CN115639292A - Mirabegron sustained-release tablet degradation impurity and preparation method and application thereof - Google Patents
Mirabegron sustained-release tablet degradation impurity and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a mirabegron sustained-release tablet degradation impurity, and a preparation method and application thereof. The mirabegron sustained release tablet provided by the invention can degrade impurities N- (4- {2- [ acetyl- ((2R) -2-hydroxy-2-phenylethyl) -amino ] -ethyl } -phenyl) -2- (2-aminothiazole-4-yl) -acetamide, is a novel mirabegron sustained release tablet degradation impurity, and can be used for controlling the quality standard of related substances of the mirabegron sustained release tablet. The mirabegron sustained release tablet degrades impurities, increases in the periods of a preparation product forced degradation experiment, a raw and auxiliary material compatibility experiment, an influence factor experiment and a stability experiment, and has the risk of exceeding the quality control limit in the stability period, so that qualitative research and quality control need to be carried out on the mirabegron sustained release tablet, the mirabegron sustained release tablet is bound into the related substance quality standard, and the control standard is accurate and reliable.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a mirabegron sustained-release tablet degradation impurity, and a preparation method and application thereof.
Background
Mirabegron, chemical name 2- (2-amino-1, 3-thiazol-4-yl) -N- [4- (2- { [ (2R) -2-hydroxy-2-phenylethyl ] amino } ethyl) phenyl ] acetamide, formula II:
mirabegron is a new anti-OAB drug, and the action mechanism of the mirabegron is different from that of the anticholinergic drug which is commonly used in clinic: mirabegron is a beta 3-adrenergic receptor agonist, improves bladder urine storage capacity by activating beta 3-adrenergic receptors in the detrusor muscle of the bladder wall mediating relaxation of the bladder, thereby alleviating OAB symptoms without affecting the voiding function of bladder contraction. The new action mechanism ensures that the medicine has less side effects caused by anticholinergic energy, such as dry mouth, constipation and the like, and has higher safety.
The active component of the mirabegron sustained release tablet is mirabegron, and the inactive components comprise: polyoxyethylene, polyethylene glycol, hydroxypropyl cellulose, dibutylhydroxytoluene, magnesium stearate, and opadry. The generation of impurities in the mirabegron sustained release tablet can affect the safety and effectiveness of medication, so the degradation impurities of the mirabegron sustained release tablet need to be researched and controlled.
Disclosure of Invention
The invention aims to provide a mirabegron sustained release tablet degradation impurity, a preparation method and application thereof, aiming at the existing problems. The invention provides a novel mirabegron slow release tablet degradation impurity which can be used for controlling the quality standard of related substances of the mirabegron slow release tablet.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a mirabegron slow release tablet for degrading impurities, which has a chemical name of N- (4- {2- [ acetyl- ((2R) -2-hydroxy-2-phenylethyl) -amino ] -ethyl } -phenyl) -2- (2-aminothiazole-4-yl) -acetamide, and has a structural formula shown in a formula I:
the invention also provides a preparation method of the mirabegron sustained release tablet degradation impurities, which comprises the following steps:
carrying out reflux reaction on the mirabegron and ethyl formate to obtain a reaction solution;
and sequentially removing the solvent from the reaction solution, and performing column chromatography separation and purification to obtain the mirabegron slow-release tablet degradation impurity.
Preferably, the molar ratio of mirabegron to ethyl formate is 1.5-2.
Preferably, the solvent for the reflux reaction comprises dichloromethane.
Preferably, the temperature of the reflux reaction is 60 to 80 ℃.
Preferably, the time of the reflux reaction is 1 to 2 hours.
Preferably, the column chromatography separation and purification column comprises a silica gel column chromatography.
Preferably, the eluent for column chromatography separation and purification is a mixed solution of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol in the mixed solution is 10.
