separated by using the method of the embodiment.
And collecting effluent liquid of corresponding peaks in the chromatograms, and respectively carrying out mass spectrum detection on the separated components, wherein the results are shown in fig. 2 and 3.
Methylprednisolone impurity B is known to have an m/z of 390.20 and Methylprednisolone 21-aldehyde impurity has an m/z of 372.19. Whereas the M/z of the [ M+H ] peak in FIGS. 2-3 was 391.21 and 373.20, respectively, it was confirmed that the component corresponding to the mass spectrum in FIG. 2 was methylprednisolone Long Zazhi B and the component corresponding to the mass spectrum in FIG. 3 was methylprednisolone 21-aldehyde impurity.
The result shows that the sample of the methylprednisolone impurity B contains methylprednisolone Long Zazhi B and methylprednisolone 21-aldehyde impurity, and the methylprednisolone impurity B and the methylprednisolone 21-aldehyde impurity can be completely separated by using the method of the embodiment, so that the separation and purification of the methylprednisolone impurity B are completed. The HPLC purity of the methylprednisolone impurity B after HPLC separation and purification is 99.34%.
Examples 1 to 2
Chromatographic conditions:
chromatographic column: ai Jieer Venusil MP C18 (250×10.0mm,5 μm);
wavelength: 260nm, ultraviolet detector;
flow rate: 2.5mL/min;
sample injection amount: 300. Mu.L;
gradient elution was performed as follows, based on 100% mobile phase volume:
the separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
there were 2 peaks in the HPLC spectrum of the methylprednisolone impurity B test sample, the retention time was 53.12min and 58.69min, respectively, and the separation degree was 2.46.
The result shows that the method of the embodiment can completely separate the methylprednisolone Long Zazhi B from the methylprednisolone 21-aldehyde impurity in the sample of the methylprednisolone impurity B, and complete the separation and purification of the methylprednisolone impurity B. The HPLC purity of the isolated methylprednisolone impurity B was 98.73%.
Examples 1 to 3
Chromatographic conditions:
chromatographic column: ai Jieer Venusil MP C18 (250×10.0mm,5 μm);
wavelength: 250nm, ultraviolet detector;
flow rate: 3.5mL/min;
sample injection amount: 300. Mu.L;
gradient elution was performed according to the following table:
the separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
there were 2 peaks in the HPLC spectrum of the methylprednisolone impurity B test sample, the retention time was 47.89min and 49.67min, respectively, and the separation degree was 1.56.
The result shows that the method of the embodiment can completely separate the methylprednisolone Long Zazhi B from the methylprednisolone 21-aldehyde impurity in the sample of the methylprednisolone impurity B, and complete the separation and purification of the methylprednisolone impurity B. The HPLC purity of the isolated methylprednisolone impurity B was 97.25%.
Examples 1 to 4
Chromatographic conditions:
chromatographic column: ai Jieer Venusil MP C18 (250×10.0mm,5 μm);
wavelength: 258nm, ultraviolet detector;
flow rate: 2.8mL/min;
sample injection amount: 300. Mu.L;
gradient elution was performed according to the following table:
the separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
there were 2 peaks in the HPLC spectrum of the methylprednisolone impurity B test sample, the retention time was 54.38min and 59.24min, respectively, and the separation degree was 2.17.
The result shows that the method of the embodiment can completely separate the methylprednisolone Long Zazhi B from the methylprednisolone 21-aldehyde impurity in the sample of the methylprednisolone impurity B, and complete the separation and purification of the methylprednisolone impurity B. The HPLC purity of the isolated methylprednisolone impurity B was 98.56%.
Examples 1 to 5
Chromatographic conditions:
chromatographic column: ai Jieer Venusil MP C18 (250×10.0mm,5 μm);
wavelength: 252nm, ultraviolet detector;
flow rate: 3.2mL/min;
sample injection amount: 300. Mu.L;
gradient elution was performed according to the following table:
the separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
there were 2 peaks in the HPLC spectrum of the methylprednisolone impurity B test sample, the retention time was 49.98min and 51.87min, respectively, and the separation degree was 1.63.
The result shows that the method of the embodiment can completely separate the methylprednisolone Long Zazhi B from the methylprednisolone 21-aldehyde impurity in the sample of the methylprednisolone impurity B, and complete the separation and purification of the methylprednisolone impurity B. HPLC of purity of methylprednisolone Long Zazhi B after isolation was 97.12%.
Comparative example 1
Preparing a solution:
methylprednisolone impurity B test solution: methylprednisolone Long Zazhi B is precisely weighed and prepared into a solution containing 1mg of Methylprednisolone Long Zazhi B per 1mL with tetrahydrofuran-water-glacial acetic acid (25:72:3).
Chromatographic conditions:
chromatographic column: octadecylsilane chemically bonded silica column (250X 4.6mm,5 μm);
wavelength: 254nm;
column temperature: 30 ℃;
flow rate: 1.0mL/min;
sample injection amount: 10. Mu.L;
mobile phase: water-tetrahydrofuran-dimethyl sulfoxide-n-butanol (149:40:10:1).
Isocratic elution.
The separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
the HPLC spectrum of the methylprednisolone impurity B test solution is shown in FIG. 4.
As can be seen from FIG. 4, there are only 1 peak, with a retention time of 20.7min.
The results show that the method of this example failed to separate methylprednisolone Long Zazhi B from methylprednisolone 21-aldehyde impurities.
