CN117510435A - Amoxicillin impurity and preparation method thereof - Google Patents
Amoxicillin impurity and preparation method thereof Download PDFInfo
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- CN117510435A CN117510435A CN202311389269.9A CN202311389269A CN117510435A CN 117510435 A CN117510435 A CN 117510435A CN 202311389269 A CN202311389269 A CN 202311389269A CN 117510435 A CN117510435 A CN 117510435A
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- amoxicillin
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- 239000012535 impurity Substances 0.000 title claims abstract description 74
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 title claims abstract description 67
- 229960003022 amoxicillin Drugs 0.000 title claims abstract description 67
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000012488 sample solution Substances 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 238000004366 reverse phase liquid chromatography Methods 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000004108 freeze drying Methods 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 7
- 239000005695 Ammonium acetate Substances 0.000 claims description 7
- 229940043376 ammonium acetate Drugs 0.000 claims description 7
- 235000019257 ammonium acetate Nutrition 0.000 claims description 7
- 239000008213 purified water Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 239000000523 sample Substances 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 2
- 230000014759 maintenance of location Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 12
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 3
- 238000004886 process control Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000010586 diagram Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 238000005100 correlation spectroscopy Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 2
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229940127249 oral antibiotic Drugs 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to an amoxicillin impurity and a preparation method thereof. In a solvent, amoxicillin reacts with hydrochloric acid, and the amoxicillin is decompressed and concentrated to obtain a crude product; dissolving the crude product by using a sodium hydroxide solution to obtain a sample solution, separating the sample solution by using reverse phase liquid chromatography, and collecting a target impurity peak solution; and (3) distilling the target impurity peak solution under reduced pressure, and then freeze-drying to obtain amoxicillin impurities. According to the invention, the structure is verified by preparing the target impurities, the attribution of the target impurities is performed, and the process control of impurity limit is facilitated. The purity of the amoxicillin impurity prepared by the method reaches more than 95%, and the amoxicillin impurity can be used as a reference substance for quality research and quality control of amoxicillin medicines. The invention has the advantages of easily available raw materials, controllable process parameters and mild reaction conditions.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an amoxicillin impurity and a preparation method thereof.
Background
Amoxicillin is a beta-lactam antibiotic, developed by the company of Beecham in 1968, is white or white-like crystal powder, has slightly specific smell and bitter taste, is a main variety of second-generation penicillin, is a broad-spectrum semisynthetic antibiotic, can inhibit the synthesis of bacterial cell walls, has high-efficiency broad-spectrum antibacterial effect and small toxic and side effects, and the World Health Organization (WHO) recommends the amoxicillin to be used as the preferred beta-lactam oral antibiotic and to occupy important positions in the oral antibiotic.
In order to fully research the quality and the property of the amoxicillin and ensure the medication safety, the company performs various destructive tests on the amoxicillin bulk drug such as acid, alkali, high temperature and the like. Thus, it was found that amoxicillin generates an unknown impurity under acidic conditions, which can reach about 0.3% over time. In order to further study the influence of the impurity on the quality of amoxicillin, belonging to the source and the category of the impurity and ensuring the medication safety, the preparation method of the impurity is researched, the target impurity with research quantity is prepared, and the structure is confirmed.
Disclosure of Invention
The invention aims to provide amoxicillin impurity which has high purity and can be used as a reference substance for quality research and quality control of amoxicillin medicines; the invention also provides a preparation method of the amoxicillin impurity.
The amoxicillin impurity has the following structural formula:
。
the preparation method of the amoxicillin impurity comprises the following steps:
(1) In a solvent, amoxicillin reacts with hydrochloric acid, and the amoxicillin is decompressed and concentrated to obtain a crude product;
(2) Dissolving the crude product by using a sodium hydroxide solution to obtain a sample solution, separating the sample solution by using reverse phase liquid chromatography, and collecting a target impurity peak solution;
(3) And (3) distilling the target impurity peak solution under reduced pressure, and then freeze-drying to obtain amoxicillin impurities.
The solvent in the step (1) is methanol or ethanol.
