CN102643251A - Linezolid degradation impurity and preparation method thereof - Google Patents
Linezolid degradation impurity and preparation method thereof Download PDFInfo
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- CN102643251A CN102643251A CN2012101128817A CN201210112881A CN102643251A CN 102643251 A CN102643251 A CN 102643251A CN 2012101128817 A CN2012101128817 A CN 2012101128817A CN 201210112881 A CN201210112881 A CN 201210112881A CN 102643251 A CN102643251 A CN 102643251A
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Abstract
The invention discloses a compound shown in the formula I and a preparation method thereof. The invention also discloses a linezolid injecta and a preparation method thereof. The compound shown in the formula I disclosed by the invention is a linezolid degradation impurity which has high purity and can be used as a related substance comparison product to detect the content of degradation products in the linezolid injecta, and guarantee is provided for further controlling the product quality of the linezolid injecta. At the same time, the invention also provides a method for preparing the linezolid injecta according to the property that linezolid is easy to degrade. According to the method, degradation reaction of the linezolid can be better prevented in a liquid preparation process, the content of the impurity in the linezolid injecta is obviously reduced, and a new choice is provided for improving the safety of a product. The formula I is disclosed in the specification.
Description
Technical field
The present invention relates to a kind of compound, i.e. the preparation method of the degradation impurity of Linezolid, and this compound; The invention still further relates to a kind of Linezolid injection liquid and preparation method thereof.
Background technology
Linezolid is the (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides microbiotic of synthetic; Obtained drugs approved by FDA in 2000; Be used to treat the coccigenic infection of gram-positive (G+), comprise by cause doubtful of MRSA or make a definite diagnosis nosocomial pneumonia (HAP), community acquired pneumonia (CAP), complicacy skin or skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) infects.Its structure is:
Chemical name: (S) N one { [3-(3-fluoro-4-(4-morpholinyl) benzene) 2-oxygen-5-oxazolidine] methyl 1-ethanamide
At present, Linezolid adopts oral or the injection form administration more.Linezolid injection formulations commonly used is many to be prepared from Linezolid, Citric Acid, Sodium Citrate, glucose and water for injection, how various supplementary materials directly is dissolved in water for injection in the preparation process.But the contriver discovers that in such injection formulations, DeR takes place Linezolid easily, produces impurity, directly preparation security is produced detrimentally affect.
Current research to Linezolid focuses mostly at chemical synthesis process, and in the research to its crystal formation, does not also see the relevant report to degradation impurity in the Linezolid injection formulations.
Summary of the invention
The object of the present invention is to provide a kind of compound, be the degradation impurity of Linezolid; The present invention also provides the preparation method of this compound; Another object of the present invention is to provide a kind of Linezolid injection liquid and preparation method thereof.
The invention provides the compound shown in the formula 1, its structural formula is following:
The present invention also provides the preparation method of above-mentioned formula 1 compound, and it comprises following operation steps:
(1) gets Linezolid, under alkaline condition, carry out ring-opening reaction;
(2) step (1) products therefrom, purified after, promptly get formula 1 compound.
Wherein, the actual conditions of the said ring-opening reaction of step (1) is: the pH of alkaline condition is 10～14, under 60-80 ℃, and reaction 10-20h.
Further, be solvent with 50-95%v/v ethanol in the ring-opening reaction.
Further, said solvent is a 75%v/v ethanol.
Wherein, the concrete operations of the said purifying of step (2) are following:
After ring-opening reaction was accomplished, conditioned reaction liquid pH was 6.5-7.0, reclaimed solvent, added ethyl acetate extraction again, and extraction liquid concentrates, crystallization, and crystallisate promptly gets formula 1 compound again with ethyl alcohol recrystallization.
Further, use the 75%v/v ethyl alcohol recrystallization.
The present invention also provides a kind of Linezolid injection liquid, in this injection liquid, contains Linezolid, buffered soln, glucose, water; Wherein, the content that contains formula 1 compound in the injection liquid is less than 0.1%w/w.
Further, the content of formula 1 compound is less than 0.05%w/w.
Further, said buffered soln is SODIUM PHOSPHATE, MONOBASIC-citric acid solution, Hydrocerol A-sodium hydroxide-hydrochloric acid buffer solution, citric acid-sodium citrate buffer, acetate-sodium acetate buffer solution, Sodium phosphate, dibasic-sodium dihydrogen phosphate buffer, Sodium phosphate, dibasic-potassium dihydrogen phosphate buffer solution, potassium hydrogenphosphate-sodium hydroxide buffer solution or Veronal sodium-hydrochloric acid buffer solution.
Further, this injection liquid is that supplementary material following weight proportion is prepared from:
300 parts of 600 parts of Linezolids, Trisodium Citrate 125-175 part, Hydrocerol A 25-75 part, glucose 10-20 part, injection liquid water.
The present invention also provides the preparation method of above-mentioned Linezolid injection liquid, and it comprises following operation steps:
Preparation pH is the buffered soln of 6-7 earlier, in this buffered soln, adds Linezolid, glucose again, behind the mixing, and the preparation injection liquid.
Further, it comprises following operation steps:
Get 150 parts of Trisodium Citrates and 50 parts of Hydrocerol As, adds 200 parts of waters for injection and be mixed with buffered soln, add 600 parts of Linezolids more successively, 15 parts of glucose add injection water to 300 again, behind the dissolving mixing, and filtration, can, the azoles amine injection of how promptly getting profit.
Provide formula 1 compound among the present invention, be the Linezolid degradation impurity, its purity is high, can be used as the related substances reference substance, is used for detecting the content of Linezolid injection liquid degraded product, for the quality product of further controlling the Linezolid injection liquid provides guarantee.Simultaneously; The present invention is directed to Linezolid and be prone to this character of degraded; The method for preparing the Linezolid injection liquid also is provided; This method can stop Linezolid in the dosing process, DeR to take place preferably, has reduced foreign matter content in the Linezolid injection liquid significantly, for improving security of products new selection is provided.
Description of drawings
The HPLC of Fig. 1 formula 1 compound measures collection of illustrative plates and data
Fig. 2 Linezolid Injection by HPLC of the present invention is measured collection of illustrative plates
The commercially available Linezolid Injection by HPLC of Fig. 3 is measured collection of illustrative plates
Embodiment
The preparation of embodiment 1 formula 1 compound of the present invention (being the alkaline degradation impurity of Linezolid)
In the 500ml reaction flask, add the 5g Linezolid, 75% ethanol 25ml drips 5% the sodium hydroxide of 25ml, 70 ℃ of reacting by heating 15h; Reaction finishes, and cooling adds 1mol/L hydrochloric acid, and regulating PH is 6.5～7.0.Concentration of reaction solution steams ethanol; Add 25ml * 3 ethyl acetate extraction liquid concentrators; Concentrated extract, crystallization; Add 75% ethanol 15ml recrystallization again, obtain the 3.5g solid, be formula 1 compound, i.e. Linezolid alkaline degradation impurity, (S)-and N-2-hydroxyl-4-N, N [[(3-fluoro-4-morpholinyl phenyl)-carboxyl] propyl group] ethanamide (1),
1HNMR (CDCl
3, 400MHz): δ 2.02 (3H), δ 2.17 (1H); δ 2.95～2.74 (4H), δ 3.04～3.18 (2H), δ 3.34～3.49 (2H); δ 3.84～3.86 (4H), δ 3.91～3.95 (1H), δ 6.00～6.43 (3H); δ 6.80～6.85 (1H), δ 7.26 (1H): MS (EI m/e)=355, mp:124.2～124.7 ℃.
The purity testing of embodiment 2 formulas 1 compound
Get the about 20mg of alkaline degradation impurity of embodiment 1 preparation, the accurate title, decide, and puts in the 50ml measuring bottle, adds the dissolving of 20% acetonitrile solution, is diluted to scale; Precision is measured 5ml, puts in the 50ml measuring bottle, is diluted to scale with 10% acetonitrile solution, shakes up; Precision is measured 10 μ l and is injected liquid chromatograph, the record color atlas; Adopt area normalization method, the purity of formula 1 compound is 99.62% (see figure 1).Chromatographic column: octadecylsilane chemically bonded silica is a weighting agent.Mobile phase A is trifluoroacetic acid aqueous solution (getting 10% trifluoroacetic acid solution 10ml joins in the 1000ml water), Mobile phase B trifluoracetic acid acetonitrile solution (getting 10% trifluoroacetic acid solution 10ml joins in the 1000ml acetonitrile); Moving phase is that (A: B), overall flow rate was PM 1.0ml in 8: 2; The detection wavelength is 254nm.
Get formula 1 compound and the commercially available Linezolid of embodiment 1 preparation, the sample of preparing two kinds of formula 1 compound different contents carries out safety evaluation.Wherein, A sample: the Linezolid of 1%w/w formula 1 compound and 99%w/w; B sample: the Linezolid of 5%w/w formula 1 compound and 95%w/w.
