A mirabegron sustained-release tablet degradation impurity, its preparation method and application

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a mirabegron sustained-release tablet degradation impurity, its preparation method and application. The mirabegron sustained-release tablet degradation impurity N-(4-{2-[acetyl-((2R)-2-hydroxy-2-phenylethyl)-amino]-ethyl}-phenyl)-2-(2-aminothiazol-4-yl)-acetamide provided by the present invention is a new mirabegron sustained-release tablet degradation impurity and can be used for the quality standard control of related substances of mirabegron sustained-release tablets. The mirabegron sustained-release tablet degradation impurity of the present invention increases during the forced degradation experiment, the compatibility experiment of raw materials and excipients, the stress test and the stability experiment of the preparation product, and there is a risk of exceeding the quality control limit during the stability period. Therefore, it is necessary to conduct qualitative research and quality control on it, include it in the quality standard of related substances of mirabegron sustained-release tablets, and the control standard is accurate and reliable.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a mirabegron sustained-release tablet degradation impurity, a preparation method thereof and an application thereof. Background Art

[0002] Mirabegron, with the chemical name of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, has a structural formula as shown in Formula II:

[0003]

[0004] Mirabegron is a new drug for treating OAB, and its mechanism of action is different from that of commonly used anticholinergic drugs in clinical practice: Mirabegron is a β3-adrenergic receptor agonist, which improves the bladder storage capacity by activating the β3-adrenergic receptor that mediates bladder relaxation in the detrusor muscle of the bladder wall, and thus alleviates OAB symptoms, but does not affect the bladder contraction and urination function. This new mechanism of action makes the drug less likely to cause side effects caused by anticholinergics, such as dry mouth, constipation, etc., and is safer.

[0005] The active ingredient in the mirabegron sustained-release tablet is mirabegron, and the inactive ingredients include: polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, dibutylhydroxytoluene, magnesium stearate and Opadry. The generation of impurities in the mirabegron sustained-release tablet will affect the safety and effectiveness of drug use. Therefore, it is necessary to study and control the degradation impurities of the mirabegron sustained-release tablet. Summary of the Invention

[0006] The purpose of the present invention is to provide a mirabegron sustained-release tablet degradation impurity, a preparation method thereof and an application thereof in view of the existing problems. The present invention provides a new mirabegron sustained-release tablet degradation impurity, which can be used for controlling the quality standard of related substances in the mirabegron sustained-release tablet.

[0007] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0008] The present invention provides a mirabegron sustained-release tablet degradation impurity, with the chemical name of N-(4-{2-[acetyl-((2R)-2-hydroxy-2-phenylethyl)-amino]-ethyl}-phenyl)-2-(2-aminothiazol-4-yl)-acetamide, and the structural formula is as shown in Formula I:

[0009]

[0010] The present invention also provides a preparation method of the above-mentioned mirabegron sustained-release tablet degradation impurity, including the following steps:

[0011] React mirabegron with ethyl formate under reflux to obtain a reaction solution.

[0012] Remove the solvent from the reaction solution successively and purify it by column chromatography to obtain the mirabegron sustained-release tablet degradation impurity.

[0013] Preferably, the molar ratio of mirabegron to ethyl formate is preferably 1:1.5 - 2.

[0014] Preferably, the solvent for the reflux reaction includes dichloromethane.

[0015] Preferably, the temperature of the reflux reaction is 60 - 80 °C.

[0016] Preferably, the time of the reflux reaction is 1 - 2 h.

[0017] Preferably, the chromatography column for the column chromatography separation and purification includes a silica gel chromatography column.

[0018] Preferably, the eluent for the 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 10:1.

[0019] The present invention also provides another preparation method of the above-mentioned mirabegron sustained-release tablet degradation impurity, which includes the following steps:

[0020] Mix mirabegron sustained-release tablets with methanol to obtain a disintegration solution.

[0021] Subject the disintegration solution to degradation, solid-liquid separation and concentration successively to obtain a sample to be separated.

[0022] Perform liquid chromatography separation on the sample to be separated to obtain the mirabegron sustained-release tablet degradation impurity.

[0023] The present invention also provides the application of the above-mentioned mirabegron sustained-release tablet degradation impurity in the quality control of mirabegron sustained-release tablets.