The ratio of the amoxicillin to the solvent in the step (1) is 1:10-12, wherein the amoxicillin is calculated by g, and the solvent is calculated by ml.
The concentration of hydrochloric acid in step (1) is 25-30wt.%.
The molar ratio of the amoxicillin to the hydrochloric acid in the step (1) is 1:1-1.2.
The reaction temperature in the step (1) is 20-40 ℃ and the reaction time is 2-4 hours.
The conditions of the reversed phase liquid chromatography described in step (2) are as follows:
chromatographic column: kromail 100-5-C18 phi 30X 250mm
Detection wavelength: 230nm and 322nm
Mobile phase a: a mixture of ammonium acetate, purified water and acetic acid, the ratio of ammonium acetate, purified water and acetic acid being 46.2:30:30, wherein ammonium acetate is in g, purified water is in L, acetic acid is in ml
Mobile phase B: methanol
Elution procedure:
flow rate: 30ml/min
Sample injection amount: 1.5-2.0ml.
The retention time of the target impurity peak in the step (2) is 12.5-13.2min.
The temperature of the reduced pressure distillation in the step (3) is 25-30 ℃.
The method uses 230nm and 322nm dual wavelength to detect the sample solution, and the coincident peak between the two curves is the target impurity peak. The method can better determine the target impurity through dual-wavelength detection and ensure the separation purity.
The amoxicillin impurity is obtained by taking amoxicillin as an initial raw material, carrying out ring opening degradation under an acidic condition, then carrying out intramolecular dehydration cyclization, and separating and purifying by reverse phase liquid chromatography.
The reaction principle of the invention is as follows:
the beneficial effects of the invention are as follows:
(1) According to the invention, the structure is verified by preparing the target impurities, the attribution of the target impurities is performed, and the process control of impurity limit is facilitated.
(2) The purity of the amoxicillin impurity prepared by the method reaches more than 95%, and the amoxicillin impurity can be used as a reference substance for quality research and quality control of amoxicillin medicines.
(3) The invention has the advantages of easily available raw materials, controllable process parameters and mild reaction conditions.
Drawings
Fig. 1 is an HPLC diagram of amoxicillin impurity obtained in example 1.
Fig. 2 is a mass spectrum of amoxicillin impurity obtained in example 1.
FIG. 3 is a nuclear magnetic resonance spectrum of amoxicillin impurity obtained in example 1.
Fig. 4 is a nuclear magnetic resonance spectrum of amoxicillin impurity obtained in example 1.
FIG. 5 is a COSY spectrum of amoxicillin impurity obtained in example 1.
Fig. 6 is a partial enlarged view of fig. 5.
FIG. 7 is a HSQC spectrum of amoxicillin impurity obtained in example 1.
Fig. 8 is an HMBC spectrum of amoxicillin impurity obtained in example 1.
Detailed Description
The invention is further described below with reference to examples.
Example 1
(1) Weighing 10.0g of amoxicillin bulk drug into a reaction bottle, adding 100ml of absolute ethyl alcohol, and stirring and mixing uniformly; 3.7g of 30wt.% hydrochloric acid solution is added under stirring, the temperature is raised to 30 ℃, the reaction is carried out for 3 hours under heat preservation, the reaction solution is concentrated under reduced pressure at 30 ℃ until the reaction solution is basically free of solvent, and the crude product is obtained, wherein the content of target impurity HPLC is 3.92%.
(2) Dissolving the crude product with equimolar 1% (g/ml) sodium hydroxide solution to obtain a sample solution, separating the sample solution by reverse phase liquid chromatography, and collecting a target impurity peak (RT is 12.8 min) solution;
the conditions for reverse phase liquid chromatography were as follows:
chromatographic column: kromail 100-5-C18 phi 30X 250mm
Detection wavelength: 230nm and 322nm
Mobile phase a:46.2g of ammonium acetate+30L of purified water+30 ml of acetic acid.