Get above-mentioned two kinds of samples, carried out the acute toxicity comparative experiments of rat according to " chemicals acute toxicity test technical director principle ", after the oral administration administration, measure the result and show: the LD50 value of A sample is 3200mg/kg.The LD50 value of B sample is 2400mg/kg.
This shows that there is certain influence in the existence of formula 1 compound (alkaline degradation impurity) to the medicinal security of Linezolid: formula 1 compounds content increases, and product toxicity raises, and security reduces.Because injection liquid directly gets in the blood of human body, impurity without liver metabolism, may cause more direct, serious toxic side effects to the toxic action of human body.Therefore, to the detection of Linezolid injection liquid Chinese style 1 compound, limit the quantity of, help further ensureing the security of injection liquid.
The preparation method of embodiment 4 Linezolid injection liquids of the present invention
In the 500L container, add Trisodium Citrate 150g, Hydrocerol A 50g adds the buffered soln that 200L water for injection is mixed with pH6-7; In buffered soln, add Linezolid 600g again, glucose 15g adds injection water 100L again; After treating to dissolve fully; Press the conventional preparation method of injection liquid and filter, can, the azoles amine injection of how promptly getting profit.
The comparison of embodiment 5 Linezolid injection liquids of the present invention and existing injection liquid
1, the composition measurement of Linezolid injection liquid of the present invention
Get the 25ml pharmaceutical composition and put in the 50ml measuring bottle, add 20% dilution in acetonitrile to scale; Precision is measured 5ml, puts in the 50ml measuring bottle, is diluted to scale with 10% acetonitrile solution, shakes up; Precision is measured 10 μ l and is injected liquid chromatograph, the record color atlas; Chromatographic column: octadecylsilane chemically bonded silica is a weighting agent.Mobile phase A is trifluoroacetic acid aqueous solution (getting 10% trifluoroacetic acid solution 10ml joins in the 1000ml water), Mobile phase B trifluoracetic acid acetonitrile solution (getting 10% trifluoroacetic acid solution 10ml joins in the 1000ml acetonitrile); Moving phase is that (A: B), overall flow rate was PM 1.0ml in 8: 2; The detection wavelength is 254nm.
Adopt area normalization method, formula 1 compound (alkaline degradation impurity) is 0.036%, less than 0.1% (Fig. 2).
2, the composition measurement of existing injection liquid
Get the commercially available Linezolid injection liquid of 25ml and put in the 50ml measuring bottle, add 20% dilution in acetonitrile to scale; Precision is measured 5ml, puts in the 50ml measuring bottle, is diluted to scale with 10% acetonitrile solution, shakes up; Precision is measured 10 μ l and is injected liquid chromatograph, the record color atlas; Chromatographic column: octadecylsilane chemically bonded silica is a weighting agent.Mobile phase A is trifluoroacetic acid aqueous solution (getting 10% trifluoroacetic acid solution 10ml joins in the 1000ml water), Mobile phase B trifluoracetic acid acetonitrile solution (getting 10% trifluoroacetic acid solution 10ml joins in the 1000ml acetonitrile); Moving phase is that (A: B), overall flow rate was PM 1.0ml in 8: 2; The detection wavelength is 254nm.
Adopt area normalization method, formula 1 compound (alkaline degradation impurity) is 0.14% (Fig. 3).
Brief summary:
Can know by above-mentioned conclusion; In the prepared Linezolid injection liquid of the inventive method; Formula 1 compound (alkaline degradation impurity) content is merely 0.036%; Be 1/3 of commercially available prod, show that the inventive method can significantly suppress the degraded that injection liquid prepares Linezolid in the process, the security that helps improving injection liquid.
In sum, formula 1 compound that provides among the present invention is the Linezolid degradation impurity; Its purity is high; Can be used as the related substances reference substance, be used for detecting the content of Linezolid injection liquid degraded product, for the quality product of further controlling the Linezolid injection liquid provides guarantee.Simultaneously; The present invention is directed to Linezolid and be prone to this character of degraded; The method for preparing the Linezolid injection liquid also is provided; This method can stop Linezolid in the dosing process, DeR to take place preferably, has reduced foreign matter content in the Linezolid injection liquid significantly, for improving security of products new selection is provided.
Claims (10)
1. suc as formula the compound shown in 1, its structural formula is following:
Formula 1.
2. the compound method of the described compound of claim 1, it is characterized in that: it comprises following operation steps:
(1) gets Linezolid, under alkaline condition, carry out ring-opening reaction;
(2) step (1) products therefrom, purified after, promptly get formula 1 compound.
3. compound method according to claim 2 is characterized in that: the actual conditions of the said ring-opening reaction of step (1) is: the pH of alkaline condition is 10～14, under 60-80 ℃, and reaction 10-20h; Be solvent with 50-95%v/v ethanol in the ring-opening reaction.
4. compound method according to claim 2 is characterized in that: the concrete operations of purifying are following in the step (2):
After ring-opening reaction was accomplished, conditioned reaction liquid pH was 6.5-7.0, reclaimed solvent, extracted with water-ETHYLE ACETATE system again, and ethyl acetate layer concentrates, crystallization, and crystallisate promptly gets formula 1 compound again with the 50-95%v/v ethyl alcohol recrystallization.
5. compound method according to claim 5 is characterized in that: use the 75%v/v ethyl alcohol recrystallization.
6. a Linezolid injection liquid is characterized in that: in this injection liquid, contain Linezolid, buffered soln, glucose, water; Wherein, the content that contains formula 1 compound in the injection liquid is less than 0.1%w/w.
7. Linezolid injection liquid according to claim 6 is characterized in that: the content of formula 1 compound is less than 0.05%w/w.
8. Linezolid injection liquid according to claim 6 is characterized in that: said buffered soln is SODIUM PHOSPHATE, MONOBASIC-citric acid solution, Hydrocerol A-sodium hydroxide-hydrochloric acid buffer solution, citric acid-sodium citrate buffer, acetate-sodium acetate buffer solution, Sodium phosphate, dibasic-sodium dihydrogen phosphate buffer, Sodium phosphate, dibasic-potassium dihydrogen phosphate buffer solution, potassium hydrogenphosphate-sodium hydroxide buffer solution or Veronal sodium-hydrochloric acid buffer solution.
9. according to any described Linezolid injection liquid of claim 6-8, it is characterized in that: this injection liquid is that the supplementary material following weight proportion is prepared from:
300 parts of 600 parts of Linezolids, Trisodium Citrate 125-175 part, Hydrocerol A 25-75 part, glucose 10-20 part, injection liquid water.
10. the preparation method of the described Linezolid injection liquid of claim 6, it is characterized in that: it comprises following operation steps:
Preparation pH is the buffered soln of 6-7 earlier, in this buffered soln, adds Linezolid, glucose again, adds water to capacity, behind the dissolving mixing, and the preparation injection liquid.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103099792A (en) * | 2012-12-10 | 2013-05-15 | 成都欣捷高新技术开发有限公司 | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving |
| CN103483294A (en) * | 2013-08-12 | 2014-01-01 | 四川大学 | Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof |
| CN104666241A (en) * | 2013-11-27 | 2015-06-03 | 北京众和民健医药科技有限公司 | Preparation method of high-stability linezolid injection liquid |
| CN105315231A (en) * | 2014-06-11 | 2016-02-10 | 成都自豪药业有限公司 | Preparation method of linezolid related substance |
| CN107573297A (en) * | 2017-08-31 | 2018-01-12 | 桂林南药股份有限公司 | A kind of preparation method of the acidic hydrolysis impurity of Linezolid |
| CN111686072A (en) * | 2020-06-28 | 2020-09-22 | 江苏吴中医药集团有限公司 | Linezolid injection and preparation method thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103099792A (en) * | 2012-12-10 | 2013-05-15 | 成都欣捷高新技术开发有限公司 | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving |
| CN103099792B (en) * | 2012-12-10 | 2014-11-26 | 成都欣捷高新技术开发有限公司 | Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving |
| CN103483294A (en) * | 2013-08-12 | 2014-01-01 | 四川大学 | Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof |
| CN103483294B (en) * | 2013-08-12 | 2015-01-28 | 四川大学 | Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof |
| CN104666241A (en) * | 2013-11-27 | 2015-06-03 | 北京众和民健医药科技有限公司 | Preparation method of high-stability linezolid injection liquid |
| CN105315231A (en) * | 2014-06-11 | 2016-02-10 | 成都自豪药业有限公司 | Preparation method of linezolid related substance |
| CN107573297A (en) * | 2017-08-31 | 2018-01-12 | 桂林南药股份有限公司 | A kind of preparation method of the acidic hydrolysis impurity of Linezolid |
| CN111686072A (en) * | 2020-06-28 | 2020-09-22 | 江苏吴中医药集团有限公司 | Linezolid injection and preparation method thereof |
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