CN102643251B - degradation impurity of linezolid and preparation method thereof - Google Patents
degradation impurity of linezolid and preparation method thereof Download PDFInfo
- Publication number
- CN102643251B CN102643251B CN201210112881.7A CN201210112881A CN102643251B CN 102643251 B CN102643251 B CN 102643251B CN 201210112881 A CN201210112881 A CN 201210112881A CN 102643251 B CN102643251 B CN 102643251B
- Authority
- CN
- China
- Prior art keywords
- linezolid
- injection
- preparation
- formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses compound shown in formula 1 and preparation method thereof.The invention also discloses a kind of Linezolid Injection and preparation method thereof.Thering is provided the compound shown in formula 1 in the present invention, for the degradation impurity of Linezolid, its purity is high, can provide guarantee as the content of catabolite in related substances reference substance detection Linezolid Injection for controlling the product quality of Linezolid Injection further.Simultaneously, the present invention is directed to Linezolid this character degradable, the method additionally providing preparation Linezolid Injection, the method can preferably stop Linezolid that degradation reaction occurs during dosing, significantly reduce impurity content in Linezolid Injection, provide new selection for improving the safety of product.
Description
Technical field
The present invention relates to the degradation impurity of a kind of compound, i.e. Linezolid, and the preparation method of this compound；This
Bright further relate to a kind of Linezolid Injection and preparation method thereof.
Background technology
Linezolid is the (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antibiotic of synthetic, within 2000, obtains U.S. FDA approval, is used for treating leather orchid
Positive (G+) coccigenic infection, including caused by MRSA doubtful or make a definite diagnosis nosocomial pneumonia (HAP), community obtains
Property pneumonia (CAP), complexity skin or skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) infect.Its
Structure is:
Chemical name: (S) N mono-{ [3-(the fluoro-4-of 3-(4-morpholinyl) benzene) 2-oxygen-5-oxazolidine] methyl 1-acetamide
At present, the many employings of Linezolid are oral or injection form is administered.By profit how, conventional Linezolid ejection preparation is many
Azoles amine, citric acid, sodium citrate, glucose and water for injection are prepared from, many by the most molten for various supplementary materials in preparation process
In water for injection.But, inventor studies discovery, and in such ejection preparation, Linezolid is susceptible to degradation reaction, produces miscellaneous
Matter, directly produces harmful effect to preparation security.
The current research to Linezolid, focuses mostly at chemical synthesis process, and in the research of its crystal formation, yet there are no
To the relevant report of degradation impurity in Linezolid ejection preparation.
Summary of the invention
It is an object of the invention to provide a kind of compound, for the degradation impurity of Linezolid；Present invention also offers this
The preparation method of compound；Another object of the present invention is to provide a kind of Linezolid Injection and preparation method thereof.
The invention provides the compound shown in formula 1, its structural formula is as follows:
Formula 1.
Present invention also offers the preparation method of above-mentioned formula 1 compound, it includes following operating procedure:
(1) take Linezolid, carry out ring-opening reaction in the basic conditions；
(2) step (1) products therefrom, purified after, obtain formula 1 compound.
Wherein, the actual conditions of step (1) described ring-opening reaction is: the pH of alkalescence condition is 10～14, at 60-80 DEG C
Under, react 10-20h.
Further, with 50-95%v/v ethanol as solvent in ring-opening reaction.
Further, described solvent is 75%v/v ethanol.
Wherein, the concrete operations of step (2) described purification are as follows:
After ring-opening reaction completes, regulation reactant liquor pH is 6.5-7.0, recycling design, adds ethyl acetate extraction, extraction
Liquid concentrates, crystallization, and crystal, again with ethyl alcohol recrystallization, obtains formula 1 compound.
Further, 75%v/v ethyl alcohol recrystallization is used.
Present invention also offers a kind of Linezolid Injection, in this injection, containing Linezolid, buffer solution, Portugal
Grape sugar, water；Wherein, injection contains the content of formula 1 compound less than 0.1%w/w.
Further, the content of formula 1 compound is less than 0.05%w/w.
Further, described buffer solution is sodium dihydrogen phosphate-citric acid solution, citric acid-sodium hydroxide-hydrochloric acid
Buffer solution, citric acid-sodium citrate buffer, acetic acid-sodium acetate buffer solution, disodium hydrogen phosphate-sodium dihydrogen phosphate are slow
Dissolved liquid, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution, dipotassium hydrogen phosphate-sodium hydroxide buffer solution or barbital sodium-
Hydrochloric acid buffer solution.