Mobile phase B: methanol
The elution procedure is shown in table 1:
flow rate: 30ml/min
Sample injection amount: 2.0ml
(3) Evaporating the target impurity peak solution under reduced pressure at 25 ℃ to remove methanol, and then putting the solution into a freeze dryer for freeze drying to obtain amoxicillin impurity with the HPLC content of 97.05%; ESI-MS M/z= 364.27 ([ M-H)] - ）； 1 H-NMR(DMSO，600MHz)：δ ppm ：1.33 (3H, s)、1.36(3H, s)、3.71 (1H, d)、4.73(1H, s)、6.76 (2H, d)、7.12 (1H, d)、7.30 (2H, d)、8.00 (1H, dd)、9.02 (1H, s)； 13 C-NMR(DMSO，600MHz)：δ ppm ：26.03、28.5、50.49、56.39、71.44、105.65、115.67、127、129.48、146.33、158.22、169.21、169.28、184.27。
The HPLC diagram of amoxicillin impurity is shown in figure 1, the mass spectrum diagram is shown in figure 2, the nuclear magnetic hydrogen spectrum diagram is shown in figure 3, the nuclear magnetic carbon spectrum diagram is shown in figure 4, the COSY spectrum diagram is shown in figure 5, the partial enlarged diagram of figure 5 is shown in figure 6, the HSQC spectrum diagram is shown in figure 7, and the HMBC spectrum diagram is shown in figure 8.
The structural formula of the amoxicillin impurity is as follows:
nuclear magnetic resonance of amoxicillin impurity 1 The H and COSY spectra are shown in Table 2, and the nuclear magnetic resonance of amoxicillin impurity 13 C. HSQC and HMBC spectral data are shown in Table 3.
Example 2
(1) Weighing 10.0g of amoxicillin bulk drug into a reaction bottle, adding 110ml of absolute ethyl alcohol, and stirring and uniformly mixing; 4.0g of 28wt.% hydrochloric acid solution is added under stirring, the temperature is raised to 40 ℃, the reaction is carried out for 2 hours under heat preservation, the reaction solution is concentrated under reduced pressure at 30 ℃ until the solution is basically free of solvent, and the crude product is obtained, wherein the content of target impurity HPLC is 3.32%.
(2) Dissolving the crude product by using an equimolar 1% (g/ml) sodium hydroxide solution to obtain a sample solution, separating the sample solution by using reverse phase liquid chromatography, and collecting a target impurity peak solution;
sample injection amount: 1.5ml, other conditions for reverse phase liquid chromatography were the same as in example 1.
(3) And (3) evaporating methanol from the target impurity peak solution at 30 ℃ under reduced pressure, and then putting the solution into a freeze dryer for freeze drying to obtain amoxicillin impurity, wherein the HPLC content is 96.59%.
Example 3
(1) Weighing 10.0g of amoxicillin bulk drug into a reaction bottle, adding 120ml of absolute ethyl alcohol, and stirring and uniformly mixing; 4.4g of 25wt.% hydrochloric acid solution is added under stirring, the temperature is raised to 30 ℃, the reaction is carried out for 3 hours under heat preservation, the reaction solution is concentrated under reduced pressure at 30 ℃ until the solution is basically free of solvent, and the crude product is obtained, wherein the content of target impurity HPLC is 3.63%.
(2) Dissolving the crude product by using an equimolar 1% (g/ml) sodium hydroxide solution to obtain a sample solution, separating the sample solution by using reverse phase liquid chromatography, and collecting a target impurity peak solution;
sample injection amount: 1.8ml, other conditions for reverse phase liquid chromatography were the same as in example 1.
(3) And (3) evaporating methanol from the target impurity peak solution at 28 ℃ under reduced pressure, and then putting the solution into a freeze dryer for freeze drying to obtain amoxicillin impurity, wherein the HPLC content is 96.81%.
Example 4
(1) Weighing 10.0g of amoxicillin bulk drug into a reaction bottle, adding 100ml of absolute ethyl alcohol, and stirring and mixing uniformly; 4.0g of 28wt.% hydrochloric acid solution is added under stirring, the temperature is raised to 20 ℃, the reaction is carried out for 4 hours under heat preservation, the reaction solution is concentrated under reduced pressure at 30 ℃ until the solution is basically free of solvent, and the crude product is obtained, wherein the content of target impurity HPLC is 3.11%.