[0024] The present invention provides a mirabegron sustained-release tablet degradation impurity, the chemical name of which 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 in Formula I.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The mirabegron sustained-release tablet degradation impurity N-(4-{2-[acetyl-((2R)-2-hydroxy-2-phenylethyl)-amino]-ethyl}-phenyl)-2-(2-aminothiazol-4-yl)-acetamide provided by the present invention is a new mirabegron sustained-release tablet degradation impurity and can be used for the quality standard control of related substances in mirabegron sustained-release tablets. The mirabegron sustained-release tablet degradation impurity of the present invention increases during forced degradation experiments, compatibility experiments of raw materials and excipients, stress tests, and stability tests of the preparation product, and there is a risk of exceeding the quality control limit during stability. Therefore, it is necessary to conduct qualitative research and quality control on it, include it in the quality standard of related substances in mirabegron sustained-release tablets, and the control standard is accurate and reliable.

[0027] The present invention provides a preparation method for a mirabegron sustained-release tablet degradation impurity, which is synthesized from mirabegron and ethyl formate. The preparation method of the present invention is simple and feasible, the raw materials are easy to obtain, the conditions are mild, and the cost is low, which is beneficial to production.

[0028] The present invention also provides another preparation method for a mirabegron sustained-release tablet degradation impurity, which is prepared from a mirabegron sustained-release tablet under light or high temperature conditions. The preparation method is simple and can be used to qualitatively verify the mirabegron sustained-release tablet degradation impurity obtained by the above synthesis method.

[0029] The present invention also provides an application of a mirabegron sustained-release tablet degradation impurity. The mirabegron sustained-release tablet degradation impurity of the present invention can be used for the development of analysis methods for related substances in mirabegron sustained-release tablets, the establishment of quality standards, and the selection of storage conditions for mirabegron sustained-release tablets, and is also of great significance for the development of other future preparation dosage forms. Description of the Drawings

[0030] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required to be used in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0031] Figure 1 Chromatogram of the chromatographic purity test of the pale yellow solid obtained in Example 1;

[0032] Figure 2 Mass spectrum of the pale yellow solid obtained in Example 1;

[0033] Figure 3 1H NMR spectrum of the pale yellow solid obtained in Example 1;

[0034] Figure 4 Linear regression curve of mirabegron (MRB);

[0035] Figure 5 Linear regression curve of mirabegron sustained-release tablets degradation impurity (Impurity A). Detailed implementation mode

[0036] The present invention provides a mirabegron sustained-release tablets degradation impurity, with the chemical name of N-(4-{2-[acetyl-((2R)-2-hydroxy-2-phenylethyl)-amino]-ethyl}-phenyl)-2-(2-aminothiazol-4-yl)-acetamide, and the structural formula is shown in Formula I:

[0037]

[0038] In the present invention, unless otherwise specified, the reagents, consumables, instruments and equipment used are all commercially available products in the art.

[0039] In the present invention, the molecular formula of the mirabegron sustained-release tablets degradation impurity is C 22 H 24 N 4 O 3 S, and the molecular weight is 424.52. The mirabegron sustained-release tablets degradation impurity of the present invention is a new mirabegron sustained-release tablets degradation impurity.

[0040] The present invention also provides a preparation method of the above-mentioned mirabegron sustained-release tablets degradation impurity, including the following steps:

[0041] Reflux react mirabegron and ethyl formate to obtain a reaction solution;

[0042] Remove the solvent from the reaction solution in sequence and purify it by column chromatography to obtain the mirabegron sustained-release tablets degradation impurity.

[0043] In the present invention, mirabegron and ethyl formate are reflux reacted to obtain a reaction solution.

[0044] In the present invention, the molar ratio of mirabegron to ethyl formate is preferably 1:1.5 - 2, more preferably 1:1.5.

[0045] In the present invention, the ethyl formate is used as an acylating agent, and the mirabegron is used as an aliphatic secondary amine. The reaction mechanism of mirabegron and ethyl formate is shown in Formula III:

[0046]

[0047] In the present invention, the solvent for the reflux reaction preferably includes dichloromethane.

[0048] In the present invention, the temperature of the reflux reaction is preferably 60 - 80 °C, more preferably 70 °C.

[0049] In the present invention, the time of the reflux reaction is preferably 1 to 2 h, more preferably 1.5 h.

[0050] After obtaining the reaction solution, the present invention removes the solvent and purifies the reaction solution by column chromatography in sequence to obtain the mirabegron sustained-release tablet degradation impurity.

[0051] In the present invention, the chromatography column for column chromatography separation and purification preferably includes a silica gel chromatography column.

[0052] 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 10:1.

[0053] After the column chromatography separation and purification, the present invention preferably further includes a drying process. The drying temperature is preferably 105 °C, and the time is preferably 24 h. The drying is to remove the moisture in the mirabegron sustained-release tablet degradation impurity.