The invention also provides another preparation method of the mirabegron slow-release tablet for degrading impurities, which comprises the following steps:
mixing the mirabegron sustained release tablet with methanol to obtain a disintegrating solution;
sequentially degrading, carrying out solid-liquid separation and concentrating the disintegration solution to obtain a sample to be separated;
and carrying out liquid chromatography separation on the sample to be separated to obtain the mirabegron slow-release tablet degradation impurities.
The invention also provides application of the mirabegron slow release tablet degradation impurities in the quality control of the mirabegron slow release tablet.
The invention provides a mirabegron slow release tablet degradation impurity, the chemical name is N- (4- {2- [ acetyl- ((2R) -2-hydroxy-2-phenylethyl) -amino ] -ethyl } -phenyl) -2- (2-aminothiazole-4-yl) -acetamide, and the structural formula is shown as formula I.
Compared with the prior art, the invention has the following beneficial effects:
the mirabegron sustained release tablet provided by the invention can degrade impurities N- (4- {2- [ acetyl- ((2R) -2-hydroxy-2-phenylethyl) -amino ] -ethyl } -phenyl) -2- (2-aminothiazole-4-yl) -acetamide, is a novel mirabegron sustained release tablet degradation impurity, and can be used for controlling the quality standard of related substances of the mirabegron sustained release tablet. The mirabegron sustained release tablet degrades impurities, increases in the periods of a preparation product forced degradation experiment, a raw and auxiliary material compatibility experiment, an influence factor experiment and a stability experiment, and has the risk of exceeding the quality control limit in the stability period, so that qualitative research and quality control need to be carried out on the mirabegron sustained release tablet, the mirabegron sustained release tablet is bound into the related substance quality standard, and the control standard is accurate and reliable.
The invention provides a preparation method of mirabegron slow release tablet degradation impurities, which is synthesized by mirabegron and ethyl formate.
The invention also provides another preparation method of the mirabegron slow-release tablet degradation impurities, the mirabegron slow-release tablet is used as a raw material and is prepared under the condition of illumination or high temperature, the preparation method is simple, and the mirabegron slow-release tablet degradation impurities obtained by the synthesis method can be qualitatively verified.
The invention also provides application of the mirabegron slow release tablet in degrading impurities, and the mirabegron slow release tablet degrading impurities can be used for development of related substance analysis methods, establishment of quality standards and selection of storage conditions of the mirabegron slow release tablet, and have important significance for development of other preparation formulations in the future.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings without creative efforts.
FIG. 1 is a chromatogram for the chromatographic purity test of a pale yellow solid obtained in example 1;
FIG. 2 is a mass spectrum of a pale yellow solid obtained in example 1;
FIG. 3 is a nuclear magnetic hydrogen spectrum of a pale yellow solid obtained in example 1;
FIG. 4 is a graph of a Mirabegron (MRB) linear regression;
fig. 5 is a linear regression graph of the degradation impurity (impurity a) of the mirabegron sustained release tablets.
Detailed Description
The invention provides a mirabegron slow release tablet for degrading impurities, which has a chemical name of N- (4- {2- [ acetyl- ((2R) -2-hydroxy-2-phenylethyl) -amino ] -ethyl } -phenyl) -2- (2-aminothiazole-4-yl) -acetamide, and has a structural formula shown in a formula I:
in the present invention, reagents, consumables, instruments and equipment used are commercially available in the art unless otherwise specified.
In the invention, the molecular formula of impurities degraded by the mirabegron sustained-release tablet is C 22 H 24 N 4 O 3 S, molecular weight 424.52. The mirabegron slow release tablet of the invention degrades impurities, and is a new mirabegron slow release tablet degradation impurity.
The invention also provides a preparation method of the mirabegron sustained release tablet degradation impurities, which comprises the following steps:
carrying out reflux reaction on the mirabegron and ethyl formate to obtain a reaction solution;
and sequentially removing the solvent from the reaction solution, and performing column chromatography separation and purification to obtain the mirabegron slow-release tablet degradation impurity.
The invention carries out reflux reaction on the mirabegron and the ethyl formate to obtain reaction liquid.
In the present invention, the molar ratio of mirabegron to ethyl formate is preferably 1.5 to 2, more preferably 1.5.
In the invention, the ethyl formate is used as an acylation reagent, the mirabegron is used as an aliphatic secondary amine, and the reaction mechanism of the mirabegron and the ethyl formate is shown as a formula III:
in the present invention, the solvent for the reflux reaction preferably includes dichloromethane.
In the present invention, the temperature of the reflux reaction is preferably 60 to 80 ℃, more preferably 70 ℃.
In the present invention, the time for the reflux reaction is preferably 1 to 2 hours, and more preferably 1.5 hours.
After the reaction liquid is obtained, the solvent and column chromatography separation and purification are sequentially carried out on the reaction liquid to obtain the degradation impurities of the mirabegron sustained release tablets.
In the present invention, the column for column chromatography separation and purification preferably comprises a silica gel column.
In the present invention, the eluent for column chromatography separation and purification is preferably a mixed solution of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol in the mixed solution is preferably 10.
After the column chromatography separation and purification, the invention preferably further comprises a drying process, wherein the drying temperature is preferably 105 ℃, and the drying time is preferably 24 hours, and the drying process is used for removing water in the mirabegron sustained release tablet degradation impurities.
The invention also provides another preparation method of the mirabegron sustained release tablet for degrading impurities, which comprises the following steps:
mixing the mirabegron sustained release tablet with methanol to obtain a disintegrating solution;
sequentially degrading, carrying out solid-liquid separation and concentrating on the disintegration liquid to obtain a sample to be separated;
and carrying out liquid chromatography separation on the sample to be separated to obtain the degradation impurities of the mirabegron sustained release tablets.
The mirabegron sustained release tablet is mixed with methanol to obtain the disintegration solution.
In the present invention, the mirabegron sustained release tablet preferably comprises an active ingredient and an inactive ingredient, the active ingredient preferably comprises mirabegron, and the inactive ingredient preferably comprises polyoxyethylene, polyethylene glycol, hydroxypropyl cellulose, dibutylhydroxytoluene, magnesium stearate and opadry.
In the present invention, the mass ratio of mirabegron to polyethylene glycol in the mirabegron sustained release tablet is preferably 1.4, the mass fraction of mirabegron in the mirabegron sustained release tablet is preferably 19.4%, and the mass fraction of polyethylene glycol in the mirabegron sustained release tablet is preferably 46.4%. In the specific embodiment of the invention, the weight of the mirabegron sustained-release tablet is 257.5mg, the content of the mirabegron in the mirabegron sustained-release tablet is 50 mg/tablet, and the content of the polyethylene glycol is 119.6 mg/tablet.
In the present invention, the ratio of the volume of methanol to the mass of the mirabegron sustained release tablet is preferably 10 to 50ml, more preferably 50ml.
In the invention, the mixing mode is preferably shaking, and the invention has no special requirement on the shaking time, so that the mirabegron sustained release tablet is completely disintegrated.
After obtaining the disintegration liquid, the invention sequentially degrades, separates solid from liquid and concentrates the disintegration liquid to obtain a sample to be separated.
In the present invention, the degradation is preferably light irradiation or high temperature, the high temperature is preferably 50 to 70 ℃, more preferably 60 ℃, and the high temperature time is preferably 5 to 30 days, more preferably 30 days.
In the present invention, the total illumination intensity of the illumination is preferably not less than 4000lx, more preferably 4000 to 4500lx, and the intensity of the ultraviolet radiation of the illumination is preferably 85 μ W/cm 2 (ii) a The time for the light irradiation is preferably 1 to 24 hours, and more preferably 12 hours.
The present invention has no special requirement on the solid-liquid separation mode, and in the specific embodiment of the present invention, filtration is adopted.
In the present invention, the concentration is preferably performed by rotary evaporation, and the concentration is performed for the purpose of reducing the solvent.
In the invention, the sample to be separated is preferably a solution containing mirabegron, mirabegron slow-release tablet degradation impurities and other unknown impurities, and the mirabegron slow-release tablet degradation impurities can be obtained by the solution through subsequent liquid chromatography separation.
After a sample to be separated is obtained, the sample to be separated is subjected to liquid chromatography separation to obtain the mirabegron slow release tablet degradation impurities.
In the present invention, the chromatographic conditions for the liquid chromatographic separation preferably include:
and (3) chromatographic column: c18
The mobile phase A is 0.018-0.022 mol/L ammonium acetate buffer solution with pH value of 3.5, the mobile phase B is acetonitrile, the gradient elution procedure is shown in Table 1, the flow rate is as follows: 0.9-1.1 mL/min;
TABLE 1 gradient elution procedure
Detection wavelength: 250nm;
column temperature: 35-45 ℃.
And collecting the component with the retention time of 1.73 relative to the main peak of the mirabegron, namely the degradation impurity of the mirabegron sustained release tablet.
In the present invention, the concentration of the mobile phase A is preferably 0.02mol/L.
In the present invention, the flow rate is preferably 1mL/min.
In the present invention, the column temperature is preferably 40 ℃.
The invention also provides application of the mirabegron slow release tablet degradation impurities in the quality control of the mirabegron slow release tablet.
The application of the impurities degraded by the mirabegron sustained release tablet in the quality control of the mirabegron sustained release tablet is preferably related substance detection, the related substance detection is preferably liquid chromatography detection, and the chromatographic conditions of the liquid chromatography detection are preferably the same as those of the liquid chromatography separation in the preparation method, so that the repeated description is omitted.
For further illustration of the present invention, the impurities for degrading mirabegron sustained release tablet provided by the present invention, the preparation method and the application thereof are described in detail below with reference to the accompanying drawings and examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The synthesis method comprises the following steps:
a dry 100mL three-necked round-bottomed flask was charged with mirabegron (3.96g, 10mmol), ethyl formate (1.11g, 15mmol), and 50mL of methylene chloride in this order, and the mixture was refluxed at 70 ℃ for 1.5 hours and cooled to room temperature. Using a rotary evaporator, distilling the solvent under reduced pressure at 40 ℃, uniformly stirring the reaction product and silica gel, putting the mixture into a silica gel column, separating and purifying by silica gel column chromatography (volume ratio dichloromethane: methanol = 10).
This example gives 500mg of a pale yellow solid in a calculated yield of 11.8%.
Test example 1
1. The chromatographic purity of the pale yellow solid obtained in example 1 was measured (the detection method was the same as that for the mirabegron sustained release tablet in application example 1), the chromatogram is shown in fig. 1, and the results of the area normalization method are shown in table 2.
TABLE 2 area normalization results
| RT | Area | Height | ％Area | USP | USP PlateCount | ||
| 1 | 20.057 | 30331 | 2549 | 0.22 | 68968 | ||
| 2 | 33.433 | 13736811 | 381906 | 98.31 | 20.74 | 18113 | |
| 3 | 35.687 | 102645 | 3037 | 0.73 | 2.38 | 23279 | |
| 4 | 39.718 | 12841 | 460 | 0.09 | 4.80 | 42668 | |
| 5 | 40.788 | 31154 | 2486 | 0.22 | 1.94 | 240006 | |
| 6 | 42.719 | 52300 | 4401 | 0.37 | 5.87 | 297802 | |
| 7 | 56.209 | 2888 | 87 | 0.02 | 22.77 | 73366 | |
| 8 | 59.387 | 3396 | 240 | 0.02 | 5.09 | 381919 |
As can be seen from fig. 1 and table 2, the chromatographic purity of the mirabegron sustained release tablet degradation impurity obtained in example 1 was 98.31%.
2. Impurity content calibration
On the basis of chromatographic purity, the water value is subtracted by loss on drying (continuous drying at 105 ℃ for 24 hours) to obtain 3.71 percent of water value, and the mass content of the mirabegron slow-release tablet degradation impurities in the light yellow solid obtained in example 1 is finally 94.6 percent.
3. The mass spectrometry of the pale yellow solid obtained in example 1 was performed, the mass spectrum is shown in fig. 2, and the mass spectrometry detection results are shown in table 3.
TABLE 3 Mass Spectrometry results
| m/z | z | Abund |
| 383.2584 | 2 | 53415 |
| 407.153 | 1 | 62791.02 |
| 425.1668 | 1 | 1031331.13 |
| 426.1682 | 1 | 349193.63 |
| 427.1655 | 1 | 117620.89 |
| 438.1277 | 1 | 81323.93 |
| 447.1454 | 1 | 118373 |
| 765.5074 | 1 | 57228.39 |
| 871.3002 | 1 | 147000.88 |
| 872.305 | 1 | 76804.65 |
From FIG. 2 and Table 3, it can be confirmed that [ M + H ] of the degraded impurities obtained in example 1] + It is 425.1668.
4. The pale yellow solid obtained in example 1 was subjected to nuclear magnetic hydrogen spectrometry, and the nuclear magnetic hydrogen spectrometry is shown in FIG. 3.
According to the analysis of the number of hydrogen in the nuclear magnetic hydrogen spectrum and chemical shift data, the hydrogen spectrum (DMSO) analysis information is shown as a formula IV and a table 4:
TABLE 4 Hydrogen Spectrum analysis information
| Peak numbering | Chemical shift δ/ | Peak assignment | |
| 1 | 10.05(s,1H) | ArNHCO— | |
| 2 | 7.85(s,0.5H),7.74(s,0.5H) | — |
|
| 3 | 7.53–7.50(m,2H) | |
|
| 4 | 7.37–7.24(m,5H) | |
|
| 5 | 7.12(dd,2H) | |
|
| 6 | 6.93(s,2H) | |
|
| 7 | 6.30(s,1H) | Hetero-ArH | |
| 8 | 5.55(dd,1H) | |
|
| 10 | 4.76–4.70(m,1H) | |
|
| 11 | 3.58–3.49(m,1H) | |
|
| 12 | 3.44(s,2H) | |
|
| 13 | 3.36(m,1H) | |
|
| 14 | 3.29–3.25(m,2H) | |
|
| 15 | 2.73–2.70(m,2H) | CH 2 |
From the nuclear magnetic hydrogen spectrum results, it is understood that the molecular formula of the impurity obtained in example 1Is C 22 H 24 N 4 O 3 S, molecular weight 424.52.
Example 2
The liquid phase method comprises the following steps:
placing 10 pieces of mirabegron sustained release tablet (tablet weight: 257.5mg, active ingredient mirabegron: 50 mg/tablet, polyethylene glycol: 119.6 mg/tablet) in a 100mL volumetric flask, adding 50mL methanol, shaking until the sample is totally disintegrated, placing the sample in a light box (total illumination is not less than 4500lx, near ultraviolet 85 μ w/cm) 2 ) And (4) internally illuminating for 24 hours, filtering to remove the auxiliary materials, and performing rotary evaporation to remove most of the solvent to obtain the sample to be separated.
Carrying out liquid chromatography separation on a sample to be separated, wherein the chromatographic conditions are as follows:
a chromatographic column: waters Xbridge C18.6 mm. Times.150mm, 3.5. Mu.m
Mobile phase: 0.02mol/LpH 3.5 ammonium acetate buffer (mobile phase A) -acetonitrile (mobile phase B) system, the specific gradient elution procedure is shown in Table 5, flow rate: 1mL/min;
detection wavelength: 250nm;
column temperature: at 40 ℃.
And collecting the component with the retention time of 1.73 relative to the main peak of the mirabegron, namely the degradation impurity of the mirabegron sustained release tablet.
Table 5 mobile phase gradient elution procedure
| Time (min) | Mobile phase a volume (%) | Mobile phase B volume (%) |
| 0 | 100 | 0 |
| 5 | 100 | 0 |
| 55 | 70 | 30 |
| 60 | 50 | 50 |
| 70 | 50 | 50 |
| 70.1 | 100 | 0 |
| 80 | 100 | 0 |
Application example 1
The impurity obtained in example 1 was used in the quality control study (related substance detection) of mirabegron sustained release tablets.
The chromatographic conditions of the detection method of the related substances of the mirabegron sustained release tablet are as follows:
and (3) chromatographic column: c18 column (Waters Xbridge C18.6 mm. Times.150mm, 3.5 μm);
mobile phase a was 0.02mol/LpH 3.5 ammonium acetate buffer, mobile phase B was acetonitrile, the specific gradient elution procedure is shown in table 5, flow rates: 1mL/min;
detection wavelength: 250nm;
column temperature: at 40 deg.c.
The impurities degraded by the mirabegron and the mirabegron sustained release tablets are tested under the chromatographic conditions, the concentration and the test result are shown in table 6, the linear regression curve chart of the mirabegron (marked as MRB) is shown in figure 4, and the impurities degraded by the mirabegron sustained release tablets (marked as impurity A) is shown in figure 5.
TABLE 6 Linear test results of mirabegron and mirabegron sustained release tablets for degrading impurities
The retention time of the impurities degraded by the mirabegron sustained release tablet relative to the mirabegron is 1.73, the impurities degraded by the mirabegron sustained release tablet obtained in the embodiment 1 are used as an impurity reference substance, and a correction factor of the mirabegron sustained release tablet degraded impurities relative to the mirabegron is 1.02 through linear research, so that the response difference between the mirabegron and the mirabegron is considered to be small, the correction factor does not need to be considered when a main component external standard method is used for detecting related substances, the content of the impurities cannot be underestimated in a detection result, and the impurities are controlled according to the known impurities in a stability and formal production stage.
Although the present invention has been described in detail with reference to the above embodiments, it is to be understood that the present invention is not limited to the details of the embodiments, and that various modifications, additions, substitutions, and equivalents may be made without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. The mirabegron sustained release tablet degradation impurity is characterized in that the chemical name is N- (4- {2- [ acetyl- ((2R) -2-hydroxy-2-phenylethyl) -amino ] -ethyl } -phenyl) -2- (2-aminothiazol-4-yl) -acetamide, and the structural formula is shown as the formula I:
2. the preparation method of the mirabegron slow release tablet degrading impurities as claimed in claim 1, characterized by comprising the following steps:
carrying out reflux reaction on the mirabegron and ethyl formate to obtain a reaction solution;
and sequentially removing the solvent from the reaction solution, and performing column chromatography separation and purification to obtain the mirabegron slow-release tablet degradation impurity.
3. The method according to claim 2, wherein the molar ratio of mirabegron to ethyl formate is 1.5-2.
4. The method of claim 2, wherein the solvent for the reflux reaction comprises dichloromethane.
5. The production method according to claim 2 or 4, wherein the temperature of the reflux reaction is 60 to 80 ℃.
6. The method according to claim 2 or 4, wherein the reflux reaction is carried out for 1 to 2 hours.
7. The preparation method according to claim 2, wherein the column chromatography separation and purification column comprises a silica gel column chromatography.
8. The preparation method according to claim 2 or 7, characterized in that the eluent for column chromatography separation and purification is a mixed solution of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol in the mixed solution is 10.
9. The preparation method of the mirabegron slow release tablet degrading impurities as claimed in claim 1, characterized by comprising the following steps:
mixing the mirabegron sustained release tablet with methanol to obtain a disintegrating solution;
sequentially degrading, carrying out solid-liquid separation and concentrating on the disintegration liquid to obtain a sample to be separated;
and carrying out liquid chromatography separation on the sample to be separated to obtain the degradation impurities of the mirabegron sustained release tablets.
10. The use of the mirabegron slow release tablet degradation impurity of claim 1 in the quality control of the mirabegron slow release tablet.
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