Comparative example 2
Preparing a solution:
methylprednisolone impurity B test solution: methylprednisone Long Zazhi B6 mg was precisely weighed into a 10mL measuring flask and dissolved with diluent (phosphoric acid-acetonitrile-water=0.1:50:50) to a constant volume.
Chromatographic conditions:
chromatographic column: octadecylsilane chemically bonded silica column (150 mm. Times.4.6 mm,3 μm);
flow rate: 1.5mL/min;
column temperature: 45 ℃;
wavelength: 247nm;
sample injection amount: 10. Mu.L;
mobile phase a: phosphoric acid-tetrahydrofuran-acetonitrile-water (0.1:1.5:10:90);
mobile phase B: phosphoric acid-tetrahydrofuran-acetonitrile (0.1:1.5:100);
gradient elution was performed as follows:
the separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
the HPLC spectrum of the methylprednisolone impurity B test solution is shown in FIG. 5.
As can be seen from FIG. 5, there are only 1 peak, with a retention time of 8.7min.
The results show that the method of this example failed to separate methylprednisolone Long Zazhi B from methylprednisolone 21-aldehyde impurities.
Comparative example 3
Preparing a solution:
methylprednisolone impurity B test solution: 25.0mg of methylprednisolone Long Zazhi B was dissolved in an equal volume of a mixture of acetonitrile and methanol, diluted to 10.0mL with the same solvent mixture.
Chromatographic conditions:
chromatographic column: octadecylsilane chemically bonded silica column (250X 4.6mm,5 μm);
column temperature: 45 ℃;
flow rate: 2.5mL/min;
sample injection amount: 20. Mu.L;
wavelength: 254nm;
mobile phase a: mixing 250mL of acetonitrile and 700mL of water uniformly, and fixing the volume to 1000mL by using water;
mobile phase B: acetonitrile;
gradient elution was performed as follows:
the separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
the HPLC profile of the methylprednisolone impurity B test solution showed only 1 peak.
The results show that the method of this example failed to separate methylprednisolone Long Zazhi B from methylprednisolone 21-aldehyde impurities.
Comparative example 4
Preparing a solution:
methylprednisolone impurity B test solution: the methylprednisolone impurity B test sample is precisely weighed to prepare 1mg/mL methylprednisolone Long Zazhi B ethanol solution.
Chromatographic conditions:
chromatographic column: hypersil ODS column (200X 4.6mm,5 μm);
wavelength: 254nm;
column temperature: 30 ℃;
flow rate: 1.5mL/min;
sample injection amount: 20. Mu.L;
mobile phase: acetonitrile-water (35:65);
isocratic elution.
The separation was performed according to the above chromatographic conditions and the effluent of the corresponding peak in the chromatogram was collected.
Separation and purification results:
HPLC profile of methylprednisolone impurity B test sample showed only 1 peak present.
The results show that the method of the embodiment cannot separate the methylprednisolone Long Zazhi B from the methylprednisolone 21-aldehyde impurity in the sample solution of the methylprednisolone impurity B.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. The method for separating and purifying the methylprednisolone impurity B is characterized by adopting a high performance liquid chromatography method, wherein the chromatographic conditions comprise: octadecyl bonded silica gel is used as a filler, a water-acetonitrile-acid reagent is used as a mobile phase A, acetonitrile is used as a mobile phase B, and gradient elution is carried out.
2. The method for separating and purifying methylprednisolone impurity B according to claim 1, wherein the gradient is set as follows, based on 100% of the volume of the mobile phase:
3. the method for separating and purifying methylprednisolone impurity B according to claim 1 or 2, wherein the gradient is set as follows, based on 100% of the volume of the mobile phase:
4. the method for separating and purifying methylprednisolone impurity B according to claim 3, wherein the volume ratio of water, acetonitrile and acid reagent in mobile phase a is selected from (92-98): (2-8): (0.5-1.5).
5. The method for separating and purifying methylprednisolone impurity B according to claim 4, wherein the acid reagent is selected from acetic acid, formic acid or phosphoric acid.
6. The method for separating and purifying methylprednisolone impurity B according to claim 1, 2, 4 or 5, wherein the flow rate is selected from the group consisting of 2.5 to 3.5mL/min.
7. The method for separating and purifying methylprednisolone impurity B as claimed in claim 6, wherein the detector is selected from ultraviolet detector, and the wavelength is selected from 250-260nm.
8. The method for separating and purifying methylprednisolone impurity B according to any one of claims 1, 2, 4, 5 or 7, wherein octadecyl bonded silica gel is used as filler, water-acetonitrile-acid reagent is used as mobile phase a, acetonitrile is used as mobile phase B, and the volume ratio of water, acetonitrile and acid reagent in mobile phase a is selected from (95-98): (2-5): (0.5-1), performing gradient elution; the detector is selected from ultraviolet detector, and wavelength is selected from 252-258nm; the flow rate is selected from 2.8-3.2mL/min; the gradient was set as follows, based on 100% mobile phase volume:
9. the method for separating and purifying methylprednisolone impurity B as claimed in claim 8, wherein the acid reagent is selected from acetic acid.
10. The method for separating and purifying methylprednisolone impurity B according to any one of claims 1, 2, 4, 5, 7 or 9, further comprising the steps of: and dissolving methylprednisolone Long Zazhi B in the solution to obtain a sample solution, and purifying and separating the sample solution.
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