[0054] The present invention also provides another preparation method of the above-mentioned mirabegron sustained-release tablet degradation impurity, which includes the following steps:

[0055] Mix mirabegron sustained-release tablets and methanol to obtain a disintegration solution;

[0056] Subject the disintegration solution to degradation, solid-liquid separation and concentration in sequence to obtain a sample to be separated;

[0057] Perform liquid chromatography separation on the sample to be separated to obtain the mirabegron sustained-release tablet degradation impurity.

[0058] The present invention mixes mirabegron sustained-release tablets and methanol to obtain a disintegration solution.

[0059] In the present invention, the mirabegron sustained-release tablet preferably includes an active ingredient and an inactive ingredient. The active ingredient preferably includes mirabegron, and the inactive ingredient preferably includes polyethylene oxide, polyethylene glycol, hydroxypropyl cellulose, dibutylhydroxytoluene, magnesium stearate and Opadry.

[0060] In the present invention, the mass ratio of mirabegron to polyethylene glycol in the mirabegron sustained-release tablet is preferably 1:2.4. 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 a specific embodiment of the present invention, the tablet weight of the mirabegron sustained-release tablet is 257.5 mg, the content of mirabegron in the mirabegron sustained-release tablet is 50 mg / tablet, and the content of polyethylene glycol is 119.6 mg / tablet.

[0061] In the present invention, the ratio of the volume of methanol to the mass of mirabegron sustained-release tablets is preferably 10-50 mL: 2.4-2.6 g, more preferably 50 mL: 2.5 g.

[0062] In the present invention, the mixing method is preferably shaking. There is no special requirement for the shaking time in the present invention, as long as all the mirabegron sustained-release tablets are disintegrated.

[0063] After obtaining the disintegration solution, the present invention sequentially degrades, separates solid from liquid, and concentrates the disintegration solution to obtain a sample to be separated.

[0064] In the present invention, the degradation is preferably light irradiation or high temperature. The temperature of the high temperature is preferably 50-70 °C, more preferably 60 °C, and the time of the high temperature is preferably 5-30 days, more preferably 30 days.

[0065] In the present invention, the total illuminance of the light irradiation is preferably not less than 4000 lx, more preferably 4000-4500 lx, and the ultraviolet radiation intensity of the light irradiation is preferably 85 μW / cm 2 ; the time of the light irradiation is preferably 1-24 h, more preferably 12 h.

[0066] The present invention has no special requirement for the method of separating solid from liquid. In the specific embodiments of the present invention, filtration is used, for example.

[0067] In the present invention, the concentration method is preferably rotary evaporation, and the purpose of concentration is to reduce the solvent.

[0068] In the present invention, the sample to be separated is preferably a solution containing mirabegron, mirabegron sustained-release tablet degradation impurities, and other unknown impurities. The mirabegron sustained-release tablet degradation impurities can be obtained by subsequent liquid chromatography separation of the solution.

[0069] After obtaining the sample to be separated, the present invention performs liquid chromatography separation on the sample to be separated to obtain the mirabegron sustained-release tablet degradation impurities.

[0070] In the present invention, the chromatographic conditions for liquid chromatography separation preferably include:

[0071] Chromatographic column: C18

[0072] Mobile phase A is ammonium acetate buffer solution with a concentration of 0.018-0.022 mol / L and a pH value of 3.5, mobile phase B is acetonitrile, and the gradient elution program is shown in Table 1, flow rate: 0.9-1.1 mL / min;

[0073] Table 1 Gradient elution program

[0074]

[0075]

[0076] Detection wavelength: 250 nm;

[0077] Column temperature: 35 - 45 °C.

[0078] Collect the component with a relative retention time of 1.73 with respect to the mirabegron main peak, which is the degraded impurity of the mirabegron sustained-release tablet.

[0079] In the present invention, the concentration of the mobile phase A is preferably 0.02 mol / L.

[0080] In the present invention, the flow rate is preferably 1 mL / min.

[0081] In the present invention, the column temperature is preferably 40 °C.

[0082] The present invention also provides the application of the above-mentioned degraded impurity of the mirabegron sustained-release tablet in the quality control of the mirabegron sustained-release tablet.

[0083] The application of the degraded impurity of the mirabegron sustained-release tablet in the quality control of the mirabegron sustained-release tablet in the present invention is preferably related substance detection. The related substance detection is preferably liquid chromatography detection. The chromatographic conditions of the liquid chromatography detection are preferably the same as those of the liquid chromatography separation in the above preparation method, which will not be elaborated here.

[0084] To further illustrate the present invention, the degraded impurity of the mirabegron sustained-release tablet provided by the present invention, its preparation method and application will be described in detail below in conjunction with the drawings and examples, but they should not be construed as limiting the protection scope of the present invention.

[0085] Example 1

[0086] Prepared by the synthesis method:

[0087] In a dry 100 mL three-necked round-bottom flask, mirabegron (3.96 g, 10 mmol), ethyl formate (1.11 g, 15 mmol) and 50 mL of dichloromethane were successively added, and the mixture was stirred and refluxed at 70 °C for 1.5 hours and then cooled to room temperature. Using a rotary evaporator, the solvent was removed under reduced pressure at 40 °C. The reaction product and silica gel were stirred evenly and put into a silica gel column for separation and purification by silica gel column chromatography (volume ratio of dichloromethane:methanol = 10:1), and the solvent was removed by rotary evaporation to obtain the target product.

[0088] 500 mg of light yellow solid was obtained in this example, and the calculated yield was 11.8%.

[0089] Test Example 1

[0090] 1. The pale yellow solid obtained in Example 1 was tested for chromatographic purity (the detection method was the same as the related substance detection of mirabegron sustained-release tablets in Application Example 1). The chromatogram is as shown in Figure 1 and the results of the area normalization method are shown in Table 2.

[0091] Table 2 Results of the area normalization method

[0092] RT Area Height %Area USP Resolution 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

[0093] From Figure 1 and Table 2, it can be seen that the chromatographic purity of the degradation impurities of the mirabegron sustained-release tablets obtained in Example 1 was 98.31%.

[0094] 2. Calibration of impurity content

[0095] Based on the chromatographic purity, the moisture value was deducted by loss on drying (continuous drying at 105 °C for 24 hours). The moisture value was 3.71%. Finally, the mass content of the degradation impurities of the mirabegron sustained-release tablets in the pale yellow solid obtained in Example 1 was 94.6%.

[0096] 3. The pale yellow solid obtained in Example 1 was tested by mass spectrometry. The mass spectrum is as shown in Figure 2 and the mass spectrometry detection results are shown in Table 3.

[0097] Table 3 Mass spectrometry test results

[0098] 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

[0099] From Figure 2 and Table 3, it can be determined that the [M+H] + of the degradation impurities obtained in Example 1 was 425.1668.

[0100] 4. The pale yellow solid obtained in Example 1 was tested by nuclear magnetic resonance hydrogen spectrum. The nuclear magnetic resonance hydrogen spectrum is as shown in Figure 3 and the results are as follows.

[0101] According to the analysis of the number and chemical shift data of hydrogen in the nuclear magnetic resonance hydrogen spectrum, the nuclear magnetic resonance hydrogen spectrum (DMSO) analysis information is as shown in Formula IV and Table 4:

[0102]

[0103] Table 4 Nuclear magnetic resonance hydrogen spectrum analysis information

[0104] Peak number Chemical shift δ / ppm Peak attribution 1 10.05(s,1H) ArNHCO— 2 7.85(s,0.5H),7.74(s,0.5H) —NCHO 3 7.53–7.50(m,2H) ArH 4 7.37–7.24(m,5H) ArH 5 7.12(dd,2H) ArH 6 6.93(s,2H) <![CDATA[NH 2 > 7 6.30(s,1H) Hetero-ArH 8 5.55(dd,1H) CHOH 10 4.76–4.70(m,1H) CHOH 11 3.58–3.49(m,1H) <![CDATA[CH 2 > 12 3.44(s,2H) <![CDATA[ArNHCOCH 2 > 13 3.36(m,1H) <![CDATA[CH 2 > 14 3.29–3.25(m,2H) <![CDATA[CH 2 > 15 2.73–2.70(m,2H) <![CDATA[CH 2 >

[0105] From the above nuclear magnetic resonance hydrogen spectrum results, it can be known that the molecular formula of the impurities obtained in Example 1 was C 22 H 24 N 4 O 3 S, and the molecular weight was 424.52.

[0106] Example 2

[0107] Preparation by liquid phase method:

[0108] Take 10 mirabegron sustained-release tablets (tablet weight: 257.5 mg, active ingredient mirabegron: 50 mg / tablet, polyethylene glycol: 119.6 mg / tablet) and place them in a 100 mL volumetric flask. Add 50 mL of methanol and shake until the sample completely disintegrates. Place the above sample in a light box (total illuminance not less than 4500 lx, near ultraviolet 85 μw / cm 2 ) and irradiate for 24 hours. Filter to remove the excipients, and rotary evaporate to remove most of the solvent to obtain the sample to be separated.