(2) Dissolving the crude product by using an equimolar 1% (g/ml) sodium hydroxide solution to obtain a sample solution, separating the sample solution by using reverse phase liquid chromatography, and collecting a target impurity peak solution;
sample injection amount: 2.0ml, other conditions for reverse phase liquid chromatography were the same as in example 1.
(3) And (3) evaporating methanol from the target impurity peak solution at 30 ℃ under reduced pressure, and then putting the solution into a freeze dryer for freeze drying to obtain amoxicillin impurity, wherein the HPLC content is 96.76%.
The present invention has been described in detail with reference to the embodiments, but the description is only the preferred embodiments of the present invention and should not be construed as limiting the scope of the invention. All equivalent changes and modifications within the scope of the present invention should be made.
Claims (10)
1. An amoxicillin impurity is characterized by having the following structural formula:
。
2. a process for the preparation of amoxicillin impurity according to claim 1, characterised in that it comprises the steps of:
(1) In a solvent, amoxicillin reacts with hydrochloric acid, and the amoxicillin is decompressed and concentrated to obtain a crude product;
(2) Dissolving the crude product by using a sodium hydroxide solution to obtain a sample solution, separating the sample solution by using reverse phase liquid chromatography, and collecting a target impurity peak solution;
(3) And (3) distilling the target impurity peak solution under reduced pressure, and then freeze-drying to obtain amoxicillin impurities.
3. The method for preparing amoxicillin impurity according to claim 2, wherein the solvent in step (1) is methanol or ethanol.
4. The method for preparing amoxicillin impurity according to claim 2, wherein the ratio of amoxicillin to solvent in step (1) is 1:10-12, wherein amoxicillin is calculated in g and solvent is calculated in ml.
5. The process for the preparation of amoxicillin impurity according to claim 2, characterized in that the concentration of hydrochloric acid in step (1) is 25-30wt.%.
6. The method for preparing amoxicillin impurity according to claim 2, wherein the molar ratio of amoxicillin to hydrochloric acid in step (1) is 1:1-1.2.
7. The method for preparing amoxicillin impurity according to claim 2, wherein the reaction temperature in step (1) is 20-40 ℃ and the reaction time is 2-4 hours.
8. The method for preparing amoxicillin impurity according to claim 2, wherein the conditions of the reversed phase liquid chromatography in step (2) are as follows:
chromatographic column: kromail 100-5-C18 phi 30X 250mm
Detection wavelength: 230nm and 322nm
Mobile phase a: a mixture of ammonium acetate, purified water and acetic acid, the ratio of ammonium acetate, purified water and acetic acid being 46.2:30:30, wherein ammonium acetate is in g, purified water is in L, acetic acid is in ml
Mobile phase B: methanol
Elution procedure:
flow rate: 30ml/min
Sample injection amount: 1.5-2.0ml.
9. The method for preparing amoxicillin impurity according to claim 2, wherein the retention time of the peak of the target impurity in step (2) is 12.5 to 13.2min.
10. The process for preparing amoxicillin impurity according to claim 2, wherein the temperature of the reduced pressure distillation in step (3) is 25 to 30 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311389269.9A CN117510435A (en) | 2023-10-25 | 2023-10-25 | Amoxicillin impurity and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311389269.9A CN117510435A (en) | 2023-10-25 | 2023-10-25 | Amoxicillin impurity and preparation method thereof |
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| Publication Number | Publication Date |
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| CN117510435A true CN117510435A (en) | 2024-02-06 |
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ID=89757536
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| CN202311389269.9A Pending CN117510435A (en) | 2023-10-25 | 2023-10-25 | Amoxicillin impurity and preparation method thereof |
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| Country | Link |
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| CN (1) | CN117510435A (en) |
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2023
- 2023-10-25 CN CN202311389269.9A patent/CN117510435A/en active Pending
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