Further, this injection is to be prepared from by the supplementary material of following weight proportion:
Linezolid 600 parts, sodium citrate 125-175 part, citric acid 25-75 part, glucose 10-20 part, injection are used
300 parts of water.
Present invention also offers the preparation method of above-mentioned Linezolid Injection, it includes following operating procedure:
First preparation pH is the buffer solution of 6-7, then adds Linezolid, glucose, after mixing, system in this buffer solution
Standby injection.
Further, it includes following operating procedure:
Take sodium citrate 150 parts and citric acid 50 parts, add 200 parts of waters for injection and be configured to buffer solution, then add successively
Enter Linezolid 600 parts, glucose 15 parts, then inject water to 300, after dissolving mixing, filter, fill, the how azoles of i.e. getting profit
Amine injection.
Thering is provided formula 1 compound in the present invention, for Linezolid degradation impurity, its purity is high, can compare as related substances
Product, for detecting the content of catabolite in Linezolid Injection, for controlling the product matter of Linezolid Injection further
Amount provides guarantee.Meanwhile, the present invention is directed to Linezolid this character degradable, additionally provide preparation Linezolid Injection
Method, the method can preferably stop Linezolid that degradation reaction occurs during dosing, significantly reduce Li Nai
Impurity content in azoles amine injection, provides new selection for improving the safety of product.
Accompanying drawing explanation
The HPLC of Fig. 1 formula 1 compound measures collection of illustrative plates and data
The HPLC of Fig. 2 Linezolid Injection of the present invention measures collection of illustrative plates
The HPLC of the commercially available Linezolid Injection of Fig. 3 measures collection of illustrative plates
Detailed description of the invention
The preparation of embodiment 1 formula 1 compound (i.e. the alkaline degradation impurity of Linezolid)
In 500ml reaction bulb, addition 5g Linezolid, 75% ethanol 25ml, the sodium hydroxide of the 5% of dropping 25ml, 70
DEG C reacting by heating 15h；React complete, cooling, add 1mol/L hydrochloric acid, regulation PH is 6.5～7.0.Concentration of reaction solution, by ethanol
Steam；Add 25ml × 3 ethyl acetate extraction concentrated solution；Concentrated extract, crystallization；Add 75% ethanol 15ml recrystallization,
Obtain 3.5g solid, be formula 1 compound, i.e. Linezolid alkaline degradation impurity, (S)-N-2-hydroxyl-4-N, N [[(fluoro-4-of 3-
Morpholino phenyl)-carboxyl] propyl group] acetamide (1),1HNMR(CDCl3, 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 DEG C.
The purity testing of embodiment 2 formula 1 compound
The alkaline degradation impurity about 20mg of Example 1 preparation, accurately weighed, put in 50ml measuring bottle, add 20% acetonitrile solution
Dissolve, be diluted to scale；Precision measures 5ml, puts in 50ml measuring bottle, is diluted to scale with 10% acetonitrile solution, shakes up；Accurate amount
Take 10 μ l and inject chromatograph of liquid, record chromatogram；Using area normalization method, the purity of formula 1 compound is 99.62% (see figure
1).Chromatographic column: octadecylsilane chemically bonded silica is filler.Mobile phase A is that trifluoroacetic acid aqueous solution (takes 10% trifluoracetic acid
Solution 10ml joins in 1000ml water), Mobile phase B trifluoracetic acid acetonitrile solution (takes 10% trifluoroacetic acid solution 10ml to add
In 1000ml acetonitrile)；Flowing is 8: 2 (A: B) mutually, and overall flow rate is 1.0ml per minute；Detection wavelength is 254nm.
The safety experiment of the embodiment 3 Linezolid Injection containing formula 1 compound
Formula 1 compound of Example 1 preparation and commercially available Linezolid, prepare two kinds of formula 1 compound different contents
Sample carries out safety evaluatio.Wherein, A sample: 1%w/w formula 1 compound and the Linezolid of 99%w/w；B sample: 5%w/w
Formula 1 compound and the Linezolid of 95%w/w.
Take above two sample, carry out the acute of rat according to " chemicals acute toxicity test technological guidance's principle "
Toxicity comparative experiments, after oral administration, measurement result shows: the LD50 value of A sample is 3200mg/kg.The LD50 value of B sample
For 2400mg/kg.
As can be seen here, the existence of formula 1 compound (alkaline degradation impurity), the pharmaceutical safety of Linezolid is existed one fixing
Ringing: formula 1 compounds content increases, product toxicity raises, and safety reduces.Owing to injection is directly entered in blood of human body, miscellaneous
The toxic action of confrontation human body, without liver metabolism, may cause the most direct, serious toxicity.Therefore, to profit how
The detection of azoles amine injection Chinese style 1 compound, limitation, be conducive to ensureing further the safety of injection.