[0109] Perform liquid chromatography separation on the sample to be separated. The chromatographic conditions are as follows:

[0110] Chromatographic column: Waters Xbridge C18 4.6 mm×150 mm, 3.5 μm

[0111] Mobile phase: 0.02 mol / L ammonium acetate buffer solution with pH 3.5 (mobile phase A)-acetonitrile (mobile phase B) system. The specific gradient elution program is shown in Table 5. Flow rate: 1 mL / min;

[0112] Detection wavelength: 250 nm;

[0113] Column temperature: 40 °C.

[0114] Collect the component with a relative retention time of 1.73 for the mirabegron main peak, which is the degradation impurity of the mirabegron sustained-release tablet.

[0115] Table 5 Mobile phase gradient elution program

[0116] 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

[0117] Application Example 1

[0118] Use the impurity obtained in Example 1 for the quality control study (related substance detection) of the mirabegron sustained-release tablet.

[0119] The chromatographic conditions for the related substance detection method of the mirabegron sustained-release tablet are as follows:

[0120] Chromatographic column: C18 chromatographic column (Waters Xbridge C18 4.6 mm×150 mm, 3.5 μm);

[0121] Mobile phase A is 0.02 mol / L ammonium acetate buffer solution with pH 3.5, and mobile phase B is acetonitrile. The specific gradient elution program is shown in Table 5. Flow rate: 1 mL / min;

[0122] Detection wavelength: 250 nm;

[0123] Column temperature: 40 °C.

[0124] Mirabegron and mirabegron extended-release tablets were degraded into impurities and tested under the above chromatographic conditions. The concentrations and test results are shown in Table 6. The linear regression curve of mirabegron (labeled as MRB) is as Figure 4 shown, and the degraded impurities of mirabegron extended-release tablets (labeled as impurity A) are as Figure 5 shown.

[0125] Table 6 Linear test results of degraded impurities of mirabegron and mirabegron extended-release tablets

[0126]

[0127]

[0128] The retention time of the degraded impurities of mirabegron extended-release tablets relative to mirabegron is 1.73. Using the degraded impurities of mirabegron extended-release tablets obtained in Example 1 as the impurity reference substance, through linear research, the correction factor of the degraded impurities of mirabegron extended-release tablets relative to mirabegron is 1.02. Therefore, it is considered that the response difference between them and mirabegron is not significant. When using the external standard method of the main component for the determination of related substances, the correction factor does not need to be considered, and the test results will not underestimate the content of this impurity. It will be controlled as a known impurity during the stability and formal production stages.

[0129] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, not all embodiments. People can also obtain other embodiments according to the embodiments of the present invention without creative labor, and these embodiments all belong to the protection scope of the present invention.

Claims

1. A method for detecting degradation impurities in mirabegron sustained-release tablets, characterized in that, the structural formula of the degradation impurities is shown in Formula I: the mass fraction of mirabegron in the mirabegron sustained-release tablets is 19.4%, and the mass fraction of polyethylene glycol is 46.4%; the detection method is liquid chromatography detection; the chromatographic conditions for the liquid chromatography detection include: chromatographic column: C18; mobile phase A is ammonium acetate buffer solution with a concentration of 0.018 - 0.022 mol / L and a pH value of 3.5, and mobile phase B is acetonitrile; the gradient elution program is as follows: detection wavelength: 250 nm; the specification of the chromatographic column is 4.6 mm × 150 mm, 3.5 μm.

2. The detection method according to claim 1, characterized in that, the flow rate of the liquid chromatography detection: 0.9 - 1.1 mL / min; column temperature: 35 - 45 °C.

3. The detection method according to claim 2, characterized in that, the concentration of the ammonium acetate buffer solution is 0.02 mol / L.

4. The detection method according to claim 2, characterized in that, the flow rate is 1 mL / min.

5. The detection method according to claim 2, characterized in that, the column temperature is 40 °C.

6. The detection method according to any one of claims 2 - 5, characterized in that, the elution program is:

7. The detection method according to claim 6, characterized in that, the concentration of mobile phase A is 0.02 mol / L, the flow rate is 1 mL / min, and the column temperature is 40 °C.

8. The application of the detection method according to any one of claims 1 - 7 in the quality control of mirabegron sustained-release tablets.

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