The preparation method of embodiment 4 Linezolid Injection of the present invention
In 500L container, add sodium citrate 150g, citric acid 50g, add 200L water for injection and be configured to pH6-7's
Buffer solution, then in buffer solution, add Linezolid 600g, glucose 15g, then inject and use water 100L, wait to be completely dissolved
After, filter by injection customary preparation methods, fill, obtain Linezolid Injection.
Embodiment 5 Linezolid Injection of the present invention and the comparison of existing injection
1, the composition measurement of Linezolid Injection of the present invention
Take 25ml pharmaceutical composition to put in 50ml measuring bottle, add 20% dilution in acetonitrile to scale；Precision measures 5ml, puts 50ml
In measuring bottle, it is diluted to scale with 10% acetonitrile solution, shakes up；Precision measures 10 μ l and injects chromatograph of liquid, records chromatogram；Color
Spectrum post: octadecylsilane chemically bonded silica is filler.Mobile phase A is that trifluoroacetic acid aqueous solution (takes 10% trifluoroacetic acid solution
10ml joins in 1000ml water), Mobile phase B trifluoracetic acid acetonitrile solution (takes 10% trifluoroacetic acid solution 10ml to join
In 1000ml acetonitrile)；Flowing is 8: 2 (A: B) mutually, and overall flow rate is 1.0ml per minute；Detection wavelength is 254nm.
Using 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
Take the commercially available Linezolid Injection of 25ml to put in 50ml measuring bottle, add 20% dilution in acetonitrile to scale；Precision measures
5ml, puts in 50ml measuring bottle, is diluted to scale with 10% acetonitrile solution, shakes up；Precision measures 10 μ l and injects chromatograph of liquid, note
Record chromatogram；Chromatographic column: octadecylsilane chemically bonded silica is filler.Mobile phase A is that trifluoroacetic acid aqueous solution (takes 10% 3
Fluorine acetum 10ml joins in 1000ml water), Mobile phase B trifluoracetic acid acetonitrile solution (takes 10% trifluoroacetic acid solution
10ml joins in 1000ml acetonitrile)；Flowing is 8: 2 (A: B) mutually, and overall flow rate is 1.0ml per minute；Detection wavelength is 254nm.
Using area normalization method, formula 1 compound (alkaline degradation impurity) is 0.14% (Fig. 3).
Brief summary:
From above-mentioned conclusion, in the Linezolid Injection prepared by the inventive method, (alkaline degradation is miscellaneous for formula 1 compound
Matter) content is only 0.036%, for the 1/3 of commercially available prod, shows that the inventive method can significantly inhibit in injection preparation process
The degraded of Linezolid, is conducive to improving the safety of injection.
In sum, formula 1 compound provided in the present invention, for Linezolid degradation impurity, its purity is high, can be as phase
Related substance reference substance, for detecting the content of catabolite in Linezolid Injection, for controlling Linezolid injection further
The product quality of liquid provides guarantee.Meanwhile, the present invention is directed to Linezolid this character degradable, how additionally provide preparation profit
The method of azoles amine injection, the method can preferably stop Linezolid degradation reaction to occur during dosing, significantly
Reduce impurity content in Linezolid Injection, provide new selection for improving the safety of product.
Claims (1)
1. the preparation method of Linezolid Injection, it is characterised in that: it includes following operating procedure:
Take sodium citrate 150g and citric acid 50g, add 200L water for injection and be configured to the buffer solution of pH6-7, then add successively
Enter Linezolid 600g, glucose 15g, then inject water to 300L, after dissolving mixing, filtration, fill, obtain Linezolid
Injection；Wherein, the content of the compound of formula I described in injection is 0.036%
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210112881.7A CN102643251B (en) | 2012-04-17 | 2012-04-17 | degradation impurity of linezolid and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210112881.7A CN102643251B (en) | 2012-04-17 | 2012-04-17 | degradation impurity of linezolid and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102643251A CN102643251A (en) | 2012-08-22 |
| CN102643251B true CN102643251B (en) | 2016-08-10 |
Family
ID=46656359
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210112881.7A Active CN102643251B (en) | 2012-04-17 | 2012-04-17 | degradation impurity of linezolid and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102643251B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN111686072B (en) * | 2020-06-28 | 2022-02-15 | 江苏吴中医药集团有限公司 | Linezolid injection and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1130379A (en) * | 1993-09-09 | 1996-09-04 | 厄普约翰公司 | Substituted oxazine and thiazine oxazolidinone antimicrobials |
| WO2001034128A2 (en) * | 1999-11-08 | 2001-05-17 | Pharmacia & Upjohn Company | Admixture for intravenous administration of linezolid and other antibacterial agents |
| CN1713924A (en) * | 2000-08-22 | 2005-12-28 | 法马西亚公司 | Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading |
| CN101948442A (en) * | 2009-07-10 | 2011-01-19 | 符健 | Preparation method of linezolid and preparation thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY127336A (en) * | 2000-03-22 | 2006-11-30 | Upjohn Co | Container for linezolid iv solution |
-
2012
- 2012-04-17 CN CN201210112881.7A patent/CN102643251B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1130379A (en) * | 1993-09-09 | 1996-09-04 | 厄普约翰公司 | Substituted oxazine and thiazine oxazolidinone antimicrobials |
| WO2001034128A2 (en) * | 1999-11-08 | 2001-05-17 | Pharmacia & Upjohn Company | Admixture for intravenous administration of linezolid and other antibacterial agents |
| CN1713924A (en) * | 2000-08-22 | 2005-12-28 | 法马西亚公司 | Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading |
| CN101948442A (en) * | 2009-07-10 | 2011-01-19 | 符健 | Preparation method of linezolid and preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| Spectrophotometric and HPLC Determination of Linezolid in Presence of Its Alkaline-Induced Degradation Products and in Pharmaceutical Tablets;Lories I. Bebawy，;《ANALYTICAL LETTERS》;20031231;第36卷(第6期);第1147-1161页 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102643251A (en) | 2012-08-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102643251B (en) | degradation impurity of linezolid and preparation method thereof | |
| de Silva et al. | Determination of clonazepam and flunitrazepam in blood by electron-capture gas-liquid chromatography | |
| CN110824093B (en) | Method for detecting brivaracetam and related substances thereof | |
| CN105566432B (en) | A kind of impurity of CDB-2914 and its preparation and detection method | |
| CN104807924A (en) | Method for detecting specific impurities in ornithine aspartate raw material and preparation thereof | |
| CN103454370A (en) | Method for measuring phenylhydrazine compound residues in crude drugs through HPLC (high performance liquid chromatography) | |
| CN101605796B (en) | Substantially pure fluorescein | |
| CN106970177A (en) | The analyzing detecting method of Pa Boxini intermediates and its impurity | |
| CN105566431A (en) | Ulipristal acetate impurities and preparation and detection method thereof | |
| CN101968467A (en) | Quality control method for edaravone and edaravone-containing preparation | |
| CN103880863B (en) | A kind of preparation method of ampicillin | |
| CN108164521A (en) | A kind of Parecoxib Sodium degradation impurity and its preparation, detection method and application | |
| CN109085277A (en) | The detection method of residual solvent pyridine in a kind of cefminox sodium | |
| CN108872431A (en) | A method of detection 4- (1- (2,5- 3,5-dimethylphenyl) ethyl) -1H- imidazoles or/and its hydrochloride | |
| CN107525877A (en) | A kind of method using liquid chromatography for separating and determining according to a piperazine azoles and its impurity | |
| CN102636600B (en) | Method for determination of optical isomers in palonosetron hydrochloride composition | |
| CN112526017A (en) | Method for detecting contents of various impurities in amimetu-yusu compound preparation by using HPLC (high performance liquid chromatography) method | |
| CN106619636A (en) | Delafloxacin impurity compounds and preparation methods thereof | |
| CN106706769B (en) | Separation and determination method of empagliflozin and optical isomer thereof | |
| CN105968042A (en) | Preparation method of migltol | |
| CN106932347A (en) | A kind of mezlocillin and its quality index detection method | |
| CN109081837A (en) | The method for separating and preparing of mezlocillin sodium impurity A | |
| CN105606741A (en) | Method for detecting content of relevant substances of Ticagrelor | |
| CN106198827B (en) | The efficiently Pharmaceutical Analysis method of measure bazedoxifene acetate and its impurity | |
| CN108264500A (en) | Substituted 2-aminopyridine class compound and preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: SICHUAN MEIDA KANGJIALE PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: CHENGDU ZIHAO PHARMACEUTICAL CO., LTD. Effective date: 20131021 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 610041 CHENGDU, SICHUAN PROVINCE TO: 611731 CHENGDU, SICHUAN PROVINCE |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20131021 Address after: 611731, No. 15, West core road, hi tech West District, Sichuan, Chengdu Applicant after: Sichuan Meida Kangjiale Pharmaceutical Co., Ltd. Address before: 610041, No. two, No. 30, West fragrant herb street, hi tech Zone, Sichuan, Chengdu Applicant before: Chengdu Zihao Pharmaceutical Co., Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |